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We evaluated the acute therapeutic effects of the oral administration of nifedipine (10 mg) and diltiazem (120 mg) alone and in combination in 16 patients with effort angina. The 16 patients (13 men and three women; mean age 59 +/- 7 years) performed a symptom-limited bicycle exercise stress test 3 h after placebo or active substance administration. Maximal work load, exercise duration and time to 1 mm ST segment depression were significantly increased and ST depression at peak exercise was significantly decreased by the combination of drugs. Nifedipine and diltiazem alone similarly improved exercise duration as markedly as their combination. One patient stopped the test after all three treatments for angina associated with ST depression2 mm. The combination of drugs yielded the best symptomatic effect: only four patients complained of angina in comparison to eight and seven patients after diltiazem and nifedipine, respectively. Nifedipine and diltiazem are effective and safe antianginal drugs. Some patients respond better to one drug than to the other. Patients who remain symptomatic in spite of maximal doses of a single drug may derive some benefit from combination therapy.

The response of coronary hemodynamics to the intracoronary (i.c.) bolus administration of gallopamil, 1.5 and 3.0 micrograms/kg, was evaluated in 14 patients with normal coronary arteries. Gallopamil, 3.0 micrograms/kg, induced a small and transient decrease in systolic and mean arterial pressure and a small increase in the preejection period. Coronary sinus blood flow increased significantly at 30 s (p less than 0.01) and returned to baseline 10 min after gallopamil administration. Coronary vascular resistance was still reduced at 10 min and returned to baseline at 15 min. Myocardial O2 consumption and extraction decreased significantly (p less than 0.01) at 30 s. While myocardial O2 consumption returned to baseline 15 min after gallopamil administration, myocardial O2 extraction was still significantly reduced at this time. Milder and more transient changes were observed after i.c. administration of the lower dose (1.5 micrograms/kg), and no significant changes were found after i.c. administration of saline. These data show that i.c. gallopamil, in patients with normal coronary arteries, induces direct, transient, and dose-related peripheral coronary vasodilation. The reduction of myocardial O2 consumption and extraction suggests a direct negative inotropic and metabolic effect of gallopamil.

We studied 40 subjects, 20 under 60 yrs old (10 normotensive and 10 hypertensive) and 20 over 60 yrs old (10 normotensive and 10 hypertensive). Each patient underwent a 24-hour ambulatory blood pressure monitoring (8:00 a.m. to 8:00 a.m.), by a noninvasive method using an ICR 5300 apparatus. Systolic blood pressure was significantly higher on random measurement and during the daytime in the older patients. Although comparison of the other parameters did not reveal significant differences, we noted a tendency to higher systolic values among the older group, and higher diastolic values in the younger one. The variability of the values was slightly higher, although not significantly, among the older patients. In both groups random systolic measurements, and in the younger group diastolic values as well, were significantly higher than mean 24 hour values. The incidence of abnormal systolic BP values ranged from 18.8% to 100% (mean 60.2% +/- 28.9) in younger hypertensives, and from 54% to 100% (mean 76.5% +/- 14.4) in older patients. The incidence of abnormal diastolic BP values ranged from 64.5% to 100% (mean 80.4% +/- 15.6) in younger patients and from 47.2% to 96% (mean 67.8% +/- 15.8) in older patients. The correlation between mean systolic and diastolic values recorded from 8:00 to 10:00 a.m., and mean 24-hour values was significant in young hypertensives, while in the older group there was a significant correlation only for diastolic BP. The lack of significance for systolic values is probably due to a greater variability in systolic pressure in elderly subjects during the morning.

