Sugao Ishiwata

Prognosis of Patients With Heart Failure and Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure

BACKGROUND Therapy with continuous positive airway pressure (CPAP) provides several benefits for patients with heart failure (HF) complicated by obstructive sleep apnea (OSA). However, the effect on the prognosis of such patients remains unknown. AIMS To determine whether CPAP therapy and compliance affects the prognosis of HF patients with OSA. METHODS We classified 88 patients with HF and moderate-to-severe OSA into a CPAP-treated group (n = 65) and an untreated group (n = 23), and then those treated with CPAP were further subclassified according to CPAP therapy compliance. The frequency of death and hospitalization was analyzed using multivariate analysis. RESULTS During a mean (+/- SD) period of 25.3 +/- 15.3 months, 44.3% of the patients died or were hospitalized. Multivariate analysis showed that the risk for death and hospitalization was increased in the untreated group (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.07 to 3.68; p = 0.030) and in less compliant CPAP-treated patients (HR, 4.02; 95% CI, 1.33 to 12.2; p = 0.014). CONCLUSION Therapy with CPAP significantly reduced the risk of death and hospitalization among patients with HF and OSA. However, reduced compliance with CPAP therapy was significantly associated with an increased risk of death and hospitalization.

Redifferentiation of Smooth Muscle Cells After Coronary Angioplasty Determined via Myosin Heavy Chain Expression

BACKGROUND The pathophysiology of phenotypic modulation of smooth muscle cells (SMCs) involved in restenosis after angioplasty is not well understood. Smooth muscle myosin heavy chain (SM MHC) isoforms (SM1 and SM2) are specific markers for SMC differentiation. In particular, SM2 is useful as a marker of mature SMCs. SMemb is a nonmuscle myosin heavy chain (NM MHC) whose expression is upregulated in immature or activated SMC. METHODS AND RESULTS To determine SMC phenotypes in neointimal tissues after percutaneous transluminal coronary angioplasty (PTCA), we performed immunohistochemistry on human coronary arteries with antibodies against alpha-SM actin, SM1, SM2, and SMemb. Tissues were obtained from six autopsied patients and from atherectomy specimens from 16 patients who had undergone PTCA. Medial SMCs were positive for alpha-actin, SM1, and SM2. Expression of SM1 and SM2 in the neointima varied with the time after intervention, whereas alpha-actin was constitutively expressed in all cases studied. Neointimal cells at 16 and 20 days after PTCA contained alpha-actin but little or no SM1 or SM2, indicating that these cells modulated their phenotype to the immature state. Neointimal SMCs recovered SM MHC expression, first SM1 and then SM2, by 6 months after PTCA. Increased expression of SMemb was found in the neointima but without apparent relationship to the time after PTCA. CONCLUSIONS Neointimal SMCs show features of an undifferentiated state, indicated by altered expression of SM MHC, and undergo redifferentiation in a time-dependent manner. The expression of SM MHC isoforms provides insight into the biology of healing after angioplasty and furnishes useful tools for the understanding of the roles of differentiation and phenotypic modulation of SMCs in human vascular lesions.

Postangioplasty restenosis: Platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis

We investigated the relationship between changes in hemostatic factors and postangioplasty restenosis by evaluating plasma levels of P-selectin, beta-thromboglobulin (BTG), and other markers of the coagulation-fibrinolysis system. Seventy-three consecutive patients (56 men and 17 women) undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were enrolled in this study. Patients with acute myocardial infarction within the previous month, unstable angina pectoris, chronic total occlusion, target lesions involving saphenous vein grafts, or coronary artery bypass grafting within the previous 6 months were excluded. Fasting blood samples were obtained before elective PTCA and at follow-up coronary angiography. In patients with restenosis, plasminogen activator inhibitor type-1 (PAI-1) levels were significantly higher (88.2 +/- 36.1 vs 118.5 +/- 50.0 ng/dl; p< 0.05) and plasmin-plasmin inhibitor complex (PIC) levels were significantly lower (0.76 +/- 0.26 vs 0.61 +/- 0.26 microg/ml; p < 0.02) than at baseline. P-Selectin levels were also significantly higher (192 +/- 68 vs 239 +/- 99 ng/ dl; p<0.01) and a positive correlation existed between P-selectin and BTG levels (r= 0.43; p< 0.05). The higher PAI-1 and lower PIC levels in patients with postangioplasty restenosis suggest that impaired fibrinolysis may play a role in the pathogenesis of restenosis, whereas the positive correlation between P-selectin and BTG levels implies a role for activated platelets in restenosis.

Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS)

Twenty-five heterozygous familial hypercholesterolemic patients treated with LDL-apheresis and drugs and 11 patients treated with drugs underwent follow-up angiography 2.3 years later. One-hundred thirteen lesions were measured by quantitative angiography. Mean LDL-cholesterol levels during the trial were 140 +/- 34 mg/dl in the apheresis group and 170 +/- 58 mg/dl (P < 0.05) in the control group. The mean changes in minimal lumen diameter of lesions were +0.19 +/- 0.30 mm (improved) in the apheresis group (n = 76) and -0.44 +/- 0.40 mm (worsened) in the control group (n = 37) (P < 0.0001). When progression and regression were defined as a change in minimal lumen diameter of +/- 0.67 mm, in the apheresis group, two (8%) patients had progression, 19 (76%) stayed unchanged and four (16%) had regression, but in the control group seven (64%) patients had progression and four (36%) stayed unchanged. The frequency of regression or no change was significantly higher in the apheresis group than in the control group (P < 0.004). Intensive cholesterol lowering therapy with LDL-apheresis and lipid lowering drugs can achieve a substantial decrease in LDL-cholesterol levels to induce regression of coronary lesions in familial hypercholesterolemic patients with advanced coronary artery disease.

Prevention of restenosis after percutaneous transluminal coronary angioplasty by reducing lipoprotein (a) levels with low-density lipoprotein apheresis

This study was designed to test the hypothesis that high plasma lipoprotein (a) (Lp[a]) levels are associated with an increase incidence of restenosis after angioplasty. Elective transluminal coronary angioplasty was performed in 66 patients (58 men and 8 women) aged 57 +/- 9 years (mean +/- SD). Two days before and 5 days after angioplasty, all patients underwent low-density lipoprotein (LDL) apheresis with a dextran sulfate cellulose column as an Lp(a) absorbent; 39 patients also received 10 mg of pravastatin and 1,500 mg of niacin daily. Restenosis was defined as a recurrent luminal stenosis of > or = 50% in a previously dilated segment. Median Lp(a) levels were reduced from 23.3 mg/dl before apheresis to 10.9 mg/dl after apheresis (p < 0.0001). Angiography performed 2 to 9 months after angioplasty revealed restenosis in at least 1 site in 38% of the 137 control patients and in 32% of the 66 patients who underwent apheresis. Restenosis also occurred in 37% of the patients who underwent apheresis alone and in 28% of the patients who also received pravastatin and niacin in combination with LDL apheresis. The restenosis rate was 21% in the 42 patients whose Lp(a) levels were significantly reduced > or = 50%, and in 50% of the 24 patients whose Lp(a) levels were significantly reduced < 50% (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Pentraxin3 and Arterial Stiffness in Men With Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea (OSA) induces inflammation and vascular damage that might contribute to an increased risk of cardiovascular disease (CVD). However, the mechanisms linking OSA and CVD are not fully understood. Pentraxin3 may play a significant role in vascular inflammation and damage. Currently, there is lack of data on pentraxin3 and its role in vascular damage associated with OSA. METHODS We enrolled 50 males with OSA and 25 controls matched for age and body mass index (BMI). Patients with OSA were further divided into mild and moderate to severe groups. We measured plasma pentraxin3 and evaluated vascular damage using an arterial stiffness parameter--the cardio-ankle vascular index (CAVI)--in all subjects. In the moderate to severe OSA group, pentraxin3 and CAVI were repeatedly measured following continuous positive airway pressure (CPAP) therapy for 1 month. RESULTS Pentraxin3 levels in the moderate-to-severe OSA group were significantly higher than those in the mild OSA and control groups, with median levels (25th-75th percentile) of 2.36 (1.79-2.78), 1.63 (1.15-2.05), and 1.53 (1.14-2.04) ng/ml, respectively (P < 0.01). Pentraxin3 level was independently correlated with CAVI (coefficient, 0.34 P < 0.01). In the moderate-to-severe OSA group, pentraxin3 and CAVI levels were significantly reduced (P < 0.01 and P = 0.04, respectively) after 1 month of CPAP therapy. CONCLUSIONS Plasma pentraxin3 and arterial stiffness levels in the moderate-to-severe OSA group were greater than the corresponding levels in patients without OSA. However, pentraxin3 level can be managed by CPAP therapy for OSA.

Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART])

To address the issue of whether probucol reduces clinical events after percutaneous transluminal coronary angioplasty (PTCA), we surveyed clinical status at 1 year after PTCA of 101 patients who had entered the Probucol Restenosis Angioplasty Trial. Repeat angioplasty at index lesions were required in 5 patients in the probucol group and in 12 in the control group, suggesting that probucol administered beginning 4 weeks before PTCA reduces repeat revascularization rates for 1 year.

Expression of Costimulatory Molecules B7–1, B7–2, and CD40 in the Heart of Patients With Acute Myocarditis and Dilated Cardiomyopathy

BACKGROUND In patients with acute myocarditis and dilated cardiomyopathy (DCM), we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the myocardial damage involved. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive a costimulatory signal provided by costimulatory molecules expressed on antigen-presenting cells (APCs) as well as the main signal provided by binding of T-cell receptors to the antigen. METHODS AND RESULTS To investigate the roles of the costimulatory molecules B7-1, B7-2, and CD40 in the development of acute myocarditis and DCM, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and DCM. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, because both killer lymphocytes are thought to damage B7-1-expressing APCs. We found that B7-1, B7-2, and CD40 were moderately to strongly expressed in the cardiac myocytes of patients with acute myocarditis. Weak to moderate expression of these antigens was also found in the cardiac myocytes of patients with DCM. There was infiltration of perforin-expressing CTLs and NK cells in the myocardial tissues of patients with acute myocarditis and DCM. CONCLUSIONS Our findings strongly suggest that expression of B7-1, B7-2, and CD40 antigens on cardiac myocytes may make them APCs for CTLs and NK cells and that they may play an important role in the direct myocardial damage by these killer cells in acute myocarditis and DCM.

Establishment of the Cardio-Ankle Vascular Index in Patients With Obstructive Sleep Apnea

BACKGROUND An arterial stiffness parameter, the cardio-ankle vascular index (CAVI), has been developed. CAVI is adjusted for BP and can be used to measure arterial stiffness with little influence of BP. The purpose of this study was to evaluate the reproducibility, validity, and clinical usefulness of CAVI among patients with obstructive sleep apnea (OSA), who often have elevated BP during measurement. METHODS Overall, 543 consecutive patients with OSA were studied. CAVI was automatically calculated from the pulse volume record, BP, and the vascular length from the heart to the ankle. First, CAVI was measured three times on different days in 25 patients to evaluate its reproducibility. Second, the correlation between CAVI and BP was assessed. Third, patients were classified into two groups (mild OSA or moderate-to-severe OSA), and the CAVIs of these groups were compared. Fourth, the correlation between CAVI and carotid intima-media thickness (IMT) was also assessed in 74 patients. RESULTS The mean coefficient of variation was 2.8. CAVI demonstrated weak or no correlations with BP (with systolic BP, r = 0.184; with diastolic BP, r = 0.223). Patients with moderate-to-severe OSA (n = 469) had a significantly greater CAVI than patients with mild OSA (p = 0.034). CAVI was positively correlated with IMT (r = 0.487). CONCLUSIONS The measurement of CAVI demonstrated good reproducibility and was not affected by the BP during measurement. Additionally, CAVI was positively correlated with another arteriosclerosis indicator. CAVI was higher in patients with more severe OSA and is regarded as a clinically useful index for the progression of vascular damage.

Relationship between atrial conduction delay and obstructive sleep apnea

Prolonged P-wave duration, indicating atrial conduction delay, is a marker of left atrial abnormality and is reported as a potent precursor of atrial fibrillation (AF). Several studies have shown that obstructive sleep apnea (OSA) is associated with AF. We evaluated the relationship between OSA and prolonged P-wave duration. Consecutive subjects who underwent overnight polysomnography and showed a normal sinus rhythm, had no history of AF or ischemic heart disease, and showed no evidence of heart failure were enrolled. Apnea–hypopnea index (AHI) is defined as the number of apnea and hypopnea events per hour of sleep. P-wave duration was determined on the basis of the mean duration of three consecutive beats in lead II from a digitally stored electrocardiogram. A total of 250 subjects (middle-aged, predominantly male, mildly obese, with a mean P-wave duration of 106 ms) were enrolled. In addition to age, male gender, body mass index (BMI), hypertension, dyslipidemia, and uric acid and creatinine levels, AHI (r = 0.56; P < 0.001) had significant univariable relationship with P-wave duration. Multivariate regression analysis showed that age, BMI, male gender, and AHI (partial correlation coefficient, 0.47; P < 0.001) were significantly independently correlated to P-wave duration. Severity of OSA is significantly associated with delayed atrial conduction time. Obstructive sleep apnea may lead to progression of atrial remodeling as an AF substrate.