Randomized study on the efficacy and safety of landiolol, an ultra-short-acting ß1-adrenergic blocker, in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: It is still controversial whether intravenous administration of ß-blocker in the very acute phase of acute myocardial infarction (AMI) is beneficial. Landiolol is an ultra-short-acting ß-blocker that has less effect on blood pressure, but little is known about its efficacy and safety for patients with AMI undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: A consecutive 96 patients with AMI not manifesting cardiogenic shock were prospectively randomized to landiolol (n = 47) or a control group (n = 49). Continuous administration of landiolol (3 µg·kg(-1)·min(-1) for 24 h) was done just after PCI in the landiolol group, but not in the control group. Heart rate decreased by 9.4 ± 1.7 beats/min after initiation of landiolol (P<0.01), but was unchanged in the control group. Left ventricular ejection fraction assessed 6 months later was greater than that at 2 weeks in the landiolol group (52.0 ± 1.5 vs. 49.1 ± 1.5%, P = 0.01), but remained unchanged in the control group. Left ventricular end-diastolic volume index assessed 6 months later was increased compared with that at 2 weeks in the control group (78.0 ± 2.7 vs. 72.5 ± 2.8 ml/m(2), P = 0.02), whereas it was unchanged in the landiolol group. CONCLUSIONS: Early intravenous administration of landiolol in patients with AMI undergoing PCI is safe and has the potential to improve cardiac function and inhibit cardiac remodeling in the chronic phase.

Effects of telmisartan on markers of ventricular remodeling in patients with acute myocardial infarction: comparison with enalapril.

Enalapril is effective in the suppression of left ventricular remodeling after acute myocardial infarction (AMI), but the effect of telmisartan is unclear. The consecutive 163 AMI patients underwent primary percutaneous coronary intervention and were randomized to telmisartan (n = 82) or enalapril (n = 81). Left ventriculography was performed in the acute and chronic (6 months) phases. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were measured by zymography in the acute (days 1, 7, and 14) and chronic (6 months) phases. Plasma pentraxin3 (PTX3), a marker of vascular inflammation, was also measured. There were no adverse effects in the telmisartan group. The analysis of the left ventriculograms in the acute and chronic phases revealed no difference between the two groups. MMP-9 activities at days 7 and 14 and in the chronic phase were decreased compared to that at day 1 in both groups. MMP-2 activity was also decreased in the acute phase, but increased in the chronic phase in both groups. There was no difference in the plasma PTX3 level in the acute phase, but in the chronic phase, PTX3 was significantly lower in telmisartan than in enalapril group (2.6 ± 1.4 vs. 3.2 ± 1.6 ng/ml, p = 0.04). Telmisartan is well tolerated, shows similar effects on the markers of left ventricular remodeling to those of enalapril, and suppresses vascular inflammation more effectively than enalapril in AMI patients. Telmisartan can be an alternative to angiotensin converting enzyme inhibitor in patients with AMI.

Comparison of the effects of long-acting nifedipine CR and diltiazem R in patients with vasospastic angina: Aomori coronary spastic angina study.

OBJECTIVES: We compared the efficacy of once-daily administration of nifedipine CR 40 mg (N) with that of twice-daily diltiazem R 100mg (D) in patients with vasospastic angina (VSA) registered in 8 cardiovascular institutes in Aomori Prefecture. METHODS AND RESULTS: VSA was diagnosed by the ischemic ST segment changes during chest pain attacks at rest and/or acetylcholine induction test done during coronary angiography. Thirty-seven patients were randomly allocated to either the N (n=20) or D group (n=17). The number of symptomatic attacks and amount of short-acting nitrate use were examined based on data in diaries written by the patients. There were no significant differences in the baseline characteristics between the two groups. The mean number (median number) of attacks per week was significantly decreased in the N group from 2.56 (2.0) at baseline to 0.41 (0.0) after 4 weeks of treatment, to 0.24 (0.0) after 8 weeks, and to 0.36 (0.0) after 12 weeks (all p<0.05 vs. baseline). It was also decreased in D group from 2.71 (2.0) at baseline to 0.55 (0.0) after 4 weeks, to 0.32 (0.0) after 8 weeks, and to 0.27 (0.0) after 12 weeks (all p<0.05 vs. baseline). The numbers of attacks before and after treatment were comparable between N and D groups. In one patient in each of the N and D groups, the allocated drug was crossed over to the other due to recurrence of the attacks. One patient in each group experienced adverse effects and the drug was changed to the other. CONCLUSION: Once-daily administration of nifedipine CR was as effective as twice-daily diltiazem R in the prevention of VSA attacks.

