The effect of neprilysin inhibition on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction

Background The development of heart failure and reduced ejection fraction (HFrEF) in survivors of myocardial infarction occurs as a result of progressive left ventricular dilatation and a reduction in systolic function, a process commonly referred to as adverse left ventricular remodelling. One of the earliest advances in the management of myocardial infarction was the finding that the angiotensin converting enzyme (ACE) inhibitor captopril which inhibits the maladaptive activation of the renin-angiotensin system (RAS) promoting the process of adverse remodelling, reduced the risk of heart failure and mortality by attenuating progressive ventricular enlargement. Subsequently, the angiotensin receptor blocker valsartan (in a dose of 160 mg twice daily) was shown to be as effective as captopril in preventing adverse clinical outcomes after myocardial infarction. Beta-blockers are believed to have similar benefits as a result of attenuating the harmful actions of excessive activation of the sympathetic nervous system (SNS). Not all neurohumoral activation following myocardial infarction (and in heart failure) is harmful. The natriuretic peptides are released in response to increased left atrial and ventricular wall stress and counteract the harmful effects of RAS and SNS activation through natriuretic, vasodilatory, anti-fibrotic and sympatholytic effects. Endogenous levels of the natriuretic peptides (along with a range of other potentially cardioprotective peptides) can be increased by preventing their breakdown by the enzyme neprilysin. In patients with symptomatic HFrEF, the combined angiotensin receptorneprilysin inhibitor sacubitril/valsartan (dosed 97/103mg twice daily), compared with the gold-standard ACE inhibitor enalapril, has been demonstrated to reduce the risk of worsening heart failure and cardiovascular death. It may be that part of the clinical benefits of sacubitril/valsartan (i.e., the addition of neprilysin inhibitor), relate to a favourable reverse remodelling effect. Therefore, the addition of a neprilysin inhibition to a RAS inhibitor in high-risk patients following myocardial infarction may result in greater attenuation of adverse left ventricular remodelling than RAS inhibition alone, and potentially reduce the attendant risk of the development of HFrEF. Aim To examine the effect of neprilysin inhibition on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction using the gold-standard method, cardiac magnetic resonance imaging (MRI). Methods I performed a prospective, randomised, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients at least 3 months following an acute myocardial infarction with a left ventricular ejection fraction (LVEF) less than, or equal to 40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association (NYHA) functional classification II or greater were excluded. The primary endpoint was change from baseline to 52-weeks in left ventricular endsystolic volume index (LVESVI) measured using cardiac MRI. Secondary endpoints included other MRI measurements of left ventricular remodelling, change in NTproBNP (a marker of left ventricular wall stress) and hs-TnI (a marker of myocardial injury), and a patient global assessment of change questionnaire. In exploratory analyses, I also examined the effect of neprilysin inhibition on a range of circulating biomarkers relating to substrates for neprilysin and myocardial fibrosis. Results In the 93 randomised patients, mean age was 60.7±10.4 years, median time from myocardial infarction 3.6 years (interquartile range [IQR] 1.2-72), mean LVEF 36.8%±7.1, median NT proBNP 230pg/ml (IQR 124-404) and a beta-blocker was taken by 94% of patients. Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; between-group difference -1.9ml/m2 (95%CI -4.8, 1.0); p=0.19. A reduction in LVESVI was seen with sacubitril/valsartan in those with NT-proBNP levels greater than or equal to the median than those below (interaction p=0.036). There were no significant between-group differences in NT-proBNP, hs-TnI, left ventricular end-diastolic volume index, left atrial volume index, LVEF, left ventricular mass index, or patient global assessment of change. Sacubitril/valsartan, compared with valsartan, significantly increased levels of atrial natriuretic peptide (ANP) (p=0.013), a substrate for neprilysin, and its intracellular secondary messenger urinary cyclic guanosine monophosphate (cGMP) (P=0.001), indicating increased natriuretic peptide bioactivity. Midregional pro-atrial natriuretic peptide (MR-proANP), which is not a substrate for neprilysin, was significantly reduced with sacubitril/valsartan (P=0.009) and may reflect a reduction in left ventricular filling pressures. No significant increase in B-type natriuretic peptide (BNP) was observed which was consistent with the greater affinity neprilysin has for ANP relative to BNP. Midregional proadrenomedullin (MR-proADM) (P<0.001), glucagon-like peptide-1 (GLP-1) (P<0.001) and galectin-3 (P=0.045) were increased with sacubitril/valsartan, as compared with valsartan. No significant favourable changes were seen with the addition of a neprilysin inhibitor in biomarkers of profibrotic processes. Conclusion In patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan compared with valsartan alone (i.e., the addition of a neprilysin inhibitor) did not have a significant reverse remodelling effect and did not reduce biomarkers of left ventricular wall stress (NT-proBNP) or myocardial injury (hs-TnI) despite augmenting natriuretic peptide activity

Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction

Aims: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. Methods and results: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation &lt;20% or ferritin &lt;100 μg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between-group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between-group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow-up (defined as haemoglobin &gt;16.5 g/dL [men] or &gt;16 g/dL [women]). Conclusions: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron-deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Accelerated and personalized therapy for heart failure with reduced ejection fraction

Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium-glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials