Effect of high-dose atorvastatin on the cardiovascular risk associated with individual components of metabolic syndrome: a subanalysis of the Treating to New Targets (TNT) study.

AIMS: To investigate the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome components [high body mass index (BMI), elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting glucose] in patients with coronary heart disease (CHD). METHODS: Patients with clinically evident, stable CHD and low-density lipoprotein (LDL) cholesterol <3.4 mmol/l (130 mg/dl) were randomized to double-blind therapy with atorvastatin 10 mg/day (n = 5006) or 80 mg/day (n = 4995) after an 8-week open-label run-in with atorvastatin 10 mg. The median follow-up was 4.9 years. The impact of individual metabolic syndrome risk factors was tested on the primary endpoint, which was the occurrence of a first major cardiovascular event. RESULTS: On-treatment LDL cholesterol was 2.6 mmol/l (101 mg/dl) with atorvastatin 10 mg and 2.0 mmol/l (77 mg/dl) with atorvastatin 80 mg. Among patients receiving atorvastatin 10 mg, the presence of each individual metabolic syndrome component significantly increased the risk of major cardiovascular events compared with the absence of each (BMI, p = 0.014; triglycerides, p = 0.006; HDL cholesterol, p = 0.0006; hypertension, p < 0.0001; and fasting glucose p < 0.0001). In patients receiving atorvastatin 80 mg, elevated triglycerides and fasting glucose were no longer significant predictors of major cardiovascular events. The predictive power of hypertension on the risk of major cardiovascular events was reduced in patients treated with atorvastatin 80 mg, although it remained a significant predictor. CONCLUSIONS: Treatment with high-dose atorvastatin to a mean LDL cholesterol level of 2.0 mmol/l (77 mg/dl) considerably attenuated the predictive power associated with three metabolic syndrome components.

Management issues in the metabolic syndrome.

The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndrome are physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity or adiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDL cholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impaired fibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed. Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolated that this country also has the largest number of patients with the metabolic syndrome. Epidemiological studies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and control of multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity, pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach for control of individual risk factors. Pharmacological therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesity drugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly control the metabolic syndrome components. Other than weight loss, there is no single best therapy and treatment should consist of treatment of individual components of the metabolic syndrome. Newer drugs such as the endocannabinoid receptor blocker,rimonabant, appear promising in this regard. Atherogenic dyslipidemia should be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipid abnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should be considered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockers are available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBS) may be more beneficial for treatment of hypertension in patients with metabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR) agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options. Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluated in long-term prospective trials in such patients.

Increased variance in blood pressure distribution and changing hypertension prevalence in an urban Indian population.

The objective of the study was to determine trends in age-specific blood pressure (BP) distribution and hypertension prevalence in an urban Indian population. In successive hypertension epidemiological studies (1995 and 2002), randomly selected 2212 subjects (1412 men, 797 women) in the first and 1123 subjects (550 men, 573 women) in the second study were evaluated. BP was measured using World Health Organization guidelines and hypertension diagnosed using the American Joint National Committee-VI report. Age-specific BP levels in the first and the second study were determined and compared. The mean values of systolic and diastolic BP were not significantly different in various age groups in the first and the second studies. There was an increased variance in the second study as denoted by the significant increase in standard deviations and coefficients of variation in systolic as well as diastolic BP levels at age groups > or =50 years in men and > or =40 years in women (P<0.05). The age-adjusted prevalence of hypertension (known or BP > or =140/> or =90 mmHg) in the first study was 29.5% (men) and 33.5% (women), and in the second study was 30.0% (men) and 30.3% (women) (P=NS). In the second as compared to the first study, there was decrease in age-adjusted prevalence of stage I hypertension (men 16.8 vs 24.9%, women 15.4 vs 27.5%), and increase in stage II hypertension (men 11.7 vs 2.8%, women 18.8 vs 3.1%), and combined stage II and III hypertension (men 13.5 vs 4.7%, women 16.7 vs 6.0%) (P<0.01). This change was associated with greater prevalence of obesity in the second study. In conclusion, increased systolic and diastolic BP dispersion over a 7-year period in this urban population is associated with unchanged hypertension prevalence, decline in stage I hypertension and upsurge in more severe grades. Increasing environmental factors, particularly obesity, appear important.

Prevention of and medical therapy for atrial arrhythmias in heart failure.

