Cardiogenetics 2016; volume 6:5862

Reversible dilated cardiomy- clinical management. The identification of pathways to recovery may show the way for Correspondence: Giovanni Quarta, Cardiova - opathy: into the thaumaturgy novel therapeutic targets ultimately benefit- scular Department, Papa Giovanni XXIII Hospital, of the heart - Part 2 ting all cardiac patients. piazza OMS 1, 24127 Bergamo, Italy. Tel.: +39.035.267.4346 - Fax: +39.035.267.4965. Giovanni Quarta,1 Raffaele Coppini,2 E-mail: [email protected] 3 4 Pier Lambiase, Pablo Garcia-Pavia, Key words: Dilated ; reversible Alice Calabrese,1 Anna Maria Iorio,1 Chemotherapy-induced causes; prevention. Niccolò Maurizi,5 Maria Iascone,6 cardiomyopathy Antonello Gavazzi,7 Iacopo Olivotto,5 Acknowledgments: Iacopo Olivotto was supported by the Italian Ministry of Health: RF-2010- Michele Senni1 Chemotherapy is a well-known cause of car- 2313451 (Hypertrophic cardiomyopathy: new 1Cardiovascular Department, Papa diomyopathy (Table 1) and the cardiac toxic insights from deep sequencing and psychosocial Giovanni XXIII Hospital, Bergamo, Italy; effects of anthracyclines, prototypal in cardio- evaluation), RF-2013-02356787 (Left ventricular oncology, have been investigated for more than 2Department of Preclinical and Clinical hypertrophy in disease and hyper- 30 years.1 Although acute cardiotoxicity is pos- trophic cardiomyopathy: genetic basis, biophysical Pharmacology and Center of Molecular sible, chronic cardiotoxicity is more common; correlates and viral therapy models), and NET- Medicine, University of Florence, its occurrence and severity are proportional to 2011-02347173 (Mechanisms and treatment of 3 Florence, Italy; Institute of the cumulative dose (for example doxorubicin coronary microvascular dysfunction in patients with genetic or secondary left ventricular hyper- Cardiovascular Science, University >400-500 mg/m2 is associated with significant trophy); and by Telethon Italy (GGP13162). Pier College and Bart’s Heart Centre, Bart’s risk) and may become evident several years Lambiase was supported by UCLH Biomedicine 4 Health NHS Trust, London, UK; Heart after exposure. Occasionally, the gap may be NIHR. Failure and Inherited Cardiac Diseases sufficiently long as to render the association Unit, Department of , Puerta between chemotherapy and cardiomyopathy Received for publication: 2 March 2016. de Hierro University-Hospital, Madrid, counterintuitive. Serial echocardiographic Revision received: 28 June 2016. Accepted for publication: Spain; 5Referral Center for assessment of left ventricular (LV) systolic only function is commonly used to evaluate , Careggi University- This work is licensed under a Creative Commons chemotherapy-induced cardiomyopathy, while Hospital, Florence, Italy; 6Medical Attribution NonCommercial 4.0 License (CC BY- cardiovascular magnetic resonance (CMR) is Genetics Lab, Papa Giovanni XXIII NC 4.0). indicated as a second-line investigation when Hospital, Bergamo, Italy; 7Research evident disease or borderline abnormalitiesuse©Copyright G. Quarta et al., 2016 Foundation (FROM), Papa Giovanni XXIII are identified.2 Historically, cardiotoxicity is Licensee PAGEPress, Italy Hospital, Bergamo, Italy Cardiogenetics 2016; 6:5862 defined by a ≥5% decline in LV ejection frac- tion (LVEF) resulting in an LVEF <55% with doi:10.4081/cardiogenetics.2016.5862 symptoms of , or a 10% decline to result in an LVEF <55% without symptoms of heart failure,1,3 or 20% or >15% LVEF decline Abstract ≥ reduces oxidative damage. In addition, preven- from baseline, but remaining ≥50%, or any LVEF decline to <50%.4 Clinical manifestations tive therapy with b-blockers (carvedilol), (DCM) is a genetic vary from mild, subclinical systolic impairment angiotensin-converting enzyme (ACE)- or acquired heart muscle disorder character- to severe dilated cardiomyopathy and refracto- inhibitors and statins may be effective, ized by dilation and impaired contraction of ry heart failure. Today, about half of the although the evidence supporting their protec- one or both ventricles. In the acquired forms of patientscommercial surviving cancer die of cardiovascular tive role is limited. A recent meta-analysis