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Angiotensin II Blockade in the Management of Cardiovascular Disease

Angiotensin II in Cardiac and Vascular Disease: Newest Evidence

A number of factors contribute to the development of cardiovascular disease in persons with obesity, including hyperlipidemia, inflammatory cytokines, and insulin resistance. “In addition, the renin angiotensin aldosterone system [RAAS] plays an important role in regulating vascular fibrinolytic balance—which is, in large part, determined by the competing effects of tissue-type plasminogen activator [t-PA] and plasminogen activator inhibitor-1 [PAI-1],” said Douglas E. Vaughan, MD, FACC, Professor of Medicine and Pharmacology, C. Sidney Burwell Professor of Medicine, and Chief, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, in Nashville, Tennessee. According to Dr. Vaughan, inhibition of vascular PAI-1 production may be a useful therapeutic target in reducing the risk for cardiovascular events, particularly in persons with obesity.

Obesity and Cardiovascular Disease
Obesity is associated with hypertension, premature atherosclerosis, coronary artery disease, congestive heart failure, and type 2 diabetes. “Body mass index has been shown to correlate directly with increased risk for hypertension, coronary artery disease, and type 2 diabetes,” said Dr. Vaughan. A number of factors drive the cardiovascular disease process in persons with obesity, including increased oxidative stress, elevated C-reactive protein, impaired lipid metabolism, low HDL, elevated triglycerides, and hyperinsulemia. Another important factor is impairment of the fibrinolytic system.

Impairment of the Fibrinolytic System
The fibrinolytic system serves to dissolve vascular clots, remodel extracellular matrix, and promote cellular migration. The net generation of plasmin in the blood is largely dependent on the balance between t-PA, which is a fibrin clot-degrading protease, and PAI-1, a natural inhibitor of t-PA. “It is the disturbance between t-PA and PAI-1 that may be responsible for the impairment of fibrinolysis found in the obese population,” Dr. Vaughan explained.

PAI-1 is manufactured in the vascular and adipose tissues, and has shown a striking correlation with body mass index. “In addition, studies have shown that PAI-1 is a risk factor for cardiovascular disease and new-onset diabetes, independent of other factors,” Dr. Vaughan said. According to Dr. Vaughan, PAI-1 likely contributes to the cardiovascular disease process by more than one mechanism, exerting a significant impact on intravascular clotting and inhibiting t-PA, activated protein C, and urokinase. Recent murine studies by Vaughan and colleagues indicate “a strong relationship between PAI-1 and vascular pathology, with transgenic mice that overexpress human PAI-1 developing spontaneous coronary arterial thrombosis, suggesting that PAI-1 alone is sufficient to promote clot formation in the coronary circulation. In addition, PAI-1 deficiency protected against fibrosis, including the vascular phenotype—arterial sclerosis and potentially hypertension,” Dr. Vaughan noted (Eren et al, Circulation 2002; Kaikita et al, Circulation 2001).

Renin Angiotensin System and PAI-1
According to Dr. Vaughan, important factors that drive increased PAI-1 production, particularly in obesity, include angiotensin II, angiotensin IV, and aldosterone. Thus, the renin angiotensin system has an important relationship to the maintenance of vascular fibrinolytic balance. “Angiotensin II drives PAI-1 production, while bradykinin drives t-PA secretion,” Dr. Vaughan explained.

Animal studies show that angio-tensin II increases PAI-1 production in the aorta and kidney, and this production is blocked with an AT1 receptor blocker. Other research indicates a strong correlation between plasma aldosterone and PAI-1 production. In one study of patients with obesity and hypertension who were pretreated with hydro-chlorothiazide, both an angiotensin-converting enzyme (ACE) inhibitor and AT1 receptor blocker were shown to reduce PAI-1 levels in the short term; however, the ACE inhibitor had a greater effect on blood pressure. Both agents also resulted in reduced oxidative stress markers, with the AT1 receptor blocker having a greater effect on F2-isoprostane levels.

The effect of bradykinin on t-PA release also plays an important role, causing a dramatic dose-dependent increased release of t-PA in the vascular bed. Vaughan and colleagues showed that endogenous bradykinin or an ACE inhibitor results in dramatic induction of t-PA release across the arterial circulation, while blockade of the bradykinin receptor obliterated this effect.

In closing, Dr. Vaughan emphasized that increased PAI-1 levels, driven in part by angiotensin II, appear to contribute to the development of hypertension and cardiovascular disease in persons with obesity. “Inhibitors of PAI-1 and augmentation of t-PA release may provide new strategies for the prevention of cardiovascular events in patients who are obese,” he concluded.


