Sex differences in efficacy of pharmacological therapies in heart failure with reduced ejection fraction:a meta-analysis

Aims: Recent studies have suggested potential sex differences in treatment response to pharmacological therapies in heart failure (HF). We performed a systematic review and meta-analysis of studies comparing treatment effects between men and women with HF and reduced ejection fraction (HFrEF) using established guideline-directed medical therapy and other emerging pharmacological treatments. Methods and results: Systematic search was performed on PubMed, Embase, and Cochrane Library for randomized controlled trials published in 1990–2021. Outcomes were all-cause mortality and combined outcome of all-cause mortality and/or hospitalization for HF. Of 618 articles identified, 25 articles and 100 213 patients (mean age 62 ± 1.7 years, women 23.1%, mean left ventricular ejection fraction 26.6 ± 1.3%) were included in the systematic review and meta-analysis. For the outcome of all-cause mortality, there was no evidence of treatment heterogeneity by sex for renin-angiotensin system inhibitors (RASi) [hazard ratio (HR) 0.86 (95% confidence interval 0.75–0.99) in men; HR 0.97 (0.77–1.23) in women; Pinteraction = 0.288], or for beta-blockers (BB) [HR 0.71 (0.59–0.86) in men; HR 0.87 (0.73–1.03) in women; Pinteraction = 0.345]. Similarly, for the composite outcome of death or HF hospitalization, there was no evidence of treatment heterogeneity by sex for RASi [HR 0.84 (0.77–0.93) in men; HR 0.94 (0.81–1.08) in women; Pinteraction = 0.210] or BB [HR 0.76 (0.64–0.90) in men; HR 0.72 (0.60–0.86) in women; Pinteraction = 0.650]. Results for mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) from previously published meta-analyses were included in the review. For the combined outcome of cardiovascular death or HF hospitalization, no significant interaction for sex was observed for MRA (Pinteraction = 0.78) or SGLT2i (Pinteraction = 0.37). Results for emerging pharmacological treatments, such as soluble guanylate cyclase stimulators and cardiac myosin activators, were included in the review and showed consistent treatment effects between men and women. Conclusions: Our meta-analysis showed no differences between sex in treatment effect for BB and RASi. Review on previously published trials for MRA, SGLT2i, and emerging therapies presented consistent treatment effects between men and women

Left atrial structure and function in heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF):systematic review and meta-analysis

Left atrial (LA) structure and function in heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF) is only established in small studies. Therefore, we conducted a systematic review of LA structure and function in order to find differences between patients with HFrEF and HFpEF. English literature on LA structure and function using echocardiography was reviewed to calculate pooled prevalence and weighted mean differences (WMD). A total of 61 studies, comprising 8806 patients with HFrEF and 9928 patients with HFpEF, were included. The pooled prevalence of atrial fibrillation (AF) was 34.4% versus 42.8% in the acute inpatient setting, and 20.1% versus 33.1% in the chronic outpatient setting when comparing between HFrEF and HFpEF. LA volume index (LAVi), LA reservoir global longitudinal strain (LAGLS(R)), and E/e' was 59.7 versus 52.7 ml/m(2), 9.0% versus 18.9%, and 18.5 versus 14.0 in the acute inpatient setting, and 48.3 versus 38.2 ml/m(2), 12.8% versus 23.4%, and 16.9 versus 13.5 in the chronic outpatient setting when comparing HFrEF versus HFpEF, respectively. The relationship between LAVi and LAGLS(R) was significant in HFpEF, but not in HFrEF. Also, in those studies that directly compared patients with HFrEF versus HFpEF, those with HFrEF had worse LAGLS(R) [WMD = 16.3% (22.05,8.61); p < 0.001], and higher E/e' [WMD = -0.40 (-0.56, -0.24); p < 0.05], while LAVi was comparable. When focusing on acute hospitalized patients, E/e' was comparable between patients with HFrEF and HFpEF. Despite the higher burden of AF in HFpEF, patients with HFrEF had worse LA global function. Left atrial myopathy is not specifically related to HFpEF

Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses

This is the published version. Copyright American Society for MicrobiologyPhylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro

A clinical prediction model for hospitalized COPD exacerbations based on “treatable traits”

10.2147/COPD.S194922International Journal of COPD14719-72

Association of diabetes mellitus on cardiac remodeling, quality of life, and clinical outcomes in heart failure with reduced and preserved ejection fraction