of a the disease, if the pathogenic agent is persist- complications of treatment. There are 2 major small number of trials showed a relative risk ent, undiagnosed or untreated, permanent types of cardiotoxicity-type 1 and 2. Type 1 reduction in risk of heart failure or LVEF ultrastructural and morphological changes (typical caused by anthracyclines) is associat- decline following chemotherapy of approxi- may lead to irreversible dysfunction. ed with ultrastructural changes, poor progno- mately 70% for b-blockers and 90% for ACE- Non 8 Conversely, when DCM is promptly recognized sis and lower recovery rates. Type 2 cardiotox- inhibitors. These data support the concept and treated, the heart may show an extraordi- icity (for example caused by trastuzumab), is that optimization of hemodynamics and neuro- nary ability to recover from left ventricular not associated with histological changes and hormonal milieu prior to anthracycline therapy (LV) systolic dysfunction. While much have better prognosis.5 Chemotherapy-induced may help to prevent myocyte injury. Another research in heart failure has focused on mor- cardiomyopathy represents 2.5% of all heart promising strategy for the management of LV bidity and mortality associated with persistent transplant recipients.6 dysfunction due to anticancer treatment relies LV systolic dysfunction, relatively little atten- Biomarkers such as troponin, natriuretic on the use of novel, more sensitive diagnostic tion has been devoted to this remarkable peptides, C-reactive proteins and others have techniques allowing earlier recognition of potential for recovery. In this two-part review been proposed as early markers of cardiotoxic- myocardial damage. Most relevantly, strain we will focus on the most common types of ity and are useful in predicting risk. Treatment and cardiac MRI, along with reversible DCM. The second part will deal with is still empirical and mainly based on standard biomarkers such as cardiac troponins and NT- chemotherapy-induced cardiomyopathy, alco- heart failure medications. Recovery of LV sys- proBNP have shown the best results in terms hol-related cardiomyopathy, and tolic function has been reported up to 55% of of risk assessment for the timing of early inter- peripartum cardiomyopathy. Although diverse patients in 2 years.7 Prevention of chemother- ventions.1,2,4 in etiopathogenesis, genetic background, ther- apy-induced cardiomyopathy involves careful To date, the pathogenesis of cardiotoxicity apeutic options and outcome, the forms of evaluation of the type and dose of oncologic associated with anthracycline therapy is still DCM characterized by reversible LV dysfunc- regimens and the use of dexrazoxane, an eth- poorly understood. The most commonly accept- tion share similar challenges in diagnosis and ylenediaminetetraacetic acid-like chelator that ed hypothesis for anthracycline-induced car-

[page 8] [Cardiogenetics 2016; 6:5862] Review diomyopathy has been the generation of exces- opathy and repeated administrations of the identified cause and a long history of heavy sive amount of reactive oxygen species (ROS) drug will gradually reduce the population of abuse. by electron exchange between the anthracy- myocyte progenitors that are activated to Data on the amount of alcohol consumption cline quinone and oxygen molecules and/or repair the damage, resulting in a time-depen- required to cause ACM are limited and contro- other intracellular molecular targets.9 Other dent accumulation of cardiac injury. The high versial in that a proportional relationship mechanisms include the formation of DNA incidence of late cardiotoxicity in the pediatric between myocardial damage and alcohol adducts by anthracyclines emiquinone or the oncology population may well be explained by intake has not been proven. In most studies on generation of superoxide anions by anthracy- the deleterious effects of anthracyclines on the the natural history and the long-term progno- cline metabolism, with subsequent cellular higher fraction of proliferating cardiomyocytes sis of ACM, an amount of 80 g a day (equiva- damage caused by superoxide anions with sub- typical of young hearts.20 Indeed, a higher lent to 10 U