Angiotensin II Blockade in High-Risk Patients: Cases in Point

“The use of an angiotensin II receptor blocker [ARB] may provide an added benefit to hypertensive patients who are at increased risk for cardiovascular events and are already receiving appropriate antihypertensive therapy,” said Clyde W. Yancy, MD, Associate Dean of Clinical Affairs, St. Paul University Hospital, Associate Professor of Internal Medicine/Cardio-logy, and Medical Director, Heart Failure/Transplantation, at University of Texas Southwestern Medical Center, in Dallas, Texas. According to Dr. Yancy, early intervention with an appropriate antihypertensive regimen may allow for reduced cardiovascular morbidity and mortality in high-risk hypertensive patients.

Angiotensin II and Cardiovascular Disease
The progression from hypertension to heart failure is facilitated by an activated neurohormonal environment (sympathetic nervous system) and renin angiotensin aldosterone system (RAAS). This process is accelerated by the metabolic syndrome, which can include obesity, insulin resistance, and diabetes. Hypertension alone constitutes predisposition to the development of heart failure, occurring either through: 1) accelerated atherosclerosis and myocardial infarction or 2) left ventricular (LV) remodeling, cardiomyopathy, and ventricular hypertrophy. “Importantly, the process of LV remodeling is associated with a significant increase in the cardiovascular event rate,” said Dr. Yancy. LV remodeling is a function of myocyte enlargement on hypertrophy and an increase in the extracellular matrix, with angiotensin II contributing to both pathways.

Who Is at High Risk?
According to Dr. Yancy, identifying those patients at high risk for cardiovascular events is essential for early and effective intervention. Persons considered at highest risk include those with:
1) already established overt systolic dysfunction;
2) apparent diastolic dysfunction;
3) diabetes, hypertension, and/or LV hypertrophy; and
4) hypertension and concomitant albuminuria.

Cases in Point
Dr. Yancy presented an overview of clinical scenarios of high-risk individuals in need of early intervention.

Case 1: Overt LV Systolic Dysfunction
In the Val-HeFT trial, more than 5000 patients with chronic LV systolic dysfunction received appropriate background therapy plus either an angiotensin-converting enzyme (ACE) inhibitor/ARB combination or ACE inhibitor/placebo. The results showed a 13.2% risk reduction (morbidity and mortality) with the combination therapy. In addition, patients with symptomatic LV dysfunction who were intolerant of an ACE inhibitor received either valsartan or placebo (plus background therapy). Valsartan was associated with a significant reduction in the risk of hospitalization and mortality. Ejection fraction was also improved with this therapy. “Comprehensive antagonism of the renin angiotensin system with an ARB and ACE inhibitor may yield improved clinical outcomes in patients with overt LV systolic dysfunction,” Dr. Yancy noted.

Case 2: Symptomatic Heart Failure with Preserved Systolic Performance
In this patient group, ventricular contractility is either normal or mildly impaired, generally with an ejection fraction of > 45% to 50%. Symptomatic heart failure with preserved systolic performance is often documented in the setting of congestive heart failure for which the typical causes of systolic dysfunction are ruled out. This condition is almost as likely as classic LV systolic dysfunction, which is usually associated with coronary disease, myocardial infarction, or alcohol use. It is more likely to be found in persons who are older, are female, have hypertension, or have LV remodeling (eg, LVH). The use of ARB therapy is currently being investigated in the CHARM trial for patients with clinical heart failure and intact systolic function. “These data, combined with those of the Val-HeFT trial, will provide much needed guidance for the development of new treatment algorithms for patients with symptomatic heart failure, including those with preserved systolic performance,” Dr. Yancy said.

Case 3: Hypertensive Diabetic with Ventricular Hypertrophy
The patient with hypertension, diabetes, and ventricular hypertrophy is at significant risk for a cardiovascular event. The LIFE study data showed a significant reduction in cardiovascular mortality with the addition of an ARB to the antihypertensive regimen. In addition, patients may also have albuminuria, a risk factor associated with end-stage renal disease, myocardial infarction, and stroke. “Hypertensive patients with microalbuminuria are at a five-fold increased risk for cardiovascular events, and those with the highest levels have the poorest survival rates,” Dr. Yancy said. Meta-analysis data clearly show that addition of an ARB to the antihypertensive regimen for patients with microalbuminuria is associated with a significant reduction in
cardiovascular mortality.

