September 2018 at a Glance: Co-Morbidities, Heart Failure with Preserved Ejection Fraction and Mineralocorticoid Receptor Antagonists

Iorio et al.1 analysed the role of 15 non-cardiac co-morbidities in 2314 outpatients with chronic heart failure (HF). Obesity and hypertension were more prevalent in HF patients with preserved ejection fraction (HFpEF), compared to those with reduced ejection fraction (HFrEF). A similar prevalence was found for other co-morbidities. An increasing number of non-cardiac co-morbidities was associated with a higher risk for all-cause mortality, HF hospitalizations and non-cardiovascular hospitalizations. The co-morbidities contributing to this increased risk were anaemia, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, and peripheral artery disease with similar results for HFrEF and HFpEF.1 A similar role of co-morbidities, independent of left ventricular (LV) ejection fraction, was also found in other analyses.2 Chronic kidney disease was more strongly associated with a poorer outcome in HFrEF than in HFpEF in the Swedish HF Registry.3 The obesity paradox, e.g. better prognosis in overweight and obese HF patients compared with leaner ones, has recently undergone further refinement. First, body surface area, in addition to the more often used body mass index (BMI), has been shown to have an inverse relation with total and cardiovascular mortality, though not with HF hospitalizations.4 Second, other variables were found to interact with the prognostic value of obesity so that, for instance, the obesity paradox was not confirmed in obese diabetic HF patients, differently from non-diabetic ones.5 Lastly, body composition and type of obesity have been shown to have a larger clinical impact than the simple BMI. In a cohort study, abdominal obesity, indicated by a higher waist circumference and waist-to-hip ratio, but not BMI, was associated with LV dysfunction, measured by global longitudinal strain.6 Abdominal obesity, defined by an increased waist circumference, was associated with larger benefits of eplerenone on outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in HF (EMPHASIS-HF).7 Streng et al.8 analysed the waist-to-hip ratio in 1479 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic HF (BIOSTAT-CHF) validation study. A higher waist-to-hip ratio was independently associated with a higher mortality and increased plasma levels of inflammatory markers in females, but not in males, with a significant interaction between the prognostic value of abdominal obesity and sex. These data suggest that fat deposition is pathophysiologically harmful and may be a target for therapy in female patients with HF.8 The relation between myocardial collagen cross-linking, evaluated by biomarkers, and the changes after spironolactone administration in diastolic function, evaluated by the the ratio of early mitral inflow to tissue velocity of the mitral annulus (E/e′), were analysed in 381 patients with HFpEF enrolled in the Aldo-DHF trial.9 The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1), an index inversely correlated with collagen cross-linking, was related to the effects of spironolactone administration. Spironolactone failed to improve the E/e′ ratio in patients in the lowest tertile of the CITP:MMP-1 ratio, which indicates a higher collagen cross-linking, whereas beneficial effects were observed in those in the higher tertiles.9 Nauta et al.10 evaluated five echocardiographic parameters of diastolic function with respect to both their correlation with invasively measured LV filling pressures and their prognostic value using data from 9 and 18 studies, respectively. The E/e′ ratio showed only a modest correlation with invasive measurements of LV filling pressure (r = 0.56) and was slightly predictive of outcomes with a hazard ratio of 1.05 (95% confidence interval 1.03–1.06) per unit increase in E/e′ for the combined outcome of all-cause mortality and cardiovascular hospitalization. The other echocardiographic parameters (left atrial volume index, LV mass index, tricuspid regurgitation velocity, and myocardial tissue velocity) had similar or lower association with prognosis.10 Administration of neurohormonal antagonists, namely angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA) and ivabradine, in patients in sinus rhythm and a heart rate ≥ 70 b.p.m. is the foundation of our current medical treatment for patients with HFrEF.11 To assess the incremental benefit of each of these agents and their combination, Komajda et al.12 performed a network meta-analysis of 58 randomized controlled trials in patients with HFrEF. This analysis showed the incremental value of combined treatments in HFrEF patients with, as the most effective combinations, those of ARNI, BB and MRA and, based on the results before the introduction of ARNI, that of ACEI, BB, MRA and ivabradine with reductions in all-cause mortality, vs. placebo, of 62% and 59%, respectively. Similar results were obtained also with respect to other endpoints, including cardiovascular mortality and all-cause and HF hospitalizations.12 Despite the evidence and the guideline recommendations, MRA are still underused in patients with HFrEF. Using data from 11 215 patients with HFrEF enrolled in the Swedish HF Registry, Savarese et al.13 identified as independently correlated with underuse of MRA the following variables, in descending order of magnitude: lower creatinine clearance, no need for diuretics, no cardiac resynchronization therapy/implantable cardioverter-defibrillator, higher blood pressure, no digoxin use, higher ejection fraction, outpatient setting, older age, lower income, ischaemic heart disease, male sex, follow-up in primary vs. specialty care, lower New York Heart Association class, and absence of a diagnosis of hypertension. Campbell et al.14 assessed the proportion of patients hospitalized for HF who need palliative care. This need was prospectively defined as persistent severe impairment of patient-reported outcome measures without improvement between ≥2 consecutive visits or followed by death. A need for palliative care was found in 27% of patients and these patients lived one third fewer days out of hospital and had less than a quarter of quality of life adjusted days out of hospital than those without need for palliative care. A low Kansas City Cardiomyopathy Questionnaire summary score at baseline was the strongest predictor of the need for palliative care.14 This study confirms that palliative care is still a major unmet need of HF treatment.