Junichiro Kondo

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.

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.

Relation of a Common Methylenetetrahydrofolate Reductase Mutation and Plasma Homocysteine With Intimal Hyperplasia After Coronary Stenting

BackgroundHyperhomocysteinemia has been identified as an independent risk factor for coronary artery disease. Recent studies have shown that a common mutation (nucleotide 677 C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to mild hyperhomocysteinemia and, therefore, to the incidence of coronary artery disease. No information exists, however, regarding the association between the mutation of the MTHFR gene or plasma homocysteine levels and morphological analysis of coronary atherosclerosis using intravascular ultrasound. Methods and ResultsTo examine the potential influence of MTHFR genotype and homocysteine on coronary arteries morphologically, we screened 62 patients with 65 lesions that were treated with 93 Palmaz-Schatz stents. The plasma homocysteine levels in the patients with the TT genotype were not significantly higher than those in the patients with non-TT (CC+CT) genotypes (13.1±5.5 versus 11.5±3.1 mmol/L, P =0.16). Angiographic analysis showed that the percent diameter stenosis in the patients with the TT genotype was significantly greater than that in those with non-TT genotypes (43.7±17.8% versus 29.0±22.0%, P =0.015). Intravascular ultrasound analysis showed that the TT genotype was significantly associated with greater intimal hyperplasia area (5.70±1.94 versus 3.72±1.38 mm2, P =0.001). In multiple stepwise regression analysis, the number of the T alleles was the only independent predictor of intimal hyperplasia after intervention (r2=0.21, P =0.004). ConclusionsThe homozygous mutant genotype of the MTHFR gene may increase the risk of in-stent restenosis more than does the normal homozygous or heterozygous genotype.

The Glu298Asp polymorphism in endothelial nitric oxide synthase gene is associated with coronary in-stent restenosis

BACKGROUND Reduced or impaired synthesis of nitric oxide promotes the proliferation of vascular smooth muscle cells, and thus may induce the neointimal formation leading to coronary in-stent restenosis. Recent reports have suggested that the Glu298Asp polymorphism in exon 7 of the endothelial nitric oxide synthase gene is associated with coronary spasm and acute myocardial infarction. In this study, we have examined the implication of this polymorphism with regard to coronary restenosis after Palmaz-Schatz stent deployment. METHODS Eighty-nine lesions in 85 consecutive patients were treated with Palmaz-Schatz stents, and were prospectively followed up for 6 months. The lesions were classified into a restenosis group (% diameter stenosis=50%) and a non-restenosis group. Assessment was made using an automated quantitative angiographic system. We performed polymerase chain reaction-restriction fragment length polymorphism analysis to detect the missense Glu298Asp variant in exon 7 of the endothelial nitric oxide synthase gene. RESULTS Coronary risk factors and angiographic findings of stenotic lesions did not differ between the groups. Univariate analyses showed that the missense Glu298Asp variant was the only statistically significant predictor of restenosis (odds ratio, 4.27; P=0.025). In addition, multiple logistic regression analysis revealed the missense Glu298Asp variant as the only independent predictor for in-stent restenosis (odds ratio, 3.90; P=0.036). CONCLUSIONS The missense Glu298Asp variant may be an independent risk factor for in-stent restenosis.

Effect of quinapril on intimal hyperplasia after coronary stenting as assessed by intravascular ultrasound

We studied whether angiotensin-converting enzyme inhibition with quinapril treatment can prevent in-stent restenosis after successful implantation of Palmaz-Schatz stents. Intravascular ultrasound study, but not quantitative coronary angiography analysis, revealed that quinapril treatment significantly prevented the loss of both minimal lumen cross-sectional area and lumen volume in stents, in addition to reducing the increase in intimal hyperplasia volume.

Decreased 1,2-diacylglycerol levels in myopathic hamster hearts during the development of heart failure

1,2-Diacylglycerol is believed to play an important role in cellular functions through protein kinase C activation, although its role in cardiac functions remains largely unexplored. We determined the level of 1,2-diacylglycerol and its fatty acid composition in heart tissues from Syrian hamsters with hereditary cardiomyopathy (BIO 14.6 strain) during the development of congestive heart failure from 90 days to 240 days of age. The myopathic hamsters had lower contents of triglyceride and of the major phospholipids, phosphatidylcholine, phosphatidylethanolamine and cardiolipin, in the myocardium when compared to normal hamsters, whereas there was no difference in the cholesterol content. No difference in the myocardial 1,2-diacylglycerol content was observed at 90 days of age. On the other hand, 1,2-diacylglycerol contents in myopathic hearts at 160 and 240 days of age were significantly lower by 21% and 52%, respectively, then in age-matched normal hamsters. The oldest hamsters (240-day-old) showed reduced 1,2-diacylglycerol levels in both groups despite an age-related increase in most lipids. The 1,2-diacylglycerol fatty acid composition profile was found to be different from that of other lipids, and there were several differences in the fatty acid composition of 1,2-diacylglycerol between the two groups at 240 days of age. These results indicate that decreased levels of 1,2-diacylglycerol occur concomitantly with congestive heart failure in the myopathic hamsters.

