Discordant effects of rosiglitazone on novel inflammatory biomarkers.

BACKGROUND: Although rosiglitazone favorably affects myriad intermediate markers of atherosclerosis, it appears to increase myocardial infarction (MI) risk. We analyzed the effects of rosiglitazone on a panel of 8 novel circulating biomarkers, 4 of which are independently associated with atherosclerosis: lymphotoxin ß receptor, peptidoglycan recognition protein 1, chemokine ligand 23, and soluble receptor for advanced glycation end products (sRAGE) as well as on high-sensitivity C-reactive protein (hs-CRP). METHODS: Blood samples were analyzed at baseline and after 6 months of study treatment from subjects with type 2 diabetes with or at high risk for coronary artery disease in a randomized trial comparing rosiglitazone versus placebo. RESULTS: Data from 111 subjects (rosiglitazone 55, placebo 56) were analyzed. Mean age was 56 years, 41% were women, and 66% were nonwhite. Compared with baseline values, rosiglitazone adversely affected levels of lymphotoxin ß receptor (1.7 vs 2.4 ng/mL, P = .002), peptidoglycan recognition protein 1 (29.0 vs 30.1 ng/mL, P = .01), and chemokine ligand 23 (0.76 vs 0.84 ng/mL, P = .02) and favorably affected levels of sRAGE (inversely associated with atherosclerosis, 1.1 vs 1.4 ng/mL, P = .003) and hs-CRP (0.42 vs 0.31 ng/mL, P = .02); no changes were observed with rosiglitazone in the other biomarkers. In the placebo group, change was observed only for sRAGE (1.0 vs 1.1 ng/mL, P = .046). CONCLUSION: Rosiglitazone adversely affected 3 novel biomarkers and favorably affected a fourth previously associated with atherosclerosis while improving hs-CRP, as has previously been shown. Whether these complex effects on circulating inflammatory biomarkers contribute to the signal of increased MI risk with rosiglitazone and whether pioglitazone has similar effects warrant further investigation.

Aortic root spontaneous echocardiographic contrast due to haemodynamic support with a percutaneous left ventricular assist device (TandemHeart).

Intra-procedural transoesophageal echocardiography (TEE) is useful in guiding device placement and monitoring for procedural complications in the interventional lab. We report a case of spontaneous echo contrast (SEC) formation in the aortic root immediately following initiation of haemodynamic support with a percutaneous left ventricular (LV) assist device for cardiogenic shock. With TEE guidance, assist device flow rates were adjusted, resulting in resolution of SEC. This case illustrates another potential use for intra-procedural TEE during LV assist device placement.

Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and function.

AIMS: To assess the effect of rosiglitazone on cardiovascular performance and cardiac function. METHODS AND RESULTS: One hundred and fifty type 2 diabetes patients with cardiovascular disease (CVD) or ≥ 1 other CVD risk factor were randomized to receive rosiglitazone vs. placebo for 6 months. The primary outcome was peak oxygen uptake indexed to fat-free mass (VO(2peak)-FFM) during maximum exercise. A subset of 102 subjects underwent cardiac magnetic resonance imaging (cMRI). On hundred and eight subjects completed the study, including 75 completing the cMRI substudy. No significant differences were observed in mean VO(2peak)-FFM between rosiglitazone and placebo (26.1 ± 7.0 vs. 27.6 ± 6.6 mL/kg-FFM/min; P = 0.26). Compared with placebo, the rosiglitazone group had lower hematocrit (38 vs. 41%; P < 0.001) and more peripheral oedema (53.7 vs. 33.3%; P = 0.03). In the cMRI substudy, compared with placebo, the rosiglitazone group had larger end-diastolic volume (128.1 vs. 112.0 mL; P = 0.01) and stroke volume (83.7 vs. 72.9 mL; P = 0.01), and a trend toward increased peak ventricular filling rate (79.4 vs. 60.5; P = 0.07). CONCLUSION: Rosiglitazone increased peripheral oedema but had no pernicious effects on cardiovascular performance or cardiac function, with modest improvement in selected cMRI measures. Changes in indirect markers of plasma volume suggest expansion with rosiglitazone. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00424762.

The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increases bone resorption in women with type 2 diabetes: a randomized, controlled trial.

