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Impairment of diastolic function by lack of frequency-dependent myofilament desensitization rabbit right ventricular hypertrophy.

ABSTRACT: 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.New Zealand white rabbits underwent a pulmonary artery banding 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 pulmonary artery banding rabbits compared with sham-operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11 + or - 0.03 versus 6.11 + or - 0.06), but the frequency-dependent desensitization that takes place in the sham group (DeltapCa 0.14 + or - 0.06, P<0.05) was not observed in the pulmonary artery banding animals (DeltapCa 0.02 + or - 0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of troponin-I is lost in pulmonary artery banding rabbits.The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy.

SUBMITTER: Varian KD

PROVIDER: S-EPMC2768816 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Impairment of diastolic function by lack of frequency-dependent myofilament desensitization rabbit right ventricular hypertrophy.

Varian Kenneth D KD Kijtawornrat Anusak A Gupta Subash C SC Torres Carlos A A CA Monasky Michelle M MM Hiranandani Nitisha N Delfin Dawn A DA Rafael-Fortney Jill A JA Periasamy Muthu M Hamlin Robert L RL Janssen Paul M L PM

Circulation. Heart failure 20090721 5

<h4>Background</h4>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.<h4>Methods and results</h4>New Zealand white rabbits underwent a pulmonary artery banding procedure to induce ...[more]

PMID: 19808378

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Project description:BackgroundPatients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function.MethodsCardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined.ResultsMyocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28% higher in IPAH but 37% lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2 =0.46, P=0.002) and change in end-systolic elastance with exercise (R2 =0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2 =0.63, P<0.002), which also was a marker of depressed contractile reserve.ConclusionsA primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.

Project description:Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca(2+) sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH.RV samples from PAH patients undergoing heart-lung transplantation were compared to non-failing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western-blot analyses using antibodies to protein-kinase-A (PKA), C? (PKC?) and Ca(2+)/calmoduling-dependent-kinase (CamKII?) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKC? sites were significantly less phosphorylated in PAH compared with donors (P<0.0001). To test the functional relevance of PKA-, PKC?-, and CamKII?-mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKC? further increased stiffness while CamKII? had no major effect. CamKII? activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca(2+) sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (P<0.05) and reduced PKA-mediated cTnI phosphorylation (Ser22/23) (P<0.001). Finally, alterations in Ca(2+)-handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca(2+) clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (P<0.05).Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca(2+) handling proteins contribute to RV diastolic dysfunction in PAH.

Dataset Information

Impairment of diastolic function by lack of frequency-dependent myofilament desensitization rabbit right ventricular hypertrophy.

Publications

Impairment of diastolic function by lack of frequency-dependent myofilament desensitization rabbit right ventricular hypertrophy.

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