Showing papers by "Hiroaki Shimokawa published in 2015"

International standardization of diagnostic criteria for vasospastic angina

Abstract: The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field.

Heart failure as a general pandemic in Asia.

Abstract: Heart failure (HF) is an epidemic in healthcare worldwide, including Asia. It appears that HF will become more serious in the near future, with the epidemiological transition and ageing of the population. However, in contrast to Western countries, information on HF epidemiology is still limited in Asia, particularly in South Asia. In this review, we will briefly summarize available information regarding the current and future burden of HF in Asia, which indicates the importance of both primary prevention of underlying diseases of HF and secondary prevention, including management of ischaemic HF, HF with preserved EF, and HF in the elderly.

Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association

Abstract: Aims Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA. Methods and results A total of 1429 VSA patients (median 66 years; male/female, 1090/339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono- and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72–2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28–2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02–4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered. Conclusions Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Temporal Trends in Clinical Characteristics, Management and Prognosis of Patients With Symptomatic Heart Failure in Japan – Report From the CHART Studies –

Abstract: Background Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan. Methods and results From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P Conclusions Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. ( Trial registration clinicaltrials.gov identifier: NCT00418041)

Current status of primary prevention of sudden cardiac death with implantable cardioverter defibrillator in patients with chronic heart failure--a report from the CHART-2 Study.

Abstract: Background:The current status of primary prevention of sudden cardiac death (SCD) with implantable cardioverter defibrillator (ICD) in patients with heart failure with reduced ejection fraction remains to be fully elucidated in Japan.Methods and Results:In the chronic heart failure (CHF) cohort study, the CHART-2 Study, we enrolled 2,778 consecutive patients with NYHA class II–III. According to the Japanese Circulation Society guideline of prophylactic ICD, we divided them into 3 groups: group A, class I indication; B, class IIa; and C, no indication. During the (median) 3.2-year follow-up, 79 fatal arrhythmic events (FAE), defined as composite of sudden cardiac/arrhythmic death, ventricular tachycardia/fibrillation and appropriate ICD therapy, occurred. In the groups A, B and C, the prevalence of FAE was 16.1%, 8.9% and 1.9%, respectively; the use of prophylactic ICD among those with FAE, however, was only 44%, 9% and 6%, respectively. In the groups A and B combined, chronic atrial fibrillation (cAF) and left ventricular end-diastolic dimension (LVDd) ≥65 mm were independent predictors of FAE, and, when combined, their prognostic impact was highly significant (hazard ratio, 7.01; P<0.001).Conclusions:Primary prevention of SCD with ICD in CHF patients is validated but is still underused in Japan, and the combination of cAF and LVDd ≥65 mm may be a useful indication of prophylactic ICD implantation. (Circ J 2015; 79: 381–390)

Prognostic Impact of Statin Use in Patients With Heart Failure and Preserved Ejection Fraction

Abstract: BACKGROUND The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

Abstract: We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

2015 ATVB Plenary Lecture Translational Research on Rho-Kinase in Cardiovascular Medicine

Abstract: Rho-kinase (ROCKs) is an important downstream effector of the small GTP-binding protein Ras homolog gene family member A. There are 2 isoforms of ROCK, ROCK1 and ROCK2, and they have different functions in several vascular components. The Ras homolog gene family member A/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases. For the past 20 years, a series of translational research studies have demonstrated the important roles of ROCK in the pathogenesis of cardiovascular diseases. At the molecular and cellular levels, ROCK upregulates several molecules related to inflammation, thrombosis, and fibrosis. In animal experiments, ROCK plays an important role in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and heart failure. Finally, at the human level, ROCK is substantially involved in the pathogenesis of coronary vasospasm, angina pectoris, hypertension, pulmonary hypertension, and heart failure. Furthermore, ROCK activity in circulating leukocytes is a useful biomarker for the assessment of disease severity and therapeutic responses in vasospastic angina, heart failure, and pulmonary hypertension. In addition to fasudil, many other ROCK inhibitors are currently under development for various indications. Thus, the ROCK pathway is an important novel therapeutic target in cardiovascular medicine.

Association of Adventitial Vasa Vasorum and Inflammation With Coronary Hyperconstriction After Drug-Eluting Stent Implantation in Pigs In Vivo

Abstract: BACKGROUND The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges. CONCLUSIONS The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo.

Prognostic Impact of Anemia in Patients With Chronic Heart Failure- With Special Reference to Clinical Background: Report From the CHART-2 Study.

Abstract: BACKGROUND We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF). METHODS AND RESULTS We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease. CONCLUSIONS These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.

Rho-Kinase Inhibition During Early Cardiac Development Causes Arrhythmogenic Right Ventricular Cardiomyopathy in Mice

Abstract: Objective—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty changes of the right ventricle, ventricular arrhythmias, and sudden death. Though ARVC is currently regarded as a disease of the desmosome, desmosomal gene mutations have been identified only in half of ARVC patients, suggesting the involvement of other associated mechanisms. Rho-kinase signaling is involved in the regulation of intracellular transport and organizes cytoskeletal filaments, which supports desmosomal protein complex at the myocardial cell–cell junctions. Here, we explored whether inhibition of Rho-kinase signaling is involved in the pathogenesis of ARVC. Approach and Results—Using 2 novel mouse models with SM22α- or αMHC-restricted overexpression of dominant-negative Rho-kinase, we show that mice with Rho-kinase inhibition in the developing heart (SM22α-restricted) spontaneously develop cardiac dilatation and dysfunction, myocardial fibrofatty changes, and ventricular arrhythmias, resulting in pr...

Four-dimensional flow magnetic resonance imaging visualizes drastic change in vortex flow in the main pulmonary artery after percutaneous transluminal pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension

Abstract: A 54-year-old woman with a history of venous thromboembolism treated with warfarin for 9 months was referred to our hospital because of exacerbating oedema and dyspnoea. A CT scan showed residual thrombus in the sub-segmental pulmonary arteries (PAs). Cine MRI demonstrated deteriorated right ventricular ejection fraction (RVEF = 24.7%), RV dilatation, RV wall-thickening, and substantial …

ROS and endothelial nitric oxide synthase (eNOS)-dependent trafficking of angiotensin II type 2 receptor begets neuronal NOS in cardiac myocytes

Abstract: Angiotensin II (Ang II), a potent precursor of hypertrophy and heart failure, upregulates neuronal nitric oxide synthase (nNOS or NOS1) in the myocardium. Here, we investigate the involvement of type 1 and 2 angiotensin receptors (AT1R and AT2R) and molecular mechanisms mediating Ang II-upregulation of nNOS. Our results showed that pre-treatment of left ventricular (LV) myocytes with antagonists of AT1R or AT2R (losartan, PD123319) and ROS scavengers (apocynin, tiron or PEG-catalase) blocked Ang II-upregulation of nNOS. Surface biotinylation or immunocytochemistry experiments demonstrated that AT1R expression in plasma membrane was progressively decreased (internalization), whereas AT2R was increased (membrane trafficking) by Ang II. Inhibition of AT1R or ROS scavengers prevented Ang II-induced translocation of AT2R to plasma membrane, suggesting an alignment of AT1R-ROS-AT2R. Furthermore, Ang II increased eNOS-Ser1177 but decreased eNOS-Thr495, indicating concomitant activation of eNOS. Intriguingly, ROS scavengers but not AT2R antagonist prevented Ang II-activation of eNOS. NOS inhibitor (L-NG-Nitroarginine Methyl Ester, L-NAME) or eNOS gene deletion (eNOS−/−) abolished Ang II-induced membrane trafficking of AT2R, nNOS protein expression and activity. Mechanistically, S-nitrosation of AT2R was increased by sodium nitroprusside (SNP), a NO donor. Site-specific mutagenesis analysis reveals that C-terminal cysteine 349 in AT2R is essential in AT2R translocation to plasma membrane. Taken together, we demonstrate, for the first time, that Ang II upregulates nNOS protein expression and activity via AT1R/ROS/eNOS-dependent S-nitrosation and membrane translocation of AT2R. Our results suggest a novel crosstalk between AT1R and AT2R in regulating nNOS via eNOS in the myocardium under pathogenic stimuli.

Comparison of cardiovascular mortality in the great East Japan and the great Hanshin-Awaji earthquakes-a large-scale data analysis of death certificates

Abstract: BACKGROUND Large earthquakes have been associated with cardiovascular disease (CVD) mortality. In Japan, the 1995 Great Hanshin-Awaji (H-A) Earthquake was an urban-underground-type earthquake, whereas the 2011 Great East Japan (GEJ) Earthquake was an ocean-trench type. In the present study, we examined how these different earthquake types affected CVD mortality. METHODS AND RESULTS We examined death certificate data from 2008 to 2012 for 131 municipalities in Iwate, Miyagi, and Fukushima prefectures (n=320,348) and from 1992 to 1996 for 220 municipalities in Hyogo, Osaka, and Kyoto prefectures (n=592,670). A Poisson regression model showed significant increases in the monthly numbers of acute myocardial infarction (AMI)-related deaths (incident rate ratio [IRR] GEJ=1.34, P=0.001; IRR of H-A=1.57, P<0.001) and stroke-related deaths (IRR of GEJ=1.42, P<0.001; IRR of H-A=1.33, P<0.001) after the earthquakes. Two months after the earthquakes, AMI deaths remained significant only for H-A (IRR=1.13, P=0.029). When analyzing the standardized mortality ratio (SMR) after the earthquakes using the Cochran-Armitage trend test, seismic intensity was significantly associated with AMI mortality for 2 weeks after both the GEJ (P for trend=0.089) and H-A earthquakes (P for trend=0.005). CONCLUSIONS Following the GEJ and H-A earthquakes, there was a sharp increase in CVD mortality. The effect of the disaster was sustained for months after the H-A earthquake, but was diminished after the GEJ Earthquake.

Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans - a validation study - .

Abstract: BACKGROUND Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Predictors and Prognostic Impact of Post-Traumatic Stress Disorder After the Great East Japan Earthquake in Patients With Cardiovascular Disease

Abstract: BACKGROUND: We examined the prevalence, predictors and prognostic impact of post-traumatic stress disorder (PTSD) after the Great East Japan Earthquake in patients with cardiovascular disease (CVD) in the CHART-2 study.METHODS and Results:The prevalence of PTSD was 14.7% at 6 months after the Earthquake. Female sex, experiencing the Tsunami, property loss, poverty, and insomnia medication use were associated with PTSD. The patients with PTSD more frequently experienced a composite of death, acute myocardial infarction, stroke and heart failure (18.5% vs. 15.0%, P=0.035). CONCLUSIONS: PTSD was frequent in CVD patients after the Earthquake and had an adverse prognostic impact. (Circ J 2015; 79: 664-667). Language: en

Light and Dark of Reactive Oxygen Species for Vascular Function: 2014 ASVB (Asian Society of Vascular Biology).

Abstract: Vascular-derived hydrogen peroxide (H2O2) serves as an important signaling molecule in the cardiovascular system and contributes to vascular homeostasis. H2O2 is a second messenger, transducing the oxidative signal into biological responses through posttranslational protein modification. The balance between oxidant and antioxidant systems regulates intracellular redox status, and their imbalance causes oxidative or reductive stress, leading to cellular damage in cardiovascular systems. Excessive H2O2 deteriorates vascular functions and promotes vascular disease through multiple pathways. The RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including production of excessive reactive oxygen species, leading to the development of cardiovascular diseases. Rho-kinase (ROCK1 and ROCK2) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. Rho-kinase plays a crucial role in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Thus, Rho-kinase inhibitors may be useful for the treatment of cardiovascular diseases in humans. In this review, we will briefly discuss the roles of vascular-derived H2O2 and review the recent progress in the translational research on the therapeutic importance of the Rho-kinase pathway in cardiovascular medicine.

Clinical Characteristics of Patients With Acute Myocardial Infarction Who Did Not Undergo Primary Percutaneous Coronary Intervention – Report From the MIYAGI-AMI Registry Study –

Abstract: BACKGROUND In the current era of primary percutaneous coronary intervention (PCI), some patients with acute myocardial infarction (AMI) still do not undergo primary PCI. METHODS AND RESULTS To examine the clinical characteristics of AMI patients who did not undergo primary PCI, we analyzed patients enrolled between 2002 and 2010 in the MIYAGI-AMI Registry Study, in which all AMI patients in the Miyagi prefecture have been prospectively registered. Among a total of 8,640 patients, 1,879 (21.7%) did not undergo primary PCI and their in-hospital mortality was significantly worse compared with those who did (21.4% vs. 6.4%, P<0.01). Multivariate analysis demonstrated that female sex was significantly associated with non-performance of primary PCI [odds ratio (95% confidence interval): 1.40 (1.22-1.61), P<0.001], along with age [1.01 (1.01-1.02), P<0.001] and heart failure on admission [2.69 (2.29-3.16), P<0.001]. When dividing by age, the non-performance rate of primary PCI in females showed a U-shaped prevalence, whereas it simply increased with aging in males. Importantly, female patients aged <80 years had a significantly higher non-performance rate of primary PCI compared with male patients, regardless of the severity of AMI. CONCLUSIONS These results indicate that in the current PCI era, various factors, including aging, heart failure on admission and sex differences, are associated with non-performance of primary PCI, which remain to be resolved in order to further improve critical care of AMI.

Improved Long-Term Prognosis of Dilated Cardiomyopathy With Implementation of Evidenced-Based Medication – Report From the CHART Studies –

Abstract: Background Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan. Methods and results We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P 40%, β-blocker use and aldosterone antagonist use. Conclusions Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan.

Opposing roles of nitric oxide and rho-kinase in lipid metabolism in mice.

Abstract: Dyslipidemia is a life-style disorder and is one of the important risk factors of cardiovascular diseases. Nitric oxide (NO) exerts beneficial effects on lipid metabolism through activation of hepatic sterol regulatory element-binding protein (SREBP)-2, a transcriptional factor for cholesterol metabolism and expression of LDL receptor, while Rho-kinase, an effecter protein of small G protein, RhoA, contributes to the pathogenesis of metabolic syndrome through suppressing the whole body energy consumption. However, the crosstalk between NO and Rho-kinase in regulation of lipid metabolism remains to be elucidated. In the present study, we used male wild-type (WT) mice and mice lacking three isoforms of NO synthase (NOSs(-/-)). WT mice were fed either normal diet (ND) or high-fat diet (HFD), while NOSs(-/-) mice were fed ND with or without a selective Rho-kinase inhibitor, fasudil (100 mg/kg/day), for 6 weeks. At 6 weeks, plasma NOx concentration was significantly decreased and Rho-kinase activity and lipid levels were significantly elevated in HFD-fed WT mice and NOSs(-/-) mice compared with ND-fed WT mice. In the liver, SREBP-2 activity was reduced in NOSs(-/-) mice. Fasudil ameliorated lipid levels in HFD-fed WT mice and NOSs(-/-) mice without affecting SREBP-2 activity or LDL receptor expression, whereas it significantly enhanced phosphorylation of AMP-activated kinase (AMPK) in the liver and skeletal muscle. Importantly, the beneficial metabolic effects of fasudil were absent in HFD-fed AMPK(-/-) mice. These results provide the first evidence that NO and Rho-kinase play opposing roles for the lipid metabolism, suggesting that Rho-kinase inhibitors could be novel therapeutic agents of dyslipidemia.

PDE1C Negatively Regulates Growth Factor Receptor Degradation and Promotes VSMC Proliferation

Abstract: The endothelium regulates the contractile status of vascular smooth muscle cells (VSMCs).1 The interaction between endothelial cells (ECs) and VSMCs plays an important role in regulating vascular homeostasis. ECs release vasoactive factors, such as prostacyclin, (nitric oxide [NO]), and endothelium-derived hyperpolarizing factor, which participate in the regulation of vascular tone.1 Endothelial dysfunction induces the increased expression of adhesion molecules for inflammatory cells. Accumulated inflammatory cells generate an oxidizing environment, which involves abundant reactive oxygen species, inflammatory cytokines/chemokines, and growth factors that contribute to VSMC phenotypic modulation.2 Thus, EC damage is a trigger underlying VSMC phenotypic change and pathological vascular remodeling. Article, see p 1120 Under normal physiological conditions, VSMCs in the media of vessels are quiescent with a low turnover rate and insignificant secretory activity. They are highly differentiated cells, which show a contractile phenotype and regulate vascular tone. However, VSMCs are among the most plastic of all cells in their ability to respond to different stimuli and retain a degree of plasticity to allow phenotypic modulation. It is thought that VSMCs change from a quiescent/contractile to an active/synthetic phenotype in several vascular diseases.3 Synthetic VSMCs downregulate contractile proteins and upregulate growth factors, receptors, extracellular matrix proteases, and inflammatory proteins. Besides VSMC phenotypic change, the transdifferentiation of adventitial fibroblasts,4 the differentiation of progenitor cells/stem cells,5,6 and endothelial-to-mesenchymal transition may also contribute as the sources of synthetic VSMCs.7 Regardless of the sources, synthetic VSMCs proliferate, migrate, and secrete proteins, including extracellular matrix proteases, proinflammatory cytokines/chemokines, and growth factors. Therefore, it is of great interest to develop novel strategies targeting the VSMC phenotypic change from the contractile to synthetic state. Vascular ECs themselves produce abundant …

Prognostic Impact of Diabetes Mellitus in Chronic Heart Failure According to Presence of Ischemic Heart Disease – With Special Reference to Nephropathy –

Abstract: Background It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy. Methods and results We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy. Conclusions The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.

Cyclophilin A: Novel biomarker for oxidative stress and cardiovascular diseases

Abstract: Intracellular redox status is closely regulated by the balance between oxidant and antioxidant systems, and their imbalance can cause oxidative or reductive stress, leading to cellular damage and dysregulation. Excessive reactive oxygen species (ROS) deteriorates vascular functions and promotes vascular diseases through multiple pathways. Recently, cyclophilin A (CyPA) has been shown to be secreted from vascular smooth muscle cells (VSMC) and to augment the destructive effects of ROS, linking it to the development of many cardiovascular diseases. In the secretion of CyPA, Rho-kinase plays an important role to organize vicious cycle for augmentation of ROS. The important role of Rho-kinase has been established in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Thus, it is important to understand Rho-kinase signaling and the role of downstream effectors such as CyPA in the vascular system in order to develop new therapeutic strategies for cardiovascular diseases. Here, we reported that plasma CyPA levels are increased in patients with coronary artery disease (CAD). Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it. A positive correlation was noted between plasma CyPA levels and significant coronary stenosis. The average number of stenotic coronary arteries and the need for coronary intervention were significantly increased in the quartiles of higher CyPA levels. Interestingly, plasma levels of CyPA increased according to the number of atherosclerotic risk factors, all of which induce oxidative stress. Furthermore, plasma levels of CyPA significantly reduced after medical treatment of risk factors. In this chapter, we will discuss the roles of VSMC-derived CyPA in promoting vascular diseases, with particular emphasis on the role of CyPA as a novel biomarker for CAD. Additionally, we will mention the beneficial effects of fasudil, a selective Rho-kinase inhibitor, for the treatment of cardiovascular diseases. List of all Abbreviations AngII Angiotensin II CAD Coronary Artery Disease Cdc42 Cell Division Control Protein 42 cGMP Cyclic Guanosine Monophosphate CyPA Cyclophilin A CyPB Cyclophilin B CyPC Cyclophilin C CyPD Cyclophilin D EC Endothelial Cells EDHF Endothelium-Derived Hyperpolarizing Factors *Email: shimo@cardio.med.tohoku.ac.jp General Methods in Biomarker Research and their Applications DOI 10.1007/978-94-007-7740-8_40-1 # Springer Science+Business Media Dordrecht 2014

Development of a novel shock wave catheter ablation system--the first feasibility study in pigs.