Twenty-four hour ambulatory blood pressure and electrocardiographic monitoring (Oxford method) was carried out in baseline conditions and after 15 days of therapy with a once a day administration of 240 mg verapamil slow-release in 11 elderly hypertensive patients. The 24 hour electrocardiographic monitoring (but not the blood pressure monitoring) was also carried out after 30 days of therapy. High-pressure liquid chromatography plasma concentrations of verapamil and its metabolite norverapamil were compared with the blood pressure and electrocardiographic responses. Systolic and diastolic blood pressure were significantly reduced after 15 days of therapy without circadian rhythm modification; mean heart rate was reduced after 15 and 30 days and the P-Q interval prolonged. Peak verapamil and norverapamil plasma concentrations were observed 8 hours after administration; at the 25th hour, the concentrations were respectively 60.9% and 68.3% of peak value (139.5 +/- 95.4 ng/ml and 126.4 +/- 60.9 ng/ml). Plasma levels of verapamil and norverapamil significantly correlated with heart-rate decrease. No correlation was observed between drug concentrations and systolic and diastolic blood pressure. A first-degree atrioventricular block was observed in 3 patients during therapy. Supraventricular premature contractions showed a decrease after 15 and 30 days of therapy. Thus, once a day administration of verapamil slow release is an effective anti-hypertensive medication in elderly hypertensive patients. Caution should be exercised in patients with P-Q interval prolongation and sinus bradycardia.

In order to evaluate whether the changes in the electrical systole/electromechanical systole ratio (QT/QS2) may reflect the effects of beta-adrenergic stimulation on the heart, we studied the variations of this ratio induced by active standing. We studied 45 healthy volunteers aged 15 to 82 years, subdivided into three groups; Group 1 (mean age 22 +/- 4 years), Group 2 (mean age 44 +/- 6 years), and Group 3 (mean age 74 +/- 6 years). Fifteen subjects repeated the test after propranolol administration (0.1 mg/kg iv). Resting QT/QS2 ratio increased slightly, but not significantly, with age. Upright position significantly increased QT/QS2 ratio in all groups. Changes in heart rate (r = -.43), electromechanical systole (r = .55) and QT/QS2 were significantly correlated with age. Propranolol prevented the increase in QT/QS2 ratio induced by active standing. Therefore, QT/QS2 changes induced by standing are correlated with age and are inhibited or reduced by beta-blockade. QT/QS2 changes can be used to monitor adrenergic activity, even if their value is limited by the overlapping responses of the individual cases.

One-hundred and seven exercise stress tests and coronary angiograms were reviewed retrospectively, in order to evaluate the usefulness of R wave amplitude changes (ΔR) during exercise compared with ST segment depression in the screening of patients with coronary artery disease (CAD). We also attempted to correlate ΔR with the severity of CAD as expressed by coronary arteriography and left ventriculography. Thirty-six patients showed no coronary artery narrowing (0-V); the remaining 71 patients with stenosis of 70% of at least one of the major coronary arteries were divided into three groups. Sixteen patients had single vessel disease (1-V); five (31%) in this group showed abnormal left ventricular wall motion. Thirty-one patients had two-vessel disease (2-V); 22 (71%) of the 31 demonstrated abnormal left ventricular wall motion. Twenty-four patients had three-vessel disease (3-V); 20 (83%) of the 24 showed abnormal left ventricular wall motion. We considered ΔR values ≥ 0 and ST segment depression ≥ 1 mm. significant for diagnosis of CAD. The sensitivity of the ΔR method in predicting CAD was superior to the method based upon ST segment depression; however, the latter was significantly (P We found ΔR values ≥ 0 more frequently in the 2-V and 3-V groups as compared with the 1-V group. Patients of the 2-V and 3-V groups had a significantly higher incidence of abnormal left ventricular wall motion (P Even though the accuracy of the ΔR method was greater in more severe CAD, it seems to be offset by a concomitant decrease in specificity.

This study was performed to determine if QT prolongation before and during early exercise is related to the occurrence of exercise-induced ventricular arrhythmias (EIVA). EIVA occurred in 47 of 142 patients with angiographic evidence of coronary artery disease (CAD); no EIVA occurred among the 22 patients without CAD (OV). Resting QTc and QT intervals during early exercise were similar in patients without EIVA, irrespective of the presence or absence of CAD; however resting QTc was significantly longer in CAD patients who showed EIVA (443 +/- 40 ms; P less than 0.01) than in CAD patients without EIVA (424 +/- 37 ms) and in OV patients (421 +/- 32 ms). During early exercise, the QT interval remained significantly longer in patients with than in those without EIVA. There was a trend toward increasing resting QTc in patients who exhibited EIVA more severe than grade 3. When resting QTc was longer than 440 ms, subsequent EIVA were correctly predicted in CAD patients with a sensitivity of 43%, a specificity of 72% and a predictive accuracy of 63%. Thus, a trend toward longer resting QTc values exists in CAD patients who develop EIVA; however, a long resting QTc (greater than 440 ms) appears to be only a weak predictor of subsequent EIVA.

