Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and causes substantial morbidity, mortality, and resource utilization, particularly among the elderly.1,2 Patients with HFpEF demonstrate pathophysiological characteristics similar to patients with HF with reduced EF (HFrEF),3 experience similar rates of HF re-hospitalization and functional decline,4,5 and face a significantly higher risk of death compared with age-matched controls.6,7 Despite multiple randomized controlled trials, no disease-specific therapy exists to improve prognosis in this heterogeneous syndrome.8–10
As reflected in professional guidelines, the primary pathophysiological abnormality in HFpEF is generally thought to be abnormal left ventricular (LV) diastolic performance,11 based largely on invasive haemodynamic studies in select highly phenotyped HFpEF patients that demonstrated both prolongation of early diastolic active relaxation and increase in LV passive stiffness.12,13 However, traditional non-invasive parameters of diastolic function have performed poorly in discriminating HFpEF patients from their co-morbidity-matched symptom-free counterparts,14 are absent in approximately one-third of HFpEF patients,15,16 and fail to predict adverse events reliably among HFpEF patients.16 Our limited understanding of the clinical and pathophysiological heterogeneity underlying the HFpEF syndrome poses a critical barrier to the development of effective therapeutic strategies to address this growing public health concern.
Two recent articles attempt to address these limitations in our understanding of the clinical and pathophysiological underpinnings of HFpEF. Ho et al. examine the clinical and biochemical factors at HF presentation distinguishing HFpEF from HFrEF, harnessing data on 712 participants with HF in the Framingham Heart Study and validating their findings in 4436 HF patients in the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study.17 While female gender and atrial fibrillation were strongly associated with HFpEF, coronary heart disease and ST segment deviation or left bundle branch block (LBBB) on electrocardiogram (ECG) were more likely to be associated with HFrEF. However, demographic and clinical findings at HF presentation overall provided only modest discrimination of HFpEF compared with HFrEF (model C statistic 0.75). Importantly, many characteristics generally considered particularly strong risk factors for diastolic dysfunction and HFpEF—including increasing age, hypertension, diabetes, and obesity—did not differentiate HFpEF from HFrEF, suggesting that these factors are common risk factors for both. Indeed, conditions such as hypertension and diabetes, classically associated with diastolic dysfunction,18–20 are also characterized by abnormal systolic function despite normal LVEF.21–23
In another paper focusing on HFpEF, Ohtani et al. provide data on a novel echocardiographic index of LV function which they term diastolic wall strain (DWS) index.24 Diastolic wall strain is defined as the difference between posterior wall thickness (PTW) at end-systole and end-diastole divided by the posterior wall thickness at end-systole,
and is thought to represent a less load-dependent measure of LV diastolic wall stiffness. In a comparison of 327 HFpEF patients and 528 younger healthy controls, they demonstrate that diastolic wall strain correlates with other non-invasive measures of diastolic dysfunction and LV concentric remodelling, is reduced on average among HFpEF patients compared with controls, and is significantly associated with death or incident HF hospitalization. Importantly, considerable heterogeneity in DWS values was noted in the HFpEF group, with significant overlap with normal controls.
The exact meaning of this novel measure is unclear. As the above equation demonstrates, DWS is also an index of degree of LV wall thickening and is therefore probably also related to LV systolic function. Although not reported, one might expect this parameter of LV posterior wall deformation to correlate with speck tracking-based measures of myocardial systolic strain. Thus, it may be impossible to determine to what extent this measure is related to diastolic ‘stiffness’ per se, vs. abnormalities of systolic function. Indeed, this interpretation of the findings of Ohtani et al. would be consistent with studies demonstrating reduced radial and longitudinal strain among HFpEF patients compared with age-matched asymptomatic controls.25 Moreover, progressive concentric remodelling has been associated with reduced longitudinal strain and myocardial shortening despite normal LVEF, similar to the findings of Ohtani et al. with DWS.26,27 Emerging data using myocardial deformation imaging suggest a distinct pattern of LV dysfunction in conditions predisposing to HFpEF, such as hypertension and diabetes. In addition to well recognized impairment in diastolic relaxation, these studies suggest that early dysfunction is also characterized by impaired longitudinal systolic function with concomitant increase in circumferential systolic function, maintaining overall LVEF (Figure 1).28–31
Model of progressive abnormalities in left ventricular (LV) diastolic and systolic function underlying heart failure across the LV ejection fraction (EF) spectrum. Early myocardial dysfunction, triggered by conditions such as hypertension and diabetes, may be associated with coupled impairments in both diastolic function and LV longitudinal deformation. Concomitant augmentation of circumferential deformation can lead to preservation of gross LVEF. Progression is characterized by worsening impairment in diastolic function and longitudinal deformation. Decline in circumferential deformation ultimately results in falling LVEF. The clinical syndrome of heart failure can occur at any point along this continuum, with varying contributions of diastolic and systolic dysfunction. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction
Together, these studies suggest that shared risk factors, leading to coupled abnormalities of cardiac systolic and diastolic performance, underlie HF across the spectrum of LVEF. Moreover, both reinforce the striking heterogeneity of HFpEF and substantial pathophysiological overlap between HFpEF, HFrEF, and normal in a variety of pathophysiological domains. Finally, these studies add support to the growing belief that abnormalities of diastolic function may not be the only pathophysiological factors at play in HFpEF and that abnormalities of systole may be just as central. These findings are particularly important in light of the limited therapeutic options available in HFpEF. Greater recognition of the breadth of abnormalities in both systolic and diastolic function in HFpEF will be necessary in order to appreciate fully the heterogeneity characterizing this disorder, to identify physiologically distinct subphenotypes, and to develop and test novel and more targeted therapeutic strategies.
Conflict of interest:A.M.S. and S.D.S. have received research support from Novartis and Abbott.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
; for the ALLHAT Collaborative Research Group. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2008;118:2259-2267.
; for the CHARM investigators, committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-781.
. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure Echocardiography associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-2550.
. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol 2009;54:36-46.
. The functional role of longitudinal, circumferential, and radial myocardial deformation for regulating the early impairment of left ventricular contraction and relaxation in patients with cardiovascular risk factors: a study with two-dimensional strain imaging. J Am Soc Echocardiogr 2008;21:1138-1144.
. Differential effects of afterload on left ventricular long- and short-axis function: insights from a clinical model of patients with aortic valve stenosis undergoing aortic valve replacement. Am Heart J 2009;158:540-545.