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The answer to the question posed in the title is that each component of cardiovascular (CV) and metabolic risk can affect others. A clustering of risk factors-overweight, smoking, hypertension, hyperlipidemia, insulin resistance, glucose intolerance-increases risk geometrically. Tantalizing recent data suggest that treatment of global risk, but particularly hypertension, can diminish the risk of cognitive function.

Applying an Understanding of Vascular Pathology to Practice

Richard B. Devereux, MD, Director, Echocardiography Laboratory, New York Hospital-Cornell Medical Center; Professor of Medicine, Cornell University Medical College, New York, New York

It’s not just the blood pressure (BP) but also target organ effects that determine the CV benefits of antihypertensive therapy. That was the main message of Dr. Richard Devereux. Dr. Devereux is particularly involved in the study of vasoconstriction, hypertension, and organ damage, as caused by excessive activity of the renin-angiotensin system (RAS) and sympathoadrenal system, nitric oxide dysregulation, and other measures of abnormal vascular reactivity. Angiotensin II (AII) stands front and center in this field and has long been a target of investigation. It is a “good cop/bad cop.” It is essential for sodium volume and potassium homeostasis, but when activity is excessive to the level of BP, it results in arterial damage, vascular cardiac hypertrophy, and nephrotoxicity.

One can impede some of these processes by blocking angiotensin II effect, which can be done with the newer classes of antihypertensives, specifically, angiotensin-concerting enzyme (ACE) inhibitors and angiotensin II receptor blockers. To illustrate this, Dr. Devereux reviewed a number of recent trials of antihypertensive agents.

The Heart Outcomes Prevention Evaluation study (HOPE) showed beneficial effects of the ACE inhibitor ramipril on CV events and disease progression. In a substudy, it investigated its value in reducing the risk of stroke. Ramipril substantially decreased the risk of stroke and transient ischemic attacks in 9297 patients with high CV risk. It yielded a 32% relative risk reduction (P=0.0002), with a reduction in BP of only 3.8 mm Hg (systolic) and 2.8 mm Hg (diastolic). This benefit was greater than expected from prior meta-analyses of epidemiologic studies or hypertension studies.

The Losartan Intervention for Endpoint Reduction (LIFE) Study compared use of the beta blocker atenolol and the AII receptor blocker losartan in CV risk reduction. The primary endpoint was a composite of CV mortality, fatal and nonfatal myocardial infarction, and fatal and nonfatal stroke. Losartan reduced CV morbidity and mortality more effectively than atenolol, with an adjusted risk reduction of 13% (P=0.021). Losartan treatment resulted in a 25% relative-risk reduction for stroke compared with atenolol. Small differences in systolic and diastolic pressure had little effect on the estimate of the benefit associated with losartan. The greater effect of losartan compared with atenolol on primary composite endpoints may have been due to the greater reduction of left ventricular mass with losartan. This benefit could result from increased protection against the detrimental effects of AII or, possibly, from specific effects of losartan.

The Second Australian National Blood Pressure Study (ANBP2) compared thiazides with ACE inhibitors in 6083 hypertensive patients aged 65-84 years. Patients and physicians were not blinded but individuals assessing the outcomes were. Hydrochlorothiazide and enalapril were suggested initial therapy. For second- and third-line therapy, beta blockers, calcium-channel blockers, and alpha blockers were recommended in both groups. The primary endpoint was all CV events (initial and recurrent) plus all-cause mortality. There was an 11% lower rate of endpoints with the ACE-inhibitor regimen, with a difference in BP of about 1 mm Hg. Once again, the difference in risk reduction was likely not due to the BP reduction.

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial, patients were randomly assigned to either amlodipine with or without perindopril or to atenolol with or without the thiazide diuretic bendroflumethiazide. The goal was to achieve and maintain a target BP of ≤140/90 mm Hg. The primary outcome was a combined endpoint of nonfatal myocardial infarction and fatal coronary artery disease. The trial was stopped in November 2004 due to a significant all-cause mortality benefit achieved in the amlodipine/perindopril arm. The Conduit Artery Function Evaluation (CAFE), a substudy of ASCOT, showed reductions in conventional BP in the brachial artery and even more of a difference in central BP that might explain the greater benefit in the arm treated with ACE inhibitors.

With more than 40,000 patients in combined studies, Dr. Devereux concludes that the effects of AII blockade may have contributed to the greater reduction in atherosclerosis, hypertrophy, and renal dysfunction. The newer antihypertensive regimens achieve more inhibition of the RAS than diuretics and beta blockers. Target organ protection-not just lowering of BP-may be the key, along with improvement in metabolic mediators.

Cardiovascular Risk from the Endocrinologist’s Perspective

James R. Gavin III, MD, PhD, Clinical Professor of Medicine, Emory University School of Medicine; Executive Vice President of Clinical Affairs, Healing Our Village, LLC, Atlanta, Georgia

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), diabetes is a “risk equivalent” of coronary heart disease. And this is why endocrinologists are so concerned about CV risk. Persons with diabetes have aggregated risks-multiple risk factors, or a clustering of these risks. The continuum of risk includes the metabolic syndrome, prediabetes, and obesity, with associated comorbidities.

