Gender differences in sudden cardiac death in the young-a nationwide study

Abstract Background Hitherto, sudden cardiac death (SCD) in the young has been described with no distinction between genders. SCD occurs more often in men (SCDm) than women (SCDw), but this disparity is not understood and has not been investigated systematically in a nationwide setting. Our objective was to report gender differences in SCD in the young in a nationwide (Denmark) setting. Methods All deaths in persons aged 1\u201335 years nationwide in Denmark between 2000 and 2009 were included. Death certificates and autopsy reports were obtained. The extensive health care registries in Denmark were used to investigate any known disease prior to death. SCDw were compared to SCDm. Results During the 10-year study period there were a total of 8756 deaths in 23.7 million person-years. In total, 635 deaths were SCD. SCDw constituted 205 deaths (32%). Women had a higher proportion of witnessed deaths (51 vs. 41%, p \u2009=\u20090.02) and died less often in a public place (16 vs. 26%, p \u2009=\u20090.01). Age at death, ratios of autopsies and sudden unexplained deaths, and comorbidities, did not differ. Causes of SCD were largely comparable between genders. The incidence rate of SCDw was half of that of SCDm (1.8 vs. 3.6 per 100,000 person-years, incidence rate ratio 2.0 (95% CI 1.7\u20132.4), p \u2009<\u20090.01). Conclusions Incidence rate ratio of SCDm vs SCDw is 2. Young SCDw and SCDm are equally investigated, have comparable comorbidity, and causes of SCD. SCD due to potentially inherited cardiac diseases is less often in young women and could reflect a protection of female gender

Variants in the CETP gene affect levels of HDL cholesterol by reducing the amount, and not the specific lipid transfer activity, of secreted CETP.

BackgroundCholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia.MethodsHEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay.ResultsFour of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, pConclusionThe effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants

Flavonoids regulate LDLR through different mechanisms tied to their specific structures

Flavonoids, polyphenolic compounds found in plant-based diets, are associated with reduced risk of cardiovascular disease and longevity. These components are reported to reduce plasma levels of low-density lipoprotein (LDL) through an upregulation of the LDL receptor (LDLR), but the mechanism is still largely unknown. In this study, we have systematically screened the effect of 12 flavonoids from six different flavonoid subclasses on the effect on LDLR. This paper provides an in-depth analysis on how these flavonoids affect LDLR regulation and functionality. We found that most but not all of the tested flavonoids increased LDLR mRNA levels. Surprisingly, this increase was attributed to different regulatory mechanisms, such as enhanced LDLR promoter activity, LDLR mRNA stabilization, or LDLR protein stabilization, of which specific effectual parts of the flavonoid molecular structure could be assigned. These types of comparative analysis of various flavonoids enhance clarity and deepen the understanding of how the different structures of flavonoids affect LDLR regulation. Our data offer useful insights that may guide future research in developing therapeutic approaches for cardiovascular health

Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay

Excess cholesterol originating from nonhepatic tissues is transported within HDL particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 interacting with the transmembrane protein ABCA1, a key player in cholesterol homeostasis. Defective ABCA1 results in reduced serum levels of HDL cholesterol, deposition of cholesterol in arteries, and an increased risk of early onset CVD. Over 300 genetic variants in ABCA1 have been reported, many of which are associated with reduced HDL cholesterol levels. Only a few of these have been functionally characterized. In this study, we have analyzed 51 previously unclassified missense variants affecting the extracellular domains of ABCA1 using a sensitive, easy, and low-cost fluorescence-based assay. Among these, only 12 variants showed a distinct loss-of-function phenotype, asserting their direct association with severe HDL disorders. These findings emphasize the crucial role of functional characterization of genetic variants in pathogenicity assessment and precision medicine. The functional rescue of ABCA1 loss-of-function variants through proteasomal inhibition or by the use of the chemical chaperone 4-phenylbutyric acid was genotype specific. Genotype-specific responses were also observed for the ability of apolipoprotein A1 to stabilize the different ABCA1 variants. In view of personalized medicine, this could potentially form the basis for novel therapeutic strategies

Vigorous exercise in patients with hypertrophic cardiomyopathy

Background: We aimed to investigate if history of vigorous exercise was associated with changes in left ventricular morphology, left ventricular function and ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy genotype positive, phenotype negative (Genotype+ LVH−) and in phenotype positive (HCM LVH+). Methods: In this cross sectional study we included 187 subjects (age 49 ± 16 years, 89(48%) female, 121(65%) HCM LVH+ and 66 (35%) Genotype+ LVH-) who answered a questionnaire on physical activity history. Exercise ≥6 metabolic equivalents was defined as vigorous. Subjects with a history of vigorous exercise ≥4 h/week during ≥6 years were defined as athletes. All underwent echocardiography and Holter monitoring. VAs were defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia. Results: In both Genotype+ LVH− and HCM LVH+, lifetime vigorous exercise correlated with larger left ventricular end-diastolic volume (rho 0.44 and 0.38 respectively, both p b 0.001). Lifetime vigorous exercise correlated with increased left ventricular mass in Genotype+ LVH− (rho 0.28, p = 0.03), but not in HCM LVH+ (p = 0.53). Left ventricular systolic function was similar between athletes and non-athletes in Genotype+ LVH− and HCM LVH+. HCM LVH+ athletes had lower E/e' (p = 0.03) and higher e' (p = 0.02) compared to non-athletes, while this difference was not observed in Genotype+ LVH−. Lifetime vigorous exercise was similar among HCM LVH+ with and without VAs (p = 0.89). Conclusions: Increased lifetime vigorous exercise was associated with larger left ventricular volumes in hypertrophic cardiomyopathy, but correlated to left ventricular mass only in Genotype+ LVH−. Vigorous exercise was associated with favorable diastolic function in HCM LVH+, and was not associated with VAs

Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy

Data presented in this paper are supplementary material to our study âVigorous exercise in patients with hypertrophic cardiomyopathyâ [1]. The current article presents supplementary data on collection and analyses of exercise parameters and genetic data in the original research article. Keywords: Hypertrophic cardiomyopathy, Exercise, Genetics, Arrhythmi