Analysis of bioMARKer Distribution and Individual Reproducibility Under Rivaroxaban Treatment in Japanese Patients with Non-Valvular Atrial Fibrillation (R-MARK Study, CVI ARO2).

The "on-therapy range" of direct oral anticoagulants is the 90% interval of drug concentration. Previously, we reported the on-therapy range of rivaroxaban in a single-center cohort. The present study aimed to confirm the range and intraindividual reproducibility in a multicenter cohort.Eligible patients with non-valvular atrial fibrillation under rivaroxaban treatment for prevention of ischemic stroke were enrolled from nine institutes in Tokyo, Japan, between June 2016 and May 2017 (n = 324). The first and second (three months later) blood samples both taken within 1-5 hours after rivaroxaban intake were analyzed (n = 219). Plasma concentration of rivaroxaban (PC-Riv) and prothrombin time (PT) with five reagents were measured.The 90% interval of PC-Riv was 47.3-532.9 ng/mL. The 90% interval of PT measured with RecombiPlasTin 2G was 11.8-22.3 seconds, the widest range among the five reagents examined. PC-Riv reproducibility within a 90% interval was evaluated bidirectionally (first-to-second and second-to-first), and 92.4% of samples were reproducible. The change rate (CR) of PC-Riv between two samplings ranged widely, and high CR (≥54.3%, cutoff for predicting non-reproducibility) was predicted by concomitant drugs (non-dihydropyridine calcium antagonist and thiazide) and mitral regurgitation.We reported the on-therapy range of rivaroxaban in a multicenter cohort. This range was consistent with that of a single-center cohort and was highly reproducible within three months in daily clinical practice. However, caution is necessary regarding several factors that may affect the intraindividual variation of PC-Riv.

Relationship between sleep disordered breathing and heart rate turbulence in non-obese subjects.

Heart rate turbulence (HRT) is regarded as a parameter of cardiac autonomic dysfunction. Several studies have suggested that patients with sleep disordered breathing (SDB) have an impaired HRT, which play a role in the relationship between SDB and risk of cardiovascular morbidity and mortality. However, the impact of SDB on HRT independent from obesity is still debatable. Data of eligible subjects who underwent sleep test and 24 h Holter electrocardiogram (ECG) recording from 2009-2012 were analyzed. HRT parameters, turbulence onset (TO), and turbulence slope (TS) in the 24 h recording, while awakening, and sleeping (TO-24 h, TO-awake, TO-sleep, TS-24 h, TS-awake, and TS-sleep, respectively) were compared across subjects with no-to-mild, moderate, and severe SDB. Univariable and multivariable regression analyses including TO or TS as a dependent variable were performed. Data from 41 subjects were evaluated. Compared with the no-to-mild and moderate SDB groups, in the severe SDB group, the TO-24 h and TO-awake were significantly greater, and the TS-24 h, TS-awake, and TS-sleep were significantly lower. In multivariable analyses, the apnea-hypopnea index (AHI) was correlated directly with TO-24 h (coefficient, 0.36; P = 0.03) and TO-awake (coefficient, 0.40; P = 0.01). SDB severity, as represented by AHI, is related to HRT impairments in non-obese subjects. SDB, independent from obesity, may affect cardiac autonomic dysfunction.

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.

Entrance skin dose during radiofrequency catheter ablation for tachyarrhythmia: a multicenter study.

BACKGROUND: To assess the entrance skin dose (ESD) during radiofrequency catheter ablation procedures for tachyarrhythmia including atrial fibrillation (Af). METHODS: This study focused on 99 consecutive patients who underwent procedures for tachyarrhythmia (Af; n = 34, non-Af; n = 65) in three institutions. The non-Af group included atrial flutter, atrial tachycardia, paroxysmal supraventricular tachycardia, ventricular tachycardia, ventricular premature contraction, atrial premature contraction, atrioventricular nodal reentry tachycardia, and Wolff-Parkinson-White syndrome. In two of the three institutions, the procedures were performed for both Af and non-Af. The ESDs were measured using 100 radiosensitive indicators attached to the back of each patient's jacket at 5-cm intervals. For statistical analyses, multiple regression analysis (the dependent variable, Max-ESD; and the independent variables, dose area product [DAP], total fluoroscopic time [TFT], body mass index, etc.), Pearson's correlation test, and the Mann-Whitney test were employed. RESULTS: The overall averages for the TFTs, the DAPs, and the Max-ESDs were 49.9 ± 28.2 minutes, 71.2 ± 73.7 Gy cm(2) , and 0.57 ± 0.51 Gy, respectively. DAP was positively related to the Max-ESD and was significant in stepwise multiple regression analysis (P < 0.0001). There was a significant association between TFT and Max-ESD in five of the six kinds of angiographic unit, and between DAP and Max-ESD in all three systems with available DAP measures. In one institution, TFT, DAP, and Max-ESD differed significantly between the Af and non-Af groups (P = 0.0002, P < 0.0001, and P < 0.0001). CONCLUSIONS: During the cardiac catheter ablation, ESDs of only a few patients exceeded the thresholds of radiation skin injuries, and the DAP proved useful to estimate each patient's Max-ESD.

