Identifying Sex-Specific Differences in Young-Onset Metabolic Syndrome Using Primary Care Electronic Medical Record.

Objectives: To apply a case definition to a Northern Alberta-based primary care practice population and to assess the sex-specific characteristics of young-onset metabolic syndrome (MetS). Design: We carried out a cross-sectional study to identify and estimate the prevalence of MetS using electronic medical record (EMR) data and perform descriptive comparative analyses of demographic and clinical characteristics between males and females. Setting: Northern Alberta Primary Care Research Network (NAPCReN) consists of EMR patient data from 77 physicians among 18 clinics. Participants: Patients with one or more clinic visit between 2015 and 2018, between 18 and 40 years old, residing in Northern Alberta. Main Outcome Measures: Comparison of prevalence in MetS between sexes as well as sex-specific distribution of MetS characteristics [body mass index (BMI), fasting blood glucose, glycated hemoglobin, triglycerides, and high-density lipoprotein cholesterol (HDL-C), presence of hypertension, and presence of diabetes]. Results: Of 15,766 patients, 4.4% (n = 700) had young-onset MetS based on recorded data, prevalence was nearly twice as high in males (6.1%, n = 354) compared with females (3.5%, n = 346). The most prevalent risk factor for MetS consisted of having an elevated BMI for both females (90.9%) and males (91.5%). In the presence of MetS, more females had lower HDL-C [68.2% females (F) vs. 52.5% males (M)], and higher prevalence of diabetes (21.4% F vs. 9.0% M), whereas more males had hypertriglyceridemia (60.4% F vs. 79.7% M) and hypertension (12.4% F vs. 15.8% M). Females also had consistently higher percentages of absent laboratory data compared with males when identified as having MetS and BMI ≥25 kg/m2. Conclusions: Males have nearly twice the prevalence of young-onset MetS compared with females, with notable sex-specific differences in the manifestation of MetS, although we suspect that this is partially due to underreporting where the absence of anthropomorphic and laboratory investigations point to a lack of testing. Sex-specific screening for MetS, especially among young females of childbearing years, is important for downstream prevention.

Feasibility of identifying and describing the burden of early-onset metabolic syndrome in primary care electronic medical record data: a cross-sectional analysis.

BACKGROUND: The prevalence of metabolic syndrome is growing worldwide, yet remains underinvestigated in Canadian young adults. We sought to explore the use of a harmonized case definition specific to early-onset metabolic syndrome and determine its feasibility in assessing the prevalence of metabolic syndrome among electronic medical record (EMR) data of young adults in Northern Alberta. METHODS: We conducted a cross-sectional study using a sample of EMR data from young adult patients aged 18-40 years and residing in Northern Alberta, who had an encounter with a participating primary care clinic between June 29, 2015, and June 29, 2018. Physical examination, laboratory investigation and disease diagnosis data were collected. A case definition and algorithm were developed to assess the feasibility of identifying metabolic syndrome, including measures for body mass index (BMI), blood pressure (BP), dysglycemia, hypertriglyceridemia, high-density lipoprotein cholesterol, diabetes and hypertension. RESULTS: Among 15 766 young adults, the case definition suggested the prevalence of metabolic syndrome was 4.4%, 95% confidence interval (CI) 4.1%-4.7%. The most frequent 3-factor combination (41.6%, 95% CI 37.9%-45.3%) of metabolic syndrome criteria consisted of being overweight or obese, having elevated BP and hypertriglyceridemia. Half of metabolic syndrome cases (51.3%, 95% CI 47.6%-55.0%) were missing measures for fasting blood glucose, and one-fifth were missing a hemoglobin A1c (HbA1c) level. Notably, most young adults with a BMI of 25 or greater were missing HbA1c (68.7%, 95% CI 67.6%-69.8%), fasting blood glucose (84.0%, 95% CI 83.2%-84.8%) and triglyceride testing (79.0%, 95% CI 78.1%-79.9%). INTERPRETATION: We have shown that our case definition is feasible in identifying early-onset metabolic syndrome using EMR data; however, the degree of missing data limits the feasibility in assessing prevalence. Further investigation is required to validate this case definition for metabolic syndrome in the EMR data, which may involve comparing this definition to other validated metabolic syndrome case definitions.

Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure.

BACKGROUND: Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure. METHOD: For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day). RESULT: Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3ß ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups. CONCLUSION: We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.

Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure.

Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is presently unknown. To address this, we utilized a tamoxifen-inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood. Control mice (CD36 floxed/floxed mice) and icCD36KO mice were treated with tamoxifen and subsequently subjected to transverse aortic constriction (TAC) surgery to generate pressure overload-induced cardiac hypertrophy. Consistent with CD36 mediating a significant proportion of FA entry into the cardiomyocyte and subsequent FA utilization for ATP production, hearts from icCD36KO mice were metabolically inefficient and displayed signs of energetic stress, including activation of the energetic stress kinase, AMPK. In addition, impaired energetics in icCD36KO mice contributed to a rapid progression from compensated hypertrophy to heart failure. However, icCD36KO mice fed a medium-chain FA diet, whereby medium-chain FAs can enter into the cardiomyocyte independent from CD36, were protected from TAC-induced heart failure. Together these data suggest that limiting FA uptake and partial inhibition of FA oxidation in the heart via CD36 ablation may be detrimental for the compensated hypertrophic heart in the absence of sufficiently elevated circulating FAs to provide an adequate energy source.NEW & NOTEWORTHY Limiting CD36-mediated fatty acid uptake in the setting of obesity and/or insulin resistance protects the heart from cardiac hypertrophy and dysfunction. However, cardiomyocyte-specific CD36 ablation in the absence of elevated circulating fatty acid levels accelerates the progression of pressure overload-induced cardiac hypertrophy to systolic heart failure.

Empagliflozin Prevents Worsening of Cardiac Function in an Experimental Model of Pressure Overload-Induced Heart Failure.

This study sought to determine whether the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved heart failure (HF) outcomes in nondiabetic mice. The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial demonstrated that empagliflozin markedly prevented HF and cardiovascular death in subjects with diabetes. However, despite ongoing clinical trials in HF patients without type 2 diabetes, there are no objective and translational data to support an effect of SGLT2 inhibitors on cardiac structure and function, particularly in the absence of diabetes and in the setting of established HF. Male C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Following surgery, mice that progressed to HF received either vehicle or empagliflozin for 2 weeks. Cardiac function was then assessed in vivo using echocardiography and ex vivo using isolated working hearts. Although vehicle-treated HF mice experienced a progressive worsening of cardiac function over the 2-week treatment period, this decline was blunted in empagliflozin-treated HF mice. Treatment allocation to empagliflozin resulted in an improvement in cardiac systolic function, with no significant changes in cardiac remodeling or diastolic dysfunction. Moreover, isolated hearts from HF mice treated with empagliflozin displayed significantly improved ex vivo cardiac function compared to those in vehicle-treated controls. Empagliflozin treatment of nondiabetic mice with established HF blunts the decline in cardiac function both in vivo and ex vivo, independent of diabetes. These data provide important basic and translational clues to support the evaluation of SGLT2 inhibitors as a treatment strategy in a broad range of patients with established HF.

Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

AIMS: Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. METHODS AND RESULTS: Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. CONCLUSIONS: The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery.

Resveratrol treatment of mice with pressure-overload-induced heart failure improves diastolic function and cardiac energy metabolism.

BACKGROUND: Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload-induced HF and identified physiological and molecular mechanisms contributing to this. METHODS AND RESULTS: C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment. CONCLUSIONS: Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism.

Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice.

Recent evidence has suggested that activation of AMP-activated protein kinase (AMPK) induced by short-term caloric restriction (CR) protects against myocardial ischemia-reperfusion (I/R) injury. Because AMPK plays a central role in regulating energy metabolism, we investigated whether alterations in cardiac energy metabolism contribute to the cardioprotective effects induced by CR. Hearts from control or short-term CR mice were subjected to ex vivo I/R and metabolism, as well as post-ischemic functional recovery was measured. Even in the presence of elevated levels of fatty acids, CR significantly improved recovery of cardiac function following ischemia. While rates of fatty acid oxidation or glycolysis from exogenous glucose were similar between groups, improved functional recovery post-ischemia in CR hearts was associated with high rates of glucose oxidation during reperfusion compared to controls. Consistent with CR improving energy supply, hearts from CR mice had increased ATP levels, as well as lower AMPK activity at the end of reperfusion compared to controls. Furthermore, in agreement with the emerging concept that CR is a non-conventional form of pre-conditioning, we observed a significant increase in phosphorylation of Akt and Erk1/2 at the end of reperfusion. These data also suggest that activation of the reperfusion salvage kinase (RISK) pathway also contributes to the beneficial effects of CR in reducing post-ischemia contractile dysfunction. These findings also suggest that short-term CR improves post-ischemic recovery by promoting glucose oxidation, and activating the RISK pathway. As such, pre-operative CR may be a clinically relevant strategy for increasing ischemic tolerance of the heart.