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Journal of the American College of Cardiology Vol. 63, No. 5, 2014 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.063

STATE-OF-THE-ART PAPER

Pre-Clinical Diastolic Dysfunction

Siu-Hin Wan, MD,* Mark W. Vogel, MD,y Horng H. Chen, MB, BCHz Rochester, Minnesota; and St. Louis, Missouri

Pre-clinical diastolic dysfunction (PDD) has been broadly defined as left ventricular diastolic dysfunction without the diagnosis of congestive heart failure (HF) and with normal systolic function. PDD is an entity that remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic HF including dyspnea, edema, and fatigue. In diabetic patients and in patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared with patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients’ morbidity and mortality. This review will focus on what is known concerning pre-clinical diastolic dysfunction, including definitions, staging, , pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed. (J Am Coll Cardiol 2014;63:407–16) ª 2014 by the American College of Cardiology Foundation

Heart failure (HF) is an epidemic that, on the basis of 2013 myofilament sensitivity to calcium (5,6). This highlights the estimates, affects 5.1 million American adults, and this importance of continued research at the molecular and epidemic will grow 25% by 2030 as the U.S. population clinical level for DD to allow for greater understanding and continues to age (1). HF is a clinical diagnosis (2).An development of effective treatment options. < ejection fraction (EF) of 50% in a patient with HF The American College of Cardiology and American symptoms is termed heart failure with reduced ejection Heart Association have categorized HF into 4 stages: stage fraction (HFrEF), and an EF of 50% in a patient with Aisdefined as high risk for HF without structural heart heart failure symptoms is termed heart failure with pre- disease or symptoms of HF; stage B is defined as structural served ejection fraction (HFpEF). Studies have de- heart disease without signs or symptoms of HF; stage C is monstrated that HFpEF is as prevalent as HFrEF (3).Itis defined as symptomatic HF; and stage D is HF refractory to important to note that these terms are not mutually exclu- treatment (7). sive, as nearly all patients with systolic dysfunction have Pre-clinical diastolic dysfunction (PDD), defined as some degree of concomitant diastolic dysfunction (4). Yet, diastolic dysfunction with normal systolic function and no the converse does not hold, which suggests that there is an symptoms of HF, therefore, resides in stage B according to unclear relationship between systolic dysfunction (SD) and the American College of Cardiology/American Heart diastolic dysfunction (DD). Association scheme (7). The importance of PDD is evident Although the endpoint of HF and clinical symptoms may in that even after controlling for comorbidities, PDD has be similar in both categories, the pathophysiology of SD been shown to be associated with development of HF and is and DD are quite different. For example, studies have predictive of all-cause mortality (4,8). Also, advanced indicated that, although SD seems largely a disease of diastolic dysfunction is associated with reduced quality of life calcium handling, DD seems to be a disease of increased and structural abnormalities that reflect increased cardio- vascular risk (9). From the *Department of Internal Medicine, Mayo Clinic and Foundation, Despite the seemingly simplistic definition of PDD, truly Rochester, Minnesota; yDivision of Cardiovascular Diseases, Washington University, St. Louis, Missouri; and the zDivision of Cardiovascular Diseases, Mayo Clinic and understanding diastolic dysfunction, HF symptoms, and Foundation, Rochester, Minnesota. This research was supported by grants from the their relationship is exceedingly complex. This complexity National Institutes of Health P01 HL 76611 and R01 HL-84155 and by the Mayo stems from the fact that in addition to diastolic dysfunction, fi Foundation. Dr. Chen is the cofounder and chief medical of cer of Zumbro comorbid conditions, including pulmonary, renal, and Discovery; has received royalties from Nile Therapeutics, Anexon Inc., and UpToDate Inc.; and, through Mayo Clinic, holds patents on chimeric natriuretic peptides. hematologic dysfunction, play an important role in devel- Drs. Wan and Vogel have reported that they have no relationships relevant to the opment of symptomatic HF (Fig. 1). It has been recognized contents of this paper to disclose. that although some patients with normal EF may have Manuscript received March 15, 2013; revised manuscript received October 8, 2013, accepted October 15, 2013. overt HF symptoms or HFpEF, others may have marked 408 Wan et al. JACC Vol. 63, No. 5, 2014 Pre-Clinical Diastolic Dysfunction February 11, 2014:407–16

Abbreviations impairment in diastolic function As the apex of the heart stays relatively stationary during the and Acronyms that may be associated with no cardiac contraction and relaxation cycle, the base moves symptoms or PDD (10). toward the apex during systole and retracts during diastole. BNP = B-type natriuretic peptide Additionally, it has been shown Therefore, the velocity at the apex is zero while the velocity that left ventricular (LV) function at the base during cardiac contraction and relaxation is at COPD = chronic obstructive pulmonary disease measured at rest can differ signif- maximum. By characterizing the rate of change of velocity

DD = diastolic dysfunction icantly from exercise tolerance and throughout the heart, or the amount of deformity of cardiac severity of HF symptoms (11). muscle, strain rate can be calculated (18). Although strain EF = ejection fraction Therefore, exercise intolerance has rate imaging has not been officially incorporated into the HF = heart failure significant diagnostic implications. diastolic classification algorithm, it has shown promise in HFpEF = heart failure with Cardiopulmonary exercise testing, differentiating between those with and without diastolic preserved ejection fraction including determination of peak dysfunction (19). However, recent evidence demonstrates HFrEF = heart failure with oxygen uptake, is an objective that peak strain is not only dependent on ventricular relax- reduced ejection fraction method used to determine the ation, but also on restoring forces and early diastolic load as LV = left ventricular functional capacity of a patient well (20). Given the recent new evidence on limitations of LVH = left ventricular with HF and for determination of using strain rate for characterizing ventricular relaxation, it hypertrophy disease severity (12). Recent pub- remains to be seen how clinically useful strain rate imaging NT-proBNP = N-terminal lished data has suggested the will be compared with traditional methods for diastolic pro–B-type natriuretic peptide importance of measuring diastolic dysfunction determination.