In closing, Dr. Yancy summarized that “angiotensin II clearly plays a role in accelerating the progression from hypertension to cardiovascular disease. RAAS inhibition, in turn, may offer a valuable target for treatment of hypertension, particularly in patients at high risk for cardiovascular events.”

Benefits of RAAS Blockade in Heart Failure: Newest Evidence

Growth and remodeling of the myocardium and vascular smooth muscle are keys to the progression of hypertension to cardiovascular disease, with angiotensin and aldosterone playing critical roles in this process. Consequently, “left ventricle [LV] remodeling represents a significant risk for heart failure morbidity and mortality,” said Jay N. Cohn, MD, Professor of Medicine, Cardiovas-cular Division, Department of Medicine, University of Minnesota Medical School, in Minneapolis. A number of treatment options and combination regimens—including angiotensin-converting enzyme (ACE) inhibitors, beta blockers, angiotensin receptor blockers (ARBs), and possibly aldosterone inhibitors—have been shown to mitigate the effects of the renin angiotensin aldosterone system (RAAS), suppressing LV remodeling and reducing the risk for cardiovascular events.

The Role of Angiotensin II
Angiotensin II is a potent constrictor, activating the sympathetic nervous system, aldosterone, and vasopressin, all of which have been implicated in the progression to heart failure. “Importantly, angiotensin is also a potent stimulator of myocyte, vascular smooth muscle and collagen growth, the major contributors to structural cardiovascular remodeling,” Dr. Cohn explained. In addition, this substance stimulates oxidative stress and causes platelet aggregation and thrombosis. A number of drug types—including beta blockers, ACE inhibitors, and ARBs—have been studied and used clinically to suppress the RAAS, thereby reducing the risk for cardiovascular
disease.

The Role of Neurohormonal Mechanisms
“Neurohormonal mechanisms may contribute in several ways to the progression of heart failure,” Dr. Cohn noted. As potent vasoconstrictors, these hormones heighten the resistance to LV ejection, thereby impairing LV function, decreasing cardiac output, and ultimately resulting in LV remodeling. “The role of these hormones in stimulating myocyte and collagen growth may be another contributor to the progression of the syndrome,” Dr. Cohn said. He added that the renin-angiotensin and sympathetic nervous systems likely feed each other, resulting in stimulation of aldosterone, endothelin, inflammatory cytokines, and oxidative stress, all of which may contribute to LV dysfunction and remodeling, and progressive morbidity. “A growing body of evidence suggests that heart failure is predominately a remodeling process, and decreased ejection fraction is a manifestation of that process,” Dr. Cohn explained.

Treatment Options
Antihypertensive therapies, such as ACE inhibitors, beta blockers, and ARBs, can be effective in curtailing the LV remodeling process. In the V-HeFT trial, for example, heart failure patients receiving only digoxin and a diuretic were randomized to receive one of three regimens. The group receiving placebo as well as the cohort receiving an alpha blocker showed a progressive decline in ejection fraction. However, the group receiving a combination of nitrate and hydralazine showed sustained improvement in ejection fraction, suggesting inhibition of the remodeling process. This group also exhibited a reduction in mortality. Similar results have been found with enalapril and carvedilol, with striking improvement in ejection fraction compared with placebo. ARB agents are also an important treatment option for high-risk hypertensive patients. In the Val-HeFT trial, hypertensive patients with ejection fractions of < 40% and a dilated LV received background therapy plus high-dose valsartan or placebo. The results showed improved event-free survival and a 13.2% risk reduction in the valsartan group. Valsartan was also associated with a significant increase in ejection fraction and reduction of LV chamber dimensions. In addition, patients receiving an ACE inhibitor and no beta blocker showed a significant clinical benefit, as well as increased inhibition of aldosterone, with addition of valsartan.

Another potential role in the heart failure disease process is that of nitric oxide. Nitric oxide inhibits the remodeling process. “My working hypothesis is that the balance between angiotensin II and nitric oxide controls cardiovascular growth and remodeling. In patients with heart failure, the balance is shifted,” Dr. Cohn said. ACE inhibitors, in particular, may be useful in stimulating nitric oxide and nitric oxide donors, such as the nitrate-hydralazine combination, may restore deficient nitric oxide.

