The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin-angiotensin system. In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range [IQR]: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m2/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m2/year] vs. -2.04 ml/min/1.73 m2/year [95% CI: -2.21 to -1.88 ml/min/1.73 m2/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.

Aims Women are more likely to develop heart failure with preserved ejection fraction (HFpEF) than men. We studied the relationship between sex and cardiovascular structure and function in patients with HFpEF. Methods and results The study included 279 participants from the PARAMOUNT study (57% women) with analysable baseline echocardiograms (mean age 71 years, 94% hypertensive, 38% diabetic). We assessed sex‐based differences in baseline clinical characteristics and measures of cardiovascular structure/function. Coronary artery disease was less common in women than in men. Women were more obese and symptomatic, and less likely to have albuminuria. Women had higher indexed left ventricular (LV) wall thicknesses, worse diastolic function (lower E′, P = 0.002; higher E/E′, P < 0.001), while LV mass and LV volumes indexed for height^2.7 were similar. Nonetheless, female sex was associated with a trend towards higher prevalence of abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) at baseline (unadjusted P = 0.028, adjusted P = 0.056) and 12 weeks' follow up (unadjusted P = 0.001, adjusted P = 0.006), but not at 36 weeks' follow up (unadjusted P = 0.81, adjusted P = 0.99). Despite higher LV ejection fraction in women, global LV strain was similar between the sexes, while Tissue Doppler Imaging S′ mitral velocity was lower in women. Both LV diastolic and systolic stiffness were higher in women than men (P < 0.001), even adjusting for LV concentricity and clinical covariates. We observed no sex differences in systolic arterial–LV coupling, as women also had higher absolute arterial elastance compared with men, although this difference was not significant after adjusting for height^2.7. Conclusion More pronounced diastolic dysfunction may contribute to the greater predisposition for HFpEF in women compared with men.

Background Increases in serum creatinine with renin–angiotensin–aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual‐acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed. Methods and results A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time‐points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m². The eGFR declined less in the LCZ696 group than in the valsartan group (–1.5 vs. –5.2 mL/min per 1.73 m²; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time‐point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4–2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1–2.0 mg/mmol; P for difference between groups = 0.016). Conclusion In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.

Tako-Tsubo cardiomyopathy is characterised by an atypical distribution of left ventricular (LV) dysynergy with apical ballooning and compensatory basal hyperkinesis. Coronary angiography is normal. Several substrates have been put forward to explain the underlying pathophysiology such as raised catecholamine levels (due to physical or emotional stress), multivessel epicardial coronary spasm or diffuse microvascular spasm. However, the pathophysiology has not yet been fully clarified. We present a series of cases whose findings could explain the mechanism underlying this syndrome. Four consecutives patients, all female, were admitted with the clinical features typical of Tako-Tsubo syndrome. In all, severe widespread transient LV mid-apical a/dyskinesia was associated with a mid-cavity dynamic obstruction which resolved prior to the resolution of the LV wall motion abnormalities. In all cases the dynamic LV obstruction was related to localised mid-ventricular septal thickening. After improvement in wall motion, a low-dose strain/strain rate dobutamine stress-echocardiography (DSE) was performed to determine the underlying ischaemic substrate. This provoked an LV mid-cavity gradient at peak dose in all. Regional deformation changes during DSE showed the affected myocardium to have the typical response diagnostic of regional stunning. We postulate that an important unrecognised factor in the development of Tako-Tsubo cardiomyopathy is the presence of abnormal myocardial functional architecture (such as localised mid-ventricular septal thickening), which in the presence of dehydration and/or raised catecholamine levels due to physical or emotional stress, leads the development of a severe transient LV mid-cavity obstruction. This effectively sub-divides the LV into two functionally different chambers with a marked increase in wall stress in the high pressure distal apical chamber. This, in combination with the abnormal high circulating catecholamine levels, induces widespread sub-endocardial ischaemia which is unrelated to a specific coronary artery territory. With rehydration/fall in catecholamine levels the interventricular gradient resolves and distal function recovers. Low dose SR/S DSE confirms that the distal ischaemic substrate is myocardial stunning.

Renal dysfunction is a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). We sought to determine whether renal dysfunction was associated with measures of cardiovascular structure/function in patients with HFpEF. We studied 217 participants from the PARAMOUNT study with HFpEF who had echocardiography and measures of kidney function. We evaluated the relationships between renal dysfunction [estimated glomerular filtration rate (eGFR) >30 and <60 mL/min/1.73 m² and/or albuminuria] and cardiovascular structure/function. The mean age of the study population was 71 years, 55% were women, 94% hypertensive, and 40% diabetic. Impairment of at least one parameter of kidney function was present in 62% of patients (16% only albuminuria, 23% only low eGFR, 23% both). Renal dysfunction was associated with abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) (adjusted P = 0.048), lower midwall fractional shortening (MWFS) (P = 0.009), and higher NT-proBNP (P = 0.006). Compared with patients without renal dysfunction, those with low eGFR and no albuminuria had a higher prevalence of abnormal LV geometry (P = 0.032) and lower MWFS (P < 0.01), as opposed to those with only albuminuria. Conversely, albuminuria alone was associated with greater LV dimensions (P < 0.05). Patients with combined renal impairment had mixed abnormalities (higher LV wall thicknesses, NT-proBNP; lower MWFS). Renal dysfunction, as determined by both eGFR and albuminuria, is highly prevalent in HFpEF, and associated with cardiac remodelling and subtle systolic dysfunction. The observed differences in cardiac structure/function between each type of renal damage suggest that both parameters of kidney function might play a distinct role in HFpEF.