Abstract-Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca 2ϩ

No abstract

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.

No abstract

Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (I(Ca,L)) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal I(Ca,L) density was not different in the 3 groups but I(Ca,L) was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V(0.5): -7.18+/-1.4 and -7.0+/-0.9 versus 0.46+/-1.1 mV). Both ISO and db-cAMP increased I(Ca,L) in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90+/-15% versus 77+/-19% versus 24+/-12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the I(Ca,L) activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the I(Ca,L) activation was not significantly different between groups. BayK also increased I(Ca,L) more in NF- (81+/-30%) and LVAD- (70+/-15%) than in F- (51+/-8%) HVMs. OA increased I(Ca, L) by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased I(Ca, L) in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal I(Ca,L) density is maintained by increasing in LTCC phosphorylation.

Background-Sarcolemmal

Background Alterations in Ca 2+ -handling proteins are thought to underlie the deranged Ca 2+ transients that contribute to deterioration of cardiac function in congestive heart failure (CHF). Clinical trials in CHF patients have shown that treatment with β-adrenergic receptor antagonists (βB) improves cardiac performance. The present study determined whether the abundance of Ca 2+ -handling proteins is different in failing hearts from patients treated or untreated with β B. Methods and Results Ca 2+ regulatory protein abundance was compared in LV myocardium of 10 nonfailing hearts (NF group) and 44 failing hearts (CHF group) removed at transplantation. Analysis was performed in βB-treated (βB-CHF) and non–βB treated (non-βB-CHF) patients and in 4 subgroups: ischemic cardiomyopathy (ICM, n=10), nonischemic dilated cardiomyopathy (DCM, n=10), ICM with βB therapy (βB-ICM, n=12), and DCM with βB therapy (βB-DCM, n=12). Sarcoplasmic reticulum Ca 2+ ATPase, phospholamban, and Na + -Ca 2+ exchanger protein abundance were determined by use of Western blot analysis. Ca 2+ transients were measured with fluo-3. Sarcoplasmic reticulum Ca 2+ ATPase was significantly less abundant whereas phospholamban and Na + -Ca 2+ exchanger were not significantly altered in non-βB-CHF versus NF. Sarcoplasmic reticulum Ca 2+ ATPase in the βB-ICM and βB-DCM was greater than in non-βB-CHF and were not different than in NF. Ca 2+ transients in non-βB-CHF myocytes had significantly smaller peaks and were prolonged versus NF myocytes. Ca 2+ transients from βB-CHF myocytes had shorter durations than in βB-CHF myocytes. Conclusions βB treatment in CHF patients can normalize the abundance of myocyte Ca 2+ regulatory proteins and improve Ca 2+ -handling.

Background-Recognizing that mechanical circulatory support with a left ventricular assist device (LVAD) induces changes in myocardial structure and contractile function, we examined whether there are changes in ventricular conduction and/or repolarization among failing human hearts after LVAD implantation. Methods and Results-We examined 12-lead electrocardiograms before surgery, immediately after LVAD placement, and at a delayed (Ͼ1 week) postoperative time point in 23 patients who were receiving LVAD support for refractory heart failure. The immediate effects of hemodynamic unloading via LVAD placement included a decrease in QRS duration from 117Ϯ6 to 103Ϯ6 ms (PϽ0.01), an increase in absolute QT duration from 359Ϯ6 to 378Ϯ8 ms (PϽ0.05), and an increase in the heart rate-corrected QT interval (QTc) from 379Ϯ10 to 504Ϯ11 ms (PϽ0.01). None of these immediate changes were observed among 22 patients undergoing routine coronary artery bypass grafting. With sustained cardiac unloading via LVAD support, there was a marked decrease in the QTc from 504Ϯ11 to 445Ϯ9 ms (PϽ0.001). Studies in isolated cardiac myocytes, obtained at the time of transplantation, confirmed that delayed decreases in heart rate-adjusted QTc were the result of decreases in action potential duration after LVAD support. Conclusions-Acute electrocardiogram responses to LVAD placement demonstrate the dependence of QRS and QT duration on load in the failing human heart. Delayed decreases in QTc and action potential duration reflect reversal of electrophysiologic remodeling in the failing heart. Shortening of the action potential duration likely contributes to the improved cellular contractile performance observed after sustained LVAD support.