Itsuro Morishima

Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction

OBJECTIVES We sought to elucidate the long-term prognostic importance of angiographic no-reflow phenomenon after percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND Angiographic no-reflow phenomenon, a reduced coronary antegrade flow (Thrombolysis in Myocardial Infarction [TIMI] flow grade < or =2) without mechanical obstruction after recanalization, predicts poor left ventricular (LV) functional recovery and survival in the early phase of AMI. We hypothesized that angiographic no-reflow phenomenon also predicts long-term clinical outcome. METHODS We studied 120 consecutive patients with their first AMI treated by PTCA without flow-restricting lesions. The patients were classified as either no-reflow (n = 30) or reflow (TIMI-3) (n = 90) based on post-PTCA cineangiograms to follow up (5.8 +/- 1.2 years) for cardiac death and nonfatal events. RESULTS Patients with no-reflow had congestive heart failure (p < 0.0001), malignant arrhythmia (p = 0.038), and cardiac death (p = 0.002) more often than did those with reflow. Kaplan-Meier curves showed lower cardiac survival and cardiac event-free survival (p < 0.0001) in patients with no-reflow than in those with reflow. Multivariate analyses disclosed that no-reflow phenomenon was an independent predictor of long-term cardiac death (relative risk [RR] 5.25, 95% confidence interval [CI] 1.85 to 14.9, p = 0.002) and cardiac events (RR 3.71, 95% CI 1.79 to 7.69, p = 0.0004). At follow-up, survivors with no-reflow had higher end-diastolic and end-systolic LV volume indices and plasma brain natriuretic peptide levels, and lower LV ejection fractions (p = 0.0002, p < 0.0001, p = 0.002, p < 0.0001, respectively) than did those with reflow, indicating that no-reflow may be involved in LV remodeling. CONCLUSIONS Angiographic no-reflow phenomenon strongly predicts long-term cardiac complications after AMI; these complications are possibly associated with LV remodeling.

Clinical significance of no-reflow phenomenon observed on angiography after successful treatment of acute myocardial infarction with percutaneous transluminal coronary angioplasty.

The clinical significance of the angiographic no-reflow phenomenon was evaluated in 93 patients with acute myocardial infarction treated by percutaneous transluminal coronary angioplasty (PTCA). On the basis of the post-PTCA angiograms, patients were divided into three groups: normal angiogram (group 1, n = 65), slight no-reflow (group 2, n = 13), and severe no-reflow (group 3, n = 15). Regional wall motion in the chronic phase was depressed in groups 2 and 3 compared with group 1. The proportion of the area of the transmural infarction to that of the total infarction determined by scintigraphy was higher in groups 2 and 3 than in group 1. A significantly higher incidence of myocardial rupture and of death resulting from cardiac causes was observed in group 3 compared with group 1. The severity of this phenomenon immediately after an emergency PTCA correlated well with the severity of myocardial damage, with patients having severe no-reflow showing the poorest prognosis.

Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury.

During postischemic reperfusion, free radicals are produced and have deleterious effects in isolated rat hearts. We investigated whether melatonin (MEL) reduces the production of hydroxyl radical (*OH) in the effluent and aids in recovery of left ventricular (LV) function. Hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. Salicylic acid (SAL) was used as the probe for *OH, and its derivatives 2,5- and 2,3-dihydroxybenzoic acid (DHBA) were quantified using HPLC. In addition, thiobarbituric acid reactive substances (TBARS) in the myocardium was measured. Plateaus in the measurement of 2,5- and 2,3-DHBA were seen from 3 to 8 min after reperfusion in each group. The group that received 100 microM MEL+ SAL had significantly reduced amounts of 2,5- and 2,3-DHBA by multiple folds, compared to the SAL group. TBARS was significantly decreased in the 100 microM MEL group (1.20+/-0.36 vs 1.85+/-0.10 micromol/g of drug-free group, p<0.001). More importantly, the 100 microM MEL group significantly recovered in LV function (LV developed pressure, +dp/dt, and -dp/dt; 63.0%, 60.3%, and 59.4% in the 100 microM MEL group; 30.2%, 29.7%, and 31.5% in the drug-free group, respectively; p<0.05). Duration of ventricular tachycardia or ventricular fibrillation significantly decreased in the 100 microM MEL group (100 microM MEL, 159+/-67 sec; drug-free, 1244+/-233 sec; p<0.05). As a result of scavenging *OH and reducing the extent of lipid peroxidation, MEL is an effective agent for protection against postischemic reperfusion injury.