PDD = pre-clinical diastolic and peripheral function variables Cardiac magnetic resonance (CMR) imaging has long dysfunction during exercise, which may not been used for assessment of systolic function, but recent

SD = systolic dysfunction correlate to rest measurements, to efforts have been made to apply CMR techniques to eval- better characterize HF severity uation of diastolic function. Tagged magnetic resonance (13–15). Future studies in PDD should include exercise imaging of the heart has the potential as a noninvasive testing, which would allow for greater diagnostic accuracy as technique to provide myocardial strain and deformation well as advance the understanding of PDD. information. CMR offers tremendous spatial resolution advantages when compared with echocardiography, and can fl Assessment of DD accurately assess left atrial size and transmitral ow (21). However, the limited temporal resolution of magnetic Although systolic function is well characterized by deter- resonance imaging along with the high costs associated with minations of ejection fraction, diastolic function character- its use compared with conventional echocardiography limits ization of the heart’s stiffness, relaxation, and pressure CMR’s widespread use. changes is more difficult. Invasive measures of rate of LV pressure decline, LV relaxation time constant, and stiffness modulus can characterize diastolic function. Echocardiog- raphy as a common noninvasive imaging technique is useful in determining the presence of SD or DD. In diastole, the LV filling pattern consists of 2 phases: early (E) and late or atrial contraction (A). The E/A ratio is used as an estimate of the relaxation pattern of the ventricle. Furthermore, tissue Doppler imaging can be used to measure myocardial motion, specifically the amount the mitral annulus recoils toward the base during early diastole (e0). The LV filling pressures can be estimated by the E/e0 ratio. DD is categorized by Doppler echocardiographic findings into the following progression: 1) mild (Grade I or Ia), defined as impaired relaxation without or with mild evidence of increased filling pressures, respectively; 2) moderate fi Cardiovascular and Noncardiac Risk Factors in the (Grade II), de ned as impaired relaxation associated with Figure 1 moderate elevation of filling pressures or pseudonormal Development and Progression of PDD and HFpEF filling; and 3) severe, defined as advanced reduction in Cardiovascular risk factors contribute to the development of pre-clinical diastolic compliance or reversible (Grade III) or fixed (Grade IV) dysfunction (PDD) (stage B). Both cardiovascular and noncardiac risk factors restrictive filling (16,17). contribute to the progression from PDD to symptomatic heart failure with To better understand and characterize the pathophysi- preserved ejection fraction (HFpEF) (stage C/D). Although survival decreases dramatically in symptomatic heart failure, the duration of stages A and B heart ology of diastolic dysfunction, recent imaging research has failure with regards to survival remains to be fully elucidated. focused on using echocardiographic strain rate imaging. JACC Vol. 63, No. 5, 2014 Wan et al. 409 February 11, 2014:407–16 Pre-Clinical Diastolic Dysfunction

Epidemiology of PDD Table 1 Prevalence of PDD fi Given the nuances in de ning ventricular DD and HF, and PDD (Redfield et al. [4]) the lack of PDD as a common diagnostic code, exact General adult population measurements of PDD prevalence are difficult. Previously, All 27.4 Fischer et al. (22) found an overall prevalence of diastolic Men 28.5 abnormalities to be 11.1% in a randomly selected sample Women 26.4 from the MONICA (Monitoring Trends and Determinants High-risk population* on Cardiovascular Diseases) project, and Kuznetsova et al. All 64.1 (23) found an overall prevalence of 27.3% for DD. Despite Men 63.3 the valuable DD prevalence data provided by these studies, Women 64.7 Elderly Population in Central Italy (25) a limitation is that this data is for DD as a whole without Men regard to symptoms, that is, it does not distinguish between All 35.8 patients with PDD and those with HFpEF. Age 65 to 74 yrs 31.3 Currently, there are 4 original publications that have Age >74 yrs 44.2 contributed most to our understanding of PDD epidemi- Women ology (4,9,24,25). All 35.0 Redfield et al. (4) conducted a survey of 2,042 randomly- Age 65 to 74 yrs 30.0 selected residents of Olmsted County, Minnesota, age 45 Age >74 yrs 44.0 years and older, from June 1997 through September 2000. Framingham Heart Study (24) Participants underwent Doppler echocardiographic assess- General adult population 36.0 Australian population (9) ment of systolic and diastolic function, and the presence of General adult population, 4.9 HF diagnosis was determined by review of the medical record. PDD with moderate to severe DD

