Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke.

Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.

Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program.

Pulse pressure has been related to higher risk of cardiovascular events in older persons. Isolated systolic hypertension is common among the elderly and is accompanied by elevated pulse pressure. Treatment of isolated systolic hypertension may further increase pulse pressure if diastolic pressure is lowered to a greater extent than systolic pressure. Little is known regarding pulse pressure as a predictor of cardiovascular outcomes in elderly persons with isolated systolic hypertension, and the influence of treatment on the pulse pressure effect. We assessed the relation between pulse pressure, measured throughout the follow-up period, and the incidence of coronary heart disease (CHD), heart failure (HF), and stroke in 4,632 participants in the Systolic Hypertension in the Elderly Program, a 5-year randomized, placebo-controlled clinical trial of treatment of isolated systolic hypertension in older adults. In the treatment group, a 10-mm Hg increase in pulse pressure was associated with a statistically significant 32% increase in risk of HF and a 24% increase in risk of stroke after controlling for systolic blood pressure and other known risk factors, as well as with a 23% increase in risk of HF and a 19% increase in risk of stroke after controlling for diastolic blood pressure and other risk factors. Pulse pressure was not significantly associated with HF or stroke in the placebo group, nor with incidence of CHD in either the placebo or treatment group. These results suggest that pulse pressure is a useful marker of risk for HF and stroke among older adults being treated for isolated systolic hypertension.

Serum complement activation in congestive heart failure.

BACKGROUND: Although activation of the complement system in myocardial infarction and cardiopulmonary bypass has been shown to contribute to myocardial injury, its role in congestive heart failure (CHF) is unknown. The purpose of this study was to determine the presence of terminal complement activation and its relation to clinical outcomes in patients with CHF. METHODS: We measured serum levels of the terminal complement complex C5b-9 in 36 patients with symptomatic heart failure and left ventricular ejection fraction <40%. We compared the serum C5b-9 levels of these patients with CHF with a group of 12 age-matched control patients. Combined clinical outcomes (death, urgent heart transplantation, or hospitalization with worsening heart failure) at 6 months were determined. RESULTS: The serum C5b-9 [median (25th to 75th percentiles)] levels in 36 patients with CHF [101.5 ng/mL (40 to 164)] were significantly (P =.003) higher than in the 12 control patients [36.5 ng/mL (22 to 50)]. Significantly more of the patients with CHF with the highest levels of C5b-9 (highest 50th percentile) had New York Heart Association class IV symptoms (67% vs 33%; P =.04) and adverse clinical outcomes by 6 months (56% vs 17%; P =.02) compared with the patients with CHF with lower levels (lowest 50th percentile). CONCLUSIONS: We have described a significant elevation in circulating C5b-9, the terminal complement complex, in patients with symptomatic heart failure and have observed an association between high levels of C5b-9 and near-term adverse events.

Cocaine, HIV, and their cardiovascular effects: is there a role for ACE-inhibitor therapy?

Cocaine abuse and HIV disease each have potentially adverse effects upon the heart and cardiovascular system which may be exacerbated when these risk factors are combined. The development of a safe and effective agent to treat both cocaine addiction and its cardiovascular sequelae, that is well-tolerated by HIV patients, would thus be of considerable clinical utility. In this article we discuss the rationale for the investigation of angiotensin converting enzyme (ACE) inhibitors, commonly used to treat hypertension, for treatment in cocaine-abusing populations, based on their potential to reduce cocaine use by modulating levels of dopamine and corticotropin releasing factor in the brain, and on their ability to reverse cardiovascular and platelet abnormalities. We present preliminary findings from echocardiographic and platelet activation studies in 16 HIV-positive, cocaine abusing patients, as well as tolerability and efficacy studies of the ACE-inhibitor, fosinopril, for the treatment of cocaine abuse in both HIV-positive (n=6) and HIV-negative (n=5) methadone-maintained cocaine abusers. Findings suggest that HIV-positive cocaine-abusing patients possess abnormalities of diastolic heart function and platelet activation that are potentially reversible with ACE-inhibitor therapy. Findings also suggest that fosinopril is well-tolerated regardless of HIV serostatus, does not appear to cause hypotension, and may possess effectiveness for reducing cocaine use. We conclude that ACE-inhibitor therapy may offer a new pharmacologic approach to the treatment of cocaine abuse and its complications, and that controlled research of this class of agents may be promising.

Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease.

