Alexander C Razavi, Harpreet S Bhatia, Natalie Marrero
et al.
Abstract Background and Aims Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. Methods This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Results Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19–.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04–.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04–.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001–.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66–1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53–4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39–1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14–1.47). Conclusions In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a).
Yulu Zheng, Jae Jeong Yang, Deepak K. Gupta
et al.
Background Despite growing evidence linking gut microbiota and microbial metabolites to human cardiometabolic health, few studies have systematically examined associations between circulating microbial metabolites and incident coronary heart disease (CHD). Methods and findings We conducted a multi-stage metabolomics study involving five prospective cohorts. Discovery involved untargeted plasma metabolite profiling of 896 incident cases and 896 age-/sex-/race-matched controls (~300 pairs per race: Black, White, Asian) from the Southern Community Cohort Study (SCCS; baseline: 2002–2009) and the Shanghai Women’s Health Study and Shanghai Men’s Health Study (SWHS/SMHS; baseline: 1996–2000 and 2002–2006). In-silico validation was conducted in the Atherosclerosis Risk in Communities Study (ARIC; N = 3,539; 663 cases; baseline: 1987–1989) and Multi-Ethnic Study of Atherosclerosis (MESA; N = 3,860; 446 cases; baseline: 2000–2002). Lastly, a quantitative assay was developed and applied to a new set of 864 cases and 864 age-/sex-/race-matched controls (~260−340 pairs per race) from the SCCS and SWHS/SMHS. Conditional logistic regression estimated odds ratios (ORs) of incident CHD per standard deviation (SD) metabolite increase in discovery and quantitative stages with a nested case-control design. Cox regression was used in ARIC and MESA with a cohort design. Similar covariates were adjusted across stages, including age, sex (if applicable), race (if applicable), education, income, smoking status, alcohol consumption, physical activity, diet quality, and body mass index (BMI). The mean (SD) time between enrollment and CHD diagnosis was 5.6 (3.8), 6.9 (4.4), 15.0 (7.4), and 8.0 (4.9) years in the SCCS, SWHS/SMHS, ARIC, and MESA, respectively. The discovery stage identified 73 circulating microbiota-related metabolites associated with incident CHD (false discovery rate <0.10). Sixty-one metabolites were available for in-silico validation, of which 24 showed a significant association ( p < 0.05) in the same direction as in the discovery. The targeted assay quantified eight of the 24 metabolites, with five significantly associated with incident CHD: imidazole propionate, 3-hydroxy-2-ethylpropionate, 4-hydroxyphenylacetate, trans- 4-hydroxyproline, and 3-hydroxybutyrate; OR per SD ranged from 1.18 to 1.27 after adjustment for sociodemographics, lifestyles, and BMI. The targeted assay measured eight other promising microbial metabolites, four of which were significant: trimethylamine N-oxide, phenylacetyl-L-glutamine, 4-hydroxyhippuric acid, and indolepropionate. Most associations were consistent across participant subgroups by demographics, lifestyles, metabolic disease history, family CHD history, and follow-up time, although some potential effect modifications were found by race, age, obesity status, and follow-up time. The main limitations of the study are the observational design and the inability to validate all significant metabolites due to differences in metabolomic assay coverage across the three stages. Conclusions We identified and validated circulating gut microbial metabolites associated with incident CHD across diverse populations. Our findings offer novel epidemiological evidence on the importance of gut microbial metabolism in CHD development and highlight specific metabolites to prioritize for mechanistic investigation, biomarker validation, and therapeutic development.
Olayinka J Agboola, Jeffrey S K Chan, Jared A Spitz
et al.
Abstract Aims Chronic inflammation has been implicated in renal decline, but long-term population-based data are limited. We aimed to evaluate the associations between baseline inflammatory markers [interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] and long-term renal function decline and incident chronic kidney disease (CKD). Methods and results This prospective cohort study included participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with estimated glomerular function (eGFR) > 60 mL/min/1.73 m2 and available IL-6 and hsCRP measurements at visit 1. Outcomes included longitudinal changes in eGFR and log-transformed urinary albumin–creatinine ratio [log(UACR)] through visit 5, and incident CKD through 2018. Mixed-effect linear regression models assessed renal function decline. Fine-Gray regression was used to model incident CKD, accounting for competing mortality. Among 4680 (hsCRP) and 4580 (IL-6) participants (median follow-up for incident CKD: 16.8 years), higher IL-6 was consistently associated with faster eGFR decline [tertile 3 (T3; vs. T1): −0.32 mL/min/1.73m2/year (95% CI: 0.23–0.42 mL/min/1.73m2/year), P < 0.001] greater log[UACR] increase [T3: 6.67 × 10−3 unit/year (2.95 × 10–3–10.39 × 10−3 unit/year), P < 0.001], and higher CKD incidence [T3: sub-hazard ratio 1.65 (1.23–2.20), P = 0.001]. Contrastingly, hsCRP exhibited weaker and inconsistent associations. Conclusion Elevated IL-6 predicts greater long-term eGFR decline, worsening albuminuria, and higher CKD risk. These results highlight IL-6’s potential as a renal risk biomarker, meriting further study in cardiovascular–kidney–metabolic (CKM) syndromes. Lay summary This study investigated how inflammation is related to deteriorations in kidney function and the occurrence of chronic (long-term) kidney disease (CKD), both of which are critical components of the cardiovascular–kidney–metabolic (CKM) syndrome. Using data from the Multi-Ethnic Study of Atherosclerosis, over 4500 volunteers had inflammation markers measured and were followed for almost 17 years. We found that higher levels of inflammation were correlated with worse deterioration in kidney function and higher risks of developing CKD. These findings reaffirmed the pivotal role of inflammation in the long-term development of kidney disease. This study highlights the need for further investigation of how inflammatory markers can be used to predict future heart and kidney disease, especially as new drugs to treat inflammation are being developed.
