Background

Diabetes and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electrical properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation versus the contribution of global metabolic defects to the increased incidence of sudden death and electrical abnormalities.

Methods and Results

In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes and obesity, we studied cardiac-specific transgenic mice expressing PPARγ1 via the cardiac α-myosin heavy-chain promoter. The PPARγ-transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults, prior to a significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals, and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice, but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ TG mice.

Conclusions

Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling and increased cardiac mortality.

BACKGROUND

The relationship between alcohol consumption and ischemic stroke or aortic atherosclerosis is unclear, but a protective effect of moderate consumption on stroke risk has been suggested. We conducted a cross-sectional analysis in a population-based sample to evaluate the possible association between alcohol consumption and aortic atherosclerotic plaque (AAP), which is associated with increased stroke risk.

METHODS

As part of the NINDS-funded Aortic Plaques and Risk of Ischemic Stroke (APRIS) study, 464 subjects over the age of 55 were studied (mean age 69.1±9.0 with 251 males and 213 females), including 255 patients with first ischemic stroke and 209 stroke-free controls. Transesophageal echocardiogram was performed for the detection of AAP. Alcohol consumption was measured in number of drinks per week during the previous year using a standardized questionnaire, and categorized as: (1) none or minimal (<1 drink per month); (2) light to moderate (between 1 drink per month and 2 drinks daily); and (3) heavy (>2 daily). Multivariate conditional logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence interval (CI) for alcohol consumption and AAP after adjustment for the potential confounding risk factors (age, sex, hypertension, diabetes, dyslipidemia, and cigarette smoking).

RESULTS

Overall, AAP were detected in 326 subjects (70.4%), and 174 subjects (37.6%) had AAP ≥ 4mm, which carry higher stroke risk. No or minimal alcohol consumption was present in 241 subjects (53.2%), and 177 subjects (39.0%) had light to moderate consumption. Prevalence of light to moderate alcohol consumption was significantly lower in stroke patients than in controls (35.5% vs. 60.3%, p<0.001) and in subjects who had AAP compared with those without it (41.6% vs. 58.8%, p=0.008). After adjusting for significant predictors of atherosclerosis, alcohol consumption of any degree was inversely associated with AAP (OR 0.61; 95%CI 0.37–0.98, p=0.042). The significance of the association was borderline for AAP ≥ 4mm (OR 0.64, 95%CI 0.41–1.00, p=0.054). In the dose-response analysis, only light to moderate alcohol consumption was significantly associated with a lower risk of having any AAP (adjusted OR 0.45; 95%CI 0.29–0.68, p<0.001) or AAP ≥ 4mm (adjusted OR 0.51; 95%CI 0.34–0.77, p=0.001).

CONCLUSIONS

Our data indicate that light to moderate alcohol consumption is associated with lower atherosclerotic burden in the proximal aortic arch. This observation may explain at least in part the lower risk of ischemic stroke observed in moderate alcohol consumers.

Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α–myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.

Background

Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous- versus pulsatile-flow LVADs on myocardial structure and function in this population.

Methods and Results

Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: Group P, n=31; continuous-flow LVAD: Group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP) and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative left ventricular (LV) ejection fraction was greater (33.2±12.6 vs. 17.6±8.8%, p<0.0001) and the mitral E/E′ was lower (9.9±2.6 vs. 13.2±3.8, p=0.0002) in Group P versus Group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9 and tissue inhibitor of MMP (TIMP)-4 were significantly lower in Group P compared to Group C (BNP: 552.6±340.6 vs. 965.4±805.7 pg/mL, p<0.01; MMP9: 309.0±220.2 vs. 475.2±336.9 ng/dL, p<0.05; TIMP4: 1490.9±622.4 vs. 2014.3±452.4 ng/dL, p<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in Group P (p=0.024).

Conclusions

Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.

Objective

Left atrial (LA) maximum volume (LAVmax) is an indicator of left ventricular (LV) diastolic function. However, LAVmax is also influenced by systolic events, whereas the LA minimum volume (LAVmin) is directly exposed to LV pressure. The authors hypothesised that LAVmin may be a better correlate of LV diastolic function than LAVmax.

Design

Cross-sectional.

Setting

University hospital.

Patients

357 participants from a community-based cohort study.

Methods

LA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e′). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking.

Results

LAVmin significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAVmax was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAVmin and LAVmax were significant predictors of E/e′, with higher parameter estimates for LAVmin. In multivariate models, LAVmin resulted strongly associated with E/e′ (β=0.45, p<0.001), whereas LAVmax was not (β=− 0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAVmax (β=− 0.15, p=0.002), LAEV (β=−0.37, p<0.001) and LAEF (β=−0.28, p<0.001) but not with LAVmin.

Conclusions

LAVmin is a better correlate of LV diastolic function than LAVmax. The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAVmax and LV diastolic function.

Objective

To explore race-ethnic differences in the relationship between plasma lipid components and risk of incident myocardial infarction (MI).

Design/Methods

As part of the Northern Manhattan Study, 2738 community residents without cardiovascular disease were prospectively evaluated. Baseline fasting blood samples were collected and lipid panel components were analyzed as continuous and categorical variables. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for incident MI after adjusting for demographic and cardiovascular risk factors.

Results

The mean age was 68.8±10.4 years; 36.7% men, 19.9% non-Hispanic white, 24.9% non-Hispanic black, and 52.8% Hispanic (over 80% from the Caribbean). Hispanics had lower mean HDL-C, and higher TG/HDL-C. During a mean 8.9 years of follow-up there were 163 incident MIs. In the whole cohort all lipid profile components were associated with risk of MI in the expected directions. However, HDL-C (adjusted HR per 10 mg/dl increase 0.93, 95%CI 0.76–1.12) and TG/HDL-C>2 (adjusted HR 0.89, 95%CI 0.51–1.55) were not predictive of MI among Hispanics, but were predictive among non-Hispanic blacks and whites. TG/HDL-C per unit increase was associated with an 8% higher risk of MI among Hispanics (adjusted HR 1.08, 95%CI 1.04–1.12).

Conclusions

In Hispanics, low HDL-C and TG/HDL-C>2 were not associated with MI risk. Our data suggests that a different TG/HDL ratio cutoff may be needed among Hispanics to predict MI risk.

Objectives

To assess the independent effect of increased body size on left ventricular (LV) diastolic function.

Background

Obese and overweight individuals are at increased risk of heart failure. LV diastolic dysfunction is an asymptomatic condition associated with future heart failure. It is unclear whether obesity and overweight are independently associated with LV diastolic dysfunction.

Methods

LV diastolic function was evaluated in 950 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study by traditional and tissue-Doppler imaging. Peak early and late trans-mitral diastolic flow velocities (E, A) and early diastolic mitral annulus velocity (E′) were measured, and E/A and E/E′ were calculated. The study sample was divided into three groups: normal weight [body mass index (BMI)<25.0], overweight (BMI 25.0–29.9) and obese (BMI≥30).

Results

In multivariate analyses, BMI was independently associated with higher E, A, and E/E′, an indicator of LV filling pressure (all p≤0.01). Overweight and obese had lower E′ (both p<0.01) and higher E/E′ (both p<0.01) than normal weight participants. E/A was lower in obese than normal weight subjects (p<0.01). The risk of diastolic dysfunction was significantly higher in overweight (adjusted odds ratio: 1.52, 95% confidence intervals 1.04–2.22) and obese (adjusted odds ratio: 1.60, 95% confidence intervals 1.06–2.41) compared to normal weight individuals.

Conclusions

Increased BMI was associated with worse LV diastolic function independent of LV mass and associated risk factors. The increased risk of LV diastolic dysfunction in both overweight and obese individuals may partially account for the increased risk of heart failure associated with both conditions.

Objectives

Increased arterial wave reflection is a predictor of cardiovascular events and has been hypothesized to be a cofactor in the pathophysiology of heart failure. Whether increased wave reflection is inversely associated with left ventricular (LV) systolic function in subjects without heart failure is not clear.

Methods

Arterial wave reflection and LV systolic function were assessed in 301 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study using 2-dimensional echocardiography and applanation tonometry of the radial artery to derive central arterial waveform by a validated transfer function. Aortic augmentation index (AIx) and wasted energy index (WEi) were used as indices of wave reflection. LV systolic function was measured by ejection fraction (LVEF) and tissue Doppler imaging (TDI). Mitral annulus peak systolic velocity (Sm), peak longitudinal strain and strain rate were measured. Participants with history of coronary artery disease, atrial fibrillation, LVEF <50% or wall motion abnormalities were excluded.

Results

Mean age of the study population was 68.3±10.2 years (64.1% women, 65% hypertensive). LV systolic function by TDI was lower with increasing wave reflection, whereas LVEF was not. In multivariate analysis, TDI parameters of LV longitudinal systolic function were significantly and inversely correlated to AIx and WEi (p values from 0.05 to 0.002).

Conclusions

In a community cohort without heart failure and with normal LVEF, an increased arterial wave reflection was associated with subclinical reduction in LV systolic function assessed by novel TDI techniques. Further studies are needed to investigate the prognostic implications of this relationship.

Background

Social isolation is associated with progression of cardiovascular disease with the most socially isolated patients being at increased risk. Increased left ventricular mass is a predictor of cardiovascular morbidity and mortality. It is not yet clear whether social isolation is a determinant of increased left ventricular mass.

Methods

We performed a cross-sectional study of Northern Manhattan Study participants who were free of clinical cardiovascular disease, had obtained transthoracic echocardiograms (n=2021) and a baseline questionnaire on social habits. Social isolation was defined as the lack of friendship networks (knowing fewer than 3 people well enough to visit within their homes). Echocardiographic left ventricular mass was indexed to height2.7, analyzed as a continuous variable and compared between exposure groups.

Results

The prevalence of social isolation was 13.5%. The average left ventricular mass was significantly higher (50.2 gm/m2.7) in those who were, as compared to those who were not (47.6 gm/m2.7), socially isolated (p<0.05). Higher prevalence of social isolation was found among those less educated, uninsured or unemployed.There were no significant race-ethnic differences in the prevalence of social isolation. In multivariate analysis, there was a trend toward an association between social isolation and increased left ventricular mass in the total cohort (p=0.09). Among Hispanics, social isolation was significantly associated with greater left ventricular mass. Hispanics who were socially isolated averaged 3.9 gm/ht2.7 higher left ventricular mass compared to those not socially isolated (p=0.002). This relationship was not present among non-Hispanic blacks or whites.

Conclusion

In this urban tri-ethnic cohort, social isolation was prevalent and associated with indices of low socioeconomic status. Hispanics who were socially isolated had a greater risk for increased left ventricular mass.

Objectives

We sought to assess the association between the presence of a septal pouch in the left atrium and ischemic stroke.

Background

Recently, a new anatomical entity, named a left septal pouch (LSP), was described in a pathology study. It was suggested that the presence of LSP may favor the stasis of blood and possibly result in thromboembolic complications. However, the embolic potential of a LSP is not known.

Methods

The association between LSP and risk of stroke was assessed using a population-based case-control study design. The presence of LSP was assessed by transesophageal echocardiography in 187 patients over age 50 with first-ever ischemic stroke (96 men, mean age 70.6 ± 9.0 years) and in 157 control subjects matched to patients by age, sex, and race/ethnicity. The association between LSP and risk of stroke was assessed after adjustment for other stroke risk factors.

Results

Patients with LSPs were younger (67.5 ± 9.1 vs. 69.6 ± 8.8; p=0.046) and had a lower proportion of hypertension (68.0% vs. 80.3%; p=0.01). There were no difference in the prevalence of LSP between stroke patients and control subjects (28.9% vs. 29.3%; p=0.93). The subgroup of 69 patients (36.9%) with crytptogenic stroke showed a similar prevalence of LSP (31.9% vs. 29.3%; p=0.70). Multivariable analysis showed that the presence of LSP was not associated with ischemic stroke (OR 1.09, 95% CI 0.64 to 1.85) or cryptogenic stroke (OR 1.41, 95% CI 0.71 to 2.78).

Conclusions

This study does not demonstrate evidence for association of the presence of LSP with ischemic stroke, or with cryptogenic stroke. The stroke risk associated with LSP may still require further evaluation in the younger stroke populations. The possibility that associated cofactors that may turn LSP from an innocent bystander into a causative mechanism for stroke remain to be elucidated.

A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD) and db/db and ob/ob mice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers. By echocardiography, ejection fraction (EF) and fractional shortening (FS) of left ventricular diameter during systole were significantly reduced. The Vmax for saturable fatty acid uptake was increased and significantly correlated with cardiac triglycerides and insulin concentrations. Vmax also correlated with expression of genes for the cardiac fatty acid transporters Cd36 and Slc27a1. Genes for de novo fatty acid synthesis (Fasn, Scd1) were also upregulated. Ten oxidative phosphorylation pathway genes were downregulated, suggesting that a decrease in cardiomyocyte ATP synthesis might explain the decreased contractile function in obese hearts.

Background

The American Society of Echocardiography (ASE) recommends to calculate LA biplane volume because of its greater accuracy and prognostic value over LA diameter. However, biplane methods are not always feasible. We sought to assess the correlation between the echocardiographic LA biplane and single-plane volume and their agreement in the classification of LA size when ASE cut-offs are applied.

Methods

We performed 2D-echocardiography in the participants of the population-based CABL (Cardiovascular Abnormalities and Brain Lesions) study. LA volume was calculated by biplane area-length and single-plane modified Simpson’s methods, and validated against three-dimensional (3D) echocardiography.

Results

The study sample consisted of 527 participants (69.6±9.7 years, 61.9% women). Both single- and biplane LA volume correlated well with 3D-echocardiography (r=0.93; p<0.001). Correlation between the single-plane and biplane methods was excellent (r=0.95, p<0.001; intraclass correlation coefficient: 0.92, 95% confidence intervals [CI] 0.80-0.96). Categorical agreement between single- and biplane was modest (k=0.51, 95% CI 0.45-0.57, disagreement rate 26.0%), mainly because of overestimation by the single-plane method. The correction of the single-plane volume by a regression equation improved the agreement (k=0.70, 95% CI 0.64-0.76), but a misclassification remained in 14.0% of cases.

Conclusions

Single- and biplane LA volume measurements have strong correlations, but their agreement for categorical classification is suboptimal. Specific cut-off points should be developed for the single-plane method.

Aim and Hypothesis

The goal of this study was to determine if individuals with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) had greater endothelial dysfunction (ED) than individuals with only CAD.

Methods

Flow mediated dilation (FMD), calculated as percentage increase in brachial artery diameter in response to post-ischemic blood flow, was measured after an overnight fast in two cohorts. The first cohort included 76 participants in the Northern Manhattan Study (NOMAS) with CAD; 25 also had T2DM. The second cohort was composed of 27 individuals with both T2DM and CAD who were participants in a study of postprandial lipemia. Combined, we analyzed 103 patients with CAD; 52 with T2DM (T2DM+) and 51 without T2DM (T2DM−).

Results

The 52 CAD T2DM+ subjects had a mean FMD of 3.9 ± 3.2%, while the 51 CAD T2DM− subjects had a greater mean FMD of 5.5 ± 4.0% (P<0.03). An investigating of various confounders known to affect FMD identified age and BMI as the only significant covariates in a multiple regression model. Adjusting for age and BMI, we found that FMD remained lower in T2DM+ subjects compared to T2DM− subjects (difference −1.99%, P<0.03).

Interpretation/Conclusion

In patients with CAD, the concomitant presence of T2DM is independently associated with greater ED, as measured by FMD. This finding may be relevant to the greater early and late morbidity and mortality observed in patients with both CAD and T2DM.

Background

Left atrial enlargement is associated with cardiovascular disease. Genetic factors contributing to the left atrium (LA) dimension are poorly understood. We sought to map susceptibility genes for LA size in a large Dominican family dataset and an independent population-based cohort from the Northern Manhattan Study (NOMAS).

Methods and Results

100 Dominican families consisting of 1350 individuals were used to estimate heritability and map quantitative trait loci for LA size using variance components analysis. LA dimension was measured by transthoracic echocardiography. A polygenic covariate screening was used to identify significant covariates. LA size had a moderate estimate of heritability (h2=0.42), after adjusting for significant covariates. Linkage analysis of 405 microsatellite markers revealed suggestive evidence on chromosome 10p19 (D10S1423, MLOD=2.00) and 17p10 (D17S974, MLOD=2.05). Ordered subset analysis found significantly enhanced (p<0.05 for increase of LOD score) evidence for linkage at 17p10 (MLOD=2.9) in families with lower LDL level. 2233 single nucleotide polymophisms (SNPs) were used to perform a peak-wide association mapping across 17p10 in 825 NOMAS individuals. Strong evidence for association were found in NTN1, MYH10, COX10, and MYOCD genes (p=0.00005 to 0.005).

Conclusions

Using non-biased genome-wide linkage followed by peak-wide association analysis, we identified several possible susceptibility genes affecting LA size. Among them, MYOCD has been shown to serve as a key transducer of hypertrophic signals in cardiomyocytes in vitro. Evidence from our linkage and association study, together with the known function, strongly suggests that polymorphisms in MYOCD gene modify LA size.

BACKGROUND

We conducted a cross-sectional analysis in a population-based cohort to compare the strength of the associations among various lipid parameters and the presence of atherosclerotic plaque (AP) in the proximal thoracic aorta.

METHODS

As part of Aortic Plaques and Risk of Ischemic Stroke (APRIS) study, 464 subjects were studied (mean age 69.1±9.0, 251 males and 213 females), including 255 patients with first ischemic stroke and 209 stroke-free controls. Presence and thickness of AP were assessed by transesophageal echocardiography. Measured lipid parameters included total cholesterol, triglycerides (TG), LDL, HDL, and non-HDL cholesterol, lipoprotein (a), apolipoprotein (Apo) B and A-I levels with their ratio.

RESULTS

Overall, AP was detected in 326 subjects (70.4%) and 37.6% of these subjects (n=174) had AP ≥4mm. After adjusting for other significant predictors of atherosclerosis, HDL cholesterol level and Apo B/A-I ratio emerged as the strongest predictors of any AP (p<0.001 and p=0.004, respectively), followed by individual Apo B (p=0.015) and A-I (p=0.016) levels, TG (p=0.027) and non-HDL cholesterol level (p=0.021). Total and LDL cholesterol levels were not significant predictors for any AP (p=0.273 and p=0.081, respectively). HDL cholesterol level (p=0.008) and Apo A-I (p=0.006) were significant predictors of AP ≥4mm. Similar trends were observed after exclusion of subjects on cholesterol lowering drugs.

CONCLUSIONS

HDL cholesterol level and Apo B/A-I ratio, but not total or LDL cholesterol levels, were strongly associated with degree of proximal aortic atherosclerosis.

Background

Racial-ethnic disparities exist in cardiovascular risk factors, morbidity and mortality. Left ventricular (LV) diastolic dysfunction is a predictor of mortality and of cardiovascular outcome including incident heart failure. We sought to assess whether race-ethnic differences in diastolic function exist. Such differences may contribute to the observed disparities in cardiovascular outcomes.

Methods

Two-dimensional echocardiography was performed in 760 participants (539 Hispanic, 117 non-Hispanic black, 104 non-Hispanic white) from the Cardiac Abnormalities and Brain Lesions (CABL) study. LV diastolic function was assessed by standard Doppler flow profile and tissue Doppler imaging (TDI). Early (E) and late (A) trans-mitral diastolic flow, and mitral annulus early diastolic velocities (E’) were recorded and E/A and E/E’ ratios were calculated.

Results

Blacks and Hispanics had higher body mass index (p=0.04, p<0.01), higher prevalence of hypertension (both p≤0.05) and diabetes (both p<0.01), and lower level of education (both p<0.01) compared to whites. In age- and sex-adjusted analyses, Hispanics and blacks showed worse indices of diastolic function than whites. Hispanics had lower E/A ratio (p=0.01), lower E’ and higher E/E’ (both p<0.01) than whites, whereas blacks had lower E’ (p<0.05) and a trend toward a higher E/E’ ratio (p=0.09) compared with whites. These race-ethnic differences in diastolic function were attenuated in multivariate models adjusted for cardiovascular risk factors.

Conclusions

Differences in LV diastolic function exist between race-ethnic groups. However, modifiable cardiovascular risk factors and socio-demographic variables, rather than intrinsic race-ethnic heterogeneity, seem to explain most of the observed differences.

Objectives

To evaluate the association between carotid intima-media thickness (CIMT) and the presence of aortic arch plaques (AP) in a community-based cohort.

Background

Large AP are associated with ischemic stroke. CIMT is a marker of subclinical atherosclerosis and a strong predictor of cardiovascular disease and stroke. The association between CIMT and AP has been studied in stroke patients, but not in the general population. Aim of this study was to investigate this association in an elderly asymptomatic cohort, and the possibility to use CIMT to predict the presence or absence of large AP.

Methods

Stroke-free control subjects from the Aortic Plaque and Risk of Ischemic Stroke (APRIS) Study underwent transesophageal echocardiography and high-resolution B-mode ultrasound of the carotid arteries. CIMT was measured at the common carotid artery, bifurcation and internal carotid artery. The association between CIMT and AP was analyzed by multivariate regression models. Positive and negative predictive values of CIMT for large (≥ 4 mm) AP were calculated.

Results

Among 138 subjects, large AP was present in 35 (25.4%) subjects. Only CIMT at the bifurcation was associated with large AP after adjustment for atherosclerotic risk factors (p=0.007). Positive and negative predictive value for AP ≥ 4 mm of CIMT at the bifurcation above the 75th percentile (≥ 0.95 mm) were 42% and 80%, respectively. Negative predictive value increased to 87% when the median CIMT value (0.82 mm) was used.

Conclusions

CIMT at the bifurcation is independently associated with AP ≥ 4 mm. Its strong negative predictive value for large arch plaque indicates that CIMT may be used as an initial screening test to exclude severe arch atherosclerosis in the general population.

An important goal in clinical cardiology is the non-invasive quantification of regional cardiac deformation. While many methods have been proposed for the estimation of 3D left ventricular deformation and strains derived from 4D ultrasound, currently there is a lack of in vivo clinical validation of these algorithms on humans. In this paper, we describe the experiments used in validating cardiac deformation and strain estimates of 4D ultrasound using correlation-based optical flow tracking on two different COPD patients with normal left ventricular function. Validation of the algorithm was done by 1) validation of cardiac volume across multiple scans of the same patient and 2) validation of the repeatability of cardiac displacement and strain results from multiple scan acquisitions of the same patient. The preliminary results are encouraging with our algorithm producing consistent cardiac volume and strain results across multiple acquisitions. Furthermore, our derived 4D cardiac strains showed qualitatively correct results. We also observed particularly interesting results in the radial displacements of the posterior and lateral walls of our COPD patients.

High-frequency ultrasound imaging using microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse microbubble suspensions, which may provide a complex and varied acoustic response. In order to study the effect of individual microbubble size populations, microbubbles of 1-2 μm, 4-5 μm, and 6-8 μm diameter were isolated using the technique of differential centrifugation. Size-selected microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on microbubble size and concentration. Large microbubbles (4-5 and 6-8 μm) strongly enhanced the ultrasound image with positive contrast, while 1-2 μm microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6-8 μm diameter microbubbles at 5×107 MB/bolus compared to 4-5 μm microbubbles at the same concentration. Interestingly, 1-2 μm diameter microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger microbubbles were more persistent in circulation. However, when volume matched, all microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging.

Aims

To assess the independent and combined effects of diabetes and hypertension on left ventricular (LV) diastolic function in a community-based cohort at high cardiovascular risk.

Methods and results

Two-dimensional echocardiography was performed in 708 subjects from the Cardiac Abnormalities and Brain Lesions (CABL) study. Peak diastolic early (E) and late (A) transmitral flow, and tissue Doppler-derived early mitral annulus velocity (E′) were recorded, and E/A and E/E′ ratios were calculated. The population was divided into four groups: those without hypertension or diabetes (HT−/DM−), those with only hypertension (HT), only diabetes (DM), and with hypertension plus diabetes (HT + DM). In multivariate analysis, hypertension and diabetes were independent predictors of worse diastolic function. The coexistence of hypertension and diabetes was associated with greater impairment of diastolic function (higher E/E′ ratio than HT−/DM−, HT, or DM, all P < 0.05), independent of covariates. The negative, synergistic effect of hypertension and diabetes on LV diastolic function was present both in lean participants and in overweight/obese ones. An E/E′ ratio >15, suggestive of increased LV filling pressure, was found in 2.2% of HT−/DM−, 8.9% of HT, 5.9% of DM, and 14.7% of HT + DM (P < 0.01).

Conclusion

Hypertension and diabetes are independently associated with impaired LV diastolic function, independent of the effect of overweight/obesity and other covariates. Their coexistence results in a negative synergistic effect on LV diastolic mechanics and is associated with higher LV filling pressures than either condition alone.

Hypertension is associated with impaired endothelial function in cross-sectional studies. However, few longitudinal data exist on whether endothelial dysfunction precedes the development of hypertension. We examined the cross-sectional and longitudinal relationships between endothelial-dependent brachial artery flow-mediated dilation (FMD) and hypertension prevalence and incidence in 3,500 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), an ethnically diverse, community-based cohort study. At baseline, the prevalence ratios (95% CI) of hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.26 (1.12 – 1.40), 1.35 (1.21 – 1.52), and 1.68 (1.50 – 1.87) (linear trend P < 0.001). This association remained (P = 0.017) after adjustment for demographics (age, gender, ethnicity), MESA site, and other risk factors. Of the 1,869 participants without hypertension at baseline, 584 (31.3%) developed hypertension over a median follow-up of 4.8 years. The unadjusted relative risks (95% CI) of incident hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.38 (1.14 – 1.67), 1.44 (1.19 – 1.74), and 1.64 (1.36 – 1.97) (linear trend P < 0.001). However, after adjustment for demographics and MESA site, the relationship between FMD and incident hypertension was attenuated and not statistically significant: 1.00 (referent), 1.26 (1.04 – 1.52), 1.19 (0.98 – 1.44), and 1.18 (0.97 – 1.44). The longitudinal results also did not appreciably change after adjustment for additional risk factors and baseline blood pressure levels. In this sample, reduced FMD was not an independent predictor of hypertension incidence, suggesting that impaired endothelial function does not play a major role in the development of hypertension.

BACKGROUND

Increased left ventricular (LV) mass and endothelial dysfunction are important risk factors for cardiovascular mortality and morbidity. However, it is not clear whether endothelial dysfunction is associated with increased LV mass. We tested the hypothesis that impaired flow-mediated vasodilatation (FMD) is associated with increased LV mass in a population-based multi-ethnic cohort.

METHODS

As a part of the Northern Manhattan Study, we performed two-dimensional echocardiography and FMD assessment during reactive hyperemia by high-resolution ultrasonography in 867 stroke-free community participants. LV mass was calculated according to an established method. LV hypertrophy was defined as the 90th percentile of sex-specific LV mass indexed for body surface area among normal subjects. Multivariable models were used to test the association of FMD with LV mass.

RESULTS

In multiple linear regression analyses adjusting for age, sex, body mass index, systolic blood pressure, antihypertensive medications, low-density lipoprotein cholesterol, diabetes, smoking, hematocrit, and race-ethnicity, FMD was inversely associated with LV mass (β = −1.21 ± 0.56, P = 0.03). The association persisted after further adjustment for any component of blood pressure (systolic, mean, and pulse pressure). In univariate logistic regression analysis, each 1% decrease in FMD was associated with a 8% higher risk of LV hypertrophy [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03–1.13 per each FMD point P< 0.01].

CONCLUSIONS

Impaired FMD is associated with LV mass, independent of other factors associated with increased LV mass. Endothelial dysfunction might be a potential risk factor for LV hypertrophy.

Background

Prior studies suggest that the causes of calcific aortic valve (AV) disease involve chronic inflammation, lipoprotein levels, and calcium metabolism, all of which may differ among race-ethnic groups. We sought to determine whether AV thickness differs by race-ethnicity in a large multi-ethnic population-based cohort.

Methods

The Northern Manhattan Study (NOMAS) includes stroke-free community-based Hispanic (57%), non-Hispanic black (22%), and non-Hispanic white (21%) participants. The relation between AV thickness on transthoracic echocardiography and clinical risk factors for atherosclerosis was evaluated among 2085 participants using polytomous logistic regression models. AV thickness was graded in three categories (normal, mild, and moderate/severe) based on leaflet thickening and calcification.

Results

Mild AV thickness was present in 44.4% and moderate/severe thickness in 5.7% of the cohort, with the lowest frequency of moderate/severe thickness seen particularly among Hispanic females. In multivariate models adjusting for age, sex, race-ethnicity, body mass index, hypertension, coronary artery disease, blood glucose, and high-density lipoprotein cholesterol, Hispanics had significantly less moderate/severe AV thickness (odds ratio (OR) 0.43, 95% confidence interval (95% CI) 0.25 to 0.73) than non-Hispanic whites. Men were almost 2-fold as likely to have moderate/severe AV thickness compared to women (OR 1.96, 95% CI 1.24 to 3.10).

Conclusions

In this large multi-ethnic population-based cohort, there were ethnic differences in the degree of AV thickness. Hispanic ethnicity was strongly protective against AV thickness. This effect was not related to traditional risk factors, suggesting that unmeasured factors related to Hispanic ethnicity and AV thickness may be responsible.

Stress echocardiography is an important screening test for coronary artery disease. Currently, cardiologists rely on visual analysis of left ventricular (LV) wall motion abnormalities, which is subjective and qualitative. We previously used finite-element models of the regionally ischemic left ventricle to develop a wall motion measure, 3DFS, for predicting ischemic region size and location from real-time 3D echocardiography (RT3DE). The purpose of this study was to validate these methods against regional blood flow measurements during regional ischemia and to compare the accuracy of our methods to the current state of the art, visual scoring by trained cardiologists. We acquired RT3DE images during 20 brief (<2 min) coronary occlusions in dogs and determined ischemic region size and location by microsphere-based measurement of regional perfusion. We identified regions of abnormal wall motion using 3DFS and by blinded visual scoring. 3DFS predicted ischemic region size well (correlation r2=0.64 against microspheres, p<0.0001), reducing error by more than half compared to visual scoring (8±9% vs. 19±14%, p<0.05), while localizing the ischemic region with equal accuracy. We conclude that 3DFS is an objective, quantitative measure of wall motion that localizes acutely ischemic regions as accurately as wall motion scoring while providing superior quantification of ischemic region size.

Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12–14/group): control (vehicle); nitro-l-arginine methyl ester (l-NAME) an NO synthase inhibitor; simvastain (SIM), an NO synthase activator; and SIM+l-NAME. Serial echocardiography was performed and blood pressure (BP) at 6 weeks was recorded using a micromanometer. Myocardial eNOS and mitogen-activated protein kinase (MAPK, including ERK, p38, and JNK) protein expression were measured. Results showed that (i) B2RKO mice had significantly lower ejection fraction than did WT mice (61% ± 1% vs. 73% ± 1%), lower myocardial eNOS and phospho-eNOS, normal systolic BP, and higher LV mass, phospho-p38, and JNK; (ii) l-NAME increased systolic BP in KO mice (117 ± 19 mm Hg) but not in WT mice and exacerbated LV hypertrophy and dysfunction; and (iii) in KO mice, SIM decreased hypertrophy, p38, and JNK, improved function, increased capillary eNOS and phospho-eNOS, and prevented l-NAME-induced LV hypertrophy without lowering BP. We conclude that disruption of the B2R causes maladaptive cardiac hypertrophy with myocardial eNOS downregulation and MAPK upregulation. SIM reverses these abnormalities and prevents the development of primary cardiac hypertrophy as well as hypertrophy secondary to l-NAME-induced hypertension.