Toshiaki Izumi

Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of δ-Isoform of Protein Kinase C in Rat Ventricular Myocardium

BACKGROUND A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.

Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

Background—In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated. Methods and Results—We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in &agr;-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (−0.87±0.18 pA/pF at −30 mV, P <0.01 versus LVH). This was associated with a significant increase in the &agr;-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of &agr;-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats. Conclusions—ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

The Cardioprotective Effects of a New 1,4-Benzothiazepine Derivative, JTV519, on Ischemia/Reperfusion-Induced Ca2+ Overload in Isolated Rat Hearts

A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 μM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 μM. In indol-loaded isolated heart preparations, 0.3 μM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 ± 3.2%; JTV(+), by 18.4 ± 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-Type Ca2+ channel (ICa). The % inhibition of the peak current of ICa was 6.2 ± 0.8% at 0.3 μM (p = n.s.), 22.0 ± 3.3% at 1.0 μM (p < 0.05), and 59.6 ± 1.4% at 3.0 μM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 μM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through ICa. In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with ICa, and by its subsequent ability of strong myocardial protection.

Association between Psoriasis Vulgaris and Coronary Heart Disease in a Hospital-Based Population in Japan

Background Psoriasis vulgaris is a chronic inflammatory skin disease with an immune-genetic background. It has been reported as an independent risk factor for coronary heart disease (CHD) in the United States and Europe. The purpose of this study was to investigate the association between psoriasis and CHD in a hospital-based population in Japan. Methods For 113,065 in-hospital and clinic patients at our institution between January 1, 2011 and January 1, 2013, the diagnostic International Classification of Diseases (ICD)-10 codes for CHD, hypertension, dyslipidemia, diabetes, and psoriasis vulgaris were extracted using the medical accounting system and electronic medical record, and were analyzed. Results The prevalence of CHD (n = 5,167, 4.5%), hypertension (n = 16,476, 14.5%), dyslipidemia (n = 9,236, 8.1%), diabetes mellitus (n = 11,555, 10.2%), and psoriasis vulgaris (n = 1,197, 1.1%) were identified. The prevalence of CHD in patients with hypertension, dyslipidemia, diabetes, and psoriasis vulgaris were 21.3%, 22.2%, 21.1%, and 9.0%, respectively. In 1,197 psoriasis patients, those with CHD were older, more likely to be male, and had more number of the diseases surveyed by ICD-10 codes. Multivariate analysis showed that psoriasis vulgaris was an independent associated factor for CHD (adjusted odds ratio [OR]: 1.27; 95% confidence interval [CI]: 1.01–1.58; p = 0.0404) along with hypertension (adjusted OR: 7.78; 95% CI: 7.25–8.36; p < 0.0001), dyslipidemia (adjusted OR: 2.35; 95% CI: 2.19–2.52; p < 0.0001), and diabetes (adjusted OR: 2.86; 95% CI: 2.67–3.06; p < 0.0001). Conclusion Psoriasis vulgaris was independently associated with CHD in a hospital-based population in Japan.

Effect on treadmill exercise capacity, myocardial ischemia, and left ventricular function as a result of repeated whole-body periodic acceleration with heparin pretreatment in patients with angina pectoris and mild left ventricular dysfunction.

Whole-body periodic acceleration (WBPA) has been developed as a passive exercise device capable of improving endothelial function by applying pulsatile shear stress to vascular endothelium. We hypothesized that treatment with WBPA improves exercise capacity, myocardial ischemia, and left ventricular (LV) function because of increased coronary and peripheral vasodilatory reserves in patients with angina. Twenty-six patients with angina who were not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting were randomly assigned to remain sedentary (sedentary group) or undergo 20 sessions of WBPA with the motion platform for 4 weeks (WBPA group) in addition to conventional medical treatment. WBPA was applied at 2 to 3 Hz and approximately ±2.2 m/s² for 45 minutes. We repeated the symptom-limited treadmill exercise test and adenosine sestamibi myocardial scintigraphy. In the WBPA group, the exercise time until 0.1-mV ST-segment depression increased by 53% (p <0.01) and the double product at 0.1-mV ST-segment depression by 23% (p <0.001). Severity score of myocardial scintigraphy during adenosine infusion decreased from 20 ± 10 to 14 ± 8 (p <0.001) and severity score at rest also decreased from 13 ± 10 to 8 ± 10 (p <0.01). On scintigraphic images at rest, LV end-diastolic volume index decreased by 18% (p <0.01) with an augmentation of LV ejection fraction from 50 ± 16% to 55 ± 16% (p <0.01). In contrast, all studied parameters remained unchanged in the sedentary group. In conclusion, treatment with WBPA for patients with angina ameliorates exercise capacity, myocardial ischemia, and LV function.