Gen-Min Lin, Donald M. Lloyd-Jones, Laura A. Colangelo
et al.
Abstract Aims There are no studies on the association between secondhand smoke (SHS) exposure and incident heart failure (HF). This cohort study aimed to examine the associations of self-reported and urinary cotinine-assessed SHS exposure with incident HF. Methods and results This study included 5548 non-active smoking participants aged 45–84 years and free of known cardiovascular diseases and HF at baseline who self-reported SHS exposure time in the Multi-Ethnic Study of Atherosclerosis (MESA) at baseline (2000–2002). A cohort subset of 3376 non-active smoking participants underwent urinary cotinine measurements. HF events were verified by medical records or death certificates and ascertained from baseline through 2019. Multivariable Cox proportional hazards regression analysis was used with adjustment for demographic variables, traditional cardiovascular risk factors, physical activity, tobacco pack-years and medications. During a median follow-up of 17.7 years, 353 and 196 HF events were identified in the self-report cohort and cohort subset, respectively. In the self-report cohort, compared with the SHS unexposed group (0 h/week), the highest tertile of the SHS exposed group (7–168 h/week) was not associated with incident HF (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49–1.00; p = 0.052). In contrast, in the cohort subset, participants with detectable urinary cotinine >7.07 ng/ml had a higher risk of incident HF than those with undetectable urinary cotinine ≤7.07 ng/ml (HR 1.45, 95% CI 1.03–2.06; p = 0.034). There were no significant heterogeneities in HF risk by age, sex, race/ethnicity, or past smoking status. Conclusion Secondhand smoke exposure reflected by modestly increased urinary cotinine (>7.07 ng/ml) rather than self-report in non-active smokers was associated with a 40–50% higher risk of any HF event.
Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): United Christian Hospital Ruttonjee and Tang Siu Kin Hospitals Background Better risk stratification in pulmonary hypertension (PH) by echocardiography (echo) to detect ventricular vascular uncoupling may act as gate-keeper for downstream management, such as MRI and expensive therapies. Studies showed modest correlation found between RV peak global longitudinal strain (RVGLS), which is afterload dependent, and right ventricular ejection fraction (RVEF) Purpose To test the accuracy and optimal cut-off of echo derived mean PA pressure-to-RVGLS ratio against MRI detected severe RV dysfunction (defined as RVEF< 35%), RV dilatation (defined as RVEDVi >87ml), and correlate native T1-values (nT1) Method Strain analyses by echo and volumetric assessment by 1.5 tesla MRI were performed in all patients. Contoured MRI short axis images provided RVEF. In a subgroup of pulmonary arterial hypertension (PAH), right heart catheterization and MRI non-contrast native T1 mapping were performed (Figure 1). Using previous study data, to identify a difference of 1.8 pressure-to-strain ratio between mild and severe PH with a variance of 2.2 , power of 80% and a significance level of 0.05, a total of 11 participants per group were needed Result Thirty-one PH patients (13 female, age 60 ± 14y, 13 had PAH) were recruited prospectively. Strong correlation was demonstrated between the mean PA pressure-to-RVGLS ratio to MRI derived RVEF (r = 0.80, p < 0.01), and to catheterization derived pulmonary vascular resistance and indexed cardiac output (r = -0.80, p= 0.001; r= -0.75, p = 0.003 respectively). The cut-off value of -2.5 had best accuracy in ROC analyses (Table 1) In PAH patients, this ratio correlated with global nT1 at basal short-axis level (r= -0.91, p = 0.004), but not at the mid short-axis level. Their basal posterior interventricular insertion regions had significantly higher nT1 than those of age-matched normal controls at the same region on the same scanner (1256 ± 217 ms vs. 932 ± 25 ms, p = 0.04) Conclusion In terms of detection of severe right ventricular dysfunction by echocardiography, mean PA pressure-to-RVGLS ratio performed better than RVGLS alone, and a ratio cutoff of -2.5 predicts MRI determined ventricular vascular uncoupling in pulmonary hypertension Table 1 Echo detect MRI AUC standard error 95% CI sens (%) spec (%) p Mean PA pressure -to-RVGLS ratio RVEF < 35% 0.86 0.073 0.71-1.00 72 83 0.007 RVEDVi > 87ml 0.81 0.081 0.65-0.97 83 70 0.004 RVGLS RVEF < 35% 0.76 0.100 0.57-0.96 60 83 0.048 RVEDVi > 87ml 0.73 0.090 0.55-0.91 67 70 0.032 PA pulmonary artery; RVGLS: RV global longitudinal strain; RVEDVi: indexed RV end-diastolic volume Abstract Figure 1
Denis Talbot, Joseph A. (Chris) Delaney, Veit Sandfort
et al.
