Beneficial effect of ACE inhibitor in congestive heart failure

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopriltreated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5–75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.     

Female reproductive fluid concentrations affect sperm performance of alternative male phenotypes in an external fertilizer

There is growing evidence that the female reproductive fluid (FRF) plays an important role in cryptic female choice through its differential effect on the performance of sperm from different males. In a natural spawning event, the male(s) may release ejaculate closer or further away from the spawning female. If the relative spatial proximity of competing males reflects the female pre-mating preference towards those males, then favoured males will encounter higher concentrations of FRF than unpreferred males. Despite this being a common situation in many external fertilizers, whether different concentrations of FRF can differentially influence the sperm performance of distinct male phenotypes (favoured and unfavoured by the female) remains to be elucidated. Here, we tested this hypothesis using the grass goby (Zosterisessor ophiocephalus), a fish with distinct territorial-sneaker reproductive tactics and female pre-mating preference towards territorial males, that consequently mate in an advantaged position and whose sperm experience higher concentrations of FRF. Our findings revealed a differential concentration-dependent effect of FRF over sneaker and territorial sperm motility only at low concentrations (i.e. at the distance where sneakers typically ejaculate), with increasing FRF concentrations (i.e. close to the eggs) similarly boosting the sperm performance of both sneaker and territorial males. The ability to release sperm close to the eggs is a prerogative of territorials, but FRF can likewise advantage the sperm of those sneakers that are able to get closer, allowing flexibility in the direction of female post-mating choice.     

Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1^−/D mice). Ckmm-Cre^+/−;Ercc1^−/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre^+/−;Ercc1^−/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre^+/-;Ercc1^−/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre^+/−;Ercc1^−/fl and Ercc1^−/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.     

Trusting the Health System and COVID 19 Restriction Compliance

We examine the extent to which exposure to higher relative COVID-19 mortality (RM), influences health system trust (HST), and whether changes in HST explain the perceived ease of compliance with pandemic restrictions during the COVID-19 pandemic. Drawing on evidence from two representative surveys covering all regions of 28 European countries before and after the first COVID-19 wave, and using a difference in differences strategy together with Coarsened Exact Matching (CEM), we document that living in a region with higher RM during the first wave of the pandemic increased HST. However, the positive effect of RM on HST is driven by individuals over 45 years of age, and the opposite effect is found among younger cohorts. Furthemore, we find that a higher HST reduces the costs of complying with COVID-19 restrictions, but only so long as excess mortality does not exceed the average by more than 20%, at which point the ease of complying with COVID-19 restrictions significantly declines, offsetting the positive effect of trust in the healthcare system. Our interpretation of these estimates is that a higher RM is interpreted as a risk signal among those over 45, and as a signal of health-care system failure among younger age individuals.     

Avicularin alleviates acute liver failure by regulation of the TLR4/MyD88/NF-κB and Nrf2/HO-1/GPX4 pathways to reduce inflammation and ferroptosis

Acute liver failure (ALF) is an inflammation-mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti-inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS-stimulated RAW 264.7 cells via blocking the toll-like receptor 4 (TLR4)/myeloid differentiation protein-88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. Moreover, AL attenuated ferroptosis in D-GalN-induced HepG2 cells by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D-GalN-induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF-κB pathway and activating Nrf2/HO-1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.     

Marginal proportional hazards models for clustered interval-censored data with time-dependent covariates

The Botswana Combination Prevention Project was a cluster-randomized HIV prevention trial whose follow-up period coincided with Botswana's national adoption of a universal test and treat strategy for HIV management. Of interest is whether, and to what extent, this change in policy modified the preventative effects of the study intervention. To address such questions, we adopt a stratified proportional hazards model for clustered interval-censored data with time-dependent covariates and develop a composite expectation maximization algorithm that facilitates estimation of model parameters without placing parametric assumptions on either the baseline hazard functions or the within-cluster dependence structure. We show that the resulting estimators for the regression parameters are consistent and asymptotically normal. We also propose and provide theoretical justification for the use of the profile composite likelihood function to construct a robust sandwich estimator for the variance. We characterize the finite-sample performance and robustness of these estimators through extensive simulation studies. Finally, we conclude by applying this stratified proportional hazards model to a re-analysis of the Botswana Combination Prevention Project, with the national adoption of a universal test and treat strategy now modeled as a time-dependent covariate.     

Prevalence of transthyretin cardiac amyloidosis in elderly patients diagnosed with heart failure

ObjectiveThere is increased interest in studying ATTR-CA, a pathology that primarily affects patients of geriatric age and is frequently underdiagnosed. We aim to establish the prevalence of ATTR-CA in a cohort of patients with a history of HFpEF and to describe its characteristics.MethodsWe conducted a prospective observational study. Patients ≥75 years, clinical history of HFpEF, atrial dilation ≥34 ml/m² and left ventricular wall thickening >13 mm, were included. Demographic and analytical parameters were collected, and a comprehensive geriatric assessment was performed, along with a transthoracic echocardiogram and cardiac scintigraphy. Finally, telephone follow-up was carried out at 6 and 12 months.Results50 patients were recruited, mean age 86 ± 6 years, 54% women. Age and functional class (I–II vs. III–IV) were factors associated with presenting with ATTR-CA. Patients with positive scintigraphy had a median time to admission of 5.2 months (confidence interval [CI] 95% 0–10.9), while in those with negative scintigraphy, it was 12.2 months (95% CI 11.7–12.8); log-rank: p = 0.064. Patients with positive scintigraphy had a median time to the combined endpoint (death and readmission) of 1.9 months (95% CI 0–6.1), and patients with negative scintigraphy of 11.9 months (95% CI 11.7–12); log-rank: p = 0.027.ConclusionsATTR-CA appears to be a prevalent etiology in elderly patients within the spectrum of HFpEF. Patients with a diagnosis of ATTR-CA had a shorter time to admission for HF and the combined event of death and admission than patients with a negative result on scintigraphy.