摘要
Objectives: We hypothesized that some aspects of left ventricular assist device(LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu. Background: The relative contributions of LVAD- induced hemodynamic unloading(provided to the left ventricle[LV]) and normalized neurohormonal milieu(provided to LV and right ventricle[RV]) to reverse remodeling are not understood. Methods: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients(MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation. Results: Compared with MED patients, diastolic pulmonary pressures trended lower(p< 0.01) and cardiac output higher(p< 0.001) in LVAD patients; V30(ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV(p< 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta- adrenergic stimulation in isolated LV(increase in developed force from 6.3± 0.6 to 18.5± 4.4 mN/m2, p< 0.01) and RV(increase in developed force, from 10.9± 2.0 to 20.5± 3.1 mN/m2, p< 0.05) trabeculae. The LVAD patients had higher myocardial beta- adrenergic receptor density in LV(p< 0.01) and RV(p< 0.01). Protein kinase A(PKA) hyperphosphorylation of the ryanodine receptor 2(RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV(p< 0.01). Conclusions: Improved beta- adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta- adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta- adrenergic pathway.
Objectives: We hypothesized that some aspects of left ventricular assist device(LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu. Background: The relative contributions of LVAD- induced hemodynamic unloading(provided to the left ventricle[LV]) and normalized neurohormonal milieu(provided to LV and right ventricle[RV]) to reverse remodeling are not understood. Methods: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients(MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation. Results: Compared with MED patients, diastolic pulmonary pressures trended lower(p< 0.01) and cardiac output higher(p< 0.001) in LVAD patients; V30(ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV(p< 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta- adrenergic stimulation in isolated LV(increase in developed force from 6.3± 0.6 to 18.5± 4.4 mN/m2, p< 0.01) and RV(increase in developed force, from 10.9± 2.0 to 20.5± 3.1 mN/m2, p< 0.05) trabeculae. The LVAD patients had higher myocardial beta- adrenergic receptor density in LV(p< 0.01) and RV(p< 0.01). Protein kinase A(PKA) hyperphosphorylation of the ryanodine receptor 2(RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV(p< 0.01). Conclusions: Improved beta- adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta- adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta- adrenergic pathway.
