AimsGenetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.Methods and resultsRespirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.ConclusionMitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
IntroductionOver time, surrogacy has become more broadly available to a variety of people (e.g. male same-sex couples or transgender women). Whether the wider public supports surrogacy, and what contributes to such support remains unclear. This study investigated what demographic and surrogacy arrangement-based (which people participate in the arrangement) factors shape attitudes towards surrogacy.MethodA representative sample of Dutch adults (N = 1,074) reported their attitudes on four (out of 30) randomly assigned vignettes in 2023. Each vignette described a surrogacy family with variations in sexuality and gender of parents, the social and genetic bonds between the parents, the surrogate, and the oocyte donor, and was followed by an attitude questionnaire (6 items). Multilevel regression analyses were conducted with attitudes as the dependent variable and demographic factors (gender, Dutch background, age, education, sexual orientation, urbanisation, and religiosity) and arrangement-based factors (parental composition, genetic and social bonds with the surrogate, and oocyte donors).ResultsParticipants held fairly positive attitudes towards surrogacy. People identifying as women, with only having a Dutch background, who were younger, more highly educated, non-heterosexual, or less religious were more likely to have positive attitudes. Participants had more positive attitudes if surrogacy arrangements entailed cis-man cis-woman parents compared to cis-man cis-man or transgender parents, and when there was no social bond between parents and oocyte donor.ConclusionsAttitudes are influenced by both demographic and arrangement-based factors. Based on these findings, families can be informed of fairly positive reactions they might encounter from their environment.
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