Craniofacial anatomical risk factors in men with obstructive sleep apnea and heart failure: a pilot study.

PURPOSE: Obstructive sleep apnea (OSA) is complicated with heart failure (HF); however, the reason for this is not well understood. Craniofacial anatomic risk factors may contribute to OSA pathogenesis in HF patients. However, there are no data about cephalometric findings among OSA patients with HF. METHODS: Consecutive patients with HF and OSA (defined as total apnea-hypopnea index (AHI) ≥15/h) were enrolled. As controls, OSA patients without HF but matching the test group in age, BMI, and obstructive AHI were also enrolled. RESULTS: Overall, 17 OSA patients with HF and 34 OSA patients without HF were compared. There are no significant differences in the characteristics or polysomnographic parameters between 2 groups. In the cephalometric findings, compared with patients without HF, patients with HF showed a significantly greater angle between the line SN to point "A" (SNA) and a longer inferior airway space and greater airway area. However, the tongue area of patients with HF was more than those without HF. CONCLUSIONS: The craniofacial structures of OSA patients with HF were different from those without HF. OSA patients with HF had an upper airway anatomy that is more likely to collapse when sleeping while recumbent, despite having a larger airway space.

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.

Deep vein thrombosis risk stratification.

Pulmonary thromboembolism (PTE) is a life-threatening disease which always presents in patients with deep vein thrombosis (DVT). There are few statements in guidelines regarding indications for anticoagulation based on the location of DVT. We investigated whether the relative risk of PTE depends on thrombus location and bleeding complications with anticoagulation therapy. Between January 1 and July 10, 2007, 461 patients underwent lower extremity venous ultrasound studies, and 129 patients were diagnosed as DVT (60 males, 66.9 ± 13.3 years). We retrospectively studied the incidence of PTE and bleeding complications associated with anticoagulation therapy. Average follow-up period was 536 ± 324 days. Above and below knee thrombosis was present in 60 and 69 patients, respectively. Warfarin was administered in 60 patients. Nine patients developed PTE. Multivariate analysis showed the absence of anticoagulation therapy and location of DVT (above knee) to be significantly correlated with onset of PTE (anticoagulation; P < 0.01, location; P = 0.02). However, the incidence of bleeding was not significantly different between above knee and below knee vein thrombosis (P = 0.72). In conclusion, below knee vein thrombosis carries a relatively low risk of PTE, but the incidence of bleeding complications does not depend on thrombosis location. This suggests that the indication of anticoagulation therapy should be based on DVT location.

High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

BACKGROUND: The incidence of cardiac events is higher in patients with diabetes than in people without diabetes. The Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS) demonstrated significant plaque regression in Japanese patients with chronic coronary disease after 76 weeks of rosuvastatin (2.5 mg once daily, up-titrated to a maximum of 20 mg/day to achieve LDL cholesterol <80 mg/dl). METHODS: In this subanalysis of COSMOS, we examined the association between HbA1c and plaque regression in 40 patients with HbA1c ≥6.5% (high group) and 86 patients with HbA1c <6.5% (low group). RESULTS: In multivariate analyses, HbA1c and plaque volume at baseline were major determinants of plaque regression. LDL cholesterol decreased by 37% and 39% in the high and low groups, respectively, while HDL cholesterol increased by 16% and 22%, respectively. The reduction in plaque volume was significantly (p = 0.04) greater in the low group (from 71.0 ± 39.9 to 64.7 ± 34.7 mm(3)) than in the high group (from 74.3 ± 34.2 to 71.4 ± 32.3 mm(3)). Vessel volume increased in the high group but not in the low group (change from baseline: +4.2% vs -0.8%, p = 0.02). Change in plaque volume was significantly correlated with baseline HbA1c. CONCLUSIONS: Despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels compared with those with low levels. Tight glucose control during statin therapy may enhance plaque regression in patients with stable coronary disease. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT00329160.

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). CONCLUSIONS: 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.

Effects of olmesartan on blood pressure and insulin resistance in hypertensive patients with sleep-disordered breathing.

