How to slice the pie: heart failure subgroups and their clinical meaning

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Heart failure has been defined and characterized in multiple ways. For instance, it has been categorized into ischaemic and non-ischaemic cardiomyopathy based on the underlying cause and to determine outcomes.1,2 More recently, genetic information has been used to differentiate different forms of non-ischaemic cardiomyopathy.3,4 The simplest and most widely used categories are based on left ventricular ejection fraction (LVEF) and, indeed, it provides important diagnostic and prognostic information.5,6 Based on that, the ESC Guidelines have proposed three forms of heart failure, i.e. heart failure with reduced ejection fraction or HFrEF, heart failure with mid-range ejection fraction or HFmrEF, and heart failure with preserved ejection fraction or HFpEF.7 This, however, has even widely criticized for several reasons,8 as also outlined in the Viewpoint ‘Time to rename the middle child of heart failure: heart failure with mildly reduced ejection fraction’ by Carolyn Lam from the National Heart Centre Singapore and colleagues.9 Indeed, the ‘middle child’ of heart failure with an LVEF between 40% and 50% was christened in 2014, in recognition of the large gap in treatment evidence in this subgroup, with prior clinical trial evidence limited to those patients with an ejection fraction of ≤40%, and recent attention being showered upon those with an LVEF of ≥50%. Obviously, an LVEF of 40–50% is a ‘grey area’ also when considering the precision and reproducibility of echocardiography that is commonly used for assessing LVEF. Furthermore, LVEF is even less insightful in those with concomitant mitral regurgitation. Although the adoption of the tongue breaker HFmrEF has inspired hundreds of publications, it remains uncertain whether this is a true entity or just a consequence of the trialists’ definition of HFrEF. Possibly, mild HFrEFF might therefore be much more appropriate. Many heart failure drugs do not work equally across the whole spectrum of LVEF; for instance spironolactone is particularly effective if the LVEF is lower than 60%.10 However, this is not precisely known for newer heart failure drugs, as outlined in the Fast Track ‘A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction’ by Scott Solomon from the Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues.11 In the PARADIGM-HF12 and PARAGON-HF13 trials, sacubitril/valsartan has been tested against enlalapril. To estimate its effects against placebo, the authors made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in heart failure across the full range of LVEF. To that end, they analysed patient-level data from the PARADIGM-HF, PARAGON-HF, CHARM-Alternative,14 and CHARM-Preserved trials,15 thus testing sacubitril/valsartan against a putative placebo. Across a range of LVEF, sacubitril/valsartan was associated with a hazard ratio of 0.54. Treatment benefits of sacubitril/valsartan varied non-linearly with LVEF, with attenuation of effects observed at LVEF above 60% (Figure 1). In comparing PARADIGM-HF with CHARM-Alternative,, the estimated risk reduction of sacubitril/valsartan was 48%. In comparing PARAGON-HF with CHARM-Preserved, risk reduction of sacubitril/valsartan was 29%. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints. Thus, this putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at an LVEF below 60%. These clinical important findings are further discussed in a interesting Editorial by Michael Böhm from the Uniklinikum des Saarlandes in Homburg, Germany and colleagues.16 Estimated treatment effects of sacubitril/valsartan vs. putative placebo across the full range of left ventricular ejection fraction. (A) Recurrent event analysis using a negative binomial model, for total heart failure hospitalizations and cardiovascular death. (B–D) Time-to-first analyses using Poisson regression models for first heart failure hospitalization or cardiovascular death, cardiovascular death, and all-cause mortality, respectively. Treatment effects were estimated using cubic spline methods by LV ejection fraction as a continuous measure. Density of patients at given left ventricular ejection fraction ranges is displayed in the table. CI, confidence interval; CV, cardiovascular; LV, left ventricular; RR, rate ratio (from Vaduganathan M, Jhund PS, Claggett BL, Packer M, Widimský J, Seferovic P, Rizkala A, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction. See pages 2356–2362). Estimated treatment effects of sacubitril/valsartan vs. putative placebo across the full range of left ventricular ejection