ReviewHeart failure with preserved ejection fraction: Refocusing on diastole
Introduction
Despite clear improvements in the treatment of cardiovascular disease over the past several decades, the incidence and prevalence of heart failure (HF) have not decreased, survival has marginally improved, and morbidity remains unacceptably high [1], [2]. One of the challenges and barriers in treating HF is the heterogeneity of the clinical syndrome. Heart failure is a syndrome of impaired cardiac function leading to symptoms of exercise intolerance and/or congestion, and is the final common pathway of abnormalities in the myocardium, coronary arteries, valvular structures and/or electrical impulse generation and conduction [3]. In nearly half of the patients with HF the syndrome is driven by impaired cardiac systolic function measured by reduced left ventricular ejection fraction (LVEF), systolic HF or HF with reduced EF (HFrEF) (Table 1). The remaining half of patients with preserved LVEF represents a heterogeneous group where multiple concomitant factors lead to HF. The abnormality most commonly seen in patients with preserved LVEF is an impaired diastolic function, which however is only present in approximately 70% of these patients. Concomitant abnormalities in the heart, vasculature, lung, and skeletal muscle are often present.
A recent consensus from the European Society of Cardiology [4] suggested refocusing on the impairment in diastolic function (LV relaxation and/or filling) as the conditio sine qua non for the definition of the syndrome of HF with preserved EF (HFpEF) (Fig. 1). While this provides a pragmatic opportunity for a defining description of the syndrome that is based not on a negative attribute (i.e. not having reduced EF) and allows to positively identify patients with HF excluding those with symptoms not due to HF, this definition also excludes a number of patients in whom other cardiac abnormalities cause HF symptoms despite apparently ‘normal’ systolic and diastolic functions.
This review will discuss the definition(s), clinical manifestation, proposed pathophysiology, diagnostic and therapeutic approaches, and prognosis of HFpEF in order to address what is known and what is not known about this complex clinical condition.
Section snippets
Methods
This review is based on an updated and comprehensive MEDLINE/PubMed search, updated on September 1, 2014.
Definition of HFpEF
The choice of selecting the term or characteristics to define the syndrome has been long-debated. While HFpEF has now become the preferred term, several different names have been used such as ‘heart failure with normal ejection fraction’ or ‘diastolic heart failure’. The term ‘diastolic heart failure’ refers to the common finding of one or more abnormalities in LV diastolic function or indirect evidence of diastolic dysfunction (i.e. left ventricular hypertrophy or left atrial enlargement) in
Clinical characteristics
While the actual signs and symptoms of HFpEF are very similar to those of HFrEF, there are many characteristics that are unique to HFpEF (Table 1). First and foremost, HFpEF is more prevalent in women and is more common with aging, with a peak prevalence in women at approximately 70 years of age [16], [17], although recent studies have identified a high prevalence of HFpEF also in obese middle-aged women [18], [19]. Large cohort studies and clinical interventional studies show that patients with
Mechanism(s) of disease
The necessary condition for a true HF diagnosis is the presence of an “impaired heart function” or even more broadly “impaired cardiovascular function”. With the advent and refinement of imaging techniques, much interest has been focused on measuring LVEF. However there are more that need to be investigated than resting LVEF alone, and these additional data improve our ability to diagnose HFpEF and understand its pathophysiologic consequences.
Diastolic function is broadly defined as the ability
When LV systolic function is not really “normal”
Global LV systolic function is by definition ‘preserved’ in HFpEF. Other conditions may however impair regional or global systolic function independent of abnormal diastolic function, and thus not really representing HFpEF. Regional abnormalities in LV systolic function, obstruction to LV inflow or outflow, or associated abnormalities in right ventricular (RV) systolic function may exist. There is a long list of conditions that needs to be therefore considered and excluded prior to labeling a
The role of comorbidities in HFpEF
Patients with HF, due to HFrEF, HFpEF or other etiologies, frequently have one or more comorbidities that contribute to symptoms, impairment of the quality of life, and a worse overall prognosis. These comorbidities may affect respiration (i.e. involving the lungs, airways or respiratory muscles), nutrition (i.e. involving the gastrointestinal tract and regulation of the mood and appetite), strength (i.e. involving the skeletal muscles and bone structures), and metabolism (i.e. involving
Diagnostic approach to HFpEF
Without the ESC criteria [4], the diagnosis of HFpEF is based on the presence of symptoms of HF and the absence of LV systolic dysfunction, after the exclusion of other conditions (i.e. ischemia, valvular disease, arrhythmia) that may cause symptoms of HF or symptoms that may be confused with HF. As defined, the diagnosis of HFpEF poses great clinical challenges. HF symptoms are not specific per se, and a long list of diseases may simulate HF. The absence of LV systolic dysfunction helps
Therapeutic approach to HFpEF
Therapy in HF is aimed at amelioration of symptoms, improvement in function/quality of life, and/or prolongation of life. During the past decades we have witnessed the success of neurohormonal blockade and vasodilator therapy in HFrEF: 1) angiotensin–aldosterone blockers; 2) β-AR antagonists; and 3) hydralazine/isosorbide have been shown to reduce mortality in one or more studies of patients with HFrEF [5], [6]. Unfortunately these treatments were mostly ineffective in reducing mortality in
Prognosis of patients with HFpEF
The LVEF is an important prognostic factor in HF, and this had initially led to focus interest in HFrEF, with HFrEF being considered to be a more benign syndrome. We now appreciated that the morbidity and mortality in HFpEF are unacceptably high and approach those seen in HFrEF [1], [2]. The 1- and 5-year mortality rates vary between studies, likely due to differences in the criteria used to define HFpEF, with rates ranging between 10 and 20% at 1 year and between 30 and 50% at 5 years [1], [2].
Conclusion
Heart failure with preserved ejection fraction (HFpEF) is a common disease characterized by significant morbidity and mortality. Despite similarities in the presenting symptoms, fundamental differences exist between HFrEF and HFpEF in terms of epidemiology, risk factors, clinical characteristics, prognosis, and response to treatment. While identification of key pathologic mechanisms led to improvements in HFrEF prognosis through targeted pharmacologic blockade of norepinephrine, angiotensin II,
Conflict of interest
Dr. Abbate and Dr. Van Tassell have received research support from Swedish Orphan BIovitrum (Stockholm, Sweden) and Novartis (Basel, Switzerland). The remaining authors report no relationships that could be construed as a conflict of interest.
Acknowledgments
Dr. Abbate and Van Tassell are supported by a R34 grant (1R34HL118348) from the National Heart, Lung and Blood Institute related to this topic.
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