Abhayaratna et al. (9) conducted a cross-sectional survey Values are % with PDD. *The high-risk population was defined by age 65 years and hypertension of 1,275 randomly-selected residents of Canberra, Australia, or coronary artery disease. ¼ ¼ age 60 to 86 years, between February 2002 and June 2003. DD diastolic dysfunction; PDD pre-clinical diastolic dysfunction. Participants underwent Doppler echocardiography and completed a self-administered regarding their Both Redfield et al. (4) and Abhayaratna et al. (9) found medical history that was cross-referenced with documenta- that the prevalence of diastolic dysfunction increased with tion in the medical records. Abhayaratna et al. (9) found on age; the presence of cardiovascular comorbidities such as echocardiography that 23.5% and 5.6% of the population hypertension, obesity, coronary artery disease, history of had mild and moderate-to-severe DD, respectively. myocardial infarction, and cardiomyopathies; diabetes; and In both studies, subjects with DD but without an HF systolic dysfunction. Abhayaratna et al. (9) also found that diagnosis by history or clinical records were considered to clinical predictors of DD with normal EF included hyper- fi have PDD (4,9).Red eld et al. (4) found a prevalence of tension, angina, myocardial infarction, and obesity. They 20.6% for mild PDD and a prevalence of 6.8% for moderate also reported that the rates of isolated DD, that is DD with to severe PDD in the general adult population. High-risk normal EF, increased with age (4,9). In the PREDICTOR groups, or patients age 65 years with diagnoses of hyper- (Assessing the prevalence of asymptomatic cardiac dysfunc- tension or coronary artery disease, were found to have tion and heart failure) investigation, an Italian population of a higher prevalence of PDD: 47.6% for mild PDD and 1,720 elderly subjects age 65 to 84 years, Mureddu et al. (25) 16.5% for moderate to severe PDD (Table 1) (4). found that 35.4% of the population had PDD (25). Doppler Redfield et al. (4) found that, even among those subjects echocardiographic data was used to evaluate cardiac func- with moderate or severe diastolic dysfunction, less than one- tion, and HF was defined on the basis of history and half had recognized HF and the majority were, therefore, in physical examination using the European Society of Cardi- the pre-clinical stage of disease. This result was consistent ology guidelines, with each subject evaluated by a panel of with the findings of Abhayaratna et al. (9), who found that 3 cardiologists. 86% of subjects with moderate to severe DD with normal EF Another finding of Abhayaratna et al. (9) was that were in the pre-clinical stage of disease as assessed by Fra- moderate to severe DD with normal EF was independently mingham criteria. Abhayaratna et al. (9) also found that 36% associated with structural abnormalities (increased LV mass of these same patients were asymptomatic as judged by New and left atrial volume) that reflect increased cardiovascular York Heart Association functional classification (4,9,26). risk, with increased circulating amino-terminal pro–B-type Similarly, Lam et al. (24) found in the Framingham natriuretic peptide concentrations, and with decreased cohort of 1,038 elderly patients that the prevalence of PDD quality of life (9). Similarly, Redfield et al. (4) determined was 36% using Doppler echocardiographic data and evalu- that increasing severity of PDD was associated with higher ating for HF symptoms of dyspnea, edema, and exertional LV mass index and mean left atrial volume index. fatigue. Furthermore, multivariate analysis revealed that DD was 410 Wan et al. JACC Vol. 63, No. 5, 2014 Pre-Clinical Diastolic Dysfunction February 11, 2014:407–16 predictive of all-cause mortality even when controlling for Although LV DD is known to be associated with the age, sex, and EF (4). development of left ventricular hypertrophy (LVH), inves- Two additional comorbidities that have profound impact tigations in both human and animal models of hypertension on DD are chronic obstructive pulmonary disease (COPD) suggest that early LV DD may precede the development of and anemia. COPD and HF are often comorbid conditions LVH. Dupont et al. (40) evaluated LV DD in spontane- that make accurate diagnosis challenging, as the presenting ously hypertensive rats at different ages and tested whether symptoms for both of these entities can be similar. However, LV DD is associated with abnormal intracellular calcium lung pathology decreases cardiopulmonary reserve and may homeostasis. The authors reported that LV myocardial DD convey an overall poorer prognosis (27,28). Anemia is also an precedes LVH in 3-week-old spontaneously hypertensive important comorbid condition in cardiac dysfunction, stem- rats and was associated with high diastolic intracellular ming from hemodilution, decreased red blood cell produc- calcium concentration, possibly due to decreased SERCA tion, and concurrent renal disease. Anemia has been shown 2a (sarcoplasmic reticulum calcium ATPase isoform 2a) and to convey a worse prognosis to those with heart failure (29). p16-PLB (phospholamban Ser16) protein levels. Previ- Aging is one of the most profound factors that influences ously, LVH regression was identified as a relevant marker of PDD and the development of HFpEF. Although the work significant improvement in LV diastolic function. Never- of both Redfield et al. (4) and Abhayaratna et al. (9) show theless, to this extent, the published report lacks consistent that DD increases with age, this remains a topic requiring data. For instance, a previous double-blind, randomized further exploration given the lack of age-adjusted reference trial reported significant LVH regression with antihy- standards for DD measurements. A better understanding of pertensive treatment (enalapril or nifedipine), but also re- normal aging with regard to diastolic function would allow ported little change in traditional Doppler diastolic for greater understanding of PDD and subsequent devel- parameters (41). In , an experimental LVH model opment of HFpEF. that demonstrated beneficial effects of phosphodiesterase-5 In summary, the prevalence of PDD