William H. Frishman

Risk Factors for Stroke and Type of Stroke in Persons With Isolated Systolic Hypertension

Background and Purpose—We sought to determine risk factors for stroke and stroke type in persons with isolated systolic hypertension (ISH). Methods—We performed proportional hazards analyses of data from the Systolic Hypertension in the Elderly Program, a double-blind, randomized, placebo-controlled trial of 4736 persons aged ≥60 years with ISH (systolic blood pressure, 160 to 219 mm Hg; diastolic blood pressure, <90 mm Hg). One treatment group received chlorthalidone (12.5 to 25 mg/d) with step-up to atenolol (25.0 to 50.0 mg/d) or reserpine (0.05 to 0.10 mg/d), if needed. The other treatment group received matching placebo. The main outcome measures were stroke, stroke or transient ischemic attack [TIA], and stroke types: ischemic (including lacunar, atherosclerotic, and embolic) and hemorrhagic. Results—During an average follow-up of 4.5 years, 384 strokes or TIAs and 262 strokes (including 217 ischemic, 66 lacunar, 26 atherosclerotic, and 25 embolic strokes) were documented. In multivariate analyses, ...

Regional and systemic metabolic effects of angiotensin-converting enzyme inhibition during exercise in patients with severe heart failure.

The acute hemodynamic and metabolic effects of captopril therapy were studied in 12 patients with severe heart failure during maximal exercise performed on an upright bicycle ergometer. During the control period, exhaustion occurred after 4.2 ± 2.7 minutes of exercise. Cardiac index increased from 1.54 ± 0.36 I/min/m2 at rest to 3.39 ± 1.54 I/min/m2 (p < 0.001) at exhaustion; systemic arteriovenous oxygen difference increased from 8.8 ± 2.1 to 12.8 ± 2.4 ml/100 ml (p < 0.001) and oxygen uptake from 3.4 ± 0.5 to 10.8 ± 3.0 ml/kg/min (p < 0.001). Pulmonary arterial oxygen content decreased from 7.3 ± 1.3 to 3.7 ± 1.5 ml/100 ml (p < 0.001) and femoral vein oxygen content from 5.0 ± 1.7 to 2.5 ± 1.2 ml/ 100 ml (p < 0.001). During captopril therapy, cardiac index significantly increased both at rest (1.83 ± 0.54 vs 1.54 ± 0.36 I/min/m2, p < 0.01) and during maximal exercise (3.67 ± 1.51 vs 3.39 ± 1.54 I/min/m2, p < 0.01). Systemic arteriovenous oxygen difference decreased significantly at rest, from 8.8 ± 2.1 to 7.7 ± 2.1 ml/100 ml (p < 0.01) and during maximal exercise from 12.8 ± 2.4 to 12.3 ± 2.2 ml/100 ml (p < 0.01). Pulmonary arterial oxygen content at exhaustion was significantly higher during captopril therapy than during the control period (4.1 ± 1.1 vs 3.7 ± 1.5 ml/100 ml, p < 0.05), while femoral venous blood content was unchanged. Captopril therapy did not significantly increase maximal oxygen uptake or exercise duration. Thus, the acute administration of captopril to patients with severe heart failure does not increase exercise capacity despite improved cardiac performance. Moreover, captopril therapy does not acutely result in metabolic benefits to the skeletal muscles during exercise.

Prognostic Significance of Myocardial Ischemia Detected by Ambulatory Electrocardiography, Exercise Treadmill Testing, and Electrocardiogram at Rest to Predict Cardiac Events by One Year (The Asymptomatic Cardiac Ischemia Pilot (ACIP) Study)

