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Aims Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. Methods and results Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg–/– mice). In 9- to 10-week-old hUgcg–/– mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg–/– mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg–/– mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors. Conclusions Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function., Graphical Abstract Cardiac glycosphingolipids are required to maintain β-adrenergic signaling and contractile capacity in cardiomyocytes and to preserve normal heart function.

Background/Introduction Elevated resting heart rate (RHR) is a known risk factor for HF. Whether elevated RHR is also associated with cardiomyopathy (CM), a common cause of heart failure in the young, is unknown. Purpose To investigate the association of resting heart rate (RHR) measured in late adolescence with long term risk of various subtypes of CM with special attention to cardiorespiratory fitness (CRF), an important predictor of RHR and myocardial dysfunction. Methods We followed a cohort of Swedish men enrolled for conscription in 1968–2005 (n=1,008,485; mean age=18.3 years) until December 2014. Outcomes of CM were collected from the national inpatient- (IPR), outpatient- (OPR) and cause of death registries and were divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Cox proportional hazard models were used to analyze the longitudinal association between RHR and outcomes while adjusting for potential confounders, including body mass index (BMI), arterial blood pressure and cardiorespiratory fitness (CRF). CRF was measured by maximum capacity ergometer testing as part of the enlistment protocol. Results During a mean follow up of 34 years, there were 3500 cases of a first hospitalization for CM (mean age at diagnosis, 50.1 years). Comparing the highest with the lowest quintile of the RHR distribution, we found a positive association between RHR and dilated CM (hazard ratio (HR) = 1.58 [confidence interval (CI) = 1.37–1.82]) after adjustment for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). There no significant association with alcohol/drug-induced (HR=1.32 [CI=0.94–1.85]) or other categories of CM. Conclusion Adolescent RHR is associated with future risk CM, independently of blood pressure, BMI and CRF. The association was driven by dilated CM. These findings are suggestive of a causal pathway between elevated heart rate and adverse cardiac remodeling that warrants further investigation. Acknowledgement/Funding The Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare

Background Cardiovascular disease (CVD) mortality is decreasing in Western countries, including Sweden. However, there are reports of increases in incidence in young people with respect to heart failure (HF) and atrial fibrillation (AF). The magnitude and causes of these changes are only partly known. Aims We investigated secular trends in incidence in CVD outcomes and their attenuation by changes in body mass index (BMI). The outcomes were risk of acute myocardial infarction (AMI), heart failure (HF) and atrial fibrillation (AF) as well as cardiovascular and all-cause death in a population of Swedish adolescents. Methods We followed a cohort of Swedish men enrolled for military service conscription in 1969–1996 (n=1,326,082; mean age=18.3) until December 2016, collected from the national inpatient (IPR) and outpatient registries (OPR). Cox-proportional hazard models were used to analyse the longitudinal change in incidence by with respect to early (0–21 years) of follow-up for subgroups with conscription 1968–1971, 1971–1976, 1976–1981, 1981–1986, 1986–1991, 1991–1996 (with the group born 1971–1976 as reference). Adjustments for potential confounders including BMI were performed. Results We found that CVD and all-cause mortality and MI decreased progressively during the follow-up with hazard ratios (HR) of 0.51, 95% confidence interval (CI) 0.43–0.62, HR 0.51 CI 0.57–0.62, and 0.60 CI 0.50–0.72, respectively. In contrast, we found increases in the incidence of HF (HR 1.86, CI 1.48–2.33], and AF (HR 8.26, CI 6.87–9.92). Adjustments for changes in BMI partly attenuated the changes in secular trends. Cubic spline models showed where the changes in secular trends were most prominent. Conclusion The incidences of cardiovascular outcomes show diverging secular changes. While MI and cardiovascular mortality are continually decreasing, there is an increase in HF and AF. The associations appear to be partly explained by changes in index BMI over time. Acknowledgement/Funding grants from the Swedish Government and the county councils, the ALF–GBG-719761, ALFGBG-751111, Swedish Stroke Association, Göteborg Medical Society

Background Cardiorespiratory fitness and physical activity have well–known cardio–protective effects. Along with reports on declining levels of physical activity globally, heart failure caused by cardiomyopathy is increasing among young people. Still, it is unknown whether poor fitness in adolescence can be associated with cardiomyopathy in adulthood. Purpose To study a possible link between cardiorespiratory fitness in adolescence and being diagnosed with cardiomyopathy in adulthood. Methods A nationwide register-based prospective cohort study of 1,668,893 young men (mean age 18.3 years, SD 0.7), enlisting for compulsory military service 1969–2005. Body mass index (BMI) and blood pressure were registered at baseline, along with test results for fitness. Values were trichotomized and about 13.5% were classified as having poor cardiorespiratory fitness. Cardiomyopathy diagnoses were identified from the National Hospital Register and Cause of Death Register, during an up to 46-year follow-up, and divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Hazard ratios (HR) were calculated with Cox proportional hazards models. Results During follow-up (median 27 years; interquartile interval 19–35 years), 4,477 cases of cardiomyopathy were registered, of which 2,631 (59%) were dilated, 673 (15%) were hypertrophic, and 480 (11%) were alcohol/drug-induced. Poor cardiorespiratory fitness was strongly associated with elevated risk of both dilated (HR 1.59, 95% confidence interval (CI) 1.38–1.83) and alcohol/drug–induced cardiomyopathy (HR 2.32, 95% CI 1.68–3.20), adjusted for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). Conclusion The present study shows that poor cardiorespiratory fitness in adolescence may be associated with both dilated and alcohol/drug–induced cardiomyopathy in adulthood. This strengthens the evidence of fitness as a cardio–protective factor, and brings further support to the importance of interventions promoting physical activity already in childhood. Acknowledgement/Funding The Swedish Research Council, The Swedish Heart and Lung Foundation