OBJECTIVES: The present study examined the association of estrogen (E2) and the inflammatory response of endothelium in coronary artery disease (CAD) by measuring circulating cellular adhesion molecules (cCAMs) in subjects with atherosclerosis. BACKGROUND: Atherosclerotic plaque demonstrates features similar to inflammation. Endothelial cell activation by inflammatory cytokines induces expression of cellular adhesion molecules (CAMs), thereby perhaps augmenting leukocyte adhesion and recruitment and subsequent development of atherosclerosis. The incidence of CAD is lower in women; this may be due to the cardioprotective effects of E2. METHODS: Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied. The groups evaluated were men, postmenopausal women receiving E2 replacement therapy (ERT), postmenopausal women not receiving ERT and premenopausal women. Control groups included men and women without CAD. Preprocedural blood samples were drawn from all groups. Measurements of cCAMs, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were performed by enzyme-linked immunoabsorbant assay. E2 levels were assessed by radioimmunoassay. RESULTS: We observed a statistically significant increase in all cCAMs in men with CAD and postmenopausal women with CAD not receiving ERT compared with postmenopausal women with CAD receiving ERT. Premenopausal women with CAD and postmenopausal women with CAD receiving ERT had a significant increase in VCAM-1 alone compared with the female control group. CONCLUSIONS: A possible mechanism by which E2 exerts one of its cardioprotective effects is by limiting the inflammatory response to injury by modulating the expression of CAMs from the endothelium.

Quantitative analysis of the technetium-99m-DTPA captopril renogram: contribution of washout parameters to the diagnosis of renal artery stenosis.

Retrospective analysis of precaptopril and postcaptopril DTPA renograms from 88 hypertensive patients was performed to refine the quantitative criteria used to diagnose renal artery stenosis (RAS). Of the 88 patients, 45 had RAS and 43 had normal renal arteries at angiography. Using time-activity curves from the essential hypertensive group, diagnostic washout criteria for a positive DTPA renogram were developed. These were based on the 20 and 30 min/peak activity ratios in each kidney. When the washout criteria were retrospectively applied to patient data as a whole, sensitivity and specificity for RAS were 67% and 79%, respectively. When previously described uptake criteria, based on the time to peak activity in each kidney and the GFR ratio between the kidneys, were applied to the same data, sensitivity and specificity for RAS were 89% and 84%, respectively. Quantitative analysis of the DTPA renogram using the time to peak and GFR ratio was both sensitive and specific for RAS. Measurement of 20 and 30 min/peak renal activity ratios did not improve the accuracy of the test.

Captopril renal scintigraphy: a new standard for predicting outcome after renal revascularization.

PURPOSE: Captopril renal scintigraphy (CRS) is a nuclear medicine technique for evaluating each kidney independently for changes in glomerular filtration rate and perfusion induced by captopril-associated alterations in vascular tone. This study was undertaken to determine the role of CRS in predicting the response to renal revascularization. METHODS: The study group consisted of all patients who underwent preintervention CRS and arteriography, followed by renal revascularization performed between December 1987 and February 1992. After cessation of administration of angiotensin-converting enzyme inhibitors for 48 hours, a standard renogram was obtained, a 50 mg dose of captopril was given, and a second renogram was obtained. A captopril-induced change in the renogram was present when a normal pre-captopril renogram became abnormal after captopril administration. An abnormal baseline scan by definition cannot have a captopril-induced change. Blood pressure before revascularization was compared with blood pressure at 3 to 6 months after the procedure according to American Heart Association criteria for hypertension response. RESULTS: Fifty patients received renal revascularization by operation (28 patients) or balloon angioplasty (22 patients). Preoperative captopril-induced changes were present in 29 of the 50 patients. Among the 29 patients with captopril-induced changes, hypertension was cured or improved in 26. When captopril-induced changes were not present, only one of 21 patients improved (p < 0.00001). CONCLUSION: On the basis of these data, CRS appears to reliably predict hypertension response to revascularization in patients with renovascular disease.

Long-term outcome in patients with congestive heart failure and intact systolic left ventricular performance.

