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Pressure Overload Is Associated With Low Levels of Troponin I and Myosin Binding Protein C Phosphorylation in the Hearts of Patients With Aortic Stenosis.

ABSTRACT: In previous studies of septal heart muscle from HCM patients with hypertrophic obstructive cardiomyopathy (HOCM, LVOT gradient 50-120 mmHg) we found that the level of phosphorylation of troponin I (TnI) and myosin binding protein C (MyBP-C) was extremely low yet samples from hearts with HCM or DCM mutations that did not have pressure overload were similar to donor heart controls. We therefore investigated heart muscle samples taken from patients undergoing valve replacement for aortic stenosis, since they have pressure overload that is unrelated to inherited cardiomyopathy. Thirteen muscle samples from septum and from free wall were analyzed (LVOT gradients 30-100 mmHg) The levels of TnI and MyBP-C phosphorylation were determined in muscle myofibrils by separating phosphospecies using phosphate affinity SDS-PAGE and detecting with TnI and MyBP-C specific antibodies. TnI was predominantly monophosphorylated and total phosphorylation was 0.85 ± 0.03 molsPi/mol TnI. This phosphorylation level was significantly different (p < 0.0001) from both donor heart TnI (1.6 ± 0.06 molsPi/mol TnI) and HOCM heart TnI (0.19 ± 0.04 molsPi/mol TnI). MyBP-C is phosphorylated at up to four sites. In donor heart the 4P and 3P species predominate but in the pressure overload samples the 4P species was much reduced and 3P and 1P species predominated. Total phosphorylation was 2.0 ± 0.2 molsPi/mol MyBP-C (n = 8) compared with 3.4 ± 0.07 (n = 21) in donor heart and 1.1 ± 0.1 (n = 10) in HOCM heart. We conclude that pressure overload may be associated with substantial dephosphorylation of troponin I and MyBP-C.

SUBMITTER: Copeland O

PROVIDER: S-EPMC7096377 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pressure Overload Is Associated With Low Levels of Troponin I and Myosin Binding Protein C Phosphorylation in the Hearts of Patients With Aortic Stenosis.

Copeland O'neal O Messer Andrew A Jabbour Andrew A Poggesi Corrado C Prasad Sanjay S Marston Steven S

Frontiers in physiology 20200319

In previous studies of septal heart muscle from HCM patients with hypertrophic obstructive cardiomyopathy (HOCM, LVOT gradient 50-120 mmHg) we found that the level of phosphorylation of troponin I (TnI) and myosin binding protein C (MyBP-C) was extremely low yet samples from hearts with HCM or DCM mutations that did not have pressure overload were similar to donor heart controls. We therefore investigated heart muscle samples taken from patients undergoing valve replacement for aortic stenosis, ...[more]

PMID: 32265736

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Project description:Background: Pressure overload can result in dilated cardiomyopathy. The beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) on heart disorders have been widely recognized. However, the molecular mechanisms underlying their protective effects against cardiomyopathy remain unclear. Methods: Pressure overload in mice induced by 8 weeks of transverse aortic constriction was used to induce dilated cardiomyopathy. A transgenic fat-1 mouse model carrying the n-3 fatty acid desaturase gene fat-1 gene from Caenorhabditis elegans was used to evaluate the mechanism of n-3 PUFAs in this disease. Echocardiography, transmission electron microscopy, and histopathological analyses were used to evaluate the structural integrity and function in pressure overloaded fat-1 hearts. mRNA sequencing, label-free phosphoprotein quantification, lipidomics, Western blotting, RT-qPCR, and ATP detection were performed to examine the effects of n-3 PUFAs in the heart. Results: Compared with wild-type hearts, left ventricular ejection fraction was significantly improved (C57BL/6J [32%] vs. fat-1 [53%]), while the internal diameters of the left ventricle at systole and diastole were reduced in the fat-1 pressure overload hearts. mRNA expression, protein phosphorylation and lipid metabolism were remodeled by pressure overload in wild-type and fat-1 hearts. Specifically, elevation of endogenous n-3 PUFAs maintained the phosphorylation states of proteins in the subcellular compartments of sarcomeres, cytoplasm, membranes, sarcoplasmic reticulum, and mitochondria. Moreover, transcriptomic analysis predicted that endogenous n-3 PUFAs restored mitochondrial respiratory chain function that was lost in the dilated hearts, and this was supported by reductions in detrimental oxylipins and protection of mitochondrial structure, oxidative phosphorylation, and ATP production. Conclusions: Endogenous n-3 PUFAs prevents dilated cardiomyopathy via orchestrating gene expression, protein phosphorylation, and lipid metabolism. This is the first study provides mechanistic insights into the cardioprotective effects of n-3 PUFAs in dilated cardiomyopathy through integrated multi-omics data analysis.

Project description:ImportanceThe outcomes of transcatheter aortic valve replacement (TAVR) in low-risk patients with bicuspid aortic valve stenosis have not been studied in a large scale, multicentered, prospective fashion.ObjectiveTo evaluate the procedural safety, efficacy, and 30-day outcomes of TAVR in patients with bicuspid aortic stenosis at low surgical risk.Design, setting, and participantsThe Low Risk Bicuspid Study is a prospective, single-arm trial study with inclusion/exclusion criteria developed from the Evolut Low Risk Randomized Trial. Follow-up is planned for 10 years. Patients underwent TAVR at 25 centers in the United States who were also participating in the Evolut Low Risk Randomized Trial from December 2018 to October 2019. Eligible patients had severe bicuspid aortic valve stenosis and met American Heart Association/American College of Cardiology guideline indications for aortic valve replacement.InterventionsPatients underwent attempted implant of an Evolut or Evolut PRO transcatheter aortic valve, with valve size based on annular measurements.Main outcomes and measuresThe prespecified primary end point was the incidence of all-cause mortality or disabling stroke at 30 days. The prespecified primary efficacy end point was device success defined as the absence of procedural mortality, the correct position of 1 bioprosthetic heart valve in the proper anatomical location, and the absence of more than mild aortic regurgitation postprocedure.ResultsA total of 150 patients underwent an attempted implant. Baseline characteristics include mean age of 70.3 (5.5) years, 48.0% female (n = 72), and a mean Society of Thoracic Surgeons score of 1.4 (0.6%). Most patients (136; 90.7%) had Sievers type I valve morphology. The incidence of all-cause mortality or disabling stroke was 1.3% (95% CI, 0.3%-5.3%) at 30 days. The device success rate was 95.3% (95% CI, 90.5%-98.1%). At 30 days, the mean (SD) AV gradient was 7.6 (3.7) mm Hg and effective orifice area was 2.3 (0.7) cm2. A new permanent pacemaker was implanted in 22 patients (15.1%). No patients had greater than mild paravalvular leak.Conclusions and relevanceTranscatheter aortic valve replacement in low-surgical risk patients with bicuspid aortic valve stenosis achieved favorable 30-day results, with low rates of death and stroke and high device success rate.Trial registrationClinicalTrials.gov Identifier: NCT03635424.

Dataset Information

Pressure Overload Is Associated With Low Levels of Troponin I and Myosin Binding Protein C Phosphorylation in the Hearts of Patients With Aortic Stenosis.

Publications

Pressure Overload Is Associated With Low Levels of Troponin I and Myosin Binding Protein C Phosphorylation in the Hearts of Patients With Aortic Stenosis.

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