Iron overload augments angiotensin II-induced cardiac fibrosis and promotes neointima formation.

BACKGROUND: Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. METHODS AND RESULTS: Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. CONCLUSIONS: Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II. In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

[Idiopathic cardiomyopathy].

Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction. They are classified as dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy. Dilated cardiomyopathy is characterized by dilatation and impaired contraction of the ventricles. Hypertrophic cardiomyopathy is characterized by ventricular hypertrophy, which is usually asymmetric. Restrictive cardiomyopathy is characterized by restrictive filling and reduced diastolic function, with normal systolic function and wall thickness. Except for cardiac failure, sudden death from arrhythmia is the leading cause of death among cardiomyopathy patients. ACE inhibitors and beta blockers are effective medicine for cardiac failure patients. However sudden death rate of cardiomyopathy patients is still high. Implantable cardioverter-defibrillator could save many cardiomyopathy patients from sudden death according to a lot of trials.

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.

Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat.

Administration of angiotensin II to rats decreases renal expression of klotho, an aging-related gene, and also causes abnormal iron deposition in renal cells. Here we have examined the effects of iron overload and iron chelation on renal expression of klotho in untreated rats and rats treated with angiotensin II. Administration of iron-dextran caused a downregulation of klotho expression, and iron chelation suppressed the angiotensin II-induced downregulation of this gene. In addition, a free radical scavenger (T-0970), which effectively decreased plasma levels of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), suppressed angiotensin II-induced downregulation of klotho. Collectively, these findings suggest that abnormal iron metabolism and increased oxidative stress are involved in the mechanism of angiotensin II-mediated modulation of klotho expression.

[Angiotensin II regulates klotho gene expression].

Regulation of the expression of the klotho gene, which suppresses the expression of multiple aging-associated phenotypes, by angiotensin II was investigated. Continuous infusion of angiotensin II downregulated renal klotho gene expression, which was an AT1 receptor-dependent, but pressor-independent event. In some experiments, adenovirus harboring mouse klotho gene(ad-klotho, 3.3 x 10(10) pfu) was intravenously administered immediately before starting angiotensin II infusion, and this resulted in an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of tubulointerstitial damage induced by this octapeptitde. Downregulation of the renal klotho gene may have a role in the development of angiotensin II-induced end organ damage.

Infective endocarditis complicated with splenic abscess successfully treated with splenectomy followed by double valve replacement.

Splenic abscess (SA) is a rare complication of infective endocarditis (IE). A successful outcome lies with a choice between medical and surgical treatments. However, there is still insufficient evidence in the decision-making process. Our patient was a 73-year-old male who complained mainly of fever and general fatigue. An echocardiography showed vegetation of 10 mm in diameter and severe mitral and aortic regurgitation and a diagnosis was made of IE. Because of a recent brain embolism, we decided to treat him initially with medical therapy. Antibiotics were effective, but on the 28th day after starting treatment, he complained of left upper abdominal pain. An abdominal computed tomography scan showed SA. The administration of vancomycin did not improve the condition. We decided that he should undergo surgical treatment. A splenectomy was performed and 9 days after the splenectomy, the mitral and aortic valves were successfully replaced. There is still no clear-cut evidence to support the order of surgical interventions. Indeed, the current guidelines, which recommend that splenectomy is to be performed first, are not supported by strong evidence. The present case report showed that splenectomy before valve surgery successfully treated the patient.

The efficacy of bare metal stent implantation for patients with acute myocardial infarction in the drug-eluting stent era.

BACKGROUND: Although several trials have demonstrated the safety of drug-eluting stent (DES) implantation for acute myocardial infarction (AMI) patients, care must be exercised when DES are implanted in AMI cases because of the risk of in-stent thrombosis or adverse side effects of antiplatelet agents. On the other hand, recently, there has been much improvement in bare metal stents (BMSs), and thus, the efficacy of BMS implantation should be reevaluated. METHODS: We investigated the primary and long-term outcome of BMS implantation for AMI patients in the DES era (July 2004 to December 2006; n=97 [Group 1]) and compared the results with those in the pre-DES era (January 2002 to June 2004; n=81 [Group 2]), retrospectively. RESULTS: The most frequently used BMS in Group 1 was the Driver stent (63.9%) and in Group 2 the Duraflex stent (44.4%). Stent length and diameter were not significantly different between Group 1 and Group 2. The rates of in-stent restenosis, and target lesion revascularization were lower in Group 1 than in Group 2. Restenosis frequently occurred in small vessel lesions and in lesions that had required more than 10atm fully to dilate the pre-dilatation balloon at the primary PCI. CONCLUSIONS: Currently available BMSs are much more effective than old-type BMSs. However, DES implantation may be considered for small vessel diseases and lesions that need high pressure to dilate.

[Long-term prognosis after coronary revascularization in patients with end-stage renal disease on dialysis: comparison of percutaneous coronary intervention and coronary artery bypass grafting].

OBJECTIVES: To investigate the optimal method of coronary revascularization in patients on dialysis. METHODS: We retrospectively analyzed 145 patients on dialysis who underwent percutaneous coronary intervention (PCI) (81 patients) or coronary artery bypass grafting (CABG) (64 patients). Survival and non-fatal cardiac event-free rates were compared between the two groups by the Kaplan-Meier method. The impact of independent predictors on survival and non-fatal cardiac event-free rates were examined by the Cox regression model. RESULTS: The number of diseased vessels was smaller and ejection fraction was greater in the PCI group compared with the CABG group (1.74 +/- 0.67 vs 2.56 +/- 0.61, p < 0.0001 and 61.1 +/- 14.3% vs 50.6 +/- 17.4%, p = 0.001). The 1-year and 5-year survival rates of the PCI group were significantly higher than those of the CABG group (93.8 +/- 2.7% and 66.6 +/- 5.7% vs 76.0 +/- 5.4% and 44.8 +/- 6.5%, p = 0.0065). However, CABG was not an independent predictor of death by multivariate analysis (p = 0.06). The 1-year and 5-year non-fatal cardiac event-free rates of the PCI group were significantly lower than those of the CABG group (63.7 +/- 5.4% and 34.7 +/- 5.8% vs 83.2 +/- 4.9% and 66.8 +/- 7.4%, p = 0.0003). PCI was an independent predictor of non-fatal cardiac event by multivariate analysis (p = 0.007). CONCLUSIONS: PCI was associated with a higher incidence of non-fatal cardiac events, but survival rate was better after PCI than after CABG. PCI is very important and acceptable as a method of coronary revascularization in patients on dialysis.

Use and long-term outcome of bare metal stent implantation in the drug-eluting stent era.

BACKGROUND: Although drug-eluting stents (DES) are widely used today, bare metal stents (BMS) are still frequently employed. We investigated the utilization and clinical outcomes of BMS implantation since we first began using DES. METHODS: The clinical course following percutaneous intervention with de novo implantation of BMS was studied beginning in July 2004, when sirolimus-eluting stents (SES) were first used in our hospital, to August 2006. Outcomes following BMS and SES implantation were compared. RESULTS: BMS implantation was carried out in 160 lesions and SES implantation in 242 lesions. Follow-up coronary angiography was performed for 208 lesions (78 lesions in which BMS were implanted and 130 lesions in which SES were implanted) within 1 year. There were no significant differences in patient characteristics between the SES and BMS groups. Regardless of the reason for BMS implantation, the rates of in-stent restenosis and target lesion revascularization were higher in the BMS group than in the SES group. However, the rate of in-stent restenosis and target lesion revascularization of BMS in lesions with a diameter of 4.0mm or greater was 0%. CONCLUSIONS: In order to reduce the risk of in-stent restenosis and target lesion revascularization, we recommend implantation of BMS with a diameter of 4.0 mm or greater or SES unless it is contraindicated.

Health-related quality of life of Japanese patients with chronic heart failure: assessment using the Medical Outcome Study Short Form 36.

Chronic heart failure is characterized by impaired cardiac function, but the relationship between clinical indices and subjective perception is not clear. This study was undertaken to investigate the relationship between cardiac function, exercise capacity and clinical classification, and the health-related quality of life (HRQOL) in 91 outpatients with an left ventricular ejection fraction (LVEF) less than 40%. Exercise capacity was evaluated by the Specific Activity Scale, and HRQOL by the Medical Outcome Study Short Form 36. Exercise capacity and the cardiothoracic ratio were correlated with the HRQOL related to physical functioning, although the correlation between exercise capacity and mental health was not significant. LVEF was not related to HRQOL. Factor analysis revealed (1) LVEF was independent of physical functioning; (2) physical function and exercise capacity comprise a factor reflecting physical HRQOL; and (3) socio-emotional functioning is the third factor independent of LVEF and physical function. Physical and socio-mental HRQOL measurement included information independent of the widely used clinical indices such as LVEF and New York Heart Association classification. The evaluation of HRQOL should be included in the assessment of patient status.

In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.