or 5 glasses of 12% wine or 3-4 sequent degradation of sarcomeric proteins, turnover leads to an increased susceptibility to pints of beer) during at least 5 years was mitochondrial dysfunction and DNA damage.10 cytotoxic insult and progressive cells death in deemed sufficient to produce the disease.32-35 Although in vivo and in vitro studies confirmed young cancer survivors. Stem cells hold the However, average alcohol consumption shown increased ROS production in cardiomyocytes great promise of regenerative therapies such by the patients included in these series was after anthracycline therapy, antioxidants and as those used for .21 much higher and consumption periods were iron chelation only showed partial positive Recent results on rats have shown that dys- much longer. Furthermore, the accepted defi- effects and none of them was able to prevent function of cardiac stem cells occurs early after nition of ACM does not take into account 11,12 cardiomyopathy. Topoisomerase (Top) 2b drug exposure and that doxorubicin-induced important factors such as body mass index was recently revealed as the main determinant cardiomyopathy can be prevented by injection (BMI) or sex. For example, women and indi- of anthracycline-induced cardiac toxicity.13 The of cardiac stem cell.22 viduals with lower BMI are significantly more physiological role of Top2 is to unfold DNA Finally, other agents such as cisplatin, 5-flu- susceptible to the negative effects of alcohol. strands during DNA replication, transcription, orouracil and rituximab may cause myocardial A recent study examined the contemporary or recombination.14 Anthracy cline-induced pro- damage mediated by , whether natural history of ACM.36 In this study involv- duction of oxygen radicals appears to be mainly through coronary artery spasm or endothelial ing 94 patients evaluated at a single referral due to a reduction in antioxidant enzyme gene impairment. Ischemia can occur in patients center during the period 1994-2011, approxi- 13 only transcription, which is also Top2b-dependent. without underlying mately one third died or needed a heart trans- Top2b-inhibition also leads to impaired mito- (CAD), but the incidence is higher in patients plant while another third showed persistent LV chondrial bioge nesis and function. Indeed, dele- with CAD.23 dysfunction despite lack of adverse events. The tion of Top2b gene from the heart fully protects final third progressively normalized their car- mice from anthracycline-induced cardiomyopa- use diac function. In this study predictors of poor thy, supporting the idea that Top2b is the pri- outcome (death and heart transplant) were mary mediator of anthracycline-induced car- Alcohol-related cardiomyopathy absence of b-blocker treatment, atrial fibrilla- diotoxicity. tion and QRS>120 ms.36 Recent studies also postulated an additional Daily consumption of low to moderate Recommended treatment in ACM does not mechanism for chemotherapy-induced car- amounts of alcohol has been shown to have differ from other forms of DCM and should diotoxicity, which is related with the dysfunc- potent beneficial effects on the cardiovascular include guideline-based anti-failure medica- 24,25 25 tion of resident myocardial stem cells. system. In contrast, it is known since late tions. Special attention should be paid to b- Historically, cardiomyocytes have been consid- 19th century that chronic exposure to high lev- blocker treatment given its protective effect in ered as terminally differentiated cells, with no els of alcohol for a long period could lead to the above mentioned study.36 Although there postnatal turnover. However, several recent progressive cardiac dysfunction and heart fail- are no specific randomized studies examining studies15-18 provided strong evidence of the ure.24,25 Excessive alcohol intake is currently the efficacy of implatable cardioverter defibril- presence of a cardiomyocyte turnover in the commercialrecognized as a common cause of dilated car- lators (ICDs) on ACM, a device should always human heart controlled by a resident stem cell diomyopathy (DCM), and DCM due to alcohol be considered in patients with ACM and population. Cardiac cell turnover has