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Aim of this study is to carry out a genetic analysis of polymorphisms of the renin-angiotensin system in a genetically homogeneous population, in patients with and without myocardial infarction (AMI) expansion and to evaluate the influence of non genetic, mechanical factors. The study was conducted on 299 patients with first AMI. Ecocardiography studies were performed on all patients on day 1 and 3 from the onset of AMI and before discharge. Eighty-four patients were excluded because of inadequate quality of echocardiograms and 215 (163 males, 52 females) were admitted. Of these, 157 had no evidence of AMI expansion (EXP-) while 58 had expansion (EXP+). DNA was extracted by standard methods from blood samples. Age and gender had no influence on AMI expansion. Anterior infarction (p < 0.000001) and Q-wave infarction (p < 0.00002) were found more frequently in EXP+. Peak of creatine phosphokinase was higher in EXP+ than in EXP- (p < 0.00001). The percent of patients treated with thrombolysis or with hypertension and/or left ventricular hypertrophy was not significantly different in the two groups. AGT MT235 polymorphism of angiotensinogen gene, I/D polymorphism of ACE gene and AT1 A1166C of AT1 receptor of angiotensin II were not significantly different in two groups. Stratified analysis showed that in patients with anterior AMI (n = 87), with a higher risk of AMI expansion, there is a significant difference (p < 0.02) in ACE genotype between EXP- and EXP+. Odds ratio assuming the dominant effect of I allele (II+ ID < DD) was 3.35 (confidence interval 1.41-7.56) with increased risk of expansion. More extension studies are need to verify if these results can contribute to early identification of patients at higher risk and to optimize therapeutic approach.

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We describe the occurrence of an intraparenchymal (thalamic) haemorrhage during a stress test in a hypertensive 52-year-old man who had suffered from myocardial infarction 3 months earlier. Common causes of spontaneous haemorrhage, such as arteriovenous malformation, aneurysms, neoplasm, bleeding disorders or vasculitis were excluded. This single neurological complication was observed from among 8000 exercise tests performed in our Institute from 1987 to 1993.

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To assess whether antihypertensive therapy by nifedipine can reverse left ventricular (LV) hypertrophy, 15 hypertensive patients, mean age 47 years, were serially studied during 12 months of treatment with nifedipine in slow release (40-60 mg/day), by recordings of blood pressure (BP), ECG and echocardiogram. Blood pressure decreased from 161 +/- 6/104 +/- 3 mmHg to 131 +/- 3/89 +/- 1 mmHg, p < 0.001, and this fall first became statistically significant at 1 month. From the hemodynamic view point, BP decreased for a reduction in total peripheral resistance. The Sokolow-Lyon voltage decreased significantly after 6 months (from 33.5 +/- 2.7 to 28.1 +/- 2.1 mm, p < 0.01) without further changes in the subsequent months. Left ventricular mass, by echocardiography, decreased after 6 months (from 189 +/- 15 to 176 +/- 13 g/m2, p < 0.05) and further after 12 months (169 +/- 13 g/m2, p < 0.001). The reduction in LV mass was secondary to the decrease in wall thickness, particularly in posterior wall thickness. No significant changes were observed in LV fractional shortening throughout the study. Thus, nifedipine was an effective antihypertensive agent and reverted LV hypertrophy secondary to arterial hypertension without impairment of LV systolic function.

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The aim of this research was to assess whether the antihypertensive therapy with nifedipine, a dihydropyridine calcium-antagonist, is able to control hypertension not only at rest but also during exercise. So, 20 male hypertensive patients, mean age 48 years, were evaluated by symptom limited bicycle exercise (10 W/min) before and after 6 and 12 months of therapy with nifedipine in a slow releasing form (40-60 mg/day). Exercise tolerance significantly increased after 12 months of antihypertensive therapy with nifedipine (from 146 +/- 5 to 153 +/- 4 W, p < 0.05). Systolic and diastolic blood pressure decreased after 6 and 12 months both at rest (from 160 +/- 6/109 +/- 9 mmHg to 132 +/- 3/91 +/- 3 and 135 +/- 4/93 +/- 1 mmHg, respectively, both p < 0.001) and during exercise (at end exercise: from 238 +/- 7/121 +/- 5 mmHg to 216 +/- 6/106 +/- 3 and 213 +/- 6/107 +/- 3 mmHg, respectively, both p < 0.001). No significant changes in heart rate were observed during antihypertensive therapy both at rest and during exercise test. In conclusion, long-term antihypertensive therapy with nifedipine was effective in the control of hypertension both at rest and during physical stress. Moreover, an improvement in effort tolerance was observed in hypertensive patients.

