Rizwan Kalani

BACKGROUND: Ischemic stroke preventive therapies have been slow to emerge due to a limited understanding of the underlying molecular mechanisms. We aimed to discover new protein risk factors that are potential etiologic factors and may be candidates for therapeutic intervention. METHODS: We included ARIC study (Atherosclerosis Risk in Communities) and CHS (Cardiovascular Health Study) participants without prevalent stroke at the time of proteomic profiling (1990–1992 in ARIC and 1992–1993 in CHS). Relative concentrations of proteins in blood were assessed with aptamers (n=4954). Ischemic stroke events were adjudicated through 2019 in ARIC and 2015 in CHS. Study-specific Cox regression adjusting for ischemic stroke risk factors was used to estimate associations between proteins and incident ischemic stroke. Study-specific estimates were combined using fixed-effects meta-analysis. Replication was conducted in 2 independent cohorts (AGES-Reykjavik, UK Biobank). Proteins with a false discovery rate q value P −5 ), of which 26 are novel. In 2 independent cohorts, 37 (84%) associations were directionally concordant, and 26 (59%) met criteria for replication. Mendelian randomization analyses suggested MMP12 (matrix metallopeptidase-12) and CNTN1 (contactin-1) may be causally related to ischemic stroke risk. In multivariable Mendelian randomization analyses, higher MMP12 levels had a direct protective effect on ischemic stroke risk, while CNTN1 had a direct harmful effect. CONCLUSIONS: This proteomic and genomic investigation of ischemic stroke identified novel risk biomarkers and 2 potential etiologic CNTN1 factors that are regulated in response to atherosclerosis and obesity. If future studies confirm our findings, these results may have implications for the development of new preventive therapies.

Background: Atrial cardiomyopathy, defined as adverse changes to the cardiac atria, is an emerging risk factor for atrial fibrillation (AF). Despite the disproportionate burden of AF‐related complications in Black adults, the relationship between electrocardiographic (ECG) measures of atrial cardiomyopathy, referred to as P‐wave indices (PWIs), and outcomes remains largely unknown in this population. Methods: In 4900 participants without AF at baseline from the JHS (Jackson Heart Study), a prospective cohort study of Black adults, we assessed atrial cardiomyopathy using PWIs from resting 12‐lead ECGs: PR interval, P‐wave duration, P‐wave axis, and P‐wave terminal force in V1 (PTFV1). Cox proportional hazards models evaluated associations of PWIs with incident AF and ischemic stroke, adjusting for established risk factors. Results: Over 13.7 years of follow‐up, 396 (9.3%) participants developed incident AF, and 135 (3.8%) experienced ischemic stroke. Each SD‐unit increase in PR interval, P‐wave duration, and PTFV1 was associated with increased AF risk, with the strongest association for PTFV1 (hazard ratio [HR], 1.27 [95% CI, 1.16–1.38]). These PWIs were also associated with AF risk using clinically accepted thresholds, including HR of 1.76 for PTFV1 ≥4000 ms×μV (95%CI, 1.38–2.25). Each SD increase in PTFV1 was associated with a 22% increased risk of ischemic stroke (HR, 1.22 [95% CI, 1.07–1.40]). Conclusions: In this large cohort study of Black adults, PWIs, particularly PTFV1, were independently associated with an increased risk of incident AF and ischemic stroke. These findings underscore the significance of PTFV1 as an underlying marker of atrial cardiomyopathy in Black adults.