in the general adult inhibition on LVH failed to properly predict the results of population is approximately 20% to 30%, with increasing age, the phosphodiesterase-5 inhibition to improve clinical coronary artery disease, cardiovascular comorbidities, and status and exercise capacity in diastolic HF (RELAX study diabetes as independent risk factors for development of PDD. [PhosphodiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure]) Pathophysiology (42,43). Future therapeutic studies are needed to determine whether the regression of LVH or the improvement of Diastole encompasses the isovolumetric relaxation and filling diastolic function would prevent the progression from PDD phases of the cardiac cycle and includes active and passive to HFpEF. components. Diastolic filling of the left ventricle (LV) is Additionally, recent evidence suggests that contractile generally biphasic, with rapid filling in early diastole, and dysfunction and myocardial remodeling may play a signifi- late filling is determined by atrial contraction, left atrial cant role in the pathophysiology of HFpEF. Although pressure, and LV operating chamber stiffness (30).DD contractile dysfunction is traditionally associated with refers to abnormal mechanical properties of the myocardium HFrEF, Dunlay et al. (44) showed that patients with and includes abnormal LV diastolic distensibility, impaired HFpEF demonstrated a progressive decline in ejection filling, and slow or delayed relaxation (30). In DD, the fraction over time. However, this hypothesis will require ventricle cannot accept blood at low pressures and ventric- further confirmatory investigations. ular filling is slow or incomplete unless atrial pressure rises Interesting recent work in animal and human models have (31). Therefore, there is an increased dependence on filling implicated titin isoform shift, oxidative stress, nitric oxide through atrial contraction and there are higher atrial synthase dysfunction, and myosin-binding protein C in dia- pressures to maintain filling or cardiac output (32–34). With stolic dysfunction. Titin isoform shift, or the overexpression regards to relaxation, any mechanism that interferes with of the stiff isoform of titin, has been found in endomyocardial actin-myosin cross-bridge detachment or with removing biopsy samples of patients with HFpEF (45). In patients with calcium from the cytosol can delay this process (35). type 1 diabetes, advanced glycation end products and oxida- DD during the late filling phase of diastole can be a result tive stress have been found to be associated with LV of increased LV operating stiffness (diastolic stiffness), which dysfunction (46). Nitric oxide is a known mediator of cardiac is determined mainly by myocardial mass and myocardial relaxation, and cardiac oxidation leading to uncoupling of composition. In fact, numerous factors can influence LV cardiac nitric oxide synthase results in DD (47). Last, myosin- stiffness including age, increased LV wall thickness relative binding protein C, a protein located in crossbridge zones of to cavity size (such as in hypertension or aortic stenosis), muscle sarcomeres, is important in regulating muscle intracellular changes in titin or microtubules, extracellular contraction. Phosphorylation of this important protein leads changes in collagen, and infiltration (e.g., amyloidosis) (35–39). to deregulations of cardiac muscle contraction and subsequent In addition, neurohormonal and cardiac endothelial activity dysfunction of the ventricles (48). Indeed, Paulus and also modulate ventricular stiffness and relaxation (31). Tschope (49) describe a paradigm shift in thinking of HFpEF JACC Vol. 63, No. 5, 2014 Wan et al. 411 February 11, 2014:407–16 Pre-Clinical Diastolic Dysfunction as a process of comorbid conditions leading to a systemic tissue Doppler imaging of diastolic function in Olmsted inflammatory state and microvascular inflammation, rather County, Minnesota, from 2001 to 2007 were identified and than focusing on myocardial structure and function. followed to determine the probability of HF development (53). Patients were excluded if they had a prior HF diag- Natural History of PDD nosis. Overall, 1,760 patients were included, and 411 of these had PDD. The 5-year cumulative probability of HF Currently, there are only a few original publications that have development among the PDD patients with diabetes was specifically addressed the natural history of PDD (50). 36.9% compared with 16.8% for those without PDD. The Additionally, the natural history of PDD is largely deter- 1-year cumulative probability of HF development among the mined by the underlying comorbidities, which provide unique PDD patients with diabetes was 13.1% compared with 5.2% prognostic determinations to those with DD. Mohammed for those without PDD. Furthermore, the 5-year cumulative et al. (51) demonstrated that comorbidities among those with probability of death among the PDD patients was 30.8% HFpEF led to different ventricular and vascular properties, compared with 12.1% for those without PDD. resulting in unique routes along a natural history continuum. It was also determined that PDD was associated with the Therefore, the evolution of PDD should be viewed in light of subsequent development of HF even after adjustment for the underlying disease contributing to DD. age, sex, body mass index, hypertension, coronary artery Hypertension and peripheral vascular disease result in the disease, left atrial size, and LV muscle mass. In addition, for