Viola Vaccarino

Background: Insulin and C-peptide are co-secreted from pancreatic β-cells in equimolar amounts but cleared differently; insulin via first-pass hepatic extraction, C-peptide via the kidneys. Whether discordance between these metabolites, estimated as the fasting C-peptide:insulin ratio, identifies cardiovascular risk in adults without diabetes is unknown.Methods: In the Emory Cardiovascular Biobank, a cohort with suspected or established coronary artery disease, with external validation in the National Health and Nutrition Examination Survey (NHANES), we examined associations of the fasting C-peptide:insulin molar ratio with major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction or stroke, or heart-failure hospitalization) and all-cause death in adults without diabetes. Using clinical cutpoints, three phenotypes were compared: low C-peptide (<3·0 ng/mL; reference); insulin-resistant (C-peptide ≥3·0 ng/mL and insulin ≥12 µU/mL); and discordant (C-peptide ≥3·0 ng/mL and insulin <12 µU/mL). Cox and Fine-Gray models were adjusted for demographic, clinical, and inflammatory covariates.Findings: Among 3,211 participants (63% men, mean age 64) followed for a median of 8 years with 709 MACE, each 1-SD higher log C-peptide:insulin ratio was independently associated with higher MACE risk (sHR 1.26, 95% CI 1.13–1.41) after full adjustment. The discordant phenotype (7% of total) carried the highest MACE risk (HR 1.40, 1.07–1.83), with intermediate risk in the insulin-resistant group (21% of total) (HR 1.28, 1.06–1.56) compared to the low C-peptide reference. Adding the ratio improved MACE discrimination (continuous NRI 0.30; IDI 0.011; both p<0.001). Interpretation: The fasting C-peptide:insulin ratio identifies a high-risk metabolic phenotype in adults without diabetes. Whether treatment with SGLT-2 or GLP-1 agents will modify this risk warrants evaluation.Findings: were similar in NHANES and for all-cause death.

Background: Young and middle‐aged women with ischemic heart disease have a higher burden of psychosocial factors compared with male counterparts. They also have worse morbidity and mortality, despite less atherosclerotic burden. Data on daily life stress and autonomic physiology could help guide targeted interventions. Methods: We studied 302 individuals ≤61 years of age recently hospitalized for a myocardial infarction. All underwent a 7‐day home monitoring of mood and stress using ecological momentary assessments, with concomitant Holter monitoring for autonomic physiology. Deceleration capacity, a prognostic marker of parasympathetic activity, was the primary autonomic outcome; heart rate variability was also examined. Results: The sample was 43% women with mean age of 51 years (SD, 7 years). Across the week of monitoring, women reported higher levels of negative mood and stress than men. Women also exhibited significantly lower parasympathetic activity (daily average of deceleration capacity) than men; heart rate variability was also lower. Among women, daily negative mood was inversely associated with lower deceleration capacity: for each 1‐log unit higher daily negative mood score, deceleration capacity declined 4.5% in women, but among men, the difference was close to zero: 0.5% ( P =0.02 for interaction). Adjustment for other risk factors did not materially affect the associations. A similar pattern of results was observed for heart rate variability metrics. Conclusions: Young and middle‐aged women who recently survived a myocardial infarction have more parasympathetic withdrawal than men in daily life, especially during moments of negative mood. These results underscore the need for greater attention to psychosocial management in women after myocardial infarction.

