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OBJECTIVES: To assess the antianginal and antiischemic efficacy, safety, and the potential for tolerance or withdrawal effects of amlodipine. BACKGROUND: The slow onset of action and long half-life of amlodipine may help avoid withdrawal effects such as the exacerbation of angina and precipitation of myocardial seen with beta-blockers. METHODS: After a 2-week single-blind placebo run-in period, 226 patients with stable exertional angina pectoris were given amlodipine (starting at 5 mg day(minus sign1) and titrated to 10 mg day(minus sign1)) in a single-blind fashion for 8 weeks. One hundred seventy-two responders (greater-than-or-equal7% improvement in symptom-limited exercise time) entered a 4-week double-blind withdrawal phase and randomly received continued treatment with amlodipine (n = 91) or placebo (n = 81). RESULTS: Treatment with amlodipine increased the exercise capacity by 14% and improved time to angina onset by 25% and time to 1-mm ST segment deviation by 18%. These variables remained essentially unchanged at the end of the 4-week withdrawal phase for the group continued on amlodipine (+0.8%, +3.2%, and +2.0%, respectively) but decreased for the group on placebo (minus sign5.8%, minus sign9.8%, and minus sign11.0%, respectively) (p < 0.001 between groups, all assessments) to values similar to those obtained during the initial placebo run-in period. Approximately one-third of the patients responded to 5 mg amlodipine during single-blind therapy and according to "usual clinical practice" remained on this dose. The results of randomized withdrawal in the subgroup receiving 5 mg also favored amlodipine over placebo. Side effects were reported by 47% of patients on amlodipine and by 22% of patients receiving placebo. The most frequently reported side effects for

A 63-YEAR-OLD white male was referred for gated radionuclide ventriculography to evaluate left ventricular reserve and possible wall motion abnormalities during exercise. He had a questionable history of a myocardial infarction 4 years before examination. He had no history of hypertension, diabetes, hypercholesterolemia, or smoking. His family history was also unremarkable. His medications included only salicylates. The patient was evaluated by semiupright bicycle ergometry using one lead for R-wave triggering. A 12-1ead electrocardiogram (ECG) was used to evaluate ST segment changes. Two-minute data acquisitions were attempted during progressive 3-minute exercise stages. The patient exercised for 12.7 minutes to a peak double product of 16,524 and stopped secondary to shortness of breath. The peak heart rate was 102 beats/min, and the actual VO2 was 14.8 mL/kg/min, representing 61% and 55% of predicted maximum, respectively. Blood pressure at rest was normal and increased appropriately during exercise. The ECG at rest showed sinus rhythm with a right bundle branch block. Reduced voltage was also seen in the limb leads. No ST segment or T wave changes were noted after hyperventilation. The patient developed 0.5 mm to 0.75 mm upsloping ST depression in the inferior and anterolateral leads. These changes resolved quickly after exercise and were not diagnostic for ischemia. The patient described no anginal symptoms. The patient's resting ejection fraction was 68% and increased to 79% and 78% during the first and second exercise stages (Fig 1). Using a 10% window for the R-R interval, all beats were accepted during rest; 13 of 143 beats were rejected during the first exercise stage; and 19 of 144 beats were rejected during the second exercise stage. Cornplete data acquisition failure was noted during the third exercise stage as significant ECG artifacts developed (Fig 2). During the postexercise period, the left ventricular ejection fraction was 84%, with 8 of 148 beats rejected. No wall motion abnormalities were noted during the study. A large number of conditions are associated with impaired data acquisition during either resting or exercise gated radionuclide ventriculography. These conditions can be divided into two groups: (1) those associated with R-R interval variability and (2) those associated with increased P or T wave amplitude or with reduced R wave amplitude. The approach to data acquisition will differ with each of these conditions. When R-R variability arises, variable windowing or list mode acquisition (when available) may be helpful. When altered P, R, or T wave amplitude is present, lead repositioning (not possible during exercise) or altered R wave trigger thresholds may be helpful.

Regional differences in cholinergic activity in the cardiac conduction system have been difficult to study. We tested the utility of (+)-m-[125I]iodobenzyl)trozamicol(+)-[125I]MIBT), a novel radioligand that binds to the vesamicol receptor located on the synaptic vesicle in presynaptic cholinergic neurons, as a functional marker of cholinergic activity in the conduction system. The (+)-[125I]MIBT was injected intravenously into four rats. Three hours later, the rats were killed and their hearts were frozen. Quantitative autoradiography was performed on 20-micron-thick sections that were subsequently stained for acetylcholinesterase to identify specific conduction-system elements. Marked similarities existed between (+)-[125I]MIBT uptake and acetylcholinesterase-positive regions. Optical densitometric analysis of regional (+)-[125I]MIBT uptake revealed significantly greater (+)-[125I]MIBT binding (nCi/mg) in the atrioventricular node (AVN) and His bundle regions compared with other conduction and contractile elements (AVN: 3.43 +/- 0.37; His bundle: 2.16 +/- 0.30; right bundle branch: 0.95 +/- 0.13; right atrium: 0.68 +/- 0.05; right ventricle: 0.57 +/- 0.03; and left ventricle: 0.57 +/- 0.03; p < 0.05 comparing conduction elements with ventricular muscle). This study demonstrates that (+)-[125I]MIBT binds avidly to cholinergic nerve tissue innervating specific conduction-system elements. Thus, (+)-[125I]MIBT may be a useful functional marker in studies on cholinergic innervation in the cardiac conduction system.

Although previous studies have suggested that aging results in an increase in vascular stiffness, diseases that increase in prevalence with advanced age may have confounded the results of some of this past research. The purpose of this investigation was to determine whether aging per se results in reduced arterial compliance by using animals that are resistant to atherosclerosis and do not develop hypertension or hyperlipidemias with advanced age. We evaluated systemic and regional (femoral) arterial compliance in older (110 ± 8 months old) and in younger (27 ± 2 months old) female beagle dogs by using a computer-based assessment of the diastolic decay of arterial pressure waveforms and a modified Windkessel model of the circulation. Although systemic arterial pressure was very similar in both age groups, cardiac output was 29% lower ( p = 0.03) and systemic vascular resistance was 24% higher ( p = 0.02) in the older dogs. Moreover, there was an age-related reduction in systemic arterial compliance, derived both from the exponential decay in the arterial pulse (C 1 ) ( p = 0.05) and that derived from the oscillatory component of the diastolic pulse wave (C 2 ) ( p = 0.04). By contrast, although femoral vascular resistance was 25% higher in the older dogs ( p = 0.04), regional (femoral) vascular compliance measured after femoral arterial occlusion was also 25% reduced but was not significantly changed with age ( p = 0.14). These results demonstrate that systemic arterial compliance is reduced with age in dogs, extending this finding to animals without age-related diseases that frequently occur in older human beings. Regional compliance, evaluated in the isolated femoral vascular bed, also tends to be reduced with age, but variability in this parameter in dogs reduces the significance of this finding.

