Vascular remodeling action of angiotensin II from bench to bedside

AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2

Previous meta-analyses of outcome trials in hypertension did not specifically focus on isolated systolic hypertension (ISH) or explained treatment benefit mainly in function of the achieved diastolic blood pressure (BP) reduction. We therefore performed a quantitative overview of the trials to further evaluate the risks associated with systolic BP in treated and untreated older ISH patients. Patients were ⱖ60 years old. Systolic BP was ⱖ160 mm Hg and diastolic BP was ⬍95 mm Hg. We used non-parametric methods and Cox regression to model the risks associated with BP and to correct for regression dilution bias. We computed pooled effects of treatment from stratified 2 ⫻ 2 contingency tables after application of Zelen’s test of heterogeneity. In 8 trials 15693 ISH patients were followed up for 3.8 years (median). After correction for regression dilution bias, sex, age and diastolic BP, the relative hazard rates associated with a 10 mm Hg higher initial systolic BP were 1.26 (p ⫽ 0.0001) for total mortality, 1.22 (p ⫽ 0.02) for stroke, but only 1.07 (p ⫽ 0.37) for coronary events. Independent of systolic BP, diastolic BP was inversely correlated with total mortality (p ⫽ 0.05), highlighting the role of pulse pressure as risk factor. Active treatment achieved mean BP decreases of 10.4 mm Hg systolic and 4.1 mm Hg diastolic. A common treatment effect existed across the trials. Active treatment reduced total mortality by 13% (95% CI 2–22, p ⫽ 0.02), cardiovascular mortality by 18% (4 –29, p ⫽ 0.01), all cardiovascular complications by 26% (17–34, p ⬍ 0.0001), stroke by 30% (18 – 41, p ⬍ 0.0001) and coronary events by 23% (10 –34, p ⫽ 0.001). In spite of similar relative benefit across all strata (p ⬎ 0.30), the number of patients to treat for 5 years to prevent one major cardiovascular event was lower in men (18 vs 38), at or above age 70 (19 vs 39) and in patients with previous cardiovascular complications (16 vs 37); it was similar in smokers and non-smokers (30 vs 26), because of opposite trends for stroke (85 vs 45) and coronary events (43 vs 72). For cardiovascular mortality the number to treat was lower in patients with a pulse pressure of 90 mm Hg or more (63 vs 119). Drug treatment is justified in older ISH patients whose systolic BP is 160 mm Hg or higher. Absolute benefit is larger in men, in older patients and in those with previous cardiovascular complications or wider pulse pressure. Treatment prevented stroke more effectively than coronary events. However, the absence of a relation between coronary events and systolic BP in untreated patients suggests that the coronary protection may have been underestimated. Key Words: Systolic hypertension; treatment

Wednesday, May 17, Broadway Ballroom North, 9:30 AM to 11:30 AM New Aspects of Blood Pressure and Cardiovascular Disease: Is Systolic, Diastolic, or Pulse Pressure the Major Culprit? SYSTOLIC OR DIASTOLIC HYPERTENSION: WHICH IS MORE IMPORTANT AND WHY? Stanley S. Franklin. University of California, Irvine In the NHANES III, a national population data base, there were two distinct hypertensive populations: 1) a smaller

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(26%), younger (⬍age 50), mainly male group with primarily diastolic hypertension; and 2) a much larger (74%), older (ⱖ age 50), mainly female group with primarily systolic hypertension of the isolated systolic hypertension (ISH) variety. The older group represented 67% of all untreated hypertensives and 86% of all hypertension treatment failures. 80% of both untreated hypertensives and treatment failures had ISH and required more than a two-fold greater reduction in SBP to reach the JNC-VI treatment goal of SBP ⬍140 mmHg as compared to their younger counterparts. Better awareness of the prevalence of this high-risk group and more aggressive therapy is necessary to address this treatment gap. The relation of blood pressure to coronary heart disease (CHD) risk as a function of age was examined in the Framingham Heart Study. In the younger age group (⬍ age 50), diastolic blood pressure (DBP), rather than SBP, was the more powerful predictor of CHD risk. With aging, the best predictors of CHD risk shifted from DBP to SBP and eventually to pulse pressure (PP). In young subjects, DBP and SBP (or DBP alone) may predict risk; they are indictors of small vessel resistance. In older subjects, SBP and PP are superior predictors; they are indicators of large vessel stiffness. These findings provide indirect evidence in support of the age-related influence of arterial pulse wave reflection on brachial artery and central aortic blood pressure. Key Words: Systolic blood pressure; diastolic blood pressure; aging; coronary heart disease; epidemiology

Wednesday, May 17, Broadway Ballroom South, 9:30 AM to 11:30 AM Angiotensin II: Antagonism in the Management of Cardiovascular Disease VASCULAR REMODELING ACTION OF ANGIOTENSIN II FROM BENCH TO BEDSIDE Ernesto L. Schiffrin. Clinical Research Institute of Montreal, Canada Angiotensin II (Ang II) exerts its vascular effects on blood pressure through its vasoconstrictor action, through its effects on remodeling of the wall of blood vessels and by contributing to induce endothelial dysfunction. Remodeling of the arterial wall results from effects of Ang II on smooth muscle cell growth and on collagen deposition. AT1 and AT2 receptors mediate the actions of Ang II. AT1 receptors appear to mediate the actions of Ang II in most tissues. AT1 receptors may be blocked by specific antagonists such as losartan, an effective orally active antihypertensive drug. Interruption of the reninangiotensin system with angiotensin converting enzyme inhibitors in humans and in experimental animals corrects vascular structure and endothelial dysfunction, whereas beta blockade does not. We therefore investigated the effects of the AT1 antagonist losartan, in comparison to the ␤-blocker atenolol, on abnormalities of gluteal subcutaneous small arteries, in essential hypertension. Nineteen untreated mild essential hypertensive patients (47 ⫾ 2 years, range 30 – 65; 57% male) were randomly assigned in double-blind fashion to losartan or atenolol treatment for one year. Nine age/sex-matched normotensive subjects were also studied. Both treatments reduced blood

