Published Online
on July 21, 2009

A more recent version of this article appeared on September 1, 2009

This Article Full Text (PDF) Supplemental Data All Versions of this Article: 2/5/472    most recent CIRCHEARTFAILURE.109.853200v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Varian, K. D. Articles by Janssen, P. M.L. PubMed PubMed Citation Articles by Varian, K. D. Articles by Janssen, P. M.L. Related Collections Contractile function Calcium cycling/excitation-contraction coupling Heart failure - basic studies Hypertrophy

Original Article

Impairment of Diastolic Function by Lack of Frequency-Dependent Myofilament Desensitization in Rabbit Right Ventricular Hypertrophy

Kenneth D. Varian; Anusak Kijtawornrat; Subash C. Gupta; Carlos A.A. Torres; Michelle M. Monasky; Nitisha Hiranandani; Dawn A. Delfin; Jill A. Rafael-Fortney; Muthu Periasamy; Robert L. Hamlin and Paul M.L. Janssen¹

The Ohio State University, Columbus, OH

¹ E-mail: janssen.10{at}osu.edu

Background—Ventricular hypertrophy is a physiological response to pressure overload that if left untreated can ultimately result in ventricular dysfunction, including diastolic dysfunction. The aim of this study was to test the hypothesis that frequency-dependent myofilament desensitization, a physiological response of healthy myocardium, is altered in hypertrophied myocardium.

Methods and Results—New Zealand White rabbits underwent a pulmonary artery banding (PAB) procedure to induce pressure overload. After 10 weeks the animals were euthanized, hearts removed, and suitable trabeculae harvested from the free wall of the right ventricle. Twitch contractions, calibrated bis-fura-2 calcium transients, and myofilament calcium sensitivity (potassium contractures) were measured at frequencies of 1, 2, 3, and 4 Hz. The force frequency response, relaxation frequency response, and calcium frequency relationships were significantly blunted and diastolic tension significantly increased with frequency in the PAB rabbits compared to sham operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11±0.03 vs. 6.11±0.06) but the frequency-dependent desensitization that takes place in the sham group (pCa 0.14±0.06, p<0.05) was not observed in the PAB animals (pCa 0.02±0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of TnI is lost in PAB rabbits.

Conclusion—The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy, and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy.

Key Words: heart rate • hypertrophy • Calcium Sensitivity • EC-coupling • Myofilaments

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