1,2-diacylglycerol content in thoracic aorta of spontaneously hypertensive rats.

Phosphoinositide metabolism participates in the control of cell calcium homeostasis. Because a notable neutral lipid (1,2-diacylglycerol) is generated from phosphoinositide hydrolysis and is assumed to be a secondary messenger, we determined 1,2-diacylglycerol content and its fatty acid profiles in the thoracic aorta of spontaneously hypertensive rats (SHR) and compared it with those of normotensive Wistar-Kyoto (WKY) rats. After the aorta was exposed to 10(-5) M norepinephrine as a stimulant, 1,2-diacylglycerol content in SHR was significantly higher by 33% than in WKY rats at 4 weeks of age, whereas there was no difference in 1,2-diacylglycerol content between the two strains at 20 weeks of age. Before norepinephrine stimulation, there was no significant difference in 1,2-diacylglycerol level between the two strains at 4 weeks of age. Analysis on a gas chromatograph showed that 1,2-diacylglycerol was composed of similar molecular species of fatty acids in aortas obtained from SHR and WKY rats. On the other hand, the cholesterol content of aortas was higher in SHR than in WKY rats at 20 weeks of age, whereas the difference at 4 weeks was not significant. Phosphatidylcholine, phosphatidylethanolamine, and triglyceride showed no significant difference between the two strains. It is concluded that norepinephrine-induced 1,2-diacylglycerol production increases in the thoracic aorta of SHR before the development of hypertension.

1,2-Diacylglycerol Content and Its Fatty Acid Composition in Thoracic Aorta of Diabetic Rats

These experiments were conducted to determine 1,2-diacylglycerol (DAG) in the thoracic aorta obtained from streptozocin-induced diabetic rats because 1,2-DAG is assumed to be a second messenger associated with phosphoinositide metabolism. After preincubation for a 25-min stabilization, 1,2-DAG content in isolated thoracic aortas 4 and 8 wk after streptozocin injection was significantly decreased by 42 and 31%, respectively, compared with age-matched control rats on 10-min norepinephrine stimulation (10−5 M). However, 4 wk of daily insulin injection after 4 wk of untreated diabetes significantly shifted 1,2-DAG toward normal levels. Analysis of its fatty acid composition showed a significant difference between control and diabetic rat aortas at both 4 and 8 wk. In particular, the percentage of arachidonate, a precursor of eicosanoids, decreased. Such alteration in the fatty acid profile in diabetic rat aortas was inhibited by insulin treatment. 1,2-DAG content in the 8-wk diabetic group was also significantly decreased by 33% compared with control in the absence of norepinephrine, whereas 1,2-DAG content was lower than in the presence of norepinephrine in both the control and diabetic groups. Cholesterol, triglyceride, and phosphatidylcholine content in diabetic rat aortas was lower than control. Lower levels of 1,2-DAG in the thoracic aorta from diabetic rats were observed in the presence and absence of norepinephrine, suggesting that a defect in 1,2-DAG production may be associated with abnormalities of vascular smooth muscle responsiveness by agonists, as described previously.

Increased 1,2-diacylglycerol content in myopathic hamster hearts at a prenecrotic stage

1,2-Diacylglycerol (DAG) has been suggested to be a secondary messenger. In this study, we determined the amount of 1,2-DAG in heart tissue from Syrian hamsters with hereditary cardiomyopathy at 30 days (prenecrotic stage) and 90 days of age by thin-layer chromatography with flame ionization detection (TLC-FID). Myocardial triglyceride contents were higher at 30 days of age and lower at 90 days of age compared to the levels in age-matched normal hamsters. Decreases in major species of phospholipids in hearts were observed only at 90 days of age. However, elevated 1,2-DAG content in myopathic hearts was found at 30 days of age, whereas there was no difference between the two groups at 90 days of age. It is suggested that the increase in 1,2-DAG at the prenecrotic stage is involved in the pathogenesis of the cardiomyopathy.