Metalloproteinases 2 and 9 are increased in plasma of patients with heart failure.

BACKGROUND: Progression of heart failure is associated with interstitial changes in the heart and in areas distant from the heart. Enhanced expression of metalloproteinases 2 and 9 and of metalloproteinases tissue inhibitors 1 and 2 have been found in ventricular tissue of patients with heart failure. Our aim was to determine whether increased activity of metalloproteinase-2, metalloproteinase-9 and of metalloproteinases tissue inhibitor-1 and metalloproteinases tissue inhibitor-2 were also present in plasma of patients with heart failure. DESIGN: Levels of metalloproteinase-2, metalloproteinase-9 and of metalloproteinase tissue inhibitor-1 and metalloproteinases tissue inhibitor-2 were measured in venous blood of 51 patients with heart failure, and were compared with levels of 52 control subjects. Samples collected from patients and control subjects were assayed for gelatinolytic activity (zymography) and for protein levels. RESULTS: Compared with the control subjects, the patients with heart failure had a significant increase in activity levels (mean +/- SE, ng mL(-1)) of prometalloproteinase-9 (95.1+/-11.2 and 38.9+/-4.5*), activ. metalloproteinase-9 (18.4+/-2.5 and 10.9+/-1.3*), and of prometalloproteinase-2 (571.4+/-26.1 and 456.8+/-21.1*) (respectively: patients and control subjects; *P<0.05). Metalloproteinases tissue inhibitor-1, but not metalloproteinases tissue inhibitor-2 protein values were higher in the patients. Among the patients, clinical status and New York Heart Association (NYHA) class did not correlate with the metalloproteinase concentrations. Positive correlations with left ventricular volumes, and negative correlations with lipid values were obtained for prometalloproteinase-2; positive correlations with total number of white cells and neutrophils were obtained for prometalloproteinase-9; and positive correlations with lactate dehydrogenase, serum fibrinogen, aspartate transaminases were found for activ. metalloproteinase-9. CONCLUSIONS: Regardless of the clinical phase of heart failure, elevated levels of activity and of circulating metalloproteinase protein levels suggest the presence of persistent extracellular remodeling in patients with heart failure.

Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity.

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.

Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients.

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/- 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.

Efficacy and pharmacokinetics of gallopamil in patients with coronary artery disease.

We prospectively studied 10 patients with stable exertional ischaemia, selected from a larger group of patients referred for suspected coronary artery disease or to detect residual ischaemia after myocardial infarction, to evaluate pharmacokinetic changes during chronic treatment with gallopamil and its correlation with clinical efficacy in patients with coronary artery disease. Our study consisted of a 1-week run-in single-blind placebo treatment and a 4-week single-blind gallopamil treatment. At the end of the run-in period patients underwent two different exercise tests, the first 2 hours and the second 7 hours after placebo administration. During active treatment all patients underwent two different exercise tests, the first 2 hours and the second 7 hours after gallopamil (50 mg) administration on the 1st and 28th days of gallopamil therapy. On the same days in eight of the patients we evaluated gallopamil pharmacokinetic changes. Our data revealed a rapid increase of unchanged gallopamil and its metabolite (norgallopamil) in the plasma, and a peak concentration of these substances about 2 hour after oral administration on both the 1st and 28th day of observation. Moreover, our results demonstrated an increase between the first and 28th day of treatment in peak concentration of unchanged gallopamil in the plasma, and of AUC 0-infinity and AUC o-c values during chronic treatment with gallopamil. Our clinical data showed an improvement in exercise results during gallopamil therapy related to increased concentration of the drug.

Failure of protective effect of captopril and enalapril on exercise and dipyridamole-induced myocardial ischemia.