We evaluated the changes in regional coronary hemodynamics induced by diltiazem, 0.25 mg/kg intravenously, in nine patients with 75% to 90% diameter stenosis of the left anterior descending coronary artery (LAD) (group 1) and in 10 patients with 100% occlusion of the LAD and collaterals to the distal LAD (group 2). Although diltiazem induced similar changes in systemic hemodynamics in the two groups, a decrease in anterior coronary vascular resistance (ACVR) and an increase in great cardiac vein flow (GCVF) were observed after administration of diltiazem in all patients in group 1 but in only 6 of 10 patients in group 2 (subgroup 2B). ACVR increased and GCVF decreased after administration of diltiazem in 4 of 10 patients in group 2 (subgroup 2A). Clinico-angiographic characteristics, origin of collaterals, and diltiazem-induced changes in systemic hemodynamics were similar in subgroups 2A and 2B. Thus diltiazem increases coronary flow distal to a stenotic coronary artery but can decrease regional coronary flow and increase regional coronary resistance in a minority of patients with an occluded coronary artery supplied by collaterals, probably through a steal mechanism.

We correlated the incidence and degree of exercise induced ventricular arrhythmias (EIVA) with the angiographic severity of coronary artery disease (CAD) in 162 patients with a history of stable effort angina, all showing a positive exercise stress test for myocardial ischemia and a greater than or equal to 70% stenosis of a major coronary artery. Patients were grouped according to the following criteria: presence of electrocardiographic evidence of old transmural myocardial infarction (MI), number of significant coronary stenoses and number of left ventricular (LV) areas showing abnormal segmental wall motion (ASWM). The incidence of EIVA in patients with multivessel CAD was higher than in patients with single vessel CAD, but this difference was not statistically significant. The number of LV areas with ASWM was better correlated with the frequency of EIVA, which was 20.0% in patients with normal LV wall motion, 31.2% in patients with 1 area of ASWM, 54.0% in patients with 2 areas of ASWM (p less than 0.005 vs normal LV wall motion), 74.1% in patients with 3 or more areas of ASWM (p less than 0.001 vs normal LV wall motion and 1 area of ASWM), and 81.8% in patients with LV aneurysm (p less than 0.001 vs normal LV wall motion and 1 area of ASWM, p less than 0.005 vs 2 areas of ASWM). Patients with old MI showed a significantly higher incidence of EIVA than those without MI (p less than 0.001), but this difference was due to the more severe LV asynergy in the MI group. In conclusion, our results show that, in a selected population of patients with CAD, the incidence of EIVA correlates better with the extent of LV segmental wall motion abnormalities than with the number of diseased coronary arteries or the presence of an old transmural MI.

We reviewed the clinical, hemodynamic and angiographic data of 105 patients with right coronary artery occlusion and 82 patients with left anterior descending coronary artery occlusion, subdivided into 3 groups by the presence and quality of collaterals to the occluded coronary (absent, poor or good collaterals). We found that patients with right coronary artery occlusion and good collaterals had a lower frequency of diaphragmatic myocardial infarction (60%) than patients with absent collaterals (100%) (P less than 0.01). In addition, in patients with old diaphragmatic myocardial infarction, both poor and good collaterals were associated with a lower frequency of severe asynergy of the diaphragmatic left ventricular segments at left ventriculography (54% and 14%, respectively), compared to patients with no collaterals to the right coronary artery (92%, P less than 0.02 vs. poor collaterals, P less than 0.001 vs. good collaterals). In contrast, in patients with left anterior descending coronary artery occlusion, the presence of either poor or good collaterals to the left anterior descending coronary artery was not associated with a lower frequency of old anterior myocardial infarction, or, in patients with old anterior myocardial infarction, with a less severe asynergy of the anterior left ventricular segments. Our results suggest that collaterals are effective in protecting the diaphragmatic left ventricular wall in patients with right coronary artery occlusion, but not the anterior left ventricular wall in patients with left anterior descending coronary artery occlusion.

