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Cardiovascular Research 2004 64(1):9-11; doi:10.1016/j.cardiores.2004.07.015
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Heart failure with preserved ejection fraction. Diastolic dysfunction, subtle systolic dysfunction, systolic-ventricular and arterial stiffening, or misdiagnosis?

Paul Steendijk*

Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

* Corresponding author. Tel.: +31 71 526 2020; fax: +31 71 526 6809. E-mail address: p.steendijk{at}lumc.nl

Received 15 July 2004; accepted 20 July 2004

See article by He et al. [19] (pages 72–83) in this issue.

Patients with signs and symptoms of congestive heart failure (CHF) may present with a normal left ventricular (LV) ejection fraction (EF). Epidemiological studies indicate that about half of the CHF patients in the community have a relatively normal or preserved EF (typically defined as EF>50%) [1–3]. This finding appears to be in line with hospital-based studies, but the heterogeneity in patient selection, diagnostic criteria for CHF, and methods for assessment of systolic function makes it difficult to compare these studies [4]. Compared to patients with CHF and depressed EF, patients with CHF and preserved EF are older, are more often women, more frequently have a history of hypertension, and less frequently have coronary artery disease [1–4]. CHF is the most frequent cause of hospitalization in persons 65 years of age or older, and a recent large-scale, population-based study [5] indicates a prevalence for CHF of 4.9% in this age group. Interestingly, only 22% of these CHF patients had overtly impaired LV systolic function (defined as EF<45%). Of note is that the mean age of patients represented in the major CHF treatment trials is typically 59–65, whereas the mean age of patients in the community at the time of first diagnosis of CHF appears to be about 77 [1,6].

It is often assumed that the prognosis of CHF patients is better for those with a preserved EF. This notion is supported by the meta-analysis by Vasan et al. [4] which covers 31 studies on CHF with preserved EF performed between 1970 and 1995. The reported annual mortality rate in the reviewed studies ranged between 1.3% and 17.5%. This wide range is partly related to variation in the patient selection criteria and to the different definitions for preserved systolic function used in the various studies. In addition, the findings are biased by the mean age of the included subjects. If we discard the studies in which mean age was >80 years, the highest reported annual mortality was 9%. This is substantially better than the prognosis which follows from studies in patients with CHF and low EF [7]. Recently, Thomas et al. [8] published an overview of 61 studies performed between 1966 and 2001. The evidence on outcome from the reviewed studies is partly contradictory, but tends to show lower hospitalization rates and mortality rates in CHF with preserved EF compared to depressed EF. However, it should be noted that several studies report that the longer-term mortality is similar. Furthermore, series in elderly cohorts with CHF show very similar mortality rates among those with preserved and depressed EF.

Despite the fact that CHF with preserved EF is very common and causes significant morbidity and mortality, optimal treatment or even guidelines for these patients have not been defined. This is in sharp contrast to CHF with low EF for which various large scale, double-blind, randomized, placebo-controlled trials have identified treatment strategies that reduce morbidity and mortality. However, several randomized clinical trials are ongoing that examine treatment of CHF with preserved EF: PEP-CHF [9] investigates ACE inhibitor perindopril, SENIORS [10] focuses on nebivolol, a beta-1-selective blocker with vasodilating properties, and MCC-135GO1 [11] tests a compound, caldaret, that modulates calcium homeostasis. These trials will all report in 2004. The first substantial trial in CHF patients with preserved EF was published in the Lancet in 2003 and investigated the effects of an angiotensin receptor blocker, candesartan [12]. This trial is part of the CHARM program, which compared candesartan with placebo in patients with depressed EF both with ACE inhibitors (CHARM-Added) and without ACE inhibitors (CHARM-Alternative), and in patients with preserved EF (CHARM-Preserved). In CHARM-Added and CHARM-Alternative, overall mortality, cardiovascular death, and hospitalization for CHF were all significantly reduced; however, the results from CHARM-Preserved were less conclusive and only showed a reduction in hospitalization. Clearly, whereas data on prevalence and prognosis of CHF with preserved EF are available, data on effects of treatment are still very scant. Therefore, at this point treatment of these patients remains empirical and there is a great need for studies that provide evidence-based management strategies.

