Genetic Loci Associated with C-reactive Protein Levels and Risk of Coronary Heart Disease.

CONTEXT: Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE: Risk of coronary heart disease. RESULTS: Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION: The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome.

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations.

Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults.

Although both inflammatory and atherosclerosis markers have been associated with coronary heart disease (CHD) risk, data directly comparing their predictive value are limited. The authors compared the value of 2 atherosclerosis markers (ankle-arm index (AAI) and aortic pulse wave velocity (aPWV)) and 3 inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)) in predicting CHD events. Among 2,191 adults aged 70-79 years at baseline (1997-1998) from the Health, Aging, and Body Composition Study cohort, the authors examined adjudicated incident myocardial infarction or CHD death ("hard" events) and "hard" events plus hospitalization for angina or coronary revascularization (total CHD events). During 8 years of follow-up between 1997-1998 and June 2007, 351 participants developed total CHD events (197 "hard" events). IL-6 (highest quartile vs. lowest: hazard ratio = 1.82, 95% confidence interval: 1.33, 2.49; P-trend < 0.001) and AAI (AAI </= 0.9 vs. AAI 1.01-1.30: hazard ratio = 1.57, 95% confidence interval: 1.14, 2.18) predicted CHD events above traditional risk factors and modestly improved global measures of predictive accuracy. CRP, TNF-alpha, and aPWV had weaker associations. IL-6 and AAI accurately reclassified 6.6% and 3.3% of participants, respectively (P's </= 0.05). Results were similar for "hard" CHD, with higher reclassification rates for AAI. IL-6 and AAI are associated with future CHD events beyond traditional risk factors and modestly improve risk prediction in older adults.

Ruling out coronary heart disease in primary care patients with chest pain: a clinical prediction score.

ABSTRACT: BACKGROUND: Chest pain raises concern for the possibility of coronary heart disease. Scoring methods have been developed to identify coronary heart disease in emergency settings, but not in primary care. METHODS: Data were collected from a multicenter Swiss clinical cohort study including 672 consecutive patients with chest pain, who had visited one of 59 family practitioners' offices. Using delayed diagnosis we derived a prediction rule to rule out coronary heart disease by means of a logistic regression model. Known cardiovascular risk factors, pain characteristics, and physical signs associated with coronary heart disease were explored to develop a clinical score. Patients diagnosed with angina or acute myocardial infarction within the year following their initial visit comprised the coronary heart disease group. RESULTS: The coronary heart disease score was derived from eight variables: age, gender, duration of chest pain from 1 to 60 minutes, substernal chest pain location, pain increases with exertion, absence of tenderness point at palpation, cardiovascular risks factors, and personal history of cardiovascular disease. Area under the receiver operating characteristics curve was of 0.95 with a 95% confidence interval of 0.92; 0.97. From this score, 413 patients were considered as low risk for values of percentile 5 of the coronary heart disease patients. Internal validity was confirmed by bootstrapping. External validation using data from a German cohort (Marburg, n = 774) revealed a receiver operating characteristics curve of 0.75 (95% confidence interval, 0.72; 0.81) with a sensitivity of 85.6% and a specificity of 47.2%. CONCLUSIONS: This score, based only on history and physical examination, is a complementary tool for ruling out coronary heart disease in primary care patients complaining of chest pain.

Progenitor cell therapy for heart disease.

Many cell types are currently being studied as potential sources of cardiomyocytes for cell transplantation therapy to repair and regenerate damaged myocardium. The question remains as to which progenitor cell represents the best candidate. Bone marrow-derived cells and endothelial progenitor cells have been tested in clinical studies. These cells are safe, but their cardiogenic potential is controversial. The functional benefits observed are probably due to enhanced angiogenesis, reduced ventricular remodeling, or to cytokine-mediated effects that promote the survival of endogenous cells. Human embryonic stem cells represent an unlimited source of cardiomyocytes due to their great differentiation potential, but each step of differentiation must be tightly controlled due to the high risk of teratoma formation. These cells, however, confront ethical barriers and there is a risk of graft rejection. These last two problems can be avoided by using induced pluripotent stem cells (iPS), which can be autologously derived, but the high risk of teratoma formation remains. Cardiac progenitor cells have the advantage of being cardiac committed, but important questions remain unanswered, such as what is the best marker to identify and isolate these cells? To date the different markers used to identify adult cardiac progenitor cells also recognize progenitor cells that are outside the heart. Thus, it cannot be determined whether the cardiac progenitor cells identified in the adult heart represent resident cells present since fetal life or extracardiac cells that colonized the heart after cardiac injury. Developmental studies have identified markers of multipotent progenitors, but it is unknown whether these markers are specific for adult progenitors when expressed in the adult myocardium. Cardiac regeneration is dependent on the stability of the cells transplanted into the host myocardium and on the electromechanical coupling with the endogenous cells. Finally, the promotion of endogenous regenerative processes by mobilizing endogenous progenitors represents a complementary approach to cell transplantation therapy.

Validation of a clinical prediction score for ruling out coronary heart disease in primary care patients with chest pain.