progression of DD via ventricular remodeling secondary to every 1 U increase above 15 in the ratio of passive transmitral increased afterload. Kane et al. (8) recently reported that LV inflow velocity to tissue Doppler imaging velocity of the 0 longitudinal evaluation of participants in the population- medial mitral annulus during passive filling (E/e ), there was based OCHFS (Olmsted County Heart Function Study) a 3% greater likelihood of HF development. cohort revealed that LV DD is highly prevalent, tends to In his editorial comment regarding the study by From worsen over time, and is associated with advancing age. The et al. (53), Greenberg (54) emphasized the importance of data suggests that persistence or progression of DD is a risk realizing that there is now evidence showing a linearly factor for HF in elderly persons. Correa de Sa et al. (50) increased risk for development of HF among diabetic reported that in a cohort of PDD patients, the 2-year patients on the basis of E/e0. In addition, he noted that cumulative probability for development of HF according to diabetic patients with PDD who developed HF and/or died Framingham criteria was 1.9%; however, the 2-year cumu- did so at rates that were similar to those reported previously lative probability for development of any HF symptoms was for patients with asymptomatic LV SD (55). Although there 31.1%. It was also found that peripheral vascular disease and have been studies that suggest that poor glycemic control hypertension were independently associated with the among those with diabetes may increase progression to progression of PDD to development of symptoms. The HFpEF, it remains unclear whether treating hyperglycemia authors, therefore, speculated that ventricular-arterial will improve or reverse the condition (56). The pathology of may be important for this progression. PDD, therefore, may not be directly related to hypergly- Those with underlying renal disease are at higher risk of cemia, but rather to oxidative stress and the structural developing HFpEF, given a chronically fluid-elevated state. remodeling that occurs. In a by Vogel et al. (52), 388 subjects were Coronary artery disease leads to ischemic cardiomyopathy, followed for a mean of 4 years to determine the progression and subsequent cardiac remodeling results in the develop- of PDD to symptomatic HF. Among those with PDD, at 1, ment of HF. Ren et al. (57) also provided information 2, and 3 years of follow-up the cumulative probabilities for regarding the natural history of PDD in a more specific development of symptomatic HF were 2.2%, 5.7%, and study . They reviewed 693 subjects with coronary heart 11.6%, respectively. Through both univariable and multi- disease (defined as a history of myocardial infarction, variable analyses, they showed that age, right ventricular angiographic evidence of 50% stenosis in 1 coronary systolic pressure, and renal dysfunction with glomerular vessel, previous evidence of exercise-induced ischemia using filtration rate <60 ml/min were independently associated treadmill electrocardiogram or stress nuclear perfusion with development of HF. Furthermore, patients with PDD imaging, or history of coronary revascularization), normal were more likely to develop atrial fibrillation and cardiac systolic function, and no history of HF. They found that 455 hospitalization for coronary artery disease, myocardial (66%) had normal LV diastolic function, 166 (24%) had infarction, or peripheral vascular disease. In addition, the mild LV DD, and 72 (10%) had moderate to severe LV 3-year mortality rate for PDD was found to be 10.1%. DD. They also found that the presence of moderate Diabetic patients, especially those with poorly-controlled to severe LV DD was strongly predictive of incident blood sugars, may develop diabetic cardiomyopathy, patho- hospitalization for HF and death from heart disease. logical changes leading to fibrosis and remodeling of cardiac Lam et al. (24) studied the risk of development of HF for muscle and leading to increased LV mass. In a recent study noncardiac risk factors, such as hemoglobin, creatinine, and by From et al. (53), a more specific PDD study group was pulmonary function parameters. They reported that, with analyzed. In this study, all diabetes mellitus patients with adjustment for established HF risk factors and the presence 412 Wan et al. JACC Vol. 63, No. 5, 2014 Pre-Clinical Diastolic Dysfunction February 11, 2014:407–16

Table 2 Natural History of PDD and Subsequent Progression to Symptomatic HF

First Author (Ref. #) Year Population Incidence of Symptomatic HF Development Correa de Sa et al. (50) 2010 PDD 2-yr incidence HF development: 1.9% (2-yr incidence of any HF symptom: 31.1%) Vogel et al. (52) 2012 PDD 1-yr incidence HF development: 2.2% 2-yr incidence HF development: 5.7% 3-yr incidence HF development: 11.6% From et al. (53) 2010 PDD þ DM 1-yr incidence HF development: 13.1% 5-yr incidence HF development: 36.9% Ren et al. (57) 2007 PDD þ CAD 3-yr incidence HF hospitalization: 8.4% Lam et al. (24) 2011 PDD þ noncardiac 4-yr incidence HF development: 4%, 7%, 10% (0, 1, 2 noncardiac risk factors, respectively) Kane et al. (8) 2011 PDD (moderate to severe 1-yr incidence HF development: 3% diastolic dysfunction) 3-yr incidence HF development: 7% 5-yr incidence HF development: 10%

