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Current Opinion in Supportive & Palliative Care:
doi: 10.1097/SPC.0000000000000035

Death by oxymoron? The enigma of heart failure with preserved ejection fraction

Beattie, James M.

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Department of Cardiology, Heart of England NHS Foundation Trust, Birmingham, UK

Correspondence to James M. Beattie, Consultant Cardiologist, Heart of England NHS Foundation Trust, Birmingham, UK. E-mail:

There is an epidemic of heart failure affecting millions of people worldwide. Often linked to lifestyle issues in the Westernized societies, an increasing incidence and better treatment of the predisposing conditions of coronary disease, hypertension and diabetes have generated a burgeoning ageing clinical cohort subject to the effects of left ventricular dysfunction. This disabling, progressive and ultimately fatal illness is characterized by fluctuating multiorgan impairment, maladaptive neuroendocrine and cytokine activation, and congestion because of salt and water retention. Those affected experience a constellation of symptoms dominated by breathlessness and anergia, have a poor prognosis and consume a significant proportion of healthcare resources.

Although difficult to differentiate clinically, heart failure due to left ventricular dysfunction is now characterized as occurring in two forms, distinguished by a reduction or preservation of left ventricular systolic function as assessed by the estimation of the ejection fraction. This is the volumetric fraction of blood expelled by the ventricle during a cardiac cycle and is usually assessed by echocardiography. About half of the total number of those presenting with the clinical features of heart failure has a reduced ejection fraction (HFREF). This is typically because of myocardial damage, for example, by a myocardial infarction or myocarditis. The other patients with a clinical diagnosis of heart failure show a preserved left ventricular ejection fraction (HFPEF). These patients tend to be older, overweight and women, with a history of hypertension or atrial fibrillation and have a relatively low prevalence of coronary disease [1]. Clearly, some of these features are also risk factors for the development of HFREF, and there has been some controversy on whether these are truly discrete syndromes or represent different ends of the spectrum of the clinical phenotype of heart failure [2]. It has been postulated that HFPEF may progress to HFREF, and indeed abnormalities of longitudinal left ventricular systolic function have been demonstrated in those with HFPEF, a parameter which may not be apparent in measuring the ejection fraction which is predominantly derived from the assessment of radial contraction [3]. However, based on the analysis of trends in ejection fraction responses to therapy, it is generally accepted that HFPEF and HFREF are distinct clinical entities [4]. Difficulties in classification have also arisen because of variation in the cutoff values selected to demarcate a reduced or preserved ejection fraction across a series of studies, and pragmatically in terms of decisions on therapy, there may be a grey area in those exhibiting an ejection fraction between 35 and 50% [1].

In an effort to resolve some of this diagnostic ambiguity, the Heart Failure and Echocardiography Associations of the European Society of Cardiology have published a consensus statement defining a variety of criteria for the diagnosis of HFPEF [5]. These include:

1. the presence of signs or symptoms of congestive heart failure

2. the presence of normal or mildly abnormal left ventricular systolic function (ejection fraction >50%); and

3. evidence of diastolic dysfunction.

Elderly individuals tend to be sedentary and might report few symptoms and it may be difficult to ascertain whether peripheral congestion is gravitational or because of HFPEF. To obviate such difficulties, a recent more comprehensive multiparametric strategy to assess diastolic function has been developed, including stress diastolic echocardiography [6].

The structural changes seen in the hearts of those with HFPEF and HFREF appear to be different. In contrast to the eccentric remodelling of the left ventricle seen in HFREF, often reflecting a response to coronary attrition, concentric remodelling is the hallmark of those with HFPEF. This increase in left ventricular mass may occur even in the absence of left ventricular hypertrophy which might be expected to result from hypertension and the other comorbidities commonly seen in this cohort. The left ventricle is usually not dilated, but left atrial enlargement is common and may be a surrogate marker for diastolic dysfunction [7]. Left ventricular diastolic dysfunction, evident as increased diastolic stiffness, may arise from an excess of collagen deposition in the extracellular matrix. Intrinsic cardiomyocyte stiffness linked to changes in the cytoskeletal protein titin as well as slow myocyte relaxation due to impaired cross-bridge detachment and sarcoplasmic reticular Ca2+ reuptake may also contribute [8].

