Showing papers by "Hiroaki Shimokawa published in 2018"

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology

Abstract: Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management

Abstract: The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: Analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Abstract: Aims Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration ClinicalTrials.gov NCT01327846.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial

Abstract: Background:Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous “more versus less statins” trials. However, no clear ev...

Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension: Possible Novel Therapeutic Target.

Abstract: Background: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combi...

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice.

Abstract: Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (cROCK1−/−) and ROCK2-deficient (cROCK2−/−) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1−/− mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2−/− mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1−/− hearts and down-regulated in cROCK2−/− hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1−/− mice, whereas their expressions were significantly lower in cROCK2−/− mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

Clinical determinants of successful weaning from extracorporeal membrane oxygenation in patients with fulminant myocarditis.

Abstract: Aims Patients with fulminant myocarditis (FM) often present with cardiogenic shock and require mechanical circulatory support, including extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD) implantation. This study sought to clarify the determinants of successful weaning from ECMO in FM patients. Methods and results We studied 37 consecutive FM patients supported by ECMO as the initial form of mechanical circulatory support between January 1995 and December 2014 in our hospital. Twenty-two (59%) patients were successfully weaned from ECMO, while 15 (41%) were not. There were significant differences in levels of peak creatine kinase and those of its MB isoform (CK-MB), left ventricular posterior wall thickness (LVPWT), and prevalence of cardiac rhythm disturbances. Receiver operating characteristic curve analysis revealed that a peak CK-MB level of 185 IU/L and LVPWT of 11 mm were the optimal cut-off values for predicting successful weaning from ECMO (areas under the curve, 0.89 and 0.85, respectively). During the follow-up [median 48 (interquartile range 8-147) months], 83% of FM patients who were weaned from ECMO survived, with preserved fractional shortening based on echocardiography. Of the 15 FM patients who were not weaned from ECMO, nine bridged to VAD, and only two were successfully weaned from VAD and survived. Conclusions These results indicate that myocardial injury, as evidenced by CK-MB and LVPWT, and prolonged presence of cardiac rhythm disturbances are important clinical determinants of successful weaning from ECMO.

The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure (HOMES-HF)

Abstract: Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0-31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548-1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina

Abstract: Aims Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone. Conclusion Rho-kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients.

Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells.

Abstract: Background —Thoracic aortic aneurysm (TAA) and dissection (TAD) are fatal diseases, which cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in AoSMCs causes TAA and TAD. Methods —To examine the role of SmgGDS in TAA formation, we employed an angiotensin II (AngII, 1,000 ng/min/kg, 4 weeks)-induced TAA model. Results —33% Apoe -/- SmgGDS +/- mice died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the two genotypes. We performed ultrasound imaging every week to follow the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe -/- SmgGDS +/- mice compared with Apoe -/- mice, whereas that of the abdominal aorta remained comparable between the two genotypes. Histological analysis of Apoe -/- SmgGDS +/- mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5) and more severe elastin degradation compared with Apoe -/- mice. Mechanistically, Apoe -/- SmgGDS +/- mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe -/- mice. For mechanistic analyses, we primary cultured aortic smooth muscle cells (AoSMCs) from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, Apoe -/- SmgGDS +/- AoSMCs showed significantly increased MMP activity and oxidative stress levels compared with Apoe -/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of FBN1, ACTA2, MYH11, MLK and PRKG1 , which are force generation genes, were significantly reduced in Apoe -/- SmgGDS +/- AoSMCs compared with Apoe -/- AoSMCs. Similar tendency was noted in AoSMCs from TAA patients compared with those from controls. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe -/- SmgGDS +/- mice. Conclusions —These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

Endothelium-dependent hyperpolarization-mediated vasodilatation compensates nitric oxide-mediated endothelial dysfunction during ischemia in diabetes-induced canine coronary collateral microcirculation in vivo.

Abstract: OBJECTIVES It has been previously demonstrated that endothelial caveolin-1 plays crucial roles to produce an endothelium-derived hyperpolarizing factor in mouse mesenteric arteries. We examined whether this mechanism is involved in the endothelium-dependent hyperpolarization-mediated responses to compensate reduced NO-mediated responses in diabetes mellitus during coronary occlusion in dogs in vivo. METHODS Canine subepicardial collateral coronary small arteries (≥100 μm) and arterioles (<100 μm) were observed by an intravital microscope. Experiments were performed during occlusion of the left anterior descending coronary artery (90 minutes) under the following conditions (n = 6 each); (i) control, (ii) diabetes mellitus, and (iii) diabetes mellitus+L-NMMA+KCa channel blockade. Vascular and myocardial levels of caveolin-1, eNOS, and caspase-3 were measured by ELISA. RESULTS Caveolin-1 levels in the ischemic area were greater in coronary microvessels than in conduit arteries in the control group. NO-mediated coronary vasodilatations of small arteries to bradykinin did not increase in diabetes mellitus associated with decreased eNOS phosphorylation at Ser1177 compared with baseline of controls and were restored by compensation of endothelium-dependent hyperpolarization and were suppressed by KCa channel blockade. CONCLUSIONS NO-mediated vasodilatations of small coronary arteries during coronary occlusion are impaired in diabetes mellitus and are compensated by endothelium-dependent hyperpolarization of arterioles in dogs in vivo.

Comparable prognostic impact of BNP levels among HFpEF, Borderline HFpEF and HFrEF: a report from the CHART-2 Study

Abstract: We aimed to compare the usefulness of plasma levels of B-type natriuretic peptide (BNP) for long-term risk stratification among patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF), borderline HFpEF, and HF with reduced LVEF (HFrEF) in the same HF cohort. In the CHART-2 Study (N = 10,219), we categorized 4301 consecutive Stage C/D HF patients (mean age 68.7 years, female 32.4%) into 3 groups: HFpEF (LVEF ≥ 50%, N = 2893), borderline HFpEF (LVEF 40–50%, N = 666), and HFrEF (LVEF ≤ 40%, N = 742). During the median 6.3-year follow-up, all-cause deaths occurred in 887 HFpEF, 330 borderline HFpEF, and 330 HFrEF patients. Although median BNP levels increased from HFpEF, borderline HFpEF to HFrEF (85.3, 126 and 208 pg/ml, respectively, P < 0.001), the relationship between log2 BNP levels and the mortality risk was comparable among the 3 groups. As compared with patients with BNP < 30 pg/ml, those with 30–99, 100–299 and ≥ 300 pg/ml had comparably increasing mortality risk among the 3 groups (hazard ratio 2.5, 4.7 and 7.8 in HFpEF, 2.1, 4.2 and 7.0 in borderline HFpEF, and 3.0, 4.7 and 9.5 in HFrEF, respectively, all P < 0.001). BNP levels have comparable prognostic impact among HFpEF, borderline HFpEF, and HFrEF patients.

Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension

Abstract: It is widely known that the incidence of pulmonary arterial hypertension (PAH) is higher in female, whereas prognosis is poorer in male patients. However, sex differences in hemodynamic response to and long-term prognosis with PAH-targeted treatment in the modern era remain to be fully elucidated. We examined the long-term prognosis of 129 consecutive PAH patients (34 males and 95 females) diagnosed in our hospital from April 1999 to October 2014, and assessed hemodynamic changes in response to PAH-targeted therapy. Female patients had better 5-year survival compared with male patients (74.0 vs. 53.4%, P = 0.003); however, higher age quartiles in females were associated with poor outcome. Follow-up examination after medical treatment showed significant decreases in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary arterial capacitance (PAC) in both sexes (both P < 0.05), whereas only females had a significant improvement in right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP), cardiac index, and mixed venous oxygen saturation (SvO2) (all P < 0.05). Baseline age significantly correlated with the hemodynamic changes only in female patients; particularly, there were significant sex interactions in RVEDP and RAP (both P < 0.10). The multivariable analysis showed that SvO2 at baseline and mPAP and SvO2 at follow-up were significant prognostic factors in males, whereas the changes in mPAP, PVR, and PAC and use of endothelin-receptor antagonist in females. These results indicate that female PAH patients have better long-term prognosis than males, for which better improvements of right ventricular functions and hemodynamics may be involved.

Protective Role of Myelocytic Nitric Oxide Synthases against Hypoxic Pulmonary Hypertension in Mice.

Abstract: Rationale: Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remain...

Recent Advances in the Development of Cardiovascular Biomarkers.

