Luis Afonso

Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A Mendelian Randomization Analysis

OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). BACKGROUND LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. RESULTS All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)). CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Homocysteine and Reclassification of Cardiovascular Disease Risk

OBJECTIVES The purpose of this study was to examine whether adding homocysteine (Hcy) to a model based on traditional cardiovascular disease (CVD) risk factors improves risk classification. BACKGROUND Data on using Hcy to reclassify individuals in various risk categories beyond traditional approaches have not been adequately scrutinized. METHODS We performed a post hoc analysis of the MESA (Multi-Ethnic Study of Atherosclerosis) and NHANES III (National Health and Nutrition Examination Survey III) datasets. Hcy was used to predict composite CVD and hard coronary heart disease (CHD) events in the MESA study and CVD and CHD mortality in the NHANES III survey using adjusted Cox-proportional hazard analysis. Reclassification of CHD events was performed using a net reclassification improvement (NRI) index with a Framingham risk score (FRS) model with and without Hcy. RESULTS Hcy level (>15 μmol/l) significantly predicted CVD (adjusted hazard ratio [aHR]: 1.79, 95% confidence intervals [CI]: 1.19 to 1.95; p = 0.006) and CHD events (aHR: 2.22, 95% CI: 1.20 to 4.09; p = 0.01) in the MESA trial and CVD (aHR: 2.72, 95% CI: 2.01 to 3.68; p < 0.001) and CHD mortality (aHR: 2.61, 95% CI: 1.83 to 3.73; p < 0.001) in the NHANES III, after adjustments for traditional risk factors and C-reactive protein. The level of Hcy, when added to FRS, significantly reclassified 12.9% and 18.3% of the overall and 21.2% and 19.2% of the intermediate-risk population from the MESA and NHANES cohorts, respectively. The categoryless NRI also showed significant reclassification in both MESA (NRI: 0.35, 95% CI: 0.17 to 0.53; p < 0.001) and NHANES III (NRI: 0.57, 95% CI: 0.43 to 0.71; p < 0.001) datasets. CONCLUSIONS From these 2 disparate population cohorts, we found that addition of Hcy level to FRS significantly improved risk prediction, especially in individuals at intermediate risk for CHD events.

Red Cell Distribution Width and Risk of Coronary Heart Disease Events

Red cell distribution width (RDW) has emerged as a powerful predictor of all-cause mortality in variety of cardiovascular settings. However, no data are available associating RDW with coronary heart disease (CHD) risk in a healthy and nationally representative multiethnic population. A total of 7,556 participants of the National Health and Nutrition Examination Surveys 1999 to 2006 (age 41.5 ± 15.8 years, 60% women) were divided into 3 categories according to their 10-year Framingham risk of hard CHD events: <10% (n = 6,173, reference category), 10% to 20% (n = 1,093, intermediate-risk category), and >20% (n = 290, high-risk category). Unadjusted and adjusted multivariate logistic regression analyses were performed evaluating RDW as a predictor of CHD risk. Each unit increase (0.1) in RDW posed a statistically significant greater odds of being in the intermediate-risk category (odds ratio -1.35, 95% confidence interval 1.27 to 1.45, p <0.001) and high-risk category (odds ratio -1.38, 95% confidence interval 1.25 to 1.53, p <0.001) compared to the reference category, after adjusting for race, body mass index, estimated glomerular filtration rate, hemoglobin A1c, C-reactive protein, hemoglobin, and mean corpuscular volume. Additional adjustments with serum iron, vitamin B(12), and folic acid levels did not affect the association. Subsequently, we divided participants into 2 categories according to their anemia status (as defined by the World Health Organization) to evaluate its effect. An RDW level greater than the seventy-fifth percentile in both anemic and nonanemic participants was a significant predictor of greater CHD risk while RDW of the seventy-fifth percentile or less in anemic participants failed to predict CHD (compared to nonanemic participants with similar RDW as the reference category). In conclusion, a higher RDW appears to be a powerful independent predictor of future CHD risk.

Echocardiography in hypertrophic cardiomyopathy: the role of conventional and emerging technologies.

Hypertrophic cardiomyopathy is a relatively common inherited cardiomyopathy that is occasionally challenging to differentiate from hypertensive heart disease and athlete hearts on the basis of morphologic or functional abnormalities alone. Echocardiography has traditionally played a preeminent role in the diagnosis, formulation of management strategies, and the prognostication of this complex disease. In this review, we briefly profile the utility and pitfalls of established echocardiographic modalities and discuss the evolving role of novel echocardiographic imaging modalities such as tissue Doppler, Doppler-based strain, 2-dimensional strain (speckle tracking imaging), and 3-dimensional imaging in the assessment of hypertrophic cardiomyopathy.

