Circulating ketone bodies and cardiovascular outcomes: the MESA study.

AIMS: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD). METHODS AND RESULTS: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]. CONCLUSION: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment.

Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

Plasma metabolomic profiling in subclinical atherosclerosis: the Diabetes Heart Study.

BACKGROUND: Incidence rates of cardiovascular disease (CVD) are increasing, partly driven by the diabetes epidemic. Novel prediction tools and modifiable treatment targets are needed to enhance risk assessment and management. Plasma metabolite associations with subclinical atherosclerosis were investigated in the Diabetes Heart Study (DHS), a cohort enriched for type 2 diabetes (T2D). METHODS: The analysis included 700 DHS participants, 438 African Americans (AAs), and 262 European Americans (EAs), in whom coronary artery calcium (CAC) was assessed using ECG-gated computed tomography. Plasma metabolomics using liquid chromatography-mass spectrometry identified 853 known metabolites. An ancestry-specific marginal model incorporating generalized estimating equations examined associations between metabolites and CAC (log-transformed (CAC + 1) as outcome measure). Models were adjusted for age, sex, BMI, diabetes duration, date of plasma collection, time between plasma collection and CT exam, low-density lipoprotein cholesterol (LDL-C), and statin use. RESULTS: At an FDR-corrected p-value < 0.05, 33 metabolites were associated with CAC in AAs and 36 in EAs. The androgenic steroids, fatty acid, phosphatidylcholine, and bile acid metabolism subpathways were associated with CAC in AAs, whereas fatty acid, lysoplasmalogen, and branched-chain amino acid (BCAA) subpathways were associated with CAC in EAs. CONCLUSIONS: Strikingly different metabolic signatures were associated with subclinical coronary atherosclerosis in AA and EA DHS participants.

Relationship of American Heart Association's Life Simple 7, Ectopic Fat, and Insulin Resistance in 5 Racial/Ethnic Groups.

BACKGROUND: The inverse association between ideal cardiovascular health (CVH) as measured by the American Heart Association's Life Simple 7 (LS7) and cardiovascular disease (CVD) incidence is well documented. However, research exploring the association between CVH and specific risk factors for cardiometabolic disease is sparse in diverse cohorts. METHODS: This study included 7717 participants from the Mediators of Atherosclerosis in South Asians Living in America and the Multi-Ethnic Study of Atherosclerosis cohorts. We assigned each LS7 component a 0, 1, and 2 and summed these scores to derive an overall CVH score. Visceral, subcutaneous, and intermuscular fat area, pericardial fat volume, and hepatic fat attenuation were measured using noncontrast computed tomography. Multivariable linear regression was used to examine associations between CVH categories and each log-transformed ectopic fat depot, as well as the homeostatic assessment for insulin resistance (HOMA-IR). RESULTS: In adjusted analysis, compared to those with ideal CVH, participants with poor CVH demonstrated 63.4% (95% CI, 54.3-73.0) higher visceral fat area, 84.0% (95% CI, 76.5-92.1) higher pericardial fat volume, 61.6% (95% CI, 50.7-73.2) higher subcutaneous fat area, and 40.6% (95% CI, 30.2-52.0) higher intermuscular fat area, and 15.1% (95% CI, 13.1-17.2) higher hepatic fat (all Ps < 0.001). Also, poor CVH was associated with 148.2% (95% CI, 131.1-166.7) higher HOMA-IR. We also found significant heterogeneity in the strengths of association by race/ethnicity for each ectopic fat depot. CONCLUSION: Poor and intermediate CVH, as defined by LS7 metrics, were associated with significantly higher measures of ectopic fat and insulin resistance among individuals from 5 racial/ethnic groups.

Association between remnant lipoprotein cholesterol, high-sensitivity C-reactive protein, and risk of atherosclerotic cardiovascular disease events in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Elevated remnant-lipoprotein (RLP)-cholesterol (RLP-C) and high-sensitivity C-reactive protein (hsCRP) are each individually associated with atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: To evaluate the interplay of nuclear magnetic resonance (NMR)-derived RLP-C and hsCRP and their association with ASCVD in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Lipoprotein particles were measured using NMR spectroscopic analysis at baseline. RLP-C includes very-low-density lipoprotein cholesterol and intermediate-density lipoprotein cholesterol. Four groups were created as follows: Group 1: RLP-C ≤ median (≤29.14 mg/dL) and hsCRP < 2 mg/L; Group 2: RLP-C ≤ median and hsCRP≥ 2 mg/L; Group 3: RLP-C > median and hsCRP level < 2 mg/L; and Group 4: RLP-C > median and hsCRP level ≥ 2 mg/L. Kaplan-Meier survival curves and multivariable-adjusted Cox proportional hazard models were used to examine the relationship between RLP-C and hsCRP with incident ASCVD. RESULTS: A total of 6,720 MESA participants (mean age 62.2 y, 53% female) with a median follow-up of 15.6 years were included. In the fully adjusted model, compared to those in the reference group (Group 1), participants in Group 2, Group 3, and Group 4 demonstrated a 20% (95% CI, -2%-48%), 18% (-4%-44%), and 43% (18%-76%) increased risk of incident ASCVD events, respectively (p < 0.01). An additive and multiplicative interaction between RLP-C and hsCRP was not statistically significant. CONCLUSION: NMR-derived RLP-C and hsCRP showed a similar independent association with incident ASCVD. Notably, the combination of increased RLP-C and hsCRP was associated with an increased risk of future ASCVD events.

