Heart failure and left ventricular remodelling in HFrEF and HFpEF

Download the Issue @ a Glance podcast Subscribe to the EHJ Podcast Due to the modern management of myocardial infarction and increasing longevity, heart failure has come to the centre stage in cardiovascular medicine.1 Thus, also in this past year numerous research projects have focused on this syndrome, and the most important ones are summarized for our readers by Michel Komajda from the CHU Pitié-Salpêtrière in Paris, France in the review ‘The year in cardiology 2015: heart failure’.2 This contribution is followed by ‘The year in cardiology 2015: valvular heart disease’ by Bernard Iung from the Bichat Hospital.3 During this year a number of interesting articles addressed the topic of valvular heart disease with a special emphasis on imaging, interventions, and the publication of the new ESC Guidelines on the management of infective endocarditis (IE). An important chain of events leading to heart failure is hypertrophy, left ventricular dysfunction, and pump failure. In their clinical review ‘Heart failure: when form fails to follow function’,4 Ellis L. Rolett and colleagues from the Dartmouth College Geisel School of Medicine in Hanover, New Hampshire, USA note that two hypertrophy phenotypes have been distinguished. One, systolic heart failure or heart failure with reduced ejection fraction (HFrEF), is characterized by ventricular dilatation and sarcomere addition in series. The other, also associated with a serious outcome,5 diastolic heart failure or heart failure with preserved ejection fraction (HFpEF), is characterized by concentric hypertrophy and sarcomere addition in parallel.6 Unlike the former, which increases wall stress and in turn initiates a vicious cycle that results in progressive dilatation or remodelling, the latter reduces wall stress by ventricular hypertrophy.7 As different cell signalling mechanisms control these two phenotypes, treatments that prolong survival in patients with dilated ventricles often do not improve prognosis in those with concentrically hypertrophied ventricles. Characterization of the signalling pathways responsible for these two different proliferative responses therefore has the potential to improve the management of these different types of heart failure. While mineralocorticoid receptor antagonists improve outcome in patients with reduced left ventricular ejection fraction,8 spironolactone did not reduce cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with HFpEF in the TOPCAT trial.9 In their paper entitled ‘Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure and preserved ejection fraction’, Scott Solomon et al. from the Brigham and Women's Hospital in Boston, Massachusetts10 utilized data from the TOPCAT trial to assess the relationship between ejection fraction, outcomes, and the efficacy of spironolactone. In order to accomplish this, they assessed differences in baseline characteristics and outcomes in 3444 patients with HFpEF, and determined whether an ejection fraction ranging from 44% to 85% modified the treatment effect of spironolactone. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction range. The ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome and for heart failure hospitalization, with stronger benefits of spironolactone at the lower end with respect to the primary endpoint and heart failure hospitalization. The authors therefore conclude that in patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by ejection fraction, and the efficacy of spironolactone was greatest at the lower end of the spectrum. The manuscript is accompanied by an excellent Editorial by Barry A. Borlaug from the Mayo Clinic in Rochester, Minnesota (USA).11 Global measures of left ventricular function, in particular ejection fraction and global myocardial strain measures, are powerful predictors of outcomes in patients with left ventricular dysfunction, heart failure, or both.12,13 However, less is known about the relationship between regional myocardial function as assessed by strain echocardiography and clinical prognosis. In their paper entitled ‘Regional cardiac dysfunction and outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction’,14 the VALIANT Investigators studied 248 patients with left ventricular dysfunction, heart failure, or both 5 days after their first infarction. They found that after 20 months of follow-up, peak longitudinal strain via B-mode speckle tracking in 12 segments from the apical four- and two-chamber views was worse in segments with abnormal wall motion score, although it was significantly impaired even in segments scored as normokinetic compared with normal controls. In multivariate Cox proportional hazards models, each additional abnormal segment was associated with an increased risk of all-cause mortality, with a hazard ratio of 1.42 even after adjustment for clinical covariates, including ejection fraction, left ventricular end-systolic volume, and number of abnormal segments by wall motion score. The authors conclude that in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction, regional longitudinal strain is significantly depressed even in segments with normal wall motion score, and this measure was related to adverse outcome. Cardiac resynchronization therapy or CRT is a recommended treatment of heart failure patients with depressed ejection fraction and wide,15 but not narrow, QRS on ECG.16 However, while optimal left ventricular lead positionng has been extensively investigated,17,18 right ventricular lead position remains a matter of debate.19 Thus, in their study reported in the paper entitled ‘Comparison of right ventricular septal pacing and right ventricular apical pacing in patients receiving cardiac resynchronization therapy defibrillators: the SEPTAL CRT study’,20 Christophe Leclercq and colleagues from the Centres Hospitalier Universitaire in Rennes, France randomized 263 patients receiving a CRT-D device to either right ventricular septal or apical pacing, with left ventricular reverse remodelling as an endpoint. Left ventricular end-systolic volume reduction at 6 months was not different between the two groups. The percentage of ‘echo-responders’, defined by a reduction in left ventricular end-systolic volume of >15% at 6 months, was 50% in both groups, with no difference in the time to first heart failure hospitalization or death. The authors conclude that right ventricular septal pacing in CRT is non-inferior to apical right ventricular pacing as regards reverse remodelling at 6 months, with no difference in clinical outcome. Thus, no recommendation for optimal right ventricular lead position can be made based on this study, and further larger trials are required in the future. Another unresolved issue is whether peri-infarct pacing prevents left ventricular remodelling and improves functional and clinical outcomes in patients with large first myocardial infarction. Thus, in their AHA FAST TRACK paper ‘Peri-infarct zone pacing to prevent adverse left ventricular remodelling in patients with large myocardial infarction’,21 Gregg W. Stone and the PRomPT Trial Investigators sought to answer this question in 126 patients recruited at 27 international sites within 10 days after an infarction with a creatinine kinase rise of >3000 U/L and a QRS duration of ≥120 ms. Patients were randomized 1:1:1 to dual-site biventricular pacing, single-site left ventricular only pacing, or non-implanted control. The primary endpoint of the change in left ventricular end-diastolic volume from baseline to 18 months averaged 15 mL in the control group and 17 mL in the pooled pacing groups, which did not reach significance. Quality of life, as assessed by the Minnesota Living with Heart Failure Questionnaire and New York Heart Association class, was also similar between groups. The 6-min walk distance improved during follow-up to an equal degree in all groups, and there were no significant differences in the 18-month rates of death or heart failure hospitalization between the pooled pacing and control groups. The authors conclude that peri-infarct pacing did not prevent left ventricular remodelling or improve functional or clinical outcomes during 18 months of follow-up in patients with a large first myocardial infarction. The manuscript is accompanied by a critical Editorial by Christophe Leclercq from Centre Hospitalier Universitaire Rennes in France.22 The editors hope that readers of this issue of the European Heart Journal will find it of interest.