Abstract: Introduction Radio-frequency catheter ablation (RFCA) using Joule heat has two fundamental weaknesses: the limited depth of treatment and the risk of thrombus formation. In contrast, focused shock wave (SW) therapy could damage tissues at arbitrary depths without heat generation. Thus, we aimed to develop a SW catheter ablation (SWCA) system that could compensate for the weaknesses of RFCA therapy. Methods and Results We developed a SWCA system where the SW generated by a Q-switched Holmium: yttrium aluminum garnet (YAG) laser beam was reflected by a reflector attached to 14-Fr catheter tip and then was converged onto the focus. We examined the feasibility of our system on pigs in vivo. When applied using the epicardial approach, the SWCA caused persistent spheroidal lesions with mild superficial injury than the RFCA. The lesions were created to a depth based on the focal length (2.0 mm) [2.36 ± 0.45 (SD) mm immediately after procedure, n = 16]. When applied to the atrioventricular (AV) node using the endocardial approach, the SWCA caused junctional escape rhythms in 2 pigs and AV block in 12 pigs (complete AV block in 9) in acute phase (n = 14). Nine of the 14 pigs survived with pacemakers for the long-term study, and the AV block persisted for 12.6 ± 3.9 (SD) days in all surviving pigs. Histological examination showed AV nodal cell body atrophy in the acute phase and fibrotic lesions in the chronic phase. Importantly, no acute or chronic fatal complications were noted. Conclusions Our novel SWCA system could be a promising modality as a non-thermal ablation method to compensate for the weaknesses of RFCA therapy. However, further research and development will be necessary as the current prototype still exhibited the presence of micro-thrombus formation in the animal studies.

Comprehensive Risk Stratification of Japanese Patients With Aortic Stenosis – A Proposal of a New Risk Score From the CHART-2 Study –

Abstract: BACKGROUND The risk of patients with aortic stenosis (AS) should be stratified not only by AS severity but also by comorbidities. METHODS AND RESULTS We aimed to develop a risk score for mortality in 412 patients with AS (pressure gradient ≥30 mmHg, mean age 74.9 years, male 52.4%) in the CHART-2 Study (n=10,219). During a 3-year follow-up, 73 (17.7%) patients died. Crude 3-year mortality of patients in New York Heart Association (NYHA) classes I, II, and III/IV was 9.5%, 16.5%, and 49.7%, respectively (P<0.001). Stepwise Cox regression analysis showed that the combination of 7 factors was the best model to predict the mortality of AS patients, who were scored according to their hazard ratios, including NYHA class III-IV (score 6), male sex (3), serum albumin level ≤4 g/dl (2), aortic peak flow ≥4.5 m/s (2), age ≥75 years (2), chronic kidney disease (2), and anemia (1). Receiver-operating characteristic analysis showed excellent association between the sum of the scores and 3-year mortality (area under the curve, 0.78). The multivariate Cox proportional hazard model demonstrated that the present risk score also well stratified the mortality risk. CONCLUSIONS The present study demonstrates that, in addition to the classical prognostic factors related to symptoms and AS severity, various comorbidities are associated with mortality. Thus, the present comprehensive risk score may be useful for risk stratification of AS patients.

Method of testing for pulmonary hypertension

Abstract: A primary object of the present invention is to provide a method for conveniently and accurately testing for pulmonary hypertension. To achieve this object, the present invention provides a method for testing for pulmonary hypertension using as an indicator the concentration of selenoprotein P protein in a sample derived from a subject.