Interrelationships Between American Heart Association's Life's Simple 7, ECG Silent Myocardial Infarction, and Cardiovascular Mortality.

Background We examined the interrelationships among cardiovascular health (CVH), assessed by the American Heart Association's Life's Simple 7 (LS7) health metrics, silent myocardial infarction (SMI), and cardiovascular disease (CVD) mortality. Methods and Results This analysis included 6766 participants without a history of coronary heart disease from the Third Report of the National Health and Nutrition Examination Survey. Poor, intermediate, and ideal CVH were defined as an LS7 score of 0 to 4, 5 to 9, and 10 to 14, respectively. SMI was defined as ECG evidence of myocardial infarction without a clinical diagnosis of myocardial infarction. Cox proportional hazard analysis was used to examine the association of baseline CVH with CVD death stratified by SMI status on follow-up. In multivariable logistic regression models, ideal CVH was associated with 69% lower odds of SMI compared with poor CVH. During a median follow-up of 14 years, 907 CVD deaths occurred. In patients without SMI, intermediate CVH (hazard ratio, 1.41; 95% CI, 1.14-1.74) and poor CVH (hazard ratio, 2.77; 95% CI, 2.10-3.66) were associated with increased risk of CVD mortality, compared with ideal CVH. However, in the presence of SMI, the magnitude of these associations almost doubled (hazard ratio, 2.17 [95% CI, 1.42-3.32] for intermediate CVH and hazard ratio, 6.28 [95% CI, 3.02-13.07] for poor CVH). SMI predicted a significant increased risk of CVD mortality in the intermediate and poor CVH subgroups but a nonsignificant increased risk in the ideal CVH subgroup. Conclusions Ideal CVH is associated with a lower risk of SMI, and concomitant presence of SMI and poor CVH is associated with a worse prognosis. These novel findings underscore the potential role of maintaining ideal CVH in preventing future CVD outcomes.

Electrocardiographic subclinical myocardial injury and alcohol consumption: a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Cardiac Infarction/Injury Score (CIIS), an electrocardiographic based scoring system, is a surrogate marker of subclinical myocardial injury (SC-MI) and has shown excellent prognostic value in predicting future cardiovascular mortality. As an association of mild to moderate alcohol consumption with cardiovascular disease (CVD) is conflicting, using an electrocardiographic based scoring system such as CIIS is a simple and cost-effective way to investigate this controversial relationship. METHODS: This analysis included 6090 participants (58.42±13.12 years, 54.2% women) free of CVD from the Third National Health and Nutrition Examination Survey (NHANES III). We used multivariable linear regression analysis to examine the cross-sectional association between each alcohol category (non-drinker (reference), 1-6 drinks/week, 7-13 drinks/week, ≥14 drinks/week, and CIIS. SC-MI was defined as CIIS ≥10 units. RESULTS: The prevalence of SC-MI was high among heavy drinkers (≥14 drinks/week) and was lower in participants who were moderate drinkers (7-13 drinks/week). There was a statistically significant and inverse association between moderate alcohol consumption and CIIS (ß (95% CI): -0.64 (-1.27, -0.007), P = 0.04) using multivariable linear regression analysis. This inverse association between moderate alcohol consumption and CIIS was more striking among whites compared to non-whites (ß (95% CI): -1.06 (-1.93, -0.19) vs. 0.05 (-0.91, 1.00) respectively; interaction p-value = 0.08). Also, the association was stronger among women and older participants, however interaction p-value did not reach statistical significance. CONCLUSION: There is an inverse association between moderate alcohol consumption and CIIS in participants without manifestations of CVD. As lower CIIS has been associated with low risk of poor outcomes including CVD mortality, these findings further support the existing evidence of the potential benefits of moderate alcohol consumption on cardiovascular health.