In previous studies, with up to 16 weeks of exposure to rosiglitazone or pioglitazone, circulating markers of bone formation [procollagen I N-terminal propeptide (P1NP), osteocalcin, and bone-specific alkaline phosphatase] decreased but no change in bone resorption markers was found. We examined the effect of rosiglitazone on bone resorption and formation markers when used for 24 weeks. This post-hoc analysis of a double-blind, placebo-controlled, randomized trial evaluated the effects of 6 months of rosiglitazone use versus placebo on circulating markers of bone turnover in 111 patients with type 2 diabetes and cardiovascular disease or additional cardiac risk factors. The principal end points for analysis were changes in bone formation and resorption markers, measured by P1NP and carboxy-terminal cross-links (CTX), respectively. There were 111 subjects who completed the study and had baseline and 6-month data; mean age was 56, including 41% women and 67% nonwhite (50 black, 18 Hispanic, and six other), and subjects were evenly distributed between placebo and rosiglitazone groups. Women treated with rosiglitazone had higher CTX levels (0.43 ng/mL) than those who received placebo (0.23 ng/mL) (P = 0.007), with no significant differences in P1NP or OPG. Overall, in stratified analyses of men and in stratified analyses among different ethnicities, there were no statistically significant differences observed in CTX, P1NP, OPG, PTH, or 25-OHD between the treatment groups. Women taking rosiglitazone had higher circulating markers of bone resorption, which is contrary to prior studies of shorter duration, where the principal observation was a decrease in markers of bone formation.

Evaluation of coronary artery calcium screening strategies focused on risk categories: the Dallas Heart Study.

BACKGROUND: A strategy using coronary artery calcium (CAC) screening to refine coronary heart disease risk assessment in moderately high risk (MHR) subjects (10-year risk 10%-20%) has been suggested. The potential impact of this strategy is unknown. METHODS: Coronary artery calcium screening strategies focused on MHR subjects were modeled in 2,610 subjects aged 30 to 65 years undergoing Framingham risk scoring and CAC assessment in the Dallas Heart Study. The proportions of subjects eligible for imaging and reclassified from MHR to high risk (HR) (10-year risk >20%) based upon CAC scores were determined. RESULTS: Only 1.0% of women and 15.4% of men were at MHR by Framingham risk scoring and thus eligible for imaging, and <0.1% and 1.1% respectively, changed from MHR to HR using a CAC threshold > or = 400. Coronary artery calcium imaging targeting MHR subjects was also relatively inefficient (>100 women, 14.3 men scanned per subject reclassified). Restricting to an older age range (45-65 years) or expanding the MHR group to 6% to 20% risk had virtually no impact on risk assessment in women. In a secondary analysis, a proposed imaging strategy targeting promotion of subjects from lower risk to MHR was more efficient and had greater yield than current recommendations targeting promotion from MHR to HR. CONCLUSIONS: Coronary artery calcium screening strategies focused on MHR subjects will have a negligible impact on risk assessment in women and a modest impact in men. Further studies are needed to optimize the use of CAC screening as an adjunct to coronary heart disease risk assessment, especially for women and those at seemingly lower risk.

The effect of a disease management algorithm and dedicated postacute coronary syndrome clinic on achievement of guideline compliance: results from the parkland acute coronary event treatment study.

BACKGROUND: The application of disease management algorithms by physician extenders has been shown to improve therapeutic adherence in selected populations. It is unknown whether this strategy would improve adherence to secondary prevention goals after acute coronary syndromes (ACSs) in a largely indigent county hospital setting. METHODS: Patients admitted for ACS were randomized at the time of discharge to usual follow-up care versus the same care with the addition of a physician extender visit. Physician extender visits were conducted according to a treatment algorithm based on contemporary practice guidelines. Groups were compared using the primary end point of achievement of low-density lipoprotein treatment goals at 3 months after discharge and achievement of additional evidence-based practice goals. RESULTS: One hundred forty consecutive patients were randomized. A similar proportion of patients returned for study follow-up in both groups at 3 months (54 [79%]/68 in the usual care group vs 57 [79%]/72 in the intervention group; P = 0.97). Among those completing the 3-month visit, a low-density lipoprotein cholesterol level less than 100 mg/dL was achieved in 37 (69%) of the usual care patients compared with 35 (57%) of those in the intervention group (P = 0.43). There was no statistical difference in implementation of therapeutic lifestyle changes (smoking cessation, cardiac rehabilitation, or exercise) between groups. Prescription rates of evidence-based therapeutics at 3 months were similar in both groups. CONCLUSION: The implementation of a post-ACS clinic run by a physician extender applying a disease management algorithm did not measurably improve adherence to evidence-based secondary prevention treatment goals. Despite initially high rates of evidence-based treatment at discharge, adherence with follow-up appointments and sustained implementation of evidence-based therapies remains a significant challenge in this high-risk cohort.

