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Although measuring right ventricular (RV) function during exercise is more informative than assessing it at rest, the relationship between RV reserve function, exercise capacity, and health-related quality of life (HRQoL) in patients with left ventricular assist devices (LVAD) remains unresolved. We aimed to investigate whether RV reserve assessed by the change in RV stroke work index (RVSWI) during exercise is correlated with exercise capacity and HRQoL in patients with LVAD. We prospectively assessed 24 consecutive patients with LVAD who underwent invasive right heart catheterization in the supine position. Exercise capacity and HRQoL were assessed using the 6-min walk distance (6 MWD) and peak oxygen consumption (VO2) in cardiopulmonary exercise testing, and the EuroQol visual analog scale (EQ-VAS), respectively. The patients were divided into two groups according to the median DRVSWI (change from rest to peak exercise). Patients with lower DRVSWI had significantly lower changes in cardiac index and absolute value of RV dP/dt than those with higher ΔRVSWI. The ΔRVSWI was positively correlated with 6 MWD (r = 0.59, P = 0.003) and peak VO2 (r = 0.56, P = 0.006). In addition, ΔRVSWI was positively correlated with the EQ-VAS (r = 0.44, P = 0.030). In contrast, there was no significant correlation between RVSWI at rest and 6 MWD (r = -0.34, P = 0.88), peak VO2 (r = 0.074, P = 0.74), or EQ-VAS (r = 0.127, P = 0.56). Our findings suggest that the assessment of RV reserve function is useful for risk stratification in patients with LVAD. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy has been reported to increase the risk of fatal ventricular arrhythmia. The beneficial effects of the selective sodium-glucose cotransporter-2 inhibitor have not been fully examined in the context of antiarrhythmic therapy, especially its direct cardioprotective effects despite the negligible SGLT2 expression in cardiomyocytes. We aimed to examine the antiarrhythmic effects of empagliflozin (EMPA) treatment on diabetic cardiomyocytes, with a special focus on Ca2+ handling. We conducted echocardiography and hemodynamic studies and studied electrophysiology, Ca2+ handling, and protein expression in C57BLKS/J-leprdb/db mice (db/db mice) and their nondiabetic lean heterozygous Leprdb/+ littermates (db/+ mice). Preserved systolic function with diastolic dysfunction was observed in 16-wk-old db/db mice. During arrhythmia induction, db/db mice had significantly increased premature ventricular complexes (PVCs) than controls, which was attenuated by EMPA. In protein expression analyses, calmodulin-dependent protein kinase II (CaMKII) Thr287 autophosphorylation and CaMKII-dependent RyR2 phosphorylation (S2814) were significantly increased in diabetic hearts, which were inhibited by EMPA. In addition, global O-GlcNAcylation significantly decreased with EMPA treatment. Furthermore, EMPA significantly inhibited ventricular cardiomyocyte glucose uptake. Diabetic cardiomyocytes exhibited increased spontaneous Ca2+ events and decreased sarcoplasmic reticulum (SR) Ca2+ content, along with impaired Ca2+ transient, all of which normalized with EMPA treatment. Notably, most EMPAinduced improvements in Ca2+ handling were abolished by the addition of an O-GlcNAcase (OGA) inhibitor. In conclusion, EMPA attenuated ventricular arrhythmia inducibility by normalizing the intracellular Ca2+ handling, and we speculated that this effect was, at least partly, due to the inhibition of O-GlcNAcylation via the suppression of glucose uptake into cardiomyocytes. [ABSTRACT FROM AUTHOR]

Aims High-mobility group box 1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic cells and activated macrophages. We investigated clinical implications of serum HMGB1 elevation in patients with acute myocardial infarction (MI). Then, we evaluated the effect of HMGB1 blockade on post-MI left ventricular (LV) remodelling in a rat MI model. Methods and results Serum HMGB1 levels were examined in patients with ST-elevation MI (n = 35). A higher peak serum HMGB1 level was associated with pump failure, cardiac rupture, and in-hospital cardiac death. Then, an experimental MI model was induced in male Wistar rats. The mRNA and protein expression of HMGB1 were increased in the infarcted area compared with those values observed in sham-operated rats. We administered neutralizing anti-HMGB1 antibody (MI/anti-H) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumour necrosis factor-α and interleukin-1β and the number of macrophages in the infarcted area were reduced on day 3 in MI/anti-H rats compared with MI/C rats. Interestingly, HMGB1 blockade resulted in thinning and expansion of the infarct scar and marked hypertrophy of the non-infarcted area on day 14. Conclusion Elevated serum HMGB1 levels were associated with adverse clinical outcomes in patients with MI. However, HMGB1 blockade in a rat MI model aggravated LV remodelling, possibly through impairment of the infarct-healing process. HMGB1, a novel predictor of adverse clinical outcomes after MI, may have an essential role in the appropriate healing process after MI. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca2+ -activated K+(SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by S-methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin (APA). Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of posttranslational modification of SK channels. NEW & NOTEWORTHY We demonstrated that pharmacological nNOS inhibition increased the atrial arrhythmia inducibility and a specific small-conductance Ca2+ -activated K+ channel blocker, apamin, reversed the enhanced atrial arrhythmia inducibility. Apamin mitigated APD abbreviation without alteration of Ca2+ transient, implying an underlying mechanism of posttranslational modification of SK channels. [ABSTRACT FROM AUTHOR]

This study was undertaken to assess the impact of acute hyperglycemia (acute-HG) and chronic hyperglycemia (chronic-HG) on short-term outcomes in patients with acute myocardial infarction (AMI). This study consisted of 696 patients with AMI. Acute-HG was defined as admission plasma glucose ≥200 mg/dl and chronic-HG as hemoglobin A1c ≥6.5%. Acute-HG was associated with higher peak serum creatine kinase (4,094 ± 4,594 vs 2,526 ± 2,227 IU/L, p <0.001) and in-hospital mortality (9.8% vs 1.6%, p <0.001). On the contrary, there was no significant difference in peak creatine kinase (2,803 ± 2,661 vs 2,940 ± 3,181 IU/L, p = 0.59) and mortality (3.3 vs 3.7%, p = 0.79) between patients with chronic-HG and those without. Multivariate analysis showed that admission plasma glucose was an independent predictor of in-hospital mortality (odds ratio 1.15, 95% con-fidence interval 1.05 to 1.27, p <0.001), but hemoglobin A1c was not. When only patients with acute-HG were analyzed, chronic-HG was associated with a significantly smaller infarct size (3,221 ± 3,001 vs 5,904 ± 6,473 IU/L, p <0.001) and lower in-hospital mortality (5.5 vs 18.9%, p = 0.01). In conclusion, these results suggested that acute-HG, but not chronic-HG, was associated with adverse short-term outcomes after AMI. Paradoxically, in patients with acute-HG, chronic-HG might abate the adverse effects of acute-HG. [ABSTRACT FROM AUTHOR]