The increased risk of cardiovascular morbidity and mortality among patients with sleep-disordered breathing (SDB) has been linked to arterial hypertension and insulin resistance. However, an effective antihypertensive agent for patients with SDB has not been identified. We investigated the effect of the angiotensin II subtype 1 receptor blocker olmesartan in hypertensive patients with SDB. This prospective, one-arm pilot study included 25 male patients with untreated SDB (mean age, 52.7 ± 11.4 years). We measured blood pressure, oxygen desaturation index (ODI), cardiac function using echocardiography, and insulin resistance using the homeostasis model assessment (HOMA) before and after 12 weeks of olmesartan therapy (mean dose, 17.6 ± 4.4 mg/day). Olmesartan significantly decreased systolic blood pressure (151.4 ± 8.0 vs. 134.0 ± 7.4 mmHg; P < 0.001), diastolic blood pressure (93.4 ± 7.1 vs. 83.9 ± 6.3 mmHg; P < 0.001), and HOMA index (3.7 ± 2.9 vs. 2.8 ± 1.9; P = 0.012). Furthermore, left ventricular ejection fraction significantly increased at 12 weeks (68.1 ± 5.1 vs. 71.6 ± 5.4%; P = 0.009). However, body mass index (BMI) and degree of SDB did not change (BMI, 26.6 ± 4.0 vs. 26.6 ± 4.2 kg/m2, P = 0.129; 3% ODI, 29.5 ± 23.1 vs. 28.2 ± 21.0 events/h, P = 0.394). Olmesartan significantly reduced blood pressure and insulin resistance in hypertensive patients with SDB without changing BMI or SDB severity.

Hypoplasia of abdominal wall muscles following massive fetal persistent chylous ascites without anemia.

Abdominal wall hypoplasia is a widely known clinical finding of genetic disorders such as the prune belly syndrome. On the other hand, there are few cases of abdominal wall muscle hypoplasia associated with fetal ascites due to fetal hydrops caused by fetal anemia have been reported. We report a case of fetal chylous ascites without anemia, resulting in abdominal wall muscle hypoplasia and flabby skin. At 17 weeks of gestation, fetal ascites was first detected and deteriorated without anemia. At 28, 33 and 36 weeks of gestation, paracentesis was performed three times because of cardiovascular impairment, confirming chylous ascites. After birth, the baby exhibited a flabby skin and lateral abdominal wall hypoplasia, resulting in difficulties in maintaining a sitting posture at 10 months of age. The genetic test using the TruSight One Sequencing Panels found no genetic variants. This case suggests that abdominal wall hypoplasia could be associated with fetal ascites without anemia.

Diabetes mellitus is a major negative determinant of coronary plaque regression during statin therapy in patients with acute coronary syndrome--serial intravascular ultrasound observations from the Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome Trial (the JAPAN-ACS Trial).

BACKGROUND: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial has found that early aggressive statin therapy in patients with acute coronary syndrome (ACS) significantly reduces the plaque volume (PV) of non-culprit coronary lesions. The purpose of the present study was to evaluate clinical factors that have an impact on plaque regression using statin therapy. METHODS AND RESULTS: Serial intravascular ultrasound observations over 8-12 months were performed in 252 ACS patients receiving pitavastatin or atorvastatin. Linear regression analysis identified the presence of diabetes mellitus (DM) and PV at baseline as inhibiting factors, and serum remnant-like particle-cholesterol level at baseline as a significant factor significantly affecting the degree of plaque regression. Significant correlation between % change of PV and low-density lipoprotein cholesterol (LDL-C) level was found in patients with DM (n=73, P<0.05, r=0.4), whereas there was no significant correlation between the 2 parameters in patients without DM (n=178). CONCLUSIONS: The regression of coronary plaque induced by statin therapy after ACS was weaker in diabetic patients than their counterparts. Moreover, vigorous reduction of the LDL-C levels might induce a greater degree of plaque regression in ACS patients with DM.

Immobilization of Pseudomonas cepacia lipase onto electrospun polyacrylonitrile fibers through physical adsorption and application to transesterification in nonaqueous solvent.

The lipase of Pseudomonas cepacia was immobilized onto electrospun polyacrylonitrile (PAN) fibers and used for the conversion of (S)-glycidol with vinyl n-butyrate to glycidyl n-butyrate in isooctane. The rate of reaction with the adsorbed lipase was 23-fold higher than the initial material. After 10 recyclings, the initial reaction rate was 80% of the original rate. This system of enzyme immobilization is therefore suitable for carrying out transesterification reactions in nonaqueous solvents.

Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

BACKGROUND: It has been suggested that intensive lipid-lowering therapy using statins significantly decreases atheromatous plaque volume. The effect of rosuvastatin on plaque volume in patients with stable coronary artery disease (CAD), including those receiving prior lipid-lowering therapy, was examined in the present study. METHODS AND RESULTS: A 76-week open-label trial was performed at 37 centers in Japan. Eligible patients began treatment with rosuvastatin 2.5 mg/day, which could be increased at 4-week intervals to

Safety and feasibility of an intravascular optical coherence tomography image wire system in the clinical setting.