Noncardiac includes renal, pulmonary, and hematologic factors. CAD ¼ coronary artery disease; DM ¼ diabetes mellitus; HF ¼ heart failure; PDD ¼ pre-clinical diastolic dysfunction. of cardiac SD and DD, subclinical renal impairment, contributions of the data presented, disease progression in pulmonary airflow limitation, or anemia was associated with specific comorbid conditions remains poorly established. On 30% increased risk of incident HF. These findings reinforce the basis of the current data, we speculate that impairment in the importance of HF as a systemic, and not purely cardiac, cardiovascular, pulmonary, and renal reserve in response to disease. DD is a manifestation of systemic disease, as there is systemic insult may be a central key in differentiating a high association of noncardiac death with DD. Supporting between patients with PDD that progress to develop this concept, I-PRESERVE (Irbesartan in Heart Failure HFpEF and those that remain asymptomatic. With Preserved Ejection Fraction Study) (58) demonstrated From a physiological level, this suggests that cardiovas- that diabetes, COPD, and renal dysfunction were inde- cular, pulmonary, and renal reserve as well as extracardiac pendent predictors of mortality and that, among those oxygen delivery and utilization are important factors in HFpEF patients who died, there was a large proportion of development of symptoms. From a clinical standpoint, noncardiac deaths. The most common cause of death in future investigations into frailty processes that predispose HFpEF patients was cardiac at 60%, with 26% from sudden one to greater stressor susceptibility may serve as one of the death, 14% from HF, 5% from myocardial infarction, and keys to elucidating this relationship between PDD and 9% from stroke. However, 30% died of noncardiac causes HFpEF. Clearly, understanding DD, including PDD, is that included renal, respiratory, and infectious causes. essential to decreasing patients’ morbidity and mortality. Chen et al. (59) reported that uncontrolled hypertension, fi new-onset atrial brillation, infection, and myocardial Management of PDD ischemia were frequently present in patients presenting with incident HFpEF. This would suggest that both cardiac and That which predisposes to the development of PDD is not noncardiac systemic insults may have a role in influencing necessarily identical to that which propagates the disease to the progression from PDD to HFpEF. Furthermore, McKie symptomatic HF or HFpEF, although there may be signif- et al. (60) reported that subjects with PDD have impaired icant overlap. In the epidemiology section, the development renal endocrine response to acute volume load. of PDD was found to be associated with established In summary, the studies reviewed in this section do cardiovascular risk factors such as increasing age, coronary provide useful natural history data regarding PDD (Table 2). artery disease, hyperlipidemia, metabolic syndrome, periph- However, what remains unknown is the specific relationship eral vascular disease, and diabetes (Fig. 1). Therefore, treat- between PDD and the progression to HFpEF. Although ment of these risk factors may prevent development of PDD. many patients progress from PDD to HFpEF, it is unclear However, once the diagnosis of PDD is established, the whether this relationship is linear, or how patients may natural history section demonstrated that in addition to the revert to a pre-clinical state after developing HFpEF. There cardiovascular comorbidities, noncardiac risk factors such as is a significant proportion of patients with PDD who renal impairment, pulmonary airflow limitation, or anemia subsequently develop HFpEF. However, not all people are involved in the progression of the disease to symptomatic with PDD progress, and those with the same degree of HFpEF (Fig. 1). Hence, the management of PDD can be DD can have vastly different clinical syndromes. This risk divided into 2 main categories: 1) prevention of development of progression to HFpEF appears to be higher among of PDD; and 2) prevention of progression of PDD to those with hypertension, peripheral vascular disease, renal HFpEF. dysfunction, COPD, anemia, diabetes, or coronary heart Prevention of development of PDD. The current data disease. It is important to note that, despite the important suggests that patients with PDD are diverse, with very JACC Vol. 63, No. 5, 2014 Wan et al. 413 February 11, 2014:407–16 Pre-Clinical Diastolic Dysfunction different cardiovascular comorbidities such as coronary artery outcomes between irbesartan and placebo, including disease, hyperlipidemia, metabolic syndrome, peripheral a composite of all-cause mortality or hospitalization for vascular disease, and diabetes. Hence, the treatment or a cardiovascular cause (p ¼ 0.35), the overall rate of death prevention of PDD needs to be tailored to the underlying (p ¼ 0.98), and the rate of hospitalization for cardiovascular cardiovascular comorbidities. causes (p ¼ 0.44) (68). The work by Arnold et al. (61) from the HOPE (Heart In the randomized, double-blind, placebo-controlled Outcomes Prevention Evaluation) study demonstrated that PEP-CHF (Perindopril in Elderly People with Chronic an angiotensin-converting enzyme inhibitor for those at Heart Failure study, it was found that in the perindo- high cardiovascular risk reduced the risk of development of pril group, there were improvements in functional class HF, especially among those with higher baseline blood (p < 0.030) and exercise capacity (p ¼ 0.011) as well as pressures, with a relative risk of 0.67. A substudy of fewer hospitalizations for HF (p ¼ 0.033) (69). ALLHAT (Antihypertensive and Lipid-Lowering Treat- The 3 ongoing, randomized, double-blind, placebo- ment