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The aim of this study was to investigate the anti-ischemic and antianginal activity and the duration of the new dihydropyridine calcium blocker nisoldipine (NIS) in patients with stable angina pectoris. The research was carried out on 16 patients, all male, 41-68 (mean of 58) years of age, with stable angina pectoris and fixed ischemic threshold (variations < 15%). After a 10-day washout period, patients were randomized to treatment with either 10 mg of nisoldipine or placebo (PL), twice daily for 21 days, according to a double-blind, crossover design. Patients underwent maximal symptom-limited exercise testing at 10 W/min on a bicycle ergometer, twice during the washout period, and once at the end of each treatment period, 3 and 12 h after oral administration of the drugs. In comparison with placebo, nisoldipine increased the ischemic threshold (N, 704 +/- 45 s; PL, 548 +/- 35 s; p < 0.01) and anginal threshold (N, 766 +/- 44 s; PL, 699 +/- 42 s; p < 0.01) for at least 12 h, and the ST-segment depression significantly decreased at maximal work (PL, 2.4 +/- 0.1 mm; N, 1.8 +/- 0.2 mm; p < 0.01) and at maximal common work (PL, 2.4 +/- 0.1 mm; N, 1.15 +/- 0.2 mm; p < 0.01). Similar to placebo the rate-pressure product was not significantly changed at higher submaximal effort after N, but it was significantly increased at the level of ischemic threshold, suggesting an increase in coronary blood flow to ischemic zones. Nisoldipine possesses anti-ischemic and antianginal activity lasting at least 12 h. This activity seems to be due to an increase in coronary blood flow to ischemic zones.

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Gallopamil (GSR) is a new calcium-channel blocker. The anti-ischemic activity of GSR was investigated in 12 patients with stable angina of effort, with fixed ischemic threshold (variations < 15%). After a 7-day washout period, patients were randomized to receive treatment with either GSR 100 mg or placebo twice daily for 7 days. Patients underwent maximal symptom-limited exercise test, 10 W/min on a bicycle, during washout (twice) and after the end of each treatment period. Patients were studied by electrocardiogram and the cuff method for determining systolic blood pressure. After treatment with GSR, ischemic and anginal thresholds were increased for at least 12 h in comparison with placebo (ischemic threshold: GSR 663 +/- 37, placebo 571 +/- 36, p < 0.01; anginal threshold: GSR 708 +/- 32, placebo 646 +/- 38, p < 0.05). Rate-pressure product was not changed at the same levels of exercise, but it was significantly increased during exercise at ischemic threshold. In conclusion, GSR possesses an anti-ischemic and antianginal activity lasting at least 12 h. This activity seems due to an increase of coronary blood flow to ischemic areas.

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The aim of this study was to evaluate the anti-ischemic efficacy of 2 different doses of benazepril (B), a new ACE-inhibitor, 10 and 20 mg, given per os. Fifteen male patients gave informed, written consent; they were aged 40-67 years, with stable effort angina pectoris and were randomly given, in double-blind condition, a tablet containing B 10 mg, B 20 mg or placebo (PL), once a day, according to a 3 x 3 latin square design. Bicycle exercise tests were performed on the same day, 2 and 10 hours after the last drug intake. B 10 mg and B 20 mg, in patients with stable effort angina, compared to placebo, increased ischemic threshold and decreased ischemic ST depression at maximal work, after 2 hours but not after 10 hours. In conclusion B 10 mg and B 20 mg showed anti-ischemic activity 2 hours after drug intake.

