Abstract 13091: Relaxation and Calcium Cycling in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction
Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). An impairment of cellular Ca2+ extrusion in diastole may contribute to this delay in relaxation. We investigated relaxation characteristics and cellular Ca2+- and Na+-handling in intact, contracting myocardial strip preparations dissected from epicardial biopsies obtained from patients with hypertensive heart disease (HHD) with and without HFpEF. Relaxation time parameters (at rates of 60/min and 180/min), cellular Ca2+- (Fura-2) and Na+- (ANG-2) cycling were studied in 20 patients with HHD without HFpEF (HHD), 12 with HHD and HFpEF (HHD(+)HFpEF) and 26 without HHD or HFpEF, who served as referent controls (CTR). Expression levels of key ion transporters were also measured. Since Ca2+-handling can be pharmacologically modified, we evaluated the therapeutic potential of the Na+-influx inhibitors ranolazine (10μM), furosemide (50μM) and amiloride (50μM) to accelerate relaxation. Compared with controls, the time to half maximal relaxation at 60/min was prolonged in both HHD and HHD(+)HFpEF (CTR: 263±5ms, HHD: 295±12ms, HHD(+)HFpEF: 296±11ms; p=0.01 and p<0.01, respectively). When the stimulation rate was increased to 180/min, this prolongation resulted in incomplete relaxation manifested as increased diastolic force in both HHD (26±3%, p=0.01) and HHD(+)HFpEF (33±9%, p=0.01). This finding was associated with an increase in diastolic Ca2+ (Fura-2: 28±6%; p<0.01) and a minor increase in Na+ (ANG-2: 0.5±0.2%; p=0.05). Expression levels of Ca2+- and Na+-handling proteins were not different between the groups. None of the pharmacologic agents accelerated relaxation or improved incomplete relaxation at high heart rates. We conclude that relaxation is prolonged in isolated myocardium from patients with HHD and HHD(+)HFpEF. An impairment of diastolic Ca2+ removal appears to play a role in incomplete relaxation at higher heart rates. This functional deficit is not due to changes in expression levels of key transporters or regulatory proteins and was not improved by pharmacologic inhibition of Na+-influx.
Author Disclosures: K.E. Runte: None. S. Bell: None. D.E. Selby: None. M.M. LeWinter: None. B.M. Palmer: None. M.F. Meyer: None.
- © 2016 by American Heart Association, Inc.