Lorraine Frazier

Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic

ABSTRACTBackground: The renin–angiotensin–aldosterone (RAA) system regulates blood pressure (BP) levels and influences responses to antihypertensive medications. Variation in RAA system genes has been reported to influence interindividual differences in BP levels and the occurrence of hypertension (HTN).Methods: We evaluated the relationship between variation in genes of the RAA system and interindividual differences in BP response to a thiazide diuretic. Analyses were carried out in a race- and gender-specific manner in 255 unrelated hypertensive African-Americans (125 men and 130 women) and 246 unrelated hypertensive non-Hispanic Whites (133 men and 113 women).Results: The angiotensin II receptor (AT1R) A1166C and angiotensinogen G-6A polymorphisms had a significant effect on systolic BP response to the diuretic in African-American women. Multilocus analyses indicated that the effects of these genes combined additively to influence response. Results of a permutation test to adjust for multiple comparisons and the possible nonindependence among genotypes remained significant at the P=0.003 level.Conclusions: Among African-American women, particular gene variations in the RAA system have additive effects on BP response to a thiazide diuretic.

Usefulness of Single Nucleotide Polymorphism in Chromosome 4q25 to Predict In-Hospital and Long-Term Development of Atrial Fibrillation and Survival in Patients Undergoing Coronary Artery Bypass Grafting

We aimed to determine whether polymorphisms in chromosome 4q25 are associated with postoperative atrial fibrillation (AF), long-term AF, postoperative or long-term stroke, and long-term survival after coronary artery bypass grafting. We performed genotyping for rs2200733 and rs10033464 in white participants (n = 1,166) from the TexGen genetic registry. The development of postoperative or long-term AF, postoperative or long-term stroke, and long-term mortality were ascertained. Both rs2200733 and rs10033464 were associated with postoperative AF (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.04 to 1.91, and OR 1.47, 95% CI 1.05 to 2.06, respectively). Carriers of the risk allele (T) had an increased risk of postoperative AF with preoperative β blocker (BB) (for rs2200733, OR 1.47, 95% CI 1.004 to 2.16 for those taking a BB, and OR 1.13, 95% CI 0.73 to 1.73 for those not taking a BB; for rs10033464, OR 1.89, 95% CI 1.22 to 2.93 for those taking preoperative a BB, and OR 1.04, 95% CI 0.65 to 1.65 for those not taking a BB). Both rs2200733 and rs10033464 were also associated with long-term AF (hazard ratio 1.32, 95% CI 1.05 to 1.67, and hazard ratio 1.28, 95% CI 1.00 to 1.66, respectively). Carriers of rs2200733 had increased long-term mortality (hazard ratio 1.57, 95% CI 1.10 to 2.24). These variants were not associated with postoperative or long-term stroke. In conclusion, variants in 4q25 are associated with an increased risk of postoperative or long-term AF and, possibly, mortality in whites undergoing coronary artery bypass grafting, and could potentially affect the choice of therapy used to decrease postoperative AF.

Influenza and atherosclerosis: vaccination for cardiovascular disease prevention.

In both animal and human studies, strong prothrombotic and pro-inflammatory effects have been observed after influenza infection. Influenza is an important trigger for acute coronary syndromes, and it has been shown that in the US it may cause up to 90,000 deaths per year simply by triggering fatal myocardial infarctions. Multiple case-control and cohort studies have shown that the influenza vaccine has a marked protective effect against cardiovascular events, decreasing the incidence of these events by 20 – 70% in the settings of primary and secondary prevention. Although influenza vaccination is an extremely cost-effective method of cardiovascular protection and is recommended for all patients with cardiac diseases, it is largely underused in these patients. Therefore, increased efforts should be directed towards educating physicians and patients about the benefits of influenza vaccination in patients with coronary heart disease.

Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: A scientific statement from the American Heart Association

Although genetics and genomics play an increasingly large role in the practice of medicine, the clinical care of patients suffering from cardiovascular disease or stroke has not been significantly affected. This is despite the tremendous strides being made to understand the genetic basis of both rare and common cardiovascular and stroke disorders through techniques such as genome-wide association studies (GWASs) and next-generation sequencing studies. Much of this knowledge remains to be translated to the clinic and must be subjected to clinical trials to ensure patient safety and a meaningful impact on clinical outcomes. However, even if this knowledge were to be successfully implemented into clinical practice, a potential barrier to widespread adoption is a lack of familiarity with basic concepts of genetics and genomics. Another concern is the possibility of the emergence of a significant gap in clinical care provided by practitioners who are informed about the clinical use of genetics and genomics knowledge and those who are not. Thus, there is a critical need to foster genetics/genomics literacy among all involved in the care of cardiovascular and stroke patients because it can be expected that these topics will transform the way medicine is practiced. The purpose of this document is to serve as a resource for practitioners in cardiovascular and stroke medicine on the application of genetics and genomics to patient care. Although not exhaustive, it contains an overview of the field written specifically to be accessible and relevant to practitioners. It also refers to additional educational materials available in the literature, in textbooks, and on the Internet. (Because this article is intended to be primarily educational in nature, rather than providing a review of the literature, citations are limited to a small number of research articles and reviews of exceptional interest.) It recommends a core knowledge base with …

PSYCHOMETRIC TESTING OF THE ADOLESCENT VERSION OF THE COOK?MEDLEY HOSTILITY SCALE

Hostility, a phenomenon that has been linked to cardiovascular disease and all-cause mortality, is often measured by the Cook-Medley hostility (Ho) scale. Although there is an adolescent version of the Ho scale, it has had little testing with only AngloAmerican samples. This pilot study tested the reliability and validity of the adolescent version of the Ho scale with a multiethnic sample of adolescents. Sixty adolescents participated. Reliability was measured using Chronbachs alpha. The Ho scale was correlated with the Speilberger State-Trait Anger Expression Inventory (1988) scales to determine concurrent validity. A factor analysis assessed construct validity; content validity was assessed by analyzing tape-recorded descriptions of a circumstance that provoked anger, as remembered by each adolescent. Internal consistency reliability was .75. The hostility measure was most highly correlated with anger expression (r = .62, p = .000) and trait anger (r = .50, p = .000). The factor analysis generated three factors (suspicious alienation, cynical aggression and justified mistrust), that accounted for 34.5% of the variance. The content analysis resulted in five anger-provoking themes: aggression, unfulfilled personal expectations, mistrust/lying, criticism of effort, and rejection. The majority of items in the scale (74%) were related to one of the themes.Hostility, a phenomenon that has been linked to cardiovascular disease and all-cause mortality, is often measured by the Cook-Medley hostility (Ho) scale. Although there is an adolescent version of the Ho scale, it has had little testing with only Anglo-American samples. This pilot study tested the reliability and validity of the adolescent version of the Ho scale with a multiethnic sample of adolescents. Sixty adolescents participated. Reliability was measured using Chronbachs alpha. The Ho scale was correlated with the Speilberger State-Trait Anger Expression Inventory (1988) scales to determine concurrent validity. A factor analysis assessed construct validity; content validity was assessed by analyzing tape-recorded descriptions of a circumstance that provoked anger, as remembered by each adolescent. Internal consistency reliability was .75. The hostility measure was most highly correlated with anger expression (r = .62, p = .000) and trait anger (r = .50, p = .000). The factor analysis generated three factors (suspicious alienation, cynical aggression and justified mistrust), that accounted for 34.5% of the variance. The content analysis resulted in five anger-provoking themes: aggression, unfulfilled personal expectations, mistrust/lying, criticism of effort, and rejection. The majority of items in the scale (74%) were related to one of the themes.

The role of serotonin in depression and clotting in the coronary artery disease population.

