Zakaria Almuwaqqat

Background: This study evaluated the potential of plasma metabolites as novel biomarkers for secondary major adverse cardiovascular event (MACE) development and risk prediction in patients with coronary artery disease. Methods: We analyzed data from 10 175 UKB (UK Biobank) participants with coronary artery disease and metabolites (n=249) measured through nuclear magnetic resonance at baseline. Cross‐validated elastic net regression models were used in the training cohort (n=7122) to select metabolites to be included in the metabolomic risk score (MRS). Hazard ratios (HRs) were estimated to examine the association between MRS and MACEs (composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death) in the testing cohort (n=3053). Predictive performance of MRS was evaluated with C‐index and calibration plots. Results: Over a median follow‐up of 10 years, 1624 (16%) MACEs occurred. Elastic net regression identified 26 metabolites for construction of the MRS. Participants in the highest 20% of the MRS had significantly increased risk of MACEs (HR, 2.19 [95% CI, 1.61–2.99]) and cardiovascular death (HR, 3.69 [95% CI, 2.35–5.78]), compared with the lowest 20%, after adjusting for traditional risk factors. Adding MRS to a traditional risk factor model modestly improved the 10‐year MACE prediction (ΔC‐index: 0.012 [95% CI, −0.003 to 0.025]); calibration slopes (0.91 [95% CI, 0.79–1.03] versus 0.88 [95% CI, 0.74–1.02]). Conclusions: Metabolomic biomarkers are independently associated with and predict MACEs, particularly cardiovascular death, in middle‐aged individuals with coronary artery disease, providing valuable insights into the biological pathways underlying MACEs in high‐risk populations.

Background: Acute psychological stress may induce physiological changes predisposing individuals to adverse health outcomes through hemodynamic and vascular effects. We studied the association between the aggregated stress‐induced changes in hemodynamic and vascular function tests with adverse cardiovascular outcomes in patients with coronary artery disease, after adjusting for sociodemographic and clinical factors. Methods and Results: Individuals with stable coronary artery disease from 2 prospective cohort studies were studied. Hemodynamic reactivity, changes in endothelial function, and vasoconstriction during mental stress were evaluated using changes in rate‐pressure product, brachial artery flow‐mediated vasodilation, and peripheral arterial tonometry, respectively. A cardiovascular reactivity risk score was calculated by allotting 0 to 3 points for each quartile of increasing abnormality for each of the 3 reactivity responses and summing the quartile points from the MIPS (Mental Stress Ischemia Prognosis Study) to yield a cardiovascular reactivity risk score ranging from 0 to 9. The outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and heart failure hospitalizations during follow‐up. A total of 629 participants were included. After adjustment for demographic and traditional risk factors, a blunted hemodynamic response, a greater decrease in flow‐mediated vasodilation, and a greater degree of peripheral vasoconstriction to mental stress were all independently associated with a higher risk of adverse outcomes in both cohorts. By adding the cardiovascular reactivity risk score, the C‐statistic increased significantly by 10% ( P <0.001). Conclusions: Among individuals with stable coronary artery disease, a risk score derived from cardiovascular reactivity to mental stress was predictive of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with maladaptive dysregulation of stress response systems, which could lead to an increased risk of heart failure. We investigated whether PTSD was independently associated with first and recurrent heart failure hospitalizations in the setting of coronary artery disease. METHODS: Individuals with stable coronary artery disease and without heart failure at baseline were enrolled in 2 parallel prospective cohort studies in metropolitan Atlanta, GA. Participants underwent a structured clinical interview to assess their lifetime history of PTSD. Current PTSD symptoms were assessed using the PTSD symptom checklist. Participants were followed up for a median time of 4.9 years. The primary end point was first or recurrent hospitalization for heart failure. Secondary end points included cardiovascular death and nonfatal myocardial infarction with and without hospitalization for heart failure. Survival analysis for repeated events was used to assess the association of PTSD with adverse events. RESULTS: We studied 736 individuals with a mean age of 60±10 years; 36% were Black, and 35% were women. In total, 69 (9.4%) patients met the criteria for PTSD. Having a PTSD diagnosis was associated with the primary end point of first or recurrent heart failure hospitalizations, with a hazard ratio of 4.4 (95% CI, 2.6–7.3). The results were minimally attenuated after adjusting for demographic and clinical factors (hazard ratio, 3.7 [95% CI, 2.1–6.3]). Similarly, a 10-point increase in the PTSD symptom checklist score was associated with a 30% (95% CI, 10%–50%) increase in heart failure hospitalizations. PTSD was not associated with an end point of cardiovascular death or nonfatal myocardial infarction, which excluded hospitalizations due to heart failure. CONCLUSIONS: Among patients with coronary artery disease, PTSD is associated with incident and recurrent heart failure hospitalizations. Future research is needed to investigate whether PTSD management can reduce the risk of heart failure.

Background: Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. Methods and Results: This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24‐hour Holter ECGs. During an average 12‐year follow‐up, all‐cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1‐SD increase in log‐transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low‐frequency HRV and DC were significantly associated with lower hazards of all‐cause death. In within‐pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1‐SD increment in low‐frequency HRV and DC, respectively. Higher low‐frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. Conclusions: Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

Introduction: Cardiac allograft vasculopathy (CAV) limits long‐term survival in heart transplant (HTx) recipients. The use of biomarkers in CAV surveillance has been studied, but none are used in clinical practice. The predictive value of high‐sensitivity troponin I (hsTnI) has not been extensively investigated in HTx recipients.Methods: HTx patients undergoing surveillance coronary angiograms and enrolled in the Emory Cardiovascular Biobank had plasma hsTnI measured. CAV grade was assessed using ISHLT nomenclature. Multivariable cumulative link mixed modeling was performed to determine association between hsTnI level and CAV grade. Patients were followed for adverse outcomes over a median 10‐year period. Kaplan‐Meier survival analysis and Cox proportional hazard modeling were performed.Results: Three hundred and seventy‐two angiograms were analyzed in 156 patients at a median 8.9 years after transplant. hsTnI levels were positively correlated with concurrent CAV grade after adjustment for age, age at transplant, sex, BMI, hypertension, diabetes, hyperlipidemia, estimated glomerular filtration rate, and history of acute cellular rejection (p = .016). In an adjusted Cox proportional hazard model, initial hsTnI level above the median (4.9 pg/mL) remained a predictor of re‐transplantation or death (hazard ratio 1.82; 95% confidence interval 1.16–2.90; p = .01).Conclusion: An elevated hsTnI level reflects severity of CAV and is associated with poor long‐term outcomes in patients with HTx.

Background: Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. Methods: In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. Results: Of 263 patients (the mean age was 51 years; range, 25–61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05–2.13]; P =0.03) among women only (sex interaction: P =0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07–1.71]; P =0.01), and the association was similar in women and men. Conclusions: Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.