Impact of telmisartan on coronary stenting in patients with acute myocardial infarction compared with enalapril.

OBJECTIVE: To determine whether telmisartan reduces in-stent restenosis (ISR) after coronary angioplasty using bare metal stent (BMS) in patients with acute myocardial infarction (AMI) compared with an angiotensin converting enzyme (ACE) inhibitor. BACKGROUND: The efficacy of inhibition of renin-angiotensin-aldosterone system in patients with AMI has been established, and the prescription of ACE inhibitor is recommended as class I indication for all AMI patients, whereas that of angiotensin II receptor blocker (ARB) as class IIa. Telmisartan is a unique ARB since it has a peroxisome proliferator-activated receptor (PPAR) gamma activating effect which is known to reduce neointimal tissue proliferation after coronary stenting. METHODS: In 64 patients, telmisartan (20-40 mg per day) was orally administered for 6 months after stenting (telmisartan group). The incidence of ISR after stenting in these patients was retrospectively compared with those in the other 60 patients administrated enalapril (2.5-5 mg per day) (enalapril group). RESULTS: There were no adverse events such as death, re-infarction and emergency bypass surgery in telmisartan group during a follow-up period for 6 months. The ISR rate was lower in telmisartan group (18.8%) than in enalapril group (33.3%) (p=0.06). However, percent diameter stenosis (%DS) at follow-up in telmisartan group was significantly smaller than in enalapril group (26.7+/-18.6% vs 38.0+/-23.9%, p=0.004). Late lumen loss was also significantly smaller in telmisartan group than in enalapril group (0.97+/-0.48 mm vs 1.19+/-0.68 mm, p=0.039). CONCLUSIONS: Telmisartan not only is tolerable in patients with AMI but has a potential to reduce neointimal tissue proliferation after AMI treated with coronary angioplasty using BMS compared with enalapril.

Aldosterone causes vasoconstriction in coronary arterioles of rats via angiotensin II type-1 receptor: influence of hypertension.

Aldosterone is involved in many cardiovascular diseases with increased oxidative stress. Aldosterone-induced cardiac fibrosis is abolished by blockade of angiotensin II Type-1 (AT1) receptor. Recently, non-genomic vasoconstrictor effects of aldosterone were reported in various vascular beds. We tested the hypothesis that aldosterone stimulates angiotensin AT1 receptor, and causes vasoconstriction by increasing oxidative stress in coronary microcirculation. Coronary arterioles (60-120 microm) were isolated from spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, aged 23-26 weeks. They were cannulated, and pressurized at 60 cm H2O. Effect of aldosterone (10(-15) to 10(-6) M) on coronary arteriolar diameter was examined. Aldosterone rapidly and dose-dependently decreased coronary arteriolar diameter in WKY rats and SHR (diameter changes, 8.4+/-0.7% vs 13.9+/-0.8%, P<0.05). Aldosterone-induced vasoconstriction was enhanced by 1.6-folds in SHR compared to WKY rats (P<0.05). Mineralocorticoid receptor antagonist spironolactone (10(-6) M) did not influence aldosterone-induced vasoconstriction. Selective angiotensin AT1 receptor blocker valsartan (10(-4) M) or candesartan (10(-7) M) abolished aldosterone-induced vasoconstriction. Similarly, superoxide dismutase (SOD, 300 U/ml), and NADPH oxidase inhibitor apocynin (10(-4) M) abolished it. Moreover, the vasoconstrictor effect of aldosterone disappeared in denuded vessels. Real-time quantitative RT-PCR revealed that angiotensin AT1 receptor mRNA level in coronary arterioles of SHR was upregulated by 1.5-folds compared to that in WKY rats (P<0.05). Aldosterone causes vasoconstriction in coronary arterioles, and this vasoconstrictor effect is enhanced by genetically defined hypertension. Aldosterone-induced vasoconstriction is mediated by angiotensin AT1 receptor presumably via oxidative stress.

[Relationship between duration of arrhythmia and subsequent preventive effect of disopyramide after cardioversion in patients with symptomatic paroxysmal and persistent atrial fibrillation].

OBJECTIVES: The relationship between the duration of arrhythmia and the subsequent long-term efficacy of disopyramide in preventing atrial fibrillation was investigated in patients with symptomatic paroxysmal and persistent atrial fibrillation. METHODS: A total of 60 patients (39 men, 21 women, mean age 65 +/- 11 years) were given disopyramide (300 mg/day) after electrical and pharmacological cardioversion based on American Heart Association Task Force on Practice Guidelines. The patients were divided into two types based on the duration of atrial fibrillation: conversion within 48 hr (group A, n = 35) and more than 48 hr (group B, n = 25) after the episode. Mean follow-up period was 47.1 +/- 28.7 months. RESULTS: Patient characteristics showed no statistically significant difference between groups A and B. The actuarial rates of maintenance of sinus rhythm at 1, 3, 6, 12, 18 and 24 months were 88.6%, 77.1%, 57.1%, 48.6%, 42.9% and 37.1%, respectively, in group A, and 72.0%, 44.0%, 28.0%, 16.0%, 12.0% and 8.0%, respectively, in group B. There was a significant difference in the rate at 24 months between groups A and B (p < 0.05). The periods for maintenance of sinus rhythm in groups A and B were 20.9 +/- 3.9 and 6.7 +/- 2.1 months, respectively, with a significant difference between groups A and B (p < 0.01). CONCLUSIONS: The efficacy of disopyramide in preventing the recurrence of atrial fibrillation varies with the duration of the previous episode. These results demonstrate that it is important to convert to normal sinus rhythm earlier to prevent the recurrence of atrial fibrillation in the long term.

[Comparison of the efficacies of disopyramide, cibenzoline and aprindine for the termination of paroxysmal and persistent atrial fibrillation in elderly and non-elderly patients].

OBJECTIVES: The relationship between the efficacy of the anticholinergic action of disopyramide, cibenzoline and aprindine and age was examined in patients with paroxysmal and persistent atrial fibrillation. METHODS: This prospective, randomized study included 278 patients (200 men, 78 women, mean age 61 +/- 11 years) divided into two groups; the non-elderly group (age below 60 years) and the elderly group (age over 60 years). Successful termination was defined as conversion of sinus rhythm within 30 min of intravenous administration of 50 mg disopyramide (n = 91), 70 mg cibenzoline (n = 93) or 100 mg aprindine (n = 94) in this prospective and randomized study. RESULTS: No statistically significant difference was found in patient characteristics between the three agents. 1) The rate of conversion to sinus rhythm after disopyramide administration in the non-elderly group(37.8%) was significantly higher than that in the elderly group (17.4%, p = 0.0361). 2) The rate of conversion to sinus rhythm after cibenzoline administration in the non-elderly group (62.2%) tended to be greater than that in the elderly group (43.8%, p = 0.0972). 3) The rate of conversion to sinus rhythm after aprindine administration in the non-elderly group (25.6%) was not significantly higher than that in the elderly group (18.2%, p = 0.4474). CONCLUSIONS: The anticholinergic action of antiarrhythmic agents has an effect on successful termination in non-elderly patients with paroxysmal and persistent atrial fibrillation.

[Long-term efficacy of combination therapy using antiarrhythmic agents and angiotensin converting enzyme inhibitor in patients with paroxysmal and persistent atrial fibrillation: importance of the timing of administration].

