Author + information
- Pierpaolo Pellicori, MD∗ (, )
- John G.F. Cleland, MD and
- Andrew L. Clark, MA, MD
- ↵∗Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom
Inclusion of patients whose symptoms are not due to left ventricular dysfunction has undoubtedly contributed to the neutral outcomes of many trials of heart failure with preserved ejection fraction (HFpEF). Exertional breathlessness is common in older people. Many are empirically prescribed loop diuretic agents in an attempt to relieve symptoms, often without further investigation. This may obscure a diagnosis of HFpEF (1). Obesity, or common problems in older age, such as chronic lung or joint disease, might provoke symptoms during exercise. Decreased activity levels will reduce skeletal muscle function, complicating the interpretation of symptoms and clinical investigations.
In landmark trials, natriuretic peptides have consistently been the strongest predictor of outcome; therefore, if HFpEF is considered a disease that has serious consequences, they must be considered a key diagnostic test (2).
We congratulate Mordi et al. (3) on their study of patients with either HFpEF (n = 62) or hypertension (n = 22) and 28 healthy control subjects. All subjects underwent cardiopulmonary exercise, very detailed echocardiography, and cardiac magnetic resonance. Two major findings were reported: first, global longitudinal strain by speckle tracking worsens as the disease progresses from healthy subjects to patients with overt HFpEF (4). In contrast, other echocardiographic measurements, such as the E/E′ ratio (endorsed by guidelines and used in clinical practice to diagnose HFpEF ), did not. Second, myocardial extracellular volume measured by cardiac magnetic resonance best discriminates among the 3 populations, leading the investigators to suggest a potential role for extracellular volume as an inclusion criterion and surrogate endpoint in clinical trials of HFpEF.
We have several concerns about the populations studied. In a large proportion of those thought to have HFpEF, cardiac dysfunction was likely not to be the primary cause of their symptoms: their median brain natriuretic peptide (BNP) level was only 52 ng/l, and more than a quarter had BNP levels <35 ng/l, a cutoff recommended by the European Society of Cardiology (5) to exclude serious cardiac dysfunction. Moreover, despite the inclusion of a group of people with severe exercise intolerance diagnosed as having heart failure, fewer than 50% were prescribed loop diuretic agents. In comparison, loop diuretic agents were prescribed to more than a third of the patients with hypertension despite a lack of recommendation from guidelines; perhaps loop diuretic agents were masking the presence of HFpEF. Finally, 25% of healthy control subjects supposed to have “normal” BNP levels had BNP levels >35 ng/l, which would have qualified them for a diagnosis of HFpEF if they had reported breathlessness at any point. There was thus substantial overlap among the 3 groups of subjects.
Baseline cardiac rhythm was also not reported: we suspect that all patients enrolled in that study were in sinus rhythm. Although sinus rhythm might be the norm for studies of hypertension, it is highly unusual for patients with HFpEF, among whom at least a third are expected to have permanent atrial fibrillation (4,5). The investigators stated that left atrial dilation was one of the key criteria used to diagnose HFpEF, but left atrial dimensions were not reported.
Future studies might confirm that global longitudinal strain and extracellular volume are useful diagnostic tools to track a patient’s journey from asymptomatic to overt heart failure and may help unravel the complex pathophysiology of HFpEF. However, a common international diagnostic standard is required, and this must include, in the current state of knowledge, natriuretic peptides.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Mordi I.R.,
- Singh S.,
- Rudd A.,
- et al.
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