Publications

Anthracyclines are a major component of chemotherapies used in many pediatric and adult malignancies. Anthracycline-associated cardiotoxicity (ACT) is a dose-dependent adverse effect that has substantial impact on morbidity and mortality. Therefore, the identification of genetic variants associated with increased risk of ACT has the potential for significant clinical impact to improve patient care. The goal of this review is to summarize the current evidence supporting genetic variants associated with ACT, identify gaps and limitations in current knowledge, and propose future directions for incorporating genetics into clinical practice for patients treated with anthracyclines. We will discuss mechanisms of ACT that could be illuminated by genetics and discuss clinical applications for the cardiologist/cardio-oncologist.

IMPORTANCE: African American individuals have disproportionate rates of coronary heart disease (CHD) but lower levels of coronary artery calcium (CAC), a marker of subclinical CHD, than non-Hispanic White individuals. African American individuals may have distinct metabolite profiles associated with incident CHD risk compared with non-Hispanic White individuals, and examination of these differences could highlight important processes that differ between them.

OBJECTIVES: To identify novel biomarkers of incident CHD and CAC among African American individuals and to replicate incident CHD findings in a multiethnic cohort.

DESIGN, SETTING, AND PARTICIPANTS: This analysis targeted plasma metabolomic profiling of 2346 participants in the Jackson Heart Study (JHS), a prospective population-based cohort study that included 5306 African American participants who were examined at baseline (2000-2004) and 2 follow-up visits. Replication of CHD-associated metabolites was sought among 1588 multiethnic participants from the Women's Health Initiative (WHI), a prospective population-based multiethnic cohort study of 161 808 postmenopausal women who were examined at baseline (1991-1995) and ongoing follow-up visits. Regression analyses were performed for each metabolite to examine the associations with incident CHD and CAC scores. Data were collected from the WHI between 1994 and 2009 and from the JHS between 2000 and 2015. All data were analyzed from November 2020 to August 2021.

EXPOSURES: Plasma metabolites.

MAIN OUTCOMES AND MEASURES: Incident CHD was defined as definite or probable myocardial infarction or definite fatal CHD in both the JHS and WHI cohorts. In the JHS cohort, silent myocardial infarction between examinations (as determined by electrocardiography) and coronary revascularization were included in the incident CHD analysis. Coronary artery calcium was measured using a 16-channel computed tomographic system and reported as an Agatston score.

RESULTS: Among 2346 African American individuals in the JHS cohort, the mean (SD) age was 56 (13) years, and 1468 individuals (62.6%) were female. Among 1588 postmenopausal women in the WHI cohort, the mean (SD) age was 67 (7) years; 217 individuals (13.7%) self-identified as African American, 1219 (76.8%) as non-Hispanic White, and 152 (9.6%) as other races or ethnicities. In the fully adjusted model including 1876 individuals, 46 of 303 targeted metabolites were associated with incident CHD (false discovery rate q <0.100). Data for 32 of the 46 metabolites were available in the WHI cohort, and 13 incident CHD-associated metabolites from the JHS cohort were replicated in the WHI cohort. A total of 1439 participants from the JHS cohort with available CAC scores received metabolomic profiling. Nine metabolites were associated with CAC scores. Minimal overlap was found between the results from the incident CHD and CAC analyses, with only 3 metabolites shared between the 2 analyses.

CONCLUSIONS AND RELEVANCE: This cohort study identified metabolites that were associated with incident CHD among African American individuals, including 13 incident CHD-associated metabolites that were replicated in a multiethnic population and 9 novel metabolites that included N-acylamides, leucine, and lipid species. These findings may help to elucidate common and distinct metabolic processes that may be associated with CHD among individuals with different self-identified race.

Genetic testing for cardiovascular (CV) disease has had a profound impact on the diagnosis and evaluation of monogenic causes of CV disease, such as hypertrophic and familial cardiomyopathies, long QT syndrome, and familial hypercholesterolemia. The success in genetic testing for monogenic diseases has prompted special interest in utilizing genetic information in the risk assessment of more common diseases such as atherosclerotic cardiovascular disease (ASCVD). Polygenic risk scores (PRS) have been developed to assess the risk of coronary artery disease, which now include millions of single-nucleotide polymorphisms that have been identified through genomewide association studies. Although these PRS have demonstrated a strong association with coronary artery disease in large cross-sectional population studies, there remains intense debate regarding the added value that PRS contributes to existing clinical risk prediction models such as the pooled cohort equations. In this review, we provide a brief background of genetic testing for monogenic drivers of CV disease and then focus on the recent developments in genetic risk assessment of ASCVD, including the use of PRS. We outline the genetic testing that is currently available to all cardiologists in the clinic and discuss the evolving sphere of specialized cardiovascular genetics programs that integrate the expertise of cardiologists, geneticists, and genetic counselors. Finally, we review the possible implications that PRS and pharmacogenomic data may soon have on clinical practice in the care for patients with or at risk of developing ASCVD.

Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure  5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of  75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.

BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.

METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women).

RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; P=2×10-8; hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; P=5×10-15). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups.

CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

SCOPE: New biomarkers are needed that are representative of dietary intake.

METHODS AND RESULTS: We assess metabolites associated with Southern dietary patterns in 1401 Jackson Heart Study participants. Three dietary patterns are empirically derived using principal component analysis: meat and fast food, fish and vegetables, and starchy foods. We randomly select two subsets of the study population: two-third sample for discovery (n = 934) and one-third sample for replication (n = 467). Among the 327 metabolites analyzed, 14 are significantly associated with the meat and fast food dietary pattern, four are significantly associated with the fish and vegetables dietary pattern, and none are associated with the starchy foods dietary pattern in the discovery sample. In the replication sample, nine remain associated with the meat and fast food dietary pattern [indole-3-propanoic acid, C24:0 lysophosphatidylcholine (LPC), N-methyl proline, proline betaine, C34:2 phosphatidylethanolamine (PE) plasmalogen, C36:5 PE plasmalogen, C38:5 PE plasmalogen, cotinine, hydroxyproline] and three remain associated with the fish and vegetables dietary pattern [1,7-dimethyluric acid, C22:6 lysophosphatidylethanolamine, docosahexaenoic acid (DHA)].

CONCLUSION: Twelve metabolites are discovered and replicated in association with dietary patterns detected in a Southern U.S. African-American population, which could be useful as biomarkers of Southern dietary patterns.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.

BACKGROUND: Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease.

METHODS: We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction.

RESULTS: Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P=1.2×10-3), diacetylspermine (hazard ratio, 1.34; P=3.4×10-3), and uridine (hazard ratio, 0.79; P, 3×10-4). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (N-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction.

CONCLUSIONS: The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.