Diastolic and Systolic Heart Failure are Distinct Phenotypes of the Heart Failure Syndrome

INTRODUCTION

Heart failure (HF) is a major worldwide public health problem. One in five persons aged 40 years in the United States will develop HF during their lifetime¹ and HF remains the leading cause for hospitalization among the elderly². While age and sex-specific HF incidence is not increasing³, overall HF survival has improved and the number of persons over age 65 is rapidly increasing. Thus, the absolute number of patients with HF will continue to increase. Half of patients with HF have a preserved ejection fraction (HFpEF) and the remainder display reduced ejection fraction (HFrEF)^4–6. The proportion of patients with normal EF is steadily increasing, due to increased incidence and/or increasing physician recognition of the syndrome⁴. Resource utilization associated with HF is high in both the inpatient and outpatient settings, regardless of EF.

HF is a syndrome that can be defined clinically by a collection of symptoms (dyspnea, fatigue, exertional intolerance) and signs (edema, gallop, rales) that are attributable to a cardiac disorder². HF may also be defined hemodynamically, by an inability to provide adequate cardiac output to the body at rest or with exertion, or to do so only in the setting of elevated cardiac filling pressures. The cardiovascular system responds to a wide variety of insults (e.g. myocardial disease, ischemia, valvular or pericardial disease) in a finite number of ways, both hemodynamically (elevated filling pressures, depressed output) and symptomatically (dyspnea, fatigue, angina). However, these similarities in clinical expression do not indicate that the underlying mechanisms of disease are the same, or that treatment will be similar. For example, a headache may be noted with a migraine or brain tumor, dyspnea may be reported with HF, emphysema, or neuromuscular disease, and diarrhea may be observed with infection, dysmotility or sprue. In each case, common treatments (analgesics, oxygen, and rehydration) will improve symptoms, but only unique interventions targeted to the specific insults causing each disease will be effective to modify long term outcomes.

HFpEF and HFrEF share the same clinical phenotype. Signs, symptoms, exercise intolerance, hemodynamics, and outcomes may be identical or highly similar in each form of HF^5–11, but this does not indicate that these disorders are due to a common etiology or that they should be treated in the same way. Indeed, the principal rationale to taxonomically distinguish diseases is based upon cause and treatment. In this review we shall examine the wealth of evidence proving that despite multiple similarities in clinical expression, HFpEF and HFrEF represent two distinct disorders in the heart failure spectrum, and as such, should be studied and treated separately.

CONCLUSIVE EVIDENCE THAT HFpEF AND HFrEF ARE DISTINCT DISEASES

Among patients with clinical diagnosis of HF, the distribution of EF is bimodal

If HFpEF and HFrEF are part of the same disease process, one would expect to observe a unimodal distribution of EF within HF populations. In an analysis of data from patients enrolled in the CHARM-Program, Solomon and colleagues observed such a unimodal distribution of EF¹². This has been interpreted to support the notion that HFpEF and HFrEF are part of the same disease spectrum¹³. However, as pointed out by Gaasch et al., the CHARM program enrolled more patients with HFrEF than HFpEF, which may skew the distribution, and analysis of two other HF trials that did not pre-specify EF enrollment criteria revealed bimodal distributions of EF¹⁴. These data are limited by selection bias, as the populations examined were referred or selected for a clinical trial, but community-based data shows similar findings. Data from the OPTIMIZE registry of >30,000 patients admitted for acutely decompensated heart failure has also shown a bimodal distribution of EF among HF patients⁹. We analyzed all consecutive patients admitted with HF to our own institution over a 16 year period (from previously published data)⁴ (Figure 1). This plot clearly shows a bimodal EF distribution. Inspection of the EF histogram stratified by gender further shows a greater female preponderance in HFpEF, as has been shown in numerous studies. These data provide strong a priori evidence that HFpEF and HFrEF represent two distinct disease processes.

Figure 1.

Bimodal distribution of ejection fraction in heart failure.

