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.

Decreased plasma and cardiac matrix metalloproteinase activities in patients with coronary artery disease and treated with pravastatin.

Matrix metalloproteinase (MMP), which is activated by oxidative stress, plays an important role in the development of ventricular remodeling in coronary artery disease. Pravastatin is shown to reduce oxidative stress. We tested the hypothesis that cardiac oxidative stress and MMP activity are reduced in patients with coronary artery disease and treated with pravastatin. Forty-eight patients who underwent coronary artery bypass graft surgery (CABG) were studied. Twenty-four patients had the serum low-density lipoprotein (LDL) cholesterol level >2.59 mM, and were treated with pravastatin (10 mg/day) for 2 months before CABG (pravastatin group). The other 24 had LDL cholesterol< or =2.59 mM, and were untreated (control group). The plasma and pericardial MMP-2 and MMP-9 activities were measured by gelatin zymography, and MMP-2 and MMP-9 levels, and pericardial 8-iso-prostagrandin F2alpha (8-iso-PGF2alpha) level, a maker of oxidative stress, by enzyme-linked immunosorbent assay. The plasma and pericardial MMP-2 and MMP-9 activities and levels were all lower by 20-30% in pravastatin than in control group (all P<0.05). The pericardial 8-iso-PGF2alpha level was lower in pravastatin than in control group (38+/-4 vs 64+/-7 pg/ml, P<0.05). The pericardial MMP-2 and MMP-9 activities were positively correlated with the pericardial 8-iso-PGF2alpha level (r=0.57 and 0.47, respectively, both P<0.01). Thus, cardiac oxidative stress and MMP activities are reduced in patients with coronary artery disease and treated with pravastatin, which may be beneficial in preventing and reducing ventricular remodeling.

A case of suspected vasospastic angina related to S-1 administration.

A 58-year-old male with advanced gastric cancer underwent a total gastrectomy after neoadjuvant chemotherapy with paclitaxel and cisplatin. The combination chemotherapy was resumed postoperatively as adjuvant chemotherapy. Although no recurrence was observed after 6 months of adjuvant chemotherapy,the patient elected to receive further adjuvant chemotherapy with an oral drug. On the night of November 9,2006, he began taking S-1 at a dose of 50 mg twice daily. Fifty minutes after taking the first 50 mg of S-1,he experienced a squeezing chest pain at rest that was later accompanied by diaphoresis and nausea. The pain continued for approximately one hour,but had subsided by the time he reached an emergency room. Coronary angiography revealed a 50% eccentric stenosis in the proximal site of the right coronary artery,but there was no coronary lesion which could caused myocardial ischemia. Cardiac scintigraphy using 123I-BMIPP (123I-labeled beta-methyl-p-iodophenyl-pentadecanoic acid) showed a decreased uptake of BMIPP within the posterior wall,which improved one month later,so transient myocardial ischemia was confirmed. Since vasospastic angina related to S-1 administration was highly suspected,re-administration of S-1 was not performed. The patient is not currently receiving chemotherapy and remains under surveillance for relapse.

Nicorandil suppresses the increases in plasma level of matrix metalloproteinase activity and attenuates left ventricular remodeling in patients with acute myocardial infarction.

Nicorandil, a hybrid KATP channel opener and nicotinamide nitrate, reduces no-reflow phenomenon and improves cardiac function in patients with acute myocardial infarction (AMI). We reported that nicorandil suppresses radical formation in patients with AMI undergoing primary percutaneous coronary intervention (PCI). In the present study, we tested the hypothesis that nicorandil treatment suppresses MMP activities and predicts ventricular remodeling in AMI. Sixty-two patients with AMI were randomized into nicorandil pretreatment (n = 31) and control (n = 31) groups after admission and underwent primary PCI. Nicorandil was administered as a bolus injection (4 mg) followed by constant infusion (8 mg/h) for 24 h just after admission. On days 1, 2, and 14 after the onset of AMI, the plasma levels of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by enzyme-linked immunosorbent assay and the activities by gelatin zymography. There were no differences in the baseline clinical characteristics between the two groups. On day 1, there were no differences in both MMP-2 and MMP-9 levels and their activities between the two groups. However, both MMP-2 and MMP-9 levels and their activities were significantly lower in nicorandil than in control group on day 2 (MMP-2 level, 1 014 +/- 39 vs 1 174 +/- 44 ng/ml; MMP-9 level, 17 +/- 1 vs 23 +/- 2 ng/ml; both P < 005) and on day l4 (MMP-2 level, 970 +/- 38 vs 1 221 +/- 44 ng/ml; MMP-9 level, 17 +/- 1 vs 23 +/- 1 ng/ml; both P < 0.05). Left ventricular end-diastolic volume index (LVEDVI) at acute phase was not different between the two groups. At 6 months after AMI, LVEDVI was significantly smaller in nicorandil than in the control group (83 +/- 4 vs 96 +/- 4 ml/m2, P < 0.05). The change in LVEDVI from acute phase to 6 months was positively correlated with MMP-2 and MMP-9 levels and activities. Nicorandil suppresses the increases in MMP levels and activities and prevents the development of ventricular remodeling in AMI.

