Myocardial sympathetic denervation prevents chamber-specific alteration of beta-adrenergic transmembrane signaling in rabbits with heart failure

Objectives.The purpose of this study was to assess the effect of myocardial sympathetic denervation on the chamber-specific alteration of beta-adrenergic signaling in left ventricular failure in rabbits.Background.Local abnormalities in sympathetic nerve terminals, including the neuronal reuptake of norepinephrine, are thought to be responsible for the chamber-specific regulation of beta-adrenergic signaling in heart failure.Methods.Sixteen rabbits were given 6-hydroxydopamine, 25 mg/kg body weight intravenously on days 1 and 2 and 50 mg/kg intravenously on days 7 and 8. Another 16 rabbits received vehicle. Aortic regurgitation was induced in eight of the 6-hydroxydopamine—treated and eight of the vehicle-treated rabbits on day 14. Another eight of the 6-hydroxydopamine—treated and eight of the vehicletreated rabbits underwent a sham operation. The hearts were excised for biochemical analysis on day 21.Results.Hemodynamic characteristics on day 21 showed left ventricular failure in both the aortic regurgitation groups. The plasma norepinephrine concentration on day 21 was higher in both the aortic regurgitation groups than in the sham groups. The beta-adrenoceptor densities and isoproterenol plus 5′guanylylimidodiphosphate-, 5′-guanylylimidodiphosphate- and sodium fluoride-stimulated adenylyl cyclase activities were decreased only in the failing left ventricle of the vehicle-pretreated aortic regurgitation group, but in both ventricles of the 6-hydroxydopamine-pretreated aortic regurgitation group. The basal and forskolin-stimulated adenylyl cyclase activities were similar in both the aortic regurgitation groups and in the sham groups.Conclusions.Sympathetic denervation prevented chamberspecific alterations in beta-adrenergic signaling in acute left ventricular failure. Local loss of sympathetic nerve endings, and especially the defective neuronal norepinephrine reuptake, are likely to be responsible for the chamber-specific alteration of the beta-adrenoceptor-G protein-adenylyl cyclase system in heart failure in rabbits

Validation of U.S. mortality prediction models for hospitalized heart failure in the United Kingdom and Japan: Validation of risk models in decompensated heart failure

Aims: Prognostic models for hospitalised heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health-care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) & Japan.Methods and Results: Patients in the UK (894) and Japan (3,158) were prospectively enrolled and similar in terms of sex (~60% men) and median age (~77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in-hospital [4.8% vs 2.5%] and 180-day [20.7% vs 9.5%] mortality. The model c-statistics for the published/derivation [range 0.70-0.76] and Japanese [range 0.75-0.77] cohorts were similar and higher than for the UK [0.62-0.75] but models consistently over-estimated mortality in Japan. For in-hospital mortality, OPTIMIZE-HF performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c-indices: 0.75 (0.74-0.77); 0.75 (0.68 - 0.81) and 0.77 (0.70 - 0.83)], and least over-estimated mortality in Japan. For 180-day mortality, the cstatistics for ASCEND-HF were similar in published/derivation [0.70] and UK [0.69 (0.64 - 0.74)] cohorts but higher in Japan [0.75 (0.71 - 0.79)]; calibration was good in the UK but again over-estimated mortality in Japan.Conclusion: Calibration of published prediction models appear moderately accurate and unbiased when applied to British patients but consistently overestimate mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest

Rationale and design of a randomized trial to test the safety and non‑inferiority of canagliflozin in patients with diabetes with chronic heart failure : the CANDLE trial

Background: Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure. Methods: A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function. Discussion: The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

Prognostic impact of chronic total coronary occlusion on long-term outcomes in implantable cardioverter-defibrillator recipients with ischemic heart disease

Aims The prognostic impact of chronic total coronary occlusion (CTO) on implantable cardioverterdefibrillator (ICD) recipients remains unclear. Methods and Results Eighty-four consecutive patients with ischemic heart disease who received ICD therapy for primary or secondary prevention were analyzed. We investigated all-cause mortality and major adverse cardiac events (MACEs) including cardiac death, appropriate device therapy, hospitalization for heart failure, and ventricular assist device implantation. Of the study patients (mean age 70 ± 8 years; 86% men), 34 (40%) had CTO. There were no significant differences in age, left ventricular ejection fraction (LVEF), NYHA functional class III or IV status, and proportion who underwent secondary prevention between patients with CTO (CTO group) and without CTO (non-CTO group). During a median follow-up of 3.8 years (interquartile range 2.7 to 5.4 years), the CTO group tended to have a higher MACE rate (log-rank P=0.054) than the non-CTO group. Within the CTO group, there was no difference in the MACE rate between patients with and without viable myocardium. In patients with ICD for secondary prevention (n=47), 16 patients (34%) with CTO had a higher MACE rate than patients without CTO (logrank P<0.01). Cox proportional hazards regression analysis showed that the presence of CTO, but 3 not LVEF, was associated with a higher MACE rate. Multivariate analysis showed that the presence of CTO was a predictor of MACE (P<0.05). Conclusion In patients with ischemic heart disease receiving ICD implantation, the presence of CTO has an adverse impact on long-term prognosis, especially as secondary prevention

Mortality after admission for heart failure in the UK compared with Japan

Objective Mortality amongst patients hospitalised for heart failure (HHF) in Western and Asian countries may differ, but this has not been investigated using individual patient-level data (IPLD). We sought to remedy this through rigorous statistical analysis of HHF registries and variable selection from a systematic literature review.Methods and results IPLD from registries of HHF in Japan (n=3781) and the UK (n=894) were obtained. A systematic literature review identified 23 models for predicting outcome of HHF. Five variables appearing in 10 or more reports were strongly related to prognosis (systolic blood pressure, serum sodium concentration, age, blood urea nitrogen and creatinine). To compare mortality in the UK and Japan, variables were imputed in a propensity model using inverse probability of treatment weighting (IPTW) and IPTW with logistic regression (doubly robust IPTW). Overall, patients in the UK were sicker and in-patient and post-discharge mortalities were greater, suggesting that the threshold for hospital admission was higher. Covariate-adjusted in-hospital mortality was similar in the UK and Japan (IPTW OR: 1.14, 95% CI 0.70 to 1.86), but 180-day postdischarge mortality was substantially higher in the UK (doubly robust IPTW OR: 2.33, 95% CI 1.58 to 3.43).Conclusions Despite robust methods to adjust for differences in patient characteristics and disease severity, HHF patients in the UK have roughly twice the mortality at 180 days compared with those in Japan. Similar analyses should be done using other data sets and in other countries to determine the consistency of these findings and identify factors that might inform healthcare policy and improve outcomes