been abuse is known as alcohol-related cardiomy- severely impaired systolic function, who seem recently quantified by measuring the amount opathy (ACM) (Table 1, Figure 1).25,26 The evi- to be at higher risk of malignant ventricular of carbon 14 (14C) integrated into DNA of car- dence supporting excessive alcohol exposure compared to other DCM diomyocytes from subjects born Non both before as a cause of DCM includes several experi- patients.37,38 On the other hand, the ultimate and after the nuclear bomb tests.16 By fitting mental studies,25 epidemiological studies decision regarding an ICD is challenging, those measurements with an appropriate showing higher prevalence of excessive alco- because LVEF can greatly improve in the first mathematical model, the calculated annual hol consumption in DCM patients than in the year after diagnosis. Only one study has specif- rate of cardiomyocyte renewal was 1% at 25 general population,27 and echocardiographic ically investigated the incidence of ventricular years of age and decreased to 0.45% at 75.16 studies in asymptomatic alcohol abusers.28 arrhythmias in ACM.38 Investigators reported Higher values are observed in non-cardiomy- Based on experimental studies the patho- that no malignant ventricular arrhythmias ocytes myocardial cells (e.g., fibroblasts). In physiology of ACM includes several processes were found among ACM patients if LVEF had 29 38 the normal human heart nearly 14 myocytes with a crucial role of apoptosis and excess improved to or remained ≥40%. per million of cells are actually dividing.15 More oxidative stress.30 In addition, genetic predis- Complete withdrawal is recommended to all than 150 cardiomyocytes per million of cells position is likely to play a major role.25,31 patients with ACM and may lead to complete are subject to apoptosis.19 Therefore, if a small Individual susceptibility to ACM is supported recovery of cardiac function, and three long- fraction of cardiac myocytes is cycling, it may by the fact that only a small subset of alcohol term studies have shown better outcomes of be sensitive to the antiproliferative action of abusers develop the disease. Prevalence of ACM in abstainers than in patients who main- anthracyclines. Proliferating myocytes ACM in DCM series range from 23 to 47% mak- tained alcohol consumption.32-34 Nevertheless, increase in the damaged human heart (e.g., ing ACM the leading cause of DCM in western there is controversy regarding the need for after ischemia).15 The same phenomenon may countries.25 The diagnosis of ACM is usually complete alcohol withdrawal in ACM. The con- be active in anthracycline-induced cardiomy- one of exclusion in a patient with DCM with no troversy emerges from the observation that

[Cardiogenetics 2016; 6:5862] [page 9] Review

studies evaluating the effect of alcohol absti- and its main metabolite, acetaldehyde. events that occur in alcohol-induced myocar- nence included patients who reduced alcohol Most studies highlight abnormalities of intra- dial damage are unresolved. intake to low/moderate levels alongside with cellular organelles causing alterations in the those who stopped consuming alcohol com- energetic metabolism and calcium homeosta- pletely.21-34 Furthermore, the only contemporary sis, which are especially relevant for the devel- study found that prognosis and degree of LVEF opment of contractile anomalies. The mecha- Myocarditis recovery in ACM patients who decreased alco- nisms described to date include: apoptosis,39 hol intake to moderate levels was comparably up-regulation of the L-type calcium channels,40 Myocarditis (Table 1) is an inflammatory favorable to that of abstainers.36 Ultimately, alterations of the excitation-contraction cou- disease of the heart muscle and is defined complete alcohol cessation appears desirable pling in cardiac myocytes,41 structural and immunohistochemically by the presence on 2 for ACM patients giving the fact that these functional alterations of the mitochondria and endomyocardial biopsy of ≥14 leucocytes/mm - patients have suffered an important addiction sarcoplasmic reticulum,42 changes in calcium including up to 4 monocytes/mm2- with the 43 and may find it extremely