UNIVERSITY OF GENOA

School of Medical and Pharmaceutical Sciences

Master’s degree course in Medicine and Surgery

DEGREE THESIS

SURGICAL VENTRICULAR REMODELING IN ISCHEMIC HEART FAILURE: THE IMPACT OF OPTIMAL VOLUME REDUCTION ON LONG-TERM OUTCOME

SUPERVISOR CANDIDATE

Francesco Santini, M.D. Francesca Zanin

CO-SUPERVISORS

Antonio Salsano, M.D.

Serenella Castelvecchio, M.D.

Lorenzo Menicanti, M.D.

Academic Year 2019-2020

Ai miei genitori, i miei punti cardinali

2 INDEX

1. Introduction ...... 6

2. Heart Failure ...... 10

2.1. Definition and classification ...... 10 2.2. Epidemiology and Impact on the population ...... 15 2.3. Etiology ...... 17 2.3.1. Ischemic etiology ...... 19 2.4. Pathophysiology ...... 22 2.4.1. Left Ventricular Remodeling ...... 25 2.5. Diagnosis ...... 29 2.5.1. Clinical presentation ...... 30 2.5.2. Physical examination ...... 31 2.5.3. Investigations ...... 33 2.5.3.1. Noninvasive single or combined Imaging techniques ...... 36 2.5.3.2. Invasive Imaging techniques ...... 38 2.5.4. Algorithm for diagnosis of HF ...... 39 2.6. Prognosis ...... 40

3. Current therapeutic strategies for chronic ischemic-based HFrEF ...... 43

3.1. Medical therapies ...... 43 3.1.1. Management of fluid retention ...... 45 3.1.2. Prevention of disease progression ...... 47 3.2. Device therapy ...... 49 3.2.1. Cardiac resynchronization therapy (CRT) ...... 50 3.2.2. Implantable cardioverter defibrillator (ICD) ...... 51 3.2.3. Left ventricular assist device (LVAD) ...... 52 3.3. Surgical strategies ...... 53 3.3.1. Cardiac transplantation ...... 53 3.3.2. Coronary artery bypass grafting (CABG) ...... 54 3.3.3. Mitral valve repair or replacement (MVR) ...... 55 3.3.4. Surgical Ventricular Reconstruction (SVR) ...... 56

4. Surgical Ventricular Reconstruction (SVR) ...... 57

4.1. Rationale to perform SVR ...... 57 4.2. Indications ...... 58 4.3. History ...... 61 4.4. Technique ...... 61 4.5. Particular conditions ...... 64 4.5.1. Mitral valve (MV) ...... 64 4.5.2. Anterior versus Postero-inferior Remodeling ...... 67 4.6. Drawbacks ...... 69

3 5. Previous studies ...... 71

5.1. Dor and co-authors ...... 71 5.2. The Restore Group ...... 71 5.3. Menicanti, Castelvecchio et al...... 72 5.4. The role of LVESVI: White et al., the GUSTO-I trial and Bax et al...... 73 5.5. The STICH trial ...... 74 5.6. Di Donato, Castelvecchio and Menicanti ...... 75 5.7. Witkowski et al...... 76 5.8. Criticisms of the STICH trial ...... 77 5.9. Michler et al...... 79 5.10. ESC/EACTS Guidelines on Myocardial Revascularization ...... 80

6. Retrospective analysis at IRCCS Policlinico San Donato ...... 82

6.1. Introduction ...... 82 6.2. Aim of the study ...... 83 6.3. Materials and Methods ...... 83 6.3.1. Study design ...... 83 6.3.2. Selection of Patients ...... 84 6.3.3. End points ...... 85 6.3.4. Methods ...... 85 6.3.5. Statistical analysis ...... 86

7. Results and discussion ...... 87

7.1. Results ...... 87 7.2. Discussion ...... 94

8. Conclusions ...... 97

Bibliography ...... 98

Acknowledgements ...... 123

4

5 1. Introduction

Heart failure (HF), to use a term widely popular at present, can be defined as a global pandemic, i.e. “an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people”1, since it is estimated to involve at least 26 million persons globally, with a 2% overall prevalence in the adult population, and >10% among individuals aged >70 years. Despite medical advances in therapies and implementation of prevention campaigns, its prevalence shows no sign of abating; indeed, it is increasing dramatically as the population ages, weighing heavily on global health expenditures. Moreover, mortality and morbidity of the disease remain high, and the quality of life remains poor. Projections for the coming years in terms of prevalence, hospitalization rates, and healthcare costs are even more alarming, making HF one of the major public health challenges worldwide.

Although it is very difficult to provide a single definition of the complexity of this disease, according to the European Society of Cardiology, HF can be defined as a clinical syndrome, characterized by typical symptoms and signs, caused by a structural and/or functional cardiac abnormality, which results in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. In short, it is a progressive condition that inevitably leads to frequent hospitalization and decreased life expectancy. HF may result from a wide range of structural or functional cardiac and non-cardiac disorders. However, in the Western world, ischemic heart disease has become the predominant cause, being accountable for 46% to 68% of cases, with significantly higher mortality than those with non-ischemic etiologies.

To date, the cornerstone of treatment remains guideline-driven medical therapy, with significant improvement in survival and quality of life, followed by use of devices and surgical procedures, such as coronary artery bypass grafting and mitral valve replacement, or ultimately, cardiac transplantation. However, progression of HF, despite optimal pharmacological management, highlights the process of left ventricular (LV) remodeling as the main culprit, due to the mechanical burden produced by the changes that accompany HF. LV remodeling, meant as a set of

6 changes in LV geometry, architecture, and in the components of the myocardium, eventually leads to a vicious cycle where LV dilation keeps increasing in a wasted effort to maintain normal cardiac output, the ejection fraction (EF) decreases, and hemodynamic overloading worsens, any or all of which are sufficient to continued aggravation of LV dilation, global ventricular function, wall stress, geometric distortion, and, therefore, the progression of HF.

Recent studies have shown that LV remodeling can be reversed, decreasing LV mass and optimizing its shape and therefore improving clinical outcomes in patients with HF and reduced ejection fraction (HFrEF). Indeed, one of the goals of therapy for HF is to prevent and/or reverse LV remodeling, which is the aim of surgery in the present analysis on surgical ventricular remodeling (SVR).

SVR has been introduced as an optional therapeutic strategy to commonly used coronary artery bypass grafting (CABG), and aims to counteract and reverse LV remodeling by reducing the LV to a more physiological volume through the exclusion of scar tissue, and optimizing the shape of the distorted chamber, thereby improving both cardiac function and clinical outcomes of patients with HFrEF. The goal of surgery is also that of decreasing myocardial systolic and diastolic wall stress, resulting in improved wall compliance and reduced filling pressure. Moreover, since wall stress is an important determinant of afterload, it may also enhance LV contractile performance by increasing the extent and velocity of systolic fiber shortening.

This procedure was originally introduced by the French cardiac surgeon Vincent Dor in 1985, based on other prior contributions. From Dor’s group onwards, several studies, mainly observational, have been carried out on HF patients in order to assess SVR true potential. Many reports have confirmed the efficacy of SVR in improving LV systolic function, NYHA functional class, and survival, through reduction in ventricular volume and an increase in the EF, not only in patients with classic dyskinetic aneurysm, but also in those with dilated ischemic cardiomyopathy and severe LV dysfunction, with favorable 5-year outcomes. However, the surgical procedure was strongly criticized after the publication of the STICH trial in 2007, in which SVR did not meet the expected results. Nowadays,

7 American surgeons seem reluctant to use the procedure, which has been substantially abandoned. Indeed, several limitations have led to significant uncertainty in making such results generalizable, which relates to the heterogeneous population of patients enrolled in the trial. While waiting for further analysis of STICH data, the 2018 Task Force of the European Society of Cardiology/European Association for Cardiothoracic Surgery on Myocardial Revascularization currently recommended SVR at the time of CABG in selected patients undergoing intervention in centers with a high level of surgical expertise.

Despite the disappointing results, when combining SVR with CABG in the STICH trial there was significantly greater reduction in the left ventricular end systolic volume index (LVESVI), and it was hypothesized that a poor reduction in volume may be related to the unsatisfactory outcomes. Later, Witkowski et al. confirmed the importance of a ‘target volume’ to be achieved with SVR, showing that a residual postsurgical LVESVI of at least 60 ml/m2 was independently associated with a favorable outcome. Moreover, a post hoc analysis from the STICH trial showed that a postoperative LVESVI of 70 ml/m2 or lower resulted in improved survival compared with CABG alone.

Several studies have already highlighted the importance of residual LVESVI in patients with ischemic-based HF undergoing SVR, showing the existence of an association between a post-operative LVESVI ≥60 mL/m2 and adverse outcomes. However, its impact on prognosis is still not well-established. Therefore, we aimed to further investigate the role played by residual LVESVI in the definition of the long- term outcomes through retrospective analysis over 14 years focusing on patients with chronic HF with and reduced EF.

This dissertation will begin with a detailed description of HF in its entirety, starting with the definition, classification, and epidemiology, followed by the etiology, pathophysiological mechanisms, diagnostic process, and prognostic factors. In particular, focus will be placed on description of ischemic-based HF, and the effects of left ventricular remodeling and its role as the primary determinant in the progression of disease and as the target of surgical treatment are later explained.

8 The current medical, device-based, and surgical therapeutic strategies adopted for chronic ischemic-based HF will be then outlined, with particular attention to SVR, the surgical procedure at the core of the present analysis.

After an overview of the relevant literature, the results of the retrospective study will be presented. The analysis was conducted under the direction and expertise of Dr. Serenella Castelvecchio and Dr. Lorenzo Menicanti at IRCCS San Donato Hospital, in Milan, which has the largest worldwide series and represents a reference center for the International surgical community. Since July 2001, the SVR team started to collect data in a prospectively manner, with regular follow-up over time, in order to keep examine changes in LV geometry and their effect on survival. This retrospective study, carried out between January 2002 and December 2016 on 297 patients, assessed the impact of the achievement of optimal left ventricular volume reduction obtained by SVR, expressed as “optimal post-operative LVESVI” < 60 ml/m2 on long-term outcomes.

9 2. Heart Failure

2.1. Definition and classification

In order to properly understand the relevance of the present analysis, it is essential to overview the basic pathophysiology of ischemic heart failure (HF).

Despite multiple attempts over time to develop an exhaustive definition that encompasses the heterogeneity and complexity of HF, no single conceptual paradigm has been determined. The current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines, updated in 2017, define HF as a complex clinical syndrome that results from structural or functional impairment of ventricular filling or ejection of blood. Consequently, there is a failure in delivering oxygen to organs and tissues according to metabolic requirements. The cardinal clinical picture includes symptoms of dyspnea and fatigue, which limit exercise tolerance, and signs of peripheral edema and rales caused by fluid retention, leading to pulmonary and/or splanchnic congestion.2–4

The latest European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic HF define it as a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/ or elevated intracardiac pressures at rest or during stress.5

Basically, both definitions agree that HF is a progressive condition which inevitably leads to frequent hospitalizations, poor quality of life, and decreased life expectancy.

HF may result from many disorders at various levels of the cardiovascular system, involving the myocardium, pericardium or endocardium, rhythm and conduction, valves, or large vessels. However, in most patients, the symptoms originate from the Left Ventricular (LV) systolic and/or diastolic dysfunction caused by a myocardial injury.

10 Although multiple criteria have been proposed to categorize HF over time, the main classification used today in Europe, as illustrated in the 2016 ESC HF Guidelines, is based on measurement of the Left Ventricular Ejection Fraction (LVEF). This value can be measured by several invasive and noninvasive imaging modalities, the most common of which is the echocardiogram. LVEF quantifies ventricular damage by estimating LV systolic function, calculated as the ratio of blood ejected during systole (stroke volume, also calculated as the difference between the end diastolic and the end systolic volume) to blood in the ventricle at the end of the diastole (end- diastolic volume).

HF encompasses a broad spectrum of LV dysfunction, from patients with normal LV size and preserved EF, to those with critical dilatation and/or significantly reduced EF.

Based on LVEF, HF can be divided into three subgroups:

• HF with reduced LVEF (HFrEF, LVEF<40%), previously referred to as systolic HF, It is defined as impaired emptying of the LV and evident as a decreased effective ejection fraction.6 These are patients who are mainly be enrolled in clinical trials on HF.7 • HF with mid-range LVEF (HFmrEF, LVEF=40-49%); studies have shown that patients in this “gray area” present clinical features that are intermediate between HFrEF and HFpEF, but with a clinical profile and outcomes that are largely similar to those with HFpEF. • HF with preserved LVEF (HFpEF, LVEF>50%), previously termed diastolic HF, “it is defined as a condition in which filling of the LV is sufficient to produce adequate cardiac output but requires elevated pulmonary venous pressure. Thus, diastolic dysfunction is clinically manifested as pulmonary congestion” 6,8. “Patients with HFpEF generally do not have a dilated LV, but instead often have an increase in LV wall thickness and/or increased left atrial (LA) size as a sign of increased filling pressures. Most have additional ‘evidence’ of impaired LV filling or suction capacity, also classified as diastolic dysfunction.” 5 These patients are more likely to be older, female, hypertensive, with atrial fibrillation, and to have a non-ischemic etiology of heart failure.

11 This classification is relevant because demographics, comorbid conditions, clinical parameters, prognosis, and response to therapies differ significantly among the three categories.

Figure 1- Definition of heart failure with preserved (HFpEF), mid-range (HfmrEF) and reduced ejection fraction (HfrEF)5

Although the 2016 ESC classification is the most relevant for the present study, there are other ways to define HF.

HF can also be described according to the time course of the disease. The term HF is commonly used to describe a symptomatic syndrome, but a patient can also be rendered asymptomatic by treatment. If a patient has never exhibited the typical clinical picture, but presents HfrEF, is described as having asymptomatic LV systolic dysfunction. Furthermore, chronic HF describes a patient who has had HF for some time, and stable refers to a patient with symptoms and signs that have remained generally unchanged for at least 1 month. If the patient’s conditions deteriorate, suddenly or slowly, as the HF is referred to as decompensated, which often leads to hospital admission, negatively impacting prognosis. The acute new onset of HF, termed de novo HF, may be a consequence of Acute Myocardial Infarction (AMI), or may develop subacutely in a patient with a preexisting dilatated cardiomyopathy (DCM). Congestive HF is used to describe acute or chronic HF with evidence of volume overload.

12 As described later, the present analysis focuses on patients presenting chronic HF with significantly reduced LVEF (HfrEF), and in particular those with an LVEF<35% with concomitant coronary disease.

Another important classification widely used in practice and clinical studies is that of the New York Heart Association (NYHA), which determines the severity of HF in relation to estimation of functional ability and exercise intolerance. It places patients in one of four categories, based on their limitations during physical activities, mainly the amount of exertion needed to provoke the onset of angina and shortness of breath.

NYHA HF classes are as follows:

Class Patient Symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. IV Unable to carry on any physical activity without discomfort. Symptoms of HF at rest. If any physical activity is undertaken, discomfort increases.

Table 1 – New York Heart Association (NYHA) Functional Classification- Patient Symptoms9

Class Objective Assessment

A No objective evidence of cardiovascular disease. No symptoms and no limitation in ordinary physical activity.

13 B Objective evidence of minimal cardiovascular disease. Mild symptoms and slight limitation during ordinary activity. Comfortable at rest.

C Objective evidence of moderately severe cardiovascular disease. Marked limitation in activity due to symptoms, even during less-than-ordinary activity. Comfortable only at rest.

D Objective evidence of severe cardiovascular disease. Severe limitations. Experiences symptoms even while at rest.

Table 2 – New York Heart Association (NYHA) Functional Classification – Objective Assessment9

In the United States, the most common definition of HF is The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classification, which describes four stages of HF development, based on structural changes and symptoms.

Figure 2 – American College of Cardiology Foundation/American Heart Association (ACCF/AHA) heart failure staging system10

14 Both classifications emphasize the development and progression of disease, focus on exercise capacity and symptoms, and provide useful information about the severity of HF. However, symptom severity correlates poorly with many measures of LV function; although there is a clear relationship between severity of symptoms and survival, patients with mild symptoms may still have an increased risk of hospitalization and death.

2.2. Epidemiology and Impact on the population

“HF has been defined as global pandemic, since it affects around 26 million people worldwide”.11,12 Despite many breakthroughs in cardiovascular medicine, HF still represents a burgeoning problem worldwide, and one of the major public health challenges in Western Countries in terms of the number of patients. HF is one of the leading causes of hospitalizations (>20%) for persons older than 65 years old, and with rates of hospital readmission within 6 months going from 25% to 50%, it appears clear that the burden of economic implications behind HF is more than heavy.13,14 Projections are even more alarming, with total costs that are expected to increase by 127% between 2012 and 2030.12 Although it depends on the definition applied, the overall prevalence of the disease in the adult population is 2%, and increases with age following an exponential pattern, and is >10% among individuals aged >70 years. Among people >65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognized HF.5,15

In North America and Europe, the lifetime risk of developing HF is estimated to be 20% for anyone older than 40 years, and at age 55 is 33% for men and 28% for women. Regarding gender distribution, the relative incidence of HF is lower in women than in men, but at least one-half of the patients with HF are women, due to their longer life expectancy.

15

Figure 3 Prevalence and Incidence of Heart Failure Worldwide12

Moreover, the 5-year survival rate of patients diagnosed with HF is still <50% and might even be underestimated16, 5-year mortality after hospitalization exceeds 40%, and 30-40% of patients die within 1 year after diagnosis.17 The most recent European studies (ESC-HF pilot study) reported that one-year all-cause mortality rates for hospitalized and stable/ambulatory HF patients were 17% and 7%, respectively, with one-year hospitalization rates of 44% and 32%, respectively. Most deaths are attributable to cardiovascular causes, and mortality rates are generally higher in HFrEF than in HFpEF.18 19

Furthermore, patients with ischemic-based left ventricular (LV) systolic dysfunction have significantly higher mortality rates than those with non-ischemic etiologies, and HF is associated with ischemic heart disease in 46% to 68% of cases.20 12

In the United States, approximately 5.7 million people have HF, leading to 271,000 deaths per year, but the projections are worrisome, since it is expected that by 2030 more than 8 million people will have the condition, accounting for a 46% increase in prevalence.17 While research has been effective in delivering major advances in therapy over the last 30 years, including drugs, devices, and surgery, the prevalence of chronic HF remains high, and prognosis is still poor, in part because improvements in treatments for cardiac diseases have dramatically allowed patients to survive longer

16 by slowing the progression of HF.2,7,21 This, together with the ageing of the population, can help to explain the increase in prevalence expected in the next few years. 12

2.3. Etiology

HF is a heterogeneous syndrome that may result from a wide range of structural or functional cardiac and non-cardiac disorders. It is not to be considered as a single pathology entity, but rather as a process that may occur in the final stages of most cardiac diseases. Moreover, establishing the etiology of HF is fundamental in order to define the appropriate management for the patient, choose the most suitable investigations and therapeutic strategies, and avoid future episodes of decompensation. Unfortunately, it is often challenging, because while the primary cause may be easy to determine, more than one underlying cause may coexist and contribute to the progression of HF.

Although disorders of the endocardium, pericardium, and large vessels are possible, myocardial disorders are the most common causes of HF, subdivided into those with preserved LVEF and those with reduced LVEF. The etiology of HF in patients with a HFpEF presents slight differences from that of HFrEF, although there is substantial overlap between the etiologies of the two conditions.

Generally, as shown in the table below, any clinical condition that results in alterations of the LV structure or function may predispose to development of HF.

17

Figure 4 Etiologies of Heart Failure2

In Western countries, coronary artery disease (CAD) has become the predominant cause of HF, being responsible for 46-68% of cases. Hypertension contributes to the development of HF in 75% of patients, most with CAD. CAD and hypertension together augment the risk of HF, as does diabetes mellitus. Other frequent causes include arrhythmias, valvular heart disease, and alcohol. In 20–30% of cases of HFrEF, the exact etiology remains unknown, and patients are referred to as having nonischemic, dilated, or idiopathic cardiomyopathy. Other conditions that may lead to a dilatated cardiomyopathy, and therefore HF, are prior viral infection or toxin exposure (e.g. alcoholic or chemotherapeutic), metabolic conditions, infection, and iatrogenic causes.

Genetic and mitochondrial anomalies have been thought to be less frequent, even if it is becoming increasingly clear that a consistent number of dilated cardiomyopathies previously termed “idiopathic” have a familial link, and are secondary to specific genetic defects, most notably those in the cytoskeleton, some of which inherited in an autosomal dominant fashion. Mutations in genes that encode cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear

18 membrane proteins (laminin) have been identified. Dilated cardiomyopathy can be also associated with Duchenne’s, Becker’s, and limb-girdle muscular dystrophies.

Finally, conditions that result in a high cardiac output (e.g. arteriovenous fistula, anemia) are rarely responsible for the development of HF in a normal heart. Nevertheless, in the presence of underlying structural heart disease, these

EDUCATION IN HEARTHeart: first published as 10.1136/hrt.2003.025270 on 14 August 2007. Downloaded from conditions can lead to clinically evident HF.

