Tadanori Aizawa

Genetic Polymorphism of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) as a Risk Factor for Coronary Artery Disease

BACKGROUND Epidemiological studies have identified hyperhomocyst(e)inemia as an independent risk factor for coronary artery disease (CAD). Recently, the alanine/valine (A/V) polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, one of the key enzymes catalyzing remethylation of homocysteine, has been reported. The VV genotype correlates with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the distribution of the MTHFR genotypes in Japanese men and the association between the VV genotype and CAD. METHODS AND RESULTS The diagnoses of CAD of all the studied patients were confirmed by coronary angiography. The MTHFR genotype was analyzed by PCR followed by HinfI digestion. In 778 healthy male subjects, the frequency of the V allele was 0.33, comparable to that in a French Canadian population. In 362 patients with CAD, the VV genotype was significantly more frequent than in control subjects (16% versus 10%, P=.0067). The association of the VV genotype with CAD was further increased in patients with > or = 99% stenotic lesions (18%, P=.0010), whereas no significant association with the VV genotype was observed in patients without a > or = 99% stenosis. When the genotype frequency was compared among patients with different numbers of stenotic coronary arteries, the frequency of the VV genotype was significantly higher in patients with triple-vessel disease (26%) than in patients with single- or double-vessel disease (15% and 14%, respectively). CONCLUSIONS The VV genotype of MTHFR was also common in the Japanese population and was significantly associated with CAD. The frequency of this genotype in particular was correlated with the severity of disease. The VV genotype associated with a predisposition to increased plasma homocyst(e)ine levels may represent a genetic risk factor for CAD.

Noninvasive assessment of left and right ventricular filling in myocardial infarction with a two-dimensional Doppler echocardiography method

Inflow characteristics of left and right ventricular filling were assessed in 40 patients with myocardial infarction and in 10 normal subjects by pulsed Doppler echocardiography. Patients with myocardial infarction were subdivided into four groups, focusing on the involvement of right ventricular and septal branches of the coronary arteries. Group I consisted of 11 patients with anterior infarction who showed an obstructive lesion of the proximal left anterior descending branch involving the first septal perforator with a patent right coronary artery. Group II consisted of 10 patients with inferior infarction who showed an obstructive lesion of the proximal right coronary artery involving the right ventricular branch. Group III consisted of 12 patients with both anterior and inferior infarction who showed obstructive lesions of both the proximal left anterior descending branch and the right coronary artery involving the right ventricular branch. Group IV consisted of seven patients with lateral infarction who showed an obstructive lesion of the diagonal branch or branches of the circumflex coronary artery with a patent left anterior descending branch and right coronary artery. Three measurements were performed from the transmitral and transtricuspidal inflow velocity patterns to assess the left and right ventricular diastolic behaviors. These measurements were: acceleration half-time, deceleration half-time of early diastolic rapid inflow, and the ratio of the peak velocity of early diastolic rapid inflow to that of the late diastolic inflow due to the atrial contraction. Impaired diastolic filling of the left ventricle compensated by enhanced left atrial contraction was observed in patients with myocardial infarction from groups I, II, III and IV.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparisons of Baseline Demographics, Clinical Presentation, and Long-Term Outcome Among Patients With Early, Late, and Very Late Stent Thrombosis of Sirolimus-Eluting Stents Observations From the Registry of Stent Thrombosis for Review and Reevaluation (RESTART)

Background— Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence. Methods and Results— The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent–associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent–associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age <65 years. For LST versus VLST, they were hemodialysis, heart failure, insulin-dependent diabetes mellitus, and low body mass index. Patients with LST had a significantly higher rate of Thrombolysis in Myocardial Infarction grade 2/3 flow (36%) at the time of ST than those with EST (13%) (P<0.0001) and VLST (17%; P<0.0001). Mortality rate at 1 year after ST was significantly lower in patients with VLST (10.5%) compared with those with EST (22.4%; P=0.003) or LST (23.5%; P=0.009). Conclusion— ST timing–dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

Increased level of advanced oxidation protein products in patients with coronary artery disease