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The aim of this study was to investigate antianginal and antiischemic activity and tolerance of a new nitrate derivative, nicorandil (N). This research has been carried out in 18 patients, aged 47-70 years, suffering from stable effort angina with fixed ischemic threshold. The study started with 10 days of washout, during which the patients exercised twice on bicycle to verify the reproducibility of the test. Then, they took N or isosorbide-5-mononitrate (ISM) for 14 days according to a double blinded cross-over balanced study. Between the 2 periods patients took placebo (PL) for 14 days. In the first day and in the last day of each period, 2 hours after the last drug intake, patients performed a stress test on bicycle. Like ISM, N significantly increased, versus PL, 1 mm of ST depression time (ischemic threshold) in the first and in the last day, without differences between the 2 drugs and between the days. Moreover, ST depression was significantly lower at maximal common work (MCW) versus PL. The rate-pressure product was not different from PL after N and ISM at maximal common work, but is was increased at the ischemic threshold. In conclusion, like ISM, N has shown antiischemic activity in patients suffering from stable angina pectoris on effort with fixed ischemic threshold. After 14 days of treatment there was no evidence of tolerance. The activity of N seems essentially due to an increase of coronary blood flow to ischemic zones.

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Aim of this study was to evaluate the efficacy of 2 different schedules of nitroglycerin (N), given by means of transdermal therapeutic system (TTS): continuous (20 mg patch at 8.00 am and at 8.00 pm NTTS/c) and high/low doses therapy (20 mg patch at 8.00 am and 10 mg at 8.00 pm NTTS/a), respectively. Eighteen volunteers, gave informed, written consent; male patients, aged 57 +/- 2 years, with stable effort angina pectoris, were randomly given, in double-blind condition, NTTS/c, NTTS/a or placebo (PL), each for 1 week period, according to a 3 x 3 latin square design. Bicycle exercise tests were performed on the first and on the last day of each period of the study, 12 hours after the last patch. NTTS/c and NTTS/a increased ischemic threshold and decreased the ischemic depression ST at maximal common work, compared to placebo, without differences between tests performed at 1 and 7 day. In conclusion, NTTS/a showed antiischemic activity after 7 days, so no tolerance was observed in those patients.

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To assess the efficacy of 2 doses of a transdermal system for nitroglycerin, 10 and 20 mg (NTTS 10 and NTTS 20) and isosorbide dinitrate 40 mg (ISD 40) on exercise tolerance test, a double-blind within patients placebo (PL) controlled study was performed: 12 male patients, aged 47-71 years, with stable effort angina, with fixed ischemic threshold, received, according to a 4 x 4 latin square design, NTTS 10, NTTS 20, ISD 40 and PL, at 7.00 am on 4 consecutive days. Bicycle exercise tests were performed 4 and 12 hours post-dosing, after which the systems were removed. NTTS 10 and 20 and ISD 40 increased significantly ischemic threshold, anginal threshold and decreased maximal ST depression at the fourth hour. Only NTTS 10 and NTTS 20 showed antiischemic activity after 12 hours. During exercise, at the fourth and twelfth hour, there was no significant difference in rate-pressure product between placebo and NTTS 10 and 20 and ISD 40. Therefore the antiischemic activity of these drugs was not related to a decrease of myocardial oxygen consumption. In conclusion, in comparison with PL, NTTS 10, 20 and ISD 40 had antiischemic and antianginal activity at the fourth hour, while at the twelfth hour this activity was observed only after NTTS 10 and 20, without differences between the 2 doses.

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This study evaluated the effect of long-term antihypertensive therapy with indenolol, a beta blocking agent with beta 2 stimulating activity, its antihypertensive hemodynamic mechanism and its effect on hypertensive left ventricular (LV) hypertrophy. Fourteen hypertensive patients, mean age of 48 years, were serially studied during 12- month therapy with indenolol (60-120 mg daily), by recording blood pressure, electrocardiogram and echocardiogram. Blood pressure, heart rate and cardiac output significantly decreased after 1 months of therapy, LV posterior wall thickness decreased after 6 months, interventricular septum thickness and LV mass decreased after 12 months. LV fractional shortening did not change throughout the study. Blood pressure normalized (less than or equal to 140/90 mmHg) in 50% of the patients; LV mass normalized in 40% of the patients. In conclusion, indenolol was an effective antihypertensive agent, also in the long-term treatment. Its antihypertensive hemodynamic effect seems to be due mainly to a reduction in cardiac output. Indenolol caused a regression of LV hypertensive hypertrophy without impairment of LV systolic function.