Background: Women with premature myocardial infarction (MI) have worse outcomes than similarly aged men despite less severe disease, and stress-related factors have been implicated. We examined sex differences in the association of mental stress-induced myocardial ischemia (MSIMI) with cardiovascular outcomes after premature MI and explored vascular and inflammatory mechanisms. Methods: We studied 602 individuals (mean age 51 years; 46% women) within 8 months of MI who underwent 99mTc-sestamibi myocardial perfusion imaging at rest and after mental stress. MSIMI was defined as a summed difference score ≥3. We measured reactive hyperemia index (RHI) as peripheral microvascular reactivity to stress and interleukin-6 (IL-6) as inflammatory response to stress. The primary endpoint was cardiovascular death or nonfatal MI; the secondary endpoint added heart failure hospitalization. Cox proportional hazards models adjusted for sociodemographic factors, clinical, and psychiatric history. Results: MSIMI was more common in women than men (19.2% vs. 13.2%, p=0.04). Over a median follow-up of 34.2 months, 51 primary and 91 secondary endpoint events occurred. The hazard ratio (HR) of MSIMI for the primary endpoint was 3.2 (95% CI, 1.3, 7.6) in women and 1.9 (95% CI, 0.8, 4.5) in men (p for interaction=0.41), which remained similar after multivariable adjustment. The adjusted population attributable fraction was 27.6% (99% CI, 3.9%, 36.9%) in women and 11.1% (95% CI, −5.8%, 18.4%) in men. In exploratory analyses, all MSIMI-related primary endpoint events among women occurred in Black women (HR, 4.3; 95% CI, 1.7–11.1). Associations with the secondary endpoint were weaker and attenuated after adjustment. IL-6 and RHI responses did not attenuate associations. Conclusions: Among women, MSIMI was associated with about threefold increased risk and over one quarter attributable fraction for cardiovascular death or nonfatal MI. Black women were at especially high risk. While larger studies are warranted to confirm sex differences and explore mechanisms, these data underscore the impact of emotional factors on morbidity and mortality in post-MI women.

Background: Information is lacking about everyday psychological states of individuals with a recent myocardial infarction (MI) and whether they influence outcomes. We investigated real world psychological experiences and their association with subsequent cardiovascular events in survivors of an MI. Methods: We studied 287 individuals ≤ 60 years of age within 8 months from an MI. At the baseline visit, we assessed sociodemographic and clinical factors, and administered a battery of psychological scales of depression, anxiety, anger, perceived stress and social support. Participants underwent a 7-day home monitoring of mood and stress using ecological momentary assessments, and a momentary negative affect (MNA) score, integrating daily mean ratings of sadness, anxiety, anger, distress and loneliness, was calculated. Participants were followed for a median time of 28 months. The study endpoint was a composite index of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal MI, stroke or hospitalizations for heart failure. Cox proportional hazards models adjusted for sociodemographic and clinical factors. Results: The mean age of the sample was 51 years, and 43% of participants were women. Each standard deviation increase in MNA was significantly associated with a 60% increased risk of MACE (95% confidence interval (CI), 20% to 100%), irrespective of adjustment for sociodemographic factors and clinical characteristics. The association was similar in women and men. Momentary positive mood and momentary perceived stress were not associated with MACE. The MNA score showed a larger independent contribution to MACE compared to the combined battery of baseline psychological assessments and the association was independent of baseline history of depression. Conclusion: Among individuals after MI, moment-to-moment negative affect during one week of monitoring in daily life is a powerful predictor of subsequent cardiovascular events. A prospective evaluation of negative mood during everyday living could represent a novel strategy to uncover residual risk after MI.

1. Despite major advances in identifying risk factors and elucidating the pathophysiology of cardiovascular disease (CVD), this condition remains a leading cause of illness and death in the United ...

Heart failure (HF) affects 6.7 million people in the US and includes two major subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), with distinct genetic architectures. We meta-analyze genome-wide association studies (GWAS) of 38,781 HFrEF cases, 38,163 HFpEF cases, and 526,135 controls across European, African, Hispanic, and Asian ancestries using the Million Veteran Program and Vanderbilt University DNA Databank (BioVU). We identify 46 genome-wide significant loci for HFrEF (9 novel) and 3 loci for HFpEF (1 novel). Four HFrEF loci are detected in African ancestry participants near CD36, SPI1, TRIM48 , and SPNS3 , with lead SNPs showing low risk-allele frequencies in European populations. In the all-cause HF meta-analysis (200,070 cases, 2,076,466 controls), we identify 136 loci (12 novel). Gene-based tests, tissue enrichment, transcriptome-wide association, and fine-mapping implicate vascular, metabolic, and TGF-β/Smad signaling pathways and nominate candidate causal genes, clarifying shared and subtype-specific risk across ancestries.