Increased level of pericardial insulin-like growth factor-1 in patients with left ventricular dysfunction and advanced heart failure.

OBJECTIVES: To test the hypothesis that the cardiac insulin-like growth factor-1 (IGF-1) system is up-regulated in the failing heart, we measured the pericardial (cardiac) and plasma (circulating) IGF-1 levels in coronary artery disease patients. BACKGROUND: Local IGF-1 systems are regulated differently from the systemic IGF-1 system. The cardiac IGF-1 system is up-regulated by the increased left ventricular (LV) wall stress. However, it remains unknown how this system is affected in LV dysfunction and heart failure. METHODS: We measured the plasma and pericardial fluid levels of IGF-1 and brain natriuretic peptide (BNP) in 87 coronary artery disease patients undergoing cardiac surgery, and examined their relationships with LV function and heart failure severity. The expressions of IGF-1 and IGF-1 receptor proteins were examined in endomyocardial biopsies obtained from other patients with normal or impaired LV function. RESULTS: The pericardial IGF-1 and BNP levels were positively correlated with the plasma BNP level (both p < 0.001). The pericardial IGF-1 level was increased in heart failure patients, whereas the plasma IGF-1 level was rather decreased. The pericardial IGF-1 level was inversely correlated with the LV ejection fraction (p < 0.001), whereas the plasma IGF-1 level was not. Positive immunostaining for IGF-1 and IGF-1 receptor proteins was enhanced in myocardial biopsies from failing hearts compared with those from nonfailing hearts. CONCLUSIONS: The pericardial IGF-1 level was increased in patients with LV dysfunction and heart failure, whereas the plasma IGF-1 level was decreased. These results may indicate that up-regulation of the cardiac IGF-1 system serves as a compensatory mechanism for LV dysfunction.

Increased pericardial fluid level of matrix metalloproteinase-9 activity in patients with acute myocardial infarction: possible role in the development of cardiac rupture.

BACKGROUND: In an animal model of acute myocardial infarction (AMI), deletion of matrix metalloproteinase (MMP)-9 results in suppression of the development of cardiac rupture. The present study sought to clarify how myocardial MMP-9 activity is related to the pathophysiologies of AMI and cardiac rupture in humans. METHODS AND RESULTS: Levels of interleukin-8 (IL-8), polymorphonuclear leukocyte (PMN) elastase, monocyte chemotactic protein-1 (MCP-1) and MMP activity were measured in the pericardial fluid obtained from 28 patients with angina pectoris (AP group) and 16 patients with AMI (AMI group) undergoing cardiac surgery. In the AMI group, 5 were complicated with ventricular septal perforation (VSP) and the remaining 11 were not (non-VSP). Levels of IL-8, PMN elastase, MMP-2 and MMP-9 activity were all higher in the AMI group than in the AP group. In the AMI group, all levels other than MMP-2 activity were further elevated in cases with VSP compared with those in the non-VSP group. There was no significant difference in MCP-1 among the groups CONCLUSIONS: Markers of neutrophil activation in the infarcted cardiac tissue seem to be elevated in AMI. Highly elevated levels of MMP-9 activity, which may be derived from neutrophils, and PMN elastase may be related to the pathophysiology of VSP or cardiac rupture in AMI.

C-reactive protein-induced upregulation of extracellular matrix metalloproteinase inducer in macrophages: inhibitory effect of fluvastatin.