Background:Despite the strong evidence that depression is an independent risk factor for coronary artery disease (CAD), the underlying physiological mechanisms linking depression and CAD remain poorly understood. Objective:This review of the literature focuses on the current understanding of the physiological effects of serotonin on depression and clotting as well as its role in CAD. Methods:Articles for this review were identified using CINAHL, PsychINFO, and MEDLINE searches. Results:Results revealed that depression is an independent risk factor for CAD. Although the physiological mechanisms underlying depression and related increases in acute coronary events remain unclear, serotonin plays an important role in depression and CAD. Elevated platelet serotonin levels promote clotting, which may be a potential underlying mechanism linking depression with CAD. Conclusions:This review of the literature suggests that elevated platelet serotonin levels may be associated with depression and the occurrence of major adverse coronary events. Future research should investigate if platelet serotonin levels contribute at least in part to the acute coronary events seen in patients with CAD who have elevated levels of platelet serotonin when depressed.

Factors influencing blood pressure: development of a risk model.

A review of the literature suggests that blood pressure (BP) is multifactorial and is affected by the interactions of genetics, physiology, responses to the environment, and lifestyle factors that have increasing influence as one ages. The effect of these factors on hypertension (HTN) risk as one ages is depicted in the authors Hypertension Risk Model. The model emphasizes HTN risk in the older adult--age 50 and older--and shows the interaction of the factors influencing HTN development and BP assessment methods. Implications of three methods of BP assessment--(1) static BP, (2) 24-hour ambulatory blood pressure monitoring, and (3) clinic blood pressure reactivity (BPR) protocol--are discussed. The model may be useful for understanding factors that contribute to HTN and for guiding BP assessment for clinical researchers. Addressing the factors associated with the sympathetic system activity from various environmental stressors requires assessing dynamic BP, particularly in the older hypertensive adult who has increased BPR. Further research should focus on ambulatory blood pressure studies in older adults that would provide the methods and instrumentation needed to assess HTN and therefore decrease mortality and morbidity in this population.

Connecting the Dots of Heart Disease, Poor Mental Health, and Abuse to Understand Gender Disparities and Promote Women's Health: A Prospective Cohort Analysis

Heart disease, poor mental health, and abuse are epidemic among women worldwide. Our purpose was to identify a group of women with heart disease and explore the relationship between a history of abuse and existing symptoms of depression and post-traumatic stress disorder (PTSD) and analyze the relationships over time. A prospective cohort analysis design with mental health measures repeated at 3 and 6 months postintake was followed. Abused women (n = 25) reported significantly more symptoms of depression (p = .004) and PTSD (p = .003) compared with nonabused women (n = 14). To promote global mental health among women with heart disease, interventions must address a history of abuse.

Inflammatory Protein Levels and Depression Screening After Coronary Stenting Predict Major Adverse Coronary Events

Background: Traditional risk factors cannot account for the majority of future major adverse coronary events (MACE) in patients diagnosed with heart disease. We examined levels of inflammatory proteins to be possible predictors of future MACE and physiological and psychological factors that initiate temporal increases in inflammatory protein levels. Methods: Peripheral blood samples and depression data were collected 4 to 12 hr after elective coronary stent insertion in 490 patients. Depression screening was assessed by a single-question screening tool. Predictive modeling for future MACE was performed by using survival analysis, with time from the index event (placement of the stent) to future MACE as the dependent variable. Results: Patients with high-sensitivity c-reactive protein (hsCRP) in the second and third quartiles were 3 and 2.5 times more likely to have a MACE than patients with hsCRP in the first quartile, respectively. As levels of vascular cell adhesion molecule and monocyte chemoattractant protein-1 increased, so did the risk of future MACE. Patients who screened positive for depression were approximately 2 times more likely to have a MACE within 24 months after stent placement than were patients who did not screen positive. Conclusions: Our results suggest that hsCRP, vascular cell adhesion molecule, and monocyte chemoattractant protein-1 levels, measured after coronary stent insertion in patients with coronary heart disease, are prognostic of future MACE. Furthermore, positive depression screening is an independent predictor of future MACE.