A large proportion of heart failure patients suffer from atrial arrhythmias, prime amongst them being atrial fibrillation (AF). Ventricular dysfunction and the syndrome of heart failure can also be a concomitant pathology in up to 50% of patients with AF. However this association is more than just due to shared risk factors, research from animal and human studies suggest a causal relationship between AF and heart failure. There are numerous reports of tachycardia-induced heart failure where uncontrolled ventricular rate in AF results in heart failure, which is reversible with cardioversion to sinus rhythm or ventricular rate control. However the relationship extends beyond tachycardia-induced cardiomyopathy. Optimal treatment of AF may delay progressive ventricular dysfunction and the onset of heart failure whilst improved management of heart failure can prevent AF or improve ventricular rate control. Prevention and treatment of atrial arrhythmias, and in particular atrial fibrillation, is therefore an important aspect of the management of patients with heart failure. This review describes the incidence and possible predictors of AF and other atrial arrhythmias in patients with heart failure and discusses the feasibility of primary prevention. The evidence for the management of atrial fibrillation in heart failure is systematically reviewed and the strategies of rate versus rhythm control discussed in light of the prevailing evidence.

Comparative effects of ACE inhibitors and an angiotensin receptor blocker on atherosclerosis and vascular function.

BACKGROUND: Both angiotensin-converting enzyme inhibitors (ACE-I(s)) and angiotensin receptor blockers (ARB(s)) provide vascular protection. This study was designed to compare ACE-I(s) with widely differing tissue affinity (captopril and quinapril) and an ARB (losartan) on vascular protection against the adverse effects of high cholesterol. METHODS AND RESULTS: Forty-two New Zealand rabbits on a 0.5% cholesterol diet were randomized into control, captopril (10 mg/kg/d), quinapril (0.3 mg/kg/d), and losartan (8 mg/kg/d) groups for 14 weeks. Captopril, quinapril, and losartan significantly attenuated aortic lipid lesions (P=0.001). Captopril and quinapril were more effective than losartan in preserving vascular relaxation. CONCLUSIONS: Captopril, quinapril, and losartan had similar protective effects against atherogenesis. Captopril and quinapril were more effective than losartan in preserving vascular function. Increased bradykinin by ACE inhibition may be responsible for this improved vascular endothelial function.

Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.

CONTEXT: A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C. OBJECTIVE: To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998. SETTING: The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites. PARTICIPANTS: A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]). INTERVENTION: Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267). MAIN OUTCOME MEASURE: Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death. RESULTS: Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events. CONCLUSIONS: Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.

Pharmacotherapy of hypertension in patients with diabetes mellitus.

The co-existence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Overwhelming evidence supports aggressive treatment of hypertension in diabetic patients. However, only a small percentage of diabetic hypertensive patients reach their treatment goal of blood pressure (BP) < 130/80 mmHg. Tight BP control is not only cost-effective but also more rewarding than glycaemic control. The optimal goal of BP control in diabetics should be 130/80 mmHg. In subjects with diabetes and renal insufficiency, the BP should be lowered to 125/75 mmHg to delay the progression of renal failure. The choice of an antihypertensive agent should be based on proven effects on morbidity and mortality rather than on surrogate parameters such as lipid or glucose. Limited data suggests that an angiotensin converting enzyme inhibitor (ACEI) is the agent of choice, especially in those with proteinuria or renal insufficiency. beta-blockers (betaBs) can be the first-line agent in diabetics with coronary heart disease, while thiazide diuretics (TD) and calcium-channel blockers (CCBs) are the second-line drugs. Angiotensin II-receptor blockers (ARBs) may be proven to be as effective as ACEIs in diabetics with hypertension. alpha-adrenergic antagonists (AAAs) should be avoided. Most hypertensive patients require more than one agent to control their BP. There is no evidence to support one combination regimen over others; nevertheless, a combination of an ACEI with a TD or a betaB may be the most cost-effective regimens compared to other combinations.

Atrial fibrillation in patients with heart failure: pharmacologic options.

