Tissue Doppler E/E' ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT substudy.

AIMS: Patients with controlled hypertension are at risk of future cardiac events, but predicting first events remains difficult. We hypothesized that modern echocardiographic measures of left ventricular diastolic function may be more sensitive than traditional echocardiographic methods of risk prediction and set out to test this in a cohort of patients with well-controlled hypertension. METHODS AND RESULTS: Conventional and tissue Doppler echocardiography was performed on 980 participants in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). All subjects had hypertension, but no known cardiac disease. Cardiac events were defined as fatal and non-fatal myocardial infarction (including silent myocardial infarction), coronary revascularization procedures, new-onset angina (stable or unstable), fatal and non-fatal heart failure, and life-threatening arrhythmias. Analysis was performed by a single, blinded observer. There were 56 primary cardiac events during 4.2 +/- 0.7 years follow-up. The ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/E') was the strongest predictor of first cardiac events in Cox-proportional hazards models. Following adjustment for covariates, a unit rise in the E/E' ratio was associated with a 17% increment in risk of a cardiac event (HR 1.17, CI 1.05-1.29; P = 0.003). CONCLUSION: Tissue Doppler E/E', a non-invasive estimate of left atrial filling pressure, independently predicts primary cardiac events in a hypertensive population and out-performed traditional echocardiographic measures in this moderately sized, well-treated hypertensive population. E/E' represents a simple, effective tool for assessing cardiac risk in a hypertensive population.

Differences in the magnitude of wave reflection account for differential effects of amlodipine- versus atenolol-based regimens on central blood pressure: an Anglo-Scandinavian Cardiac Outcome Trial substudy.

Antihypertensive agents may differ in their effects on central systolic blood pressure, and this may contribute to treatment-related differences in cardiovascular outcomes. In a substudy of the Anglo-Scandinavian Cardiac Outcome Trial, we investigated whether directly measured carotid systolic blood pressure differed between people randomized to amlodipine- and atenolol-based therapies and whether this is accounted for by differences in wave reflection patterns. Additional analysis was undertaken to establish whether differences in carotid systolic blood pressure predicted left ventricular mass, accounting for between-treatment differences in left ventricular mass index. Blood pressure and flow velocity were measured in the right carotid artery of 259 patients. Wave intensity analysis was used to separate and quantify forward and backward waves. Brachial blood pressure did not differ significantly between groups, but carotid systolic blood pressure (127 [12] versus 133 [15] mm Hg; P<0.001), the ratio of backward:forward pressure (0.48 [0.17] versus 0.53 [0.19]; P=0.01), and wave reflection index (19.8% [10.9%] versus 23.3% [13.3%]; P=0.02) were significantly lower in patients randomized to amlodipine-based therapy. Left ventricular mass index was also lower in this group, and adjustment for carotid blood pressure attenuated treatment differences to a greater extent than brachial blood pressure. Carotid systolic blood pressure was also a significant independent predictor of left ventricular mass index in a multivariate model. Carotid systolic blood pressure is lower in people randomized to amlodipine-based compared with atenolol-based treatment despite there being no significant difference in brachial blood pressure. This difference is attributable to a lesser magnitude of wave reflection in patients randomized to the amlodipine-based regimen.

Ethnicity and left ventricular diastolic function in hypertension an ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) substudy.

OBJECTIVES: We investigated whether diastolic function differs between hypertensive patients of African-Caribbean or white European origin and established whether differences could be explained by confounding variables. BACKGROUND: African Caribbeans are known to have a higher prevalence of heart failure than white Europeans but it is unclear whether this is a result of known risk factors. Tissue Doppler technology now allows accurate quantification of diastolic function, which is recognized as an important factor in the development of heart failure. METHODS: Participants from a single center participating in the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), composed of patients with hypertension but no evidence of heart failure, were studied. Left ventricular structure and function were measured in 509 patients using conventional and tissue Doppler echocardiography. Diastolic function was assessed using the tissue Doppler early diastolic velocity E' (averaged from 3 left ventricular segments) and the ratio of this and the transmitral early filling velocity E (E/E'). RESULTS: In African-Caribbean patients, mean E' was significantly lower (7.7 cm/s vs. 8.6 cm/s, p = 0.003) and mean E/E' was significantly higher (8.85 vs. 7.93, p = 0.003). After adjustment for confounding variables-age, gender, systolic blood pressure, pulse pressure, cholesterol, smoking, ejection fraction, left ventricular mass index, and diabetes mellitus-the effect of African-Caribbean ethnicity on diastolic function remained highly significant (E': 7.52 vs. 8.51; p < 0.001; E/E': 8.89 vs. 7.93; p = 0.003; African Caribbeans vs. white Europeans for both comparisons). CONCLUSIONS: Diastolic function is significantly worse in hypertensive patients of African-Caribbean origin than in white Europeans. This difference in diastolic performance is not due to known confounding variables.

Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. METHODS AND RESULTS: This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. BACKGROUND: =0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95). CONCLUSIONS: Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.

A retrospective evaluation of congestive heart failure and myocardial ischemia events in 14,237 patients with type 2 diabetes mellitus enrolled in 42 short-term, double-blind, randomized clinical studies with rosiglitazone.

PURPOSE: Retrospectively investigate potential associations between rosiglitazone and congestive heart failure (CHF) and, separately, events of myocardial ischemia. METHODS: Data from 14 237 individuals in 42 short-term, double-blind, randomized studies of rosiglitazone versus placebo or active diabetes medications were analyzed across seven treatment comparisons using an exact logistic regression model, adjusted for number of major cardiovascular risk factors and duration of exposure. RESULTS: CHF incidence ranged 0-1.27% (SAEs) and 0.12-2.42% (all AEs) with rosiglitazone versus 0.07-0.75% (SAEs) and 0.25-1.36% (all AEs) with control. Higher odds ratios (95%CI) were observed for CHF SAEs with sulfonylurea- and insulin-containing combinations: rosiglitazone monotherapy versus placebo, 0.25 (<0.01-4.75); rosiglitazone monotherapy versus sulfonylurea/metformin monotherapy, 0.23 (<0.01-2.14); sulfonylurea + rosiglitazone versus sulfonylurea monotherapy, 0.95 (0.01-75.20); metformin + rosiglitazone versus metformin monotherapy, 0.60 (0.00-8.28); metformin + rosiglitazone versus metformin + sulfonylurea, 1.04 (0.39-2.86); sulfonylurea + metformin + rosiglitazone versus sulfonylurea + metformin, 3.15 (0.35-150.52); insulin + rosiglitazone versus insulin monotherapy, 1.63 (0.52-6.01). Myocardial ischemia incidence ranged 0.75-1.40% (SAEs) and 1.49-2.77% (all AEs) with rosiglitazone versus 0.21-2.04% (SAEs) and 0.56-2.38% (all AEs) with control. Each comparison had an OR >1, with wide confidence intervals generally including unity. With data pooling, more events of myocardial ischemia were observed with rosiglitazone (2.00%) versus control (1.53%) (HR 1.30, 95%CI 1.004-1.69). CONCLUSIONS: CHF incidence may be greater when rosiglitazone is combined with sulfonylureas or insulin. When data were pooled, more events of myocardial ischemia were observed with rosiglitazone versus control. Final results from RECORD will allow a more rigorous evaluation of the cardiovascular safety profile.

Effect of the addition of rosiglitazone to metformin or sulfonylureas versus metformin/sulfonylurea combination therapy on ambulatory blood pressure in people with type 2 diabetes: a randomized controlled trial (the RECORD study).

BACKGROUND: Hypertension and type 2 diabetes are common co-morbidities. Preliminary studies suggest that thiazolidinediones reduce blood pressure (BP). We therefore used ambulatory BP to quantify BP lowering at 6-12 months with rosiglitazone used in combination with metformin or sulfonylureas compared to metformin and sulfonylureas in people with type 2 diabetes. METHODS: Participants (n = 759) in the multicentre RECORD study were studied. Those taking metformin were randomized (open label) to add-on rosiglitazone or sulfonylureas, and those on sulfonylurea to add-on rosiglitazone or metformin. RESULTS: 24-Hour ambulatory BP was measured at baseline, 6 months and 12 months. At 6 and 12 months, reductions in 24-hour ambulatory systolic BP (sBP) were greater with rosiglitazone versus metformin (difference at 6 months 2.7 [95% CI 0.5-4.9] mmHg, p = 0.015; 12 months 2.5 [95% CI 0.2-4.8] mmHg, p = 0.031). Corresponding changes for ambulatory diastolic BP (dBP) were comparable (6 months 2.7 [95% CI 1.4-4.0] mmHg, p < 0.001; 12 months 3.1 [95% CI 1.8-4.5] mmHg, p < 0.001). Similar differences were observed for rosiglitazone versus sulfonylureas at 12 months (sBP 2.7 [95% CI 0.5-4.9] mmHg, p = 0.016; dBP 2.1 [95% CI 0.7-3.4] mmHg, p = 0.003), but differences were smaller and/or not statistically significant at 6 months (sBP 1.5 [95% CI -0.6 to 3.6] mmHg, p = NS; dBP 1.3 [95% CI 0.0-2.5] mmHg, p = 0.049). Changes in BP were not accompanied by compensatory increases in heart rate, did not correlate with basal insulin sensitivity estimates and were not explained by changes in antihypertensive therapy between the various strata. CONCLUSION: When added to metformin or a sulfonylurea, 12-month treatment with rosiglitazone reduces ambulatory BP to a greater extent than when metformin and a sulfonylurea are combined. TRIAL REGISTRATION: NCT00379769 http://clinicaltrials.gov/

Reduced systolic wave generation and increased peripheral wave reflection in chronic heart failure.