Abstract: Cardiovascular diseases (CVD) are initiated by endothelial dysfunction and resultant expression of adhesion molecules for inflammatory cells.1–3 Inflammatory cells secrete cytokines/chemokines and growth factors and promote CVD.4 Additionally, vascular cells themselves produce and secrete several factors, some of which can be useful for the early diagnosis and evaluation of disease severity of CVD.5–7 Among vascular cells, abundant vascular smooth muscle cells (VSMCs) secrete a variety of humoral factors that affect vascular functions in an autocrine/paracrine manner.8,9 Among these factors, we reported that CyPA (cyclophilin A) is secreted mainly from VSMCs in response to Rho-kinase activation and excessive reactive oxygen species (ROS).10–12 Additionally, extracellular CyPA augments ROS production, damages vascular functions,13 and promotes CVD.8,14–24 Importantly, a recent study in ATVB demonstrated that ambient air pollution increases serum levels of inflammatory cytokines.25 Moreover, Bell et al26 reported an association of air pollution exposure with high-density lipoprotein (HDL) cholesterol and particle number. In a large, multiethnic cohort study of men and women free of prevalent clinical CVD, they found that higher concentrations of PM2.5 over a 3-month time period was associated with lower HDL particle number, and higher annual concentrations of black carbon were associated with lower HDL cholesterol. Together with the authors’ previous work on biomarkers of oxidative stress, they provided evidence for potential pathways that may explain the link between air pollution exposure and acute cardiovascular events.25,26 The objective of this review is to highlight the novel research in the field of biomarkers for CVD. Endothelial dysfunction induces the development of atherosclerotic disease.3,27,28 In the maintenance of endothelial function and vascular homeostasis, AMPK (AMP-activated protein kinase) and its downstream signaling of endothelial …

Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension.

Abstract: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins.

Important role of endothelium-dependent hyperpolarization in the pulmonary microcirculation in male mice: implications for hypoxia-induced pulmonary hypertension

Abstract: This study provides novel evidence that both endothelium-dependent hyperpolarization and nitric oxide play important roles in endothelium-dependent relaxation in the pulmonary microcirculation unde...

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Abstract: Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Prognostic Impact of Statin Intensity in Heart Failure Patients With Ischemic Heart Disease: A Report From the CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2) Study.

Abstract: Background The beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low‐density lipoprotein cholesterol levels. Methods and Results We examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART‐2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin‐intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate‐high)‐intensity (n=868), lower (low)‐intensity (n=526), and no statin (n=1050). The median follow‐up period was 6.4 years (13929 person‐years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher‐intesity group (hazard ratio [HR]: 0.68; P P P P P Conclusions These results suggest that statin use, particularly the use of higher‐intensity statins, has a beneficial prognostic impact in HF patients with ischemic heart disease, regardless of low‐density lipoprotein cholesterol levels. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00418041.

Prognostic Significance of PR Interval Prolongation in Adult Patients With Total Correction of Tetralogy of Fallot.

Abstract: Background: Several studies have demonstrated the importance of mechanoelectrical interaction in patients with surgically corrected tetralogy of Fallot. However, the significance of atrioventricula...

Isolated Late Activation Detected by Magnetocardiography Predicts Future Lethal Ventricular Arrhythmic Events in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract: Background Risk stratification of ventricular arrhythmias is vital to the optimal management in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We hypothesized that 64-channel magnetocardiography (MCG) would be useful to detect isolated late activation (ILA) by overcoming the limitations of conventional noninvasive predictors of ventricular tachyarrhythmias, including epsilon waves, late potential (LP), and right ventricular ejection fraction (RVEF), in ARVC patients.Methods and Results:We evaluated ILA on MCG, defined as discrete activations re-emerging after the decay of main RV activation (%magnitude >5%), and conventional noninvasive predictors of ventricular tachyarrhythmias (epsilon waves, LP, and RVEF) in 40 patients with ARVC. ILA was noted in 24 (60%) patients. Most ILAs were found in RV lateral or inferior areas (17/24, 71%). We defined "delayed ILA" as ILA in which the conduction delay exceeded its median (50 ms). During a median follow-up of 42.5 months, major arrhythmic events (MAEs: 1 sudden cardiac death, 3 sustained ventricular tachycardias, and 4 appropriate implantable cardioverter defibrillator discharges) occurred more frequently in patients with delayed ILA (6/12) than in those without (2/28; log-rank: P=0.004). Cox regression analysis identified delayed ILA as the only independent predictor of MAEs (hazard ratio 7.63, 95% confidence interval 1.72-52.6, P=0.007), and other noninvasive parameters were not significant predictors. Conclusions MCG is useful to identify ARVC patients at high risk of future lethal ventricular arrhythmias.