to Prevent Heart Attack Trial) assessed the relative controlled phase III trials regarding aldosterone antagonism effect of chlorthalidone, lisinopril, and amlodipine in in HFpEF are the ARCTIC-D (Aldosterone-blockade preventing HF. It reported that diuretic agents are superior Randomized Controlled Trial in CHF–Diastolic), PIE-II to calcium-channel blockers in preventing HF in hyper- (Pharmacological Intervention in the Elderly II), and tensive patients (62). Indeed, these studies suggested that TOPCAT (Trial of Aldosterone Antagonist Therapy in good hypertension control may lead to regression of PDD, Adults with Preserved Ejection Fraction Congestive Heart although this requires further validation (63). As discussed Failure) trials. The ARCTIC-D study examines the effects in the natural history section, diabetes contributes to of spironolactone on collagen turnover and correlates that to progression of DD. Iribarren et al. (56) demonstrated that, measures of LV mass regression and diastolic function on among those with diabetes, poor glycemic control may be magnetic resonance imaging after 4 months of aldosterone associated with the development of HF, suggesting the blockade. The PIE-II study examines the effects of spi- importance of diabetes treatment for the prevention of DD ronolactone on exercise tolerance and quality of life in elderly progression. patients with isolated HFpEF. The TOPCAT study eval- There are several trials that studied the modulation of LV uates the effectiveness of spironolactone therapy in reducing DD through pharmacological . The Hong Kong dia- all-cause mortality in patients who have HFpEF (70). stolic HF study demonstrated that, in an elderly group of The Aldo-DHF (Aldosterone Receptor Blockade in HF patients with normal EF, diuretic agents in combination Diastolic Heart Failure) trial results were recently published, with an angiotensin-converting enzyme inhibitor or an and demonstrated that there was significant improvement angiotensin receptor blocker improved LV diastolic function of diastolic function on the basis of echocardiographic longitudinally and led to decreased N-terminal pro–B-type measurements, but there were no significant improvements natriuretic peptide (NT-proBNP) levels (64). The SWEDIC in exercise capacity, symptoms, or quality of life in patients (Swedish Doppler echocardiographic study) showed that treated with spironolactone (71). carvedilol resulted in echocardiographic improvements in Finally, the RELAX (Phosphodiesterase-5 Inhibition to patients with HFpEF (65). Studies are needed to determine Improve Clinical Status and Exercise Capacity in Diastolic the efficacy of these strategies in PDD to improve clinical Heart Failure) study is a randomized, double-blind, placebo- outcomes. controlled trial examining the effects of sildenafil on exercise Prevention of progression of PDD to HFpEF. Given the capacity and clinical status in patients with HFpEF (72). true paucity of PDD-specific treatment trials and the fact This study did not demonstrate a significant improvement in that PDD can progress to HFpEF, the following discussion exercise capacity or clinical status with sildenafil adminis- will focus mainly on treatment of HFpEF. In a randomized, tration among those with HFpEF (43). However, even with double-blind, placebo-controlled trial by the Digitalis therapeutic PDE5 levels, there were minimal increases in Investigation Group (66), patients with HF and LV ejection plasma cyclic guanosine monophosphate (cGMP). Further fraction >45% on digoxin had a risk ratio of 0.82 for the studies may focus on the up-regulation of cGMP through combined outcome of death or hospitalization due to increased production by the nitric oxide pathway or worsening HF (95% confidence interval: 0.63 to 1.07) natriuretic peptide pathway. compared with placebo. Over the past several years, there have been investigations In the CHARM (Candesartan in Heart failure: Assess- into the use of ranolazine, an inhibitor of the late sodium ment of Reduction in Mortality and morbidity)-Preserved transmembrane current. This late sodium current diverts study, it was found that among patients with HF and extracellular sodium away from the sodium calcium LVEF >40%, candesartan compared with placebo had exchanger, therefore resulting in decreased intracellular a moderate impact in preventing admissions for HF calcium removal. It is thought that delayed removal of (p ¼ 0.014), yet there was no difference in rates of cardio- calcium leads to delayed relaxation and, therefore, diastolic vascular death (67). In the I-PRESERVE study, patients dysfunction. Recent evidence in rat models has also with HF and EF 45% had no significant differences in proposed an additional mechanism of action for ranolazine, 414 Wan et al. JACC Vol. 63, No. 5, 2014 Pre-Clinical Diastolic Dysfunction February 11, 2014:407–16 by reducing atrial fibrillation in HF via increase in repolar- Neprilysin is an enzyme that degrades biologically active ization refractoriness and increase in conduction time (73). natriuretic peptides including BNP. NT-proBNP, which Initial results are promising, and in mice models, ranolazine can serve as a marker of HF severity, is not affected by has been shown to reverse diastolic dysfunction (74). neprilysin. Therefore, neprilysin inhibitors enhance the RALI-DHF (Ranolazine for the Treatment of Diastolic concentration and effects of endogenous BNP and may lead Heart Failure), a small proof of concept randomized to improved