fraction. (A) Recurrent event analysis using a negative binomial model, for total heart failure hospitalizations and cardiovascular death. (B–D) Time-to-first analyses using Poisson regression models for first heart failure hospitalization or cardiovascular death, cardiovascular death, and all-cause mortality, respectively. Treatment effects were estimated using cubic spline methods by LV ejection fraction as a continuous measure. Density of patients at given left ventricular ejection fraction ranges is displayed in the table. CI, confidence interval; CV, cardiovascular; LV, left ventricular; RR, rate ratio (from Vaduganathan M, Jhund PS, Claggett BL, Packer M, Widimský J, Seferovic P, Rizkala A, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction. See pages 2356–2362). Hypertension is a well-established heart failure risk factor, especially for adverse left ventricular remodelling.17 Coronary microvascular dysfunction does occur in hypertension and in heart failure.18 This is further investigated in a Fast Track entitled ‘Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure’ where Marcelo di Carli from Brigham and Women’s Hospital in Boston, Massachusetts, USA and colleagues used myocardial flow reserve and global longitudinal strain, markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive heart failure risk.19 Of 194 patients, 155 had adaptive, while 39 had maladaptive remodelling, which was associated with lower myocardial flow reserve and impaired global longitudinal strain. Across the remodelling spectrum, diastolic parameters, global longitudinal strain, and N-terminal probrain natriuretic peptide (NT-proBNP) were independently associated with myocardial blood flow reserve. Maladaptive left ventricular remodelling was associated with increased adjusted incidence of heart failure hospitalization and death. Importantly, the combination of abnormal myocardial flow reserve and global longitudinal strain was associated with a higher rate of heart failure hospitalization compared with normal myocardial flow reserve and global longitudinal strain, with a hazard ratio of 3.2, including in the adaptive remodelling subset, with a hazard ratio of 3.9 (Figure 2). Thus, coronary microvascular dysfunction and myocardial mechanics closely correlate in refining heart failure risk assessment of hypertensives. These novel insights are put into context in an Editorial by Javier Escaned from the Hospital Clinico Universitario San Carlos in Madrid, Spain.20 The Kaplan–Meier survival curves heart failure HF hospitalization based on adaptive vs. maladaptive remodelling. *Adjusted for age, sex, history of diabetes, and history of coronary artery disease (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting), and left ventricular ejection fraction. The presence of subclinical injury is associated with a higher risk of heart failure hospitalization in the context of adaptive remodelling (left panel) but not once maladaptive remodelling has developed (right panel) (from Zhou W, Brown JM, Bajaj NS, Chandra A, Divakaran S, Weber B, Bibbo CF, Hainer J, Taqueti VR, Dorbala S, Blankstein R, Adler D, O'Gara P, Di Carli MF. Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure. See pages 2366–2375). The Kaplan–Meier survival curves heart failure HF hospitalization based on adaptive vs. maladaptive remodelling. *Adjusted for age, sex, history of diabetes, and history of coronary artery disease (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting), and left ventricular ejection fraction. The presence of subclinical injury is associated with a higher risk of heart failure hospitalization in the context of adaptive remodelling (left panel) but not once maladaptive remodelling has developed (right panel) (from Zhou W, Brown JM, Bajaj NS, Chandra A, Divakaran S, Weber B, Bibbo CF, Hainer J, Taqueti VR, Dorbala S, Blankstein R, Adler D, O'Gara P, Di Carli MF. Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure. See pages 2366–2375). Sodium–glucose transport type 2 (SGLT2) inhibitors have shown impressive protection in diabetics,21 and are now recommended as first-line therapy in diabetics with atherothrombotic cardiovascular disease.22 More recently, in the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with HFrEF irrespective of diabetes.23 However, it remains unclear how background heart failure therapy affects outcomes with dapagliflozin. In their Fast Track ‘Effects of dapagliflozin in DAPA-HF according to background heart failure therapy’, John J.V. McMurray from the Western Infirmary, Glasgow, UK on behalf of the DAPA-HF Investigators examined this issue in a post-hoc analysis.24 They analysed