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.
BACKGROUND: Findings on the association between early high protein provision and mortality in ICU patients are inconsistent. The relation between early high protein provision and mortality in patients receiving CRRT remains unclear. The aim was to study the association between early high protein provision and hospital and ICU mortality and consistency in subgroups.METHODS: A retrospective cohort study was conducted in 2618 ICU patients with a feeding tube and mechanically ventilated ≥48 h (2003-2016). The association between early high protein provision (≥1.2 g/kg/day at day 4 vs. <1.2 g/kg/day) and hospital and ICU mortality was assessed for the total group, for patients receiving CRRT, and for non-septic and septic patients, by Cox proportional hazards analysis. Adjustments were made for APACHE II score, energy provision, BMI, and age.RESULTS: Mean protein provision at day 4 was 0.96 ± 0.48 g/kg/day. A significant association between early high protein provision and lower hospital mortality was found in the total group (HR 0.48, 95% CI 0.39-0.60, p = <0.001), CRRT-receiving patients (HR 0.62, 95% CI 0.39-0.99, p = 0.045) and non-septic patients (HR 0.56, 95% CI 0.44-0.71, p = <0.001). However, no association was found in septic patients (HR 0.71, 95% CI 0.39-1.29, p = 0.264). These associations were very similar for ICU mortality. In a sensitivity analysis for patients receiving a relative energy provision >50%, results remained robust in all groups except for patients receiving CRRT.CONCLUSIONS: Early high protein provision is associated with lower hospital and ICU mortality in ICU patients, including CRRT-receiving patients. There was no association for septic patients.
Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post-viral fatigue syndrome. Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.