Background: Diabetes mellitus frequently coexists with heart failure (HF), but few studies have compared the associations between diabetes mellitus and cardiac remodeling, quality of life, and clinical outcomes, according to HF phenotype. Methods and Results: We compared echocardiographic parameters, quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire), and outcomes (1‐year all‐cause mortality, cardiovascular mortality, and HF hospitalization) between HF patients with and without type 2 diabetes mellitus in the prospective ASIAN‐HF (Asian Sudden Cardiac Death in Heart Failure) Registry, as well as community‐based controls without HF. Adjusted Cox proportional hazards models were used to assess the association of diabetes mellitus with clinical outcomes. Among 5028 patients with HF and reduced ejection fraction (HFrEF; EF &lt;40%) and 1139 patients with HF and preserved EF (HFpEF; EF ≥50%), the prevalences of type 2 diabetes mellitus were 40.2% and 45.0%, respectively (P=0.003). In both HFrEF and HFpEF cohorts, diabetes mellitus (versus no diabetes mellitus) was associated with smaller indexed left ventricular diastolic volumes and higher mitral E/e′ ratio. There was a predominance of eccentric hypertrophy in HFrEF and concentric hypertrophy in HFpEF. Patients with diabetes mellitus had lower Kansas City Cardiomyopathy Questionnaire scores in both HFpEF and HFrEF, with more prominent differences in HFpEF (Pinteraction&lt;0.05). In both HFpEF and HFrEF, patients with diabetes mellitus had more HF rehospitalizations (adjusted hazard ratio, 1.27; 95% CI, 1.05–1.54; P=0.014) and higher 1‐year rates of the composite of all‐cause mortality/HF hospitalization (adjusted hazard ratio, 1.22; 95% CI, 1.05–1.41; P=0.011), with no differences between HF phenotypes (Pinteraction&gt;0.05). Conclusions: In HFpEF and HFrEF, type 2 diabetes mellitus is associated with smaller left ventricular volumes, higher mitral E/e′ ratio, poorer quality of life, and worse outcomes, with several differences noted between HF phenotypes

Satin associated lower cancer risk and related mortaity in patients with heart failure

Aims Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse. Methods and results Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 +/- 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to = 6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR= 0.74; 95% CI, 0.67-0.81). Conclusion Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent. [GRAPHICS]

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction:insights from BIOSTAT-CHF and ASIAN-HF registries

Background: Angiotensin‐converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β‐blockers are guideline‐recommended first‐line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under‐dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up‐titration of ACEi/ARBs and β‐blockers with all‐cause mortality and its combination with hospitalization for HF. Methods and results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT‐CHF; n = 2100) and Asian (ASIAN‐HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline‐recommended target doses (GRTD) of combination ACEi/ARB and β‐blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β‐blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β‐blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26–0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up‐titrating β‐blockers was associated with a consistent and greater reduction in hazards of all‐cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25–0.63) than corresponding ACEi/ARB up‐titration (HR 0.75, 95% CI 0.53–1.07). Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β‐blockers, unfortunately this was rarely achieved. Achieving &gt;50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up‐titrating β‐blockers to target dose was associated with greater mortality reduction than up‐titrating ACEi/ARB

Ethnic differences in atrial fibrillation among patients with heart failure in Asia

Aims We aimed to characterize ethnic differences in prevalence, clinical correlates, and outcomes of atrial fibrillation (AF) in heart failure (HF) with preserved and reduced ejection fraction (HFpEF and HFrEF) across Asia. Methods and results Among 5504 patients with HF prospectively recruited across 11 Asian regions using identical protocols in the Asian Sudden Cardiac Death in Heart Failure study (mean age 61 +/- 13 years, 27% women, 83% HFrEF), 1383 (25%) had AF defined as a history of AF and/or AF/flutter on baseline electrocardiogram. Clinical correlates of AF were similar across ethnicities and included older age, prior stroke, higher NT-proBNP, and larger left atria. Diabetes was associated with lower odds of AF in HFrEF [adjusted odds ratio (AOR) 0.79, 95% CI 0.66-0.95] and HFpEF (AOR 0.58, 95% CI 0.39-0.84) regardless of ethnicity. Compared with Chinese ethnicity, Japanese/Koreans had higher odds of AF in HFrEF (AOR 1.76, 95% CI 1.40-2.21), while Indians had lower odds in HFrEF (AOR 0.18, 95% CI 0.13-0.24) and HFpEF (AOR 0.28, 95% CI 0.16-0.49) even after adjusting for clinical covariates. Interaction between ethnicity and region was observed among Indians, with Southeast Asian Indians having higher odds of AF (AOR 3.01, 95% CI 1.60-5.67) compared with South Asian Indians. AF was associated with poorer quality of life and increased risk of 1 year all-cause mortality or HF hospitalisation (adjusted hazard ratio 1.39, 95% CI 1.18-1.63) regardless of ethnicity. Conclusions Among patients with HF across Asia, clinical correlates and adverse outcomes associated with AF are similar across ethnicities; however, there are striking ethnic variations in the prevalence of AF that are not accounted for by known risk factors