Table 5 Causes of heart failure in population based studies suggest that improved survival following myocardial infarction is not a major contributor to the occurrence of heart failure. Framingham heart Bromley The incidence of heart failure in men participating in the study15 Hillingdon heart heart failure failure Framingham heart study did not change over the last 50 years Cause Men Women studyw24 study16 (1950–1999), whereas the incidence in women declined 30– w46 Ischaemic 59 48 36 52 40%. A larger population-based study in Olmsted County, 1142 Non-ischaemic: Minnesota (4537 heart failure patients, 42% of whom were Hypertension 70 78 14 4 diagnosed as outpatients) reported no change in heart failure Valvular heart disease 22 31 7 10 23 Atrial fibrillation 5 3 incidence between 1979 and 2000. Alcohol 4 Taken together, the data indicate that the incidence of heart Other 77 4 5 failure has not declined over the last two decades and that the Unknown 34 23 ageing of the population in combination with improved Because of rounding, the percentages do not always add up to 100. prognosis fuel the heart failure epidemic. It follows that Framingham heart study: ischaemic heart disease and hypertension could prevention of the occurrence of heart failure is needed to stem be co-named as causing heart failure. the epidemic.w42

PROGNOSIS OF HEART FAILURE Figure 5 Causes of heartTrends failure in heartin population failure- incidencebased studies: “The variation in frequencies of causes ‘‘A poor prognosis’’ and prognostication in daily Bonneux et al predicted a steady increase in the number of of heart failure reported in different studies can be explained by differences in studypractice population, from patients with heart failure: the ageing of the population, There is no doubt that the prognosis of heart failure patients the highly selected group of participants in clinical trials to relatively unselected participants in improvements in the treatment of acute coronary syndromes, remains poor, even in the realm of the development of a myriad and a longer survival of heart failure patients all contribute15 to a of effective pharmacological and non-pharmacological inter- population-based studies, differences in definitions, and time differences”14 w42 larger pool of (potential) heart failure patients. The ageing ventions. This is illustrated by the title of a paper on the of the population is undisputed as is the improvement of prognosis of the syndrome: ‘‘More malignant than cancer’’.w47 prognosis in heart failure patients. Any doctor treating heart failure patients will confirm that life Few studies have addressed trends in the incidence of heart expectancy in heart failure patients is ‘‘reduced’’ and that 2.3.1. Ischemicfailure post-myocardial etiology infarction. Despite a decrease in sudden cardiac death is a ‘‘major’’ cause of death, that (acute)Protected by copyright. coronary heart disease and all cause mortality in 546 worsening of CHF occurs ‘‘quite often’’, leading to ‘‘frequent’’ Framingham heart study participants who suffered a non-Q hospitalisations, and that quality of life in these patients is HF is correlated with ischemic heart disease (IHD) in 46% to 68% of cases. As http://heart.bmj.com/ wave myocardial infarction between 1950 and 1989, the ‘‘impaired considerably’’. We included the quotation marks in percentage of them developing heart failure remained the latter sentence to indicate the implicit nature of prognos- discussed later, the presentw43 analysis involves only patients suffering from ischemic- stable. In a group of 1537 patients who suffered a tication in clinical practice. based HF, and thusmyocardial it is necessary infarction (notto place excluding focus non-Q on wave this myocardialspecific etiology.Although information on the natural history of a disease is infarctions) between 1979 and 1994 in Olmsted County, relevant to illustrate its burden for health care and the society Minnesota, a 28% reduction in the occurrence of post- at large, prognostication in individual patients plays a crucial IHD is responsiblemyocardial for more infarctiondeaths and heart disabilit failure wasies and documented. greater18 Theeconomicrole in cost dailys clinical than practice. After the diagnosis (and possible Worcester heart attack study reported a decline in heart failure aetiology) of heart failure has been established, a doctor will on March 25, 2020 at Sistema Bibliotecario - Università degli Studi di Genova. any other disease duringin thehospitalisation western world for myocardial. According infarction to the between ISTAT 1975 2017estimate Report an on individual the patient’s probability of developing and 1995.w44 clinically relevant prognostic outcomes—for example, a 5 year 25 leading causes ofThe death reduction in Italy of post-myocardial in 2003 and infarction 2014, IHD heart is failure the isleadingsurvival cause probability., with Such estimates are typically based on consistent with the declining severity of myocardial infarction patients’ characteristics, including age, comorbidity, severity 69,653 deaths in 2014following, followed the introduction by cerebrovascular of reperfusion treatment—a diseases decline (57,230and), causeand ofother heart failure that are known to influence cardiac disorders that(49,554 may) well. Together, continue giventhese the three increasingly pathologies aggressive are responsibleprognosis. This for information, together with the anticipated, (primary percutaneous interventions) and timely interventions preferably evidence-based, effect of possible therapeutic inter- 29.5% of deaths inin Italy patients each with year, acute even coronary though syndromes. fromw45 2003These to data2014 thereventions has and been patient preferences, is instrumental in the 22 a significant decreaseTable in 6mortalitRisk factorsy rates. for the occurrence of heart failure in three population based studies15 w13 w31

Framingham heart study Rotterdam study Cardiovascular health Men Women study Men Women

Risk factor RR (95% CI) PAR RR (95% CI) PAR RR PAR RR (95% CI) RR (95% CI) 19 Hypertension 2.1 (1.3 to 3.2) 39 3.4 (1.7 to 6.7) 59 1.4 13 1.0 (0.5 to 1.9) 2.6 (1.6 to 4.2) MI 6.3 (4.6 to 8.7) 34 6.0 (4.4 to 8.3) 13 – – 1.9 (1.1 to 3.6) 1.8 (0.9 to 3.5) Angina pectoris 1.4 (1.0 to 2.0) 5 1.7 (1.2 to 2.3) 5 – – 1.3 (0.6 to 2.8) 1.3 (0.7 to 2.6) Diabetes mellitus 1.8 (1.3 to 2.6) 6 3.7 (2.7 to 5.2) 12 1.8 8 2.1 (1.0 to 4.4) 1.6 (0.8 to 3.2) LVH 2.2 (1.5 to 3.2) 4 2.9 (2.0 to 4.1) 5 2.3 6 1.6 (0.4 to 6.7) 0.8 (0.1 to 5.5) Valvular disease 2.5 (1.7 to 3.6) 7 2.1 (1.5 to 2.9) 8 – –– – Atrial fibrillation 2.1 2 1.5 (0.5 to 5.1) 0.6 (0.1 to 4.6) COPD 1.4 6 0.8 (0.3 to 2.6) 3.2 (1.7 to 7.4)

CI, confidence interval; COPD, chronic obstructive pulmonary disease; LVH, left ventricular hypertrophy; MI, myocardial infarction; PAR, population attributable risk (%); RR, relative risk.

www.heartjnl.com IHD is the most common and fatal illness in the United States as well, where it affects over than 15.5 million persons ≥20 years of age, as reported in the 2016 Heart Disease and Stroke Statistics update of the American Heart Association (AHA)23,24, and it kills approximately one person every minute. Moreover, according to the WHO 2000-2016 Report, IHD is the leading cause of death not only in Italy or the U.S., but also worldwide, accounting for more than 9 million deaths in 2016.25

IHD, also known as Coronary Heart Disease (CHD) or Coronary Artery Disease (CAD), is the main cause of HF in the western world16; CAD remarkably increases the chance of developing HF.15 Furthermore, it is estimated that for 7–8 years after AMI, up to 36% of patients will experience HF, especially those with LV systolic dysfunction documented during admission15.

The term IHD refers to all cardiovascular disorders caused by narrowed coronary arteries. At the basis of the disease there is an inadequate supply of blood and oxygen to a portion of the myocardium, which typically happens when there is an inequality between supply and demand of myocardial oxygen. This is due to blockage of one or more blood vessels, as a result of a blood clot or constriction of the vessel, or, most commonly, of an atherosclerotic plaque. It is a chronic and progressive condition defined by the ESC as “a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive”26, but still sufficient to provoke reduction of myocardial blood flow and hence poor perfusion in the region supplied by that artery.

IHD may present with several different clinical pictures, generally stable, but with a chance of becoming unstable at any time, due to its dynamic process: AMI, chronic ischemia, stable or unstable angina pectoris and/or dyspnea, acute, chronic or decompensated HF, arrhythmia, and also sudden cardiac death (SCD)1 or clinically asymptomatic reduced LV function.

1 Sudden cardiac death describes the unexpected natural and non-traumatic death from a cardiac cause occurring within a short time period, generally ≤1 hour from the onset of symptoms, in an apparently healthy subject. The term SCD is used when a congenital or acquired potentially fatal cardiac condition was known to be present during life, or Autopsy has identified a cardiac or vascular anomaly as the probable cause of the event, or No obvious extra-cardiac causes have been identified by post-mortem examination and therefore an arrhythmic event is a likely cause of death.27

20 If the narrowing involves less than 50% of the vessel, symptoms and discomfort may only occur when the demand for oxygen increases, such as during physical exertion, which is referred to as stable angina pectoris. This stage is usually characterized by chest and arm discomfort and is relieved promptly with rest or nitroglycerin. The Canadian Cardiovascular Society (CCS) provides one of the main classifications of angina:

Figure 6 Canadian Cardiovascular Society grading of angina pectoris28,29

As the narrowing increases, symptoms may worsen and also be present at rest, with the clinical picture becoming overt. If the blood flow to a portion of the myocardium is completely blocked, myocytes die, leading to AMI. Unfortunately, patients may have silent ischemia, ischemia without pain, and even AMI without prior warning.30

HF in the setting of CHD may be the result of multiple factors that can possibly contribute to the development of HF and LV systolic dysfunction.

Firstly, as detailed in the next chapter, previous AMI leads to the loss of myocytes, development of myocardial fibrosis, and consequent LV remodeling, resulting in

21 dilation of the chamber and neurohormonal activation. LV remodeling represents the anatomical substrate of ischemic-based HF. This leads to progressive deterioration of the remaining functioning myocardium.

Second, patients with a history of CAD or AMI commonly have relevant atherosclerotic disease in other coronary arteries, in addition to the infarcted artery. Therefore, in addition already irreversibly damaged tissue, there is often a significant portion of jeopardized myocardium, only partially perfused by a stenotic artery, which may deteriorate in myocardial ischemia/hibernation. As a consequence, there is the risk of recurrent MI, which may provoke, as in a loop, further deterioration in LV function and even SCD.

Lastly, endothelial dysfunction, a characteristic feature of atherosclerosis, may independently contribute to progression of the dysfunction.31

In the next chapter, the pathophysiology of ischemic HF will be detailed, as well its consequences on the myocardium.

2.4. Pathophysiology

The classical definition of HF as the “inability of the heart to provide sufficient oxygen to the metabolizing tissues despite an adequate filling pressure”32 is essentially a pathophysiological description. However, despite multiple attempts to define a single pathophysiological process that can exhaustively explain every aspect of this complex syndrome, a consensus has not been reached yet.

In describing the pathophysiology of HF, focus will be placed on the molecular and cellular changes that underlie HFrEF, placing further emphasis on the role of LV remodeling as a primary determinant in the progression of HF and as the target of surgical treatment.

HF is a progressive disorder that originates after an index event that either damages the heart muscle, resulting in a loss of function of cardiac myocytes or interferes with the ability of the myocardium to generate force, thereby keeping the heart from contracting properly. The index event may have an acute presentation, such as in the case of AMI, a more gradual onset, as for example in hemodynamic pressure or

22 volume overloading, or it can also be hereditary as in several genetic cardiomyopathies.

Aside from its mechanism of presentation, each of these index events affects and worsens the heart’s ability to pump blood and therefore LV function.

However, most patients remain asymptomatic or minimally symptomatic for long periods after the initial episode, thanks to the introduction of several compensatory mechanisms activated by the decrease of the cardiac output, which allow the patient to maintain LV function that is only minimally depressed, modulated within a homeostatic range varying from months to years. These mechanisms consist in the activation of:

• the renin-angiotensin-aldosterone system (RAAS), triggered by increased sympathetic stimulation of the kidney and renal hypoperfusion due to impaired cardiac output. The RAAS is responsible for maintaining cardiac output by increased reabsorption of sodium and water in exchange for potassium, promoting release of arginine vasopressin and catecholamines,

vasoconstriction, and cell growth in vasculature through AT1 receptors,

whereas activation of AT2, predominant in the myocardium, leads to vasodilatation, inhibition of cell growth, natriuresis, and release of bradykinin;

• the adrenergic nervous system: the increased activation of β1-adrenergic receptors enhances myocardial contractility and increases heart rate, with a resultant improvement in cardiac output. Moreover, the stimulation of

myocardial α1 -adrenergic receptors is responsible for peripheral arterial vasoconstriction and a modest inotropic effect; it is accompanied by a contemporaneous withdrawal of parasympathetic tone. • a family of countervailing vasodilatory molecules and inflammatory mediators, including atrial and brain natriuretic peptides (ANP and BNP), bradykinin, prostaglandins (PGE2 and PGI2), and nitric oxide (NO), which counterbalance the excessive peripheral vascular vasoconstriction, and unload the heart by counteracting RAAS and the salt and water homeostatic dysregulation. These mechanisms are responsible for cardiac repair and remodeling.

23 Although patients may remain minimally symptomatic or even asymptomatic for months, at some point they become frankly symptomatic. The progression to overt HF is the result of the overexpression of the neurohormonal, adrenergic, and cytokine systems previously mentioned, sustained by the loss of inhibitory input from baroreceptors in the left ventricle, aortic arch, carotid sinus, and renal afferent arterioles. While in the short term they succeed in preserving the patient’s functional capacity, in the long term they have a deleterious impact on the heart and circulation, ultimately leading to a series of unfavorable adaptive changes within the myocardium, termed LV remodeling. Some of these negative effects include augmented myocardial energy requirements (and therefore possible ischemia if oxygen delivery is restricted), triggering of ventricular tachycardia and SCD, decreased NO levels, excessive peripheral arterial vasoconstriction, increased inflammation and oxidative stress, high norepinephrine levels, and fibrosis and hypertrophy of the heart, vessels, kidneys, and other organs.

455

elicits a modest positive inotropic effect, as well as peripheral arterial Index event vasoconstriction (Fig. 22-2). Although NE enhances both contrac- Compensatory 22 60 mechanisms tion and relaxation and maintains blood pressure, myocardial energy Pathophysiology of Heart Failure requirements are augmented, which can intensify ischemia when

myocardial O2 delivery is restricted. The augmented adrenergic Secondary outflow from the central nervous system also may trigger ventricular damage tachycardia or even sudden cardiac death, particularly in the pres- ence of myocardial ischemia. Thus activation of the sympathetic 20 nervous system provides short-term support that has the potential to TIME (yr) become maladaptive over the long term (see Fig. 22-2). Moreover, increasing evidence suggests that apart from the deleterious effects EJECTION FRACTION (%) ASYMPTOMATIC SYMPTOMATIC A of sympathetic activation, parasympathetic withdrawal also may con- tribute to the pathogenesis of heart failure. Withdrawal of parasym- Index event pathetic nerve stimulation has been associated with decreased nitric oxide (NO) levels, increased inflammation, increased sympathetic activity and worsening LV remodeling. Two ongoing clinical trials, INOVATE-HF (Increase of Vagal Tone in CHF) (NCT01303718) and Secondary damage NECTAR-HF (Neural Cardiac Therapy for Heart Failure Study) • LV remodeling Neurohormones Endothelium (NCT01385176), are examining the effects of vagal nerve stimulation • Contractility↓ • ↑SNS activity • Vasoconstriction on LV structure and clinical outcomes in patients with New York • Hypertrophy • ↑RAS • NOS/ROS • Apoptosis • ↑Endothelin Heart Association (NYHA) class III heart failure. • Structural change • Fibrosis • ↑ANP/BNP • Cytokines • NOS/ROS • ↑Cytokines Activation of the Renin-Angiotensin System • Electrophysiology In contrast with the sympathetic nervous system, the components of the RAS are activated comparatively later in heart failure. The pre- sumptive mechanisms for RAS activation in heart failure include B Progressive heart failure renal hypoperfusion, decreased filtered sodium reaching the macula densa in the distal tubule, and increased sympathetic stimulation of FIGURE 22-1 Pathogenesis of heart failure. A, Heart failure begins after a the kidney, leading to increased renin release from jutaglomerular so-called index event produces an initial decline in pumping capacity of the heart. apparatus (Fig. 22-3). As shown in Figure 22-4, renin cleaves four B, After this32 initial decline in pumping capacity of the heart, a variety of compensa- Figure 7 Pathogenesistory of mechanisms HF are activated, including the adrenergic nervous system, the RAS, amino acids from circulating angiotensinogen, which is synthesized and the cytokine systems. In the short term, these systems are able to restore in the liver, to form the biologically inactive decapeptide angiotensin cardiovascular function to a normal homeostatic range, with the result that the I. Angiotensin-converting enzyme (ACE) cleaves two amino acids patient remains asymptomatic. With time, however, the sustained activation of from angiotensin I to form the biologically active octapeptide(1-8) Unlike HFrEF, understandingthese systems can lead of to secondarythe pathophysiological end-organ damage within the mechanisms ventricle, with of HFpEF is worsening LV remodeling and subsequent cardiac decompensation. As a result of angiotensin II. Most ACE activity (approaching 90%) in the body is still in progress. “Thatthese changes, is, although patients undergo diastolic the transition dysfunction from asymptomatic was to symptomatic thought foundto be in the tissues; only the remaining 10% is found in a soluble (non– heart failure. ANP/BNP = atrial natriuretic peptide/brain type natriuretic peptide; membrane-bound) form in the interstitium of the heart and vessel NOS/ROS = nitric oxide synthase/reactive oxygen species; SNS = sympathetic wall. The importance of tissue ACE activity in heart failure is nervous system. (From Mann DL: Mechanisms and models in HF: a combinatorial approach. Circulation 100:99, 1999; and Kaye DM, Krum H: Drug discovery for heart suggested by the observation that ACE messenger RNA (mRNA) failure: A new era or the end of the pipeline? Nat Rev Drug Discov 6:127, 2007.) and ACE-binding sites and ACE activity are increased in explanted human hearts.3 Angiotensin24 II also can be synthesized using renin- independent pathways through the enzymatic conversion of angio- As a result of the increase in sympathetic tone, there is an increase tensinogen to angiotensin I by kallikrein and cathepsin G (see Fig. in circulating levels of NE, a potent adrenergic neurotransmitter. 22-4). The tissue production of angiotensin II also may occur along The elevated levels of circulating NE result from a combination of ACE-independent pathways, through the activation of chymase. This increased release of NE from adrenergic nerve endings and its con- latter pathway may be of major importance in the myocardium, par- sequent “spillover” into the plasma, as well as reduced uptake of NE ticularly when the levels of renin and angiotensin I are increased by by adrenergic nerve endings. In patients with advanced heart failure, the use of ACE inhibitors. Angiotensin II itself can undergo further the circulating levels of NE in resting patients are two to three times proteolysis to generate three biologically active fragments: angioten- those found in normal subjects. Indeed, plasma levels of NE predict sin III2-8 and angiotensin IV,3-8 which promote vasconstriction,4 and mortality in patients with heart failure. Whereas the normal heart angiotensin,1-7 which may act to counteract the deleterious effects of usually extracts NE from the arterial blood, in patients with moderate angiotensin II on endothelial function. heart failure the coronary sinus NE concentration exceeds the arterial Angiotensin II exerts its effects by binding to two G protein–coupled

concentration, indicating increased adrenergic stimulation of the receptors, the angiotensin type 1 (AT1) and angiotensin type 2 (AT2) heart. However, as heart failure progresses there is a significant receptors. The predominant angiotensin receptor in the vasculature

decrease in the myocardial concentration of NE. The mechanism is the AT1 receptor. Although both the AT1 and AT2 receptor subtypes responsible for cardiac NE depletion in severe heart failure is not are present in human myocardium, the AT2 receptor predominates in clear and may relate to an “exhaustion” phenomenon resulting a 2:1 molar ratio. Cellular localization of the AT1 receptor in the heart from the prolonged adrenergic activation of the cardiac adrenergic is most abundant in nerves distributed in the myocardium, whereas

nerves in heart failure. In addition, there is decreased activity of the AT2 receptor is localized more specifically in fibroblasts and the myocardial tyrosine hydroxylase, which is the rate-limiting enzyme interstitium. Activation of the AT1 receptor leads to vasoconstriction, in the synthesis of NE. In patients with cardiomyopathy, iodine-131– cell growth, aldosterone secretion, and catecholamine release,

labeled metaiodobenzylguanidine (MIBG), a radiopharmaceutical whereas activation of the AT2 receptor leads to vasodilation, inhibi- that is taken up by adrenergic nerve endings, is not taken up normally, tion of cell growth, natriuresis, and bradykinin release. Studies have

suggesting that NE reuptake also islso impaired in heart failure. shown that the AT1 receptor and mRNA levels are downregulated in Increased sympathetic activation of the beta1-adrenergic receptor failing human hearts, whereas AT2 receptor density is increased or 4 results in increased heart rate and force of myocardial contraction, unchanged, so that the ratio of AT1 to AT2 receptors decreases. with a resultant increase in cardiac output (see Chapter 21). In addi- Angiotensin II has several important actions that are critical tion, the heightened activity of the adrenergic nervous system leads to maintaining short-term circulatory homeostasis (see further on).

to stimulation of myocardial alpha1-adrenergic receptors, which The sustained expression of angiotensin II is maladaptive, however, mechanism responsible, community-based studies suggest that additional extracardiac mechanisms may be important, such as increased vascular stiffness and impaired renal function.” 21 However, as already said, this type of HF will not be discussed in this thesis.

2.4.1. Left Ventricular Remodeling

Despite the pharmacological management of the neurohormonal compensatory mechanisms previously described, in the vast majority of patients, HF is progressive. This points to a role for LV remodeling as one of the main culprits in contributing to the progression of HF.32,33

LV remodeling refers to changes in LV mass, volume, shape, and composition at the cellular and molecular levels that the heart develops in reaction to cardiac injury, for example after a myocardial infarction, and dysfunctional hemodynamic loading conditions, like in HF. LV remodeling plays an important part in the progression of HF due to the mechanical burden produced by changes in LV geometry and architecture and in the components of the myocardium.

These changes comprise32:

• Alterations in the biology of cardiac myocytes:

- Eccentric hypertrophy à this typical hypertrophy pattern develops in response to chronic volume overload: increased diastolic wall stress results in an extension in the length of myocytes with the addition of sarcomeres in series, thus worsening LV dilation. It may also be accompanied by wall thinning, due to the addition of sarcomeres in parallel as a consequence of pressure overload. - Disruptions in cellular organization à there is upregulation of the cytoskeletal protein desmin and membrane-associated proteins such as vinculin and dystrophin, an increase in the number of myofibrils and mitochondria, an expansion of nuclei and mitochondria, myofibril displacement, alterations in contractile elements (myofibrillar ATPase,

25 actomyosin, myosin, troponin, tropomyosin, titin activity and/or expression reduced) and regulatory proteins. - β-adrenergic signaling desensitization à downregulation of beta adrenergic receptor density takes place probably due to the increased number of NE nearby, and reduced contractile response to beta adrenergic agonists; as a consequence, there is a reduction in LV contractility. - increased expression of β myosin and decreased expression of a myosin heavy chain gene à reactivation of fetal genes generally not expressed postnatally, and silencing of others normally expressed, may play a relevant role in contractile dysfunction. This genetic reprogramming is triggered by local and systemic mechanisms: the mechanical stretching of the myocyte, neurohormones, such as norepinephrine or angiotensin II, inflammatory cytokines like TNF or IL-6, other peptides and growth factors, and reactive oxygen species. - Myocytolysis à in the end stage of hypertrophy, myocytolysis occurs, with disruption of Z-bands and the normal parallel arrangement of sarcomeres, and tortuosity of T tubules. - Alterations in excitation-contraction coupling à failure in the mechanism that, starting from the cardiac action potential, under normal circumstances leads to myocyte contraction and relaxation, most evident at high heart rates, with resultant impaired force-frequency coupling. This is due to the decline of the systems usually responsible for the adjustment of cardiac performance to a higher contraction frequency. Contrary to what normally occurs, in HF there is a reduction in the amount of intracellular Ca2+, a protracted deterioration of transient Ca2+, and an increased quantity of diastolic Ca2+. At the basis of the reduced transient intracellular Ca2+ there are three critical defects in Ca2+cycling, resulting in depletion of Ca2+ from the sarcoplasmic reticulum (SR): (1) increased Ca2+leakage through the ryanodine receptor, (2) impaired calcium uptake by sarcoplasmic reticulum due to reduced levels and function of SERCA2a (a sarcoplasmic reticulum Ca2+pump) , and (3) increased expression and function of the sarcolemmal Na+/Ca2+ exchanger (NCX). - abnormal energetics and metabolism;

26 • Myocardial Changes:

- progressive loss of myocytes à this is due to a continuum of cell death responses: necrosis, apoptosis, and autophagic cell death pathways; - reorganization of the extracellular matrix à the organized structural type I and III collagen weave that usually ensures the integrity of myocytes and the alignment of myofibrils is degraded and replaced by an interstitial collagen matrix that does not provide structural support, but ultimately leads to fibrosis.2,21

• Alterations in Left Ventricular Chamber Geometry:

As a consequence of the changes in myocyte biology and myocardial structure, the LV undergoes several alterations in its geometry that contribute to worsening HF.

