Relaxation and the Role of Calcium in Isolated Contracting Myocardium from Patients with Hypertensive Heart Disease and Heart Failure with Preserved Ejection Fraction

K. Elisabeth Runte, Stephen P. Bell, Donald E. Selby, Tim N. Häußler, Takamuru Ashikaga, Martin M. Lewinter, Bradley M. Palmer, Markus Meyer

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Background Relaxation characteristics and Ca2+ homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study, we evaluated relaxation parameters, myocardial calcium (Ca2+), and sodium (Na+) handling, as well as ion transporter expression and tested the effect of Na+-influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF. Methods and Results Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60 and 180 per minute. Intracellular Ca2+ and Na+ were simultaneously assessed using Fura-2 and AsanteNATRIUMGreen-2, whereas elemental analysis was used to measure total myocardial concentrations of Ca, Na, and other elements. Quantitative polymerase chain reaction was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na+-influx inhibitors ranolazine, furosemide, and amiloride was evaluated. Myocardial left ventricular biopsies were obtained from 36 control patients, 29 HHD and 19 HHD+HFpEF. When compared with control patients, half maximal relaxation time (RT50) at 60 per minute was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both P<0.05). Elevated resting Ca2+ levels and a tachycardia-induced increase in diastolic Ca2+ were associated with incomplete relaxation and an increase in diastolic tension in HHD and HHD+HFpEF. Na+ levels were not increased, and expression levels of Ca2+- or Na+-handling proteins were not altered. Na+-influx inhibitors did not improve relaxation or prevent incomplete relaxation at high stimulation rates. Conclusions Contraction and relaxation are prolonged in isolated myocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither a result of an impaired Na+ gradient nor expression changes in key ion transporters and regulatory proteins.

Original languageEnglish (US)
Article numbere004311
JournalCirculation: Heart Failure
Issue number8
StatePublished - Aug 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
The target sample preparation and quantitative polymerase chain reaction of myocardial tissue samples was performed by the University of Vermont Cancer Center, which is supported by an Institutional Development Award from the National Institutes of Health (P20GM103449). Technical help was provided by Richard Lachapelle (experimental stage) and Zengyi Chien (Western blots). We would like to express their profound appreciation to all patients and surgeons, for their willingness to donate and procure myocardial biopsies.

Funding Information:
This research was supported by the National Institutes of Health R01 HL-118524 (Dr LeWinter), R01 HL-122744 (Dr Meyer), and a grant from Gilead Sciences provided by Louis Belardinelli.

Publisher Copyright:
© 2017 American Heart Association, Inc.


  • Fura-2
  • diastole
  • heart failure
  • sodium


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