OBJECTIVE: Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-9 were reported to be expressed at the macrophage-rich area in human coronary atherosclerotic plaque. We examined whether C-reactive protein (CRP) activates macrophages to express EMMPRIN and MMP-9 in vitro and whether statins inhibit it. METHODS AND RESULTS: Rat peritoneal macrophages were collected by peritoneal lavage, and were incubated in the presence or absence of CRP. CRP at 5 microg/ml increased the gene expression of EMMPRIN relative to GAPDH, measured by RT-PCR, by 1.67+/-0.07 fold at 24 h and by 1.85+/-0.49 fold at 48 h (both p<0.05). The gene expression of MMP-9 in the presence of CRP at 5 microg/ml was followed by 1.36+/-0.11 fold increase at 24 h and by 3.95+/-0.81 fold at 48 h (both p<0.05). CRP at 5 microg/ml for 48 h increased by 6 fold MMP-9 activity, measured by zymography, without affecting tissue inhibitor of metalloproteinases-1. Boiled CRP at 5 mug/ml for 48 h unaffected MMP-9 activity. Fluvastatin blocked the CRP-induced increases in EMMPRIN and MMP-9 expression and activity. Diphenylene iodonium, an inhibitor of NADPH oxidase, had a similar effect on MMP-9 activity. Fluvastatin suppressed the CRP-induced increases in 8-epi-prostaglandin F(2alpha) levels in the condition media. CONCLUSIONS: CRP is an activator for macrophages to enhance EMMPRIN and MMP-9 expression. Fluvastatin inhibits them presumably through its antioxidant effect.

Circulating level of gelatinase activity predicts ventricular remodeling in patients with acute myocardial infarction.

BACKGROUND: Matrix metalloproteinase (MMP) plays an important role in the development of ventricular remodeling in an animal model of acute myocardial infarction (AMI). We examined whether circulating MMP activity can predict left ventricular (LV) remodeling after AMI in humans. METHODS: We measured the circulating level of MMP-2 and MMP-9 activities (gelatinase activity) at 14 days after the onset of AMI by gelatin zymography in 52 consecutive patients (age 62+/-2). All patients underwent direct PTCA and stenting at an acute stage, and were treated subsequently with losartan or enalapril. Biplane left ventriculography was performed at admission, and 2 weeks and 6 months after the onset of AMI. RESULTS: We expressed gelatinolysis activity as the ratio to MMP-2 standard. Mean gelatinase activity was 0.721+/-0.013. We divided patients into two groups, groups with gelatinolysis activity <0.72 (low group, n=27) and >0.72 (high group, n=25). Either change in LV end-diastolic volume index (LVEDVI, ml/m(2)) or end-systolic volume index (LVESVI, ml/m(2)) from admission to 2 weeks was not different between the two groups. Changes in both LVEDVI and LVESVI from 2 weeks to 6 months were greater in high gelatinolysis activity group than those in low activity group. Moreover, circulating level of gelatinolysis activity was positively correlated with changes in LVEDVI and LVESVI from 2 weeks to 6 months. CONCLUSION: These results demonstrate that circulating level of gelatinase activity can predict LV remodeling after AMI. Inhibition of gelatinase activity at the acute phase may be a therapeutic strategy for the prevention of remodeling after AMI.

Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease. Possible role for left ventricular remodelling.

AIMS: Oxidative stress is implicated in the progression of heart failure, and matrix metalloproteinase (MMP) activity is increased in patients with congestive heart failure. We examined the role of oxidative stress on MMP activity in humans. METHODS AND RESULTS: We measured the MMP activity and the level of 8-iso-prostagandin F2alpha (8-iso-PGF2alpha), a specific and quantitative maker of oxidant stress, in the pericardial fluid (PF) in 47 consecutive patients with coronary artery disease who underwent coronary artery bypass surgery. Zymography of PF showed bands at 92-85kDa (MMP-9) and 72-65kDa (MMP-2). The MMP activity was expressed as the ratio to MMP-2 standard. MMP-2, MMP-9 and total gelatinolysis activities were positively correlated with left ventricular end-diastolic volume index (LVEDVI), and MMP-2 and total gelatinolysis activities were also positively correlated with LV end-systolic volume index. Moreover, MMP-2, MMP-9 and total gelatinolysis activities were all positively correlated with pericardial level of 8-iso-PGF2alpha. Also, LVDEVI was positively correlated with pericardial level of 8-iso-PGF2alpha. CONCLUSIONS: Oxidative stress may play an important role in the regulation of MMP activity. Augmented MMP activity may be involved in the development of ventricular remodelling in patients with coronary artery disease.

[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.