- LV dilation à leads to an increase in LV end-diastolic volume and afterload, worsened by delayed LV filling due to reduced LV compliance from hypertrophy or fibrosis. - Increased LV sphericity index à there is a shift from an elliptical to a spherical shape that has the effect of increasing wall stress, maintaining HF. The sphericity index (SI) is an effort to quantify the abnormal geometric changes that accompany HF and assess the shape by measuring the ratio of either the long axis to short axis or end diastolic volume to the volume of the sphere having the measured long axis diameter. An inferior MI induces a regional remodeling of the basal and mid segments of the inferopostero-lateral wall, with a significant increase in LV transverse diameters and consequently in the SI. However, as the SI evaluates the entire LV chamber, in some cases the it fails to detect regional abnormalities, like those at the apical level. For that reason, the apical conicity index (ACI) was introduced, described as the ratio of the apex to the short axis. This ACI, easily measured by echocardiography, is significantly greater in patients with an anterior MI, where the apex is primarily involved, quantifying the changes in enlarged, less conical apex.34 (Figure 8 and 9)

27 - LV wall thinning à along with LV dilation, contributes to the “afterload mismatch” that worsens cardiac output. It also causes the constant expression or activation of stretch-activated genes and hypertrophic signaling pathways. Furthermore, it may provoke episodes of hypoperfusion of the subendocardium and increase oxidative stress. - Mitral valve incompetence à distancing of papillary muscles leads to functional mitral regurgitation and further hemodynamic volume overloading of the ventricle.

Taken together, LV remodeling lead to a vicious cycle where LV dilation keeps increasing in a wasted effort to maintain a normal cardiac output, the EF decreases, and hemodynamic overloading worsens, any or all of which are sufficient to continued aggravation of LV function, wall stress, geometric distortion and therefore the progression of HF.32,35–40

Furthermore, mitral regurgitation may occur as a result of the LV dilation, due to the displacement of the papillary muscles and annular enlargement, worsening the prognosis.41

Recent studies have shown that LV remodeling can be reversed, decreasing LV mass and optimizing its shape. Reverse LV remodeling is also associated with improved clinical outcomes in patients with HFrEF. Indeed, one of the goals of therapy for HF is to prevent and/or reverse LV remodeling, which is the aim of surgery in the present analysis.20,42

Figure 8 Left panel: the LV apex is primarily involved after an anterior MI. As a consequence, the conicity index (CI, obtained from the apical – c – to short axis ratio – b)

28 is significantly greater in the anterior remodeling compared to posterior remodeling group. Right panel: a previous inferior MI induces a regional remodeling of the basal and mid segments of the inferopostero-lateral wall, with a sig- nificant increase in LV transverse diameters and conse- quently in the sphericity index (SI, obtained from the short – b -to long axis ratio – a)43

Figure 9 Geometric measures in normal and dilated cardiomyopathy. Sphericity index (SI) is calculated as the short- to long-axis ratio (S/L), and conicity index (CI) as the apical to short-axis ratio (Ap/S). Apical diameter is determined by using the diameter of the sphere that best fits the apex. Note that the SI has the same value in normal subjects and in patients with dilated cardiomyopathy, because the elongation of the ventricle is proportional to the increase in width, so the ratio remains stable, whereas the CI is markedly abnormal in the patients.44

2.5. Diagnosis

Although HF is a complex clinical syndrome that may present with several different clinical pictures, the vast majority of patients show a classical constellation of symptoms related to impairment of myocardial performance, with findings that may range from normal ventricular size and function to severe dilation and reduced ejection fraction. If HF is suspected, the goals of the clinician are to confirm diagnosis, outline the underlying cause(s), estimate the severity and prognosis, and choose the most suitable therapy.

Diagnosis of HF can be relatively straightforward when the patient presents with the classic manifestations. Nevertheless, as the signs and symptoms of HF and the diagnostic physical findings are neither specific nor sensitive, the clinical picture

29 alone is not sufficient to establish a diagnosis, and additional laboratory testing, cardiac imaging, and functional studies should be performed.

The assessment of patients with HF should always begin with complete medical history, in order to explore possible causes of the disease and exacerbating factors, as well as obtain crucial data for proper management.

2.5.1. Clinical presentation

As mentioned above, HF may present with a wide range of possible clinical pictures, none of which are specific to HF, and much less to HFpEF versus HFrEF. However, the classic set of symptoms usually includes fatigue, due to low cardiac output, and shortness of breath, as a result of pulmonary congestion, restricted cardiac output, and increased filling pressure. Other factors may also contribute to worsening of fatigue, such as reduction in pulmonary compliance, increased airway resistance, skeletal muscle (respiratory muscles and diaphragm) abnormalities, and other noncardiac comorbidities (e.g., anemia, renal dysfunction, endocrinologic abnormalities)45.

In the early stages of HF, dyspnea develops only during exercise. As the disease degenerates, it can occur even with less demanding activity, until it eventually becomes present at rest. Moreover, 40% of patients with advanced HF shows Cheyne-Stokes respiration, also known as periodic respiration, characterized by cycles of apneic phases followed by hyperventilation and hypocapnia. It is attributable to the increased sensitivity of the respiratory center to arterial pCO2 and a lengthy circulatory time.

Although dyspnea is considered a cardinal symptom of HF, its initial absence does not allow to exclude a diagnosis, just like its presence is not sufficient to establish a diagnosis, since it is a possible red flag of many other medical conditions.

With progression of the disease, the so-called ‘air hunger’ starts to develop in recumbency (orthopnea), especially on the left side (trepopnea), due to the redistribution of fluids from the splanchnic to the central circulation and the consequent increase in pulmonary capillary pressure. Therefore, it is most evident during the night (paroxysmal nocturnal dyspnea), with acute episodes of severe

30 shortness of breath frequently accompanied by coughing or wheezing, awakening the patient and forcing them to sleep with the head elevated in order to relieve dyspnea. Orthopnea and paroxysmal nocturnal dyspnea are high reliable indicators of HF.

Symptoms related to right heart congestion may also be present, such as weight gain, increasing abdominal girth, early satiety, upper quadrant pain related to liver congestion and the onset of edema in dependent organs.

Other possible manifestations include gastrointestinal symptoms, like anorexia, nausea, cachexia, cerebral symptoms such as confusion and disorientation, especially in elderly patients, sleep and mood disturbances, and nocturia caused by the reabsorption of fluid during sleep.

2.5.2. Physical examination

Scrupulous physical examination completes the information collected through the medical history; therefore, it is the basis in the evaluation of patients with HF, in order to determine the aetiology, assess severity, and choose best treatment. The first aspect that should be considered is the patient’s general appearance, immediately followed by measurement of vital signs in seated and standing positions, evaluation of heart and pulse, and assessment of other organs, in search of signs of congestion or hypoperfusion or indications of comorbidities.

The clinician should inspect the patient’s habitus and state of alertness, with particular attention to the possible presence of discomfort, shortness of breath, coughing, pain, or Cheyne-Stokes respiration. In the initial stages of HF, the patient usually complains of moderate distress only when recumbent, but when HF worsens, the shortness of breath becomes disabling, preventing them from carrying out daily activities, even speaking, and forcing them to sit in the upright position in order to breath. Pulse and systolic blood pressure are generally reduced in severe HF, due to LV dysfunction, but in the initial stages may be normal or even high. The color of the skin, particularly of the extremities, may suggest underperfusion due to peripheral vasoconstriction if pallid or cyanotic, but it can also show signs of

31 alcohol abuse, such as spider angioma or palmar erythema, or even underlying diseases like bronzing due to hemochromatosis, or easy bruising from amyloidosis.

Despite its importance, cardiac examination may not be always helpful to assess the severity of the disease. Heart size and the quality of the point of maximal impulse can be estimated through inspection and palpation. The apical impulse may be palpable and displaced over two interspaces below the fifth intercostal space and/or lateral to the midclavicular line, if cardiomegaly is present. In advanced HF, a palpable third sound may be present.

Instead, auscultation plays a key role in HF evaluation. A third heart sound (S3), defined as protodiastolic gallop, is generally audible, and is a highly specific red flag of ventricular volume overload. A fourth sound may be also present in the case of diastolic dysfunction. In severe HF, these two sounds may overlap, resulting in a summation gallop. Moreover, a typical holosystolic murmur of mitral regurgitation and a left sternal border murmur of tricuspid insufficiency are common findings in many patients with severe HF. Recognizing reduced cardiac output is also of great importance: poor mentation, reduced urine output, mottled skin, and cool extremities may suggest a condition of systemic hypoperfusion.

One of the aims of the clinician in assessment of HF is to quantify the presence of volume retention, with or without pulmonary and/or systemic congestion. The measurement of jugular venous pressure (JVP) on the recumbent patient, with the head tilted at 45°, provides an estimation of right atrial pressure and therefore left-sided filling pressure, being an indirect way to evaluate the volume status of the patient. JVP is measured by calculating the height of the venous column of blood above the sternal angle and then adding 5 cm. It is expressed in cm of water (normal ≤8 cm). Especially in the early stages, where JVP may be normal at rest, it can be accentuated by applying pressure on the right upper quadrant of the abdomen while determining venous pulsations in the neck (hepatojugular reflux). If right failure or tricuspid regurgitation are present, JVP may not be reliable, as well as in patients with pulmonary arterial hypertension.

32 Pulmonary congestion is another typical sign of HF, with variable clinical manifestations. Transudation of fluid from pulmonary capillaries into alveoli results in fine pulmonary crackles rising from the base upwards over both lung fields, namely rales and crepitations or rhonchi, accompanied by expiratory wheezing (cardiac asthma) if reactive bronchoconstriction is also present. However, these sounds are frequently absent in patients with severe chronic HF, thanks to the compensatory increase in local lymphatic drainage. Leakage of fluids may also occur into the pleural cavities, resulting in pleural effusions, which is clinically evident in dullness to percussion and diminished breath sounds. Bilateral effusions are more frequent, but if unilateral, is usually right sided.

Other common but late findings in volume-overloaded patients with HF include hepatomegaly, ascites as a result of increased pressure in the hepatic veins, and jaundice secondary to the hepatic disfunction. Furthermore, in these patients lower- extremity edema is commonly found, but it needs to be related with JVP measurement, as it is non-specific and may be the result of venous insufficiency, or as a side effect of medications such as calcium channel blockers. Peripheral edema is usually symmetric and bilateral, mainly affecting the ankles and pretibial region, or the sacral area and the scrotum in bedridden patients.

2.5.3. Investigations

Routine Laboratory Testing Patients with new-onset HF as well as those with chronic HF should undergo a complete laboratory panel including electrolytes, blood urea nitrogen, serum creatinine, hepatic enzymes, fasting lipid profile, thyroid- stimulating hormone, transferrin saturation, uric acid, complete blood count, and urinalysis. If comorbidities are suspected, patients should be tested for diabetes mellitus (fasting serum glucose or oral glucose tolerance test), HIV infection, hemochromatosis, rheumatologic diseases, amyloidosis, or pheochromocytoma. Frequent findings in patients with HF include abnormalities of sodium (hyponatremia is the most common) and potassium (mostly hypokalemia, common in patients treated with diuretics), abnormalities in renal function, urea nitrogen and serum creatinine (suggesting a cardiorenal syndrome), hyperglycemia, elevated serum uric

33 acid levels, abnormalities in hepatic function and hematologic abnormalities, especially low hemoglobin levels and red cell distribution width.

Biomarkers The measurement of plasma concentration of biomarkers has become an important adjunctive tool in the initial evaluation of patients with HF. It is used to define an initial working diagnosis and identify patients who require further investigations, as well as to assess the severity of the disease and establish a prognosis in chronic HF, if serially measured, as its concentration increases with worsening of LV systolic dysfunction. The most commonly used biomarkers are natriuretic peptides (NPs), in particular B-type natriuretic peptide (BNP) and its N- terminal cleavage equivalent, pro-BNP (NT-proBNP), which circulate in the bloodstream at different levels according to their half-lives. They are released from the failing ventricle cardiomyocytes in response to stretch and wall stress and represent precise indicators for the presence of HFrEF. Patients with a level of NPs below the established cut-off values are unlikely to have HF. The upper limit of normal in the non-acute setting for BNP is 35 pg/mL and for NT- proBNP is 125 pg/mL.5 In the acute setting, higher values should be considered: a BNP value of 100 pg/mL, as shown in the Breathing Not Properly study46, is likely to be accurate for diagnosis of acutely decompensated HF, and NT-proBNP of 300 pg/ mL should exclude it, as reported in the ICON study47. However, despite their significant role, it is important to always keep in mind that natriuretic peptide levels may also be altered for other reasons. For example, they appear to be disproportionally low in obese patients, and greatly increased with valvular heart disease, pulmonary hypertension, IHD, atrial arrhythmias, renal impairment, and hyperdynamic conditions, and may also vary according to age and gender. Therefore, due to their high negative but low positive predictive values, the results with biomarkers should always be interpreted in the light of sound clinical assessment and integrated with all information available, and their use should be limited to exclude HF and not be interpreted as a diagnostic tool.

Other newer biomarkers, such as soluble ST-2 and galectin-3, have given promising results and are currently being studied to complement natriuretic peptides.

Electrocardiogram (ECG) A routine 12-lead ECG is a standard starting point in the assessment of patients with symptoms suggestive of HF, where it is rarely normal,

34 usually showing nonspecific alterations. With a normal ECG, LV systolic dysfunction is highly unlikely. The major role of ECG is to assess cardiac frequency and rhythm and identify signs of LV hypertrophy, such as increased QRS voltage or prior MI based on the presence/absence of Q-waves. Moreover, QRS width is relevant to the choice of resynchronization therapy. Other possible findings may include sinus tachycardia, atrial arrythmia, signs of RV hypertrophy, prolongation of the PR and QT interval, and low QRS voltage suggesting infiltrative disease or pericardial effusion.

Exercise Testing While exercise intolerance is one of the first symptoms of HF, quantifying it is not easy. NYHA criteria and a 6-minute walk test are too non- specific, and the most commonly used test is the cardiopulmonary exercise testing (CPET). CPET quantifies exercise capacity through the analysis of the gas exchange during exercise on a treadmill or cycle-ergometer. The parameters measured breath-by-breath by modern software are oxygen intake (VO2), expiratory ventilation (VE), carbon dioxide output (VCO2), and analysis of gas exchange. CPET provides also a series of additional parameters that help the diagnosis process: peak VO2, ventilatory threshold (VT), VE/VCO2 slope, peak respiratory exchange ratio

(VCO2/VO2), peak heart rate, heart rate recovery, end tidal VCO2, VO2 efficiency slope and peak VE/maximal voluntary ventilation. These elements are combined in the assessment of severity, prognosis and mortality rate48 estimates of advanced HF, and also in the evaluation of the patient before heart transplant. Moreover, thanks to its high negative predictive value, normal CPET response may help in ruling out 49,50 significant heart diseases. Generally HF patients show reduced VO2, VT < 40% of the predicted VO2 curve, peak VO2 < 85%, increased VE/VCO2, but normal 51 O2 saturation.

Recently, the combination of CPET with exercise stress echocardiography (ESE) has proven to be valuable in the diagnosis and managing of HFrEF and valve disease, allowing to integrate structural and functional data and identifying non- cardiopulmonary causes of dyspnea52. “The combination CPET-ESE can non- invasively evaluate aspects of the cardiovascular system, otherwise obtainable only with invasive hemodynamic monitoring, offering a more personalized O2 pathway analysis.”53 Applied to HFrEF patients, the integrated CPET-ESE approach offers

35 the possibility to study direclty both LV and right ventricular (RV) contractility, increasing patient risk stratification.49,54,55 Specifically, “a compromised ESE-derived peak ESPVR (End-Systolic Pressure Volume Relation), that reflects impaired LV contractility, resulted to be the most powerful predictor of adverse LV remodeling, defined on the basis of LV volumes and relative wall thickness.”56 Moreover, it also allows to better evaluate the MV apparatus, therefore it is particularly useful when assessing patients who combine HF with MR.

2.5.3.1. Noninvasive single or combined Imaging techniques

Noninvasive cardiac imaging is widely used in every step of HF management. It is vital to confirm diagnosis, evaluate the severity, define prognosis, guide the choice of treatment, and monitor the efficacy of therapy during follow-up. It helps in recognition of structural and functional changes of the heart, as well as determine a possible etiology, stratify risk, and allow identification of HFrEF versus HFpEF. X- ray, echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) are the most used noninvasive cardiac imaging techniques. Nuclear imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) may also be helpful in some cases to assess ischemia and myocardial viability.

Chest X-Ray A plain chest radiography should be part of early routine assessment, especially in the acute setting, since it gives useful information about cardiac size, shape, and pulmonary vasculature, and helps in recognizing possible noncardiac causes of symptoms i.e. pulmonary malignancy and interstitial pulmonary disease, even if CT is the standard of care. In patients with acute HF, X-ray may show signs of pulmonary hypertension, interstitial edema, or pulmonary edema with the classic butterfly pattern of interstitial and alveolar opacities bilaterally. “In patients with chronic HF, instead, the x-ray may show more subtle findings, such as pleural effusions, interstitial markings including Kerley B lines (thin horizontal linear opacities extending to the pleural surface caused by accumulation of fluid in the interstitial space), peri bronchial cuffing, and evidence of prominent upper lobe vasculature indicating pulmonary venous hypertension.”

36 Transthoracic echocardiography (TTE) “Echocardiography is the method of choice in patients with suspected HF, for reasons of accuracy, availability, safety and cost.”5 Echocardiogram, which includes 2D/3D echocardiography, pulsed and continuous wave Doppler, color flow Doppler, tissue Doppler imaging (TDI) contrast echocardiography, and deformation imaging (strain and strain rate) provides a semiquantitative assessment of LV volume and myocardial systolic and diastolic function, along with information about intracardiac pressures and flows, valvular status and/or regional wall motion abnormalities (indicative of a prior MI). LVEF is the most useful index of LV systolic function. “For measurement of LVEF, the modified biplane Simpson’s rule is recommended. LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV) are obtained from apical four- and two-chamber views.”5 EF is considered normal above ≥50%, meaning that systolic function is adequate, while under 30–40% contractility is significantly depressed. 3D echocardiography improves the accuracy of the measurement, while the Doppler technique allows quantification of hemodynamic variables (e.g. stroke volume, cardiac output). Diastolic function should be assessed with a comprehensive echocardiography examination, including Doppler and 2D measurements, since no single technique is sufficiently accurate alone. The 2-D echo/Doppler is also vital in assessing RV structure and function, right atrial dimensions, and pulmonary pressures. Transesophageal echocardiography (TEE) may be useful if TTE is insufficient, or in some scenarios with specific suspected etiologies, such as endocarditis or congenital heart disease, and to rule out intracavitary thrombi in AF patients requiring cardioversion. Exercise stress echocardiography (ESE) is recommended by the latest European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines for the evaluation of HF patients, in order to assess inducible ischemia, myocardium viability and also valve diseases57,58. It allows the measurement of the cardiovascular response to exercise in term of cardiac function, valve status and hemodynamic adaptation. The recent combination of CPET -ESE can relate and implement this information with gas exchange analysis.

Cardiac MRI (CMR) Using steady-state free precession imaging (SSFP), MRI provides a high-quality imaging analysis of cardiac morphology, LV and RV

37 volumes, mass and function, and it has therefore become the gold standard. Moreover, it is also helpful in assessing LV structure, wall motion analysis and valve evaluation. T1 ans T2 mapping for tissue characterization help in distinguishing among the possible underlying aetiologies of HF. Specifically, CMR can differentiates ischemic and non-ischemic cardiomyopathies, based on the distribution pattern of late gadolinium enhancement (LGE) from T1-weighted images. Ischemic cardiomyopathy can be recognized from its characteristic subendocardial enhancement at sites of previous infarctions, matching the fibrosis/scars location5. LGE has also a prognostic value, relating to the overall cardiovascular outcome59, and it is associated with poor prognosis in setting of a MI.60,61 “CMR plays an important role in predicting late myocardial recovery and in identifying areas at risk after MI.62–64 The excellent visualization of the myocardium allows an evaluation for LV thrombus, aneurysms, and pseudoaneurysms. Additionally, as demonstrated by Kim et al.65, LGE can determines myocardial viability, reversible and irreversible areas of myocardial injury prior to revascularization, which in turn is an important marker of likelihood of contractile recovery. Finally, it is useful in guiding the implantation of LV lead in candidates to CRT.

Cardiac CT Unlike the other techniques, CT involves radiation exposure and also iodinated contrast administration for angiography, and thus should be used with caution. With CT angiography, it is possible to determine the presence or absence of obstructive coronary artery disease, and possibly assess coronary venous anatomy before cardiac resynchronization therapy.

2.5.3.2. Invasive Imaging techniques

Invasive imaging techniques that allow measurement of intracardiac pressures and hemodynamics are less commonly performed and are increasingly supplanted by noninvasive techniques that provide much of the information previously available only with heart catheterization. However, in some cases of uncertainty or if precise measurements are needed to guide choice of therapy, they may be useful.

Right heart catheterization Right heart catheterization allows precise assessment of hemodynamics and filling pressures; therefore, it should be considered in patients

38 with persistently symptomatic HF despite therapy, or with severe hypotension, hypoperfusion, or dependence on inotropic infusion. This technique is particularly useful in the assessment of the pulmonary vascular resistance, in order to determine an acceptable candidate for cardiac transplantation, or to assess volume status through measurement of pulmonary artery wedge pressure, which estimates LV end-diastolic pressure. Use of hemodynamic monitoring to guide therapy was evaluated in patients with advanced HF in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial66. The results did not show any clear benefit on morbidity and mortality of pulmonary artery pressure–guided management compared with careful clinical assessment.

Endomyocardial biopsy Biopsy of the myocardium is usually reserved for cases with unique prognosis or impossibility of diagnosis by conventional methods. The advantages of a biopsy must be weighed against the risks of the procedure.

2.5.4. Algorithm for diagnosis of HF

For patients presenting with a non-acute onset of symptoms or signs for the first time, the probability of HF should be estimated based on clinical history (in particular CAD, arterial hypertension, and diuretic use), reported symptoms, physical examination, and ECG.

If all elements are normal, HF is highly unlikely and other diagnoses need to be taken into consideration. Otherwise, if at least one element is abnormal, plasma natriuretic peptides should be measured, and if above the threshold, echocardiogram is indicated to establish a diagnosis and determine the most appropriate treatment. Other tests may be required only if the diagnosis remains uncertain and should be performed only if they have a meaningful clinical consequence.

39 ESC Guidelines 2141 Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/27/2129/1748921 by guest on 16 March 2020

Figure 4.1 Diagnostic algorithm for a diagnosis of heart failure of non-acute onset BNP B-type natriuretic peptide; CAD coronary artery disease; HF heart failure; MI myocardial infarction; NT-proBNP N-terminal ¼ ¼ ¼ ¼ ¼ pro-B type natriuretic peptide. aPatient reporting symptoms typical of HF (see Table 4.1). bNormal ventricular and atrial volumes and function. c Consider other causes of elevated natriuretic peptides (Table 12.3).