difficult to maintain sensitivity of myofilaments, alterations of presence of CD3 positive T-lymphocytes ≥7 low-moderate intakes over time. mitochondrial oxidation,39 deregulation of pro- cells/mm2.46 Myocarditis can be suspected clin- Basic research studies have described sev- tein synthesis, decrease of contractile pro- ically in symptomatic subjects [chest pain, eral mechanisms that could be involved in teins44 and activation of the renin-angiotensin pseudoischemic electrocardiographic (ECG) determining the functional and structural system and of the sympathetic nervous pattern, dyspnea, unexplained arrhythmias, alterations found in ACM, linked both to system.45 To date, however, the sequence of cardiogenic shock] in the presence of one or

Table 2. Reversible dilated cardiomyopathies. Disease Diagnosis Etiology Prevalence Recovery Prognosis Specific therapy

Chemotherapy- A ≥5% decline LVEF - ROS generation 3-26% of Up 55% in - Poor for type - Reduce dose/ induced CMP resulting in an LVEF - Formation of DNA adducts patients undergoing 2 years7 I cardiotoxicity: 60% discontinuation of the <55% with symptoms - Top2 inhibition chemotherapy1 mortality at 2-3 chemotherapic agent of heart failure, or a - Dysfunctionβ of resident yearsonly for doxorubicin, - Earlier detection ≥10% decline to result myocardial stem cells up to 40% for of myocardial damage in an LVEF <55% - Ischemia (cisplatin, cyclophosphamide (strain echocardiography, without symptoms 5-fluorouracil - Low mortality for type CMR, proBNP, etc.) of heart failure1,3 and rituximab)1-5 use II cardiotoxicity:5 - Dexrazoxane (debated) 2.5% of all heart - b-blockers, transplant6 ACE-inhibitors and statins (debated) - Stem cell therapy (experimental) Alcohol-related CMP Dilatation and 80 g a day of Up to 40% of 37% at 4 years At 4 years from - Complete alcohol impaired alcohol intake DCM pts in from diagnosis, withdrawal contraction (equivalent western diagnosis36 30% dies or - Standard anti-failure of the left ventricle To 10 U or 5 countries36 needs a heart medications, or both ventricles glasses of 12% transplant, 33% with special priority related to excessive wine or 3-4 pints shows persistent to -blockers alcohol intake of beer) for at LV dysfunction36 β least 5 years commercial Myocarditis Inflammatory - Viral infections 9-16% of DCM - 50% At 11 years follow Antiviral agents disease of the (PVB19, HHV6, adult patients46 non-fulminant up 93% of fulminant (interferon), heart muscle enterovirus, acute myocarditis pts alive immunosuppression on EMB: adenovirus, myocarditis46 compared to 45% (azathioprine, cortisone), 2 ≥14 leucocytes/mm - Non influenza A virus, - Up to 90% of of acute immunomodulation including up to 4 EBV, CMV, fulminant myocarditis pts57 (intravenous monocytes/mm2- HCV, HIV) myocarditis56 immunoglobulin) with the presence - Other infectious (debated and of CD3 positive agents (bacterial, controversial) T-lymphocytes fungal, protozoal) 2 46 ≥7 cells/mm - Immuno-mediated toxic agents Peri-partum CMP LVEF <45% or FS - Viral myocarditis 1:4000 to Up to 65% - If dilation and - Avoid all teratogenic <30% or both58 - Auto-immunity 1:1000 of patients systolic dysfunction drugs if pregnancy/ presenting - Inflammation live births within 6 months persist, the prognosis lactation is ongoing, with signs - Increased oxidative in the Western of delivery62 is poor including of cardiac stress and apoptosis World60,61 - If there is full ACE-inhibitors failure during - Malnutrition recovery within and ARBs the last month - Prolactin 6 months from - Bromocriptine (debated) of pregnancy or - Hemodynamic stress delivery, the prognosis - Pentoxifylline within 5 months - Genetic milieu is excellent (debated) of delivery26 (Titin gene)65 CMP, cardiomyopathy; LVEF, left ventricular ejection fraction; ROS, reactive oxidative species; CMR, cardiovascular magnetic resonance; ACE-inhibitors, angiotensin-converting enzyme inhibitors; DCM, dilated cardiomyopathy; EMB, endomy- ocardial biopsy; PVB19, parvovirus B19; HHV6, human herpesvirus 6; EBV, Epstein-Barr virus; CMV, citomegalovirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; FS, fractional shortening; ARBs, angiotensin II receptor blockers.