Myocardial ischemia identified by ambulatory electrocardiography (AECG), exercising treadmill testing, (ETT), or 12-lead electrocardiogram at rest is associated with an adverse prognosis, but the effect of improving these ischemic manifestations by treatment on outcome is unknown. The Asymptomatic Cardiac Ischemia Pilot (ACIP) study was a National Heart, Lung, and Blood Institute funded study to determine the feasibility of conducting a large-scale prognosis study and to assess the effect of 3 treatment strategies (angina-guided strategy, AECG ischemia-guided strategy, and revascularization strategy) in reducing the manifestations of ischemia as indicated by AECG and ETT. The study cohort for this database study consisted of 496 randomized patients who performed the AECG, ETT, and 12-lead electrocardiogram at rest at both the qualifying and week 12 visits. The effect of modifying ischemia by treatment on the incidence of cardiac events (death, myocardial infarction, coronary revascularization procedure, or hospitalization for an ischemic event) at 1 year was examined. In the 2 medical treatment groups (n = 328) there was an association between the number of ambulatory electrocardiographic ischemic episodes at the qualifying visit and combined cardiac events at 1 year (p = 0.003). In the AECG ischemia-guided patients there was a trend associating greater reduction in the number of ambulatory electrocardiographic ischemia episodes with a reduced incidence of combined cardiac events (r = -0.15, p = 0.06). In the revascularization strategy patients this association was absent. In the medical treatment patients the exercise duration on the baseline ETT was inversely associated with an adverse prognosis (p = 0.02). The medical treatment strategies only slightly improved the exercise time and the exercise duration remained of prognostic significance. In the revascularization group strategy patients this association was absent. Thus, myocardial ischemia detected by AECG and an abnormal ETT are each independently associated with an adverse cardiac outcome in patients subsequently treated medically.

Systemic inflammation as a cardiovascular disease risk factor and as a potential target for drug therapy

Inflammation-related processes play a key role the current etiologic model of atherosclerosis and its acute complications. Recent evidence suggests that blood-based biomarkers that reflect systemic inflammation may contribute to our ability to predict future risk of cardiovascular disease. Global markers of inflammation, such as C-reactive protein and fibrinogen, have been well studied as potential cardiovascular risk factors. A variety of additional markers that reflect various elements of the complex systems governing inflammation, including proinflammatory and antiinflammatory cytokines, mediators of cellular adhesion, and matrix degradation enzymes, are also worthy of study. Although many previous studies have examined the relation of inflammation to myocardial infarction, emerging evidence suggests that other cardiovascular phenotypes such as ischemic stroke and early-stage atherosclerosis may also be related to inflammation. Further elucidating the role of inflammation in cardiovascular disease may lead to the identification of new targets for preventive or therapeutic interventions. In addition, markers of inflammation may be useful as a means to predict or monitor an individuals response to currently available cardiovascular therapies, such as aspirin or HMG coenzyme A reductase inhibitors, that may act via antiinflammatory mechanisms.

Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study).

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001).

Comparative effects of abrupt withdrawal of propranolol and verapamil in angina pectoris

The potential hazards of abrupt withdrawal of propranolol have been described in patients with angina pectoris; however, the effects of abrupt withdrawal from long-term therapy with verapamil have not previously been investigated. The comparative effects of withdrawal from long-term treatment with propranolol and verapamil were assessed in a placebo-controlled double-blind randomized crossover study of 20 patients received placebo for 2 weeks, then increasing doses of propranolol (60 to 320 mg/day) or verapamil (240 to 480 mg/day) for 3 weeks. Patients were then abruptly withdrawn from drug onto placebo for 1 week, followed by crossover to the other drug treatment and a second withdrawal period. All 20 patients were withdrawn from verapamil without evidence of a rebound increase in frequency of anginal attacks, blood pressure, heart rate, or rate-pressure product and without a rebound deterioration in exercise tolerance. In contrast, with propranolol withdrawal, 2 patients (with the highest baseline angina attack rate) had a severe exacerbation of their anginal syndrome and could not undergo formal exercise testing; the other 18 patients were withdrawn from propranolol without incident. Plasma catecholamines were increased during exercise compared with rest during all treatments; however, the levels of catecholamines during exercise were significantly higher with propranolol than with verapamil and placebo (p less than 0.05). Levels of exercise catecholamines returned to placebo baseline values after withdrawal of propranolol.

Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: Relationship Between Exercise-Induced and Ambulatory Ischemia in Patients With Stable Coronary Disease

BACKGROUNDnWe investigated whether the presence and frequency of asymptomatic ischemic episodes recorded during ambulatory ECG (AECG) monitoring could be predicted on the basis of clinical characteristics or exercise treadmill test (ETT) performance in patients with stable coronary disease and whether the estimate of ischemia severity was similar between the AECG and ETT.nnnMETHODS AND RESULTSnPatients screened for the Asymptomatic Cardiac Ischemia Pilot (ACIP) study were selected for the current analysis if data were available from 48-hour AECG monitoring as well as from an ETT during which the patient developed > or = 1-mm ST-segment depression. Exercise ECG data were available for 143 of the 910 patients without ischemic episodes and for 659 of the 910 patients with ischemic episodes during AECG monitoring. Angina was more frequent among patients with ambulatory ischemic episodes than among patients without such ischemia (P < .001). Patients with AECG ischemia had a consistently more marked ischemic response on the ETT than patients without AECG ischemia; patients likely to have AECG ischemia could be predicted on the basis of ETT performance characteristics. However, the correlation coefficients between the severity of ischemia estimated by ETT and by AECG were small.nnnCONCLUSIONSnThere are significant relations between ischemia detected by AECG monitoring and by ETT, but the relations are limited, indicating that the two tests are not redundant to characterize coronary patients. A larger study investigating the prognostic significance of the ischemia identified by each modality, with follow-up for clinical events, will be necessary to determine the most appropriate methods to evaluate patients with stable coronary disease.

Controlled Beta-Receptor Blockade with Esmolol and Flestolol

Beta‐receptor‐blocking agents are commonly used in the management of various cardiovascular diseases. Recently, esmolol, a pharmacokinetically novel cardioselective beta‐receptor‐blocking agent, has been introduced for use in the treatment of critically ill patients. It is devoid of intrinsic sympathomimetic activity and in doses used clinically, it has no direct depressant effect on the heart. Esmolol is an ester and is metabolized by choline‐esterase to ASL 8123, an inactive molecule. Esmolol has an elimination half‐life of nine minutes which accounts for its ultra‐short duration of action. This unique pharmacokinetic property provides two advantages over other longer‐acting beta‐receptor‐blocking agents. First, the magnitude of beta‐receptor blockade can be titrated to a desired level. Second, if adverse effects are experienced, reducing the dosage or terminating the infusion results in rapid reversal of its pharmacological effects. Another ultra‐short‐acting, non‐cardioselective beta‐receptor blocking agent, flestolol is undergoing clinical evaluation. Esmolol has been approved for the management of supraventricular tachycardia. The clinical safety of these novel drugs will expand the use of beta‐receptor‐blocking agents in the management of cardiovascular diseases in critically ill patients.

Sirolimus-eluting coronary stents: novel devices for the management of coronary artery disease.

Despite major technological advances in the practice of percutaneous coronary intervention, restenosis of the treated arteries remains a challenge for many interventional cardiologists. Sirolimus is a macrolide antibiotic with potent antifungal, immunosuppressive, and antimitotic activities. Sirolimus inhibits instent restenosis via 2 major mechanisms of action: by blocking the process of neointimal hyperplasia by inhibiting smooth muscle cell proliferation and by inhibiting inflammatory cell activity. In pivotal clinical trials, the sirolimus-eluting stent has demonstrated significant improvements in angiographic and clinical outcomes compared with bare metal stents in patients with de novo lesions in native coronary arteries. Since the systemic exposure of sirolimus in patients who received the drug-eluting stent is minimal, adverse effects resulting from systemic exposure of sirolimus are unlikely to occur. Further studies are needed to determine the safety and effectiveness of sirolimus-eluting stents in patients with more complex coronary artery lesions. In addition, the long-term safety, efficacy, and cost-effectiveness of this novel drug-eluting device will need to be established in ongoing clinical trials. This review article focuses on the pharmacology as well as clinical studies of the sirolimus-eluting stent.

Risk Factors for Atherosclerosis in the Elderly

Coronary artery disease (CAD), peripheral arterial disease (PAD), atherothrombotic brain infarction (ABI), and extracranial carotid arterial disease (ECAD) are more common in old individuals than in middle-aged ones. CAD is the leading cause of death in old persons, especially those with PAD, ABI, or ECAD. This chapter discusses risk factors for CAD, PAD, ABI, and ECAD in old persons.