Objective: Active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) utilizes a hand-held suction device with a pressure gauge that enables the operator to compress as well as actively decompress the chest. This new CPR method improves hemodynamic and ventilatory parameters when compared with standard CPR. ACD-CPR is easy to perform but may be more labor intensive. The purpose of this study was to quantify and compare the work required to perform ACD and standard CPR. Methods: Cardiopulmonary testing was performed on six basic cardiac life support- and ACD-trained St. Paul, MN fire-fighter personnel during performance of 10 min each of ACD and standard CPR on a mannequin equipped with a compression gauge. The order of CPR techniques was determined randomly with >1 h between each study. Each CPR method was performed at 80 compressions/min (timed with a metronome), to a depth of 1.5–2 inches, and with a 50% duty cycle. Results: Baseline cardiopulmonary measurements were similar at rest prior to performance of both CPR methods. During standard and ACD-CPR, respectively, rate-pressure product was 18.2 ± 3.0 vs. 23.8 ± 1.7 (×1000, P < 0.01); mean oxygen consumption 15.98 ± 2.29 vs. 20.07 ± 2.10 ml/kg/min or 4.6 ± 0.7 vs. 5.7 ± 0.6 METS (P < 0.01); carbon dioxide production 1115.7 ± 110 vs. 1459.1 ± 176 ml/min; respiratory exchange ratio 0.88 ± 0.04 vs. 0.92 ± 0.04 (P = NS); and minute ventilation 35.5 ± 5.1 vs. 45.6 ± 9.2 l/min (P < 0.01). Conclusions: Approximately 25% more work is required to perform ACD-CPR compared with standard CPR. Both methods require subanaerobic energy expenditure and can therefore be sustained for a sufficient length of time by most individuals to optimize resuscitation efforts. Due to the slightly higher work requirement, ACD-CPR may be more difficult to perform compared with standard CPR for long periods of time, particularly by individuals unaccustomed to the workload requirement of CPR, in general.

Aging significantly affects reflex cardiovascular (CV) responses to induced muscular contraction in anesthetized dogs. To further investigate whether age-related changes in beta-adrenergic responsiveness contribute to these previously reported changes in reflex CV responses associated with advanced age, hemodynamic and regional blood flow (BF) responses to static hindlimb contraction (HLC) were evaluated during alpha-chloralose anesthesia before and after beta-adrenergic blockade (AB) in younger (2-3 years) and older (8-14 years) beagles. AB with propranolol resulted in significant (Por = 0.05) reductions in cardiac output, heart rate and mean arterial pressure at baseline, regardless of age. However, baseline stroke volume and systemic vascular resistance were only changed by AB in the older dogs. During HLC, AB had a similar effect (or lack of effect) on each of the five hemodynamic responses evaluated in both age groups. AB did not significantly change baseline BF (microspheres) to any of the individual abdominal organs evaluated in the younger dogs, but resulted in a reduction in baseline BF to five of eight abdominal organs in the older dogs. By contrast, AB resulted in attenuated, rather than accentuated, BF reductions during HLC to six of eight abdominal organs in the younger dogs but in only one of eight abdominal organs in the older dogs. Likewise, the combined BF reduction to all eight abdominal regions during HLC was attenuated only in the younger dogs, probably reflecting age-related changes in reflex sympathetic nerve responses to HLC rather than the effects of age on beta-adrenergic mediated CV responses. Baseline BF was reduced in three of eight muscles after AB only in the older beagles. However, the BF response to three of four contracting muscles was unchanged after AB, regardless of age. These results demonstrate that baseline differences in the level of beta-adrenergic stimulation and/or function in younger and older dogs are generally not associated with age-related differences in CV responses to HLC initiated in contracting muscles and mediated by reflex beta-adrenergic CV stimulation.

In Reply. —We fully agree with the statement by Dr Hirsch and colleagues that exercise performance is not solely dependent on large artery blood flow and that intermittent claudication can be improved without revascularization. Our meta-analysis, along with the additional articles cited by Hirsch and colleagues, supports the notion that exercise rehabilitation is an effective treatment for patients with peripheral arterial occlusive disease and disabling claudication pain. Hirsch and colleagues raise another key point concerning the availability of vascular rehabilitation programs in health care facilities. Patients with intermittent claudication frequently have concomitant atherosclerosis in the coronary and cerebrovascular arteries, as well as a host of other comorbidities. Consequently, the risks associated with exercise in patients with claudication are similar to those of patients with cardiac disease, emphasizing the need for a closely supervised program that can only be accomplished in a health care facility. An additional benefit of a supervised