In order to evaluate the clinical implications of QT/QS2 ratio during manoeuvres of sympathetic stimulation we studied the effects of handgrip (75% of maximal voluntary contraction) in 18 middle-aged normal subjects and in 16 patients with previous myocardial infarction. We also evaluated the effects of propranolol (0.1 mg/kg i.v.) in all normal subjects and in 10 of the 16 patients with coronary artery disease. At rest the two groups had similar heart rate, blood pressure, QT, QS2 and QT/QS2 ratio values. A significant increase in heart rate and systolic blood pressure was recorded during handgrip both in normal subjects and in patients with coronary artery disease; QT/QS2 significantly increased in normal subjects but did not show significant variations in patients with coronary artery disease, with significant differences between the two groups at peak exercise. Handgrip-induced QT/QS2 changes showed a marked variability both in normal and diseased subjects. After propranolol, QT/QS2 showed no significant difference at peak exercise in the two groups. The variability of ratio changes was nullified by the administration of the drug. These findings suggest that handgrip-induced QT/QS2 changes might be an expression of beta-adrenergic discharge. The clinical value of handgrip-induced QT/QS2 changes in detecting patients with coronary artery disease is limited by the variability of the response of the ratio observed in the two groups.

The antianginal effects of 360 mg/day of diltiazem were evaluated, using intrapatient comparisons, in a double/blind, randomized, placebo/controlled trial in 24 young patients (50 +/- 7 years) and in 16 elderly patients (67 +/- 3 years) with stable effort angina. All patients had angiographic documentation of significant coronary artery disease. An open-labelled, randomized, crossover design was employed. For 1 week prior to beginning the study, the patient was on no medication except sublingual nitrates. The study consisted of an initial 2-week single-blind placebo run-in period followed by a 4-week randomized double-blind crossover between diltiazem, 120 mg t.i.d., and placebo. A diary of chest pain and nitroglycerin usage was kept during this period and run-in. Exercise tests were carried out during the run-in period (2 tests) and at the end of the 4-week treatment. After diltiazem 12 of the 24 young patients stopped the exercise test because of angina. A similar number (9/16) of elderly patients stopped the exercise test because of angina. During diltiazem treatment, weekly angina frequency was significantly reduced in the young patients (1.25 +/- 0.67 vs 3.87 +/- 1.19-run-in, 4.08 +/- 1.24-placebo; p less than 0.01) and in the elderly patients (0.87 +/- 0.71 vs 4.06 +/- 1.48-run-in, 4.12 +/- 1.5-placebo; p less than 0.01). Weekly TNT consumption significantly decreased in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of coronary artery bypass (CAB) by comparison with medical treatment were evaluated on exercise tolerance in 68 patients with stable angina on effort, who underwent coronary and left ventricular cineangiography. Stress tests were performed by bicycle ergometer before medical and surgical treatment, and 6 and 12 months thereafter. Thirty-five patients (31 males and 4 females; 7 with one 70% stenosed vessel, 12 with two, 16 with three) underwent CAB; 33 (30 males and 3 females; 9 with one 70% stenosed vessel, 11 with two, 13 with three), having refused CAB, only underwent medical treatment. Both groups were given long-acting oral nitrates, none received digitalis and/or propranolol; antiarrhythmic drugs were only administered in 5% of medical and 4% of surgical patients. Both groups at 6 and 12 months follow-up showed a significant improvement in exercise tolerance. Surgical patients showed a significant increase in exercise tolerance with lower angina incidence (from the preoperative 100% to 26% and 22%, respectively), higher work load (P.001), and a significant reduction of S-T segment depression (P.001). Medical treatment induced an increase of exercise tolerance; angina on effort decreased (from 100% to 74% and 72%, respectively) with higher work load, and a significant reduction of S T depression (in both cases P.001). Comparing the data of the two groups, we observed that surgical patients showed higher exercise tolerance (P.01), lower S-T depression (P.001) and angina incidence. Our results suggest that surgical treatment is able to improve exercise tolerance more remarkably than medical treatment.