Figure 10 Algorithm for diagnosis of HF in the non-acute setting5

2.6. Prognosis

Despite progresses in the management of HF, the overall mortality rate remains high, and the development of symptomatic HF still has a poor prognosis. “Community-based studies indicate that 30–40% of patients die within 1 year of diagnosis and 60–70% die within 5 years, mainly from worsening HF or as a sudden

40 event (probably because of a ventricular arrhythmia)”2. Several factors have been associated with increased mortality, among which age remains the strongest predictor of adverse outcomes67. Functional status is another important predictor of the outcome, patients with symptoms at rest (NYHA class IV) have an annual mortality rate of 30–70%, whereas patients with symptoms during moderate activity (NYHA class II) have an annual mortality rate of 5–10%.68 The role of gender is still discussed, but it seems that although women have a better overall prognosis than men, they also appear to have a greater degree of functional incapacity for the same degree of LV dysfunction. Biomarkers may also be useful, as inverse correlations have been reported between survival and plasma levels of norepinephrine, renin, AVP, aldosterone, ANP, BNP, NT-proBNP, endothelin-1, and inflammatory markers. Many other factors, such as anemia, have been studied in relation to their influence on adverse outcomes, but it remains extraordinarily difficult to determine which variable is the most relevant to the prediction of prognosis in the individual patient. Towards this aim, a variety of multivariable scores for clinical risk stratification have been developed, such as the Seattle Heart Failure model for ambulatory HF patients, available as an Internet-based application2, or the Acute Decompensated Heart Failure National Registry (ADHERE)68 for patients with acute decompensation symptoms. The use of the ACC/AHA and NYHA HF staging systems in combination provides a more complete picture for prognostication.

2 Available at http://depts.washington.edu/shfm

41 ESC Guidelines Page 3 of 17

1. Web Tables

Web Table 3.2 New York Heart Association functional classification based on severity of symptoms and physical activity

Web Table 3.3 ACCF/AHA stages of heart failure

ACCF/AHA American College of Cardiology Foundation/American Heart ¼ Association; HF heart failure. ¼

Web Table 3.5 Markers of worse prognosis in patients with heart failure

Demographic data Older age, male sex, low socio-economic status.

Severity of heart failure Advanced NYHA Class, longer HF duration, reduced peak oxygen consumption, high VE-VCO2 slope, Cheyne–Stoke ventilation, short 6-minute walking distance, reduced muscle strength, poor quality of life. Clinical status oedema, jugular venous dilatation, hepatomegaly), clinical features of peripheral hypoperfusion, body wasting, frailty. Myocardial remodeling and severity of heart dysfunction LV hypertrophy, left atrial dilatation, RV dysfunction, pulmonary hypertension, dyssynchrony, vast area of hypo/akinesis,

Biomarkers of neurohormonal Low sodium, high natriuretic peptides, high plasma renin activity, high aldosterone and catecholamines, high endothelin-1, activation high adrenomedullin, high vasopressin. Other biomarkers collagen markers, markers of organ damage/dysfunction. Genetic testing (see section 5.10.1) Certain mutations in inherited cardiomyopathies associated with high-risk of sudden cardiac death or rapid HF progression. Cardiovascular co-morbidities arterial disease. Non-cardiovascular co-morbidities Non-adherence Non-adherence with recommended HF treatment. Clinical events HF hospitalization, aborted cardiac arrest, ICD shocks.

CMR=cardiac magnetic resonance; COPD = chronic obstructive pulmonary disease; HF = heart failure; ICD = implantable cardioverter defibrillator; LV = left ventricular; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; QRS = Q, R, and S waves (combination of three of the graphical deflections); RV = right ventricular; TIA = transient ischaemic attack; VE-VCO2 = ventilatory equivalent ratio for carbon dioxide.

Figure 11 Markers of poor prognosis in patients with HF5

42 3. Current therapeutic strategies for chronic ischemic-based HFrEF

The main goals of current therapeutic strategies for ischemic-based HFrEF are to reduce symptoms, prolong survival, and improve the quality of life, as well as prevent complications and progression of the disease.

In patients at high risk for development of HF, it is vital to treat preventable conditions that are known to lead to HF, including hypertension, hyperlipidemia, and diabetes, in which case ACE inhibitors have shown to be particularly useful. Once HF becomes overtly symptomatic, the choice of therapy for patients with HFrEF is guided by NYHA functional classification. In asymptomatic patients in NYHA class I, the aim should be to slow down progression of HF by acting on neurohormonal systems that ultimately lead to cardiac remodeling. In patients in NYHA class II to IV, the focus should be on reducing fluid retention, minimizing disability, and mitigating the risk of further deterioration and death.5

Treatment plans generally combine more than one strategy, starting from pharmacological treatment.

Clearly, a pivotal point in the treatment of HF is to identify and correct the conditions that may contribute to the development and worsening of LV structural and functional abnormalities. In particular, this should include screening and treating comorbid hypertension, diabetes, anemia, CAD, and sleep-disordered breathing. Furthermore, other factors that may cause acute decompensation, and which should be monitored, are dietary indications of sodium intake, which should be limited to 2 to 3 g daily, and correct management of HF therapy. Certain measures should also be taken by the patient, like stopping smoking, limiting alcohol consumption, and keeping body weight under control on a regular basis. The patient with HF should also avoid extreme temperatures, heavy physical exertion, and avoid taking certain drugs known for their risk of renal failure and excessive fluid retention, such as NSAIDs, including COX-2 inhibitors.

3.1. Medical therapies

43 Medical therapies are aimed to relieve clinical manifestations, prevent disease progression and, when possible, reverse cardiac remodeling. Therefore, their actions mainly focus on the use of diuretics to manage excessive fluid retention, which is responsible for symptoms related to vascular and extravascular volume expansion. A diuretic should always be combined with an angiotensin converting enzymes inhibitor (ACEI) and a betablocker, or a mineralocorticoid receptor antagonist (MRAs), to counteract the overactivation of RAAS and the adrenergic nervous system, accountable for cardiac remodeling and its consequences. Patients should be monitored for complications and therapy should be adjusted on a regular basis as needed. The therapeutic algorithm recommended by the 2016 ESC Guidelines for the diagnosis and treatment of HF is illustrated in Figure 12.

44 ESC Guidelines 2149 Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/27/2129/1748921 by guest on 16 March 2020

Figure 7.1 Therapeutic algorithm for a patient with symptomatic heart failure with reduced ejection fraction. Green indicates a class I recom- mendation; yellow indicates a class IIa recommendation. ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; ¼ ¼ ARNI angiotensin receptor neprilysin inhibitor; BNP B-type natriuretic peptide; CRT cardiac resynchronization therapy; HF heart fail- ¼ ¼ ¼ ¼ Figureure; HFrEF12- heartTherapeutic failure with reduced ejection algorithm fraction; H-ISDN forhydralazine a and patient isosorbide dinitrate; with HR heart symptomatic rate; ICD implantable HFrEF. ¼ ¼ ¼ ¼ a cardioverter defibrillator; LBBB left bundle branchb block; LVAD left ventricular assistc device; LVEF left ventricular ejection fraction; MR Symptomatic1⁄4NYHAClassII¼ -IV. HFrEF1⁄4LVEF,40%.¼ If ACE inhibitor¼ not tolerated/contra¼ - mineralocorticoid receptor;d NT-proBNP N-terminal pro-B type natriuretic peptide; NYHA New York Heart Association;e OMT optimal ¼ ¼ ¼ indicated,medical use therapy; ARB. VF ventricular If MR fibrillation; antagonist VT ventricular not tolerated/contra tachycardia. aSymptomatic-indicated,NYHA Class II-IV. usebHFrEF ARB.LVEF With,40%. c aIf ACE hospital ¼ ¼ ¼ ¼ admissioninhibitor for not HF tolerated/contra-indicated, within the last use 6 ARB.monthsdIf MR antagonist or with not elevated tolerated/contra-indicated, natriuretic use peptides ARB. eWith a (BNP>250 hospital admission pg/ml for or NTproBNPHF within >500 the last 6pg/ml months orin withmen elevated and natriuretic 750 pg/ml peptides in (BNP women).. 250 pg/ml f orwith NTproBNP an elevated. 500 pg/ml plasma in men and 750 natriuretic pg/ml in women). peptide fWith an elevated plasma natriuretic peptide level (BNP 150 pg/mL or plasma NT-proBNP 600 pg/mL, or if HF hospitalization within recent level (BNP ≥ 150 pg/mL or plasma NT-proBNP≥ ≥ 600 pg/mL, ≥or if HF hospitalization within recent 12 months plasma BNP 100 pg/mL or plasma NT-proBNP 400 pg/mL). gIn doses equivalent to enalapril 10 mg b.i.d. hWith a hospital admis- ≥ ≥ g 12monthssion for plasma HF within the BNP previous ≥ year.100pg/mLiCRT is recommended or plasma if QRS NT130- msecproBNP and LBBB ≥ (in 400pg/mL). sinus rhythm). jCRT should/mayIn doses be consideredequivalent if to ≥ QRS 130 msec with non-LBBBh (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individua-i enalapril ≥ 10mgb.i.d. With a hospital admission for HF within the previous year. CRT is recommendedlized decision). if For QRS further ≥ details, 130 see msec Sections and 7 and 8LBBB and corresponding (in sinus web pages.rhythm). jCRT should/may be considered if QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision).5

3.1.1. Management of fluid retention

Reducing excessive sodium and water retention with diuretics results in the improvement not only of clinical symptoms, but also LV dilatation, mitral function,

45 and subendocardial ischemia.69 In particular, the use of diuretics leads to reductions in jugular venous pressure, pulmonary congestion, peripheral edema, and body weight within a few days, and in the medium term improves cardiac function, increases exercise tolerance, and reduces the risk of hospitalization.70 The use of diuretics is recommended in patients with symptoms and/or signs of congestion (Class of Recommendation I, Level of Evidence B of the 2016 ESC Guidelines)5, even though the use of digitalis and low doses of ACEI may enhance urinary sodium excretion in some patients. Euvolemia should be achieved and maintained with the lowest dosage possible, which should also be reviewed and adjusted over time, according to the patient’s needs. Once the congestion has been relieved, diuretics should be continued to prevent the recurrence of fluid retention. Major side effects of diuretics include electrolyte and metabolic disturbances3, volume depletion, and worsening of azotemia. Among all classes of diuretics, loop and thiazide and thiazide-like diuretics are all have shown to reduce the risk of death, worsening of the disease, and exercise capacity.70,71 They may be also carefully used in combination, usually furosemide in combination with metolazone, to treat resistant or insufficient volume overload. Specifically, loop diuretics can increase sodium excretion by up to 25% of the filtered load, compared to 10% for thiazide diuretics. Moreover, loop diuretics improve free water clearance and remain effective until severe renal impairment, unlike benzothiadiazides. Thus, they often are the preferred choice. Other diuretic classes that may be useful in combination therapy include potassium- sparing diuretics, such as triamterene and amiloride, and MRAs, namely spironolactone and eplerenone, which “are recommended in all symptomatic patients with HFrEF and LVEF<35%, and in patients who remains symptomatic despite treatment with an ACEI and a betablocker, in order to reduce mortality and hospitalization.”5,72,73 The most commonly prescribed diuretics are summarized in Figure 13.

3 Diuretic use can lead to potassium depletion, also exacerbated by the increased levels of aldosterone, and ultimately result in cardiac arrythmias. Other common metabolic disturbances include hyponatremia, hypomagnesemia, metabolic alkalosis, hyperglycemia, hyperlipidemia and hyperuricemia.

46 2150 ESC Guidelines mortality and morbidity have not been studied in RCTs. A Co- Loop diuretics produce a more intense and shorter diuresis chrane meta-analysis has shown that in patients with chronic HF, than thiazides, although they act synergistically and the combin- loop and thiazide diuretics appear to reduce the risk of death ation may be used to treat resistant oedema. However, adverse and worsening HF compared with placebo, and compared effects are more likely and these combinations should only be with an active control, diuretics appear to improve exercise used with care. The aim of diuretic therapy is to achieve and main- capacity.178,179 tain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to the individual needs over time. In selected asymptomatic euvolaemic/hypovolaemic patients, the use of a diuretic drug might be (temporarily) discontinued. Pa- tients can be trained to self-adjust their diuretic dose based on

Table 7.2 Evidence-based doses of disease-modifying monitoring of symptoms/signs of congestion and daily weight Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/27/2129/1748921 by guest on 16 March 2020 drugs in key randomized trials in heart failure with measurements. reduced ejection fraction (or after myocardial Doses of diuretics commonly used to treat HF are provided in infarction) Table 7.3.Practicalguidanceonhowtousediureticsisgivenin Web Table 7.7.

Starting dose (mg) Target dose (mg) ACE-I Captoprila 6.25 t.i.d. 50 t.i.d. Enalapril 2.5 b.i.d. 10–20 b.i.d. Lisinoprilb 2.5–5.0 o.d. 20–35 o.d. Ramipril 2.5 o.d. 10 o.d. Trandolapril a 0.5 o.d. 4 o.d. Table 7.3 Doses of diuretics commonly used in Beta-blockers patients with heart failure Bisoprolol 1.25 o.d. 10 o.d. Carvedilol 3.125 b.i.d. 25 b.i.d.d Diuretics Initial dose (mg) Usual daily dose (mg) Metoprolol succinate (CR/XL) 12.5–25 o.d. 200 o.d. a Nebivololc 1.25 o.d. 10 o.d. Loop diuretics ARBs Furosemide 20–40 40–240 Candesartan 4–8 o.d. 32 o.d. Bumetanide 0.5–1.0 1–5 Valsartan 40 b.i.d. 160 b.i.d. Torasemide 5–10 10–20 b Losartanb,c 50 o.d. 150 o.d. Thiazides MRAs 2.5 2.5–10 Eplerenone 25 o.d. 50 o.d. Hydrochlorothiazide 25 12.5–100 Spironolactone 25 o.d. 50 o.d. Metolazone 2.5 2.5–10 c ARNI lndapamide 2.5 2.5–5 d Sacubitril/valsartan 49/51 b.i.d. 97/103 b.i.d. Potassium-sparing diuretics If-channel blocker +ACE-I/ -ACE-I/ +ACE-I/ -ACE-I/ ARB ARB ARB ARB Ivabradine 5 b.i.d. 7.5 b.i.d. Spironolactone/ 12.5–25 50 50 100– eplerenone 200 ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker; ¼ ¼ Amiloride 2.5 5 5–10 10–20 ARNI angiotensin receptor neprilysin inhibitor; b.i.d. bis in die (twice daily); ¼ ¼ MRA mineralocorticoid receptor antagonist; o.d. omne in die (once daily); ¼ ¼ Triamterene 25 50 100 200 t.i.d. ter in die (three times a day). ¼ aIndicates an ACE-I where the dosing target is derived from post-myocardial infarction trials. ACE-I angiontensin-converting enzyme inhibitor, ARB angiotensin receptor ¼ ¼ bIndicates drugs where a higher dose has been shown to reduce morbidity/ blocker. mortality compared with a lower dose of the same drug, but there is no substantive aOral or intravenous; dose might need to be adjusted according to volume status/ randomized, placebo-controlled trial and the optimum doseFigure is uncertain. 13 Doses of diureticsweight; commonly excessive doses mayused cause in renal patients impairment with and heart ototoxicity. failure5 aOral or intravenous; dose c b 2 Indicates a treatment not shown to reduce cardiovascularmight or all-cause need mortality to inbe adjustedDo notaccording use thiazides ifto estimated volume glomerular status/ filtration weight; rate ,30 excessive mL/min/1.73 m ,doses may cause renal except when prescribed synergistically with loop diuretics. patients with heart failure (or shown to be non-inferior to a treatment that does). b 2 dA maximum dose of 50 mg twice daily can be administeredimpairment to patients weighing and ototoxicity.clndapamide Do is a non-thiazidenot use sulfonamide. thiazides if eGFR< 30mL/min/1.73m , except when d c d over 85 kg. prescribed synergisticallyA with mineralocorticoid loop diuretics. antagonist (MRA)lndapamide i.e. spironolactone/eplerenone is a non-thiazide is always sulfonamide. An MRA is always preferred. Amiloridepreferred. and Amiloride triamterene and triamterene should should not not be combinedbe combined with an MRA. with an MRA.

3.1.2. Prevention of disease progression

ACEI and beta blockers are the cornerstones in HFrEF therapy, with the purpose of slowing down progression of disease and remodeling, therefore improving survival, reducing mortality, and morbidity.74–82 They should be started together as soon as HF is diagnosed. As stated in the 2016 ESC HF Guidelines, “Neuro-hormonal antagonists are recommended for the treatment of every patient with HFrEF, unless contraindicated or not tolerated”, while “ARBs have not been consistently proven to reduce mortality in patients with HFrEF and their use should be restricted to patients intolerant of an ACEI or those who take an ACEI but are unable to tolerate an MRA.”5 ACEIs and beta blockers should be given at the maximum tolerated dose, gradually titrated, in order to counterbalance the RAAS and reduce the risk of death and progression of disease. ACEI should be administered with caution in patients receiving potassium-sparing diuretics or potassium supplements, to avoid the risk

47 of hyperkalemia, while use of beta blockers should be carefully monitored in patients with bradycardia, second- or third-degree heart block or symptomatic hypotension, and avoided in patients with asthma and active bronchospasm. In addition, other drugs, such as angiotensin receptor neprilysin inhibitor (ARNIs),

If-channel inhibitors and angiotensin II receptor antagonists (ARBs), that may be useful in specific situations. Sacubitril/valsartan is a combination of an ARNI, acting on the RAAS and neutral endopeptidase system, and an ARB, respectively. It should be considered as a replacement for an ACEI in patients who remain symptomatic despite optimal treatment with an ACEI, a beta blocker, and an MRA. It has also been demonstrated to be more effective than an ACEI in reducing hospitalization and mortality in patients with LVEF ≤ 40%, elevated plasma NP levels, and an estimated GFR (eGFR) ≥30 mL/min/1.73 m2.83 However, long-term safety needs to be further addressed, especially considering its potential effects on amyloid deposition in the brain.84

Ivabradine, an If-channel inhibitor, has been approved by the European Medicine Agency (EMA) for use only in patients in sinus rhythm, due to its mechanism of action4, and with a resting heart rate ≥75 bpm, as this is the only group of patients in which benefit has been demonstrated.85 Ivabradine can be considered in patients with an adequate heart rate and LVEF<35% who remain symptomatic after other treatments, in order to reduce the risk of death and hospitalization. ARBs use may be considered only as an alternative in patients who are unable to tolerate an ACEI, due to side effects like cough, skin rash and angioedema. Among ARBs, candesartan and valsartan stand out for their well-documented benefits on mortality and hospitalization.86,87 Finally, other treatments with less certain benefits include digoxin, which may be used to slow a rapid ventricular rate if other options are not available, and n-3 polyunsaturated fatty acids (n-3 PUFAs)5.

4 Ivabradine reduces the heart rate and controls cardiac rhythm by selectively blocking funny channels in the sinus node. 5 Only preparations containing 850-882 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters in an average ratio of 1:1.2.

48 2150 ESC Guidelines

mortality and morbidity have not been studied in RCTs. A Co- Loop diuretics produce a more intense and shorter diuresis chrane meta-analysis has shown that in patients with chronic HF, than thiazides, although they act synergistically and the combin- loop and thiazide diuretics appear to reduce the risk of death ation may be used to treat resistant oedema. However, adverse Statins, oral anticoagulantsand worsening, antiplatelet HF compared with thera placebo,py, and and compared renin inhibitorseffects are are more not likely and these combinations should only be indicated for managementwith an active of control,HFrEF, diuretics due to appear lack to of improve beneficial exercise effectsused5,88 with–91 care., while Theaim of diuretic therapy is to achieve and main- capacity.178,179 tain euvolaemia with the lowest achievable dose. The dose of the calcium-channel blockers (CCBs) are believed to be unsafe, except amlodipinediuretic must beand adjusted according to the individual needs over time. In selected asymptomatic euvolaemic/hypovolaemic patients, 92–94 felodipine. the use of a diuretic drug might be (temporarily) discontinued. Pa- tients can be trained to self-adjust their diuretic dose based on

Table 7.2 Evidence-based doses of disease-modifying monitoring of symptoms/signs of congestion and daily weight Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/27/2129/1748921 by guest on 16 March 2020 The most commonlydrugs used in drugs key randomized for HFrEF trials are in heart summarized failure with in the tablemeasurements. below. reduced ejection fraction (or after myocardial Doses of diuretics commonly used to treat HF are provided in

infarction) Table 7.3.Practicalguidanceonhowtousediureticsisgivenin Web Table 7.7.

Starting dose (mg) Target dose (mg) ACE-I Captoprila 6.25 t.i.d. 50 t.i.d. Enalapril 2.5 b.i.d. 10–20 b.i.d. Lisinoprilb 2.5–5.0 o.d. 20–35 o.d. Ramipril 2.5 o.d. 10 o.d. Trandolapril a 0.5 o.d. 4 o.d. Table 7.3 Doses of diuretics commonly used in Beta-blockers patients with heart failure Bisoprolol 1.25 o.d. 10 o.d. Carvedilol 3.125 b.i.d. 25 b.i.d.d Diuretics Initial dose (mg) Usual daily dose (mg) Metoprolol succinate (CR/XL) 12.5–25 o.d. 200 o.d. a Nebivololc 1.25 o.d. 10 o.d. Loop diuretics ARBs Furosemide 20–40 40–240 Candesartan 4–8 o.d. 32 o.d. Bumetanide 0.5–1.0 1–5 Valsartan 40 b.i.d. 160 b.i.d. Torasemide 5–10 10–20 b Losartanb,c 50 o.d. 150 o.d. Thiazides MRAs 2.5 2.5–10 Eplerenone 25 o.d. 50 o.d. Hydrochlorothiazide 25 12.5–100 Spironolactone 25 o.d. 50 o.d. Metolazone 2.5 2.5–10 c ARNI lndapamide 2.5 2.5–5 d Sacubitril/valsartan 49/51 b.i.d. 97/103 b.i.d. Potassium-sparing diuretics If-channel blocker +ACE-I/ -ACE-I/ +ACE-I/ -ACE-I/ ARB ARB ARB ARB Ivabradine 5 b.i.d. 7.5 b.i.d. Spironolactone/ 12.5–25 50 50 100– eplerenone 200 ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker; ¼ ¼ Amiloride 2.5 5 5–10 10–20 Figure 14- Evidence-basedARNI targetangiotensin doses receptor of neprilysin disease inhibitor;-modifying b.i.d. bis in diedrugs (twice daily);in key randomized trials in a ¼ ¼ HFrEF. Indicates an ACEMRA-I wheremineralocorticoid the dosing receptor target antagonist; is o.d.derivedomne from in die (once post daily);-myocardial infarction trials. ¼ ¼ Triamterene 25 50 100 200 b t.i.d. ter in die (three times a day). Indicates drugs where a higher¼ dose has been shown to reduce morbidity/ mortality compared with aIndicates an ACE-I where the dosing target is derived from post-myocardial a lower dose of the sameinfarction drug, trials. but there is no substantive randomized, placebo-controlledACE-I angiontensin-converting trial and enzyme inhibitor, ARB angiotensin receptor c ¼ ¼ the optimum dose is uncertain.bIndicates drugs Indicates where a higher a dosetreatment has been shown not to shown reduce morbidity/ to reduce cardiovascularblocker. or all- cause mortality in patientsmortality with compared heart with failure a lower (or dose ofshown the same to drug, be but non there- isinferior no substantive to a treatmentaOralor that intravenous; does). dose might need to be adjusted according to volume status/ dA maximum dose of 50 randomized,mg twice placebo-controlled daily can be trial administered and the optimum dose to ispatients uncertain. weighing overweight; 85 excessivekg. 5 doses may cause renal impairment and ototoxicity. cIndicates a treatment not shown to reduce cardiovascular or all-cause mortality in bDo not use thiazides if estimated glomerular filtration rate ,30 mL/min/1.73 m2 , patients with heart failure (or shown to be non-inferior to a treatment that does). except when prescribed synergistically with loop diuretics. dA maximum dose of 50 mg twice daily can be administered to patients weighing clndapamide is a non-thiazide sulfonamide. over 85 kg. dA mineralocorticoid antagonist (MRA) i.e. spironolactone/eplerenone is always 3.2. Device therapy preferred. Amiloride and triamterene should not be combined with an MRA.