[page 10] [Cardiogenetics 2016; 6:5862] Review more diagnostic criteria: ECG and/or Holter Little is known about the early stages of ated during which can further potentiate car- monitoring abnormalities (brady- and tach- acute viral myocarditis in patients. diomyocyte damage and reduce contractile yarrhythmias), elevated cardiac enzymes, Enteroviruses (e.g., Coxsackie-B viruses) are function. Phase 2 (the subacute phase) can functional and structural abnormalities detect- responsible for one quarter of cases49 and their last weeks to months; in most patients, ven- ed by cardiac imaging including tissue abnor- mechanism of damage to the myocardium has tricular contractile function improve as the malities detected by CMR. The diagnosis can been well characterized in animal models. amount of replicating viruses diminishes. also be suspected in asymptomatic subjects Enteroviruses gain access to the host via the However, the cardiomyopathy may enter a when two or more diagnostic criteria from dif- gastrointestinal or respiratory tracts, the heart chronic phase, which becomes irreversible. ferent categories are met. Estimated incidence being a secondary target. Myocardial infection Other viruses cause myocarditis by different is 22/100,000/year.47 Viral infections [par- occurs in 3 subsequent phases: i) viral entry mechanisms. PVB19 can hibernate after a pri- vovirus B19 (PVB19), human herpesvirus 6, into cardiomyocytes and activation of innate mary infection in childhood and later infect enterovirus, adenovirus, influenza A virus, immunity; ii) viral replication and activation of the cardiac endothelium. PVB19 genomes have Epstein-Barr virus, citomegalovirus, hepatitis acquired immune responses; iii) resolution been found in cardiac endothelial cells in C virus, human immunodeficiency virus] are with recovery or development of chronic dilat- patients with fulminant myocarditis.55 Though the most common cause of myocarditis, fol- ed cardiomyopathy. Initial viral entry is medi- not directly infecting cardiomyocytes, the virus lowed by other infectious agents (bacterial, ated by a specific cell-surface receptor. exerts its pathogenic effects by local activation fungal, protozoal, etc.), immuno-mediated Enteroviruses and adenoviruses recognize a of cytokines [tumor necrosis factor (TNF- ) causes and toxic agents. Using polymerase common transmembrane receptor on car- a a and interleukin-6 (IL-6)] and induction of chain reaction technology, viral RNA or DNA is diomyocytes, the coxsackievirus and aden- endothelial apoptosis. Endothelial damage may commonly identified within the myocardium of ovirus receptor.51,52 This is essential for the ini- in turn compromise tissue perfusion, causing affected patients.48 Extensive studies per- tiation of the infection53 and subsequent viral myocardial ischemia. Moreover, accumulation formed in biopsy and autopsy myocardial spec- replication leading to myocyte necrosis.54 of lymphocytes in the coronary microcircula- imens have linked specific viral infections Natural killer cells, macrophages, and T lym- tion leads to a sustained rise in coronary with up to 69% of cases of clinical myocardi- phocytes migrate towards the infection site, resistance, contributing to myocyte necrosis. tis.49 Moreover, elevated serum levels of anti- causing additional myocardial injury. The lat- bodies against specific viruses have been ter starts the second phase, where autoim- onlyAlthough myocarditis is an acquired dis- detected in patients with idiopathic dilated mune reactions activate T cells that target host ease, genetic polymorphisms may facilitate cardiomyopathy.50 myocardium. High levels of cytokines are liber- viral infection and direct cellular damage and may play a role in subsequent immuno-mediat- ed injury. In addition, genetically determined use DCM may represent a preferential substrate for myocarditis. Clinical presentation may be: i) fulminant (lymphocytic, giant cell myocardi- tis), which can rapidly evolve towards cardio- genic shock and death, but may resolve com- pletely in survivors; ii) acute, which often resolves completely; and iii) chronic active myocarditis, characterized by ongoing inflam- mation and damage leading to DCM. Complete recovery of LV function occurs in about 50% of patients with non-fulminant commercial acute myocarditis46 and up to 90% of patients with fulminant myocarditis.56 In one study, at 11 years follow up 93% of fulminant myocardi- tis patients were alive compared to 45% of patients with acute myocarditis.57 Supportive Non and standard anti-failure medications are still the cornerstone of treatment. The evidence favoring specific therapy with antiviral agents (for example interferon), immunosuppression (azathioprine, cortisone), immunomodulation (intravenous immunoglobulin) is still based on small studies46 and controversial. It is unclear why some patients have full recovery and others have persistent LV dysfunction. In addition, it is not clear how long heart failure Figure 1. Echo still frame images (diastole top panels, systole bottom panels) from a 52- treatment is needed after normalization of LV year old male admitted for acute heart failure and past medical history including hyper- function. Finally, it is still controversial tension, atrial and consumption of 100 g of alcohol per day for more than 20 whether family screening should be consid- years and normal coronary arteries. An echocardiogram (left panels) showed a very dilat- ed left ventricle (LV), with LV ejection fraction <25% and right ventricular (RV) mild to ered, as evidence of myocardits does not moderate systolic dysfunction. An echocardiogram performed 6 years after first evalua- exclude genetically determined DCM or - in tion (right panels), after standard heart failure medication and complete alcohol intake patients presenting with sudden cardiac death withdrawal, shows normal LV and RV size and function. - a channellopathy.