Diagnostic accuracy of myocardial perfusion imaging and stress echocardiography for the diagnosis of left main and triple vessel coronary artery disease: a comparative meta-analysis

Objectives Compare the diagnostic performance of stress echocardiography (SE) and myocardial perfusion imaging (MPI) for the diagnosis of left main disease (LM) and triple vessel disease (TVD). Background Limited comparative data on MPI and SE for the detection of LM and TVD (high-risk coronary artery disease) exist in the literature. Methods Quantitative meta-analysis was performed using studies identified by systematic electronic literature search. Articles were included if they reported data on exercise, dobutamine SE or exercise, adenosine, dipyridamole, thallium201, technetium 99m sestamibi MPI and used coronary angiography as the reference test. Summary receiver-operating characteristic (SROC) curves were constructed for each imaging modality. Additionally, pooled sensitivity, specificity and likelihood ratios were calculated per modality. Meta-regression was performed to adjust for patient and study characteristics. Results Thirty-two studies met inclusion criteria; 23 (MPI-15; SE-14; Common studies-6) provided sufficient data for analysis. In a SROC model comparing the two imaging modalities, SE was associated with higher area under curve (0.82 (0.03) vs 0.73 (0.02), p=0.01) and index Q* value (0.75 (0.02) vs 0.67 (0.02), p=0.01). Using pooled summary point estimates, SE had higher pooled sensitivity (94% vs 75%, p<0.001) and lower negative likelihood ratio (0.21 vs 0.47, p<0.001) compared to MPI. No evidence of a difference in the pooled specificity (40% vs 48%, p=0.16) and positive likelihood ratio (1.52 vs 1.58, p=0.36) was seen between the two stress modalities. Pooled diagnostic OR on meta-regression (9.78 vs 4.06, p=0.02) remained significantly higher for SE compared to MPI for identification of LM and TVD even after adjustment for study characteristics. Conclusions Since LM alone or in combination with TVD are categorised as representing potentially life-threatening variants of CAD, a screening test with high sensitivity, low negative likelihood ratio or higher discriminatory capacity would be desirable for risk stratification. In the absence of a direct head-to-head comparison of the diagnostic accuracies of SE and MPI, our findings indicate that SE appears to be the preferred screening modality for high-risk coronary artery disease.

Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis

Objective Late gadolinium enhancement (LGE) on cardiac MRI that indicates the extent of myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is a potential risk factor of sudden cardiac death (SCD) in non-high-risk patients according to conventional clinical markers. Methods The present study was designed to systematically review prospective trials and assess the association between LGE and SCD in HCM. We systematically searched the electronic databases, MEDLINE, PubMed, Embase and Cochrane for prospective cohort studies of the effects of LGE on clinical outcomes (SCD/aborted SCD, all-cause mortality, cardiac and heart failure death) in HCM. Results We identified six clinical studies, examining 1414 patients without LGE and 1653 with LGE and an average follow-up of 3.05 years. The incidence of SCD/aborted SCD in patients with HCM and LGE was significantly increased as compared with patients without LGE (OR 2.52, 95% CI 1.44 to 4.4, p=0.001). The all-cause mortality and cardiac death rates were also significantly increased in patients with LGE. The extent of LGE was not significantly related to the risk of SCD. Conclusions LGE is significantly associated with SCD risk, cardiac mortality and all-cause mortality in patients with non-high-risk HCM according to conventional risk factors.

Association of novel biomarkers with future cardiovascular events is influenced by ethnicity: Results from a multi-ethnic cohort

BACKGROUND We sought to define the influence of ethnicity on associations between novel biomarkers and cardiovascular disease (CVD) events among Multi-Ethnic Study of Atherosclerosis (MESA) study participants, a community based population of asymptomatic US adults. METHODS Baseline (log transformed) levels of biomarkers namely C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), D-dimer, plasmin-antiplasmin complex (PAP) and factor VIII were used to predict the cumulative incidence of all CVD events in an ethnicity stratified study cohort from Cox-proportional hazard analysis where models were adjusted for relevant confounders. RESULTS Ethnic cohorts included 2362 Caucasians, 1601 African Americans, 1353 Hispanics, and 751 Chinese. At mean 4.6 years of follow-up, 286 CVD events were identified with cumulative incidence of 11.3% in Caucasians, 9.8% in African Americans, 11.3% in Hispanics and 6.9% in Chinese. Biomarker risk association with CVD events incidence was significantly influenced by ethnicity with positive association (HR, 95% CI, p value) being shown for: CRP among Caucasians only (1.23, 1.04-1.47, <0.01) IL-6 among African Americans only (1.69, 1.15-2.48, <0.01) and fibrinogen among Caucasians (3.05, 1.21-7.69, 0.02), African Americans (3.51, 1.09-11.2, 0.03) and Hispanics (4.16, 1.23-14.1, 0.02) only. None of the biomarkers were able to predict CVD in Chinese. Association between above biomarkers and CVD was bi-directional: cases with CVD events had higher mean levels of biomarkers; cases in higher quartiles of biomarkers had increased cumulative incidence of CVD events. CONCLUSION Study results from a vast, ethnically diverse, asymptomatic US adult population suggest that biomarker association with incident CVD events is significantly influenced by ethnicity.