Renal protective effects and the prevention of contrast-induced nephropathy by atrial natriuretic peptide.

OBJECTIVES This study was designed to examine the protective effects of atrial natriuretic peptide (ANP) on contrast-induced nephropathy (CIN) after coronary angiography. BACKGROUND Contrast-induced nephropathy is a common complication after angiography. Some studies have shown that ANP has renal protective effects, but the beneficial effects for CIN prevention remain to be clearly shown. METHODS In a prospective, controlled, randomized trial in 254 consecutive patients with serum creatinine concentrations of > or =1.3 mg/dl, patients received either ANP (0.042 microg/kg/min; ANP group, n = 126) or Ringer solution alone (control group, n = 128). Treatment of either type was initiated 4 to 6 h before angiography and continued for 48 h. RESULTS There were no significant differences in age, sex, diabetes mellitus, or baseline serum creatinine level between the 2 groups. The prevalence of CIN, defined as a 25% increase in creatinine or an increase in creatinine of > or =0.5 mg/dl from baseline within 48 h, was significantly lower in the ANP group than in the control group (3.2% vs. 11.7%, respectively; p = 0.015). Multivariate analysis revealed that the use of >155 ml of contrast medium (odds ratio: 6.89; p < 0.001) and ANP treatment (odds ratio: 0.24; p = 0.016) were significant predictors of developing CIN. The incidence of an increase in creatinine of > or =25% or of > or =0.5 mg/dl from baseline at 1 month was also significantly lower in the ANP group than in the control group (p = 0.006). CONCLUSIONS In addition to hydration, ANP administration is effective in the prevention of CIN in patients with chronic renal failure, and the effect was maintained for 1 month.

Melatonin, a pineal hormone with antioxidant property, protects against adriamycin cardiomyopathy in rats

Adriamycin (ADR) is a potent, broad-spectrum chemotherapeutic agent whose clinical use is limited by its cardiotoxicity. Since the pathogenesis of ADR-induced cardiomyopathy may involve free radicals and lipid peroxidation, the antioxidant, melatonin (MEL) may protect against toxic effects of ADR. We therefore tested this hypothesis using a rat model of ADR-induced cardiomyopathy. Sprague-Dawley rats were given ADR (cumulative dose, 15 mg/kg), MEL (cumulative dose, 84 mg/kg), ADR+MEL, ADR plus probucol (PRB, cumulative dose, 90 mg/kg), or vehicle alone, according to known regimens. The rats were maintained for 3 weeks following treatment, after which their cardiac performance was measured. Following sacrifice, their myocardial ultrastructure was examined, and their myocardial lipid peroxidation was assessed. Mortality was observed only in rats treated with ADR alone. When compared to control rats, surviving rats in the ADR group showed significant decreases in ratio of heart to body weight, arterial pressure, and left ventricular fractional shortening as well as a significant accumulation of ascites. The amount of myocardial thiobarbituric acid reactive substances was significantly higher in ADR-treated than in control rats. Both antioxidants, MEL and PRB, significantly prevented these ADR-induced changes. Electron microscopic examination revealed myocardial lesions indicative of ADR-induced cardiomyopathy in the ADR-treated rats. In contrast, treatment of these rats with MEL or PRB preserved myocardial ultrastructure. By preventing lipid peroxidation, MEL may be highly effective in protecting against ADR-induced cardiomyopathy.

Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats.