In addition, the pathophysiological mechanisms underlying CHF with preserved EF need to be further clarified. It has been proposed that virtually all of these patients exhibit abnormal diastolic function. This view is substantiated in an editorial by Zile [13]. In an earlier paper, Zile et al. [14] measured pressure-derived and echo-Doppler-derived indices of diastolic function and found that one or more indexes were abnormal in every patient with CHF and preserved EF. It was concluded, therefore, that objective evidence of abnormal LV relaxation, filling, or distensibility is not necessary to make the diagnosis of diastolic heart failure in this group of patients. However, some limitations and caveats should be mentioned. First, primary right heart failure and left-sided valvular disease may also lead to CHF with preserved EF, and such patients should thus be excluded. Obviously, alternative non-cardiac causes for symptoms, such as obesity and lung disease, should also be rigorously investigated to avoid misdiagnosis [15]. Furthermore, Burkhoff et al. [16] argue that the only way to truly demonstrate clinically relevant abnormalities of diastolic properties is by showing changes (i.e. upward shifts) of the ventricular end-diastolic pressure–volume relationship, since echocardiographic parameters of diastolic function are load-dependent and cannot be viewed as specific indices of passive diastolic function [17]. However, Zile's group has taken up this challenge and very recently provided additional evidence that abnormal active relaxation and increased passive stiffness is generally present in these patients [18]. Although there is little doubt that diastolic dysfunction plays an important role in many patients with CHF and preserved EF, there are other mechanisms that deserve attention.

In this issue of Cardiovascular Research, He et al. [19] present a study in dogs that received daily coronary microembolization until an end-diastolic pressure >18 mm Hg was reached. The animals subsequently developed overt signs of heart failure. The authors found that a subgroup had preserved EF and dP/dtmax, and examined diastolic function in these animals by detailed analysis of ventricular pressure–volume relations. No consistent changes in diastolic function were found, leading to the conclusion that CHF with preserved EF does not automatically imply diastolic dysfunction. The authors propose that a more subtle systolic impairment, which was evident from parallel shifts of the systolic pressure–volume relations but not detected by EF or dP/dtmax, was sufficient to cause neurohormonal activation, intravascular volume expansion, and elevated end-diastolic pressure to a degree comparable with that found in animals with reduced EF and dP/dtmax. Therefore, a message from this paper would be that measurement of EF (or even dP/dtmax) is not sufficient to exclude systolic dysfunction as the primary cause of CHF. A similar conclusion was reached earlier by Petrie et al. [20] who proposed to use atrioventricular plane displacement as a more sensitive echocardiographic marker. Interestingly, in He's study the position of the end-systolic pressure–volume relation rather than its slope (end-systolic elastance) proved to be the most sensitive marker of systolic dysfunction. This confirms previous findings from our group in an animal model with a critical coronary stenosis [21] and suggests that absolute end-systolic volume is a valuable index of subtle systolic dysfunction. A potential limitation of He’s study is that the animal model may not reflect some typical characteristics of CHF with preserved EF in humans. One particular finding was that vascular afterload decreased following development of CHF in the animals with preserved EF, whereas it was maintained in the animals with reduced EF. Thus, this decrease in afterload may very well explain the preserved EF. However, a recent study by Kawaguchi et al. [22] shows that patients with CHF and preserved EF have an increased arterial stiffening (beyond that expected with aging and/or hypertension), and the authors speculate that the arterial stiffening, combined with the ventricular systolic stiffening that was also found in these patients, elevates systolic load to prolong relaxation, compromizes filling, and raises end-diastolic pressure. The importance of arterial stiffening is also shown in a study by Hundley et al. [23] showing that this parameter closely correlates with exercise tolerance in older persons with CHF and preserved EF. The paper provides strong evidence that reduced aortic distensibility is a possible cause of cardiac failure in these patients.

In conclusion, it is likely that the pathophysiology of heart failure with preserved EF is heterogeneous. Cardiac failure may be caused primarily by diastolic dysfunction, by subtle systolic dysfunction, or result from excessive arterial stiffening. Further research into the underlying mechanisms is needed because each may require a different treatment. If so, identification of reliable markers and finding appropriate methods to determine these markers would be the next step to optimize treatment of this very large group of patients.


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