[Cardiogenetics 2016; 6:5862] [page 11] Review

immune system effectiveness is restored prompt family screening. The molecular mech- Peripartum cardiomyopathy shortly after delivery.68 The hemodynamic anisms underlying these conditions are often stress associated with pregnancy (increased unclear and it is still unknown how long heart Peripartum cardiomyopathy (PPCMP) preload and decreased afterload) has been failure treatment needs to be continued once (Table 1) is an increasingly recognized entity shown to cause LV remodeling and hypertro- LV function has recovered and whether pri- characterized by LV dysfunction (defined as LV phy.69 The physiological reduction in LV sys- mary or secondary prevention is possible, for ejection fraction <45% or fractional shorten- tolic function brought on by the reverse- example before starting a potential cardio- ing <30% or both58 presenting with signs of car- remodeling process after delivery may be more toxic chemotherapy or planning a new preg- diac failure during the last month of pregnancy exaggerated in subjects with peripartum car- nancy. Specific treatments are emerging for or within 5 months of delivery,26 where no diomyopathy. Animal studies supported the some conditions (e.g., peripartum cardiomy- other cause of heart failure is found. LV func- role of prolactin in peripartum cardiomyopa- opathy or autoimmune myocarditis), but still tion tends to recover in the majority of cases thy. Decreased levels of myocardial signal based on small studies. In all these forms, early within 6-12 months. Duration of standard anti- transduction lead via catabolism of prolactin to recognition appears a cornerstone for clinical failure medication after normalization of LV an antiangiogenic and proapoptotic isoform of management, before permanent ultrastructur- function is unknown. The risk of PPCMP with the hormone in the heart, which may cause al and structural damage occur, in order to subsequent pregnancies, although still uncer- PPCMP.70 Of note, these results have been con- improve likelihood of recovery. For example, tain, depends on recovery of LV function, and firmed in patients, supporting a specific anti- recognizing TIC is fundamental as LV dysfunc- has been described in up to 50% of patients prolactin therapeutic strategy. tion may be completely reversible once tachy- with persistent dysfunction compared to 20% Recovery of LV systolic function has been cardia has been controlled, even though it may in patients with LVEF normalization.59 The reported in up to 65% of patients within 6 have been so severe as to be considered for mechanism of relapse remains unclear and it months of delivery.62 Management of PPCMP transplantation.75 It is also important to note is unknown whether preventive measure can includes standard heart failure regimen, but that a significant minority of cases of dilated be implemented in patients with prior history careful consideration must be made to avoid cardiomyopathy recover even in absence of of PPCMP undergoing a new pregnancy. all teratogenic drugs if the pregnancy is ongo- reversible factors. Finally, these conditions The prevalence of PPCMP has been estimat- ing, including angiotensin-converting enzyme represent paradigms of cardiac recovery sug- ed to be 1:4000 to 1:1000 live births in the inhibitors and angiotensin-receptor blockers. gestingonly a number of molecular mechanisms, Western world.60,61 Advanced maternity age, Hydralazine and nitrates may be safely used as which might be exploited in other cardiac con- race (African), twin gestation, multiparity, alternative therapies. b-adrenoceptor blockers ditions that are at present progressive and gestational hypertension, chronic hyperten- may also be used during pregnancy. unresponsive to therapy. The identification of sion, preeclampsia, prolonged use of tocolytics Immunosuppressive agents and immunoglob-usepathways to recovery also shows the way for are known risk factors for PPCMP.62 The etiolo- ulins