Impact of the left ventricular mass index on the outcomes of severe aortic stenosis

Objective To elucidate the factors associated with high left ventricular mass index (LVMI) and to test the hypothesis that high LVMI is associated with worse outcome in severe aortic stenosis (AS). Methods We analysed 3282 patients with LVMI data in a retrospective multicentre registry enrolling consecutive patients with severe AS in Japan. The management strategy, conservative or initial aortic valve replacement (AVR), was decided by the attending physician. High LVMI was defined as LVMI >115 g/m2 for males and >95 g/m2 for females. We compared the risk between normal and high LVMI in the primary outcome measures compromising aortic valve-related death and heart failure hospitalisation. Results Age was mean 77 (SD 9.6) years and peak aortic jet velocity (Vmax) was 4.1 (0.9) m/s. The factors associated with high LVMI (n=2374) included female, body mass index ≥22, absence of dyslipidemia, left ventricular ejection fraction <50%, Vmax ≥4 m/s, regurgitant valvular disease, hypertension, anaemia and end-stage renal disease. In the conservative management cohort (normal LVMI: n=691, high LVMI: n=1480), the excess adjusted 5-year risk of high LVMI was significant (HR: 1.53, 95% CI 1.26 to 1.85, p<0.001). In the initial AVR cohort (normal LVMI: n=217, high LVMI: n=894), the risk did not differ significantly between the two groups (HR: 0.96, 95% CI 0.60 to 1.55, p=0.88). There was a significant interaction between the initial treatment strategy and the risk of high LVMI (p=0.016). Conclusions The deleterious impact of high LVMI on outcome was observed in patients managed conservatively, but not observed in patients managed with initial AVR. Trial registration number UMIN000012140; Post-results.

Cardiac tamponade during transesophageal echocardiography in a patient with infective endocarditis.

An 81-year-old man with a history of diabetes mellitus and end-stage renal disease was admitted because of infective endocarditis. During transesophageal echocardiography (TEE), pericardial effusion rapidly increased and led to cardiac tamponade. Despite intensive therapy, the patient did not recover. Autopsy showed hemopericardium, ruptured sinus of Valsalva, and vegetation on the aortic valve. Our case suggests that cardiac tamponade due to the rupture of a sinus of Valsalva can occur in patients with aortic valve endocarditis complicated by perivalvular abscess. Therefore, we must be aware of this devastating complication and take preventive measures when performing TEE in such patients.

Risk stratification for major adverse cardiac events and ventricular tachyarrhythmias by cardiac MRI in patients with cardiac sarcoidosis

Background The presence of myocardial fibrosis by cardiac MRI has prognostic value in cardiac sarcoidosis, and localisation may be equally relevant to clinical outcomes. Objective We aimed to analyse cardiac damage and function in detail and explore the relationship with clinical outcomes in patients with cardiac sarcoidosis using cardiac MRI. Methods We included 81 consecutive patients with cardiac sarcoidosis undergoing cardiac MR. Left ventricular mass and fibrosis mass were calculated, and localisation was analysed using a 17-segment model. Participants underwent follow-up through 2015, and the development of major adverse cardiac events including ventricular tachyarrhythmias was recorded. Results Increased left ventricular fibrosis mass was associated with increased prevalence of ventricular tachyarrhythmias (p<0.001). When localisation was defined as the sum of late gadolinium enhancement in the left ventricular basal anterior and basal anteroseptal areas, or the right ventricular area, it was associated with ventricular tachyarrhythmias (p<0.001). Kaplan-Meier analysis during a median follow-up of 22.1 months showed that both the mass and localisation groupings for fibrosis were significantly associated with major adverse cardiac events or ventricular tachyarrhythmias and that when combined, the risk stratification was better than for each variable alone (p<0.001, respectively). By Cox-proportional hazard risk analysis, the localisation grouping was an independent predictor for the both. Conclusions In patients with cardiac sarcoidosis, both fibrosis mass and its localisation to the basal anterior/anteroseptal left ventricle, or right ventricle was associated with the development of major adverse cardiac events or ventricular tachyarrhythmias. Cardiac MR with late gadolinium enhancement may be useful for improving risk stratification in patients with cardiac sarcoidosis.