Structural brain abnormalities and cardiac dysfunction in patients with chronic heart failure

Abstract: Chronic heart failure (CHF) induces brain structural abnormalities that are associated with depressive symptoms and cognitive impairment.1–3 We have previously shown that CHF rats have histological abnormalities of the hippocampus characterized by reduction in neurogenesis and neurite outgrowth and increase in the number of astrocytes.1 Our experimental findings are consistent with clinical studies with brain magnetic resonance imaging (MRI) that demonstrated reduced grey matter volume in several cortical and subcortical regions including the hippocampus in CHF patients.2,3 A possible mechanism for brain damage in CHF patients is cerebral hypoperfusion due to cardiac dysfunction; decreasing cardiac index (CI), even at normal levels (CI <2.92 L/min/m2), is associated with reduction in total brain volume.4 However, it remains unclear which brain regions are susceptible to haemodynamic impairment in CHF patients. In this study, therefore, we examined whether there is a correlation between brain damage (e.g. the hippocampus) and cardiac dysfunction using cardiac and brain MRI recordings that had been acquired in the Brain Assessment and Investigation in Heart Failure Trial (B-HeFT).5 We enrolled 40 asymptomatic Stage B and 40 symptomatic Stage C CHF patients aged 45–90 years as described previously.5 The study protocol was approved by the ethics committee of the Tohoku University Graduate School of Medicine (no. 2012-231) and was registered in the University Hospital Medical Information Network (UMIN000008584). We performed cine cardiac (Intera Achiva 1.5 T Nova Dual, Philips Medical Systems, Best, the Netherlands) and structural T1 brain (Signa HDxt 1.5 T GE Medical Systems, Milwaukee, WI, USA) MRI within 6 months in each patient. Left ventricular stroke volume index (LVSVI) and CI were calculated using the Simpson’s method and expressed as mean± standard deviation. We performed pre-processing for brain MRI analyses as described previously.1,5 Briefly, grey matter maps were segmented from structural brain MRI scans and normalized to the standard Montreal Neurological Institute space to perform voxel-wise statistical analyses. The normalized grey matter maps were unmodulated with Jacobian determinants and were then smoothed with an isotropic Gaussian kernel by convolving a 16 mm full width at half maximum to produce grey matter concentration (GMC) maps. Only voxels with GMC value >0.05 were included.6 To explore brain regions associated with cardiac dysfunction, we first performed a voxel-wise regression analysis of the whole brain, which examined correlations between

Immunosuppressive therapy ameliorates refractory vasospastic angina, severe pulmonary hypertension, and bronchiolitis in a patient with eosinophilic granulomatosis with polyangiitis: a case report

Abstract: Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by tissue and blood eosinophilia, vasculitis of small to medium-sized vessels, and allergy symptoms, and can cause various manifestations, including heart, lung, gastrointestinal, skin, and peripheral nerve disorders. Case presentation A 34-year-old woman with a history of asthma, nasal polyp, and sinusitis presented with ventricular fibrillation after severe chest pain. Emergent coronary angiography showed no coronary stenosis. After admission, she suffered from hypoxaemia and recurrent chest pain with ST-segment changes, suggesting vasospastic angina (VSA). Chest computed tomography (CT) showed centrilobular nodular shadows, suggesting bronchiolitis. Since she had hypereosinophilia, we administered oral prednisolone, which resulted in improvements of hypereosinophilia, hypoxaemia, and recurrent chest pains in 3 days. Right heart catheterization showed severe pulmonary hypertension (PH) with a mean pulmonary artery pressure (mPAP) of 48 mmHg and pulmonary vascular resistance (PVR) of 12 Wood units (WU). Ergonovine provocation test induced severe diffuse spasm of the left coronary artery including the left main trunk. Based on asthma, sinusitis, hypereosinophilia, and chest CT findings, the diagnosis of EGPA associated with VSA and PH was made. Thereafter, we started intravenous cyclophosphamide (IV-CY) pulse therapy in addition to prednisolone and pulmonary vasodilators. Six months after IV-CY therapy, mPAP and PVR decreased to 34 mmHg and 5.1 WU, respectively. Moreover, repeated ergonovine provocation test was negative without coronary spasm or electrocardiogram (ECG) changes. Discussion This case indicates that EGPA can cause severe PH, refractory VSA, and bronchiolitis, which could be markedly improved by treating underlying conditions with immunosuppressive therapy.

Combination Therapy of Renin Angiotensin System Inhibitors and β-Blockers in Patients with Heart Failure.

Abstract: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and β-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to β-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and β-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.