One of the important aspects in this continuum is abdominal obesity, defined by waist circumference. Dr. Gavin considers obesity “the ugly new face of public health in the 21st century.” Dyslipidemia, hypertension, and glucose intolerance-all more common in obese patients-are all key players in the metabolic syndrome.

However, the metabolic syndrome has somewhat disparate definitions. The World Health Organization considers the presence of insulin resistance a cornerstone, coupled with abdominal obesity, dyslipidemia, and hypertension. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III considers abdominal obesity a key component. But all definitions of the metabolic syndrome consider abdominal obesity an important component. In particular, visceral fat drives atherosclerosis in persons with diabetes. The adipocytes seen in this disorder are insulin resistant. They produce cytokines, and inhibit production of adiponectin. Insulin resistance is associated with dyslipidemia, glucose intolerance, diabetes, hypertension, and visceral obesity. Elevated triglyceride levels and decreased high-density lipoprotein cholesterol levels are characteristic of this syndrome. This clustering begins to play out at the level of the vascular endothelium, which acts as a barrier between blood flow and the vascular wall. It is very responsive and reactive. Fatty meals inhibit vasodilation of the vasculature. In short, changes in the release and balance of vasoactive substances change the properties of the blood vessels. This contributes to an increase in pro-inflammatory molecules in the vascular endothelium.

Agents useful for treatment of the metabolic syndrome and prevention of diabetes are thiazolidinediones, lifestyle intervention, metformin, and acarbose; importantly, nonglucose therapies that modulate the RAS are very effective in reducing the development of full-blown diabetes. Modification of the RAS, as seen in trials like the Valsartan Antihypertensive Long-term Use Evaluation Trial (VALUE; valsartan vs a calcium channel blocker), are very effective. The LIFE study further supports the importance of nonglucose therapies in preventing diabetes.

In summary, Dr. Gavin suggests that treatment issues that must be addressed include overweight, obesity, hypertension, hyperglycemia, and dyslipidemia; global risk reduction is the key. Treatment of the root causes of the metabolic syndrome is essential.

Kidney Function and Cardiovascular Risk

George L. Bakris, MD, Vice Chairman, Department of Preventive Medicine; Senior Director, Hypertension/Clinical Research Center, Rush Presbyterian/St. Luke’s Medical Center, Chicago, Illinois

Dr. Bakris, a nephrologist, views kidney function as an important component in CV risk: that is, if one reduces CV risk, the kidney is protected. Early, aggressive therapy is essential in this regard. Although the role of salt has often been minimized as a factor in reducing hypertension and, therefore, CV risk, Dr. Bakris notes that excessive dietary salt intake increases oxidative stress and mitigates against the positive aspects of ACE inhibitors and AII blockers. It blunts the beneficial effect of reducing albuminuria.

The JNC 7 report is very clear that albuminuria is a CV risk factor, and Dr. Bakris urges early measurement of albuminuria and glomerular filtration rate (GFR). He adds that patients with kidney disease without diabetes have a risk of CV disease similar to that of patients with diabetes without kidney disease.

A Kaiser Permanente study examined the importance of GFR in more than 1 million patients. A GFR of 30-59-considered stage 3 kidney disease, the most prevalent stage in the United States-substantially increases CV risk.

Thus, proposes Dr. Bakris, if a diabetic patient has albuminuria and hypertension, with a BP even 20 mm Hg over goal, antihypertensive therapy should begin, preferably with an ACE inhibitor or AII receptor blocker, and the dose should be ample. Diuretics often need to be used because BP is volume dependent.

Cognitive Impairment: An Often Forgotten Link to Metabolic Risk

Philip B. Gorelick, MD, MPH, John S. Garvin Professor and Head Director, Center for Stroke Research; Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, Illinois

The link between the metabolic syndrome and cognitive impairment is “the new frontier,” according to Dr. Gorelick. Prevention or treatment of metabolic syndrome also protects the brain. He noted that CV risk factors are important to preservation of brain size and cognition. As CV risk factors aggregate, brain volume shrinks. This is a very significant recent finding.

Hypertension in mid or late life contributes to cognitive impairment. The East Finland Study and the National Heart, Lung and Blood Institute Twin study showed that elevated systolic BP results in greater cognitive impairment. Follow-up in the Syst-Eur trial showed that vascular dementia was reduced with BP control, as was Alzheimer’s disease.

The mechanisms of the link between hypertension and cognitive impairment may be AII, which leads to cerebral insufficiency. The RAS may be important, as well as BP dipping and nondipping during sleep. Insulin resistance may play a role. The ABC trial, which included 2600 participants, suggested that persons with elevated C-reactive protein have a greater risk of cognitive impairment. Diabetes and hyperinsulinemia are players, and Dr. Gorelick proposes that metformin, which improves glycemic control, added to diabetes care therapy will improve cognitive function.

In summary, Dr. Gorelick notes that nonprimary analyses suggest the importance of global reduction of CV risk factors in improving cognitive function.