Carvedilol (CAR) is a vasodilating beta-blocker which also has antioxidant properties. CAR produces dose-related reduction in mortality in patients with congestive heart failure. In the present study, we tested the hypothesis that CAR protects against doxorubicin (DOX)-induced cardiomyopathy in rats. Sprague-Dawley rats were treated with DOX, CAR, CAR+DOX, or atenolol (ATN)+DOX. DOX (cumulative dose, 15 mg/kg) was administered intraperitoneally, and CAR (30 mg/kg daily) or ATN (150 mg/kg daily) was administered orally. Three weeks after the completion of these treatments, cardiac performance and myocardial lipid peroxidation were assessed. Mortality was observed in the DOX (25%) and ATN+DOX (12.5%) groups. Compared with control rats, DOX significantly decreased systolic blood pressure (104+/-4 vs. 120+/-4 mmHg, P<0.05) and left ventricular fractional shortening (38.8+/-3.1 vs. 55.4+/-1.3%, P<0.01), and resulted in a significant accumulation of ascites (14.4+/-4.9 vs. 0 ml, P<0.01). CAR significantly prevented the cardiomyopathic changes caused by DOX, while ATN did not. The myocardial thiobarbituric acid reactive substances (TBARS) content was significantly higher in DOX-treated rats than in control rats (80.4+/-7.1 vs. 51.5+/-1.2 nmol/g heart, p<0.01). CAR prevented the increase in TBARS content (48.8+/-3.0 nmol/g heart, P<0.01 vs. DOX group), whereas ATN had no significant effect (74.3+/-5.2 nmol/g heart). CAR also significantly prevented the increase in both myocardial and plasma cholesterol concentrations caused by DOX. These data indicate that CAR protects against DOX-induced cardiomyopathy and that this effect may be attributed to the antioxidant and lipid-lowering properties of CAR, not to its beta-blocking property.

Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease.

OBJECTIVES The purpose of this study was to investigate the effects of angiotensin II receptor blockers on the prevention of cardiovascular events in patients with coronary artery disease (CAD). BACKGROUND Angiotensin II may contribute to the pathogenesis of CAD. Long-term clinical trials have shown that blockade of the renin-angiotensin system can reduce cardiovascular events in patients with acute myocardial infarction complicated by heart failure. METHODS Patients with a history of coronary intervention and no significant coronary stenosis on follow-up angiography 6 months after intervention were randomly assigned into a candesartan group (n = 203; baseline treatment plus candesartan 4 mg/d) or a control group (n = 203; baseline treatment alone). The primary end point was a composite of revascularization, nonfatal myocardial infarction, or cardiovascular death. The secondary end point was hospitalization for cardiovascular causes. RESULTS There were no changes in blood pressure and in other coronary risk factors in either group during a mean follow-up of 24 months. Primary end point risk was significantly lower in the candesartan group (n = 12) than in control group patients (n = 25) (P =.03). Candesartan treatment reduced primary end point risk (5.9% vs 12.3% for control subjects; relative risk, 0.47; 95% CI, 0.24 to 0.93). The incidence of all events including secondary end points and noncardiovascular death was significantly lower in the candesartan group than in control group patients (23 vs 40 cases) (P =.02). CONCLUSIONS Relatively low-dose candesartan, which did not alter blood pressure levels, reduces cardiovascular risk in high-risk patients with CAD.

Zinc accumulation in adriamycin‐induced cardiomyopathy in rats: Effects of melatonin, a cardioprotective antioxidant