Atrial fibrillation is a common arrhythmia in patients with heart failure. The presence of atrial fibrillation deteriorates cardiac function and increases the risk of thromboembolic events. The management of patients with atrial fibrillation in association with heart failure should consist of ventricular rate control, prevention of thromboembolic events, and conversion to normal sinus rhythm. Traditionally, digoxin has been widely used in patients with heart failure and atrial fibrillation; however, it does very little to restore sinus rhythm and requires the addition of another rate-limiting agent to control ventricular rate. The likelihood of successful cardioversion is dependent on the duration of heart failure and the degree of neurohormonal activation. The initiation of antiarrhythmic drug therapy in patients with heart failure should be guided by safety issues as well as consideration of potential benefits vs. risks associated with therapy. Amiodarone has been evaluated in numerous clinical trials and appears to be safe and effective when used in low dosage. Treatment with dofetilide is another option. Comparative studies with oral dofetilide vs. amiodarone are needed to evaluate their efficacy in restoration and maintenance of sinus rhythm in patients with heart failure. Such trials will clearly define the role of dofetilide in the treatment of atrial fibrillation. Routine prophylactic use of antiarrhythmic drug therapy for chronic atrial fibrillation in the setting of heart failure is not recommended due to a low efficacy rate and high proarrhythmic risk. Anticoagulation with warfarin and rate control remain the standard therapy. (c)2001 by CHF, Inc.

Early invasive versus ischaemia-guided strategies in the management of non-Q wave myocardial infarction patients with and without prior myocardial infarction; results of Veterans Affairs Non-Q Wave Infarction Strategies in Hospital (VANQWISH) trial.

AIMS: To compare the role of early invasive vs conservative management strategies in treating patients with non-Q wave myocardial infarction with or without a prior myocardial infarction. BACKGROUND: In patients recovering from non-Q wave myocardial infarction, the prognosis among patients with a first non-Q wave myocardial infarction is significantly better than in patients with a prior myocardial infarction, yet physicians often adopt an early invasive strategy to treat patients with a first non-Q wave myocardial infarction. METHODS: Non-Q wave myocardial infarction patients enrolled in the VANQWISH trial with a history of prior myocardial infarction were compared to those with a first non-Q wave myocardial infarction, for the trial primary end-point of death or myocardial infarction at 1 and 12 months, as well as for the initial randomized treatment strategy. RESULTS: Of the 920 non-Q wave myocardial infarction patients, 396 had a history of prior myocardial infarction and 524 did not. Patients with a history of prior myocardial infarction were older and had a higher incidence of multiple high-risk baseline characteristics than those with a first non-Q wave myocardial infarction. Compared to the group with a first myocardial infarction, the prior myocardial infarction group suffered more events at both 1 month (11% vs 6%, P=0.007) and at 12 months (29% vs 16%, P<0.001). This difference in outcome remained significant even after adjusting for confounding variables (P<0.0001 at 12 months). Among the non-Q wave myocardial infarction patients with a prior myocardial infarction, the frequency of death or recurrent myocardial infarction was similar in both invasive and conservative groups during the first year of follow-up. Among the first non-Q wave myocardial infarction group, those assigned to the conservative strategy had significantly fewer events (3% vs 9%, P=0.009 at 1 month; 12% vs 20%, P=0.016 at 12 months) and mortality (1% vs 5%, P=0.012 at one month; 5% vs 11%, P=0.009 at 12 months) than those assigned to early invasive strategy. CONCLUSION: A history of prior myocardial infarction identifies a moderately high-risk subset of non-Q wave myocardial infarction patients who display similar long-term outcomes regardless of the strategy assignment; however, patients with a first non-Q wave myocardial infarction may fare better with a conservative or ischaemia-guided approach during the first post infarction year.

Silent myocardial ischaemia in the elderly.

Coronary artery disease (CAD) is a leading cause of death and disability in the elderly. Several recent studies have shown that silent myocardial ischaemia (SMI) is a common manifestation of CAD, especially in the elderly. As many as 40% of elderly patients with no prior history of CAD may have underlying asymptomatic disease and up to 50% of elderly patients with known CAD might have evidence of SMI. The results of studies in elderly patients with CAD have also shown that SMI might exist despite antianginal therapy that is considered adequate for symptom control. In order to diagnose such residual SMI, the clinician would need to perform 24- to 48-hour Holter monitoring in the ambulatory setting while the patient is performing routine daily activities. Although a number of anti-ischaemic drugs have been evaluated for the treatment of SMI, available data suggest that beta-blocker given alone or in combination with a nitrate compound or calcium antagonist provides the best therapeutic choice. The long term benefit of SMI suppression in elderly patients has not been established. Future studies need to evaluate the clinical benefits of therapy given for SMI in the elderly.