Although we are beginning to understand some of the heterogeneous pathophysiological mechanisms which lie behind this increasingly encountered variant of left ventricular dysfunction, to date, elucidation of effective treatments to improve mortality and morbidity for those exhibiting HFPEF remain elusive [1,9]. Three randomized controlled trials which examined the effects of candesartan (CHARM-Preserved), perindopril (PEP-CHF) and irbesartan (I-Preserve) showed no significant reduction in the rates of cardiovascular mortality or hospitalization [10–12]. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial was a randomized controlled trial designed to establish whether treatment with the mineralocorticoid receptor antagonist spironolactone would reduce morbidity and mortality in 3445 patients with HFPEF [13]. The results, presented at the American Heart Association Scientific Sessions at Dallas in November 2013, showed no effect on mortality, but offered a signal suggesting a modest reduction in heart failure related hospitalizations. Initial studies with beta-blockers and angiotensin receptor neprilysin inhibitors show early promise, but need to be confirmed [14]. To date, the only recommended therapy for HFPEF rests in the use of diuretic therapy to control salt and water retention, thereby relieving congestion and breathlessness, and optimizing the treatment of the commonly associated hypertension, obesity and diabetes. Control of arrhythmias and reducing myocardial ischaemia may also be important in some patients [1]. The apparently dismal results of the present therapy for HFPEF stand out against the response to treatments developed for those with HFREF. Many of the principal pathophysiological mechanisms underlying HFREF have been characterized over the last 20 years with the elaboration of evidence-based guidelines describing effective pharmacological, device and cardiac surgical interventions [1]. With the application of this guideline-driven therapy, patients with HFREF may now survive a decade or more after diagnosis [15].

Given the considerable differences in the nature of these types of left ventricular dysfunction and the disparity in responses to therapy, do these variously affected patients show dissimilar trends in mortality and modes of death? Mortality for those with HFPEF (ejection fraction >50%) and HFREF (ejection fraction <40%) was compared as part of the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study of 2802 heart failure patients admitted to the hospitals across Ontario. There was no significant difference in the 1-year mortality between HFPEF (22%) and HFREF (26%) [16]. A similar pattern emerged in data on 4596 patients from the Olmsted County Registry, with a 1-year and 5-year mortality of 29 vs. 32% and 65 vs. 68% for HFPEF (ejection fraction >50%) and HFREF (ejection fraction <50%), respectively [17]. These results were consistent with those of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) study, which showed a mortality of 21% for those with HFPEF (ejection fraction >45%) against 22% for HFREF patients (ejection fraction <45%) over an 18-month follow-up period [18]. In contrast, a literature-based meta-analysis suggested a better prognosis for those with HFPEF compared with HFREF (32 vs. 41%) followed for an average of 47 months [19]. Although the better prognosis for HFPEF may be real for the studies analysed, the authors conceded that a relatively high proportion of patients were excluded from the analysis because of missing data and the inclusion of some patients from randomized controlled trials may have introduced some selection bias.

The causes and modes of deaths have been compared for HFPEF and HFREF. For both clinical subtypes, cardiovascular deaths predominate and these are commonly manifested as deaths from heart failure or sudden death. Sudden death is more common in those with coronary disease, perhaps linked to the distorted ventricular geometry intrinsic to eccentric remodelling with resultant electrophysiological instability. Whereas up to 60% of patients with HFPEF die from a cardiovascular cause, proportionately less than those with HFREF, relatively more die from unrelated comorbidities [20–22]. We know that most patients with chronic heart failure exhibit at least four comorbidities after the age of 65 years, and therefore the effects of this preponderance of non-cardiac conditions on outcome in the more aged HFPEF population is not unexpected [23].

Heart failure and non heart failure related hospitalizations are a marker for a poorer prognosis for both HFPEF and HFREF, and the majority of patients die in hospital [18]. Age, male sex and obesity are adverse prognostic indicators, as are the burden of comorbidities, particularly anaemia and renal failure [21]. For both HFPEF and HFREF, B-type natriuretic peptide (BNP) levels are elevated; however, BNP levels tend to be lower in those with HFPEF [24]. Some caution is required in interpreting the BNP responses as these levels tend to rise with age or the onset of atrial fibrillation and are higher in women. However, BNP testing has been recommended as a prognostic marker in HFPEF, as have some parameters of diastolic function based on data from the I-Preserve study [7,20].

Thus, the increasingly aged heart failure population are affected by these widely different variants of left ventricular dysfunction. This includes those with HFPEF, likely to become the dominant form of congestive heart failure and for which current treatment is relatively ineffective, and those with HFREF, surviving but declining despite a successful and complicated therapeutic regimen [25]. Both pathophysiological phenotypes confer significant morbidity and mortality burdens on those suffering from these distinctive heart failure syndromes, which will continue to challenge the clinicians responsible for the care of those with advanced disease.

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Conflicts of interest

There are no clonflicts of interest.

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