Witko-Sarsat et al. previously reported that advanced oxidation protein products (AOPP), which were determined by measurements of optical density (OD) at 340 nm under acidic conditions, were present at high levels in the plasma of uremic patients. We measured AOPP in the plasma of 392 patients who underwent coronary angiography because of suspected coronary artery disease (CAD) and examined the association between plasma AOPP levels and CAD. We also collected plasma from hemodialysis patients and healthy volunteers for AOPP assay. Plasma fractionation by size-exclusion chromatography was performed to determine the weights of the molecules involved in the AOPP activity. The elution patterns obtained after plasma fractionation by size-exclusion chromatography were the similar in both CAD and hemodialysis patients, but differed from those of the healthy volunteers, whose AOPP levels were low. We also found that, the severity score of CAD obtained by the Gensini scoring system had good correlation with AOPP quartiles. Multivariable regression models revealed that the plasma AOPP level was significantly related to CAD status. This is the first report of an association between AOPP and CAD. AOPP was an independent risk factor for CAD. Oxidative stress is speculated to be associated with the pathogenesis of CAD.

Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors

Objective—Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT)n repeats, short (GT)n repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD). Methods and Results—We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 577 patients who underwent coronary angiography. Because the distribution of numbers of (GT)n repeats was bimodal, we divided the alleles into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (≥27) repeats. Multivariate logistic regression models including standard coronary risk factors revealed that the genotypes were significantly related to CAD status in hypercholesterolemic, diabetic patients or in smokers. In this study, the patients with shorter GT repeats were less likely to have CAD. Conclusions—Length polymorphism in the HO-1 gene promoter is related to CAD susceptibility in Japanese people who also have coronary risk factors such as hypercholesterolemia, diabetes, and smoking. HO-1 may play an antiatherogenic role in Japanese patients with these coronary risk factors.

Impact of tranilast on restenosis after coronary angioplasty: Tranilast Restenosis Following Angioplasty Trial (TREAT)☆☆☆

BACKGROUND Tranilast is an antiallergic drug that suppresses the release of cytokines such as platelet-derived growth factor, transforming growth factor-beta1, and interleukin-1beta and prevents keloid formation after skin injury. Treatment with this drug reduced the restenosis rate after percutaneous transluminal coronary angioplasty in a preliminary study. METHODS AND RESULTS We conducted a multicenter, randomized, double-blind, placebo-controlled trial. A total of 255 patients with 289 lesions were randomly assigned to treatment with the oral administration of 600 mg/d tranilast, 300 mg/d tranilast, or a placebo for 3 months after successful angioplasty. Angiographic follow-up was done at 3 months, and a clinical follow-up examination was performed at 12 months. Two hundred ten (72.7%) lesions of 188 (73.7%) of the patients met the criteria and were eligible for the assessment of restenosis. The restenosis rates defined as >/=50% loss of the initial gain were 14.7% in the 600 mg/d tranilast group, 35.2% in the 300 mg/d tranilast group, and 46.5% in the placebo group (P <. 0001 for 600 mg/d tranilast vs placebo). The restenosis rates defined as percent diameter stenosis of >/=50% at follow-up were 17. 6% in the 600 mg/d tranilast group, 38.6% in the 300 mg/d tranilast group, and 39.4% in the placebo group (P =.005 for 600 mg/d tranilast vs placebo). CONCLUSIONS The oral administration of 600 mg/d of tranilast for 3 months markedly reduced the restenosis rate after percutaneous transluminal coronary angioplasty.

Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria

Background—Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF. Methods and Results—The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood. Conclusions—Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.

What are Arrhythmogenic Substrates in Diabetic Rat Atria

Introduction: Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated.

A new echocardiographic method for identifying vortex flow in the left ventricle: numerical validation.

A new mathematical method for estimating velocity vectors from color Doppler datasets is proposed to image blood flow dynamics; this method has been called echodynamography or vector flow mapping (VFM). In this method, the concept of stream function is exploited to expand a 2-D distribution of radial velocities in polar coordinates, observed with color Doppler, to a 2-D distribution of velocity vectors. This study was designed to validate VFM using 3-D numerical flow models. Velocity fields were reconstructed from the virtual color Doppler datasets derived from the models. VFM captured the gross features of flow structures and produced comparable images of the distribution of vorticity, which correlated significantly with the original field (for velocity magnitudes, standard error of estimate = 0.003 to 0.007 m/s; for vorticity, standard error of estimate = 0.35 to 2.01/s). VFM may be sensitive for depicting flow structures derived from color Doppler velocities with reasonable accuracy.

Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions

OBJECTIVES This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression. BACKGROUND Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis. METHODS We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test. RESULTS The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions. CONCLUSIONS Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.