In order to study whether different heart rates achieved at peak exercise by normal subjects and patients with coronary artery disease (CAD) affect the results of analysis of R-wave amplitude changes (delta R), we evaluated delta R at progressively increasing heart rate (HR) steps in 60 normal subjects with negative exercise tests (ET), in 130 patients with CAD, in 88 patients with true positive and 42 with false negative ET, and in 43 patients with no CAD and false positive ET. We found that the sensitivity and specificity of delta R were HR dependent, the former decreasing and the latter increasing with progressively increasing HR steps. Mean values of delta R did not discriminate among the four groups for HRs up to 150 bpm; significant differences were found between normal subjects and CAD patients, both with true positive and false negative stress tests, at HR greater than 150 bpm. False positive patients had mean delta R similar to those found in normal subjects. We hypothesize that quantitative delta R analysis could be useful in ECG diagnosis of false negative and false positive patients at HR greater than 150 bpm

We evaluated the protective effect of Diltiazem from pacing-induced myocardial ischemia in 9 patients (pts) with coronary heart disease (CAD) and stable effort angina by studying the changes in systemic and coronary hemodynamics during pacing. Hemodynamic parameters were evaluated at baseline and at peak pacing before and after Diltiazem, 25 mg i.v. Diltiazem prevented angina in 6 of 7 pts who presented angina in the control pacing. This beneficial effect was accompanied at peak pacing rate by a significant fall in ST depression, arterial pressure, rate-pressure product and left ventricular (LV) end-diastolic pressure, while no significant changes were observed in LV dp/dt max, coronary blood flow and coronary vascular resistance. Therefore, Diltiazem exerts a protective effect from pacing-induced myocardial ischemia in pts with CAD and stable effort angina, without impairing LV function. This beneficial effect is due to a reduction in myocardial metabolic requirements, rather than to an improvement of blood supply to the ischemic myocardium.

The autonomic tone has been shown to influence the duration of the QT interval, however the independent contribution of sympathetic and parasympathetic tone is not fully elucidated. The influence of autonomic tone on QT duration was studied in 10 young healthy volunteers by evaluating the changes in QT and RR duration induced by i.v. isoproterenol infusion and by standing before and after i.v. administration of propranolol or atropine. Furthermore, the relationship between RR interval and QT duration was evaluated during nocturnal sinus arrhythmia and submaximal exercise test. Low doses of isoproterenol reduced RR (p0.01) but not QT interval duration, while higher doses influenced both RR (p0.0001) and QT (p0.001) duration. Propranolol did not influence standing-induced shortening of RR and QT intervals; on the contrary, atropine administration abolished standing-induced QT interval shortening, without influencing RR changes. QT duration resulted significantly related to preceding RR interval at peak exercise (r = 0.87, p0.001) and during nocturnal sinus arrhythmia (r = 0.73, p0.0005), however, the regression lines showing the correlation between QT and preceding RR interval were different. Both sympathetic and parasympathetic tone appear to contribute to heart rate-independent changes in QT duration. In the basal state parasympathetic more than sympathetic tone influences the relation QT-heart rate. Major increases of sympathetic nervous system activity may change the relation QT-heart rate. Thus, in case of abrupt autonomic changes, any proposed formula for heart rate correction of QT may result inappropriate, also in the normal range of heart rate.