Therapies with Proven Benefit in HFrEF have failed to improve outcome in HFpEF

If HFpEF and HFrEF were part of the same HF disease spectrum, they would be expected to respond similarly to treatment. However, medications which have been shown to produce unequivocal improvements in HFrEF have not produced similar beneficial effects in HFpEF (Figure 2). While survival for patients with HFrEF has improved over the past two decades, there has been no improvement in HFpEF survival⁴. The CHARM-Preserved study (n=3023) compared the angiotensin receptor blocker (ARB) candesartan versus placebo in patients with HF and EF>40% and did not evidence a significant reduction in the composite outcome of death and cardiovascular hospitalization¹⁵. There was a trend toward benefit overall, but this study included a large proportion of patients with mild systolic dysfunction (EF 40–49%) and more patients with coronary disease and male gender than are typically noted in community-based HFpEF populations. The larger I-PRESERVE trial (n=4128) similarly showed no reduction in death or hospitalization with the ARB irbesartan over 4 years of followup¹⁶. Angiotensin converting enzyme inhibitors (ACEI) have also failed to show benefit in HFpEF. The PEP-CHF trial (n=850) randomized HFpEF patients aged ≥70 years to perindopril or placebo and found over the 3 year study period there was no reduction in mortality or HF hospitalizations¹⁷. A recent trial of enalapril in elderly patients with HFpEF reported no improvement in exercise capacity, aortic distensibility or neurohormonal profile compared with placebo¹⁸.

Figure 2.

Differential response to treatment in HFpEF and HFrEF. Summary of hazard ratios observed in trials or registries studying patients with HFpEF and HFrEF.

Observational data from the OPTIMIZE registry has failed to demonstrate reduced hazard of mortality and hospitalization in association with discharge ACEI/ARB use in HFpEF, in striking contrast to reductions in events observed in HFrEF⁹. The unique disease-specific responses to anti-angiotensin therapies is further highlighted by a recent ancillary analysis of the very large ALLHAT Trial (n=42,418), where chlorthalidone reduced incidence of both HFpEF and HFrEF compared with amlodipine and doxazosin; yet lisinopril was only effective in reducing incident HFrEF, with no benefit in HFpEF incidence compared with the other agents¹⁹.

The efficacy of beta blockers (BB) in HFpEF remains unresolved, though they remain one of the most prescribed medications in this population⁹. Observational studies from OPTIMIZE observed no reduction in morbidity and mortality in short term⁹ or long term²⁰ followup in HFpEF, in contrast to HFrEF where significant reductions in maladaptive remodeling, HF hospitalizations and mortality are observed with BB in both registry^{9, 20} and trial data². Ancillary analysis from the SENIORS Trial suggested the benefits of the beta blocker nebivolol were also observed in the patients with preserved EF²¹, though few patients in the trial had EF>50–55%. A recent observational study noted that women with HFpEF (EF>50%) discharged on beta blockers had higher 6 month rehospitalization rates compared with those not prescribed beta blockers²², and it is speculated that this could be related to deleterious effects of heart rate reduction in normal to small sized ventricles in HFpEF where chronotropic incompetence is common^23–25. The effects of BB on cardiomyocytes appear to differ in HFpEF and HFrEF, with higher resting tension observed in HFpEF patients treated with BB, but no apparent BB effect on myocyte stiffness in HFrEF²⁶.

In an ancillary analysis of 988 patients with HFpEF (EF>45%) enrolled in the DIG trial, Ahmed et al. found that while digoxin did lower HF hospitalization²⁷, this benefit was over-come by an equivalent increase in coronary syndrome hospitalizations²⁸. Other therapies with proven benefit in HFrEF, such as aldosterone antagonists or devices, are less investigated in HFpEF. Myocardial ischemia and infarction cause systolic and diastolic dysfunction, and revascularization for triple vessel disease among patients with reduced EF is associated with improved survival²⁹. The role of revascularization is less well-studied in HFpEF, though a case series from Little and colleagues found that episodes of pulmonary edema tend to recur despite revascularization in this setting³⁰.

HFpEF and HFrEF display unique patterns of Ventricular and Cellular Remodeling

While increased LV mass is characteristic of most forms of HF, the patterns of ventricular remodeling in HFpEF and HFrEF are highly distinct¹⁰. Left ventricular chamber dilation is a defining characteristic of HFrEF. Indeed, in chronic, compensated HFrEF, the EF is reduced because the chamber size (denominator of EF equation) is larger, while the stroke volume (numerator) is typically similar to normal controls^{7, 10}. Chamber dilation in HFrEF is coupled with pathologic electrical remodeling, as left bundle branch block is much more common in HFrEF compared with HFpEF^{31, 32}. In contrast, most^{6, 7, 25, 33–40}, though not all^{41, 42} studies have reported that ventricular chamber size is normal or near-normal in HFpEF, with increased wall thickness, greater ratio of wall thickness to chamber dimension, and increased ratio of ventricular mass to chamber volume when compared with HFrEF and healthy controls. These changes are similar to those observed with chronic pressure overload due to arterial hypertension⁴³, and indeed, abundant data suggests that HFpEF develops as a progression from asymptomatic hypertensive heart disease^{25, 33, 34, 44}. In contrast, while hypertension is a potent risk factor for all forms of HF⁴⁵, it is an uncommon solitary cause of HFrEF⁴⁶.

