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Flavonols are a particular subclass of polyphenols that are found in cocoa products. They have previously been shown to lower blood pressure and improve endothelial function. However, this involved consumption of high doses of chocolate and follow‐up was limited to 2 weeks only. Taubert et al therefore set out to determine the effect of low doses of polyphenol‐rich dark chocolate on blood pressure (BP).
Forty‐four adults aged between 56 and 73 years were randomised to receive either 6.3 g (30 kcal) a day of dark chocolate containing 30 mg of polyphenols or a matching polyphenol‐free white chocolate. All had untreated upper‐range prehypertension or stage 1 hypertension, without concomitant risk factors. The primary outcome measure was the noted change in BP at 18 weeks. Secondary outcome measures were changes in plasma markers of vasodilative nitric oxide (S‐nitrosoglutathione) and oxidative stress (8‐isoprostane), and bioavailability of cocoa phenols.
From baseline to 18 weeks, dark chocolate intake reduced mean (SD) systolic BP by 2.9 (1.6) mm Hg (p<0.001) and diastolic BP by 1.9 (1.0) mm Hg (p<0.001), but no changes were noted in body weight, plasma levels of lipids, glucose and 8‐isoprostane. Hypertension prevalence declined from 86% to 68% and the decrease in BP noted was accompanied by a sustained increase of mean (SD) S‐nitrosoglutathione of 0.23 (0.12) nmol/l (p<0.001). Phenols were also noted in the plasma after a dark chocolate dose. White chocolate caused no changes in BP or plasma biomarkers.
Although conducted on a small sample, this study showed that dark chocolate intake was associated with a reduction in BP and improved formation of nitric oxide. However, it should be remembered that excessive intake of any form of chocolate may lead to weight gain and an increase in saturated fat levels that may negate the potential benefits shown here.
Taubert D, Roesen R, Lehmann C, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide. JAMA 2007;298:49–60.
Many animal models have provided evidence that β blockers can slow the development of atherosclerosis in humans. Although the beneficial effects of β blockade after myocardial infarction have been well proved, it is not known whether or not they exert any direct effect on coronary atherosclerosis. Sipahi et al therefore decided to investigate whether or not β blocker treatment was associated with reduced atheroma progression by performing a pooled analysis of four major trials: REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), CAMELOT IVUS (Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis Intravascular Ultrasound), ACTIVATE (Acyl‐CoA: Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation) and ASTEROID (A Study to Evaluate the Effect of Rosuvastatin On Intravascular‐Derived Coronary Atheroma Burden).
A total of 1515 patients were used in the analysis. Of these, 1154 (76%) received concomitant β blocker treatment during the trials, on average for 91% of the trial durations. The frequency of β blocker use did not differ significantly among the trials, and metoprolol was the most common β blocker used followed by atenolol. Patients who received β blockers were more likely to have histories of myocardial infarction, angina and hypertension than those who did not.
The estimated annual change in mean (SE) atheroma volume was greater in those patients who received β blockers than in untreated patients, even after correcting for myocardial infarction, angina and hypertension (−2.4 (0.5) mm3 vs −0.4 mm3 (0.8 mm3), p=0.034, respectively). This result did not change even after adjustment for low‐density lipoprotein cholesterol level, concomitant drugs and clinical trial.
Of course other drugs used in these trials, such as statins, might also have affected the atheromas, and it is also currently uncertain whether changes in atheroma volume predict cardiovascular outcomes. Despite these limitations, this study provides an interesting insight into a topic on which little definitive information exists.
Sipahi I, Tuzcu EM, Wolski KE, et al. Beta‐blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10–8.
Torcetrapib is an inhibitor of cholesterol ester transfer protein (CETP) that is known to raise levels of high‐density lipoprotein (HDL) cholesterol; however, previous studies have shown no evidence of any clinical benefit from the drug. This study looked at changes in carotid intima‐media thickness (CIMT) in patients taking torcetrapib as opposed to those taking placebo.
Overall 752 patients were randomised to a combination of either atorvastatin and 60 mg of torcetrapib, or atorvastatin and placebo. Carotid ultrasound images were taken at 12 different segments at baseline and at 6‐monthly intervals for 24 months.
The mean (SD) change in maximum CIMT was 0.025 (0.005) mm a year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm a year in those given atorvastatin alone (p=0.46). Patients in the combined‐treatment group had a 63.4% relative increase in HDL cholesterol, and a 17.7% relative decrease in low‐density lipoprotein cholesterol compared with controls. Noticeably, systolic blood pressure increased by 6.6 mm Hg in the combined‐treatment group and 1.5 mm Hg in the atorvastatin‐only group (p<0.0001).
Therefore although torcetrapib did improve lipid profile substantially, it raised systolic blood pressure and showed no improvement in measures of CIMT. Two other imaging trials have shown no evidence of benefit with torcetrapib, and one clinical trial has also shown excess mortality. Even if there had been no blood pressure raising effect, it is unlikely that any benefits seen from torcetrapib would be as great as the changes in the lipid profile would suggest. Currently, the future for CETP inhibitors looks limited.
Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima‐media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double‐blind trial. Lancet 2007;370:153–60.
The complex relationship between hypertriglyceridaemia and atherosclerosis was investigated by two papers in JAMA this month.
Nordestgaard et al tested the hypothesis that high levels of non‐fasting triglycerides predict myocardial infarction (MI), ischaemic heart disease (IHD) and death. They performed a prospective cohort study of 7587 women and 6394 men from the general population over a 28‐year period; all were aged between 20 and 93 years. Non‐fasting triglyceride levels were measured at baseline, and the participants stratified into the following groups: 1–1.99 mmol/l, 2–2.99 mmol/l, 3–3.99 mmol/l, 4–4.99 mmol/l and 5 mmol/l; all were compared with patients with triglyceride levels of <1 mmol/l.
During a mean follow‐up of 26 years, 1793 participants (691 women, 1102 men) had an MI, 3479 developed IHD, and 7818 died. For MI among women, the age‐adjusted hazard ratios (HR) for each respective category per 1 mmol/l increase in non‐fasting triglyceride levels were 2.2, 4.4, 3.9, 5.1 and 16.8 compared with 1.6, 2.3, 3.6, 3.3 and 4.6, respectively, for men. The HRs for IHD among women were 1.7, 2.8, 3.0, 2.1 and 5.9, respectively, compared with 1.3, 1.7, 2.1, 2.0 and 2.9 for men. HRs for deaths among women were 1.3, 1.7, 2.2, 2.2 and 4.3, and men 1.3, 1.4, 1.7, 1.8 and 2.0. Thus, in this general population cohort, raised fasting triglyceride levels were associated with an increased risk of MI, IHD and death in both men and women.
In a second study Bansal et al looked at the risk of fasting vs non‐fasting triglyceride levels in 26509 patients participating in the Women's Health Study. The median follow‐up was 11.4 years, over which 1001 women had a cardiovascular event (276 MIs, 265 ischaemic strokes, 628 coronary revascularisations and 163 cardiovascular deaths), giving an overall rate of 3.46 cardiovascular events per 1000 person‐years of follow‐up. Both fasting and non‐fasting triglyceride levels predicted cardiovascular events when correction for age, blood pressure, smoking and hormone therapy were made. However, correction for total and high‐density cholesterol, as well as measures of insulin resistance, weakened this association for fasting triglyceride levels but not non‐fasting triglyceride levels. Analysis of the timing of non‐fasting samples found that triglyceride levels measured 2–4 hours after eating had the strongest association with cardiovascular events (for highest vs lowest tertiles of levels, HR=4.48), and that this association progressively decreased with longer periods of fasting.
These studies seem to confirm previous suggestions that women have a higher risk for hypertriglyceridaemia than men, although the risk of raised postprandial triglyceride levels increased the risk for both sexes overall. When triglyceride levels are between 1.70 and 11.30 mmol/l (150 and 1000 mg/dl), the risk for atherosclerosis related events is increased significantly.
Nordestgaard BC, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischaemic heart disease, and death in men and women. JAMA 2007;297:299–308.
Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;297:309–16.
McBride PE. Triglycerides and risk for coronary heart disease. JAMA 2007;297:336–8.
Following on the results of a recent meta‐analysis demonstrating a potentially increased cardiovascular risk associated with the use of rosiglitazone (see JournalScan October 2007), the steering committee of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study group performed an unplanned interim analysis of their data to date.
RECORD is a randomised multicentre open‐label non‐inferiority trial of 4447 patients with type 2 diabetes mellitus for whom glycaemic control was inadequate despite metformin or sulphonylurea treatment. A total of 2220 patients were randomised to receive add‐on rosiglitazone (1117 with metformin and 1103 with sulphonylurea) while 2227 were randomised to the control arm (metformin plus sulphonylurea); target HbA1c was <7%.
The primary end point was admission to hospital (for acute myocardial infarction, congestive heart failure, stroke, unstable angina pectoris, transient ischaemic attack, unplanned cardiovascular revascularisation, amputation of extremities or any other definite cardiovascular reason) or death from cardiovascular causes.
The mean follow‐up was 3.75 years, giving this interim analysis only limited power to detect treatment differences. Two hundred and seventeen patients in the rosiglitazone arm and 202 patients in the control group had the adjudicated primary end point (hazard ratio (HR)=1.08, 95% CI 0.89 to 1.31). After the inclusion of end points pending adjudication, the HR was 1.11 (95% CI 0.93 to 1.32). There were no statistically significant differences between the two arms with respect to the primary end point. More patients in the rosiglitazone arm had heart failure than in the control group (HR=2.15, 95% CI 1.30 to 3.57. Ten per cent of patients were lost to follow‐up and this, combined with the low rate of the primary end point, resulted in further lowering of the statistical power of the analysis.