OBJECTIVES AND METHODS: This study examined the long-term efficacy of combination therapy using antiarrhythmic agents and angiotensin converting enzyme inhibitor (ACE-I) to maintain sinus rhythm in patients with paroxysmal and persistent atrial fibrillation (Paf). There were 246 patients (176 men, 70 women, mean age 67.3 +/- 11.7 years, mean follow-up period 48.9 +/- 29.3 months) divided into two groups: the ACE-I(+) group (n = 74) and the ACE-I(-) group (n = 172). RESULTS: The incidence of hypertension and underlying heart disease in the ACE-I(+) group (85.1% and 34.3%, respectively) was significantly higher than those in the ACE-I(-) group (37.8% and 25.0%, respectively) (both p < 0.01). Left ventricular ejection fraction in the ACE-I(+) group (65.6 +/- 12.5%) was significantly lower than that in the ACE-I(-) group (71.9 +/- 8.9%) (p < 0.01). The actuarial rate of the maintenance of sinus rhythm at 48 months in the ACE-I(+) group (86.5%) was similar to that in the ACE-I(-) group (83.1%). Among the 104 patients who had suffered from Paf for < 3 months after the first episode, the actuarial rate of maintenance of sinus rhythm at 48 months in the ACE-I(+) group (97.1%, n = 35) was significantly higher than that in the ACE-I(-) group (82.6%, n = 65), and the period of maintenance of sinus rhythm in the ACE-I(+) group (54.8 +/- 30.8 months) was significantly longer than that in the ACE-I(-) group (28.4 +/- 20.5 months) (both p < 0.05). CONCLUSIONS: ACE-I must be additionally administered within 3 months of the first Paf episode to maintain normal sinus rhythm in patients with Paf.

[Relationship between long-term preventive efficacy of cibenzoline and atrial natriuretic peptide in patients with paroxysmal atrial fibrillation].

OBJECTIVES: The relationship between the long-term efficacy of the antiarrhythmic agent cibenzoline in preventing lone paroxysmal atrial fibrillation (PAf) and plasma concentrations of atrial natriuretic peptide (ANP) and catecholamine was investigated during sinus rhythm and PAf. METHODS: Plasma concentrations of ANP, epinephrine, norepinephrine and dopamine during sinus rhythm and PAf were measured in 87 patients (70 men, 17 women, mean age 64 +/- 11 years) with lone-PAf. All patients received cibenzoline (300 mg/day) after cardioversion, and they were divided into the no recurrence group (n = 28) and the recurrence group (n = 59). Mean follow-up period was 41 +/- 29 months. RESULTS: The plasma concentration of ANP was significantly higher during PAf (110.2 +/- 65.0 pg/ml) than during sinus rhythm (39.9 +/- 27.8 pg/ml, p < 0.01) for all patients. The concentrations of epinephrine, norepinephrine and dopamine during PAf were all similar to those during sinus rhythm. Patient characteristics showed no statistically significant difference between the no recurrence and recurrence groups. In the recurrence group, the incidence of thromboembolism was significantly higher (30.5% vs 10.7%) and the period of PAf was significantly longer (26.8 +/- 43.6 vs 12.4 +/- 21.2 months) than in the no recurrence group (both, p < 0.05). The plasma concentrations of ANP during sinus rhythm were similar in the no recurrence group (33.1 +/- 20.1 pg/ml) and the recurrence group (43.5 +/- 30.3 pg/ml), but was significantly higher during PAf in the no recurrence group (142.6 +/- 76.5 pg/ml) than in the recurrence group (95.8 +/- 54.2 pg/ml, p < 0.01). The ratio of ANP level during PAf to that during sinus rhythm in the no recurrence group (5.0 +/- 2.5) was significantly greater than that in the recurrence group (3.2 +/- 2.5, p < 0.01). CONCLUSIONS: Patients without recurrence of PAf under treatment with cibenzoline have preserved capacity of ANP secretion compared with patients with recurrence.