In human heart failure the role of wave generation by the ventricle and wave reflection by the vasculature is contentious. The aim of this study was to compare wave generation and reflection in normal subjects with patients with stable compensated heart failure. Twenty-nine normal subjects and 67 patients with heart failure (New York Heart Association class II or III) were studied by noninvasive techniques applied to the common carotid artery. Data were analyzed by wave intensity analysis to determine the nature and direction of waves during the cardiac cycle. The energy carried by an early systolic forward compression wave (S wave) generated by the left ventricle and responsible for acceleration of flow in systole was significantly reduced in subjects with heart failure (P < 0.001), and the timing of the peak of this wave was delayed. In contrast, reflection of this wave was increased in subjects with heart failure (P < 0.001), but the timing of reflections with respect to the S wave was unchanged. The energy of an expansion wave generated by the heart in protodiastole was unaffected by heart failure. The carotid artery wave speed and the augmentation index did not significantly differ between subjects with heart failure compared with normal individuals. The ability of the left ventricle to generate a forward compression wave is markedly impaired in heart failure. Increased wave reflection serves to maintain systolic blood pressure but also places an additional load on cardiac function in heart failure.

A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure.

OBJECTIVES: This study investigated the effects of rosiglitazone (RSG) on left ventricular ejection fraction (LVEF) in subjects with type 2 diabetes (T2DM) and pre-existing chronic heart failure (CHF) (New York Heart Association [NYHA] functional class I to II). BACKGROUND: Fluid retention is an important consideration in the use of thiazolidinediones in T2DM patients because it could exacerbate symptoms or precipitate decompensation in those with previously stable CHF. METHODS: A total of 224 patients with T2DM and NYHA functional class I to II CHF with LVEF < or =45% were randomized to a 52-week treatment with RSG (4 to 8 mg daily, n = 110) or placebo (PLB) (n = 114) in addition to background antidiabetes therapy. Treatment was uptitrated to achieve target fasting plasma glucose <126 mg/dl; CHF medications were adjusted as appropriate. RESULTS: The LVEF was similar in both groups at baseline (RSG 35.3 +/- 6.2%, PLB 35.7 +/- 7.8%) and after 52 weeks of treatment (mean difference 1.49%, p = 0.1). Glycemic control was significantly better in the RSG group (mean difference in hemoglobin A1c -0.65%, p < 0.0001). There were significantly more adjudicated events in the RSG group of new or worsening edema (RSG n = 28 [25.5%]; PLB n = 10 [8.8%]; p = 0.005) and increased CHF medication (RSG n = 36 [32.7%], PLB n = 20 [17.5%]; p = 0.037), but no significant difference between groups for other adjudicated end points. A similar proportion of patients withdrew from each treatment group because of adverse events. CONCLUSIONS: After 52 weeks of treatment, RSG improved glycemic control but did not adversely affect LVEF in patients with T2DM and NYHA functional class I to II CHF. More fluid-related events occurred with RSG, although these generally did not lead to withdrawal from the study.

Candesartan- and atenolol-based treatments induce different patterns of carotid artery and left ventricular remodeling in hypertension.

BACKGROUND AND PURPOSE: Angiotensin receptor blocker (ARB)-based treatment reduces cardiovascular events and stroke more than does beta-blocker-based treatment despite similar blood pressure (BP) reduction. We investigated whether these treatments have different effects on cardiac and large-artery remodelling and evaluated the relation of arterial remodelling to hemodynamic changes in subjects with hypertension. METHODS: We compared the treatment effects of an ARB (candesartan cilexetil)-based regimen and a beta-blocker (atenolol)-based regimen for 52 weeks on common carotid artery (CCA) and left ventricular structure in hypertensive patients in a randomized, double-blind study. Clinic brachial BP and 24-hour ambulatory BP, carotid BP, left ventricular mass index, CCA intima-media thickness, lumen diameter, intima-media area, and carotid blood flow were measured. Distensibility, circumferential tensile stress, Young's elastic modulus (E(m)), and shear stress (tau) in the CCA were also calculated. RESULTS: Both candesartan and atenolol reduced intima-media thickness and intima-media area and increased distensibility to similar extents after 52 weeks of treatment. Despite similar reductions in BP, treatment with atenolol resulted in a lesser reduction in left ventricular mass index, a decrease in lumen diameter, and a reduction in carotid blood flow compared with candesartan. CONCLUSIONS: BP-independent effects of ARB on cardiac and arterial structure may contribute to the beneficial effects of these agents on cardiovascular disease.