Adaptive servoventilation versus oxygen therapy for sleep disordered breathing in patients with heart failure: a randomised trial

Background Both adaptive servoventilation (ASV) and nocturnal oxygen therapy improve sleep disordered breathing (SDB), but their effects on cardiac parameters have not been compared systematically. Methods and results 43 patients with chronic heart failure (CHF; left ventricular ejection fraction (LVEF) ≤50%) with SDB were randomly assigned to undergo ASV (n=19, apnoea hypopnoea index (AHI)=34.2±12.1/h) or oxygen therapy (n=24, 36.9±9.9/h) for 3 months. More than 70% of SDB events in both groups were central apnoeas or hypopnoeas. Although nightly adherence was less for the ASV group than for the oxygen group (4.4±2.0 vs 6.2±1.8 h/day, p<0.01), the improvement in AHI was larger in the ASV group than in the oxygen group (−27.0±11.5 vs −16.5±10.2/h, p<0.01). The N-terminal pro-brain natriuretic peptide (NT-proBNP) level in the ASV group improved significantly after titration (1535±2224 to 1251±2003 pg/mL, p=0.01), but increased slightly at follow-up and this improvement was not sustained (1311±1592 pg/mL, p=0.08). Meanwhile, the level of plasma NT-proBNP in the oxygen group did not show a significant change throughout the study (baseline 1071±1887, titration 980±1913, follow-up 1101±1888 pg/mL, p=0.19). The significant difference in the changes in the NT-proBNP level throughout the study between the 2 groups was not found (p=0.30). Neither group showed significant changes in echocardiographic parameters. Conclusions Although ASV produced better resolution of SDB in patients with CHF as compared with oxygen therapy, neither treatment produced a significant improvement in cardiac function in the short term. Although we could not draw a definite conclusion because of the small number of participants, our data do not seem to support the routine use of ASV or oxygen therapy to improve cardiac function in patients with CHF with SDB. Trial registration number NCT01187823 (http://www.clinicaltrials.gov).

A Propensity Score-Matching Analysis of Transthoracic Echocardiography and Abdominal Ultrasonography for the Detection of Abdominal Aortic Aneurysms

Introduction We previously reported that the prevalence of abdominal aortic aneurysms (AAAs) was higher in patients undergoing scheduled transthoracic echocardiography (TTE) than in patients undergoing abdominal ultrasonography (AUS); however, intergroup patient backgrounds differed significantly in that report. Purpose We tested the hypothesis that TTE could detect AAA as effectively as AUS. Design A propensity score-matching analysis of a cross-sectional study was adopted as the design for this study. Methods We enrolled 7,619 and 15,433 patients scheduled to undergo TTE with additional evaluation of abdominal aorta at the end of the routine study and AUS, respectively, from 2009 to 2010 in our hospital, as reported. A propensity score for profiles of patients who underwent TTE or AUS was developed to adjust for potential confounding bias. Consequently, 4,388 patients in each group were matched for analyses. Results In propensity-matched patients, AAA was detected in 59 patients of the TTE group and in 48 patients of the AUS group; the prevalence of AAA detection did not differ significantly between TTE and AUS groups (P = 0.331). Positive associations were observed between AAA detection and male sex (adjusted odds ratio [OR]: 3.25; 95% confidence interval [CI], 2.05-5.15; P < 0.001), older age (adjusted OR: 1.029; 95% CI: 1.01-1.04; P < 0.001), and the presence of ischemic heart disease (adjusted OR: 1.78; 95% CI: 1.04-3.03; P = 0.033) and hypertension (adjusted OR: 2.16; 95% CI: 1.38-3.37; P = 001). Conclusion TTE detected AAA with comparable efficacy as AUS in propensity-matched groups who underwent scheduled TTE and AUS.