Early use of mineralocorticoid receptor antagonists in ST-elevation myocardial infarction: is it ever too early?

No abstract available

Angiotensin receptor-neprilysin inhibitors: a new paradigm in heart failure with reduced ejection fraction

Despite significant advances in the last 30 years in reducing morbidity and mortality from heart failure with reduced ejection fraction (HFrEF) with pharmacological and device-based therapies, patients remain at a high risk of adverse cardiovascular outcomes. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitors (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalisation and improve symptoms in patients with chronic, ambulatory, symptomatic HFrEF in a large, phase 3, multicentre, international, randomised controlled trial, PARADIGM-HF, when compared to the gold-standard angiotensin converting enzyme inhibitor, enalapril. This article will review the development of sacubitril/valsartan, the evidence for its use and its current and future role in the management of HFrEF

Sacubitril/valsartan in Asian patients with heart failure with reduced ejection fraction

The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF

Catheter ablation for atrial fibrillation with heart failure

No abstract available

SOLOIST-WHF: Sodium-glucose cotransporter 2 (SGLT2) inhibitors should be initiated in patients hospitalised with worsening heart failure

No abstract available

The Dapagliflozin And Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF) in context

No abstract available

Inducing energetic switching using Klotho improves vascular smooth muscle cell phenotype

The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival

Effect of neprilysin inhibition on Alzheimer disease plasma biomarkers: a secondary analysis of a randomized clinical trial

Amyloid-β (Aβ) accumulation is critical in Alzheimer disease (AD), and neprilysin is involved in physiologically clearing Aβ. Concerns exist regarding long-term use of sacubitril/valsartan, a neprilysin inhibitor and angiotensin receptor blocker used for heart failure, and its potential to increase AD risk. We evaluated neprilysin inhibition’s effect on AD blood biomarkers in patients with coronary heart disease

The four pillars of HFrEF therapy : is it time to treat heart failure regardless of ejection fraction?

The syndrome of heart failure (HF) has historically been dichotomized based on clinical trial inclusion criteria into patients with a reduced or preserved left ventricular ejection fraction (LVEF) using a cut-off of above or below 40%. The majority of trial evidence for the benefits of disease-modifying pharmacological therapy has been in patients with HF with reduced ejection fraction (HFrEF), i.e. those with an LVEF ≤40%. Recently, the sodium-glucose co-transporter 2 inhibitors empagliflozin and dapagliflozin have been shown to be the first drugs to improve outcomes in HF across the full spectrum of LVEF. There is, however, growing evidence that the benefits of many of the neurohumoral modulators shown to be beneficial in patients with HFrEF may extend to those with a higher LVEF above 40% but still below the normal range, i.e. HF with mildly reduced ejection fraction (HFmrEF). Whether the benefits of some of these medications also extend to patients with HF and preserved ejection fraction (HFpEF) is an area of ongoing debate. This article will review the evidence for HF treatments across the full spectrum of LVEF, provide an overview of recently updated clinical practice guidelines, and address the question whether it may now be time to treat HF with some therapies regardless of ejection fraction

Effect of PCI on health status in ischemic left ventricular dysfunction: insights from REVIVED-BCIS2

Background In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). Objectives This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. Methods Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ–Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. Results A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. Conclusions PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up