Many patients with advanced HF remain symptomatic despite medical therapy, and above all, are at high risk of lethal arrythmias. Device therapy plays an important

49 role in the management of these patients by improving morbidity and survival and preventing SCD by acutely treating ventricular tachycardia (VT) or fibrillation. The first device for cardiac resynchronization therapy was approved in 2001 by the U.S. FDA, clearing the way for a new era of HF implantable device therapy. Since that time, several other devices have been approved. The applications of device therapy range from acute hemodynamic support devices, cardiac resynchronization therapy (CRT), hemodynamic support with left ventricular assist devices (LVAD) as a destination therapy, or as a bridge to cardiac transplantation.95,96

3.2.1. Cardiac resynchronization therapy (CRT)

The target of CRT is the correction of ventricular dyssynchrony, described as ventricular delays that produce suboptimal ventricular filling, reduction in LV contractility, prolonged duration of mitral regurgitation, and paradoxical septal wall motion97,98. This is manifested by prolonged QRS duration on ECG. “With placement of a pacing lead via the coronary sinus to the lateral wall of the ventricle, left or right, cardiac resynchronization therapy enables a more synchronous ventricular contraction by aligning the timing of activation of the opposing walls.”2 In this way, CRT improves cardiac function and therefore HF symptoms, also reducing morbidity and mortality.99,100 As suggested by the 2016 ESC HF guidelines with class I recommendation5, CRT should be used in symptomatic patients (NYHA class III or IV) in sinus rhythm, with a QRS duration ≥130 msec, with LVEF ≤35% despite a sufficient trial of optimal pharmacological treatment6.101–103 This benefit is greatest in patients with left bundle branch block and QRS width ≥150 ms.104,105 However, the debate about whether QRS duration or QRS morphology is the main predictor of a beneficial response to CRT is still open. In such settings, CRT has become the standard of care. In addition to improving quality of life, CRT improves survival and rates of hospitalization 101,102,106–108 by slowing down progression of heart failure and possibly by reducing ventricular arrhythmia from reverse ventricular remodeling109. The large majority of studies have focused on LVEF ≤35%, although RAFT107 and MADIT-CRT108,110 enrolled

6 Optimal pharmacological therapy should have included an ACEI/ARB, a beta blocker, and an aldosterone antagonist for at least 3 months.

50 patients with LVEF <30%, while REVERSE106,111,112 specified LVEF <40% and BLOCK-HF113 LVEF <50%. CRT may also be considered in selected patients with NYHA I and II, and regardless of NYHA class, rather than RV pacing, when they have an indication for ventricular pacing and high degree AV block, including patients with AF, in order to decrease morbidity. On the contrary, CRT should be avoided when QRS duration is <130 ms, as suggested by the Echo-CRT114,115 trial and the IPD100 meta-analysis. However, not all patients may react positively to CRT. In particular, patients with ischemic etiology will have less improvement in LV function due to the presence of myocardial scar tissue, which is less likely to undergo favorable remodeling. 116 Pacing thresholds are higher in scarred myocardium and, if possible, lead placement should avoid such regions.117,118 Moreover, women usually respond better than men, which can be explained by the smaller dimensions of body and heart.119–121 For eligible patients with HFrEF and ventricular dyssynchrony, implantation of CRT with an ICD (CRT-ICD) should be considered, given that it has been demonstrated to reduce morbidity and mortality. CRT-ICD (CRT-D) should be considered for patients in sinus rhythm scheduled to receive an ICD with a QRS duration ≥130 ms, and it is strongly recommended with a QRS >150 ms. If the aim of CRT implantation is relief of symptoms, the choice between CRT-P (with a pacemaker) and CRT-D ( with a defibrillator) should be based on the experience of the clinician, since to date there are no studies demonstrating a difference in morbidity or mortality.116 Otherwise, in order to improve prognosis, CRT-D should be the therapy of choice in patients in NYHA II, and CRT-P for patients in NYHA III-IV.

3.2.2. Implantable cardioverter defibrillator (ICD)

Sudden cardiac death (SCD) is the leading cause of mortality in patients with HF and LV dysfunction, especially in those with milder symptoms, occurring at a rate 6- 9 times that seen in the general population. Many of these deaths can be accounted for by electrical disturbances, and almost half (40%)96 to ventricular arrythmias, most commonly a VT degenerating into VF.2 ICDs are effective in continuously monitoring heartbeat, detecting and stopping abnormal rhythms, and therefore preventing bradycardia and potentially lethal ventricular arrhythmias in HFrEF

51 patients, thus reducing the risk of SCD and all-cause mortality122–125. The 2016 ESC HF guidelines strongly recommend, with class I indications, the prophylactic implantation of ICDs in patients with symptomatic HF (NYHA class II or III), an LVEF ≤35% despite 3 months of optimal medical therapy5, and with an expectation of survival longer than one year with a good functional status and IHD or dilated cardiomyopathy. The most robust evidence supporting the prophylactic use of an ICD has been provided by the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), published in 2005122. Implantation of an ICD is also recommended as secondary prevention for patients who have recovered from sudden cardiac arrest or a ventricular arrythmia causing hemodynamic instability. Multiple trials have demonstrated the superiority of ICD over antiarrhythmics.126–134 In patients in NYHA class IV with severe symptoms that are refractory to pharmacological therapy, ICD should be avoided due to limited life expectancy, unless the patient is a candidate for CRT, LVAD, or transplantation.

3.2.3. Left ventricular assist device (LVAD)

Left ventricular assist device (LVAD) is a mechanical circulatory support (MCS) used to assist failing heart function that pumps blood from the LV to the ascending aorta. It was initially conceived as a temporary bridge to cardiac transplantation, but thanks to advancements in medical technology, it has gradually become a reasonable treatment option for patients with end-stage HF, most of which are on inotropic support, even as a destination therapy, as well as a bridge to recovery or bridge to decision-making in selected patients. Data from the NIH-supported INTERMACS registry show that around 10% of patients receive an LVAD as destination therapy.135 However, selection of candidates to LVAD must be accurate and based on strict prognostic parameters that have been shown to predict outcomes, which include physical examination findings, laboratory test, neurohormonal activity, and functional and hemodynamic variables.136,137 Patients with severe renal, pulmonary or hepatic dysfunction, active infections, or cardiogenic shock, should be excluded.138 First generation VADs had a pulsatile flow in order to mimic the normal function of the heart, while most newer devices currently in use, such as the HVAD or the

52 HeartMate II, have continuous flow patterns and are capable of generating up to 10 liters/minute.139 Regarding the choice of whether to implant a continuous or a pulsatile flow device, recent trials suggest that continuous one may be superior in terms of survival rates, adverse events, hospitalization rates, quality of life, and functional capacity.140,141 New devices that are more physiologic, smaller, and easier to implant and manage are currently being developed and evaluated in clinical trials.142,143

3.3. Surgical strategies

Despite the variety of medical and device therapies available, 30-40% of patients still remain symptomatic ,cannot undergo such procedures, or are at high risk of complications due to clinical condition. In particular, patients with ischemic etiology tend to have lower rates of response than those without an ischemic etiology. In selected patients, faced with a poor quality of life and prognosis, surgical intervention may be a treatment option. Surgical strategies offer options that are effective in treating ischemia, such as coronary artery bypass grafting (CABG), which relieves valvular dysfunction, and mitral valve repair (MVR), which counteracts ventricular remodeling, as does surgical ventricular restoration (SVR). When all the other options have failed, cardiac transplantation remains the best option available.

3.3.1. Cardiac transplantation

Between January 2010 and July 2018, 32% of heart transplantations globally were performed to treat ischemic cardiomyopathy.144 Without doubt, cardiac transplantation markedly reduces cardiac filling pressures and augments cardiac output. Despite the absence of controlled trials, it is widely known that cardiac transplantation increases survival and exercise capacity, and improves the quality of life compared with other available treatments. Moreover, post-transplant survival has improved over time, reaching 12.5 years overall and 14.8 years among 1-year survivors; over 70% of recipients are able to perform normal daily activities with minimal to no symptoms.144

53 While these considerations should render heart transplantation the gold standard for HF treatment, it has two main limitations. The first is the shortage of donors. Although continuous advancements in the field of transplantation led to the loosening of criteria for donor hearts, and the increase in donor availability due to rising number of deaths, the demand continues to outpace the supply. The second limit is represented by the long-term consequences of life-long immunosuppressive therapy to which the transplanted is subject, which include antibody-mediated rejection, infection, hypertension, renal failure, malignancy, and coronary artery vasculopathy. The 2016 ESC Guidelines for diagnosis and treatment of HF recommend that heart transplantation be reserved to end-stage HF patients with severe symptoms, poor prognosis, and no remaining alternative treatment options. Moreover, the patient should be motivated, well informed, and emotionally stable, and be capable of complying with the intensive postoperative treatment regimen. Contraindications include active infection, severe peripheral arterial or cerebrovascular disease, cancer, serious comorbidities and organ dysfunction, alcohol and drug abuse, and BMI >35 kg/m2.145,146

3.3.2. Coronary artery bypass grafting (CABG)

Coronary artery bypass grafting (CABG) is the most common surgical procedure. Although the technique has been refined several times throughout the years147, its aim remains the same: restore normal blood flow in the coronary artery or arteries by bypassing all epicardial vessels with a diameter exceeding ³1.5 mm and a luminal reduction of >50% in at least one angiographic view148with an arterial or vein graft, usually the internal mammary artery (IMA), radial artery, or saphenous vein. The available evidence suggests that the left IMA is the best choice, especially to the left anterior descending artery (LAD), followed by the radial artery for non-LAD targets149, in order to maximize patency of the graft.150–152

As recommended with class I indications in the 2018 ESC/EACTS Guidelines on myocardial revascularization153, this procedure should be considered in patients with chronic HF with severe LV systolic dysfunction and coronary artery disease who are suitable for intervention154,155, and it should be the first choice of

54 revascularization in patients with multivessel disease and acceptable surgical risk.155–158

The Surgical Treatment of Ischemic Heart Failure (STICH)159 trial and its Extension Study (STICHES)155 is the only randomized clinical trial evaluating the outcomes of revascularization in patients with ischemic cardiomyopathy and LV dysfunction (LVEF ≤35%)160. This study demonstrated no significant initial benefit from CABG compared to medical therapy alone, but CABG combined with medical therapy was superior in improving survival over a 10-year observation period, with lower rates of death from cardiovascular causes, and death from any cause, or hospitalization for cardiovascular causes. Therefore, CABG is strongly recommended in clinical practice in the cases stated above.

However, to perform this surgery the presence of jeopardized but still viable myocardium is crucial, the so-called hibernating or stunned myocardium, defined as abnormal myocardial tissue with preserved cellular function that can recover after revascularization. In the viability substudy of the STICH trial161, the presence of viable myocardium was associated with a greater likelihood of survival by univariate analysis, but not multivariable analysis. Therefore, myocardial viability should be assessed7 before taking a decision on revascularization, but it should not be the only parameter used to define the most suitable therapy. In fact, clinical status, coronary anatomy, expected completeness of revascularization, coexisting valvular disease, and comorbidities should all be accurately assessed.153

3.3.3. Mitral valve repair or replacement (MVR)

Patients with HF and concomitant valvular heart disease represents a high-risk population, because valvular dysfunction may aggravate HF. Among all valvular diseases, secondary mitral regurgitation (MR) in its varying degrees is the most common in patients with ischemic HFrEF and dilated ventricles, because LV

7 “Non-invasive stress imaging (cardiac MR, stress echochardiography, SPECT or PET) may be considered for the assessment of myocardial ischemia and viability in patients with HF and CAD (considered suitable for coronary revascularization) before the decision on revascularization.”153,161–163

55 enlargement and remodeling lead to annular dilatation and abnormal wall motion and geometry, therefore preventing leaflet tethering and displacement.

Medical therapy that aims to reverse the LV remodeling process may be helpful, but in symptomatic patients combined valve and coronary surgery should be considered. Recent studies did not demonstrate that the addition of MVR to CABG can help reverse remodeling in patients with severe ischemic MR,164, and did not find that valve replacement was superior to repair in terms of outcomes.165 “In the absence of dedicated trials in this setting, the decision to combine mitral valve (MV) surgery with CABG in patients with an effective regurgitant orifice area (EROA) >0.2 cm2 and regurgitant volume >30 mL needs to be made on a case-by-case basis by the Heart Team.“153

In patients who are not candidates for surgical coronary revascularization, mitral valve repair remains questionable, and medical and device therapy are usually preferred. If inoperable or at high surgical risk, percutaneous MV intervention may be considered to relieve symptoms, but there is no evidence that improvement is obtained.166–168

Finally, it should be pointed that, despite the common definition of ischemic MR as functional MR, without organic lesions of the valve, pathologic studies have shown that in these patients the mitral leaflets are thinned out, with altered collagen composition compared with normal autopsy control. Therefore, it could be hypothesized that MR in HF patients might not be purely functional, arising implications for alternative therapeutical options.169

3.3.4. Surgical Ventricular Reconstruction (SVR)

Surgical ventricular reconstruction (SVR) is a technique that aims to surgically reshape the LV in patients with ischemic based HFrEF in order to restore physiological volume and physiological shape through scar resection and wall reconstruction. It may be considered in selected patients treated in centers with expertise. 153

For the purpose of this dissertation, SVR will be analyzed in further depth in Chapter four, since it is relative to the present real-world analysis.

56 4. Surgical Ventricular Reconstruction (SVR)

CABG and MVR lead to clinical improvement in most patients. However, in some LV dilation and dysfunction are so critical that direct ventricular surgery may be proposed to optimize cardiac function. As will be seen further on, the main goal of surgical ventricular reconstruction (SVR) is to exclude the infarcted portion of the myocardium, in order to restore physiological ventricular shape and size, as well as to reduce wall stress and end-systolic volume. Concomitant CABG may be needed, and if severe MR is present, this should be corrected separately.

4.1. Rationale to perform SVR

As outlined in chapter 2.4.1., LV remodeling is one of the main culprits that contribute to the progression of HF, due to the mechanical burden produced by changes in LV geometry and architecture and in the components of the myocardium. LV dilation, increased sphericity index, wall thinning, altered myocytes, are just a few of the changes that occur in the LV of a patient with HFrEF (see chapter 2.4.1.), and ultimately lead to a decline in global ventricular function. SVR aims to counteract and reverse LV remodeling process, by reducing the LV to a more physiological volume through exclusion of the scar tissue, and optimizing the shape of the distorted chamber, thereby improving both cardiac function and clinical outcomes of patients with HFrEF. The aim of surgery is also to decrease myocardial systolic and diastolic wall stress. The ventricle follows the principle of Laplace’s law8, meaning that wall stress is directly proportional to the LV internal pressure and radius, and inversely proportional to twice the wall thickness. Accordingly, optimizing this ratio means improving wall compliance and reducing the filling pressure. Moreover, since wall stress is an important determinant of afterload, it may also enhance LV contractile performance by increasing the extent and velocity of systolic fiber shortening.43,169,170

8 P= (2⋅H⋅T)/r Laplace’s law states that under equilibrium conditions, the pressure (P) within a vessel containing a fluid is directly proportional to the wall stress (H) and the wall thickness (T) and inversely proportional to the radius (r) of the vessel. This principle of physics is applied in medicine in the physiology of blood flow, in this case to ventricle, comparable to a vessel containing fluid.

57

Furthermore, SVR may be combined with CABG to simultaneously treat the underlying coronary disease, and, also with MVR if needed, even though the indications for MR correction are still debated. MV competence may be improved also by SVR itself, thanks to the reduction of LV volumes and papillary muscle distance.171–173

Figure 15 Anterior left ventricular remodeling following a previous anterior myocardial infarction in echocardiographic apical 4-chamber (A) and 3-chamber views (B) showing extensive involvement of the anterior septum, the posterior septum and the apex.42

4.2. Indications

The patient undergoing SVR should be selected after accurate clinical evaluation carried out by surgeons, cardiologists, and radiologists, in which HF symptoms should be assessed, combined with an imaging and laboratory workup, in order to get scrupulous measurements of the LV geometric and hemodynamic parameters, a complete evaluation of the MV apparatus, assessment of scar tissue extension and of the viability of regions distant from the scar. Moreover, SVR should be performed only in centers with a high level of expertise.153

In particular, the echocardiographic evaluation (M-mode and TTE) is crucial in the diagnostic workup of the patient who is a candidate for SVR, since it allows obtaining accurate information about wall thickness, systolic and diastolic chamber size and volumes, motion abnormalities, dilation, and global cardiac function5. Moreover, TTE is useful to assess the MV apparatus in terms of geometry (leaflet tethering,

58 annulus dilation, tenting area and height, interpapillary muscle distance) and severity. If combined with color- and tissue Doppler (TDI), it provides also information about transmitral flow velocity and TDI measurements. Deformation imaging using 2-D speckle-tracking echocardiography (STE) has proven to be an effective method for quantifying myocardial function174, improving prognostic risk stratification thanks to assessment of myocardial strain, a parameter that is not derived from volume, and as such does not suffer from multicollinearity, unlike EF. Recently, 3-D STE has been implemented to measure 3-D strain, gaining the potential to become the gold standard to assess LV systolic parameters. However, the feasibility of a reliable echocardiography may be impaired by major limitations, such as a poor acoustic window, inadequate endocardial border definition or visualization of the apex, and patient non-cooperation for breath holding. Exercise echocardiography can be helpful to unmask higher degrees of MR.

Figure 16 Three-dimensional echocardiographic speckle-tracking analysis (TomTec Imaging Systems GmbH, Unterschleissheim, Germany) in a patient with previous anterior myocardial infarction, extensive remodeling (A) and a markedly impaired longitudinal deformation (B). Global 3-dimensional longitudinal strain measured by 3-dimensional speckle-tracking is -7% (lower limit of normality is -15%). 42

Cardiac MRI (CMR) is nowadays the gold standard imaging technique to assess myocardial anatomy, LV, RV, and global structure and status.175,176 In particular, it allows quantification of the function of ventricles of any size and shape, detect the transmural extent of the myocardial scar with LGE9, and “assess the thickness and function of the rest of the myocardium, which may be hibernating (ischemic but viable, likely for functional recovery after CABG) or non-ischemic but dysfunctional

9 LGE imaging visualizes irreversible damage due an accumulation of contrast agent in areas with increased extracellular space. Viable myocardium appears dark, whereas necrotic or fibrotic tissue appears bright.

59 due to the high wall stress and likely for functional improvement after volume reduction obtained through SVR177,178”. Moreover, cardiac MRI is also useful in estimating the degree of LV functional recovery after SVR, based on the detection of the scar by LGE. If myocardial fibrosis is detected in the non-enhanced regions, especially at the level of the basal segments,179 in the proximal anterior LV, an unsatisfactory response to SVR may be expected, meaning a higher postoperative LV end-systolic volume index and a poor prognosis. Instead, LGE extension is apparently not associated with the outcome.180

“The indications for SVR may be summarized as follows178:

• Previous anterior or posterior MI, as evaluated by ECG or cardiac MRI; MRI should be preferred, when available and not contraindicated;

2 • LVESVI >60 ml/m : Pre-operative LVESVI should be carefully evaluated to avoid selection of patients with small ventricles for which the likelihood for diastolic function worsening is high; 181 • Regional LV asynergy, either dyskinetic or akinetic: in the presence of severe and diffuse LV asynergy, the procedure should be performed only if regions remote from the scar show detectable contraction, as indicated by CMR when feasible; • Predominant HF symptoms [NYHA functional class III/IV] or in the presence of ventricular arrhythmias and/or angina needing surgical revascularization if the previous conditions are present.

Suggested absolute contraindications:

• Severe right ventricle dysfunction (biventricular dilated cardiomyopathy); in our experience, right ventricular dysfunction, as reflected by an impaired TAPSE, correlates with LV dysfunction and is an important predictor of long- term outcomes in HF patients undergoing SVR 182; • Restrictive diastolic pattern associated with high functional class and MR; it has been shown that diastolic dysfunction (E/A ratio >2) increases the operative risk of mortality when associated with MR and NYHA class >II 173“

60 Patients with pacemakers or devices for CRT and the poor quality of images in patients with significant arrhythmia or severe shortness of breath should be excluded.

4.3. History

The procedure was originally introduced by the French cardiac surgeon Vincent Dor in 1985, based on prior contributions 177,183–185 by Cooley, who described the linear suture in 1958, and Keith and Jatène, who defined the circular external suture in 1984. The Dor procedure is performed under total cardiac arrest and has the aim to exclude the akinetic or dyskinetic portion and to restore the shape of the ventricle, with a suture passed through the transitional zone, using a circular Dacron patch fixed at the junction between scarred tissue and endocardial muscle to reconstruct the LV cavity.186 The procedure is also known as Endoventricular Circular Patch Plasty (EVCPP). In 1998, Dor refined the technique by adding a volume-measuring device into the ventricle before suturing, in order to standardize both the procedure and the size of the new cavity. From that moment, the Dor procedure has been performed and tailored by many surgeons, making the standardization process increasingly difficult. For example, McCarthy uses a double purse-string suture without patch technique, Mickleborough suggested a tailored scar excision with septoplasty if indicated, followed by a linear closure.169 The technique performed by Menicanti in the present study is summarized in the next chapter.

4.4. Technique42,43,169,178

SVR is performed under total cardiac arrest with antegrade cold crystalloid cardioplegia.173

First, if required, total myocardial revascularization is carried out, with a special focus on revascularizing the proximal LAD artery to protect the upper septum. The best graft to the LAD artery, in order to maximize patency, is the left IMA. If other

61 coronary arteries are involved, sequential saphenous vein CABG may complete the revascularization.

After the CABG procedure, the ventricle is opened with an incision, parallel to the LAD, from the middle-scarred region to the apex, and the cavity is checked for the presence of thrombi, which, in present, are removed. Next, when the transitional zone between scarred and non-scarred tissue is defined with the help of cardiac MRI with LGE, or echocardiography, a conical pre-shaped mannequin (TRISVRTM, Chase Medical Richardson, TX) size-selected according with the BSA (body surface area) and the dilation degree, is introduced into the ventricle and expanded with 50 mL/m2 saline (Figure 17, upper panel on the left).

