Background— Chronic β-adrenergic receptor (β-AR) blockade improves cardiac contractility and prolongs survival in patients with heart failure; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the calcium (Ca ²⁺ ) release channel/cardiac ryanodine receptor (RyR2), required for cardiac excitation-contraction (EC) coupling, activating the RyR2 channel, and increasing cardiac contractility. The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. We tested the hypothesis that improved cardiac muscle function attributable to β-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure. Methods and Results— We assessed the effects of β-AR blockade on left ventricular volume using isolated perfused hearts and β-agonist responsiveness using muscle strips from patients undergoing transplantation. Twenty-four human hearts were examined, 10 from patients with heart failure treated with β-AR blockers (carvedilol, metoprolol, or atenolol), 9 from patients with heart failure without β-AR blocker treatment, and 5 normal hearts. RyR2 PKA phosphorylation was determined by back-phosphorylation, FKBP12.6 in the RyR2 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. β-AR blockers reduced left ventricular volume (reverse remodeling) and restored β-agonist response in cardiac muscle from patients with heart failure. Improved cardiac muscle function was associated with restoration of normal FKBP12.6 levels in the RyR2 macromolecular complex and RyR2 channel function. Conclusions— Improved cardiac muscle function during β-AR blockade is associated with improved cardiac Ca ²⁺ release channel function in patients with heart failure.

Background —Left ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca ²⁺ transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca ²⁺ handling. Methods and Results —The isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca ²⁺ -ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na ⁺ -Ca ²⁺ exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca ²⁺ uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca ²⁺ uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts. Conclusions —LVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca ²⁺ cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

Background — Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown. Methods and Results — Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for ≥30 days had higher central venous pressures (11±6 versus 8±5 mm Hg, P =0.04), lower pulmonary artery diastolic pressures (14±9 versus 21±9 mm Hg, P =0.01), and higher cardiac outputs (5.1±1.6 versus 3.7±1.0 L/min, P <0.001). In LVAD versus transplantation hearts, V ₃₀ (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179±75 versus 261±118 mL, P =0.005) but not in the right ventricle (RV) (140±59 versus 148±52 mL, P =NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P =0.05) than in the RV (11%, P =NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51±0.26 versus 1.04±0.34, P <0.001) but not in the RV (0.48±34 versus 0.67±0.55, P =NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae ( P =0.01) but not RV trabeculae. Conclusions — Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.