Abstract: We have recently reported that melatonin protects against adriamycin‐induced cardiomyopathy whose pathogenesis may involve free radicals and lipid peroxidation. Melatonin has also been shown to affect zinc turnover. Since zinc may act as an antioxidant, we investigated the role of zinc in the pathogenesis of adriamycin‐induced cardiomyopathy as well as in the treatment of melatonin against this disorder. Sprague Dawley rats were given adriamycin (cumulative dose, 15 mg/kg); melatonin (cumulative dose, 84 mg/kg); adriamycin plus melatonin; adriamycin plus probucol, another antioxidant (cumulative dose, 90 mg/kg); or vehicle alone, according to previously‐used regimens. Cardioprotective effects of both antioxidants (melatonin and probucol) were confirmed by the parameters of fractional shortening, heart weight, heart/body weight ratio, ascites volume, and mortality. Adriamycin increased both the myocardial and plasma levels of thiobarbituric acid reactive substances (TBARS) and myocardial zinc levels, and decreased plasma zinc levels. The significant negative correlation observed between the myocardial and plasma zinc levels (r =0.73, P < 0.01) among the samples of adriamycin‐treated and control rats suggested an internal redistribution of zinc. Melatonin and probucol were equally effective in inhibiting the increase in myocardial TBARS as well as zinc levels, suggesting that myocardial zinc accumulation might be a protective response against adriamycin‐induced oxidative stress. Melatonin also inhibited the adriainycin‐induced decrease in plasma zinc levels; probucol was not as effective in doing so. In addition to melatonins antioxidative effect, it may have the effect of maintaining the plasma zinc levels.

Risk stratification of patients with prior myocardial infarction and advanced left ventricular dysfunction by gated myocardial perfusion SPECT imaging

AbstractBackground. The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) has shown that the prophylactic implantable cardiac defibrillator improves the survival rate of patients with prior myocardial infarction and advanced left ventricular (LV) dysfunction. However, a more accurate noninvasive predictor should be found to identify subgroups at high risk, one that would allow implantable cardiac defibrillator therapy to be directed specifically to the patients who would benefit most. Methods and Results. To elucidate whether technetium 99m tetrofosmin electrocardiogram-gated single photon emission computed tomography (SPECT) imaging at rest can determine the risk of arrhythmic death, 106 patients who met the MADIT-II criteria (LV ejection fraction ≤0.3, myocardial infarction τ;1 month earlier, and no sustained ventricular tachyarrhythmia) were recruited from a pool of 4628 consecutive patients who had undergone resting Tc-99m tetrofosmin SPECT imaging. By use of the endpoints of lethal arrhythmic events, which included documentation of sustained ventricular tachycardia, ventricular fibrillation, or diagnosis of sudden cardiac death, we performed follow-up for a mean of 30 months. Lethal arrhythmic events occurred in 14 patients. Patients with lethal arrhythmic events had a lower LV ejection fraction, greater LV end-systolic and end-diastolic volume indices, and a greater perfusion defect volume than the remaining patients. By receiver operating characteristic curve analysis, myocardial defect volume was the strongest predictor for the development of lethal arrhythmic events. Conclusion. Our results confirm that perfusion defect volume by Tc-99m tetrofosmin scintigraphy is the most pivotal predictor of the future occurrence of lethal arrhythmic events and of sudden cardiac death. Tc-99m tetrofosmin SPECT images may assist in identifying subsets of patients with a greater likelihood of arrhythmic death among patients with LV dysfunction.

Verapamil-sensitive left anterior fascicular ventricular tachycardia associated with a healed myocardial infarction : changes in the delayed Purkinje potential during sinus rhythm

Uncommon association of left anterior fascicular ventricular tachycardia (VT) with a healed myocardial infarction (MI) is described. A 55-year-old man with a history of anteroseptal MI had verapamil-sensitive VT. The VT exhibited a right bundle branch block configuration and right-axis deviation. The VT exit was located at the left ventricular anterolateral wall. At the mid-anterior left ventricular septum, delayed Purkinje potentials were seen during sinus rhythm, and the optimal pace map was obtained with pace delay. During the VT, diastolic and systolic Purkinje potentials were simultaneously recorded at the same site. Ablation targeting the delayed potentials during sinus rhythm prolonged the time between QRS onset and the delayed potentials, and the VT no longer became inducible when the delayed potentials were completely eliminated. Left anterior fascicular VT develops in post-MI patients; ischemia-injured His-Purkinje system may be involved in the mechanism of the VT.