Mechanism of the deadly quartet.

A deadly quartet of risk factors places diabetics at a particularly high risk for adverse cardiovascular events; these factors are hypertension, hyperlipidemia, hyperglycemia and hyperinsulinemia. A number of metabolic abnormalities are common to diabetes. Many of them, including dyslipidemia, have been linked to both insulin resistance and endothelial dysfunction. Several lines of evidence have led to the hypothesis that insulin resistance may be a key pathophysiological mechanism leading to endothelial dysfunction and atherosclerosis in patients with diabetes and possibly other illnesses. In both diabetic and nondiabetic populations, the common risk factors for coronary artery disease events are dyslipidemia, insulin resistance, obesity and high blood pressure. A number of strategies are recommended to prevent the potentially deadly consequences of these factors.

Hypertension and diabetes: new therapeutic options.

The treatment of high-risk hypertensive patients with diabetes presents clinicians with challenges and opportunities. The coexistence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Perhaps most important among these is the increased risk of cardiovascular events in this patient population, an observation that can be best appreciated by the increased number of deaths attributed to cardiovascular-related diseases in diabetic patients aged 45 to 65 years. Consequently, aggressive therapy in this population offers the promise of significantly reducing excess cardiovascular deaths. Despite this opportunity for reducing mortality in these high-risk patients, several challenges to treatment remain. While aggressive blood pressure reduction has been documented to reduce the rate of events in these patients, questions remain as to the level to which blood pressure should be reduced. The recent guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasized the importance of treating patients with hypertension and diabetes as if they already have target organ damage. Low blood pressure targets of 130/85 mm Hg, with an optimal goal of 120/80 mm Hg, can reduce the risk of events in hypertensive patients with diabetes, regardless of the pharmacological means used. However, there are physiologic and clinical rationale for renin angiotensin system blockade, with angiotensin-converting enzyme inhibition as the preferential therapy in these patients. In this regard, preliminary data with the new class of angiotensin II receptor blockers suggest that these agents may offer benefits equivalent to those observed with angiotensin-converting enzyme inhibitors while offering better tolerance.

Hypercholesterolemia. Is lipid-lowering worthwhile for older patients?

Despite some indications to the contrary, evidence continues to accumulate that controlling cholesterol levels with drug therapy in older persons is a worthwhile goal. Older persons with hypercholesterolemia have an elevated risk of coronary heart disease morbidity and mortality, and this risk increases as they age. Recent clinical trials have suggested that older persons benefit from lipid-lowering therapy as much as younger patients do. Therefore, intervention appears to be justified--as is greater vigilance in identifying untreated patients.

Effects of L-arginine on atherogenesis and endothelial dysfunction due to secondhand smoke.

Secondhand smoke (SHS) and hypercholesterolemia increase cardiovascular risk. We hypothesized that L-arginine, the precursor of nitric oxide (NO), might protect against atherogenesis and endothelial dysfunction caused by SHS. The effects of L-arginine supplementation (2.25% solution ad libitum) and SHS (smoking chambers for 10 weeks) were examined in 32 hypercholesterolemic rabbits. Eight normal rabbits served as controls. Acetylcholine- and nitroglycerin-induced vasorelaxation was assessed in aortic rings precontracted with norepinephrine. Hypercholesterolemia increased intimal lesion area (P=0.012), reduced endothelium-dependent relaxation (P=0.009), and reduced basal (P=0.005) and stimulated (P<0.0005) production of NOs. SHS increased intimal lesion area (P=0. 01) norepinephrine-induced contraction (P=0.001) and reduced endothelium-dependent relaxation (P=0.02). SHS-induced increase in norepinephrine contraction was abolished by the inhibition of NO synthase and removal of endothelium. L-Arginine improved endothelium-dependent relaxation (P=0.001) and attenuated SHS-induced endothelial dysfunction (P=0.007) and atherogenesis (P=0. 001). Basal production of nitrogen oxides correlated inversely with intimal lesion area (r=-0.66; P<0.0005) and stimulated production of NOs correlated with endothelium-dependent relaxation (r=-0.66; P<0. 001). SHS causes endothelial dysfunction and increased adrenergic responsiveness and atherogenesis in hypercholesterolemic rabbits. Chronic dietary supplementation with the NO precursor L-arginine mitigates these effects. The adverse vascular consequences of SHS appear to be mediated via deleterious effects on endothelial function.