Nifedipine, diltiazem and verapamil are three effective calcium-antagonists in the treatment of angina pectoris. We compared their effects on effort angina to evaluate whether one of them is more efficacious. The data were collected from 42 patients (37 males, 5 females; mean age 51 +/- 4) entering one of 3 different trials; the beginning of all trials comprised a two-week, single blind, placebo run-in phase. An exercise stress test was performed at the end of this period and it was considered as basal test for the statistical analysis. Then the 42 patients were divided in 3 groups of 14 and entered a double-blind, randomized phase of drug treatment. The 3 groups started 3 parallel trials: 1) placebo/nifedipine 60 mg/day; 2) placebo/verapamil 360 mg/day; 3) placebo/diltiazem 240 mg/day. The duration of each trial was of 6 weeks (3 weeks of treatment with placebo and 3 weeks with active substance). Exercise stress tests were performed at the end of each phase of the trials, and the resulting data were compared with the data of the test performed at the end of run-in period. Parameters evaluated were: heart rate, blood pressure and rate pressure product at basal conditions, at submaximal and peak exercise; moreover we considered workload, maximal ST segment depression, total exercise duration and frequency of exercise-induced angina. Verapamil reduced rate pressure product at basal condition; all three drugs reduced rate pressure product at submaximal exercise, but a significant statistical difference was found only for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was undertaken to evaluate the efficacy of coronary artery by-pass grafting (CABG) in elderly patients with coronary artery disease. A consecutive series of 79 patients, 65 years of age and older, who underwent CABG from 1975 to 1981 was analysed and their follow up status ascertained. This group was compared with a consecutive series of 397 patients under the age of 65 who underwent CABG during the same period. The patients aged 65 years or greater had a higher incidence of unstable angina pectoris (p less than 0.05). Coronary angiographic and left ventriculographic features were comparable in both age groups; also comparable were the number of saphenous veins graft utilized and the number of left ventricular aneurysmectomies and mitral valve replacements performed. The hospital mortality rate for patients aged 65 years and older was 12.6%, for those aged less than 65, it was 8.3%; if the other cardiac procedures are excluded mortality rates become 12.5% and 6.0% respectively (n.s.). Survival at 6 years was 92% for patients in both age groups. However, the symptomatic status was less favourable in older patients, compared with that obtained in younger patients (p less than 0.05).

We studied the short-term effects of oral administration of nisoldipine (10 mg) and propranolol (80 mg) alone and in combination in 14 patients with chronic exertional angina pectoris in a double-blind, randomized, cross-over study. The 14 patients (13 men and 1 woman, mean age 56 +/- 7 years) performed symptoms-limited bicycle exercise stress test 3 h after placebo or active substance administration. Maximal work load, exercise duration, and time to 1-mm ST segment depression were significantly increased and ST depression at peak exercise was significantly decreased by drugs alone and in combination. Propranolol and nisoldipine alone improved exercise duration similarly and as well as the combination; however, a different response to the three pharmacologic interventions was found in patients treated with single drugs. The improvement in exercise tolerance was associated with rate-pressure product values at peak exercise, unchanged after nisoldipine and significantly reduced after both propranolol alone and in combination. After placebo, all patients had exercise-induced angina, in 9, 8, and 4 patients after nisoldipine, propranolol, and the combination of the two drugs, respectively. Nisoldipine is effective in the treatment of effort angina and its combination with propranolol may be useful and superior in patients who show poor response to monotherapy.

The effects of oral administration of guaiacolic ester of acetyl salicilic acid in 24 patients with chronic obstructive lung disease have been evaluated. 1.5 g of this drug were given daily into 3 administrations improving both objective and subjective symptomatology in 19 of the 24 patients after 1 or 3 weeks of treatment. Moreover, a statistically significant improvement of FEV 1" (p less than 0.001), Raw (p less than 0.005) and FEV 1"/VC (p less than 0.01) was observed. The remaining 5 patients discontinued the treatment failing the improvement of the subjective symptomatology.

1 The effects of the stimulation of the cephalic endings of the depressor nerve on the resistance in the perfused hindlimb were studied in the rabbit. 2 The vasodilatation thus elicited in the perfused hindlimb was reduced either by administration of guanethidine or by sympathectomy and abolished by subsequent treatment with atropine. 3 These data confirm the existence of two components in the genesis of the reflex vasodilatation: a passive component, due to the inhibition of sympathetic discharge, and an active component which in the rabbit is cholinergic in nature.