Optical coherence tomography (OCT) is a fiber-optic technology that enables high-resolution intracoronary imaging. The aim of this study was to evaluate the safety and feasibility of intracoronary imaging with OCT in the clinical setting; 76 patients with coronary artery disease from 8 centers were enrolled. The OCT imaging system (ImageWire, Light Imaging Inc., Westford, Massachusetts) consists of a 0.006 inch fiber-optic core that rotates within a 0.016 inch transparent sheath. OCT imaging was performed during occlusion of the artery with a compliant balloon and continuous flushing. Intravascular ultrasound (IVUS) imaging was performed in the same segments. We assessed the safety and feasibility of the OCT imaging, compared with IVUS. Vessel occlusion time was 48.3 +/- 13.5 seconds and occlusion-balloon pressure was 0.4 +/- 0.1 atmospheres. Flushing with lactated Ringer's solution was performed at a rate of 0.6 +/- 0.4 ml/s. No significant adverse events, including vessel dissection or fatal arrhythmia, were observed. Procedural success rates were 97.3% by OCT and 94.5% by IVUS. The OCT image wire was able to cross 5 of 6 tight lesions that the IVUS catheter was unable to cross. Of the 98 lesions in which both OCT and IVUS were successfully performed, OCT imaging had an advantage over IVUS for visualization of the lumen border. Minimum lumen diameter and area measurements were significantly correlated between OCT and IVUS imaging (r = 0.91, p <0.0001 and r = 0.95, p <0.0001, respectively). In conclusion, this multicenter study demonstrates the safety and feasibility of OCT imaging in the clinical setting.

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.

[Definition and pathophysiology of acute coronary syndrome].

Acute coronary syndrome is a clinical state induced by the thrombosis following the rupture of unstable atherosclerotic plaque. Atherosclerotic plaque increases its vulnerability by the accumulation of foam cells, inflammation, oxidative stress, and apoptosis of vascular wall cells including macrophage. Inflammation and oxidative stress stimulates macrophages to produce matrix metalloproteinase (MMP), which degrades extracellular matric proteins and causes thinning of the fibrous cap. When the fibrous cap of the plaque tears, thrombogenic lipid core is exposed to blood, and platelets accumulate at the site, resulting in the significant reduction of coronary blood flow. Treatment of acute coronary syndrome patients should be focused on the stabilization of the plaque as well as vasodilatation, oxygen supply, or control of hemodynamics.

Prevalence and distribution of coronary calcium in asymptomatic Japanese subjects in lung cancer screening computed tomography.

BACKGROUND: Coronary artery calcium (CAC) is associated with a risk of coronary heart disease. The prevalence and distribution of the CAC score have been examined in Western countries, but few studies have been performed in Asia, and especially in Japan. The goal of this study was to investigate CAC scores in an asymptomatic Japanese population. METHODS: CAC score and risk factors were analyzed in 1834 asymptomatic subjects who underwent lung cancer screening computed tomography. RESULTS: CAC was present in 26.9% of all the subjects, 29.8% of the males, and 17.1% of the females. In all age groups, the CAC score was higher in males. In multivariate analysis, male gender [odds ratio (OR) 2.461, 95% confidence interval (CI) 1.361-4.452, p=0.002], aging (OR 1.102, 95% CI 1.081-1.123, p<0.001), dyslipidemia (OR 1.740, 95% CI 1.216-2.490, p=0.002), and fasting glucose (OR 1.008, 95% CI 1.002-1.015, p=0.012) were significantly associated with a CAC score >100. CONCLUSION: The results of this study provide a pattern of CAC distribution based on age and gender in asymptomatic Japanese subjects. This pattern was similar to that in Western countries, although the absolute CAC scores were lower. High CAC scores were associated with male gender, aging, dyslipidemia, and fasting glucose.

Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury.

BACKGROUND: Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (IRS-1-/-) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2-/-) mice showed insulin resistance with type 2 diabetes. METHODS AND RESULTS: We investigated neointima formation in the IRS-1-/- and IRS-2-/- mice at 8 and 20 weeks. The IRS-2-/- mice showed much greater neointima formation than the IRS-1-/- and wild-type mice at 8 weeks. At 20 weeks, the IRS-2-/- mice had greater neointima formation than the IRS-1-/- mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1-/- and IRS-2-/- mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2-/- mice had more metabolic abnormalities than the IRS-1-/- mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels. CONCLUSIONS: The neointima formation in the IRS-1-/- and IRS-2-/- mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2-/- mice than in the IRS-1-/- mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.

Chlamydia pneumoniae immunoreactivity in coronary artery plaques of patients with acute coronary syndromes and its relation with serology.