cardiac function. In a recent multicenter, double-blind trial, attempts to bridge the gap between basic randomized, double-blind trial of 266 subjects with HFpEF, science research and clinical application (75). The recently those given an angiotensin receptor neprilysin inhibitor had published results from the RALI-DHF trial demonstrated significantly lower NT-proBNP levels after 12 weeks that ranolazine infusion significantly reduced LV end dia- compared with those who received valsartan (82). stolic pressure from 21.3 to 19.1 mm Hg and improved hemodynamic measurements such as pulmonary capillary Gaps in Knowledge/Areas for Future Research wedge pressure, there was no improvement in the relaxation parameter of rate of LV pressure decline, E/e0 ratio, or As noted previously, there are very few original studies that NT-proBNP (76). Further large human trials should better have focused on PDD. As a result, PDD as an entity elucidate the efficacy of ranolazine for HFpEF, and further remains poorly understood. Although the baseline charac- studies are necessary before consideration of ranolazine use teristics of clinical DD have been established, the only in the clinical setting. natural history studies to date (Correa de Sa et al. [50], As discussed in the pathophysiology section, nitric oxide Vogel et al. [52], and Kane et al. [8]) that are focused synthase uncoupling can occur with depletion of its cofactor broadly on PDD were limited by a small, enriched tetrahydrobiopterin and subsequently lead to DD given population (4,8,9,50,53). These and the work by From et al. impairment of cardiac relaxation. Recent promising work (53), Ren et al. (57), and Lam et al. (24) are the only studies has shown that supplementation of tetrahydrobiopterin may at present that have focused closely on the progression of prevent or reverse DD in hypertensive mice (47). PDD to HF and the associated risk factors for this The use of antifibrotic agents has also been studied in progression. rat models, and recent work has been promising. Tranilast, It remains unknown what the specific relationship is a medication for asthma and other allergic disorders, has between PDD and the progression to HFpEF. Hence, antifibrotic activity via inhibition of collagen synthesis in future prospective natural history and physiological studies fibroblasts. It has previously been studied for prevention are needed to better define the mechanisms of progression of of restenosis after coronary revascularization with mixed PDD to HFpEF. results (77). Among diabetic rats, tranilast prevented The current data suggests that patients with PDD are development of diastolic dysfunction (78). Given the diverse, with very different cardiovascular comorbidities such physiological action of this agent, it may also prevent pro- as coronary artery disease, hyperlipidemia, metabolic gression of PDD. syndrome, peripheral vascular disease, and diabetes. Hence, Atrial dyssynchrony has been proposed as a potential the treatment for PDD needs to be tailored to the underlying mechanism causing HFpEF. In a series of cases, Eicher cardiovascular comorbidities. et al. (79) demonstrated that interatrial mechanical delay was In addition to the cardiovascular comorbidities, noncardiac present among 59% of subjects with HFpEF, but none in risk factors such as renal impairment, pulmonary airflow control subjects. This led to the proposal of atrial resynch- limitation, and anemia are suggested to be involved in the ronization therapy for treatment of HFpEF as well as progression of PDD to symptomatic HFpEF. Hence, we prevention of atrial fibrillation development (80). Further- hypothesize that whereas therapeutic strategies focusing on more, Kim et al. (81) demonstrated that LV dyssynchrony cardiovascular comorbidities have not been shown to be may also play an important role in DD, both among those effective in improving outcomes in HFpEF, therapeutic with HF symptoms (HFpEF) and without (PDD). strategies aimed at both systemic and cardiovascular The use of B-type natriuretic peptide (BNP) in PDD has comorbidities may play a crucial role in delaying the also been studied. Recent evidence has shown that im- progression from PDD to HFpEF as well as improve pairment in renal endocrine and natriuretic response may outcomes in patients with HFpEF. This hypothesis needs to contribute to the underlying physiology of PDD. Following be tested in clinical trials comparing patients with PDD and volume expansion, subjects with PDD were less able to those with HFpEF. adapt given decreased urinary excretion of cGMP and sodium. In the setting of LV DD, a state of low levels of Conclusions cGMP and high oxidative stress exists. Given this patho- physiological mechanism, McKie et al. (60) showed that Although PDD remains poorly understood, it has clear administration of subcutaneous BNP may restore the normal clinical significance. PDD is prevalent and has been shown physiological cGMP and sodium excretion post-volume to progress to overt HF (HFpEF). In the setting of expansion. a worsening HF epidemic, further PDD research will be JACC Vol. 63, No. 5, 2014 Wan et al. 415 February 11, 2014:407–16 Pre-Clinical Diastolic Dysfunction essential to better characterize this entity, to identify risk pulsed Doppler tissue imaging of the mitral annulus. J Am Soc – factors for progression to overt HF, and to identify thera- Echocardiogr 2001;14:264 74. 19. Sutherland GR, Di Salvo G, Claus P, D’Hooge J, Bijnens B. 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