may be considered in patients with biop- novel therapeutic targets ultimately benefit- gy remains largely unknown. Viral myocardits, sy-proven myocarditis that have not improved ting all cardiac patients. However, the road auto-immunity, inflammation, increased after two weeks of standard heart failure ther- ahead towards definite evidence and practical oxidative stress and apoptosis, genetic predis- apy.66,71 Bromocriptine, which inhibits pro- application remains long and winding. position, malnutrition, prolactin and hemody- lactin secretion, has been shown to promote namic stress have all been proposed as patho- recovery of LV function in a small PPCMP genetic or contributing mechanisms. Familial cohort,72 but safety issues have limited its use occurrence of PPCMP has been described and in clinical practice.73 The anti-inflammatory References genetic association has been shown in mice agent pentoxifylline has been investigated in a and humans.63,64 Recently, a large study on 172 small trial74 and shown to be effective, but fur- 1. Yu AF, Steingart RM, Fuster V. PPCMP patients, showed a prevalence of trun- ther evidence is required. Cardiomyopathy associated with cancer cating variants (especially in the Titin gene) commercial therapy. J Card Fail 2014;20:841-52. similar to DCM patients, suggesting that these 2. Plana JC, Galderisi M, Barac A, et al. variants may predispose to the condition.65 Expert consensus for multimodality imag- Myocarditis appears to be the main patho- Clinical perspective ing evaluation of adult patients during and physiological mechanism in PPCMP. A 76% after cancer therapy: a report from the incidence of myocarditis at myocardialNon biopsy The diverse forms of dilated cardiomyopathy American Society of Echocardiography and was reported in a study on a large number of associated with a potential for recovery of LV the European Association of Cardiova - patients with PPCMP.66 Inflammatory cytokines dysfunction share a number of features. The scular Imaging. Eur Heart J Cardiovasc have also been named as possible leading etiology may be uncertain and a specific diag- Imaging 2014;15:1063-93. causative factors for PPCMP. In patients with nosis may be often difficult. An history of 3. Seidman A, Hudis C, Pierri MK, et al. PPCMP, some studies found elevated plasma stressful events may lack in Tako-Tsubo car- Cardiac dysfunction in the trastuzumab levels of cytokines, such as TNF-a and IL-6, as diomyopathy, the role of concomitant tach- clinical trials experience. J Clin Oncol well as Fas/APO-1 (a apoptosis-signaling sur- yarrhythmias may be unclear in - 2002;20:1215-21. face receptor).67 Cytokines may lead to PPCMP induced cardiomyopathy (TIC), patients may 4. Khouri MG, Douglas PS, Mackey JR, et al. through initiation of an inflammatory cascade have had chemotherapy in the past with dubi- Cancer therapy-induced cardiac toxicity in when they come in contact with fetal cells that ous impact on later occurrence of LV dysfunc- early breast cancer: addressing the unre- have reached the maternal circulation during tion, the amount of alcohol consumption may solved issues. Circulation 2012;126:2749-63. delivery. These cells may have initially escaped be difficult to ascertain and DCM found during 5. Nolan MT, Lowenthal RM, Venn A, the maternal immune system because of the pregnancy may be pre-existing. Sometimes, Marwick TH. Chemotherapy-related car- immunosuppressive state of pregnancy. These more than a possible cause is found, and all diomyopathy: a neglected aspect of cancer cells are therefore able to settle in various these conditions may represent acquired dis- survivorship. Intern Med J 2014;44:939-50. organs, including cardiac tissue, leading to an ease sponsored by genetic predisposition or 6. Mukku RB, Fonarow GC, Watson KE, et al. autoimmune trigger when the maternal unmask true genetic DCM, which should Heart failure therapies for end-stage

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