High-Sensitivity Cardiac Troponin T and Cardiovascular Risk After Ischemic Stroke or Transient Ischemic Attack.

Background: High-sensitivity cardiac troponin T (hs-cTnT) is associated with cardiovascular disease (CVD) risk in general and various high-risk populations. Objectives: The purpose of this study was to precisely characterize the association of hs-cTnT with CVD risk in patients following acute ischemic stroke or transient ischemic attack. Methods: We conducted post hoc analyses of data from the STROKE-CARD trial (NCT02156778), a pragmatic randomized controlled trial of a disease management program in patients with acute ischemic stroke or transient ischemic attack (ABCD2 score ≥3). We measured hs-cTnT on admission (Roche Elecsys, detection limit 5 ng/L) and quantified HRs for a composite CVD outcome (ie, stroke, myocardial infarction, CVD death) adjusted for age, sex, prior coronary heart disease, prior heart failure, diabetes, smoking, systolic blood pressure, and low- and high-density-lipoprotein cholesterol. Results: Among 1,687 patients (mean age, 69.3 ± 13.7 years; 40.7% female), hs-cTnT was detectable in 80.7%. Median hs-cTnT was 10 ng/L (IQR: 6-18 ng/L). Over a median follow-up of 12.1 months, 110 patients had a CVD event. The association of hs-cTnT level with CVD risk was of log-linear shape, with a multivariable-adjusted HR of 1.40 (95% CI: 1.15-1.70; P < 0.001) per 1-SD higher log-transformed hs-cTnT value. The strength of association was similar when further adjusted for other potential confounders and across clinically relevant subgroups. Corresponding outcome-specific HRs were 1.33 (95% CI: 1.06-1.68; P = 0.016) for stroke, 1.28 (95% CI: 0.69-2.37; P = 0.430) for myocardial infarction, 1.98 (95% CI: 1.43-2.73; P < 0.001) for CVD death, and 1.93 (95% CI: 1.54-2.41; P < 0.001) for all-cause death. Conclusions: High hs-cTnT is associated with increased CVD risk in ischemic stroke and transient ischemic attack patients.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian Randomisation study.

Background: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. Aims: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. Methods: We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. Results: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Conclusions: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian randomization study.

BACKGROUND: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. AIMS: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. METHODS: We conducted a sex-specific two-sample Mendelian randomization study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e. aSAH and unruptured IA combined) as outcomes. RESULTS: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (p-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (p-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (p-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. CONCLUSIONS: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

Association of desphospho-uncarboxylated matrix gla protein with incident cardiovascular disease and all-cause mortality: Results from the prospective Bruneck Study.

BACKGROUND AND AIMS: Matrix Gla protein (MGP), a vitamin K-dependent protein, is a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP), a marker of vitamin K insufficiency, has been shown to predict cardiovascular disease (CVD) and all-cause mortality in high-risk populations. Whether the increased risk associated with dp-ucMGP also applies to the general, and especially, the elderly population has not yet been fully elucidated. METHODS AND RESULTS: Plasma dp-ucMGP was measured in 684 individuals aged 50-89 years of the prospective population-based Bruneck Study (baseline evaluation in 2000). Baseline median dp-ucMGP was 478.4 (IQR 335.0-635.2) pmol/L. Over a median follow-up of 15.5 years, 163 CVD events occurred and 235 participants died. Age-/sex-adjusted hazard ratios (HRs) per 1-SD higher level of loge transformed dp-ucMGP were 1.30 (95%CI: 1.09-1.55; p=0.004) for incident CVD and 1.36 (95%CI: 1.17-1.57; p<0.001) for all-cause mortality. After multivariable adjustment, the associations remained significant with HRs of 1.23 (95%CI: 1.02-1.47, p=0.029) for CVD and 1.40 (95%CI: 1.20-1.64; p<0.001) for all-cause mortality. The associations remained virtually unchanged after additional adjustment for dietary quality as measured with the Alternative Healthy Eating Index. We found no association of dp-ucMGP with myocardial infarction and sudden cardiac deaths, but a strong association with other vascular deaths and non-vascular/non-cancer deaths. CONCLUSIONS: This study shows a significant association of plasma dp-ucMGP with incident CVD and a significant and even stronger association with all-cause mortality. Clinical trials are needed to investigate whether vitamin K substitution results in improved health outcomes.

