Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive AlrC131S mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alrC131S is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis

Women's Participation in Cardiovascular Clinical Trials From 2010 to 2017

Background: Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials. Methods: We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation). Results: We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (P=0.007) and heart failure (P=0.01) trials compared with previous periods. Conclusions: Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials

Epidemiology and Clinical Features of Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection (HFpEF) constitutes a large and growing proportion of patients with HF around the world, and is now responsible for more than half of all HF cases in ageing societies. While classically described as a condition of elderly, hypertensive women, recent studies suggest heterogeneity in clinical phenotypes involving differential characteristics and pathophysiological mechanisms. Despite a paucity of disease-modifying therapy for HFpEF, an understanding of phenotypic similarities and differences among patients with HFpEF around the world provides the foundation to recognise the clinical condition for early treatment, as well as to identify modifiable risk factors for preventive intervention. This review summarises the epidemiology of HFpEF, its common clinical features and risk factors, as well as differences by age, comorbidities, race/ethnicity and geography

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 <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<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>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

Prevalence and Prognostic Significance of Frailty in Asian Patients With Heart Failure:Insights From ASIAN-HF

Background: Frailty is common in patients with heart failure (HF) and can adversely impact outcomes. Objectives: This study examined the prevalence of frailty among Asian patients with HF, its association with 1-year outcomes, and if race-ethnicity, HF subtypes, and sex modify this relationship. Methods: In the multinational ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry, a baseline frailty index (FI) was constructed using a cumulative deficits approach with 48 baseline variables, and patients were followed for the 1-year primary outcome of all-cause death or HF hospitalization. Results: Among 3,881 participants (age 61 ± 13 years, 27% female), the mean FI was 0.28 ± 0.11, and 69% were frail (FI &gt;0.21). Higher FI was associated with older age, Malay ethnicity, and Southeast Asian residency. While comorbidities were more frequent in frail patients (by definition), body mass index was not different across frailty classes. Compared with FI class 1 (&lt;0.21, nonfrail), FI class 2 (0.21-0.31) and FI class 3 (&gt;0.31) had increased risk of the 1-year composite outcome (hazard ratios of 1.84 [95% confidence interval (CI): 1.42-2.38] and 4.51 [95% CI: 3.59-5.67], respectively), even after multivariable adjustment (adjusted hazard ratios of 1.49 [95% CI: 1.13-1.97] and 2.69 [95% CI: 2.06-3.50], respectively). Race-ethnicity modified the association of frailty with the composite outcome (Pinteraction = 0.0097), wherein the impact of frailty was strongest among Chinese patients. The association between frailty and outcomes did not differ between men and women (Pinteraction = 0.186) or for HF with reduced ejection fraction versus HF with preserved ejection fraction (Pinteraction = 0.094). Conclusions: Most Asian patients with HF are frail despite relatively young age. Our results reveal specific ethnic (Malay) and regional (Southeast Asia) predisposition to frailty and highlight its prognostic importance, especially in Chinese individuals.</p

Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction

Aims: Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF. Methods and results: Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high-throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non-overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy-associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin-like growth factor-binding protein 1, phage shock protein D, CUB domain-containing protein 1, prostasin, decorin, FMS-like tyrosine kinase 3, ligand growth differentiation factor 15, spondin-1, delta/notch-like epidermal growth factor-related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation-mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13-kinase and transforming growth factor-beta signalling pathway among women with HFpEF. Conclusion: While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women