Congestive heart failure (CHF) is typically associated with impaired left ventricular (LV) systolic performance. Few reports exist describing the long-term outcome in patients with CHF and normal LV systolic function. Fifty-two patients initially hospitalized with CHF and intact LV function (ejection fraction greater than or equal to 45%) were followed for 7 years. Mean age when initially identified was 71 +/- 11 years (range 36 to 96), and average LV ejection fraction was 61 +/- 11%. CHF was graded by a clinicoradiographic index, with a mean of 7.0 +/- 2.3 (range 3 to 12, 13 indicates worst CHF). A third heart sound was present in 19 patients (37%), and 17 (33%) had presented with acute pulmonary edema. Principal cardiovascular diagnoses were coronary artery disease in 27 (52%), hypertensive heart disease in 16 (31%) and restrictive cardiomyopathy in 7 (13%). At 7 years, cardiovascular mortality was 46% (24 of 52), and noncardiovascular mortality was 10% (5 of 52). Survival was not correlated with age, principal diagnosis, third heart sound, pulmonary edema at presentation, LV ejection fraction, or presence or degree of LV diastolic dysfunction. Cardiovascular morbidity, consisting of nonfatal recurrent CHF, myocardial infarction, unstable angina or other cardiovascular events occurred in 29% (15 of 52). Combined cardiovascular mortality and morbidity was 75% (39 of 52). In patients with CHF, intact LV systolic function does not confer the same favorable prognosis it defines in other clinical situations. For such patients, the risk of future cardiovascular events is high, a finding that should be considered when designing therapeutic strategies in this group.

The right ventricle in disorders causing pulmonary venous hypertension.

The right ventricle is frequently affected by pulmonary arterial hypertension of postcapillary obstructive origin. The disorders that cause states of pulmonary venous hypertension arise in the left ventricle, left atrium, or pulmonary veins. Biochemical factors, the pericardium, interventricular septum, and pulmonary arterial system combine to communicate the effects of these disorders to the right ventricle. Although not ideally suited to pressure loading, the right ventricle undergoes a series of structural and hemodynamic adaptations that allow for chronic compensation until failure supervenes, with characteristic clinical findings. Exercise may serve to magnify the abnormalities of right ventricular function. Correction of left-sided heart lesions with improvement in pulmonary venous hypertension is associated with favorable effects on the right ventricle. In states of left-sided heart failure, the level of right ventricular function may provide important prognostic information.

Right ventricular infarction.

Right ventricular myocardial infarction, long unrecognized because of a lack of diagnostic methods and unsupported beliefs regarding the dispensability of the right ventricle, may now be diagnosed using well-accepted criteria. Right ventricular infarction is clearly associated with anterior left ventricular infarction as well as inferior infarction. It may occur in 30% to 40% of patients with inferior infarction, although a much smaller percentage experience hemodynamic instability on the basis of right ventricular infarction. Pathophysiologically, right ventricular systolic and diastolic dysfunction are exacerbated by pericardial restraint and concomitant left ventricular dysfunction, accounting for the characteristic findings of cardiogenic shock and marked preload dependence in many patients. Right ventricular infarction may be suspected on the grounds of clinical presentation, physical examination, and enzymatic findings, and is confirmed using well-defined electrocardiographic, radionuclide, echocardiographic, and hemodynamic criteria. Once diagnosed, right ventricular infarction requires specific hemodynamic and pharmacologic management, including the judicious use of volume expansion and inotropic support. Several forms of mechanical and surgical intervention are of therapeutic value in treating hemodynamic disturbances and recognized complications. With appropriate management, the prognosis for patients with right ventricular infarction is generally favorable.

Report of the Working Party Group for Patient Selection and Preparation.

Captopril renography is a valuable test in the diagnosis of patients with renal artery stenosis. We examined the criteria for selecting patients for this procedure and the best methods for preparing the patient for renography.

Captopril renography in the diagnosis of renal artery stenosis and the prediction of improvement with revascularization. The Yale Vascular Center experience.

To enhance diagnosis and predict improvement in blood pressure control following surgery or renal angioplasty in patients with hypertension and renal artery stenosis (RAS), we employed captopril renography in 113 clinically selected patients, all of whom had renal angiography to verify the diagnosis. Criteria for normal captopril renograms were established from an initial cohort of 23 hypertensive patients with normal angiograms who had been judged to be at high risk for RAS using the same clinical criteria. Renal revascularization or nephrectomy was performed in 45 patients and the success of the procedure was determined in the 40 patients for whom 3-month follow-up was available. In these 113 patients, 58 (51%) had RAS. Captopril renography was 91% sensitive and 87% specific in identifying or excluding RAS. Diagnostic utility was preserved in those patients with renal insufficiency (serum creatinine equal to or greater than 1.5 mg/dL) (n = 46). Scintigraphic abnormalities induced by captopril were strongly associated with cure or improvement in blood pressure control following revascularization or nephrectomy (16 of 19), while the lack of captopril-induced change was associated with failure of such intervention (17 of 21) (P = .0001). We conclude that captopril renography is sensitive and specific for the diagnosis of RAS in a clinically selected high-risk group of hypertensives, and that the test accurately predicts the success or failure of therapeutic intervention.