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The aim of this study was to investigate the anti-ischemic activity of propionyl carnitine (PC) in 18 informed, volunteer male patients, aged 37-70, suffering from a typical stable effort angina. The study design was randomized, balanced, crossover, and double blinded. The study lasted 75 days. In the first 15 days of washout the patients performed two maximal symptom-limited bicycle tests to verify the repeatability of the parameters examined. Then one group received PC for 30 days 500 mg three times a day, and the other group received placebo (PL) three times a day. At the end of 30 days the groups exchanged treatments. At the end of each period, 2 hours after the last oral administration, the patients performed a maximal symptom-limited bicycle exercise test with increased loads of 10 watts/min. No significant differences were observed between the two tests performed during the wash-out period, for a 1 mm ST-segment depression time, for the time to the end of exercise, and for the rate x pressure product at the same experimental time. The oral administration of PC in coronary patients increased both the 1 mm ST-segment depression time and the time to the end of exercise. Furthermore, the drug reduced the ischemic depression of ST at maximal common work and at maximal work. After PC, the rate x pressure product was not significantly different in relation to placebo at submaximal and maximal exercise. Thus PC seems to have an antiischemiclike effect, probably related to its metabolic activity.

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To assess the anti-anginal and anti-ischaemic efficacy of the ACE-inhibitor enalapril in normotensive coronary patients, a double-blind, cross-over, placebo-controlled study was performed. Eight male patients, aged 45-68 years, with stable effort angina were given enalapril (10 mg) once a day or placebo for 7 days. Maximal exercise stress tests 10w/min in the upright position were performed at the end of each period. In comparison to placebo, enalapril increased significantly 1 mm of ST depression time and decreased significantly ST depression at maximal common work. Moreover, enalapril increased significantly the angina threshold and exercise duration. Three of the eight patients ended the exercise without pain. The rate-pressure product was not significantly modified at any time. Thus, the anti-ischaemic and anti-anginal activity may be due to an increase of coronary blood flow, rather than a reduction of MVO2 consumption.

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An echocardiographic study was performed in 21 young patients with thalassemia major (TM, age 16-22 years), with no cardiac symptoms, and in 24 age-matched normals (N) at rest and during sitting bicycle exercise (EX). All TM were receiving blood transfusions regularly to maintain hemoglobin level above 11 g/dl and subcutaneous infusion of desferrioxamine (40 mg/Kg/day) to reduce hemosiderosis. At rest, in comparison to N, TM showed a significant increase in LV end-diastolic dimension (EDD), septal, posterior wall thickness and mass, whereas wall thickness to EDD ratio and LV fractional shortening (FS) were not different. Stress echocardiography was recorded with success in 90% of TM and 83% of N. During EX, FS increased progressively with increase of heart rate in both groups, though the increase of FS was lower in TM. Thus, asymptomatic young patients with thalassemia major, under well transfusion-chelation therapy, showed cardiac changes from volume overload. LV systolic function, normal at rest, was moderately impaired during exercise test.

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To assess the anti-anginal and anti-ischaemic activity of the beta-blocker atenolol (ATN) and the calcium antagonist nifedipine (NIFE) and their combination in coronary patients, a double-blind, cross-over, placebo-controlled study was performed. Ten male patients (mean age: 58 +/- 2.9 years) suffering from a stable effort angina were studied. The study lasted 14 weeks: after 2 weeks of wash-out, patients were randomly assigned to ATN (100 mg/day) and placebo-NIFE, or placebo-ATN and NIFE (10 mg three times/day), or ATN (100 mg) plus NIFE (10 mg three times/day) for 4 weeks. Maximal symptom-limited stress tests on a bicycle (10 watt/min) during the wash-out period (on days 10 and 14) and at the end of each treatment period were performed. All treatments significantly increased the work load at 1 mm ST depression, the angina threshold and the total work, and reduced ST depression at the maximal common work and at the maximal work. Also the atenolol-nifedipine combination significantly reduced ST depression at maximal common work and maximal work as compared to ATN and NIFE alone. In conclusion, this study confirms the anti-ischaemic and anti-anginal activity of both atenolol and nifedipine in stable effort angina and shows that their combination is able to increase anti-ischaemic activity.

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