Heart Failure in Humans Reduces Contractile Force in Myocardium From Both Ventricles

Blair, Cheavar A.; Brundage, Elizabeth A.; Thompson, Katherine; Stromberg, Arnold J.; Guglin, Maya; Biesiadecki, Brandon J.; Campbell, Kenneth S.

doi:10.1016/j.jacbts.2020.05.014

Cited by 20 publications

(19 citation statements)

References 49 publications

(63 reference statements)

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“…In cases of genetic heart failure, decreased F max may be explained by structural alterations to proteins involved in the crossbridge cycle, which are detrimental to their function 29,30 . However, functional deficits have also been observed in nongenetic heart failure 6,7,9,29 , which makes up the majority of cases. We therefore sought to determine the underlying mechanism for myofilament dysfunction in heart failure using left ventricle (LV) samples from patients with idiopathic dilated cardiomyopathy (DCM) and heart failure (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The sarcomere is a highly organized protein complex that mediates contraction through myosin and actin filaments, which engage in the calcium-dependent crossbridge cycle. Increased myofilament calcium sensitivity and decreased maximum forcegenerating capacity (F max ) are well-documented in heart failure [5][6][7][8][9][10] . However, while altered calcium sensitivity is uniformly attributed to changes in site-specific post-translational modifications, most commonly phosphorylation of troponin I 11 , the molecular mechanisms for decreased F max are incompletely understood.…”

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confidence: 99%

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Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

et al. 2021

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The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

et al. 2021

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“…The mechanism of depressed sarcomere function in HFrEF as measured by maximal calcium activated tension has been explored in previous studies (15, 16). For example, myofilament disarray has shown to be responsible for diminished force production in a canine model of heart failure (17).…”

Section: Discussionmentioning

confidence: 99%

“…Tissue was then rapidly dissected, snap-frozen in liquid nitrogen, and stored at −80°C until transport. RV septal tissue from patients showing low RV Fmax (15, 16) was used in all RV studies.…”

Section: Methodsmentioning

confidence: 99%

Myofibril orientation as a metric for characterizing heart disease

Gong

Jani

et al. 2021

Preprint

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Myocyte disarray is a hallmark of cardiomyopathy. However, the relationship between alterations in the orientation of individual myofibrils and myofilaments to disease progression has been largely underexplored. This oversight has predominantly been due to a paucity of methods for objective and quantitative analysis. Here we introduce a novel, less-biased approach to quantify myofibrillar and myofilament orientation in cardiac muscle under near physiological conditions and demonstrate its superiority as compared to conventional histological assessments. Using small-angle X-ray diffraction, we first investigated changes in myofibrillar orientation at increasing sarcomere lengths in permeabilized, relaxed, wildtype mouse myocardium by assessing the angular spread of the 1,0 equatorial reflection (angle sigma). At a sarcomere length (SL) of 1.9 microns, the angle sigma was 0.23 +/- 0.01 rad, decreased to 0.19 +/- 0.01 rad at a SL of 2.1 microns, and further decreased to 0.15 +/- 0.01 rad at a SL of 2.3 microns (p<0.0001). Angle sigma was significantly larger in R403Q (a MYH7 HCM model) porcine myocardium (0.24 +/- 0.01 rad) compared to WT myocardium (0.14 +/- 0.005 rad, p<0.0001) as well as in human heart failure tissue (0.19 +/- 0.006 rad) when compared to non-failing samples (0.17 +/- 0.007 rad, p=0.01). These data indicate that diseased myocardium suffers from greater myofibrillar disorientation compared to healthy controls. Finally, we showed that conventional, histology-based analysis of disarray can be subject to user bias and/or sampling error and lead to false positives. Our method for directly assessing myofibrillar orientation avoids the artifacts introduced by conventional histological methods that directly assess myocyte orientation and only indirectly assess myofibrillar orientation, and provides a precise and objective metric for phenotypically characterizing myocardium. The ability to obtain excellent X-ray diffraction patterns from frozen human myocardium provides a new tool for investigating the structural bases of cardiomyopathies.

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“…This is one of the first studies to examine RV myofilament dysfunction in advanced human HF 7 and the first to establish its relation to RHF haemodynamic indices, and most prominently, PAPi. Since all RHF indices lack precision in detecting RHF, the question of which index actually represents intrinsic RV disease is relevant.…”

Section: Figurementioning

confidence: 99%

Pulmonary artery pulsatility index predicts right ventricular myofilament dysfunction in advanced human heart failure

Aslam

Jani

Lin

et al. 2021

European J of Heart Fail

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Heart Failure in Humans Reduces Contractile Force in Myocardium From Both Ventricles

Abstract: Visual Abstract

Cited by 20 publications

References 49 publications

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

Myofibril orientation as a metric for characterizing heart disease

Pulmonary artery pulsatility index predicts right ventricular myofilament dysfunction in advanced human heart failure

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