The mannequin helps the surgeon to optimize the size and shape, identifying the correct position of the apex and keeping the long axis of the ventricle in a physiologic range (7.5/8.5 cm), therefore reducing the risk of sphericalization of the new ventricle, associated with a worsening of diastolic function and MR at follow-up. Since its introduction in 2001, it has also helped in standardizing the procedure.

Following this, the dyskinetic or akinetic LV free wall is excluded with an endoventricular circular suture passed in the transitional zone, oriented obliquely towards the aortic flow tract by the cone-shape of the mannequin (Figure 17, upper panel on the right). In this way, the new apex is reconstructed. This step may be complicated if the apical and inferior regions are heavily damaged; in that case, a short plication of the distal inferior wall is performed before patch suturing to avoid the amputation of the apex. The result should be an elliptical new ventricle. If the dilation begins near the aortic valve, a running suture is made from the inner of the ventricle over the mannequin towards the apex.

Finally, the mannequin is deflated and removed, and the opening is closed with a direct suture (simple stiches) if <3 cm large, and a second stratum with excluded tissue is sutured over the first one to avoid bleeding.

Otherwise, if >3 cm, an elliptical, synthetic patch (usually a Dacron patch) is used to avoid deformity of the chamber, paying attention to leave a few mm of border when sewing the patch in an everting way, in order to guarantee good hemostasis

62 and allow the possibility for additional stiches, if needed. The oblique orientation of the patch, toward the aortic outflow tract, is fundamental in giving shape to the new ventricle and in avoiding the box-like shape (Figure 17, lower panel).

In the last years, the increased use of percutaneous coronary intervention (PCI) in AMI has changed the pattern of LV remodeling: the classical dyskinetic aneurysm with a clear transition zone almost disappeared, giving way to large akinetic regions. In this case, the use of the shaper is fundamental in guiding the chamber reconstruction, and avoiding the patch, using running suture over the mannequin instead, allows achieving better results.

Figure 17 SVR procedure for anterior remodeling. Upper panel: the mannequin is inside the ventricle (on the left); the circular suture follows the curvature of the mannequin to re-shape the ventricle in an elliptical way (on the right). Lower panel: The patch is used to close the ventricular opening.43

63

Figure 18 Left ventricle before (A) and after (B) surgical remodeling in echocardiographic apical 4- chamber view.42

4.5. Particular conditions 4.5.1. Mitral valve (MV)

Chronic ischemic MR can be seen as a consequence of LV adverse remodeling (see chapter 3.3.3.) in 50% of patients with post-infarct congestive HF, 20–25% after anterior MI, and 50– 60% in case of inferior MI, and 50– 60% in case of inferior MI187, due to the displacement of the papillary muscles, leaflet tethering, and annular dilation. MR negatively impacts survival rates after myocardial revascularization188,189, as well as the natural history of the patients with HFrEF41. Moreover, pre-operative severe MR is an independent predictor of late mortality in patients with previous anterior MI, because it usually occurs in the setting of a global LV dilation, reflecting a more advanced stage of disease with respect to those who had an inferior MI.190

Despite the evidence of the adverse impact chronic ischemic MR has on HF, its management strategy has not been clearly defined, and it is still one of the most controversial topics debated among cardiologists and surgeons191. To date, the data are contradictory. Some support the importance of performing MVR, justified by its negative effect on long-term outcome192,193; others prefer CABG alone194, claiming the absence of a survival benefit from combining MVR with CABG in patients with CABG in patients with MR195. Several studies have demonstrated the benefits of CABG alone on MR in the short term196,197, whereas others show that MR is not only

64 not reversed198, but it may also progress further199. Results from STICH Hypothesis 1 patients with moderate or severe MR showed that adding MVR to CABG may improve long-term survival compared with CABG alone200, which was confirmed later by Samad et al. in patients with moderate or severe MR and severe LV dysfunction.201

Furthermore, a study by Castelvecchio and co-workers between January 2001 and October 2014, demonstrated the favorable effect of MVR on survival. Among all the 175 patients undergoing SVR combined with MVR, added to CABG when indicated, “all but one patient had an MR grade equal or<2; only one patient had moderate MR (3+). At a median follow-up of 36 months, most patients were in NYHA class I/II (75%); none were in NYHA class IV. The actuarial survival rate of the entire patient population, including operative mortality (14,3%) at 3, 5, and 8 years following surgery was 72 ±4%, 65 ±4% and 45 ± 6%, respectively.”202 Therefore, adding MVR to SVR and CABG may further improve the survival rate at 5 years, which reached 65% in that study, thanks to the role of SVR in improving the LV adverse remodeling.

When indicated, SVR allows the surgeon to repair the MV using the ventricular opening with a double arm suture from one trigone to the other, incorporating the two arms in the posterior annulus of the MV (Figure 17). The suture is then reinforced with a Teflon strip to avoid tears of the posterior leaflet and tied to undersize the orifice. In order to size the mitral annulus, a Hegar sizer no. 26 may be used, or, alternatively, if the LV opening is not large enough, a restrictive mitral annuloplasty with a ring implantation may be performed in selected patients. “In presence of extensive anterior LV remodeling, with an internal diameter>65mm, valve replacement is preferred to reduce the rate of recurrence of MR.” 42

65

Figure 19 MVR. Mitral valve is repaired through the ventricular opening with a double arm stitch running from one trigone to the other 43

Figure 20 Ischemic mitral regurgitation. Apical 4-chamber view showing ischemic mitral regurgitation. The left ventricular internal diameter is increased, and the shape is spherical due to the presence of mitral regurgitation.42

However, data from a study recently conducted in our center observed a recurrence of moderate or severe MR (grade 3 or 4+) of 29% after 6 months follow-up in a subgroup of patients with previous anterior MI undergoing CABG plus SVR combined with MVR, performed according to the above-mentioned technique. The most sensitive and specific geometric factor involved in recurrence is shortening of

66 the postoperative long axis (<7.5), which is strongly associated with an increase in the sphericity index. Therefore, surgeons must be careful to preserve the length of the ventricle.

“Anyway, it should be pointed out that chronic ischemic MR is a complex and dynamic disease, involving coronary arteries, mitral annulus, subvalvular apparatus, and ventricle, in which the large number of geometric and hemodynamic variables carries the risk of a sub-optimal result at follow- up.”169

4.5.2. Anterior versus Postero-inferior Remodeling

The surgical technique explained in chapter 4.4 is generally used to reverse LV remodeling after anterior MI. However, the procedure may be adjusted to different patterns of LV remodeling also affecting the posterior or postero-inferior region of the myocardium, from the global LV dilation with infero-posterior wall involvement (Fig.22), to the more common posterior aneurysm with a bulging of the inferior wall (Fig.21).

In the case of a posterior aneurysm, the use of a patch to close the neck of the aneurysm is usually required. However, treatment of global dilatation of the infero- posterior wall is more complex and changes depending on the location of scarring and the dilatation (with or without involvement of the posterior septum) in relation to the papillary muscles.

After an inferior MI, the dilation may localize either mainly between the two papillary muscles or between the posteromedial papillary muscle and the septum. The SVR applied to postero-inferior remodeling allows two possible strategies. One option is to open the scarred wall at the level of the scar or at the level of the collapsed area, parallel to the posterior descending artery, and then use a continuous 2/0 Prolene suture to obtain the re-approximation of the two papillary muscles and exclusion of the entire damaged zone. The stiches should start at the beginning of the dilatation (sometimes just at the level of the mitral annulus) and continue to the apex. The other option is opening the wall and bringing the continuous suture behind the posteromedial papillary muscle, moving the posterior wall against the septum.

67

Figure 21 SVR procedure for posterior remodeling (schematic). The picture shows the two different techniques, from top to bottom on the left (which is applied when the dilatation occurs mainly between the two papillary muscles) and from top to bottom on the right (which is applied when the dilatation occurs between the posteromedial papillary muscle and the septum)43

Figure 22 Posterior remodeling. The classic posterior aneurysm with a bulging of the inferior wall and a well- defined neck43

68

Figure 23 Posterior remodeling. Global LV dilatation (left) with scar tissue at the inferior and posterior region (right)43

Surgical postero-inferior reconstruction is performed less commonly, probably due to the lower incidence10 of MI affecting this area, and because it is technically more demanding. Therefore, the reported rates of mortality are higher compared to anterior remodeling, even if the data are somewhat limited. “Tavakoli and coworkers207, found the posterior location to be an independent predictor of early and late adverse outcomes at multivariate analysis, while Bechtel and colleagues208 reported significantly higher 30-day mortality in posterior reconstruction, mainly because of perioperative low cardiac output syndrome. Mickleborough and coworkers209, in their 20-year single-center experience, found comparable early mortality results between anterior and posterior remodeling, whereas 5-year survival was significantly better in posterior SVR.”190 Recently, Castelvecchio and co-workers compared early and long-term outcomes in a consecutive population of 501 patients undergoing SVR for anterior and posterior remodeling. The study has shown no difference between anterior and posterior remodeling in terms of outcomes.190 This may be explained by the preserved wall thickness, and hence systolic function, of the remote myocardium in the posterior group, which is an important prognostic determinant.210

4.6. Drawbacks

Despite the use of a mannequin, residual LV volume after SVR may not achieve the desired result, since it also depends on the preoperative shape, location and size of

10 Previous studies reported an incidence of posterior dilatation between 4% and 13% in patients with previous MI203–206

69 papillary muscles, presence of trabeculae, and LV compliance, in addition to the preoperative volume. The actual anatomy of the chamber and extension of damage may not be completely clear before opening the cavity, especially if the anterior septum is deeply involved. In this case, noninvasive imaging is mandatory to evaluate the feasibility of the procedure and adapt the surgery to the specific patient.

Moreover, careful echo Doppler evaluation is fundamental to avoid recruiting patients with a preoperative LV volume that is too small, which will result in an insufficient postoperative residual volume. It has also been recently reported181 that the likelihood for diastolic function worsening after SVR is higher when the LV cavity is globally dilated (i.e., akinetic aneurysm) or too small. Furthermore, in the same study, it was reported that “diastolic dysfunction (early-to-late diastolic filling pressure >2) increases intraoperative mortality when associated with MR and NYHA class >II, reinforcing the need for a more comprehensive and accurate preoperative evaluation of diastolic function, if possible.”169

70 5. Previous studies

5.1. Dor and co-authors

The French cardiac surgeon who first performed this surgery procedure back in 1985, Vincent Dor, was also the first to report significant results on SVR prior to 2000. In his reports, he showed that in large ischemic akinetic ventricles the procedure leads to improvement in LV systolic and diastolic function, wall tension, NYHA functional class, and survival by reshaping the chamber and restoring physiological volumes.170,177,211

The long-term results from 1984 to 2000, based on 950 patients with congestive heart failure undergoing SVR, revealed a 10-year life expectancy near 60% for those with an ESVI over 90 ml and an EF below 30%, and reaching 80% in those with a preoperative EF above 30%.211

Moreover, the increase in EF did not only affect patients with classic large dyskinetic aneurysm (EF from 26 ± 7% to 46 ± 11%), but also those with dilated akinetic ischemic cardiomyopathy and severely depressed preoperative pump function (EF from 25 ± 9% to 41 ± 12%), thereby reducing wall tension and oxygen demand, since the surgical outcome relates to the extent of LV asynergy rather than the type of aneurysm.212

After that, a large number of reports mainly based on observational and non- randomized studies173,213–215, including one conducted at our center173 (see chapter 5.3.), confirmed that SVR is relatively safe and effective in reducing LV volume and improving LV function, mechanical synchrony214 and the patients’ clinical status, with favorable 5-year outcomes213 and an acceptable operative mortality.

5.2. The Restore Group

The RESTORE Group (The Reconstructive Endoventricular Surgery returning Torsion Original Radius Elliptical shape to the left ventricle) enlisted cardiologists and surgeons from 12 centers on four continents to establish the first international SVR registry and assess the effects of SVR on early and late survival with 5-years of follow-up. Between 1998 and 2003, SVR was performed in 1198 patients with a

71 previous MI, LV dilation (LVESVI ≥60 ml/m2), and a regional asynergic LV circumference ≥35%. “Global systolic function significantly improved postoperatively: EF increased from 29.6 ± 11.0% preoperatively to 39.5 ± 12.3% postoperatively (P < 0.001) and the LVESVI decreased from 80.4 ± 51.4 ml/m2 preoperatively to 56.6 ± 34.3 ml/m2 postoperatively (P < 0.001). Thirty-day mortality after SVR was 5.3%, and it was higher among patients undergoing concomitant MVR (8.7%) versus patients in whom no mitral valve procedure was required (4.0%, P < 0.001). Overall, 5-year survival was 68.6 ± 2.8%, with no difference in the survival curves between patients who underwent MVR and those who did not (68.7 ± 3.9% vs. 70.8 ± 3.3%), and 5-year freedom from hospital readmission for CHF was 78%. Preoperatively, 67% of patients were NYHA functional class III or IV and postoperatively, 85% were class I or II.”213 Therefore, the study concluded that SVR improves ventricular function and as such, it is a highly effective therapy for treatment of ischemic cardiomyopathy with excellent 5-year outcomes.

The study identified also risk factors for death at any time after surgery, which included preoperative EF ≤30%, LVESVI ≥80 ml/m2, advanced NYHA functional class, and age ≥75 years. “Patients with EF ≥30% had survival 76.7 ± 3.2% as compared with 63.8 ± 3.9% for those with EF ≤30%, patients with EF >40% had survival 83.0 ± 4.0% as compared with 67.4 ± 3.0% for those with EF ≤40% (p < 0.001) and patients with LVESVI <80 ml/m2had survival 79.4 ± 3.3% as compared with 67.2 ± 3.2% for those with hearts >120 ml/m2 (p<0.001).”213

The results of the RESTORE groups served as a benchmark for design of the more complex STICH trial, which will be mentioned later.

5.3. Menicanti, Castelvecchio et al.

In 2007, Menicanti, Castelvecchio, and colleagues published the largest single center experience with SVR173based on 1161 patients who underwent SVR at our center, with or without concomitant CABG or MVR, between 1989 and 2005. The aim of this observational, non-randomized study was to assess operative and long- term mortality, outline the effects of SVR on EF, LV volumes, MR degree, and NYHA class, and to define predictors of operative mortality.

72 Thirty-day cardiac mortality was 4.7%. MR ≥2, associated with NYHA class >II and, for the first time, severe diastolic dysfunction (early-to-late diastolic filling pressure > 2) were recognized as predictors of operative mortality. Moreover, it was found that patients requiring MVR (18%) had a significantly higher (13% versus 3.0%, P < 0.001) operative mortality rate, in agreement with the results from RESTORE.173

Regarding the effects of SVR, it emerged that global systolic function improved postoperatively, and that the degree of MR significantly decreased: EF went from 33% ± 9% to 40% ± 10% (P < .001); LVESV decreased from 211 ± 73 to 142 ± 50 and 145 ± 64 to 88 ± 40 mL, respectively (P < 0.001) early after surgery. NYHA class improved from 2.7 ± 0.9 to 1.6 ± 0.7 (P < .001) late after surgery. Repaired moderate-to-severe MR decreased significantly (P < .001) from 3.0 1 to 0.7 ± 0.8 and to 1.5 ± 1.2 at follow-up (time from surgery 6 months to 2 years). Long-term survival in the overall population was 63% at 120 months.173

As a result, the conclusions made by the study were clear: SVR for ischemic heart failure is effective in reducing ventricular volumes, improving LV mechanical synchrony, cardiac function, and functional status in terms of EF, MR, and NYHA class. Furthermore, it carries an acceptable operative mortality, and offers promising long-term survival, even in patients with severely reduced EF.

Other contributions have been published by many centers performing SVR, but most were not randomized to compare the potential additional benefit of SVR with CABG alone. Only one single center study randomized a small number of patients (n= 74) with dyssynergic myocardium aiming to compare short-term and mid-term outcomes of CABG alone to CABG + SVR as treatment strategies for ischemic cardiomyopathy, reporting a better result for the latter216. However, the question of whether adding SVR to CABG will improve survival and clinical status was definitively answered by the STICH trial (see chapter 5.5).

5.4. The role of LVESVI: White et al., the GUSTO-I trial and Bax et al.

In 1987, White and co-workers proved LVESVI is the primary predictor of survival after an MI, showing that patients with LVESVI >60 ml/m2 had approximately a 5- fold increase in mortality compared to those with normal volumes. They recognized

73 the limitation of infarct size and prevention of ventricular dilation as the aims of MI treatment.217

Ten years later, the GUSTO-I trial emphasized the key role of ventricular volume on outcomes, confirming that an ESVI ≥ 40 ml/m2 is an independent predictor of early and late mortality after MI. The purpose of the trial was to assess the impact of LVESVI at 90 to 180 minutes into thrombolytic therapy for MI on outcomes. Mortality at one year was 16% among those with LVESVI 40 to 50 ml/m2, 21% with LVESVI 50 to 60 ml/m2, and 33% with LVESVI >60 ml/m2.213,218

It has recently been reported by Bax and co-workers that patients with extensive LV remodeling, i.e. severely dilated left ventricles, have a low likelihood of showing improvement in EF after revascularization, despite the presence of substantial myocardial viability. They showed that the change in EF after revascularization was linearly related to baseline LVESV, with a higher LVESV being associated with a low likelihood of functional recovery after revascularization. In addition, during the 3-year follow-up, patients with a large LVESV had a higher event-rate (67% in patients without viable myocardium, 38% in those with viable myocardium), and therefore worse long-term prognosis compared to patients with a smaller LVESV (24% without viable myocardium and 5% with viable myocardium.219

5.5. The STICH trial

The Surgical Treatment for Ischemic Heart Failure (STICH) trial was the first, multicenter, nonblinded, randomized controlled trial (RCT) conducted at 127 clinical sites in 26 countries220. The goal of the study was to outline the role of cardiac surgery in the treatment of patients with CAD and HF, and in particular to assess potential superiority of CABG over medical therapy alone in improving long-term survival (Hypothesis 1), and the efficacy of SVR combined with CABG in decreasing mortality and hospitalization rates for cardiac events compared to CABG alone in patients with LV systolic dysfunction (EF ≤ 35%) and CAD amenable to surgical revascularization (Hypothesis 2)220. Between 2002 and 2007, 2136 patients were enrolled in the STICH trial, 1000 of whom were allocated to Hypothesis 2.

74 Results from Hypothesis 2 showed that the addition of SVR to CABG led to significantly greater reduction in LVESVI, compared to CABG alone (reduction of 19%, 16 ml/m2, versus 6%, 5 ml/m2). However, this improvement did not translate into a measurable benefit for patients in terms of survival or improvements in symptoms; indeed, postoperative LVESVI still remained large (>60 ml/m2) in both arms. Moreover, no relevant difference was seen between the two groups in the primary outcome of death or hospitalization for cardiac causes (59% in CABG alone group versus 58% in the CABG+SVR group). 30-day mortality was similar (5% for CABG alone and 6% for CABG + SVR), and no difference in the rate of death from any cause was observed over a median follow-up of 48 months. Both CABG alone and the combined procedure were equally successful in improving postoperative CCS angina class and NYHA functional class, and showed similar improvements in the 6-minute walk test and similar reductions in symptoms. Finally, operative rates of death, intubation, and initial hospitalization times were longer in patients treated with the combined procedure.221

Therefore, based on all these findings, the trial did not support the use of SVR in the population studied. The relatively small percentage in LVESVI reduction observed in the combined group raised concerns about the extent of the SVR procedure that was used in this trial, meaning that the selected ventricles were too small or that the volume reduction was inadequate.

5.6. Di Donato, Castelvecchio and Menicanti

In order to better understand the results of STICH, Di Donato, Castelvecchio, and Menicanti further explored the impact on survival of a residual LVESVI of ≥60 or <60 mL/m2 following SVR, in a group of 216 patients with previous MI and a preoperative LVESVI ≥ 60 mL/m2. 222

Overall, after surgery, performed in some cases with concomitant CABG (91.2%) and MVR (29%), LV volumes significantly decreased, and EF improved. Patients were then divided into two subgroups based on residual LVESVI at discharge, ≥ 60 mL/m2 (Group 1) or < 60 mL/m2 (Group 2). Mean LVESVI decreased by 41%, from 109 ± 37 (median 110) to 78 ± 15 (median 76) mL/m2 in Group 1 (−31%), P = 0.001 and from 85 ± 30 (median 79) to 43 ± 10 (median 44) mL/m2 in Group 2 (−44%), P =

75 0.001.222 Despite the mean increase in LV volumes observed over time, at follow- up the reduction in LVESVI was still significant compared to baseline in both groups. At 10 months, Group 1 had a 28% reduction in LVESVI, whereas Group 2 had a 32% reduction compared to baseline.222

Survival rates were then compared between the two subgroups. Overall, long-term survival was 82% at 5 years, but patients in Group 1 had a significantly higher mortality rate, compared to Group 2 (30% vs. 18%). LVESVI >60 mL/m2 was the strongest predictor of mortality at follow-up when pre- and post-operative risk factors were added to the model. Furthermore, the analysis showed that a preoperative ESV of 94 mL/m2 is a good cut-off value for an optimal residual volume of <60 mL/m2. Preoperative ESVs of >94 mL/m2 (median 110 mL/m2 in Group 1), despite an adequate reduction in more than 30% over time, with a post-operative LVESVI of ≥60 mL/m2, carries a significantly lower survival rate.

Therefore, the study confirmed the role of LVESVI in predicting survival following MI and SVR217,218,223,224, with a risk of all-cause death being significantly higher in patients who remain with a postoperative LVESVI of ≥60 ml/m2222, and emphasize the importance of a proper LVESVI reduction in achieving good outcomes.

Finally, as a response to the STICH trial (see previous chapter), it was hypothesized that the lack of additional improvement in terms of survival in the SVR group observed in STICH might be related to inadequate volume reduction (-19%), which left patients in the two arms (CABG alone or CABG + SVR) at identical risk. Thus, it is still possible to hypothesize the existence of a definable group of patients who could benefit from SVR.

5.7. Witkowski et al.

The results of the previous research were later extended by Witkowski and colleagues in a study evaluating the independent determinants of 2-year morbidity and mortality rates after SVR.

Conducted between 2002 and 2008 on 79 patients with ischemic heart disease and EF ≤ 35%, the study reported a significant improvement in HF symptoms, NYHA

76 functional class (from 2.6 ± 0.7 to 1.9 ± 0.6; p < 0.0001) and LVESVI (from 75 mL/m2to 45 mL/m2, with a mean reduction of 41% overall), as well as an increase in EF (from 0.27 ± 0.07 to 0.36 ± 0.10; p < 0.001).225 At 6 months, patients with a midterm LVESVI < 60 mL/m2 showed a significantly superior NYHA functional class compared to patients with an LVESVI of at least 60 mL/m2 (1.8 ± 0.6 versus 2.2 ± 0.5; p = 0.013). During a median follow-up of 2.7-years, baseline NYHA functional class was an independent determinant of survival, with NYHA functional class IV associated with worse prognosis, and a residual postsurgical LVESVI of at least 60 ml/m2 was independently associated with almost 8-fold increased risk for a composite endpoint (all-cause mortality and HF rehospitalization) after SVR. The cumulative event-free survival at 2 years was 83%, but patients with a midterm LVESVI of at least 60 mL/m2 had lower event-free survival at 2 years than patients with LVESVI < 60 mL/m2 (59% versus 91%; p < 0.001).225

Therefore, Witkowski et al. confirmed that SVR is an efficient therapeutic option for patients with ischemic HF, and that a large postsurgical LVESVI and a baseline NYHA IV significantly reduce the survival benefits of the therapy.