A gender-stratified comparative analysis of various definitions of metabolic syndrome and cardiovascular risk in a multiethnic U.S. population.

INTRODUCTION We sought to evaluate the ability of various metabolic syndrome definitions in predicting primary cardiovascular disease (CVD) outcomes in a vast multiethnic U.S. cohort. METHODS This study included 6,814 self-identified men and women aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) study. Gender-stratified analyses were performed to calculate hazard ratios of CVD, stroke, and mortality associated with various metabolic syndrome definitions and their individual constructs. RESULTS The hazard ratios [95% confidence interval (CI)] for all-cause CVD in men were 2.90 (2.18-3.85), 2.64 (1.98-3.51), 2.16 (1.62-2.88), 2.56 (1.91-3.44), 1.82 (1.35-2.46), and 2.92 (2.15-3.95) for the National Cholesterol Education Program (NCEP), American Heart Association (AHA), World Health Organization (WHO), International Diabetes Federation (IDF), European Group for the Study of Insulin Resistance (EGIR), and the newly defined consensus criteria. Hazard ratios in women were 2.11 (1.41-3.15), 2.17 (1.45-3.27), 2.04 (1.37-3.06), 1.91 (1.27-2.88), 1.85 (1.23-2.79), and 2.08 (1.37-3.14), respectively. Metabolic syndrome was strongly associated with stroke risk only in males. In men, all constitutive metabolic syndrome components were continuously and strongly associated with CVD. In women, high-density lipoprotein and triglycerides did not appear to be associated with short term CVD risk. CONCLUSION We found the newly defined consensus criteria for metabolic syndrome to be similarly predictive of cardiovascular events when compared to existing definitions. Significant gender differences exist in the association between metabolic syndrome, its individual components, and CVD.

Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction

Almost 50% of patients with congestive heart failure (HF) have preserved ejection fraction (PEF). Data on the effect of HF-PEF on atrial fibrillation outcomes are lacking. We assessed the prognostic significance of HF-PEF in an atrial fibrillation population compared to a systolic heart failure (SHF) population. A post hoc analysis of the National Heart, Lung, and Blood Institute-limited access data set of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was carried out. The patients with a history of congestive HF and a preserved ejection fraction (EF >50%) were classified as having HF-PEF (n = 320). The patients with congestive HF and a qualitatively depressed EF (EF <50%) were classified as having SHF (n = 402). Cox proportional hazards analysis was performed. The mean follow-up duration was 1,181 ± 534 days/patient. The patients with HF-PEF had lower all-cause mortality (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.46 to 0.85, p = 0.003) and cardiovascular mortality (HR 0.56, 95% CI 0.38 to 0.84, p = 0.006), with a possible decreased arrhythmic end point (HR 0.39, 95% CI 0.16 to 1.006, p = 0.052) than did the patients with SHF. No differences were observed for ischemic stroke (HR 1.08, 95% CI 0.48 to 2.39, p = 0.86), rehospitalization (HR 0.89, 95% CI 0.75 to 1.07, p = 0.24), or progression to New York Heart Association class III-IV (odds ratio 0.80, 95% CI 0.42 to 1.54, p = 0.522). In conclusion, although patients with HF-PEF have better mortality outcomes than those with SHF, the morbidity appears to be similar.

Two-dimensional strain profiles in patients with physiological and pathological hypertrophy and preserved left ventricular systolic function: a comparative analyses.

Objective This study was designed to examine the utility of two-dimensional strain (2DS) or speckle tracking imaging to typify functional adaptations of the left ventricle in variant forms of left ventricular hypertrophy (LVH). Design Cross-sectional study. Setting Urban tertiary care academic medical centres. Participants A total of 129 subjects, 56 with hypertrophic cardiomyopathy (HCM), 34 with hypertensive left ventricular hypertrophy (H-LVH), 27 professional athletes with LVH (AT-LVH) and 12 healthy controls in sinus rhythm with preserved left ventricular systolic function. Methods Conventional echocardiographic and tissue Doppler examinations were performed in all study subjects. Bi-dimensional acquisitions were analysed to map longitudinal systolic strain (automated function imaging, AFI, GE Healthcare, Waukesha, Wisconsin, USA) from apical views. Results Subjects with HCM had significantly lower regional and average global peak longitudinal systolic strain (GLS-avg) compared with controls and other forms of LVH. Strain dispersion index, a measure of regional contractile heterogeneity, was higher in HCM compared with the rest of the groups. On receiver operator characteristics analysis, GLS-avg had excellent discriminatory ability to distinguish HCM from H-LVH area under curve (AUC) (0.893, p<0.001) or AT-LVH AUC (0.920, p<0.001). Tissue Doppler and LV morphological parameters were better suited to differentiate the athlete heart from HCM. Conclusions 2DS (AFI) allows rapid characterisation of regional and global systolic function and may have the potential to differentiate HCM from variant forms of LVH.