These disparate ventricular structural changes in HFpEF and HFrEF are associated with diametrically opposing effects on ventricular-arterial interaction, particularly involving the end-systolic pressure-volume relationship or end-systolic elastance (Ees)⁴⁷. Ees is markedly reduced in HFrEF, and as a result HFrEF patients respond very favorably to arterial vasodilators, with minimal drop in blood pressure and substantial improvement in stroke volume^{47, 48}. In contrast, Ees is elevated in HFpEF patients^{33, 44, 49}. This leads to more exaggerated drops in blood pressure with vasodilator therapy in HFpEF, while similarly promoting more marked increases in blood pressures during stress⁴⁸. These fundamental differences in clinical response to alterations in ventricular loading may partially explain the failure of vasodilators to improve outcomes in clinical trials for HFpEF^15–18. Remodeling in both forms of HF may be associated with mechanical dyssynchrony^{2, 50}, though the type of dyssynchrony that is amenable to device therapy⁵¹ (bundle branch block) is much more common in HFrEF, where eccentric remodeling predominates^{31, 32}.

Differences between HFrEF and HFpEF extend to the level of the interstitium and cardiomyocyte. The balance of matrix metalloproteinases and their inhibitors differs in HFrEF and HFpEF, and this difference is hypothesized to contribute to the distinct patterns of chamber remodeling observed in these diseases⁵². Histopathologic studies from Paulus and colleagues have shown that the cardiomyocyte is narrow and elongated in HFrEF, with reduced myofibrillar density, whereas myocyte diameter and resting tension are both increased in HFpEF^{40, 53}, particularly among diabetics⁵⁴. Furthermore, the mechanisms responsible for increased myocyte stiffness appear to differ in diabetic HFrEF, where enhanced deposition and cross-linking of advanced glycation end-products predominate, in contrast to HFpEF where higher cardiomyocyte resting tension has been observed, presumably related to sarcomeric protein phosphorylation status⁵⁴. There is an increased ratio of the stiffer isoform of the macromolecule titin in HFpEF compared with HFrEF, which may contribute to higher resting tension and the larger drop in tension in response to phosphorylation⁴⁰.

SUGGESTIVE EVIDENCE THAT HFpEF AND HFrEF ARE DISTINCT DISEASES

HFpEF and HFrEF tend to arise among different patient populations

Community-based studies have demonstrated that HFpEF patients differ from HFrEF in a number of characteristic ways, though there is considerable overlap when large community-based studies are examined^{4–6, 8, 9, 31, 32, 36} (see Supplemental table and references). Most studies have found that HFpEF patients are older (weighted average 74 vs 70 years), more often hypertensive (weighted average 74 vs 65 %) and less likely to have coronary disease (weighted average 46 vs 58 %). The most robust difference is female gender (weighted average 63 vs 38 %) possibly related to less coronary disease, enhanced concentric remodeling and age-related vascular stiffening in women^{55, 56}. These differences in age, gender, hypertensive history and coronary disease become more prominent when defining HFpEF more stringently by EF≥50–55%^{9, 57}, providing further evidence that these represent two distinct disease processes.

Arterial loading conditions differ in HFpEF and HFrEF: vasoconstriction is common to both forms of HF, but pulse pressure is higher in HFpEF, and this vascular stiffening produces greater blood pressure lability with changes in preload, afterload and stress in HFpEF^{48, 49, 57}.

