Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women

Abstract

Background Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, valine) are strong predictors of type 2 diabetes (T2D), but their association with cardiovascular disease (CVD) is uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk, and evaluated whether this was dependent on an intermediate diagnosis of T2D. Methods Participants enrolled in the Women’s Health Study prospective cohort were eligible if free of CVD at baseline blood collection (N=27,041, mean baseline age=54.7 years). Plasma BCAA metabolites were measured via NMR spectroscopy, ln-transformed, and standardized for analysis. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for total and individual BCAAs with incident CVD (myocardial infarction [MI], stroke, coronary revascularization). Results We confirmed 2,207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, BMI, smoking, diet, physical activity, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD HR=1.13, CI=1.08 to 1.18), comparable in magnitude to modeling the association of LDL cholesterol with CVD (per SD HR=1.12, CI=1.07 to 1.17). In particular, BCAAs were associated with coronary events (MI: per SD HR=1.16, CI=1.06 to 1.26; revascularization: per SD HR=1.17, CI=1.11 to 1.25), but not with stroke (per SD HR=1.07, CI=0.99 to 1.15). Isoleucine, leucine, and valine were each separately associated with CVD (p<0.05). The BCAA-CVD association was greater (p-interaction=0.036) among women who developed T2D prior to CVD (HR=1.20, CI=1.08 to 1.32), vs. women without T2D (HR=1.08, CI=1.03 to 1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance, cardiometabolic biomarkers that may be downstream mediators of risk, eliminated the associations of BCAAs with CVD. Conclusions Circulating plasma BCAAs were positively associated with incident CVD in a prospective cohort of US women. Impaired BCAA metabolism may represent a shared pathway of metabolic dysfunction that links T2D and CVD, and plasma BCAAs may capture the long-term cardiometabolic risks of this common etiology, in particular among women who develop T2D prior to a CVD event.

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

“…Our study has several limitations. First, the association of HF and BCAAs was based on a single measurement on banked samples in a repository for years, although many studies have also used samples with storage time ranging from 6 months to 22 years . The HKDR was established as a research‐driven quality improvement program using standard protocols for procedures, data collection, and sample processing/storage to minimize analytical errors.…”

“…In a post hoc, nested case‐control analysis of the Prevención con Dieta Mediterránea (PREDIMED) trial involving 970 individuals at high cardiovascular risk (51% with T2D), those in the highest quartile of fasting plasma BCAAs at baseline had 70% excess risk of CVD than individuals in the lowest quartile . In the U.S. Women's Health Study of 27 041 female health professionals (2.6% with T2D), every SD increase in plasma BCAAs at baseline was independently associated with 13% excess risk of CVD during a 19‐year follow‐up period, an effect size comparable to every SD increase in LDL‐C . Likewise, carotid intima‐media thickness, a surrogate marker of ASCVD, was also positively associated with circulating levels of BCAAs in general populations of European and Chinese ancestry …”

“…BCAAs was based on a single measurement on banked samples in a repository for years, although many studies have also used samples with storage time ranging from 6 months to 22 years. 16,30,34,35 The HKDR was established as a research-driven quality improvement program using standard protocols for procedures, data collection, and sample processing/ storage to minimize analytical errors. Although mass spectrometry is the gold standard for measuring BCAAs, 3 we have used a validated commercial assay with internal control 19 and yielded results comparable to that reported in other Chinese cohorts (6.5%-17.6% patients with T2D;…”

Metabolic profiling of elite athletes with different cardiovascular demand

“…35 Elevations in several metabolites associated with high CD including BCAAs, PC, and PE may also suggest an increased risk of cardiovascular disease among athletes who belong to this group. Whereas BCAAs were previously correlated with increased risk of cardiovascular disease, 36 PC were shown to be associated with increased cardiovascular mortality independent of traditional risk factors. 37 PE (precursors of PC) have also been shown previously to be among the strongest predictive lipid species for risk of cardiovascular disease.…”

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

“…Previously studied as the basis of an autosomal recessive metabolic disorder called maple syrup urine disease (MSUD) (Lu et al, 2009), the accumulation of BCAAs has been implicated in cardiac pathogenesis with metabolic reprogramming deemed vital in the progression of heart failure in mice and conserved in the metabolic signature of failing human hearts (Sun et al, 2016; Sun & Wang, 2016). A decrease in energy metabolism and increase in BCAA metabolism has further been associated with high‐glucose‐induced cardiomyocyte death (Zhang et al, 2018), and found to be a reliable predictor of susceptibility to type 2 diabetes, thereby circulating plasma BCAAs were also positively associated with incident cardiovascular disease (CVD) in U.S. Women (Tobias, Lawler, et al, 2018). These studies, among others, have collectively concluded that altered BCAA metabolism and consequently the accumulation of BCAA breakdown byproducts may herald insulin resistance and manifest as cardiometabolic disease.…”