Fifteen patients with angiographic evidence of significant coronary artery disease, exertional myocardial ischemia, and positive dipyridamole echocardiographic test results at basal conditions and after 7 days of placebo treatment were prospectively studied to see whether captopril (containing sulfhydryl) and enalapril (nonsulfhydryl) modify myocardial ischemia induced by exercise testing and the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to captopril (150 mg/day in 3 separate doses) or enalapril (20 mg/day) for 1 week. At the end of this period each patient crossed over to the alternate regimen after a washout period of 7 days. Exercise stress testing and dipyridamole echocardiographic testing were repeated at the end of each treatment period. Neither captopril nor enalapril had a significantly greater anti-ischemic effect than placebo in any patient. Exercise duration, time to onset of ST-segment depression, maximal workload, degree of ST-segment depression, and rate-pressure product were not affected by either drug. Neither captopril nor enalapril improved dipyridamole-induced mechanical dysfunction or ST-segment depression.

Relation between age, left ventricular mass and ventricular arrhythmias in patients with hypertension.

To evaluate the effect of age on left ventricular hypertrophy-related arrhythmias in patients with essential arterial hypertension, 68 hypertensives (47 men and 21 women, mean age 59.4 +/- 9.5 years) without other cardiovascular disorders were studied. All patients underwent M-mode and two-dimensional echocardiogram and 24 h ambulatory electrocardiographic monitoring to measure left ventricular internal dimension, septum and posterior wall thickness, left ventricular mass index, premature ventricular beats and modified Lown grade. Premature ventricular beats (PVB) and modified Lown grade were significantly related to left ventricular mass index, but not to left ventricular internal dimension, fractional shortening, systolic and diastolic blood pressure. There was no relation between age and number of PVB, or severity of arrhythmias. In conclusion, in hypertensive patients only left ventricular hypertrophy, and not age, plays a significant role in the pathophysiology of the increased incidence of ventricular arrhythmias by a different mechanism than age-related increased ventricular arrhythmias.

Comparison of the safety and efficacy of delapril with enalapril in patients with congestive heart failure.

To evaluate the safety and efficacy of delapril versus enalapril in patients with congestive heart failure (CHF), New York Heart Association (NYHA) class II and III, 198 patients were enrolled in a study in 13 centers involving a double-blind parallel group design. After completing a 2-week run-in period on placebo, patients were randomized to receive delapril 7.5 mg twice daily or enalapril 2.5 mg twice daily for 2 weeks. The dose was then doubled for the remaining 6 weeks. In this phase, 1 patient in each group experienced orthostatic hypotension; the dose was then reduced to the initial dose for study completion. A total of 195 patients received active treatment (96 delapril, 99 enalapril). After 8 weeks' treatment, bicycle ergometry demonstrated a significant increase in exercise duration (p < 0.01) and workload (p < 0.01). Echo Doppler investigations showed a significant reduction (p < 0.01) in left ventricular end-systolic volume associated with a significant increase (p < 0.01) in ejection fraction and cardiac output. No clinically significant changes in blood pressure, heart rate, electrocardiogram, or biochemical and hematologic tests were found. There were no significant differences between treatment groups. Three patients in each group experienced adverse reactions requiring withdrawal of 1 patient in each group. Delapril 15 mg twice daily, like enalapril 5 mg twice daily, was effective in improving signs and symptoms of CHF and was well tolerated.

Left ventricular diastolic filling in diabetes mellitus with and without hypertension.