5.8. Criticisms of the STICH trial

The STICH trial has been strongly criticized226, and several limitations have led to substantial uncertainty in making the results widely generalizable. The trial has been defined as “misleading, since SVR procedures were not uniformly or effectively performed in properly selected patients”226. The trial also enrolled a very heterogeneous group of patients, being faulty in many ways.

First, the study focused on a wide variety of ischemic patients, rather than concentrating only on those with HF, and therefore enrolled a population more representative of the real world of ischemic patients, rather than of those occurring in daily clinical practice. For example, only 49% of patients in STICH were in NYHA class III or IV versus >66% in the RESTORE registry, where patients all had well- defined characteristics.11

11 Patients from the RESTORE Group had prior history of MI, akinesia, or dyskinesia involving ≥35% of the LV, reduced EF, and LVESVI ≥60 mL/m2

77 Second, accurate viability and LV volume were not assessed in all patients (STICH measured LVESVI 43% in the CABG-only group and 33% in the CABG plus SVR group by echocardiography) as originally planned, even though inclusion criteria originally included evidence of non-viability in 35% of the anterior ventricular wall. Surgeons cannot say if a patient is eligible for SVR without accurate viability and volume information. Hibernated or post-infarction stunned myocardium may be present, and they are not indications to SVR.

The presence of dyskinesia or akinesia was another original eligibility criterion, but the trial reported that only half of patients had akinesia or dyskinesia, and 13% had no previous history of MI. SVR has never been reported or recommended in patients with regional dysfunction alone and no scarring, and may be a reason why LGE- CMR should be considered as an essential tool to identify a subset of ischemic HF patients likely to benefit from surgical therapies.

Moreover, STICH reported that SVR lowered LVESVI by an average of only 19%, despite having previously defined SVR as “any ventricular reconstruction method that consistently results in a low operative mortality, an average EF increase of ≥10%, and an average LVESVI decrease of ≥30% as assessed on the four-month post-operative CMR measurement”.226 Patients should have been excluded from the analysis if the originally defined goals were not met.

Furthermore, the design of the STICH trial changed during the study12, but the publication does not give details on the changes. It initially excluded patients with a LVESVI <60 ml/m2. However, as the STICH study evolved, it was decided to liberalize inclusion criteria to include patients amenable to SVR in the opinion of the investigators. This led to the inclusion of patients with a broad range of baseline LVESVI in the STICH population (ranging from 22 to 231 ml/m2), reinforcing the question of which ventricles were randomized. Changing the inclusion criteria was an effort to apply the concept of SVR to a larger population with low EF in which SVR has still unknown effects.

12 STICH trial original protocol deviations can be viewed in ‘history of changes on: http://clinicaltrials.gov/show/NCT00023595.

78 The STICH patients cannot be compared with previously reported patients with SVR, and therefore the trial “has failed to meet the goals expected from an evidence-based study”226, and “all the extensive registry data on the long-term efficacy of SVR cannot be ignored on the basis of a single flawed study”.226

5.9. Michler et al.

To further explore ambiguous questions left by the STICH trial and the implications of the results, Michler and colleagues published a post hoc analysis from the STICH. They evaluated the distribution of LV volumes at baseline and 4 months postoperatively and the individual reductions in LV volume with surgery to determine whether a threshold post-SVR LVESVI, or any magnitude of postoperative reduction in LVESVI, affected survival after CABG plus SVR compared with CABG alone.

From September 2002 to January 2006, 555 patients with an EF< 35% and anterior akinesia or dyskinesia were randomized to receive CABG alone or CABG plus SVR. They were grouped according the baseline LVESVI: Group 1 <60 mL/m2, Group 2 60-90 mL/m2 and Group 3 60-90 mL/m2. The magnitude of LVESVI reduction was significantly greater with SVR across the entire spectrum of baseline LVESVI. In Group 1, neither treatment arm had a significant decrease in LVESVI at 4 months. In Group 2, patients receiving CABG plus SVR had a significant decrease in LVESVI at 4 months (36% of the patients had a greater than 30% reduction in LVESVI from baseline, mean 15 mL/m2; P<.0001), but those receiving CABG alone did not (18% had a greater than 30% reduction in LVESVI, and nearly one half had no change). In group 3, patients receiving CABG plus SVR had a significant decrease in LVESVI at 4 months (mean, 32 mL/m2; P < .0001), 45% of patients had ≥30% reduction in LVESVI from baseline; while patients receiving CABG alone had a mean decrease in LESVI of 18 mL/m2, and only 26% had ≥30% reduction in LVESVI.227

Regarding survival rates, the study showed no significant survival benefit according to the 3 baseline LVESVI subgroups, only suggesting that patients with relatively smaller ventricles did better with SVR than those with larger ventricles. However, when considering postoperative LVESVI, the analysis indicated enhanced survival with CABG plus SVR compared with CABG alone for patients who achieved a 4- month ESVI of 70 mL/m2 or less and a worse outcome for patients with a higher 4-

79 month LVESVI. The 4-month postoperative LVESVI had little effect on survival in patients undergoing CABG alone. In patients treated with CABG plus SVR, a significant reduction in mortality was achieved in patients attaining an ESVI <60 mL/m2 compared with CABG plus SVR patients attaining an ESVI of 60 mL/m2 or more. A similar trend was observed regarding the magnitude of decrease in LVESVI after CABG plus SVR, using a threshold of 30% or more reduction in LVESVI.

“Several major observations are evident from the present post hoc STICH subgroup analysis. First, a postoperative LVESVI of 70 mL/m2 or less after CABG plus SVR resulted in improved survival compared with CABG alone, and the contrary was true with a postoperative LVESVI of 70 mL/ m2 or more. Second, in patients treated with CABG plus SVR, those who achieved a postoperative LVESVI less than 60 mL/m2 manifested statistically significant improved survival compared with those CABG plus SVR and a post- operative LVESVI of 60 mL/m2 or more. This was not true for those treated with CABG alone. Third, compared with CABG alone, survival after SVR was not influenced by whether SVR achieved a large or small volume reduction (< 25 or ≥25 mL/m2). Finally, in the limited number of patients achieving a postoperative LVESVI reduction of 30% or more compared with baseline, CABG plus SVR did not provide a statistically significant survival benefit compared with CABG alone.”227

The study concluded that very large, extensively remodeled LV at baseline might limit the ability of SVR to achieve a sufficient reduction in LVESVI and, therefore, to derive a clinical benefit. Moreover, in patients undergoing SVR, survival will be improved in those achieving a postoperative LVESVI of 70 mL/m2 or less.

5.10. ESC/EACTS Guidelines on Myocardial Revascularization

Based on previous studies221,222, the Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for Cardio- Thoracic Surgery recognized the merit of SVR, which was included in the 2010 Guidelines on myocardial revascularization as a surgical option combined with CABG in selected HF patients with predominant HF symptoms, scarred LAD territory, and LVESVI ≥ 60 mL/m2 (Class of Recommendation IIb; level of evidence B), only performed in centers with a high level of surgical expertise. 228

80 Based on more recent studies221,222,227,229,230, the indications were slightly modified in the 2014 Guidelines, where CABG with SVR was recommended in patients with scarred LAD territory, especially if post-operative LVESVI<70 mL/m2 can be predictably achieved.231

Finally, in agreement with all previous results, the latest 2018 version of the Guidelines on myocardial revascularization suggest that SVR may be performed at the time of CABG in experienced centers, if HF symptoms are more predominant than angina, and if myocardial scar and moderate LV remodeling are present.153 It was also pointed out that a post-operative LVESVI ≤ 70 mL/m2 after CABG plus SVR resulted in improved survival compared with CABG alone.221,229

81 6. Retrospective analysis at IRCCS Policlinico San Donato

Several studies have already highlighted the importance of residual LVESVI in patients with ischemic-based HF undergoing SVR, showing an association between post-operative LVESVI ≥60 mL/m2 and adverse outcomes. However, its actual impact on the prognosis is still not clear. We aimed to further investigate the central role played by residual LVESVI in definition of long-term outcomes through a 14- year retrospective analysis focusing on patients with chronic HF and significantly reduced EF.

6.1. Introduction

The IRCCS Policlinico San Donato has the largest worldwide series (Figure 24) of patients with HF undergoing SVF and represents a reference Center for the International surgical community. The series has changed over the course of 25 years of experience, both in terms of number and types of patients treated. The decline in number is primarily attributable to improvements in the treatment of AMI, which also has an impact on survivors, meaning that patients with the classical dyskinetic remodeling of the apex decreased, while we observed an increase in patients with LV chambers that were severely distorted with more global LV dilatation.

Since July 2001, the SVR team, including cardiologists, cardiac surgeons, and research nurses, began to prospectively collect data, carrying out regular clinical and echocardiographic follow-ups over time, with the aim to assess changes in LV geometry, dimension, and function and the impact on long-term survival. Furthermore, more recently, a newer tool for quantification of regional and global LV function has been adopted (3D speckle tracking echocardiography; 3DST).

82

Figure 24 The overall center experience

6.2. Aim of the study

The present study is an extension of a previous work222 outlining the central role of the residual LVESVI obtained after SVR. The aim of the current retrospective analysis is to assess the impact of an “optimal post-operative ESVI” (< 60ml/m2) on long-term outcomes.

6.3. Materials and Methods

6.3.1. Study design

The study design is reported in Figure 25. Demographic, clinical and echocardiographic data were retrieved from the institutional Registry approved by the local Ethics Committee (REMODEL-HF Registry, 179/Int/2019). The study was conducted following the ethical principles of the Declaration of Helsinki in according with the current Good Clinical Practice international guidelines.

83 Figure 25

January 2002- December 2016

SVR plus CABG n=582

2 2 Pre-op ESVI ≥ 60 mL/m Pre-op ESVI n/a Pre-op ESVI ≤ 60 mL/m

n=419 n=2 n=161

Operative deaths n=32

Lost to follow-up Not in the study n=90

Study Population n=297

6.3.2. Selection of Patients

Between January 2002 and December 2016, 582 consecutive patients underwent SVR at IRCCS Policlinico San Donato. Of these, we included 297 patients (median age 64 [IR 58-71]) with a pre-operative LVESVI of ≥60 mL/m2 who also had an LVESVI measurement at the 6-months follow-up. CABG was performed in all patients; mitral valve surgery was added in 103 cases (34.7%). Patients who suffered peri-operative death or who were lost to follow-up were excluded from the analysis. Indications for surgery were HF, angina, and/or a combination of the two.

84

6.3.3. End points

• The primary endpoint was all-cause death; • The secondary endpoint was a combined endpoint (all-cause death or first hospital admission).

6.3.4. Methods

Echocardiographic examination was performed at baseline, before surgery, and at follow-up (6 months after SVR) using a GE Vivid 7 machine (GE Healthcare, Waukesha, WI). The mean measurements of three cardiac cycles were obtained for each patient. A standard 2-dimensional (2D) echocardiographic study was performed for assessment of LV wall thickness and dimensions according to ASE/EAE recommendations232. Diastolic and systolic LV internal diameters (mm) were measured from the parasternal long-axis view, as well as the LA diameter (mm). Septal wall thickness (SWT) and posterior wall thickness (PWT) were measured in end-diastole. The relative wall thickness (RWT) was calculated as 2 times PWT divided by the LV diastolic diameter. The LV mass index (LVMI) was calculated using the modified Devereux equation232. The sphericity index was calculated as the short- to long-axis ratio, in diastole and systole. The conicity index was calculated as the ratio between the apical and short axis to assess the shape of the apex, in diastole and systole. LV end-diastolic (EDV) and end-systolic (ESV) volume (ml) were measured from apical 4- and 2-chamber views by applying the Simpson method; LV volumes were indexed for body surface area (EDVI and ESVI, ml/m2). EF and stroke volume index (SVI) were derived from LV volumes. LA volume was calculated using the biplane area-length formula and indexed for body surface area232. Systolic pulmonary artery pressure (sPAP) was calculated from the tricuspid regurgitation trace using continuous wave (CW) Doppler232,233. Measures of E and peak late (A) filling velocities (cm/sec), E/A ratio, and E-velocity deceleration time (DT, msec) were done on the pulsed-wave (PW) Doppler mitral- inflow profile. Follow-up was conducted in the hospital and completed in 100% of the population of the study.

85

6.3.5. Statistical analysis

Descriptive statistics were expressed with means and percentages for categorical variables median (Q1-Q3) for continuous variables, as appropriate. Mann-Whitney U Test was performed to verify statistically significant differences among groups (Group I, post-operative ESVI” (< 60ml/m2) (n=158) and Group II post-operative ESVI” (≥ 60ml/m2) (n=139)). Changes over time between preoperative and postoperative echocardiographic characteristics were compared with Wilcoxon signed-rank test. Fisher’s exact test or Chi-square test were used to compare categorical data. The univariate association of potential risk factors with the presence of a post- operative ESVI” (≥ 60ml/m2) was explored through logistic regression analysis. The multivariable logistic regression analysis was based on a multivariable stepwise logistic regression analysis. A receiver operating characteristic (ROC) analysis was used to identify optimal cut- off points of variables predicting a post-operative ESVI” (≥ 60ml/m2). Kaplan–Meier curves were used to explore all-cause mortality and the composite outcome of all-cause mortality or first hospital admission at long-term. P < 0.05 was considered as the threshold for statistical significance. Statistical analysis was performed with SAS 9.4 statistical software (SAS Institute, Cary, NC).

86

7. Results and discussion

7.1. Results

Demographic and clinical data are reported in Table 3.

87 Table 3

Post LV ESVI <60 Post LV ESVI ≥60 n=297 Group I (n=158) Group II ( n=139) p-value Demographic Age, years 64[58-71] 65[58-71] 63[57-61] 0.3354 BSA 1.85[1.74-1.94] 1.84[1.73-1.94] 1.85[1.75-1.94] 0.6640 Creatinine 1.10 [0.92-1.30] 1.06 [0.91-1.26] 1.10 [0.95-1.33] 0.1372 Female sex, n (%) 33 (11.11) 22 (13.92) 11 (7.91) 0.1001

Medical History, n (%) Family history of CAD 138 (46.46) 77 (48.73) 61 (43.88) 0.4031 Smokers or ex-smokers 219 (73.74) 108 (68.35) 111 (79.86) 0.0246 Hypertension 183 (61.62) 105 (66.46) 78 (56.12) 0.0675 Atrial fibrillation 42 (14.14) 19 (12.03) 23 (16.55) 0.2645 Stroke 18 (6.06) 12 (7.59) 6 (4.32) 0.2374 Angina 96 (32.32) 57 (36.08) 39 (28.06) 0.1404 Chronic renal failure 13 (4.38) 5 (3.16) 8 (5.76) 0.2762 Diabetes mellitus 71 (23.99) 40 (25.48) 31 (22.30) 0.5231 Hypercholesterolemia 172 (57.91) 87 (55.06) 85 (61.15) 0.2890 NYHA class III/IV 161 (54.21) 74 (46.84) 87 (62.59) 0.0065

Previous procedures No 158 (53.20) 94 (59.49) 64 (46.04) 0.0075 PCI 81 (27.27) 45 (28.48) 36 (25.90) PCI+ICD 27 (9.09) 7 (4.43) 20 (14.39) ICD 23 (7.74) 8 (5.06) 15 (10.79) Other 8 (2.69) 4 (2.53) 4 (2.88)

Therapy, n (%) ACE inhibitor 241 (81.69) 125 (79.11) 116 (84.67) 0.2183 β-blockers 224 (75.93) 118 (74.68) 106 (77.37) 0.5901 Aspirin 241 (81.69) 135 (85.44) 106 (77.37) 0.0738 Digitalis 16 (5.42) 6 (3.80) 10 (7.30) 0.1854 Statins 213 (671.96) 112 (70.89) 101 (73.19) 0.6600 Diuretic 259 (87.50) 131 (82.91) 128 (92.75) 0.0106 Amiodarone 80 (27.12) 36 (22.78) 44 (32.12) 0.0722 Nitrates 84 (28.47) 46 (29.11) 38 (27.74) 0.7939

BSA= body surface area; CAD= coronary artery disease; NYHA= New York Heart Association; PCI=percutaneous coronary intervention; ICD= implantable cardioverter-defibrillator Data are median [Q1 – Q3] or number (%)

The population was divided in two groups according to post-operative LVESVI <60ml/m2 (Group I, 158 patients) or ≥ 60 ml/m2 (Group II, 139 patients).

88 At baseline, no significant differences were observed between groups, except for a higher New York Heart Association classification (class III/IV 62.5 % versus 46.8%, P=0.0065), for a higher rate of previous PCI plus implantable cardioverter- defibrillator (ICD) or ICD alone (P=0.0075 for all) and greater use of diuretics (92.7 % versus 82.9 %, P=0.0106) in Group II compared to Group I. Baseline echocardiographic parameters and changes at follow-up are reported in Table 4. At follow-up, Group I showed significant shorter internal diameters, smaller volumes, and a higher EF compared to Group II. Diastolic function, in terms of diastolic pattern, E/A ratio, and DT, was less impaired in Group I compared to Group II. Considering geometry, Group I had ventricles that were more conical, in systole and diastole, (P < 0.001 for both) and less spherical, in systole and diastole, (P < 0.001 and <0.0002, respectively).

After surgery, LVESVI decreased from 79.7 (69.5 – 93.7) to 47.3 (41.0 – 53.4) mL/m2 in Group I (−41%), P < 0.001, and from 94.9 (78.5 – 113.7) to 72.3 (66.6 - 83) mL/m2 in Group II (−24%), P < 0.001. Preoperative factors associated with a post-operative LVESVI of ≥60 mL/m2 at univariate analysis are reported (odds ratio, OR with 95% CI) in Table 5. A preoperative internal systolic diameter of 53 mm was the value with the highest sensitivity and specificity at the ROC analysis to predict a post-operative LVESVI of ≥60 mL/m2. The AUC was 0.73 (95% CI: 0.68 – 0.79, P <0.001). The cut-off value for preoperative ESV was 88 mL/m2 (AUC = 0.66, CI: 0.60 – 0.72, P< 0.001). At multivariate analysis, systolic diameter (OR = 1.06; [1.01-1.10]), EF (%) (OR = 0.92; [0.86-0.97]), left atrium (OR = 1.08; [1.02-1.14]), and diastolic conicity index (OR = 0.97; [0.94-0.99]) were independent predictors of post LVESVI ≥ 60 mL/m2 (Table 6).

Median follow-up was 8.4 years [range 1 to 16 years] for the entire cohort: 7.7 years (range, 1 to 16 years) in Group I and 8.7 years (range, 1 to 15 years) in Group II. The probability of all-cause death and the combined secondary endpoint (death or first hospital admission) were different between the two groups (Log-rank=0.0024 and 0.0003 respectively.

89 The Kaplan-Meier estimate of mortality was 6.7% (3.3% –11.8%) in Group I and 18.9% (12.6%–26.3%) in Group II at 4 years, and 26.83% (18.4% – 36.0%) in Group I and 40.39% (30.7%–49.9%) in Group II at 8 years (Fi). The Kaplan-Meier estimate of the combined endpoint was 28.0% (20.8%–35.6%) in Group I and 48.7% (39.8%–57.1%) in Group II at 4 years, and 45.2% (35.8%– 54.2%) in Group I and 65.0% (54.9%–73.4%) in Group II at 8 years. (Figure 27)

90

Table 4 Baseline echocardiographic parameters and changes at follow-up.

Post LV ESVI <60 Group I (n=158) Post LV ESVI ≥60 Group II (n=139) Pre vs Pre vs Pre vs Pre Post post Pre Post post Pre

N Median Q1 Q3 N Median Q1 Q3 p-value N Median Q1 Q3 N Median Q1 Q3 p-value p-value Diastolic diameter (mm) 151 64.0 58.0 69.0 151 60.0 55.0 64.0 <0.001 132 69.0 65.0 74.5 132 67.0 62.5 73.0 0.0007 <0.001

Systolic diameter (mm) 142 50.0 44.0 56.0 142 45.0 40.0 50.0 <0.001 126 57.0 52.0 64.0 126 56.0 50.0 62.0 0.0155 <0.001 EDV index (ml/m2) 158 116.7 104.7 133.7 158 82.8 73.8 90.0 <0.001 138 130 111.4 154.8 138 111.0 100.5 122.6 <0.001 0.0002 ESV index (ml/m2) 158 79.7 69.5 93.7 158 47.3 41.0 53.8 <0.001 139 94.9 78.5 113.7 139 72.3 66.7 83.0 <0.001 <0.001 EF (%) 158 30.0 26.0 36.0 43.0 38.0 47.0 <0.001 138 27.0 23.0 32.0 138 32.0 28.0 36.0 <0.001 <0.001 SV index(ml/m2) 155 37.8 31.3 43.9 155 34.7 28.3 39.8 0.0001 137 34.9 29.7 42.4 137 35.4 29.7 41.6 0.6215 0.1282 Cardiac mass index (g/m2) 63 161.5 135.5 184.3 63 142 121 170 0.0011 70 184 161 218 70 174.5 151.0 203.0 0.0339 0.0002 Left atrium diameter (mm) 121 46.0 42.0 49.0 121 46.0 42.0 50.0 0.0440 114 49.0 44.0 53.0 114 50.0 45.0 53.0 0.4756 <.0001 Left atrial volume(ml) 84 80.0 62.0 96.5 84 76.0 66.0 87.0 0.1551 75 102 78.0 120 75 97.0 71.0 119.0 0.4182 <.0001 DP 109 1.0 1.0 2.0 109 2.0 1.0 2.0 0.0119 94 2.0 1.0 3.0 2.0 1.0 3.0 0.0386 0.0003 E/A ratio 102 0.8 0.7 1.3 102 1.1 0.77 1.6 0.0010 90 1.3 0.6 2.4 90 1.3 0.8 2.9 0.0248 0.0223 DT (m sec) 95 192 155 249 95 194 153 250 0.3753 79 169 140 214 79 178 140 220 0.6676 0.0135 TAPSE 128 21.0 18.0 23.0 128 17.0 15.5 19.5 <.0001 106 20.0 18.0 23.0 106 16.0 15.0 18.0 <.0001 0.6738 Systolic PAP (mm hg) 111 37.0 30.0 45.0 111 32.0 26.0 38.0 <.0001 99 40.0 32.0 50.0 99 39.0 28.0 45.0 0.0053 0.0210 Mitral annulus (mm) 59 32.0 29.0 36.0 59 30.0 29.0 32.0 0.0242 57 34.0 30.0 38.0 57 31.0 28.0 35.0 0.0004 0.0145 Diastolic sphericity index 102 0.6 0.5 0.7 102 0.6 0.6 0.7 <.0001 97 0.7 0.6 0.7 97 0.7 0.6 0.8 <.0001 <.0001 Systolic sphericity index 102 0.5 0.4 0.6 102 0.5 0.5 0.6 0.0001 97 0.6 0.5 0.6 97 0.6 0.6 0.7 <.0001 0.0002 Diastolic conicity index 100 0.9 0.8 1.0 100 0.8 0.8 0.9 <.0001 96 0.9 0.8 0.9 96 0.8 0.8 0.9 0.0041 <.0001 Systolic conicity index 100 1.0 0.8 1.2 100 0.9 0.8 1.0 <.0001 95 0.9 0.8 1.0 95 0.8 0.8 0.9 0.0011 <.0001