the various subgroups as to the presence or absence of a diuretic, digoxin, mineralocorticoid receptor antagonist, sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillator devices, and/or cardiac resynchronization therapy. Further, they examined the effect of the study drug according to the dosage above and below the median. Patients were treated with a diuretic in 84%, a renin–angiotensin system blocker in 94%, and a beta-blocker in 96%. Half of those on a beta-blocker and almost as many taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB ) were treated with ≥50% of the recommended dose. Overall, the hazard ratio of dapagliflozin vs. placebo was 0.74 for the primary endpoint, which was consistent in all subgroups These clinically most relevant findings are accompanied by an Editorial by Milton Packer from Baylor University Medical Center at Dallas in Texas, USA.25 Stem cell therapy has been a big hope in heart failure. However, many trials have been neutral or only borderline positive,26 and the field has been hit by a fraud scandal as well.27 As a consequence, embryonic stem cell-based therapies have been the last hope. In a clinical review article entitled ‘A realistic appraisal of the use of embryonic stem cell-based therapies for cardiac repair’, Marcin Wysoczynski and Roberto Bolli from the University of Louisville in Louisville, Kentucky, USA note that despite the well-documented capacity of embryonic stem cells to differentiate into cardiomyocytes, transplantation of embryonic stem cells is plagued by several problems, including graft rejection, arrhythmias, and potential risk of teratomas.28 Indeed, life-long immunosuppression is a disease. Transplantation of human embryonic stem cells in primates causes life-threatening arrhythmias. In contemporary clinical research, the margin of tolerance for such catastrophic effects as malignancies is zero, and although the probability of tumours can be reduced by embryonic stem cell differentiation, it is unlikely to be eliminated, particularly when billions of cells are injected. Although embryonic stem cells were touted as capable of long-term regeneration, these cells disappear rapidly after transplantation and there is no evidence of long-term engraftment. There is, however, mounting evidence that they act via paracrine mechanisms—just like adult cells do. To date, no controlled clinical trial of embryonic stem cells in cardiovascular disease has been conducted or even initiated. In contrast, adult cells have been used in thousands of patients with heart disease, with no significant adverse effects and with results that were sufficiently encouraging to warrant phase II and III trials. Furthermore, induced pluripotent stem cells offer pluripotency like embryonic stem cells without the need for lifelong immunosuppression. The most reasonable interpretation of current data is that embryonic stem cell-based therapies are not likely to have clinical application for heart disease any time soon. Cardiac function relies on the interplay of several specialized cell types and a precisely regulated network of chemical and mechanical stimuli. In the Current Opinion article entitled ‘Living myocardial slices: a novel multicellular model for cardiac translational research’ Thomas Thum and colleagues from the Hannover Medical School in Germany note that progress in translational research has been hindered by the lack of appropriate research models.29 Living myocardial slices are ultrathin, i.e. 100–400 μm, sections of living cardiac tissue, that maintain the native multicellularity, architecture, and structure, and can provide information at a cellular/subcellular level. They overcome most of the limitations of other in vitro models. This technology can bridge the gap between in vitro and in vivo human studies and has the potential to revolutionize translational research approaches. The issue is complemented by various Discussion Forum contributions. In a contribution entitled ‘Intravenous vasodilators in acute heart failure patients with low basic blood pressure: may the benefit come from targeting perfusion rather than pressure?’ Pier Paolo Bocchino and colleagues from the Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino in Italy discuss the recent contribution entitled ‘How much can acute heart failure patients with low basic blood pressure (systolic blood pressure 90–100 mmHg) benefit from the use of vasodilators?’ by Zhou et al. that was a contribution discussing the ‘2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association’.30–32 Zhou et al. respond in a separate statement.33 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.