Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297). METHODS: MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH. RESULTS: Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66-.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74-.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality. CONCLUSIONS: Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

Sex differences in the perception of cardiovascular risk in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH), a common genetic condition, is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Recent data indicate an undertreatment of females with FH. OBJECTIVE: To characterize the role of sex in the perception of FH, its associated ASCVD risk and treatment. METHODS: A survey investigating for sex differences in the perception of FH was sent to 1073 patients with FH using a cross sectional study design. RESULTS: A total of 412 patients (51.9 % male) responded to the survey; mean age was 56.2 ± 14.4 years. There was a higher proportion of males with ASCVD than females (41.5 % vs. 16.5 %, respectively, p<0.001). Analyses of the survey responses showed that a majority of both males and females agreed that their risk of ASCVD is higher than healthy individuals of same age (70.8 % vs. 74.7 %, respectively, p = 0.434). Females were more concerned about having high LDL-C levels (67.5 % vs. 56.5 % in males, p = 0.024), especially those in secondary prevention programs. As for treatment of FH, approximately 75 % of both sex groups considered statins to be efficient in reducing the risk of myocardial infarction, but less than half of the females considered statins to be safe (44.8 % vs. 60.0 % in males, p = 0.003). No major sex differences were noted regarding the influence of the doctor in their understanding of FH as a disease. CONCLUSION: Overall, both males and females with FH were well informed about FH, although females were more concerned about having high LDL-C levels and they feared the safety of statins.

Genetic testing for familial hypercholesterolemia in Quebec, Canada: a single-centre retrospective cohort study.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. METHODS: We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the LDLR, APOB and PCSK9 genes, and multiplex ligation-dependent probe amplification of the LDLR gene to detect genetic variants, were performed. RESULTS: Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the LDLR (146 [86.4%]) or APOB (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. INTERPRETATION: Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. Trial registration: ClinicalTrials.gov, no. NCT02009345.

Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation.

KEY POINTS: The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health. ABSTRACT: Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function is therefore critical for muscle cells. Mitochondria are now well known as highly dynamic organelles, able to change their morphology through fusion and fission processes. Solid experimental evidence indicates that mitochondrial dynamics play key roles in mitochondrial quality control, and alteration in the expression of proteins regulating mitochondrial dynamics have been reported in many conditions associated with muscle atrophy and wasting. However, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. To address this issue, we investigated the impact of Drp1 (a protein regulating mitochondrial fission) knockdown, introduced via intramuscular injection of adeno-associated virus (AAV) on adult mouse skeletal muscle. Knocking down Drp1 for 4 months resulted in very severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration and increases in markers of muscle regeneration, denervation, fibrosis, oxidative stress and impaired autophagy. Our findings indicate that Drp1 is essential for the maintenance of normal mitochondrial function and that Drp1 suppression severely impairs muscle health.

Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice.

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMPK is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high-fat (HF)-fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/lox littermates (wild-type [WT]). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was approximately twofold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mammalian target of rapamycin (mTOR), a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.