Effect of treatment with rosiglitazone on high-sensitivity cardiac troponin levels among patients with type 2 diabetes mellitus.

OBJECTIVE: To assess the impact of intermediate-term treatment with rosiglitazone on high-sensitivity cardiac troponin T levels among patients with type 2 diabetes mellitus with or at high risk of coronary artery disease. METHODS: High-sensitivity cardiac troponin T level was measured at baseline and after 6 months of study treatment in a randomized trial comparing rosiglitazone versus placebo in patients with type 2 diabetes and prevalent cardiovascular disease or multiple cardiovascular disease risk factors. Univariable and multivariable linear regression analyses were performed to assess the effect of rosiglitazone versus placebo on high-sensitivity cardiac troponin T levels. RESULTS: The study included 150 randomized participants, of whom 106 had paired baseline and end-of-study blood samples for analysis (mean age: 56 ± 8 years, 42% women; 8.8 years average type 2 diabetes duration; mean haemoglobin A1c of 7.5). Almost all study participants (93%) had detectable high-sensitivity cardiac troponin T (⩾ 3 ng/L) at baseline, including 23% with high-sensitivity cardiac troponin T levels exceeding the threshold commonly used to diagnose myocardial infarction (⩾ 14 ng/L). Change in high-sensitivity cardiac troponin T levels from baseline to follow-up was not significantly different between rosiglitazone and placebo groups (p = 0.316). CONCLUSION: Rosiglitazone did not impact high-sensitivity cardiac troponin T levels, adding to the growing body of literature suggesting that the incremental heart failure risk associated with rosiglitazone is not mediated by direct myocardial injury.

Is cardiorespiratory fitness a determinant of cardiomyopathy in the setting of type 2 diabetes?

OBJECTIVE: The aim of this study was to determine whether high fitness attenuates the defects in left ventricular (LV) structure, function and triglyceride (TG) content in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Patients (n = 74) with T2DM and ≥1 additional cardiac risk factor were recruited to participate in this cross-sectional study. Outcome measures of interest were LV structure and function by magnetic resonance imaging (MRI) and myocardial TG content by (1)H-magnetic resonance spectroscopy (MRS). The primary exposure variable was cardiorespiratory fitness defined by peak oxygen consumption scaled to fat-free mass (FFM; VO2peak-FFM). RESULTS: Mean age was 53.5 years; 42.9% were women and mean glycosylated haemoglobin (HbA1c) was 8.0% with the mean duration of T2DM 8.2 years. VO2peak-FFM was crudely associated with both LV end systolic (r = 0.35, p = 0.002) and diastolic volumes (r = 0.32, p = 0.004), but not with ejection fraction (r = -0.15, p = 0.206), myocardial TG (r = -0.04, p = 0.734) or early diastolic peak filling rate (PFR; r = -0.01, p = 0.887). In multiple linear regression analyses, among measures of LV structure/function, VO2peak-FFM was independently associated only with LV end-diastolic volume (EDV) (ß = 1.037, p = 0.038). CONCLUSION: In individuals with T2DM at increased cardiovascular (CV) risk, cardiorespiratory fitness is not associated with LV morphology, function or myocardial TG content.

The effects of rosiglitazone on myocardial triglyceride content in patients with type 2 diabetes: a randomised, placebo-controlled trial.

This was a nested sub-study of a randomised placebo-controlled trial of the effect of 6 months of treatment with rosiglitazone added to existing therapy on myocardial triglyceride (mTG) content in patients with type 2 diabetes (T2D) and prevalent cardiovascular disease (CVD) or at least one additional risk factor. The primary endpoint, mTG content, was measured with cardiac (1)H-magnetic resonance spectroscopy. Of the 99 randomised participants selected for the imaging sub-study, 49 (48%) had complete and interpretable spectroscopy data (age = 58 years, duration of T2D = 9.5 years; 57% women and 69% non-white). There was no significant change in mTG in either group (-0.1 ± 0.6% and -0.05 ± 0.8% respectively) and the changes in mTG were not associated with changes in left ventricular structure or function. Compared with placebo, treatment with rosiglitazone for 6 months had no discernible effect on mTG or left ventricular function in this population with long-standing diabetes and CVD.

