In heart failure (HF), Ca 2+ /calmodulin kinase II (CaMKII) expression is increased. Altered Na + channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na + channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδ C on Na + current (I Na ) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδ C overexpression shifted voltage dependence of Na + channel availability by -6 mV (P < 0.05), and the shift was Ca 2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIδ C markedly increased persistent (late) inward I Na and intracellular Na + concentration (as measured by the Na + indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδ C overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na + channels. In vivo, transgenic CaMKIIδ C overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na + channels. This alters I Na gating to reduce availability at high heart rate, while enhancing late I Na (which could prolong action potential duration). In mice, enhanced CaMKIIδ C activity predisposed to VT. Thus, CaMKIIdependent regulation of Na + channel function may contribute to arrhythmogenesis in HF.

By discriminating failing human hearts according to their diastolic function, we identified different phenotypes. Disturbed diastolic function occurs in hearts with decreased SR Ca2+-ATPase and unchanged Na+-Ca2+ exchanger, whereas increased expression of the Na+-Ca2+ exchanger is associated with preserved diastolic function.

Abstract-Disturbed sarcoplasmic reticulum (SR) Ca 2ϩ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca 2ϩ content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37°C), nonfailing human myocardium (nϭ7) exhibited a parallel increase in postrest twitch force (at 240 s by 121Ϯ44%; PϽ0.05) and RCC amplitude (by 69Ϯ53%; PϽ0.05). In contrast, in failing myocardium (nϭ30), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 25Ϯ9% and 53Ϯ9%, respectively; PϽ0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (nϭ7) by 71Ϯ17% (at 3 Hz; PϽ0.05) and RCC amplitude increased in parallel by 247Ϯ55% (PϽ0.05). In contrast, in failing myocardium (nϭ26), twitch force declined by 29Ϯ7% (PϽ0.05) and RCC amplitude increased only slightly by 36Ϯ14% (PϽ0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca 2ϩ uptake and Na ϩ /Ca 2ϩ exchange to cytosolic Ca 2ϩ removal during relaxation. SR Ca 2ϩ uptake (relative to the Na ϩ /Ca 2ϩ exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca 2ϩ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca 2ϩ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca 2ϩ content.

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Background — In the failing human heart, altered Ca 2+ homeostasis causes contractile dysfunction. Because Ca 2+ and Na + homeostasis are intimately linked through the Na + /Ca 2+ exchanger, we compared the regulation of [Na + ] i in nonfailing (NF) and failing human myocardium. Methods and Results — [Na + ] i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37°C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4±1.2 versus 7.2±1.9 mN/mm 2 ), but [Na + ] i and diastolic force were greater in failing (22.1±2.6 mmol/L and 15.6±3.2 mN/mm 2 ) than in NF (15.9±3.1 mmol/L and 3.50±0.55 mN/mm 2 ; P <0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na + ] i without changes in diastolic tension. At 2.0 Hz, force increased to 136±17% of the basal value ( P <0.05), and [Na + ] i to 20.5±4.2 mmol/L ( P <0.05). In contrast, in failing myocardium, force declined to 45±3%, whereas [Na + ] i increased to 27.4±3.2 mmol/L (both P <0.05), in association with significant elevations in diastolic tension. [Na + ] i was higher in failing than in NF myocardium at every stimulation rate. [Na + ] i predicted in myocytes from Na + pipette -contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P <0.05) myocardium at 0.25 Hz. Reverse-mode Na + /Ca 2+ exchange induced significant Ca 2+ influx in failing but not NF myocytes, compatible with higher [Na + ] i in failing myocytes. Conclusions — Na + i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na + ] i in failing myocardium appears to enhance Ca 2+ influx through Na + /Ca 2+ exchange and maintain sarcoplasmic reticulum Ca 2+ load and force development. At faster rates, failing myocytes with high [Na + ] i cannot further increase sarcoplasmic reticulum Ca 2+ load and are prone to diastolic Ca 2+ overload.

AimsThe aim of this study was to investigate the effect of contact-to-balloon time on mortality in ST-segment elevation myocardial infarction (STEMI) patients with and without haemodynamic instability.Methods and resultsUsing data from the prospective, multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial, we assessed the prognostic relevance of first medical contact-to-balloon time in n = 12 675 STEMI patients who used emergency medical service transportation and were treated with primary percutaneous coronary intervention (PCI). Patients were stratified by cardiogenic shock (CS) and out-of-hospital cardiac arrest (OHCA). For patients treated within 60 to 180 min from the first medical contact, we found a nearly linear relationship between contact-to-balloon times and mortality in all four STEMI groups. In CS patients with no OHCA, every 10-min treatment delay resulted in 3.31 additional deaths in 100 PCI-treated patients. This treatment delay-related increase in mortality was significantly higher as compared to the two groups of OHCA patients with shock (2.09) and without shock (1.34), as well as to haemodynamically stable patients (0.34, P < 0.0001).ConclusionsIn patients with CS, the time elapsing from the first medical contact to primary PCI is a strong predictor of an adverse outcome. This patient group benefitted most from immediate PCI treatment, hence special efforts to shorten contact-to-balloon time should be applied in particular to these high-risk STEMI patients.Clinical Trial RegistrationNCT00794001.

Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibition), whereas small inotropic effects of levosimendan may result predominantly from calcium sensitization.

Background Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δC mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. Methods and Results Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10−8 M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]i rose clearly on ISO in TG but not in wild-type cells (+20±5% versus +3±4% at 10−6 M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9±0.5 versus 2.0±0.4 sparks per 100 μm−1·s−1, P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIδ-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05). Conclusions We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIδC mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.