The Val-HeFT trial showed patients taking no neurohormonal-blocking therapy as having high mortality rates, while those receiving valsartan (no ACE inhibitor or beta blocker) showed a significant reduction in mortality from sudden death and pump failure. Those taking an ACE inhibitor (no beta blocker) and those taking a beta blocker (no ACE inhibitor) also demonstrated a favorable effect of valsartan on mortality rates. Remarkably, in those taking an ACE inhibitor and beta blocker, overall mortality was reduced to 11% from sudden death and 2% from pump failure (2-year period).

In closing, Dr. Cohn noted that neurohormonal activation clearly contributes to vascular and LV remodeling and progression of cardiovascular disease. “Reduction of angiotensin II and stimulation of nitric oxide may be keys to therapeutic efficacy in patients at risk for heart failure,” he concluded.


Angiotensin II Blockade in High-Risk Post-MI Patients

“It is important for clinicians caring for patients with hypertension or diabetes to realize that the cardiovascular risk patients had before a myocardial infarction [MI] is one that they continue to carry after a myocardial infarction. The increased cardiovascular risk persists,” said Marc A. Pfeffer, MD, PhD, Professor of Medicine, Harvard Medical School, Cardiovascular Division, at Brigham & Women’s Hospital, in Boston, Massachusetts. According to Dr. Pfeffer, patients having had an MI need to continue to be treated with appropriate lifestyle modifications that include smoking cessation and weight loss. When needed, antihypertensive and lipid-lowering agents must also be employed.

Predictors of Outcome
Once patients have had an MI, the goal is to minimize the damage from the event and to reduce the risk for future events, said Dr. Pfeffer. Outcomes for patients with MI can be predicted by a number of factors. Patients with hypertension, diabetes, advanced age, lower ejection fraction, and other comorbities are well known to be at higher risk for subsequent events. Further, increased heart size is associated with an exponential increased risk of death after MI (White et al, Circulation 1987). In addition, manifestation of pulmonary congestion has been consistently shown to be associated with approximately a six-fold increased risk of death in the hospital phase of MI, even after adjusting for other risk factors (Krumholz et al, J Am Coll Cardiol 2001).

“In the VALIANT registry, 40% of patients with acute MI had either pulmonary congestion and/or depressed ejection fraction. Moreover, 80% of all deaths during infarct occurred in this group,” Dr. Pfeffer said (Velazquez et al, JACC 2003, In Press). “These data suggest that to improve the prognosis for patients after acute or chronic MI, clinicians need to target this group at higher risk for poor outcomes,” Dr. Pfeffer noted.

Treatment in Post-MI Patients
“Fortunately, inhibition of the renin-angiotensin aldosterone system [RAAS] results in reduced cardiovascular morbidity and mortality,” Dr. Pfeffer said. Current treatment options include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).

Indeed, studies show that ACE inhibitor therapy is associated with an approximate 20% reduction in risk of death and of re-infarction in post-MI patients who have depressed ejection fraction or pulmonary congestion (Pfeffer et al, N Engl J Med 1992). In the CAPRICORN study, the addition of a beta blocker to ACE inhibitor therapy in post-MI patients resulted in additional clinical benefit (Dargie et al, Lancet 2001).

“ARBs represent an area of important potential for the treatment of patients who have had an MI,” said Dr. Pfeffer. In one large study, post-MI patients with a depressed ejection fraction or anterior MI received either losartan or captopril. Surprisingly, these data showed no improvement with the ARB compared to the ACE inhibitor. However, Pfeffer and colleagues are currently analyzing the findings from an even larger study, directly comparing
valsartan to captopril (Dickstein & Kjekshus, Am J Cardiol 1999) as well as the combination of valsartan added to captopril to captopril (Pfeffer et al, Am Heart J 2000). “These results are anxiously awaited and should be available shortly,” Dr. Pfeffer noted.

Another promising therapeutic area is that of aldosterone inhibition. The EPHESUS study involved treatment of high-risk post-MI patients with an ACE inhibitor and/or beta blocker, plus either placebo or the aldosterone antagonist, eplerenone. The group receiving the aldosterone antagonist had significantly reduced overall mortality rates (Pitt et al, N Engl J Med 2003).

“All patients who had an MI should be on therapy to control hypertension, modify cholesterol levels, and reduce other risk factors. Recent data show that patients with low ejection fraction or pulmonary congestion require additional measures to reduce morbidity and mortality rates. A combination of therapies, such as aspirin, beta blockers, ACE inhibitors, and, in more selected patients, aldosterone antagonists, should be employed. The potential of ARBs for further improvement is being actively investigated,” Dr. Pfeffer concluded.

 

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