Assessment of cardiac structure and function in patients without and with peripheral oedema during rosiglitazone treatment.

BACKGROUND: Thiazolidinediones cause peripheral oedema, the aetiology of which remains poorly understood. METHODS: In a sub-study of a 6-month trial comparing rosiglitazone (Rsg) versus placebo, we compared those with versus without oedema among the 74 subjects treated with Rsg with respect to peak oxygen consumption indexed to fat-free mass (VO(2peak-FFM) ), cardiac MRI and markers of plasma volume expansion. RESULTS: Almost half (49%) of the Rsg-treated patients developed oedema. Baseline VO(2peak-FFM) was not different between those with versus without oedema (25.8 versus 28.2 ml/kg/min; p = 0.22) and declined 5% in the oedema group (Δ -1.3 ml/min/kg; p = 0.005) with no change in those without oedema. Stroke volume increased in both groups (Δ 8.7 and 8.8 ml; p < 0.001 for each); end-diastolic volume increased only in those with oedema (+13.1 ml; p = 0.001). No other cardiac function changes were observed. In both groups, weight increased (3.6 and 2.2 kg) and haematocrit decreased (-3.2% and -2.1%; p < 0.001 for each). In those with oedema, albumin decreased (-0.2 g/dl) and brain natriuretic peptide increased (11.9 pg/ml; p < 0.03 for each). CONCLUSIONS: Oedema was associated with a small decline in VO(2peak FFM), no adverse effects on cardiac function, and changes in selected measures suggesting that volume expansion underpins Rsg oedema.

The effect of rosiglitazone on integrated cardiovascular performance, cardiac structure, function and myocardial triglyceride: trial design and rationale.

The thiazolidinedione (TZD) class of medications has been associated with increased risk for peripheral oedema, as well as incident and worsening heart failure (HF). The mechanism of these observed effects remains unclear. Here we present the rationale and study design for a randomised clinical trial designed to evaluate the cardiac effects of rosiglitazone on integrated cardiovascular performance, cardiac structure and function. The study is a randomised, single-centre, double-blind, placebo-controlled, parallel-group clinical trial to evaluate the effect of rosiglitazone on integrated cardiovascular performance in a cohort of patients with type 2 diabetes mellitus (T2DM) at increased risk for developing heart failure (HF). Participants will be randomised to receive rosiglitazone or matching placebo for six months. All subjects will undergo maximal treadmill cardiopulmonary exercise testing at baseline and after six months on study drug, with the primary trial end point of peak oxygen uptake indexed to fat-free mass (VO 2peak-FFM). Approximately two-thirds of the study cohort will undergo cardiac magnetic resonance imaging (MRI) and spectroscopy (MRS) at baseline and after six months of study therapy to assess cardiac structure, function and myocardial triglyceride content. While concerns for peripheral oedema and HF continue to confound clinical use of TZD medications, the direct cardiac effects of these drugs remain poorly understood and the clinical relevance of these clinical observations remains unclear. The present study will combine a series of state-of-the-art assessments to evaluate the cardiac effects of rosiglitazone treatment.

Application of the screening for Heart Attack Prevention and Education Task Force recommendations to an urban population: observations from the Dallas Heart Study.

BACKGROUND: The Screening for Heart Attack Prevention and Education (SHAPE) Task Force recommends noninvasive atherosclerosis imaging of all asymptomatic men (aged 45-75 years) and women (aged 55-75 years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms. METHODS: Among 2611 participants in the Dallas Heart Study aged 30 to 65 years who underwent computed tomography to measure coronary artery calcification, low-density lipoprotein cholesterol (LDL-C) therapeutic targets were calculated using both National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and SHAPE algorithms. The proportion of subjects reclassified as being "at goal" for LDL-C vs "not at goal" after implementation of the SHAPE recommendations was determined. RESULTS: More subjects were identified with LDL-C levels greater than or equal to goal based on SHAPE than on NCEP-ATP III (27.4% vs 21.6%), with 7.0% of individuals reclassified as having unmet LDL-C goals and 1.1% of individuals reclassified as at goal. When more aggressive optional LDL-C goals were implemented, 31.7% had LDL-C levels greater than or equal to goal using SHAPE recommendations vs 28.1% using NCEP-ATP III recommendations, with 6.3% of subjects reclassified as being not at goal and 2.7% as being at goal. CONCLUSIONS: The SHAPE recommendations resulted in bidirectional reclassification of eligibility for lipid-lowering therapy in subjects aged 30 to 65 years. While broad implementation of these recommendations would modestly increase cholesterol-lowering drug use in this age range, the magnitude of the increase depends on whether standard or optional LDL-C goals are targeted.