Left ventricular diastolic filling by Doppler echocardiography was investigated in 84 diabetic patients without evidence of heart disease and in 84 normotensive nondiabetic age- and sex-matched control subjects. Diabetic patients were subdivided into two groups on the basis of the presence of arterial hypertension. Group 1 comprised 41 normotensive diabetic patients (19 men, 22 women, mean age 63.7 +/- 9.1 years); Group 2 comprised 43 hypertensive diabetics (15 men, 28 women, mean age 65.6 +/- 9.6 years). Doppler measures of diastolic filling were significantly altered in the two groups as compared with control subjects. Peak atrial flow velocity, velocity integral for the atrial filling period, and atrial filling fraction were increased, whereas the ratio of peak early to peak atrial flow velocity and the ratio of flow velocity integrals were decreased, especially in Group 2 patients. Thirteen patients in Group 1 (32%) and 17 in Group 2 (40%) had evidence of diastolic dysfunction, as assessed by the presence of at least two independent abnormal indices (outside age-corrected 95% confidence interval). In each group, patients with altered diastolic filling differed slightly from diabetic patients with normal Doppler indices, tending to increased wall thickness and left ventricular mass. In conclusion, diastolic filling of the left ventricle is frequently altered in diabetic patients and is adversely affected by arterial hypertension whose coexistence further impairs left ventricular relaxation.

Age-related changes of antianginal effects of verapamil in patients with stable effort angina. A medium term randomized double-blind placebo controlled trial.

Our study evaluated the effects of verapamil in elderly patients with stable effort angina using a medium-term double-blind placebo-controlled protocol. Thirty-nine consecutive patients, 23 middle-age patients (50 +/- 6 years; range 38-60 years) and 16 elderly patients (66 +/- 2 years; range 65-70 years) with exertional angina were chosen. After a run-in period, both groups received treatment with either placebo or verapamil--360 mg daily--for 4 weeks. During treatment, weekly angina frequency and nitroglycerin consumption were significantly reduced in both groups. Verapamil significantly decreased the rate-pressure product at rest in elderly patients and in both groups at submaximal exercise, due to a reduction in heart rate in both groups and to a more marked decrease in arterial pressure in older patients. At peak exercise, the rate-pressure product was unchanged in both groups after verapamil, while exercise capacity showed a significant improvement in the middle-aged, and ST segment depression was reduced in both groups. After verapamil, 30% of middle-aged patients and 44% of elderly patients had to stop exercising because of angina. Side effects were rare and no drop-out was recorded. Verapamil exerted its antianginal action by means of a decrease in myocardial oxygen consumption at rest and at submaximal exercise in the elderly, while only at submaximal exercise in the middle-aged. Therefore verapamil at the dose of 360 mg daily proved an effective antianginal drug with a safe effect profile also in elderly patients.

Left ventricular diastolic filling in elderly hypertensive patients.

OBJECTIVE: To evaluate the effects of mild to moderate hypertension and of LVH on diastolic filling and other Doppler indices in the elderly. DESIGN: Survey with a control group. SUBJECTS: Seventy-one hypertensives (34 men, 37 women) referred for echocardiograms and 32 age- and sex-matched normotensive volunteers. Thirty-six of the hypertensives had LVH; 34 did not. SETTING: Echocardiographic laboratory. MEASUREMENTS: M-mode, two-dimensional, and pulsed Doppler echocardiograms. A wide variety of Doppler-derived indices of diastolic function were assessed. RESULTS: All Doppler derived indices of left ventricular diastolic filling (peak E, peak A, their ratio, EF slope, time-velocity integrals, atrial filling fraction, and isovolumic relaxation time) were similar among the three groups. CONCLUSION: Elderly mild to moderate hypertensives with or without LVH have LV diastolic filling that is normal for age. The identification of pathological diastolic dysfunction requires comparison to age-matched controls, since aging, a major factor influencing diastolic filling, can mask the effect of hypertension.

Effect of beta-adrenoceptor blockade on dipyridamole-induced myocardial asynergies in coronary artery disease.

