@article {7448, title = {PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, pages = {e001632}, abstract = {

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3\%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1\%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95\% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95\% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95\% CI, 0.28-0.92) in blacks and 0.82 (95\% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95\% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95\% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001632}, author = {Kent, Shia T and Rosenson, Robert S and Avery, Christy L and Chen, Yii-der I and Correa, Adolfo and Cummings, Steven R and Cupples, L Adrienne and Cushman, Mary and Evans, Daniel S and Gudnason, Vilmundur and Harris, Tamara B and Howard, George and Irvin, Marguerite R and Judd, Suzanne E and Jukema, J Wouter and Lange, Leslie and Levitan, Emily B and Li, Xiaohui and Liu, Yongmei and Post, Wendy S and Postmus, Iris and Psaty, Bruce M and Rotter, Jerome I and Safford, Monika M and Sitlani, Colleen M and Smith, Albert V and Stewart, James D and Trompet, Stella and Sun, Fangui and Vasan, Ramachandran S and Woolley, J Michael and Whitsel, Eric A and Wiggins, Kerri L and Wilson, James G and Muntner, Paul} } @article {7931, title = {Validation of the REGARDS Severe Sepsis Risk Score.}, journal = {J Clin Med}, volume = {7}, year = {2018}, month = {2018 Dec 11}, abstract = {

There are no validated systems for characterizing long-term risk of severe sepsis in community-dwelling adults. We tested the ability of the REasons for Geographic and Racial Differences in Stroke-Severe Sepsis Risk Score (REGARDS-SSRS) to predict 10-year severe sepsis risk in separate cohorts of community-dwelling adults. We internally tested the REGARDS-SSRS on the REGARDS-Medicare subcohort. We then externally validated the REGARDS-SSRS using (1) the Cardiovascular Health Study (CHS) and (2) the Atherosclerosis Risk in Communities (ARIC) cohorts. Participants included community-dwelling adults: REGARDS-Medicare, age >=65 years, = 9522; CHS, age >=65 years, = 5888; ARIC, age 45$^{-}$64 years, = 11,584. The primary exposure was 10-year severe sepsis risk, predicted by the REGARDS-SSRS from participant sociodemographics, health behaviors, chronic medical conditions and select biomarkers. The primary outcome was first severe sepsis hospitalizations, defined as the concurrent presence of ICD-9 discharge diagnoses for a serious infection and organ dysfunction. Median SSRS in the cohorts were: REGARDS-Medicare 11 points (IQR 7$^{-}$16), CHS 10 (IQR 6$^{-}$15), ARIC 7 (IQR 5$^{-}$10). Severe sepsis incidence rates were: REGARDS-Medicare 30.7 per 1000 person-years (95\% CI: 29.2$^{-}$32.2); CHS 11.9 (10.9$^{-}$12.9); ARIC 6.8 (6.3$^{-}$7.3). SSRS discrimination for first severe sepsis events were: REGARDS-Medicare C-statistic 0.704 (95\% CI: 0.691$^{-}$0.718), CHS 0.696 (0.675$^{-}$0.716), ARIC 0.697 (0.677$^{-}$0.716). The REGARDS-SRSS may potentially play a role in identifying community-dwelling adults at high severe sepsis risk.

}, issn = {2077-0383}, doi = {10.3390/jcm7120536}, author = {Wang, Henry E and Donnelly, John P and Yende, Sachin and Levitan, Emily B and Shapiro, Nathan I and Dai, Yuling and Zhao, Hong and Heiss, Gerardo and Odden, Michelle and Newman, Anne and Safford, Monika} } @article {8786, title = {Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies.}, journal = {JAMA Neurol}, volume = {78}, year = {2021}, month = {2021 Jul 01}, pages = {809-816}, abstract = {

Importance: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown.

Objective: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction.

Design, Setting, and Participants: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020.

Exposure: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria.

Main Outcomes and Measures: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications.

Results: Of 55 131 participants, 47 866 (27 639 women [57.7\%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95\% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95\% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95\% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95\% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95\% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95\% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95\% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95\% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95\% CI, 1.1-2.1).

Conclusions and Relevance: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2021.0925}, author = {Murthy, Santosh B and Zhang, Cenai and Diaz, Ivan and Levitan, Emily B and Koton, Silvia and Bartz, Traci M and DeRosa, Janet T and Strobino, Kevin and Colantonio, Lisandro D and Iadecola, Costantino and Safford, Monika M and Howard, Virginia J and Longstreth, W T and Gottesman, Rebecca F and Sacco, Ralph L and Elkind, Mitchell S V and Howard, George and Kamel, Hooman} }