Pathogenesis and Disease Progression in HFpEF and HFrEF Appear Distinct

Hypertension is the single largest risk factor for development of HF, regardless of EF⁴⁵, and while prevalence of hypertension is greater in HFpEF, it is common to both forms of HF. Changes in cardiovascular structure and function in arterial hypertension are similar to those seen with normal maturation, leading some to refer to hypertension as “accelerated aging”⁴³. The dominant risk factors for HFpEF are age and hypertension, and many of the pathophysiologic derangements in HFpEF present as a continuum with asymptomatic hypertensive heart disease^{25, 33, 34, 44}, suggesting that HFpEF may be a form of “accelerated hypertension”. Age, hypertensive and in some cases diabetes related ventricular remodeling thus create the slowly progressive substrate upon which HFpEF is formed (Figure 3), and recent evidence suggests that progression of a number of abnormalities in cardiovascular function may promote the transition to overt HFpEF, including loss of contractile reserve, diastolic reserve, chronotropy, vasodilation and endothelial function^{23–25, 58}. In contrast, HFrEF most commonly develops in response to distinct pathophysiologic perturbations leading to accelerated and larger-scale myocyte loss/dysfunction, with the most common etiologies including acute myocardial infarction, genetic abnormalities, myocarditis or toxin effects (e.g. alcohol or chemotherapy)². These more distinct processes may occur in younger patients where they predominate or later in life on a background of age/hypertension/diabetic remodeling (e.g. anterior myocardial infarction in an elderly woman with hypertension), leading to the appearance of greater overlap between the clinical phenotype. However, the common appearance of some characteristics such as this in both forms of HF should not be taken as evidence that they represent the same underlying disease process.

Figure 3.

Distinct pathophysiology of HFpEF and HFrEF.

It has been suggested that HFpEF may “progress” to HFrEF, consistent with the notion that the two diagnoses exist in a continuum. However, in the absence of coronary disease/myocardial infarction (the leading cause of HFrEF), there is little evidence that this “transition” occurs⁵⁹. Increased LV mass is indeed a risk factor for the development of depressed EF, but this relationship is observed principally in the setting of eccentric hypertrophy, not in concentric remodeling as is typical of HFpEF⁶⁰. These longitudinal data provide further evidence that HFpEF and HFrEF develop in two distinct mechanistic pathways—eccentric remodeling in the latter and concentric in the former.

FEATURES WHICH ARE SHARED BY HFpEF AND HFrEF YET DO NOT PROVE A COMMON DISEASE PROCESS

Ventricular and Vascular Dysfunction are common to all HF

Diastolic dysfunction is characteristic of both forms of HF and is evidenced clinically by the presence of elevated filling pressures, abnormal relaxation and increased chamber stiffness^{10, 35}. Systolic dysfunction had traditionally been considered to be unique to HFrEF³⁸, but a number of recent studies have shown that regional and chamber-level systolic dysfunction are also common in HFpEF^{10, 25, 44}, though not as severe as in HFrEF. Systolic dysfunction becomes more apparent and limiting during the stress of exercise in HFpEF^{23, 25}, where it is potently associated with depressed functional capacity²⁵, possibly because mild systolic dysfunction has more severe consequences in the absence of chamber dilation. Chronotropic incompetence is also common in both HFpEF and HFrEF, likely related to autonomic dysfunction and/or β-receptor desensitization^{23–25, 61}, processes which are common to all HF. Abnormal vasorelaxation and endothelium-dependent vasodilation are observed in both HFpEF and HFrEF, both in the systemic circulation^{23, 25, 62} and the pulmonary vasculature^{63, 64}. Each of these abnormalities may exacerbate ventricular dysfunction in either form of HF. However, the presence of many common abnormalities in ventricular-vascular functional response to HF does not indicate that HFpEF and HFrEF share the same initial or predominant pathogenic mechanism.

Neurohormonal Activation and Renal Dysfunction are common to all HF

Pathologic activation of the renin-angiotensin-aldosterone axis, natriuretic peptides and the sympathetic nervous system are characteristic of both HFrEF and HFpEF, but have been studied much more extensively in HFrEF. Norepinephrine levels are similarly elevated in HFpEF and HFrEF⁷. Natriuretic peptide levels are elevated in both forms of HF, though they are elevated to a greater extent in HFrEF^{7, 65, 66}. This is not surprising, as the stimulus for myocardial BNP release is wall stress, which varies directly with filling pressures (elevated in both HFpEF and HFrEF) and chamber size (elevated in HFrEF but normal in HFpEF)⁶⁵. Aldosterone levels are similar in HFrEF and HFpEF⁶⁶, but other neurohormones such as plasma renin activity, angiotensin II and vasopressin have not been compared in these groups.

Renal dysfunction is similarly problematic in HFpEF and HFrEF^{4–6, 8}, but recent evidence suggests that patients with HFpEF may be more vulnerable to the development of renal dysfunction during the course of treatment for HF decompensation⁵⁷, and renal-associated mortality was higher in HFpEF in a post-hoc analysis from the DIG trial⁶⁷. Regardless of the similarities in neurohormonal activation and renal dysfunction in both forms of HF, these maladaptations are fundamentally a common response to hemodynamic derangements (elevated filling pressures and low output) which are shared by both HFpEF and HFrEF but that do not indicate that the disease processes are the same.

