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Yesterday, at a joint session with the American Heart Association, we heard about the ‘conundrum of heart failure with preserved ejection fraction’ (HFpEF; left ventricular ejection fraction [LVEF] ≥50%). Ahead of further sessions on HFpEF, Professor John Cleland (National Heart and Lung Institute, Imperial College, London and University of Glasgow, UK) describes the current state of play:
“Many patients with heart failure (HF) have an LVEF ≥50%—they are generally older and have multiple comorbidities. When other potential reasons for breathlessness and ankle swelling exist, such as lung disease or obesity, a diagnosis of HFpEF is often missed and diuretics given without further cardiac investigation. Even when an echocardiogram is done, if the LVEF is ‘normal’, it is interpreted as excluding HF. A combination of elevated natriuretic peptides and cardiac imaging is needed to determine whether HF is present and whether it is due to HFpEF, HF with reduced ejection fraction (HFrEF; LVEF <40%) or another cause. The hallmark of HFpEF is left atrial dilation, often accompanied by left ventricular hypertrophy and increased stiffness.
The pathophysiology of HFpEF is heterogenous. Hypertension, left ventricular hypertrophy and inflammation, possibly driven by obesity, diabetes and epicardial fat deposits, leading to myocardial fibrosis appear important. Many patients have co-existing coronary artery disease, atrial fibrillation and renal dysfunction. Conceptually, there is a spectrum of HFpEF pathophysiology; one extreme is characterised by myocardial hypertrophy and slow early relaxation of the ventricle and the other by infiltration of the myocardium by collagen or amyloid, which arrests filling in mid-diastole, causing a restrictive defect.
For those with an LVEF of 40–49%, the term ‘HF with mid-range ejection fraction (HFmrEF)’ was introduced in the 2016 ESC Guidelines—it caused some controversy but is now accepted as an important innovation. Measurement of LVEF is only accurate to within 5–10%; HFmrEF comprises those who genuinely have an LVEF of 40–49% and also those found to have an LVEF <40% or >50% if subsequently re-measured. HFmrEF is a zone of uncertainty, providing clear separation between HFrEF and HFpEF, where clinicians and trialists are obliged to think twice about what they are doing.
Taking a fresh look at randomised-trial data of patients with LVEF >40% over the last 15 years, it appears that HFmrEF and HFrEF respond similarly to treatment. This has led to suggestions that HFrEF should be re-defined as an LVEF <50% or even <55%. However, there is value in retaining HFmrEF for interpreting trial results. Consider a trial including patients with an LVEF >40% for a treatment already known to be effective for HFrEF. Overall, the trial might be positive because of benefit only in those with HFmrEF (some of whom would have had an LVEF <40% if re-measured); even if the treatment was ineffective for HFpEF, these patients might be recommended an ineffective therapy based on the positive result of the overall trial. Alternatively, the trial might be neutral overall, due to a lack of effect in HFpEF, leading to patients with HFmrEF being denied an effective treatment. In the future, new categories may be needed; for instance, there are patients with supra-normal LVEF who still have a poor prognosis.1
To date, trials for HFpEF have not shown clear reductions in morbidity and mortality; however, patients often have other medical conditions that are therapeutic targets, e.g. atrial fibrillation (anticoagulation and optimal rate control) and hypertension. Although guidelines indicate that the treatment of HFrEF and HFpEF should be very different, in clinical practice, because of such comorbidities, patients often receive the same treatment but for different reasons as we will show in a moderated poster presentation tomorrow (Abstract P4148).
This afternoon in a Hot Line Session, we will hear the first results from PARAGON-HF that investigated angiotensin receptor neprilysin inhibition with sacubitril/valsartan vs valsartan alone in HFpEF. In contrast to many other trials of HFpEF, elevated natriuretic peptide levels and echocardiographic evidence of cardiac dysfunction (particularly left atrial dilation) were inclusion criteria in PARAGON-HF. This is the first trial of HFpEF with robust diagnostic criteria; some previous trials were probably neutral because they included many patients who did not have HF! The results are eagerly awaited, especially following the PARADIGM-HF trial, which showed that sacubitril/valsartan was superior to enalapril for HFrEF, throughout the studied range of LVEF (up to 40%).2
There are still many gaps in understanding about the aetiology, pathophysiology and treatment of HFpEF with a clear need to improve both diagnosis and treatment—further research is a key component to improving the well-being and longevity of our patients.”
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