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pressure to a comparable degree. Resistance arteries (luminal diameter, 150 –350 ␮m) dissected from gluteal subcutaneous biopsies were studied on a pressurized myograph. Following one year of treatment, the media width to lumen diameter ratio of arteries from losartan-treated patients was significantly reduced (P ⬍ 0.01). Arteries from atenololtreated patients were unchanged. Endothelium-dependent relaxation was normalized by losartan but not by atenolol. Stress-strain relationships of small arteries were shifted to the right by losartan but unchanged in atenolol-treated patients. Thus, treatment for 1 year with the AT1 angiotensin antagonist losartan corrected resistance artery structure and mechanics, and the endothelial dysfunction in hypertensive patients, whereas atenolol had no effect. This vascular protective effect of losartan could contribute to reduce complications of hypertension, which remains to be demonstrated. Key Words: Small artery remodeling; endothelial dysfunction

Wednesday, May 17, Broadway Ballroom North, 12:30 PM to 2:30 PM Targeting Blood Pressure Goals and End-Organ Protection: Advances in RAS Blockade VASCULAR INJURY, VASCULAR HEALING, HYPERTENSION AND THE RENIN SYSTEM E.L. Schiffrin. Clinical Research Institute of Montreal, Canada Alterations in structure and function of blood vessels that occur in hypertensive patients and in experimental hypertensive models may contribute to blood pressure elevation and to the complications of hypertension. Angiotensin II may influence the vasculature in hypertension through its effects on the atherogenic process and on hypertensive vascular disease per se. The actions of angiotensin II on inflammation, smooth muscle cell growth (hypertrophy or hyperplasia) and collagen deposition in blood vessels participate in mechanisms of atherogenesis and hypertensive vascular damage, and are mediated via AT1 receptors, whereas AT2 receptors appear to inhibit growth and stimulate programmed cell death or apoptosis. There is increasing evidence that angiotensin II plays a pivotal role in remodeling of both large and small arteries in experimental and human hypertension. Interruption of the renin-angiotensin system thus appears an interesting approach for the treatment of hypertension in order to correct vascular abnormalities that may contribute to cardiovascular events in hypertension. Treatment of spontaneously hypertensive rats (SHR) with angiotensin converting enzyme (ACE) inhibitors and AT1 angiotensin receptor antagonists results in regression of the altered structure of blood vessels in different vascular beds. Endothelium-dependent relaxation is also improved. Studies in hypertensive patients have now shown that treatment with some ACE inhibitors and more recently AT1 antagonists may induce similar potentially beneficial effects, particularly at the level of small arteries: both structure and endothelium-dependent relaxation are significantly improved. In contrast, treatment with the beta blocker atenolol does not result in any improvement in vascular structure or endothelial function in hypertensive patients with equally well-controlled blood pressure in different studies. It still

AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2

remains to be determined whether the apparently beneficial vascular effects of blockade of the renin-angiotensin system with ACEI or with AT1 receptor antagonists and their vascular protective properties, beyond blood pressure lowering itself, will result in reduced morbidity and mortality and improved outcomes in hypertensive patients. Key Words: Vascular remodeling; endothelial dysfunction; resistance arteries TARGETING HIGH-RISK HYPERTENSIVE PATIENTS WITH RAS BLOCKADE: APPLICATION OF FINDINGS Matthew R. Weir, M.D. Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD High blood pressure is a common clinical illness whose etiology has not been well described. It contributes substantially to the development of cardiovascular disease. Efforts at controlling blood pressure to levels of less than 140/90 mmHg have been limited to some degree by an inexact understanding of the pathophysiology of the disease process as well as its asymptomatic nature. A larger problem may also exist: the maximum benefit of therapy may not be achieved at the goal levels currently targeted in clinical practice. Epidemiologic evidence supports the need for more intensive control of blood pressure to a systolic less than 130 mmHg in many patients, particularly those with diabetes or target organ damage. Health care providers and patients need to be aware of the overwhelming evidence supporting the need for more intensive blood pressure control and how important this is in reducing cardiovascular morbidity and mortality. Abundant data from the HOT, UKPDS, SHEP, and the Syst-Eur trials demonstrate the need for controlling both systolic, diastolic, and pulse pressure, even in older patients, in order to prevent cardiovascular morbidity and mortality. Lower levels of blood pressure reduce mechanical stretch, strain, and turbulence within the vascular beds and in the target organs. This reduces the impetus for vascular and target organ production of neurohormones like angiotensin II which leads to maladaptive restructuring and remodeling. Controlling blood pressure may be the critical factor in lessening this risk, and breaking the vicious cycle whereby vascular disease begets higher levels of systemic blood pressure, which begets more vascular disease. Although newer classes of medications which specifically target the renin angiotensin system, like ACE inhibitors or angiotensin type 1 receptor blockers as part of their antihypertensive activity do show some advantage in delaying progression of cardiovascular and renal disease, these agents should not be used as a substitute for intensive blood pressure control, but as an aid in achieving this overall goal. Therapeutic strategies which employ well tolerated medications in lower doses may be the critical strategy to improve blood pressure control in asymptomatic patients. Key Words: Systolic; diastolic blood pressure; angiotensin II; cardiovascular outcome

Wednesday, May 17, Broadway Ballroom North, 3:00 PM to 5:00 PM