Antihypertensive drug therapy and regression of left ventricular hypertrophy: a review with a focus on diuretics.

Regression of LVH is a reasonable adjunctive goal of blood pressure treatment, given the well described risks of hypertrophy and the possible benefits inherent in its reversal. Data suggest that any of the presently recommended agents for initial monotherapy, i.e. diuretics, beta adrenergic inhibitors, ACE inhibitors, or calcium blockers, are effective in achieving regression of hypertrophy if blood pressure lowering is achieved. While there may be other factors that play a role in the genesis and maintenance of cardiac hypertrophy in the hypertensive subject, it would appear that blood pressure elevation is probably the most important one. If reduction of blood pressure to normotensive levels can be achieved and maintained by the use of any of the antihypertensive agents (including the vasodilators, if used in combination with adrenergic inhibitors and/or diuretics), there is a reasonable chance that cardiac hypertrophy can be prevented or reversed and prognosis improved.

Simplified captopril renography in diagnosis and treatment of renal artery stenosis.

To improve the diagnosis and forecast the response to surgery or renal angioplasty in patients with hypertension and renal artery stenosis, we employed a simplified captopril renography protocol in conjunction with renal arteriography in 94 clinically selected patients. Fifty hypertensive patients (group 1) with a high clinical likelihood of renovascular hypertension were evaluated using a simplified captopril renography protocol and renal angiography on the arterial side. Criteria for normal captopril renal scintigrams were established based on this original cohort and validated in an additional 44 clinically comparable patients (group 2). Renal revascularization or nephrectomy was performed in 39 patients, and success of the procedure was determined in the 34 patients for whom 3-month follow-up was available. In the 94 patients, 44 (47%) had renal artery stenosis. Simplified captopril renography was 91% sensitive and 94% specific in identifying or excluding renal artery stenosis in the combined group, with no difference in the diagnostic utility between groups 1 and 2, or in those with renal insufficiency (n = 38) or those with bilateral disease (n = 17). Scintigraphic abnormalities induced by captopril were strongly associated with cure or improvement in blood pressure control following revascularization or nephrectomy (15 of 18), while the lack of captopril-induced changes was associated with failure of such intervention (13 of 16) (p = 0.0004). We conclude that simplified captopril renography is highly sensitive and specific in the diagnosis of renal artery stenosis in a clinically selected high-risk population and that the test accurately predicts the success or failure of therapeutic intervention.

Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance.

Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.

Patients at high risk for renal artery stenosis: a simple method of renal scintigraphic analysis with Tc-99m DTPA and captopril.

Fifty patients with suspected renal artery stenosis (RAS) were studied with renal scintigraphy before and after administration of captopril. Twenty-three patients had RAS (greater than or equal to 75% RAS or greater than or equal to 50% RAS with poststenotic dilatation) and 27 had normal renal arteries at angiography. Angiotensin-converting enzyme inhibitors were discontinued 24 hours prior to renal scintigraphy; all other medications were continued. Each patient was evaluated with a simplified captopril renal scintigraphic protocol: renal imaging after administration of 12 mCi (444 MBq) of technetium-99m diethylenetriaminepentaacetic acid (DTPA), a 3-hour wait, oral administration of 50 mg of captopril, a 1-hour wait, and another scintigram obtained after administration of 12 mCi (444 MBq) of Tc-99m DTPA. Times of peak renal activity (Tmax) were determined from renal time-activity curves, and glomerular filtration rates (GFRs) were calculated with the Gates technique. A Tmax greater than or equal to 11 minutes after injection or a GFR ratio (larger GFR/smaller GFR) greater than 1.5 enabled detection of RAS with 91% sensitivity, 93% specificity, and 92% accuracy. Renal scintigraphy without captopril had only 43%-68% sensitivity in detecting RAS, depending on the criteria used.

Severe Takayasu's arteritis in pregnancy: the role of central hemodynamic monitoring.

Maternal cardiovascular complications have been attributed to the dramatic hemodynamic changes associated with labor and delivery in patients with Takayasu's arteritis. The role of central hemodynamic monitoring in the management of a pregnant patient with severe Takayasu's arteritis is discussed.