The trial is scheduled to end when there is a median of 6 years of follow‐up and may yet be inconclusive, again owing to possible lack of statistical power. It was felt that the clinical impact of the data needed to be clarified and to this end several editorials by a diabetologist, a cardiovascular epidemiologist and a drug‐safety expert were commissioned—all express uncertainty about the safety of rosiglitazone. Furthermore, the choice of the active comparator (metformin plus sulphonylurea) has come under scrutiny since it has previously been reported by the United Kingdom Prospective Diabetes Study (UKPDS) to be associated with a 96% increase in diabetes‐related mortality (p=0.039). For now patients and doctors will need to weigh up the benefits and risks of rosiglitazone treatment on a case‐by‐case basis.
Home PD, Pocock SJ, Beck‐Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis (for the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes, RECORD study group). N Engl J Med 2007;357:28–38.
In: Drazen JM, Morrissey S, Curfman GD, eds. Rosiglitazone – continued uncertainty about safety. N Engl J Med 2007;357:63–4.
In: Nathan DM, ed. Rosiglitazone and cardiotoxicity – weighing the evidence. N Engl J Med 2007;357:64–6.
In: Psaty BM and Furberg C, eds. The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med 2007;357:67–9.
About 50% of patients with heart failure have diastolic dysfunction, and the prognosis is as poor as for those people with systolic heart failure. Currently it is not known whether lowering blood pressure with antihypertensive drugs improves diastolic dysfunction in hypertensive patients without left ventricular hypertrophy, and hence reduces progression to heart failure. The renin–angiotensin–aldosterone system (RAAS) has a key role in the development of myocardial fibrosis and suppression of this axis in particular may reverse the development of these conditions.
The Valsartan in Diastolic Dysfunction (VALIDD) trial examined the effect of valsartan on diastolic function in patients with hypertension and normal ventricular ejection fractions (>50%) who concomitantly received background antihypertensive treatment (other than RAAS inhibitors). This was a double‐blind, randomised, placebo‐controlled multicentre trial enrolling patients aged >45 years with a history of stage 1 or 2 essential hypertension (mean blood pressure measurement >140 mm Hg systolic or >90 mm Hg diastolic), without a history of admission for heart failure within the past year, and who had not been taking RAAS inhibitors in the previous 3 months.
Patients were randomised to receive valsartan (160 mg once daily, titrated to 320 mg once daily) or matched placebo with the aim of reaching a blood pressure (BP) target of <135 mm Hg systolic and <80 mm Hg diastolic for all participants being treated with a systematic add‐on treatment regimen of diuretics, β blockers or calcium channel blockers and α blockers. The study drug was titrated even if the target BP was reached at lower doses of valsartan or by reduction of the concomitant treatment if the patient achieved target BP with the first dose. Patients could not receive other angiotensin receptor blockers, ACE inhibitors or aldosterone antagonists during the study. The primary end point was change in diastolic myocardial relaxation velocity of the lateral mitral annulus (E′) from baseline to follow‐up (38 weeks). Secondary efficacy measures included differences between treatment groups in changes in blood pressure, left ventricular wall thickness, left ventricular mass and the ratio of mitral inflow velocity to annular relaxation velocity (E/E′).
Three hundred and eighty‐four patients entered the study, with 186 randomly assigned to receive valsartan and 198 to placebo. Forty‐three patients were lost to follow‐up or discontinued the assigned treatment. Over 38 weeks there was a mean (SD) reduction in blood pressure in the valsartan arm 12.8 (7.2)/7.1 (9.9) mm Hg and a reduction of 9.7 (17.0)/5.5 (10.2) mm Hg in the placebo group, but this difference was not significant (p=0.10). Mean SD) diastolic relaxation velocity increased by 0.60 (1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. There was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29).
The data suggest that subtle changes in diastolic function may precede the development of left ventricular hypertrophy. The study also demonstrates that aggressive treatment of BP can improve measures of diastolic filling independently of the regimen used, even in the absence of left ventricular hypertrophy and irrespective of age, baseline BP and baseline diastolic function. The lack of a further effect for valsartan beyond that achieved with BP control suggests that further studies of larger groups with longer follow‐up, including patients with advanced stages of ventricular remodelling, will be necessary to assess the relationship between abnormalities of diastolic filling and progression to heart failure. It will also be useful to assess specific antihypertensive regimens and whether they improve cardiac function/outcome independently of BP control. In the interim we should concentrate on early recognition and prompt reduction of raised blood pressure.
Solomon SD, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet 2007;369:2079–87.
In: Ahmed A, Perry GJ, Husain A, eds. VALIDD should not invalidate angiotensin‐receptor blockers. Lancet 2007;369:2053–4
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax
Dr Alistair Lindsay, Dr Katie Qureshi