AbstractPurposeEstimating how much of the impact of statins on coronary heart diseases (CHD), cardiovascular disease (CVD), and mortality risk is attributable to their effect on low‐density lipoprotein cholesterol (LDL), high‐density lipoprotein cholesterol (HDL), and triglycerides.MethodsA semi‐parametric g‐formula estimator together with data from the Multi‐Ethnic Study of Atherosclerosis (a prospective multi‐center cohort study) was utilized to perform a mediation analysis. A total of 5280 participants, men and women of various race/ethnicities from multiple sites across the United States, were considered in the current study.ResultsThe adherence adjusted total relative risk reduction (RRR) estimate (95% confidence interval) of statins on CHD was 14% (−16%, 37%), and the indirect component through LDL was 23% (−4%, 58%). For CVD, the total RRR was 23% (2%, 40%), and the indirect component through LDL was 5% (−13%, 25%). The total RRR of mortality was 18% (−1%, 35%), and the indirect component through LDL was −4% (−17%, 12%). The estimated indirect components through HDL and triglycerides were close to zero with narrow confidence intervals for all 3 outcomes.ConclusionsThe estimated effect of statins on mortality, CVD, and CHD appeared to be independent of their estimated effect on HDL and triglycerides. Our study provides evidence that the preventive effect of statins on CHD could be attributed in large part to their effect on LDL. Our g‐formula estimator is a promising approach to elucidate pathways, even if it is hard to make firm conclusions for the LDL pathway on mortality and CVD.
AbstractBACKGROUNDA number of lipoprotein(a) [Lp(a)] analytical techniques are available that quantify distinct particle components, yet their clinical efficacy has not been comprehensively evaluated. This study determined whether Lp(a) mass [Lp(a)-M], Lp(a) cholesterol content [Lp(a)-C], and particle concentration [Lp(a)-P] differentially discriminated risk of calcific aortic valve disease (CAVD) or incident coronary heart disease (CHD) among 4679 participants of the Multi-Ethnic Study of Atherosclerosis (MESA).METHODSLp(a)-M, Lp(a)-C, and Lp(a)-P were measured in individuals without clinical evidence of CHD at baseline. Relative risk regression and Cox proportional analysis determined associations between Lp(a) and the presence of CAVD or 12-year risk of CHD, respectively. To control for the relatively high lower limits of quantification for Lp(a)-C and Lp(a)-P assays, the upper 25th and 15th percentiles were selected as analytical cutoff points.RESULTSRegardless of method or analytical cutoff, high Lp(a) concentrations were significantly associated with CAVD and CHD in MESA participants following adjustment for typical cardiovascular risk factors. Stratifying by race/ethnicity rendered most associations nonsignificant after correction for multiple comparisons, but Lp(a) remained associated with CAVD in whites irrespective of method (all P < 0.0001).CONCLUSIONSAssociations of Lp(a)-C, Lp(a)-P, and Lp(a)-M with CAVD or incident CHD were similar in this entire MESA sample using a dichotomized statistical approach. However, the high lower limits of quantification and imprecision of the Lp(a)-C and Lp(a)-P assays limited their usefulness in our analyses and would likely do so in research and clinical settings.
Significance Therapies for myocardial infarction consequent to ischemia/reperfusion injury (I/R) have been lacking. The netrin-1 receptor deleted in colorectal cancer (DCC) mediates netrin-1–dependent cardioprotective signaling. It is anticipated that any means of augmenting DCC signaling may induce cardioprotection on its own and enhance netrin-1/NO–dependent cardioprotection. The present study identifies a novel mechanism by which NO upregulates DCC abundance. NO inhibits seven in absentia homolog (SIAH), an E3 ubiquitin ligase that suppresses DCC. Inhibition of SIAH by in vivo RNA interference markedly reduces infarct size to improve cardiac function that was determined by echocardiography. Combined with netrin-1 perfusion, it further potentiated netrin-1’s cardioprotective effect. SIAH may therefore serve as a novel therapeutic target for myocardial infarction, particularly those suffering from cardiac I/R injury.