Breastfeeding Is Associated With a Reduced Maternal Cardiovascular Risk: Systematic Review and Meta-Analysis Involving Data From 8 Studies and 1 192 700 Parous Women.

Background Breastfeeding has been robustly linked to reduced maternal risk of breast cancer, ovarian cancer, and type 2 diabetes. We herein systematically reviewed the published evidence on the association of breastfeeding with maternal risk of cardiovascular disease (CVD) outcomes. Methods and Results Our systematic search of PubMed and Web of Science of articles published up to April 16, 2021, identified 8 relevant prospective studies involving 1 192 700 parous women (weighted mean age: 51.3 years at study entry, 24.6 years at first birth; weighted mean number of births: 2.3). A total of 982 566 women (82%) reported having ever breastfed (weighted mean lifetime duration of breastfeeding: 15.6 months). During a weighted median follow-up of 10.3 years, 54 226 CVD, 26 913 coronary heart disease, 30 843 stroke, and 10 766 fatal CVD events were recorded. In a random-effects meta-analysis, the pooled multivariable-adjusted hazard ratios comparing parous women who ever breastfed to those who never breastfed were 0.89 for CVD (95% CI, 0.83-0.95; I2=79.4%), 0.86 for coronary heart disease (95% CI, 0.78-0.95; I2=79.7%), 0.88 for stroke (95% CI, 0.79-0.99; I2=79.6%), and 0.83 for fatal CVD (95% CI, 0.76-0.92; I2=47.7%). The quality of the evidence assessed with the Grading of Recommendations Assessment, Development, and Evaluation tool ranged from very low to moderate, which was mainly driven by high between-studies heterogeneity. Strengths of associations did not differ by mean age at study entry, median follow-up duration, mean parity, level of adjustment, study quality, or geographical region. A progressive risk reduction of all CVD outcomes with lifetime durations of breastfeeding from 0 up to 12 months was found, with some uncertainty about shapes of associations for longer durations. Conclusions Breastfeeding was associated with reduced maternal risk of CVD outcomes.

The dimension of preventable stroke in a large representative patient cohort.

OBJECTIVE: To analyze the frequency of inadequately treated risk factors in a large representative cohort of patients with acute ischemic stroke or TIA and to estimate the proportion of events potentially avertable by guideline-compliant preventive therapy compared to the status quo. METHODS: A total of 1,730 patients from the Poststroke Disease Management STROKE-CARD trial (NCT02156778) were recruited between 2014 and 2017. We focused on 8 risk conditions amenable to drug therapy and 3 lifestyle risk behaviors and assessed pre-event risk factor control in retrospect. RESULTS: The proportion of patients with at least 1 inadequately treated risk condition was 79.5% (95% confidence interval [CI] 77.6%-81.4%) and increased to 95.1% (95% CI 94.1%-96.1%) upon consideration of the lifestyle risk behaviors. Risk factor control was worse in patients with recurrent vs first-ever events (p < 0.001), men vs women (p = 0.003), and patients ≤75 vs >75 years of age (p < 0.001). The estimated degree of stroke preventability ranged from 0.4% (95% CI 0.2%-0.6%) to 13.7% (95% CI 12.2%-15.2%) for the individual risk factors. Adequate control of the 5 most relevant risk factors combined (hypertension, hypercholesterolemia, atrial fibrillation, smoking, and overweight) would have averted ≈1 of 2 events or 1 in 4 with a highly conservative computation approach. CONCLUSIONS: Our study confirms the existence of a considerable gap between risk factor control recommended by guidelines and real-world stroke prevention. Our study intends to increase awareness among physicians about stroke preventability and provides a quantitative basis for the emerging discussion on how to best tackle this challenge.

Osteoprotegerin and Cardiovascular Events in High-Risk Populations: Meta-Analysis of 19 Prospective Studies Involving 27 450 Participants.

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias ( P value from Egger's test=0.013). Correction for publication bias using the trim-and-fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03-1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow-up. Conclusions In populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants.

BACKGROUND: Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population. METHODS: Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis. RESULTS: When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05). CONCLUSIONS: Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.