NATURAL HISTORY OF HFpEF - IMPLICATIONS FOR DIAGNOSIS AND MODE OF DEATH

Exertional dyspnea and fatigue are common symptoms in patients with HF, particularly among the elderly. When echocardiography demonstrates a depressed EF, these symptoms are usually ascribed to HFrEF. However, when symptoms of exertional intolerance are noted in a patient with preserved EF, diagnosis is more challenging and symptoms may be related to deconditioning, obesity, pulmonary disease, pulmonary vascular disease or HFpEF. In relation to a lack of awareness and/or a lack of established treatment options, the diagnosis of HFpEF is often not entertained, even among cardiovascular specialists. Many patients with earlier-stage HFpEF may be younger, more active or have fewer comorbidities and present with predominantly exertional (NYHA functional class II) symptoms at a time when the severity of the underlying cardiovascular remodeling and dysfunction is less severe and potentially, still amenable to treatment (Figure 4). Indeed, recent studies have shown that despite normal examination, echocardiography, and resting hemodynamics, patients with early-stage HFpEF may display hemodynamic abnormalities (elevated filling pressures) exclusively during the stress of exercise⁵⁸.

Figure 4.

Variable natural history in HFpEF.

Earlier recognition of HFpEF may enable investigation of treatment and preventive strategies where the potential for benefit is increased. In contrast, elderly patients who are inactive and have many co-morbidites may present with more severe symptoms (NYHA III-IV) during an episode of hemodynamic stress (often due to a co-morbidity) and at a time when pathologic abnormalities may be less reversible (Figure 4). In many such patients, their subsequent clinical course may be more driven by the comorbidity than their HF. Indeed, patients with HFpEF are more likely to die from non-cardiovascular causes compared with HFrEF^{15, 68, 69}. Importantly, a recent-community based study directly comparing mode of death in HFpEF and HFrEF found that the greater rate of non-cardiovascular death in HFpEF was primarily attributable to fewer coronary disease deaths in HFpEF with similar rates of HF death and otherwise comparable comorbidity scores in the two groups⁷⁰.

THE PROBLEM OF THE “INTERMEDIATE GROUP” (EF 40–50%)

The definition of “preserved EF” has varied considerably between studies, ranging from ≥35% to ≥55%. Lumping together patients with mildly depressed EF with truly normal EF may lead to the appearance of a continuous spectrum while also producing confusing results when attempting to properly interpret the trial data. As discussed above, recent studies have suggested that this intermediate group has many features more typical of HFrEF—greater male predominance, more coronary disease, less hypertension, more chamber dilation and greater risk of dying from cardiovascular causes, compared with more stringently defined HFpEF (>50–55%). It is most likely that this intermediate EF group is populated by patients with either mild or well-treated HFrEF, rather than patients whose EF is gradually diminishing—in either case, these patients would be more appropriately treated according to established HFrEF guidelines. We would propose that “definite” HFpEF be defined by EF>50%, and that this intermediate group be included in HFrEF. At this time there is insufficient rationale to alter the established EF-based nosology to distinguish the two forms of HF. While EF is not synonymous with contractility⁴⁴, it is easy to conceptualize, measure, and is universally available—making it a useful marker to distinguish the two forms of HF.

CONCLUSIONS

Great strides have been made to better understand the pathophysiology of HFpEF and HFrEF, but important questions remain unanswered. The two forms of HF differ fundamentally in the acuity and extent of myocardial loss/dysfunction, the pattern of remodeling at the chamber and ultrastructural level, and the response to therapeutic interventions. Progression to HFpEF is gradual and tends to develops in concert with typical age-acquired comorbidities, particularly hypertension with concentric remodeling. In contrast, HFrEF may develop acutely or indolently, but typically in response to a larger-scale myocardial insult. Drug and device therapies which target maladaptive eccentric ventricular remodeling improve outcome in HFrEF, because these are the processes that drive the pathogenesis. In contrast, the pathophysiologic derangements in HFpEF include concentric remodeling, ventricular-vascular stiffening and loss of ventricular-vascular reserve function, so it is perhaps not surprising that therapies targeting HFrEF pathophysiology have not improved outcome in HFpEF. Future basic and clinical research should separate these two distinct forms of HF so as to better understand its unique mechanisms of disease and define optimal treatment strategies.