Background: A patient's chest pain raises concern for the possibility of coronary heart disease (CHD). An easy to use clinical prediction rule has been derived from the TOPIC study in Lausanne. Our objective is to validate this clinical score for ruling out CHD in primary care patients with chest pain. Methods: This secondary analysis used data collected from a oneyear follow-up cohort study attending 76 GPs in Germany. Patients attending their GP with chest pain were questioned on their age, gender, duration of chest pain (1-60 min), sternal pain location, pain increases with exertion, absence of tenderness point at palpation, cardiovascular risks factors, and personal history of cardiovascular disease. Area under the curve (ROC), sensitivity and specificity of the Lausanne CHD score were calculated for patients with full data. Results: 1190 patients were included. Full data was available for 509 patients (42.8%). Missing data was not related to having CHD (p = 0.397) or having a cardiovascular risk factor (p = 0.275). 76 (14.9%) were diagnosed with a CHD. Prevalence of CHD were respectively of 68/344 (19.8%), 2/62 (3.2%), 6/103 (5.8%) in the high, intermediate and low risk category. ROC was of 72.9 (CI95% 66.8; 78.9). Ruling out patients with low risk has a sensitivity of 92.1% (CI95% 83.0; 96.7) and a specificity of 22.4% (CI95% 18.6%; 26.7%). Conclusion: The Lausanne CHD score shows reasonably good sensitivity and can be used to rule out coronary events in patients with chest pain. Patients at risk of CHD for other rarer reasons should nevertheless also be investigated.

Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule.

BACKGROUND: The Marburg Heart Score (MHS) aims to assist GPs in safely ruling out coronary heart disease (CHD) in patients presenting with chest pain, and to guide management decisions. AIM: To investigate the diagnostic accuracy of the MHS in an independent sample and to evaluate the generalisability to new patients. DESIGN AND SETTING: Cross-sectional diagnostic study with delayed-type reference standard in general practice in Hesse, Germany. METHOD: Fifty-six German GPs recruited 844 males and females aged ≥ 35 years, presenting between July 2009 and February 2010 with chest pain. Baseline data included the items of the MHS. Data on the subsequent course of chest pain, investigations, hospitalisations, and medication were collected over 6 months and were reviewed by an independent expert panel. CHD was the reference condition. Measures of diagnostic accuracy included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, likelihood ratios, and predictive values. RESULTS: The AUC was 0.84 (95% confidence interval [CI] = 0.80 to 0.88). For a cut-off value of 3, the MHS showed a sensitivity of 89.1% (95% CI = 81.1% to 94.0%), a specificity of 63.5% (95% CI = 60.0% to 66.9%), a positive predictive value of 23.3% (95% CI = 19.2% to 28.0%), and a negative predictive value of 97.9% (95% CI = 96.2% to 98.9%). CONCLUSION: Considering the diagnostic accuracy of the MHS, its generalisability, and ease of application, its use in clinical practice is recommended.

Association of major and minor ECG abnormalities with coronary heart disease events.

CONTEXT: In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction. OBJECTIVE: To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997-1998 and 2006-2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events. MAIN OUTCOME MEASURE: Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization). RESULTS: At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02-1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20-1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%-19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%-2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33-3.02; and HR, 1.66; 95% CI, 1.18-2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, -0.4% to 11.8%). CONCLUSIONS: Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.

Evaluation of prenatal diagnosis of congenital heart disease in a regional controlled case study.

AIMS: This study evaluated the evolution of the prenatal diagnosis of congenital heart disease (CHD) between 2003 and 2008 and its repercussion for the CHD prevalence rate at birth in a well-defined population (Canton of Vaud, Switzerland). METHODS AND RESULTS: All 572 cases of CHD reported in the Eurocat Registry of Vaud-Switzerland between 1.5.2003 and 31.12.2008 were analysed and compared with the cases in our clinical database. CHD cases were divided into five different groups according to heart disease severity. The prenatal detection rates increased significantly between 2003 and 2008, with a mean detection rate of 25.2%. There was a significantly higher rate of prenatal diagnosis in the first four groups of CHD severity, with the highest detection rate (87.5%) found in the group with the most severe CHD (group 1). In this group, 85.7% of cases resulted in a termination of pregnancy, and there was a consequent 75% reduction in the prevalence of severe major cardiac malformation at birth. Detection rates were 66% in group 2, 68.6% in group 3, and the lowest in groups 4 and 5, with rates of 25.9% and 12.9%, respectively. CONCLUSION: This study shows that the prenatal detection rate for CHD increased in a well-defined population over the study period. Prenatal diagnosis thus has had a major impact on patients with the most severe types of CHD and has resulted in a significant reduction in severe CHD at birth.