Twenty-one patients with angiographic evidence of significant coronary artery disease, and positive dipyridamole echocardiographic test results at basal condition and after 7 days of placebo treatment were prospectively studied to see whether beta blockade modifies the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to propranolol (120 mg/day) or placebo treatment in 3 divided doses for 7 days, after which each patient crossed over to the alternate regimen. Dipyridamole-echocardiographic testing was repeated at the end of each treatment. Propranolol abolished new mechanical signs of transient dipyridamole-induced ischemia (new wall motion abnormalities or an increase in degree of basal asynergies, or both) in 13 of 21 patients. The remaining 8 patients had positive results on dipyridamole echocardiographic testing after the propranolol treatment period. At basal conditions both heart rate and rate-pressure product were significantly reduced with propranolol; there was also a significant decrease in these parameters at peak dipyridamole infusion. At peak dipyridamole infusion heart rate and rate-pressure product were significantly lower in patients with negative than in those with positive echocardiographic test results after propranolol. Our data show that administration of beta blockade significantly reduces the development of transient dipyridamole-induced myocardial asynergies, the earliest markers of acute myocardial ischemia, detected with 2-dimensional echocardiography.

[Aging and left ventricular diastolic function]. / Invecchiamento e funzione diastolica del ventricolo sinistro.

Several studies have demonstrated that physiological aging significantly affects cardiovascular function. Experimental researches, conducted on cardiac muscle of senescent animals, have shown a prolongation of both contraction and relaxation times. This phenomenon was explained by a reduced Ca(++)-stimulated ATPase pump activity, responsible for the reduced sarcoplasmic reticulum Ca++ uptake rate. The myofilament response to Ca++ in the aging heart is normal as are peak contractile force production and post-extrasystolic twitch potentiation during continual paired stimulation. On the other hand, the inotropic response to cardiac glycosides and beta-adrenoceptor stimulation is diminished in senescent compared to adult myocardium. This decreased contractility could result mainly from mechanisms controlling Ca++ reuptake from sarcoplasmic reticulum and relaxation time (diastolic phase) rather than those determining force generation and contraction time (systolic phase). Age-related physiologic structural changes are not associated with significant variations in left ventricular diastolic and systolic sizes, but they seem a direct consequence of the rising systolic blood pressure observed in these age decades. Myocardial hypertrophy should not be considered a specific marker of the senescent heart, but rather an adaptive response to increased afterload conditions. As regard the relationship between age and diastole, it is important to underline that the alterations in aging cardiac muscle function primarily involve the isovolumic relaxation time and diastolic phase. With age, the early diastolic phase declines while the contribution of atrial contraction to ventricular diastolic filling increases as well as the isovolumic relaxation time.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effects of slow-release verapamil in relation to plasma concentration in aged hypertensives. A study with continuous monitoring of arterial pressure and electrocardiogram]. / Effetti del verapamil slow release negli ipertesi anziani in rapporto alle concentrazioni plasmatiche. Studio mediante monitoraggio continuo della pressione arteriosa e dell'elettrocardiogramma.

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.

Evaluation of the efficacy of slow-release nifedipine in systemic hypertension by ambulatory intraarterial blood pressure monitoring.

We assessed the effect on blood pressure of administration of slow-release nifedipine tablets (20 mg) by continuous intraarterial blood pressure monitoring (Oxford system) in 10 patients with untreated essential hypertension. Blood pressure was recorded under control conditions and during nifedipine therapy. During each monitoring period patients were instructed to perform various types of exercise. The initial dose of nifedipine was 20 mg twice a day (8:00 a.m. and 8:00 p.m.). For patients in whom arterial pressure control was not achieved, the dose of the drug was increased at weekly intervals, first to 40 mg in the morning and 20 mg at night and then to 40 mg twice a day. The average daily dose was 52 mg. Nifedipine twice a day significantly reduced systolic and diastolic blood pressures both during the day and during the night. The rise in blood pressure due to dynamic or isometric exercise or to mental testing was blunted. Heart rate did not change. Orthostatic hypotension was not observed, and there were only minor side effects, which did not require withdrawal of the patient from the trial. Bioavailability of nifedipine from this preparation was satisfactory, as shown by plasma concentrations which remained constantly in the therapeutic range. Thus, slow-release nifedipine given twice a day represents an effective treatment in patients with essential arterial hypertension. The reduced frequency of administration required may improve patient compliance with this treatment.