Circulating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension

HomeCirculation: Genomic and Precision MedicineVol. 16, No. 1Circulating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCirculating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension Shengyuan Luo, Aditya Surapaneni, Casey M. Rebholz, Lawrence J. Appel, Josef Coresh and Morgan E. Grams Shengyuan LuoShengyuan Luo Correspondence to: Shengyuan Luo, MBBS, MHS, Department of Internal Medicine, Rush University Medical Center, 1700 W. Van Buren St, Fifth Floor, Chicago, IL 60612. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3235-6832 Department of Internal Medicine, Rush University Medical Center, Chicago, IL (S.L.). Search for more papers by this author , Aditya SurapaneniAditya Surapaneni https://orcid.org/0000-0003-4978-5980 Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G). Division of Neprhology, Department of Medicine, Johns Hopkins University, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G.). Division of Precision Medicine, Department of Medicine, New York University, NY (A.S., M.E.G.). Search for more papers by this author , Casey M. RebholzCasey M. Rebholz https://orcid.org/0000-0002-5442-8745 Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G). Division of Neprhology, Department of Medicine, Johns Hopkins University, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G.). Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (C.M.R.). Search for more papers by this author , Lawrence J. AppelLawrence J. Appel https://orcid.org/0000-0002-0673-6823 Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G). Division of Neprhology, Department of Medicine, Johns Hopkins University, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G.). Search for more papers by this author , Josef CoreshJosef Coresh https://orcid.org/0000-0002-4598-0669 Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G). Division of Neprhology, Department of Medicine, Johns Hopkins University, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G.). Search for more papers by this author and Morgan E. GramsMorgan E. Grams https://orcid.org/0000-0002-4430-6023 Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G). Division of Neprhology, Department of Medicine, Johns Hopkins University, Baltimore, MD (A.S., C.M.R., L.J.A., J.C., M.E.G.). Division of Precision Medicine, Department of Medicine, New York University, NY (A.S., M.E.G.). Search for more papers by this author Originally published30 Jan 2023https://doi.org/10.1161/CIRCGEN.122.003729Circulation: Genomic and Precision Medicine. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 30, 2023: Ahead of Print Branched-chain amino acids (BCAAs), that is, leucine, isoleucine, and valine, are essential amino acids involved in glucose regulation, immunity, and cell signaling.1 Excessive circulating BCAAs predict type 2 diabetes and subsequent cardiovascular disease (CVD) in the general population.2 Chronic kidney disease (CKD) alters circulating metabolites and is a strong CVD risk factor. We leveraged the AASK trial (African American Study of Kidney Disease and Hypertension) to evaluate BCAAs’ cardiovascular effects in CKD outside the context of diabetes.AASK is a multicenter randomized trial studying the effects of 3 antihypertensives and 2 blood pressure control goals on hypertensive-attributed CKD progression in African Americans.3 Between 1995 and 1998, a total of 1094 patients with hypertension-attributed CKD (baseline measured glomerular filtration rate 20–65 mL/min per 1.73 meter squared) and without diabetes were enrolled. They were followed until renal replacement therapy or death. Follow-up was extended among 691 individuals not needing renal replacement therapy upon completion of the trial from 2002 through 2007. The study was approved by an institutional review committee. All participants gave informed consent. Data, methods, and materials supporting findings can be made available upon request.Fasting serum samples at baseline were used for metabolomic profiling at Metabolon, Inc (Morrisville, NC). Metabolites were quantified with area under the curve of liquid chromatography-mass spectrometry peaks. Quality control processes were previously described.4 Circulating BCAA levels were available for analysis in 962 participants. Coefficient of variation in blind duplicates was 4.8%, 5.3%, and 6.8% for leucine, isoleucine, and valine, respectively.Outcomes of this study were incident CVD (composite of hospitalization for nonfatal myocardial infarction, cardiac revascularization procedure, heart failure, stroke, or cardiovascular death, all adjudicated by the AASK Cardiovascular Outcomes Committee), cardiovascular death, and all-cause mortality.Continuous variable correlations were assessed with Spearman coefficients. To evaluate associations between BCAAs and outcomes, we used multivariable Cox models with adjustment for baseline covariates including age, sex, randomized groups, body mass index, history of smoking, history of heart disease, measured glomerular filtration rate, proteinuria, fasting blood glucose, low-density lipoprotein cholesterol, and C-reactive protein. Missing data (n=4 for proteinuria and n=206 for low-density lipoprotein cholesterol) were imputed with median values. Competing risk of death was assessed with Fine-Gray models adjusting for the same covariates. The cutoff for statistical significance was a Bonferroni-corrected 2-sided P-value of 0.017 (0.05/3 metabolites evaluated). Analyses were performed using Stata 17.0 (StataCorp, College Station, TX) and R (R Foundation, Vienna, Austria).Among 962 participants (mean age 56 [SD, 11] years, 39% women, mean glomerular filtration rate 48 [SD, 13] mL/min per 1.73 meter squared, mean fasting blood glucose 94 [SD, 15] mg/dL), BCAAs were mutually highly correlated, but less so with other covariables (Figure [A]). During follow-up (median 7.4 years), there were 192 CVD events (myocardial infarction or revascularization, n=57; stroke, n=74; heart failure, n=74) and 220 deaths of which 54 were cardiovascular deaths. Adjusted for covariates, BCAAs were not associated with incident CVD with or without accounting for the competing risk of death (Figure [B]). However, higher leucine and isoleucine were associated with lower cardiovascular death (per doubling, hazard ratio [HR]=0.52 [95% CI, 0.31–0.87]; P=0.013 for isoleucine; HR=0.30 [95% CI, 0.13–0.68]; P=0.004 for leucine). Higher valine was associated with lower cardiovascular death (HR=0.39 [95% CI, 0.16–0.94]; P=0.036), leucine and isoleucine were associated with lower all-cause mortality (HR=0.70 [95% CI, 0.49–1.00]; P=0.049 for isoleucine; HR=0.57 [95% CI, 0.36–0.96]; P=0.035 for leucine) with nominal statistical significance.Download figureDownload PowerPointFigure. Circulating branched-chain amino acid, cross-sectional Spearman correlations, and associations with incident cardiovascular event, cardiovascular death, and all-cause mortality in the African American Study of Kidney Disease and Hypertension. Hazard ratios are modeled per doubling of each BCAA and adjusted for baseline age, sex, randomized treatment groups, body mass index, history of smoking, history of heart disease, measured GFR, proteinuria, blood glucose, low-density lipoprotein cholesterol, and C-reactive protein. Proteinuria, LDLc, and CRP had skewed distributions and were log-transformed in all analyses. BCAA indicates branched-chain amino acid; BMI, body mass index; CRP, C-reactive protein; GFR, glomerular filtration rate; and LDLc, low-density lipoprotein cholesterol.Evidence supports a causal role of excessive circulating BCAAs in insulin resistance, diabetes, and obesity.5 In a general population (primarily White individuals with preserved kidney function), circulating BCAAs were positively associated with incident CVD with insulin resistance being the mediator.2 Outside the context of diabetes, relatively few studies have assessed the cardiovascular effects of BCAAs, with findings being less consistent. In animals, myocardial stress impaired myocardial BCAA catabolism, causing local accumulation of BCAAs and branched-chain α-keto acids, and BCAA transamination products that can negatively impact the cardiovascular system.5 It is less clear whether systemic alterations in these metabolites also have cardiovascular effects. Our study expands the evidence base with a unique study population. The lack of association between BCAAs and CVD here may be attributable to the population’s advanced kidney disease, a condition that substantially alters metabolite excretion. While excessive BCAAs can reflect catabolic defects and predict insulin resistance, a healthy level of BCAAs supports cellular metabolism, cardiomyocyte signaling, and may be antiaging.1 We speculate that higher BCAAs in those with advanced CKD and without diabetes may be closer to the general population’s normal range, reflecting relative health.This study’s observational nature limits assessment of causality. The relatively small sample size and metabolite quantification on a relative scale complicate comparison with other studies. This study also lacked measurements of branched-chain α-keto acids, potentially toxic byproducts of impaired BCAA catabolism.In summary, we observed lower cardiovascular death and all-cause mortality, but not higher CVD risk, with higher circulating BCAAs in individuals with advanced nondiabetic CKD. These findings expand on current evidence of BCAAs and cardiovascular health.Article InformationSources of FundingDr Rebholz is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; R03 DK128386) and the National Heart, Lung, and Blood Institute (NHLBI; R01 HL153178). Drs Coresh and Grams are supported by the CKD Biomarkers Consortium (NIDDK U01 DK085689). Dr Grams is supported by the NIDDK (R01DK108803 and K24HL155861).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 89.Correspondence to: Shengyuan Luo, MBBS, MHS, Department of Internal Medicine, Rush University Medical Center, 1700 W. Van Buren St, Fifth Floor, Chicago, IL 60612. Email Shengyuan_luo@rush.eduReferences1. Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit?.Cardiovasc Res. 2011; 90:220–223. doi: 10.1093/cvr/cvr070CrossrefMedlineGoogle Scholar2. Tobias DK, Lawler PR, Harada PH, Demler OV, Ridker PM, Manson JE, Cheng S, Mora S. Circulating branched-chain amino acids and incident cardiovascular disease in a prospective cohort of US women.Circ Genom Precis Med. 2018; 11:e002157. doi: 10.1161/CIRCGEN.118.002157LinkGoogle Scholar3. Gassman JJ, Greene T, Wright JT, Agodoa L, Bakris G, Beck GJ, Douglas J, Jamerson K, Lewis J, Kutner M, et al. Design and statistical aspects of the African American Study of Kidney Disease and Hypertension (AASK).J Am Soc Nephrol. 2003; 14:S154–S165. doi: 10.1097/01.asn.0000070080.21680.cbCrossrefMedlineGoogle Scholar4. Luo S, Coresh J, Tin A, Rebholz CM, Appel LJ, Chen J, Vasan RS, Anderson AH, Feldman HI, Kimmel PL, et al. Serum metabolomic alterations associated with proteinuria in CKD.Clin J Am Soc Nephrol. 2019; 14:342–353. doi: 10.2215/cjn.10010818CrossrefMedlineGoogle Scholar5. Neinast M, Murashige D, Arany Z. Branched chain amino acids.Annu Rev Physiol. 2019; 81:139–164. doi: 10.1146/annurev-physiol-020518-114455CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails February 2023Vol 16, Issue 1 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.122.003729PMID: 36716198 Manuscript receivedJanuary 26, 2022Manuscript acceptedJanuary 3, 2023Originally publishedJanuary 30, 2023 Keywordsglomerular filtration rateAfrican American Study of Kidney Disease and Hypertensioncardiovascular diseasehypertensionbranched-chain amino acidsPDF download Advertisement SubjectsBiomarkersCardiovascular DiseaseClinical StudiesMetabolismSecondary Prevention