Does CRP Play a Causal Role in the Development of Coronary Heart Disease: Results of a Mendelian Randomisation Experiment Involving 128,935 People

Background: C-reactive protein (CRP) is associated with risk of coronary heart disease (CHD). Whether CRP is causally associated with CHD or merely a marker of underlying atherosclerosis is uncertain. Methods: We used a Mendelian randomisation design to investigate the causal relationship of CRP with CHD. We identified three genetic variants in the CRP locus (rs7553007, rs1130864 and rs1205) which influence CRP levels. We tested the three SNPs for association with CHD amongst 28,112 CHD cases and 100,823 controls. We then compared the observed relationship between the SNPs and CHD, with that predicted from the association of SNPs with CRP levels, and of CRP levels with CHD. Results: SNPs in the CRP locus were not associated with CHD: rs7553007, OR 0.98 (95% CI, 0.94-1.01); rs1130864, OR 1.00 (95% CI, 0.86-1.15); rs1205, OR 1.03 (95% CI, 0.99-1.07); combined OR for all three SNPs, 1.00 (95% CI, 0.97-1.02), per 20% lower CRP (figure). In contrast, the predicted OR for CHD from a 20% lower CRP level is 0.94 (95% CI, 0.94- 0.95), based on meta-analysis of observational studies. Conclusions: Though CRP variants are associated with CRP levels, and CRP levels with risk of CHD, we observed that CRP variants are not associated with CHD risk. Our Mendelian randomisation experiment strongly argues against a causal association of CRP with CHD.

Subclinical hyperthyroidism and the risk of coronary heart disease and mortality

Contexte L'hyperthyroïdie infra-clinique est une perturbation de la fonction thyroïdienne, définie par une thyrotropine (TSH) basse et des taux normaux de thyroxine libre (T4L) et triiodothyronine (T3). Cette dysfonction affecte de 1% à 5% des adultes de plus de 65 ans, surtout les femmes, et pourrait être associée avec les maladies cardiovasculaires, la fibrillation auriculaire et l'insuffisance cardiaque. Toutefois, les conclusions des différentes études de cohortes sont contradictoires, avec des limites méthodologiques empêchant leur comparaison de manière formelle. L'objet du travail de thèse était d'estimer le risque de mortalité de toute cause, le risque de mortalité de cause cardiovasculaire, le risque d'événements cardiovasculaires et le risque de fibrillation auriculaire associés à l'hyperthyroïdie infra-clinique dans toutes les grandes études de cohorte prospectives disponibles à ce jour. Méthode et Résultats Les données individuelles de 52'674 participants provenant de 10 études de cohorte prospectives des Etats-Unis, d'Europe, du Brésil et d'Australie ont été analysées pour évaluer les risques à long-terme de l'hyperthyroïdie infra-clinique. L'euthyroïdie était définie par une TSH entre 0.45 et 4.49 mUI/l et l'hyperthyroïdie infra-clinique par une TSH inférieure à 0.45 mUI/l avec un taux normal de T4L, après exclusion des participants prenant des médicaments pouvant perturber la thyroïde. Sur les 52'674 participants, 2188 (4.2%) avaient une hyperthyroïdie infra-clinique. Pendant un suivi de plus de 8 ans, 8527 participants sont décédés (dont 1896 de cause cardiovasculaire), 3653 sur 22'437 ont eu un événement cardiovasculaire et 785 sur 8711 ont développé une fibrillation auriculaire. Dans des analyses ajustées pour l'âge et le sexe, l'hyperthyroïdie infra-clinique était associée à une hausse de la mortalité de toute cause (hazard ratio [HR] 1.24, intervalle de confiance à 95% [IC] 1.06-1.46), de la mortalité cardiovasculaire (HR 1.29, IC 1.02-1.62), des événements cardiovasculaires (HR 1.21, IC 0.99- 1.46) ainsi qu'une hausse de l'incidence de fibrillation auriculaire (HR 1.68, IC 1.16-2.43). Les risques ne différaient pas significativement dans les analyses stratifiées selon l'âge, le sexe ou la présence de maladies cardiovasculaires préexistantes, et étaient similaires après ajustement multiple pour les facteurs de risque cardiovasculaire. Le risque de mortalité cardiovasculaire et de fibrillation auriculaire était plus élevé avec une TSH très basse (< 0.10 Ul/I) comparé à une TSH modérément abaissée (0.10-0.44 mUI/l, valeurs ρ for trend < 0.03). Conclusions et perspectives L'hyperthyroïdie infra-clinique est associée à un risque augmenté de mortalité de toute cause, de cause cardiovasculaire et de fibrillation auriculaire, avec un risque plus élevé quand la TSH est inférieure à 0.10 mUI/l. Ces résultats sont cohérents avec les dernières recommandations internationales conseillant de considérer un traitement de l'hyperthyroïdie infra-clinique pour les adultes de plus de 65 ans ou les patients avec maladie cardiaque, en particulier si la TSH est inférieure à 0.10 mUI/l. Toutefois, des études cliniques randomisées sont encore nécessaires pour prouver l'efficacité du traitement et déterminer si l'on devrait dépister les problèmes de thyroïde dans la population générale.

Randomized trial of a computerized coronary heart disease risk assessment tool in HIV-infected patients receiving combination antiretroviral therapy.

BACKGROUND: Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD. METHODS: We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score. RESULTS: A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09-0.06), systolic blood pressure -0.4 mmHg (-1.6-0.8), diastolic blood pressure -0.4 mmHg (-1.5-0.7) and Framingham 10-year risk score -0.2% (-0.5-0.1). CONCLUSIONS: Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART.