Usefulness of biventricular volume as a predictor of mortality in patients with diabetes mellitus (from the Diabetes Heart Study).

Patients with type 2 diabetes mellitus are at increased risk for cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. The aim of this study was to examine the relationship between BiVV and risk for mortality in European Americans with type 2 diabetes mellitus from the Diabetes Heart Study (DHS). BiVV was calculated from 771 noncontrast computed tomographic scans performed to image coronary artery calcified plaque. Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional-hazards regression was performed to determine risk for mortality (all-cause and CVD mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years of follow-up, 23% of the patients died. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, coronary artery calcified plaque, history of hypertension, and previous myocardial infarction (p <0.0001 to 0.012). BiVV was significantly associated with all-cause (hazard ratio 2.45, 95% confidence interval 1.06 to 5.67, p = 0.036) and CVD (hazard ratio 4.36, 95% confidence interval 1.36 to 14.03, p = 0.014) mortality in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p = 0.04) and from 0.74 to 0.77 (p = 0.02) for all-cause and CVD mortality with the inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contraindicated, BiVV from computed tomography may be considered a tool for the stratification of high-risk patients, such as those with type 2 diabetes mellitus.

Effect of muscadine grape seed supplementation on vascular function in subjects with or at risk for cardiovascular disease: a randomized crossover trial.

BACKGROUND: Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function. OBJECTIVES: To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk. DESIGN: In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models. RESULTS: There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation. CONCLUSIONS: Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.

Chronic kidney disease and dipstick proteinuria are risk factors for stent thrombosis in patients with myocardial infarction.

BACKGROUND: Kidney failure (stage 5 chronic kidney disease [CKD]) is an independent risk factor for stent thrombosis (ST). Moderate (stage 3-4) CKD and proteinuria are both associated with adverse cardiovascular events, including worse outcomes after myocardial infarction (MI). Whether moderate CKD and proteinuria increase the risk of ST after MI is not known. This study evaluated the risk of ST associated with moderate CKD and dipstick proteinuria. METHODS: We retrospectively analyzed clinical and laboratory data from 956 non-stage 5 CKD patients who were admitted with MI and received intracoronary stenting. Clinical follow-up was collected at 1 year for definite or probable ST, as well as for all-cause mortality, nonfatal MI or death, and target vessel revascularization or coronary artery bypass graft surgery. RESULTS: After adjustment for multiple clinical and biochemical covariates, patients with both estimated glomerular filtration rate (GFR) of 15 to 59 mL min(-1) 1.73 m(-2) and > or =30 mg/dL dipstick proteinuria had increased cumulative incidence of ST (hazard rate [HR] 3.69, 95% CI 1.54-8.89), all-cause mortality (HR 2.68, 95% CI 1.34-5.37), and nonfatal MI or death (HR 3.20, 95% CI 1.77-5.81) at 1 year. In addition, estimated GFR of 15 to 59 mL min(-1) 1.73 m(-2) was a significant independent predictor of ST (HR 2.61, 95% CI 1.33-5.10). Dipstick proteinuria > or =30 mg/dL was associated with a trend toward increased risk for all outcomes. CONCLUSIONS: In an acute MI population, moderate CKD was identified as a novel prognostic marker for ST. In addition, patients with both decreased GFR and proteinuria had higher incidences of all-cause mortality and nonfatal MI or death than patients with either condition alone.

Effect of aldosterone antagonism on exercise tolerance, Doppler diastolic function, and quality of life in older women with diastolic heart failure.

Optimal therapy for diastolic heart failure (DHF), the most common form of heart failure in older persons, is unclear. To determine the effect of aldosterone antagonism in DHF, the authors conducted an open-label preliminary trial of spironolactone 25 mg/d in 11 women with DHF. Cardiopulmonary exercise testing, Doppler echocardiography, and a quality-of-life survey were administered at baseline and after 4 months. Peak exercise VO(2) increased by 8.3% (P=.001), the ratio of Doppler diastolic early filling velocity to mitral annulus velocity decreased by 25% (P=.02), quality-of-life score improved by 21% (P=.16 for trend), and median New York Heart Association class improved from class III to class II (P=.004). Findings from this preliminary study confirm the role of aldosterone in the pathophysiology of DHF and suggest that aldosterone antagonism may benefit such patients. These hypotheses are currently being tested in two separated National Institutes of Health-funded, randomized trials, the Spironolactone for Failure in the Elderly (SPIFFIE) and the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trials.

Relationship between genetic variants in myocardial sodium and potassium channel genes and QT interval duration in diabetics: the Diabetes Heart Study.

BACKGROUND: Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval. METHODS: We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index. RESULTS: Within KCNQ1 there was weak evidence for association between the minor allele of IVS12 +14T>C and increased QTc (P = 0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (P = 0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (P = 0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation. CONCLUSIONS: We found weak evidence of association between three previously reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remain to be determined.

Hepatic steatosis and subclinical cardiovascular disease in a cohort enriched for type 2 diabetes: the Diabetes Heart Study.

OBJECTIVES: To explore mechanisms whereby hepatic steatosis may be associated with cardiovascular risk, we investigated cross-sectional relationships between hepatic steatosis, regional fat accumulation, inflammatory biomarkers, and subclinical measures of atherosclerosis in the Diabetes Heart Study. METHODS: The Diabetes Heart Study is a family study of sibling pairs concordant for type 2 diabetes. A subset of 623 randomly selected participants was evaluated for hepatic steatosis, defined as a liver:spleen attenuation ratio of <1.0 by computed tomography. We quantified visceral fat, subcutaneous fat, coronary, aortic, and carotid artery calcium by computed tomography; and carotid atherosclerosis by ultrasound. Associations between the liver:spleen attenuation ratio and these factors were expressed as Spearman correlations. RESULTS: After adjustment for age, race, gender, body mass index, and diabetes status, the liver:spleen attenuation ratio correlated with visceral fat (r =-0.22, P < 0.0001) and subcutaneous fat (r =-0.13, P= 0.031). Hepatic steatosis was associated with lower high-density lipoprotein (r = 0.21, P < 0.0001), higher triglycerides (r =-0.25, P < 0.0001), higher C-reactive protein (r =-0.095, P= 0.004), and lower serum adiponectin (r = 0.34, P < 0.0001). There were no significant associations between the liver:spleen attenuation ratio and coronary, aortic, or carotid calcium, or carotid intimal thickness. CONCLUSIONS: This suggests that hepatic steatosis is less likely a direct mediator of cardiovascular disease and may best be described as an epiphenomenon. The strong correlations between pro-atherogenic biomarkers, visceral fat, and elements of the metabolic syndrome suggest that hepatic steatosis reflects more than general adiposity, but represents a systemic, inflammatory, pro-atherogenic adipose state.

Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.

Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the posttranslational modification of intra- and extracellular proteins and implicated in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (LOPAC and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor, and its metabolite ZM449829 were the most potent inhibitors with IC(50) of 10 and 5 nM, respectively. In addition, two other inhibitors, including tyrphostin 47 and vitamin K(3), were found to have an IC(50) in the micromolar range. These agents used in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intramolecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.

Associations between electrocardiographic interval durations and coronary artery calcium scores: the Diabetes Heart Study.

BACKGROUND: The mechanisms underlying the associations between QT interval duration and risk of cardiovascular disease (CVD) remain unclear. It has been assumed that these associations are driven by abnormal myocardial repolarization. We examined the relationship between coronary artery disease, measured by coronary artery calcified plaque (CAC), and the duration of QRS, JT, and QT intervals, among predominantly type two diabetic participants. METHODS: The study sample included 1,123 subjects from the Diabetes Heart Study, of whom 85% had type 2 diabetes. Correlations between electrocardiogram interval durations and log-transformed coronary artery calcified (CAC) were assessed in univariate and sequential multivariable generalized estimating equation models adjusted for familial correlations, heart rate, age, race, gender, diabetes status, hypertension status, Body Mass Index (BMI), smoking status, systolic blood pressure, Low Density Lipoprotein (LDL) cholesterol, QT-prolonging medications, and use of exogenous estrogen. RESULTS: QT interval duration significantly correlated with the extent of CAC in univariate (r = 0.09, P = 0.01) and multivariable models (r = 0.08, P = 0.01). We observed strong correlations between the QRS duration and CAC in univariate (r = 0.23, P < 0.0001) and adjusted models (r = 0.10, P = 0.01). In contrast, the JT interval was not associated with CAC. A strong correlation existed between the QRS interval and CAC in men (QRS: r = 0.24, P < or = 0.0001) and diabetics (QRS: r = 0.25, P < or = 0.0001) but was absent in women and nondiabetics. These relationships were not modified by CVD, race, or presence of bundle branch block. CONCLUSION: QT duration correlates with the amount of CAC in a predominantly diabetic population. The association between QT duration and CAC is driven by QRS and not JT interval duration.

Association of NOS1AP genetic variants with QT interval duration in families from the Diabetes Heart Study.

OBJECTIVES: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes-enriched sample of European ancestry. RESEARCH DESIGN AND METHODS: Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications. RESULTS: In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 x 10(-5)); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 x 10(-6)). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 x 10(-5); 13.9-ms difference, P = 1.6 x 10(-6), respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans. CONCLUSIONS: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

Comparison of methods to measure heart size using noncontrast-enhanced computed tomography: correlation with left ventricular mass.

OBJECTIVE: Left ventricular (LV) mass is a useful independent predictor of cardiovascular events. We sought to develop a new correlate of LV mass using noncontrast-enhanced cardiac computed tomography (NCE-CCT). METHODS: We assessed 22 different ventricular measurements made with NCE-CCT in 60 participants in the Multi-Ethnic Study of Atherosclerosis. The primary outcome was the correlation between the NCE-CCT measurements and magnetic resonance imaging (MRI)-derived LV mass. RESULTS: Correlation coefficients (r) for the 22 NCE-CCT techniques in comparison to MRI-derived LV mass ranged from 0.12 to 0.80, with 14 of the 22 techniques having r > 0.7. The highest correlation was achieved using the modified Simpson Rule method to determine the biventricular volume (r = 0.80; P < 0.001). Interrater reliability was good, with intraclass correlation coefficients of 0.84 to 0.90 for the best (r > 0.75) NCE-CCT methods. CONCLUSIONS: Noncontrast-enhanced cardiac computed tomography measurements of both biventricular volume and LV volume correlated well with MRI-derived LV mass in a population free of clinical cardiovascular disease.

Diastolic heart failure in the elderly.

Most elderly patients, particularly women, who have heart failure have a normal ejection fraction. Patients who have this syndrome have severe symptoms of exercise intolerance, frequent hospitalizations, and increased mortality. The pathophysiology and treatment are not well defined. Control of systemic hypertension may be a key to prevention and treatment. Several large trials of specific agents are currently underway.

Diastolic heart failure in the elderly.

Most elderly patients, particularly women, who have heart failure have a normal ejection fraction. Patients who have this syndrome have severe symptoms of exercise intolerance, frequent hospitalizations, and increased mortality. The pathophysiology and treatment are not well defined. Control of systemic hypertension may be a key to prevention and treatment. Several large trials of specific agents are currently underway.