Table 5 Pre-operative factors associated with a post-operative LVESVI ≥ 60 mL/m2 by univariate analysis

Risk Odds P-value Best MAX category Ratio 95 % CI P-value AUC SE AUC AUC cut-off SP MAX SE Diastolic diameter (mm) 1.104 1.068 1.141 <.0001 0.7074 0.0299 <0.0001 65 0.6 0.7153 Systolic diameter (mm) 1.106 1.072 1.141 <.0001 0.7372 0.0288 <0.0001 53 0.63 0.7353 EDV index(ml/m2) 1.006 1.000 1.013 0.0613 0.6234 0.0330 0.0002 126.4 0.67 0.5942 ESV index(ml/m2) 1.010 1.002 1.018 0.0159 0.6582 0.0319 <0.0001 88.18 0.66 0.6043 EF (%) 0.922 0.887 0.959 <.0001 0.6450 0.0319 <0.0001 29 0.64 0.5949 SV index(ml/m2) 0.987 0.963 1.011 0.2902 0.5562 0.0339 0.0965 35.86 0.6266 0.55 RWT (*100) 0.951 0.923 0.980 0.0011 0.6350 0.0336 0.0001 0.301 0.63 0.5986 Cardiac mass index (g/m2) 1.011 1.005 1.017 0.0002 0.6353 0.0348 0.0001 193.6 0.77 0.4454 Left atrium(diam in mm) 1.093 1.050 1.138 <.0001 0.6590 0.0333 <0.0001 47 0.66 0.5891 DP 1.889 1.403 2.543 <.0001 0.6430 0.0334 0.0001 1 0.57 0.6491 E/A ratio 1.633 1.220 2.185 0.0010 0.5921 0.0384 0.0161 1.13 0.68 0.5364 DT (m sec) 0.994 0.990 0.998 0.0043 0.6118 0.0379 0.0031 171 0.54 0.6949 TAPSE 0.952 0.897 1.011 0.1066 0.5592 0.0338 0.08 19 0.5 0.6429 Systolic PAP(mm hg) 1.025 1.006 1.045 0.0113 0.6079 0.0346 0.0018 37 0.54 0.69 Mitral annulus(mm) 1.068 1.006 1.134 0.0306 0.5877 0.0411 0.0328 35 0.71 0.444 Papillary distance diast(cm) 1.776 1.098 2.873 0.0193 0.5981 0.0482 0.0413 3.1 0.67 0.5342 Papillary distance syst(cm) 2.231 1.320 3.773 0.0027 0.6524 0.0464 0.001 2.3 0.71 0.5068 Diastolic sphericity index 1.073 1.041 1.105 <.0001 0.6946 0.0359 <0.0001 0.618 0.67 0.654 Systolic sphericity index 1.054 1.028 1.081 <.0001 0.6776 0.0362 <0.0001 0.523 0.59 0.7115 Diastolic conicity index 0.957 0.935 0.979 0.0001 0.6629 0.0370 <0.0001 0.905 0.76 0.5182 Systolic conicity index 0.967 0.952 0.982 <.0001 0.6677 0.0373 <0.0001 0.943 0.71 0.5818

Mitral Regurgitation 3/4 <3 2.711 1.649 4.456 <.0001 Site of remodelling Anterior 1.827 1.013 3.297 0.0452

Table 6 Pre-operative factors associated with a post- LVESVI ≥ 60 mL/m2 by multivariable analysis

Odds Ratio 95 % CI P-value

Systolic diameter (mm) 1.058 1.014 1.104 0.0095 EF (%) 0.915 0.863 0.971 0.0032

Left atrium (diam in mm) 1.078 1.022 1.137 0.0061 Diastolic conicity index 0.970 0.946 0.994 0.0165

Figure 26 Probability of all-cause death

93

Figure 27 Kaplan-Meier estimate of the combined endpoint

7.2. Discussion

The results of the present study show that LVESVI following SVR has an impact on the probability of death from any cause or first hospital admission at long-term follow-up. Both adverse events were significantly higher in patients who remain with a post-SVR LVESVI of ≥ 60 mL/m2 at 6-month echocardiography. Although the percentage of LVESVI reduction was significant in both groups (−41%, P < 0.001 in Group I and −24%, P < 0.001 in Group II) and higher than reported in previous studies215, the failure to achieve an optimal volume carried a greater risk of long- term adverse events. Conversely, the probability of death was significantly lower in patients who achieved a post-operative LVESVI of <60 mL/m2 (6.7% and 18.9% at

94 4 years and 8 years, respectively) and acceptably low in consideration of the high- risk profile of this population and the poor prognosis of patients affected by ischemic HF, as reported in the literature16. It is noteworthy that although reverse remodeling was achieved in different percentages in the two groups, it is far greater than the degree of reverse remodeling achieved with any other treatment for HF (see Chapter 3).

In this study, we firstly confirm the role of an optimal residual LVESVI after surgery on outcomes. Furthermore, we extended the follow-up period up to 8 years and included the first hospitalization as an outcome measure. Unlike the all-cause mortality curves that overlapped for the first two years, the curves that explore the combined endpoint immediately diverge. This means that even if a patient with a residual LVESVI > 60 ml/m2 survives, the probability of being hospitalized is greater than that of a patient with residual LVESVI <60 ml/m2.

The complex interaction between volume and geometry to get the result

LV adverse remodeling is a dynamic process as is LV reverse remodeling, even when the latter is achieved through surgical intervention. Both evolve over time, with the latter depending on baseline geometric and volumetric variables, completeness of revascularization, residual volume and shape of the LV, and function of “the remote regions” (not scarred), which may be hibernating (ischemic but viable myocardium likely for functional recovering after CABG) or non-ischemic. Notwithstanding, they may be dysfunctional because of the high local tension that reduces shortening and likely for functional improvement after volume reduction obtained through SVR, as well as the complex interaction between each other.

In this study, the preoperative internal systolic diameter (>53 mm) and the diastolic conicity index (< 0.94), but not volumes, were independent predictors of post- operative ESVI of ≥60 mL/m2, which impacted survival. Whether the shape, as expressed by the internal systolic diameter or by the conicity index, is a function of the volumes or vice versa remains to be established. The conicity index defines the relationship between the internal diameter and the apical dilatation (see Figure 8 and 9 in chapter 2.4.1.). Larger volumes with a favorable shape (i.e. internal systolic

95 diameter < 53 mm and a conicity index >1) are suitable for more extensive reduction compared to smaller volumes with a less favorable shape (i.e. internal systolic diameter> 53 mm and a conicity index <1). Indeed, if the internal diameter is too large it cannot be completely corrected by a surgical gesture that leaves a volume of the ventricle which is too large.

96 8. Conclusions

Substantial research has outlined the importance of residual LVESVI in patients with ischemic-based HF undergoing SVR, showing an association between a post- operative LVESV ≥60 mL/m2 and adverse outcomes. However, the actual impact on prognosis is a subject of debate.

The findings of the present study confirm the role of LVESVI in predicting long-term survival. Despite the controversy generated by publication of the results of the STICH trial, SVR stills seems to have a role in the treatment of ischemic HF patients, especially if a post-operative LVESVI <60 mL/m2 can be predictably achieved. Careful selection of patients, emerging from close collaboration between surgeons, cardiologists, and radiologists is warranted to obtain an optimal surgical result, which can translate in favorable long-term outcomes.

Regarding the limitations of the study, it is evident that it did not have a control group and was not randomized. However, it should be recognized that some information can be better collected from registries and observational studies, rather than from randomized trials. In fact, the latter can be interpreted as a strong point of the present analysis. The present study has the largest and most extensive cohort available worldwide on SVR for HF, with data collected throughout more than 14 years in a center with a high level of surgical expertise with SVR. This study thus provides additional information that will help cardiologists and surgeons to better understand the role of SVF as treatment of HF.

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120 and Is Associated With Worse Long-Term Prognosis. Circulation. 2004;110(11_suppl_1):II-18-II-22. doi:10.1161/01.CIR.0000138195.33452.b0 220. Velazquez EJ, Lee KL, O’Connor CM, et al. The rationale and design of the Surgical Treatment for Ischemic Heart Failure (STICH) trial. The Journal of Thoracic and Cardiovascular Surgery. 2007;134(6):1540-1547.e4. doi:10.1016/j.jtcvs.2007.05.069 221. Jones RH, Velazquez EJ, Michler RE, et al. Coronary Bypass Surgery with or without Surgical Ventricular Reconstruction. N Engl J Med. 2009;360(17):1705- 1717. doi:10.1056/NEJMoa0900559 222. Di Donato M, Castelvecchio S, Menicanti L. End-systolic volume following surgical ventricular reconstruction impacts survival in patients with ischaemic dilated cardiomyopathy. Eur J Heart Fail. 2010;12(4):375-381. doi:10.1093/eurjhf/hfq020 223. Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation. 1993;87(3):755-763. doi:10.1161/01.CIR.87.3.755 224. Mann DL, Bristow MR. Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond. Circulation. 2005;111(21):2837-2849. doi:10.1161/CIRCULATIONAHA.104.500546 225. Witkowski TG, ten Brinke EA, Delgado V, et al. Surgical Ventricular Restoration for Patients With Ischemic Heart Failure: Determinants of Two-Year Survival. The Annals of Thoracic Surgery. 2011;91(2):491-498. doi:10.1016/j.athoracsur.2010.09.074 226. Buckberg GD, Athanasuleas CL, Wechsler AS, Beyersdorf F, Conte JV, Strobeck JE. The STICH trial unravelled. European Journal of Heart Failure. 2010;12(10):1024-1027. doi:10.1093/eurjhf/hfq147 227. Michler RE, Rouleau JL, Al-Khalidi HR, et al. Insights from the STICH trial: Change in left ventricular size after coronary artery bypass grafting with and without surgical ventricular reconstruction. The Journal of Thoracic and Cardiovascular Surgery. 2013;146(5):1139-1145.e6. doi:10.1016/j.jtcvs.2012.09.007 228. Developed with the special contribution of the European Association for Percutaneous Cardiovascular Interventions (EAPCI), Authors/Task Force Members, Wijns W, et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).

121 European Heart Journal. 2010;31(20):2501-2555. doi:10.1093/eurheartj/ehq277 229. Dor V, Civaia F, Alexandrescu C, Sabatier M, Montiglio F. Favorable effects of left ventricular reconstruction in patients excluded from the Surgical Treatments for Ischemic Heart Failure (STICH) trial. The Journal of Thoracic and Cardiovascular Surgery. 2011;141(4):905-916.e4. doi:10.1016/j.jtcvs.2010.10.026 230. Oh JK, Velazquez EJ, Menicanti L, et al. Influence of baseline left ventricular function on the clinical outcome of surgical ventricular reconstruction in patients with ischaemic cardiomyopathy. European Heart Journal. 2013;34(1):39-47. doi:10.1093/eurheartj/ehs021 231. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541-2619. doi:10.1093/eurheartj/ehu278 232. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-271. doi:10.1093/ehjci/jev014 233. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70(4):657-662. doi:10.1161/01.CIR.70.4.657 WJC. 2017;9(5):407. doi:10.4330/wjc.v9.i5.407

122 Acknowledgements

In primis, vorrei ringraziare il Professor Francesco Santini, per avermi incoraggiata e guidata nello svolgimento di tutto il lavoro, permettendo così la stesura di questa tesi. Un grande grazie va anche al Professor Antonio Salsano, per l’attenzione con cui mi ha seguita e sostenuta ad ogni passo.

Un sincero ringraziamento va al “team SVR” dell’IRCCS Policlinico San Donato. Ringrazio il Dottor Lorenzo Menicanti, artefice del meraviglioso intervento qui trattato, che purtroppo, per cause di forza maggiore, non ho ancora avuto il piacere di vedere all’opera, nella speranza di riuscirci prossimamente. Un grandissimo ringraziamento va alla Dottoressa Serenella Castelvecchio, per la sua infinita disponibilità. Nonostante l’emergenza Covid e gli innumerevoli impegni lavorativi, ha sempre trovato il tempo per sostenermi e guidarmi, e non mi ha mai lasciata da sola in questo percorso. Grazie anche alla Dottoressa Valentina Milani, per l’importante lavoro statistico alla base del progetto.

Un grazie speciale va a Patrick Moore, probabilmente l’unica altra persona che abbia veramente letto la tesi oltre ai relatori, per la sua preziosa e indispensabile revisione.

Ed arriva ora il momento dei ringraziamenti più personali, quelli che ci ho messo una vita a scrivere (tra le lacrime), che ho cancellato e riscritto mille volte nella speranza di migliorarli perché non mi sembravano mai abbastanza, ma la verità è che è davvero difficile esprimere in poche parole la forza dei pensieri e delle emozioni che questi anni mi hanno lasciato.

Grazie a tutte le persone che hanno condiviso con me questi anni di Università, a quelle che ci sono sempre state e non se ne andranno e a quelle che sono state solo di passaggio, perché tutte, in un modo o nell’altro, hanno lasciato un segno nella mia vita.

123 In primis le mie compaesane venete, Maria, una delle persone più sincere e amiche che abbia conosciuto, ed Elena, prima amicizia in assoluto in questo nuovo percorso, che ancora oggi va avanti. Grazie perché nonostante i chilometri, dopo sei anni siete qui a festeggiare con me, e significa tanto. Grazie a Greta, per la compagnia che siamo riuscite a farci insieme, ma anche a chilometri di distanza. E poi grazie a tutti gli altri, le piccanti Young Signorine, le Casse, gli amici e le amiche, per aver reso questi anni davvero felici e indimenticabili, e soprattutto meritevoli di essere vissuti e ricordati.

Un ringraziamento importante va anche al SISM e alla SL di Genova nelle sue varie versioni, che mi ha permesso di crescere all’interno di un’associazione e mi ha insegnato a cimentarmi in nuove realtà senza timore. Ho vissuto esperienze incredibili, ma soprattutto ho conosciuto persone uniche, ognuna a modo loro, e che mi hanno lasciato qualcosa che porterò nel cuore, in particolare Monica, Sara e Giulia (non pensate che abbia finito di chiedervi pareri e consigli solo perché mi laureo eh!).

Un grazie immenso va alle mie coinquiline, Chiara e Silvia, che anno dopo anno hanno fatto di via Manuzio un posto che nel cuore chiamerò sempre Casa (soprattutto dopo la quarantena). Sappiate che siete state il primo ringraziamento buttato giù d’impulso dopo l’ennesima sera sedute in cucina, a parlare di tutto e niente (probabilmente di gatti), insieme. Grazie a Chiara, compagna di sventure fin dal mio primo passo in questa città, per condividere la quotidiana dose di cinismo verso la vita e il genere umano, che alla fine ci strappa sempre un sorriso. Grazie perché 6 anni fa non avrei mai pensato di trovarmi a vivere con un’altra come me (critica o complimento non lo so, prendila come vuoi). Sei la Sandra al mio Raimondo. E grazie a Silvia, coinquilina, amica, confidente e mentore medico allo stesso tempo, per la forza con cui mi ha sostenuta negli ultimi tempi ed esami.

Un ringraziamento importante va a Laura, l’amica saggia che mi ha sempre accompagnata e spronata con i suoi consigli, che mi ha insegnato a non fermarsi mai nella vita, a non accontentarsi delle cose semplici, a porsi mille domande e

124 andare a cercare altrettante risposte, ma che soprattutto mi ha insegnato a cercare sempre la bellezza nel mondo, e a trovarla anche dentro noi stessi. Grazie ad Anna, per l’affetto instancabile e la sua sincerità, sempre e comunque. Un grande grazie va anche ai “butei”, perché senza la vostra compagnia, i primi anni di università sarebbero stati più difficili da sopportare. Tra loro, una menzione speciale va a Daniele, che è sempre stato disponibile e presente, nel momento del bisogno.

Grazie a Giulio, perché è una di quelle persone che non sai mai dove sono, ma sai che ci sono.

Grazie a Caterina, con la quale mi sono divertita come non mai, e ho riso davvero di cuore, dall’Argentina al Brasile.

Un grandissimo grazie va alle mie quattro amiche di una vita, che per quanto io possa ricordare, ci sono sempre state. In primis, con un record di quasi 20 anni di conoscenza, grazie ad Alice, che dalla prima elementare mi regala sorrisi (e irritazioni) con la sua biondaggine, e che per prima mi ha insegnato il valore della vera amicizia. Grazie ad Alessia, confidente speciale e soprattutto fedelissima compagna di colazioni pre-biblioteca e studio (arriverà anche il tuo momento Ale, tieni duro!). Grazie anche a Carolina, che, pur silenziosamente, fa sempre sentire la propria bellissima presenza. E per ultima, grazie alla mia Homeless, Rebecca, compagna di vita, direi quasi in simbiosi, per anni, con cui ho condiviso molto più di quanto potrò mai raccontare a parole. Nonostante la distanza, continui ad essere la mia persona, quella dalla quale volerei anche adesso, anche in capo al mondo, per essere la tua Home. Per quanto sia difficile riuscire a vederci, con voi sembra che il tempo non sia mai passato, torniamo ad avere sempre 14,15,16 anni, e tutto diventa naturale. Grazie perché 6 anni fa mi avete dato la forza di iniziare questo percorso con un meraviglioso striscione il giorno del test d’ammissione, e da allora non avete mai smesso di credere in me. Se oggi sono un medico (quasi), lo devo anche a voi.

Un ringraziamento speciale va a tutta la mia famiglia, i miei zii Gianfranco, Barbara, Stefano e Daniela, i miei cugini “piccoli” Fabio e Marco e il grande Riccardo, e

125 soprattutto alle mie rocce, i miei incredibili nonni, Giulia, Edo, Franca e Guerrino, che, chi da quaggiù e chi da lassù, mi sostengono sempre.

In particolare, il grazie più grande va ai miei genitori, i miei punti cardinali, Laura e Massimo, che ad ogni passo mi hanno sempre appoggiata e sostenuta con tutta la loro forza, senza chiedere niente in cambio (forse “solo” qualche viaggio…). A loro che sono stati sempre presenti, ma mai invadenti, e che mi hanno dato tutti gli strumenti perfetti per permettermi di crescere da sola. Hanno ascoltato per anni le mie infinite lamentele, rassicurandomi, spronandomi a migliorare, ma anche consolandomi al bisogno, e non hanno smesso di credere in me neanche quando io stessa ero sconfortata. Capisco ora l’importanza della solidità che mi avete dato, senza la quale non avrei sicuramente raggiunto questo traguardo, che alla fine è anche un po’ vostro. Un grazie speciale va anche a Francesco, che con la sua presenza silenziosa ma costante occupa un posto speciale nella mia vita, in cui lascia un’impronta insostituibile. Grazie poi a mia sorella Natalia, sempre vicina anche da lontano.

Il ringraziamento più sentimentale va a te. Di solito non siamo persone che mettono in mostra tante emozioni, ma qui non puoi mancare. Se ho raggiunto questo traguardo oggi, è anche grazie a te. A te che da oltre sette anni mi accompagni tenendomi la mano, nonostante la distanza materiale che non ha ancora smesso di separarci; a te che hai vissuto insieme a me tutto questo percorso, lungo il quale non ho mai camminato da sola; a te che sei sempre stato a fianco a me, non un passo avanti e non uno indietro, e che se rimanevo indietro, venivi a recuperarmi; a te, che nonostante le difficoltà che si sono presentate, neanche per un attimo hai pensato di rinunciare; a te che nonostante i chilometri, sei sempre il più vicino. Grazie Michael, per schiarire il mio mondo quando vedo tutto nero, per farmi ridere nel cuore e nello spirito, e per ricordarmi perché ogni giorno valga la pena di essere vissuto (anche se non hai mai letto la mia tesi!).

Per ultimo, il ringraziamento più vero, ad Alice ed Alessandra, molto più che semplici compagne di università. Siete state i sorrisi (anche i mugugni) che ogni mattina speravo di vedere per cominciare la giornata, i miei riferimenti, le quotidiane compagne di vita per sei lunghi anni. Siete state le mani amiche che nonostante

126 tutto trovavo sempre aperte, senza le quali non avrei mai trovato la forza per portare a termine questo percorso. Grazie Ale, perché con il tuo pessimismo cosmico (e comico) mi tieni con i piedi per terra, ma poi mi fai volare altissimo con la passione contagiosa che ti ho sempre vista mettere nelle cose, e che ti ammiro. Mi hai insegnato che a metterci il cuore nelle cose si finisce per vincere, sempre, a prescindere dal risultato. Grazie Ally, perché con la tua solare spontaneità, porti sempre una ventata di vita ovunque tu vada (anche se bisogna sapere come prenderti…). Mi hai insegnato ad essere un po’ meno orso e un po’ più amore. E ovviamente sei stata la migliore compagna di studi mai avuta, le reclusioni con te avevano tutto un altro sapore (mi mancherai!). Grazie amiche mie, per gli innumerevoli esami preparati insieme (a partire da anatomia ad Artesina), per la condivisione del perenne disagio esistenziale, per le lacrime che a turno ci siamo asciugate a vicenda, per i crolli emotivi e le risate a crepapelle, per i travestimenti dei medical che ci siamo cucite, per i concerti in giro per l’Italia, per le serate di festa in cui abbiamo perso la dignità (soprattutto), per quelle passate su un letto a spettegolare, ma anche quelle a studiare disperate fino a notte fonda. Con voi nulla è mai scontato o noioso. Avete profumato questi anni di felicità, e non potrei essere più felice di aver raggiunto questo traguardo insieme a voi, con la gioia nel cuore. Grazie amiche mie, voi siete la cosa più bella che questi anni mi abbiano regalato, quella che porterò nel cuore per sempre, e che spero che la distanza non affievolisca mai. Insieme siamo una forza. Three peas in a pod, anzi, in a Pata (amarela).

E infine un grazie se lo merita anche Genova, questa incredibile e magica città che a braccia aperte mi ha accolto e mi ha fatto innamorare perdutamente, tra le sue slerfe di fugassa, il pesto (chi mi conosce sa che lo metterei ovunque), i vicoli loschi e il mare a due passi. Quando mi sono trasferita, mai avrei pensato che mi sarei trovata così bene qui, tanto da non volerla più lasciare.

Ah, si, forse un grazie me lo merito anche io, per ogni volta che ho pensato che non ce l’avrei fatta, e invece mi sono rialzata (dopo fiumi di lacrime, ovvio), e sono arrivata fin qui, e forse arriverò anche un po’ più in là.

127 Non so quante volte avevo cercato di immaginare questo momento, e mi è sempre sembrato irraggiungibile, lontanissimo. E invece sono arrivata alla fine dei ringraziamenti, segno che questo lungo percorso volge davvero al termine, anche se mi ci vorrà del tempo per realizzarlo. Qui si chiude un grande capitolo, e so che tante cose cambieranno nei prossimi mesi, ma spero che la bellezza e l’amore delle persone che sono qui con me oggi, fisicamente o con il pensiero, possa non cambiare mai.

Francesca

128