Influence of race and sex on lipoprotein-associated phospholipase A2 levels: observations from the Dallas Heart Study.

AIMS: Most lipoprotein-associated phospholipase A2 (Lp-PLA2) studies included mainly white men. We sought to determine whether Lp-PLA2 levels differ according to race and sex. METHODS: Lp-PLA2 mass and activity were measured in 3332 subjects age 30-65 participating in the Dallas Heart Study, a multiethnic, population-based, probability sample. Lp-PLA2 levels were compared between different race and sex groups. RESULTS: Mean age was 45+/-9 years and 44% were men; 30% were white, 17% hispanic, and 53% black. Mean Lp-PLA2 activity and mass were 146+/-40 nmol/min/mL and 191+/-60 ng/mL, respectively. Lp-PLA2 activity was lower in women compared with men (134+/-35 vs. 161+/-40, p=0.001) and was lowest in black (136+/-38), intermediate in hispanic (151+/-36), and highest in white subjects (161+/-39) (trend p=0.0001). In multivariable linear regression models, after adjusting for age, body mass index (BMI), smoking, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and high sensitivity C-reactive protein (hsCRP), Lp-PLA2 activity was 19 nmol/min/mL higher in men vs. women (p<0.001); compared with black subjects, adjusted Lp-PLA2 activity was 11 and 20 nmol/min/mL higher in white and hispanic subjects, respectively (both p<0.001). Similar race and sex differences were observed for Lp-PLA2 mass. CONCLUSION: Race and sex independently influence Lp-PLA2 activity and mass. Thresholds to define Lp-PLA2 elevation may need to be sex and race specific.

The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study.

OBJECTIVES: This study sought to evaluate the associations between different measures of obesity and prevalent atherosclerosis in a large population-based cohort. BACKGROUND: Although obesity is associated with cardiovascular mortality, it is unclear whether this relationship is mediated by increased atherosclerotic burden. METHODS: Using data from the Dallas Heart Study, we assessed the association between gender-specific obesity measures (i.e., body mass index [BMI]; waist circumference [WC]; waist-to-hip ratio [WHR]) and prevalent atherosclerosis defined as coronary artery calcium (CAC) score >10 Agatston units measured by electron-beam computed tomography and detectable aortic plaque measured by magnetic resonance imaging. RESULTS: In univariable analyses (n = 2,744), CAC prevalence was significantly greater only in the fifth versus first quintile of BMI, whereas it increased stepwise across quintiles of WC and WHR (p trend <0.001 for each). After multivariable adjustment for standard risk factors, prevalent CAC was more frequent in the fifth versus first quintile of WHR (odds ratio 1.91, 95% confidence interval 1.30 to 2.80), whereas no independent positive association was observed for BMI or WC. Similar results were observed for aortic plaque in both univariable and multivariable-adjusted analyses. The c-statistic for discrimination of prevalent CAC was greater for WHR compared with BMI and WC in women and men (p < 0.001 vs. BMI; p < 0.01 vs. WC). CONCLUSIONS: We discovered that WHR was independently associated with prevalent atherosclerosis and provided better discrimination than either BMI or WC. The associations between obesity measurements and atherosclerosis mirror those observed between obesity and cardiovascular mortality, suggesting that obesity contributes to cardiovascular mortality via increased atherosclerotic burden.

Current status of risk stratification methods in acute coronary syndromes.

Distinguishing which patients with chest pain are at high risk versus which are at low risk remains an important clinical problem despite modern risk stratification strategies. Current approaches often over-utilize hospital resources, yet still miss a significant number of true acute coronary syndromes (ACS). This review focuses on important developments in risk stratification in ACS from 2004 through 2005. Risk models have been developed that use readily available patient characteristics, and head to head comparisons of the various models have been performed to guide clinicians in selecting between the different options. The most powerful models now include measurement of renal function, which has emerged as an important marker of risk. In addition to cardiac troponins, B-type natriuretic peptide (BNP) clearly augments risk prediction, and in the past year serial BNP measurement after discharge has shown promise as a simple way to monitor patient risk following ACS. Newer biomarkers are on the horizon but have not yet established their clinical value. Finally, advances in coronary CT angiography and bedside echocardiography offer hope that noninvasive imaging may play a more important role in early risk stratification in the near future.