BACKGROUND: An association between Chlamydia pneumoniae (Cpn) infection and coronary artery disease has been reported and examined by different techniques. However, its immunoreactivity in coronary artery plaques of patients with acute coronary syndrome (ACS) and its relation with serology are less well defined. METHODS: We divided 40 coronary plaque specimens from 40 patients who underwent thrombectomy or directional coronary atherectomy into an ACS group (n = 22) and a non-ACS group (n = 18). Cpn in specimens was detected immunohistochemically and compared quantitatively. Serum immunoglobulin (Ig)A and IgG antibodies to Cpn and high-sensitivity C-reactive protein (hs-CRP) were measured. The relation between serology and immunohistochemical analysis was also investigated. RESULTS: Cpn immunopositive cells per square millimeter (Cpn+ cells/mm2) in the ACS group were significantly more numerous than in the non-ACS group (median 7.44 vs 1.50, P = .0018). Cpn IgA seropositivity rates and titers in the ACS group were significantly higher than those in the non-ACS group (86.3% vs 22.2%, P = .0002; median titer 1.403 vs 0.545, P = .003). There were no differences in IgG antibodies between the 2 groups. The hs-CRP values (in milligrams per liter) in ACS group were significantly higher than in non-ACS group (median 2.8 vs 1.2, P = .0019). Serum IgA titers in patients with at least 5 Cpn+ cells/mm2 in the specimens were significantly higher than in patients with fewer Cpn+ cells (median 1.52 vs 0.86, P = .026). There was no difference in serum hs-CRP values in patients with more Cpn+ cells but a trend to an increase. CONCLUSION: Immunohistology frequently detected Cpn in coronary plaques; Cpn+ cells were more prevalent in plaques associated with ACS, and Cpn IgA but not IgG titers were increased with ACS and with high densities of Cpn+ cells within plaque.

Randomized, Double-Blind, Dose-Finding, Phase II Study of Prasugrel in Japanese Patients Undergoing Elective Percutaneous Coronary Intervention.

AIM: Prasugrel is a novel platelet P2Y12 receptor blocker with a faster onset of action and greater platelet inhibition with less response variability than clopidogrel. Our objective was to determine the optimal prasugrel dose in Japanese patients undergoing elective percutaneous coronary intervention (PCI) with respect to the incidence of bleeding and platelet inhibition. METHODS: A total of 422 patients were randomly assigned to receive clopidogrel or prasugrel in two strata (standard group: ＜75 years of age and body weight ＞50 kg, n=312; high-risk group: ≥75 years of age and/or body weight ≤50 kg, n=110). The standard group received 20/3.75 or 20/5mg (loading/maintenance doses for three months) of prasugrel or 300/75mg of clopidogrel, while the high-risk group received 20/2.5 or 20/3.75mg of prasugrel or 300/75mg of clopidogrel. RESULTS: The rates of TIMI major and minor bleeding (primary endpoint) were similar among the three treatment arms in the standard group (20/5mg of prasugrel: 0%; 20/3.75mg of prasugrel: 3.8%; 300/75mg of clopidogrel: 2.9%) and the high-risk group (20/3.75mg of prasugrel: 2.7%; 20/2.5mg of prasugrel: 0%; 300/75mg of clopidogrel: 2.8%). VerifyNow assays revealed sufficient levels of platelet inhibition at Weeks 4 and 12 in both the prasugrel arms of the standard group and the 20/3.75mg of prasugrel arm in the high-risk group. Platelet inhibition was not affected by the CYP2C19 phenotype in the prasugrel groups. CONCLUSIONS: The prasugrel dosing regimen of 20/3.75mg has strong antiplatelet effects and the risk of bleeding events is low in Japanese patients undergoing PCI.

Characteristics and trends of POBA in current DES Era.

The aim of this study is to clarify the characteristics and trends of POBA in current drug-eluting stent (DES) era. We examined retrospectively the cases of POBA performed in our institute during the years from 2008 to 2012. For control, bare metal stents (BMS) and DES implantation done in 2011 were analyzed. During the period, 85 cases of POBA, 63 BMS and 132 DES were identified. In the result, the rate of restenosis in POBA was significantly higher than BMS and DES (39.7, 14.9, 3.7%, POBA, BMS, DES, respectively, p < 0.001). We assumed three categories depending on the reasons for selecting POBA. (1) Stent delivery failure or expected difficulty of stent delivery due to calcification, etc. (n = 14), (2) intervention for in-stent restenosis or stent thrombosis (n = 34), (3) successful POBA applied to small vessels without complication (n = 14). According to it, category 1 showed significantly high probability of restenosis compared with others [(1) 10/14, 71.4%, (2) 12/34, 35.3%, 3; 2/14, 14.3%, p < 0.05]. In addition, category 3 showed nearly as good as BMS. Balloons used in POBA contained 32 non-compliant balloons and 14 scoring balloons, whereas 30 were semi-compliant balloons only. ACC/AHA lesion type B2/C was 85.7, 45.7 and 50.0%, and cases treated only with semi-compliant balloon were 57.1, 14.3, 92.9% (category (1), (2) and (3), respectively, both p < 0.05). Therefore, this fact shows that a case of small vessel of which diameter is less than 2.5 mm would have a favorable outcome with POBA when treated well only with semi-compliant balloon under the current DES era.