Background/Objectives: Human immunodeficiency virus (HIV) infection is characterized by chronic systemic inflammation. Antiretroviral therapy (ART) can reduce persistent inflammation, as measured by C-reactive protein (CRP). The CRP methylation risk score (MRS_CRP) acts as proxy for plasma CRP, but longitudinal changes in this score for people with HIV (PWH) before and after initiating ART have not been described. Methods: We evaluated a previously published MRS_CRP in the Emory Twin Study (N = 352), testing its correlation with plasma CRP and CRP-responsive biomarkers, as well as associations with cardiometabolic traits using generalized estimating equations (GEEs). We then applied MRS_CRP in the HIV AIDS Drug Resistance Surveillance Study (ADReSS) cohort (N = 440) to assess longitudinal changes before and after ART, using paired t-tests and linear mixed-effects models. Results: MRS_CRP showed moderate correlation with CRP (r = 0.38) and other inflammatory biomarkers (r = 0.25–0.34). MRS_CRP was associated with hypertension, type 2 diabetes, coronary artery disease, and obesity, and remained independently associated with obesity (odds ratio = 1.49) after adjusting for measured CRP. Z-score-standardized MRS_CRP decreased by 0.254 standard deviation units between baseline and follow-up among PWH receiving ART, confirmed by linear mixed-effects models. Conclusions: MRS_CRP showed associations with chronic inflammation and cardiometabolic diseases. The observed decline in MRS_CRP following ART initiation may reflect changes in inflammatory status among PWH. These findings highlight the potential of MRS_CRP as a marker of inflammation-related changes and comorbidity risk in PWH.

Cognitive impairment and Alzheimer disease and related dementias are increasingly prevalent and carry significant morbidity. Growing evidence has highlighted the complex interactions between cardiovascular and brain health, implicating vascular dysfunction in the pathogenesis of many forms of cognitive impairment. The American Heart Association (AHA) and the American Stroke Association have outlined a comprehensive framework, known as Life's Essential 8, that includes 4 behavioral health factors (healthy dietary pattern, physical activity, avoidance of nicotine, and healthy sleep) and 4 health factors (cholesterol, blood glucose, blood pressure, body mass index) that collectively define optimum cardiovascular health. Modifiable risk factors account for an estimated 40% of worldwide dementia. Adherence to Life's Essential 8 principles may also help individuals mitigate the risk of cognitive impairment via improved cardiovascular health. However, a comprehensive understanding of the causal relationships between vascular and behavioral risk factors and Alzheimer disease and related dementias remains unclear and requires further study. This narrative review summarizes well‐established data and highlights new data for how health and behavioral factors included in Life's Essential 8 also promote optimal brain and cognitive health.

To enable timely intervention and reduce risk of returning to use in individuals with opioid use disorder (OUD), there is a need to monitor opioid withdrawal severity using physiological biomarkers. However, in the context of opioid withdrawal, prior studies have relied on data recorded in controlled lab settings over short periods of time and have only focused on a limited set of biomarkers. To address these limitations, using multimodal wearable signals, we extracted and characterized 32 cardiorespiratory features from 16 individuals with OUD experiencing varying levels of withdrawal severity over a 7-day period. Across all participants, we found statistically significant ( p < 0.05) differences in 6 features between high and low withdrawal. For machine learning-based classification of high vs. low withdrawal, we found that performance improved when leveraging respiratory-focused and sex-/BMI-stratified models (highest macro F1 of 0.812). Finally, in 14 out of 16 participants, at least 1 feature statistically significantly ( p < 0.1) tracked changes in withdrawal scores over the 7-day period. Therefore, our analyses of these features uncovered substantial phenotype sensitivity and physiological heterogeneity across the study cohort. These findings underscore the need for phenotype-aware and personalized modeling approaches for continuous, sensor-based monitoring of withdrawal severity in the future.