Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF

Tschöpe, Carsten; Linthout, Sophie Van; Spillmann, Frank; Klein, Oliver; Biewener, Sebastian; Remppis, Andrew; Gutterman, David D.; Linke, Wolfgang A.; Pieske, Burkert; Hamdani, Nazha; Roser, Mattias

doi:10.1016/j.ijcard.2015.10.208

Cited by 47 publications

(39 citation statements)

References 14 publications

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“…The complete N2A element and the constitutive part of the PEVK domain were also tested in vitro for PKA-dependent phosphorylation, but were excluded as substrates of this kinase (Krüger et al 2009). Phospho-specific antibodies were generated against conserved p-S4010 (human)/p-S3991 (mouse) and used to quantify N2Bus phosphorylation by western blot in mouse, dog, or human heart tissue (Hamdani et al 2013a, b, c; Kötter et al 2013, 2016; Mohamed et al 2016; Rain et al 2014; Tschöpe et al 2016). …”

Section: Phosphorylation Sites Of the Cardiac-specific N2bus Elementmentioning

confidence: 99%

“…Thus, at least S12884 (mouse)/S12022 (human) can be phosphorylated by both CaMKIIδ and PKCα. The phospho-specific antibodies against p-S11878 and p-S12022 (p-S12742 and p-S12884 in mouse titin) have been used repeatedly to quantify PEVK phosphorylation by western blot in mouse, rat, dog, or human hearts (Hamdani et al 2013a, b, c; Hidalgo et al 2014; Hudson et al 2011; Hutchinson et al 2015; Kötter et al 2013, 2016; Kovács et al 2016; Mohamed et al 2016; Rain et al 2014; Tschöpe et al 2016; Zile et al 2015). …”

Section: Phosphorylation Sites Of the Pevk Domainmentioning

confidence: 99%

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Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes

2017

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Reversible post-translational modifications of various cardiac proteins regulate the mechanical properties of the cardiomyocytes and thus modulate the contractile performance of the heart. The giant protein titin forms a continuous filament network in the sarcomeres of striated muscle cells, where it determines passive tension development and modulates active contraction. These mechanical properties of titin are altered through post-translational modifications, particularly phosphorylation. Titin contains hundreds of potential phosphorylation sites, the functional relevance of which is only beginning to emerge. Here, we provide a state-of-the-art summary of the phosphorylation sites in titin, with a particular focus on the elastic titin spring segment. We discuss how phosphorylation at specific amino acids can reduce or increase the stretch-induced spring force of titin, depending on where the spring region is phosphorylated. We also review which protein kinases phosphorylate titin and how this phosphorylation affects titin-based passive tension in cardiomyocytes. A comprehensive overview is provided of studies that have measured altered titin phosphorylation and titin-based passive tension in myocardial samples from human heart failure patients and animal models of heart disease. As our understanding of the broader implications of phosphorylation in titin progresses, this knowledge could be used to design targeted interventions aimed at reducing pathologically increased titin stiffness in patients with stiff hearts.Electronic supplementary materialThe online version of this article (doi:10.1007/s12551-017-0263-9) contains supplementary material, which is available to authorized users.

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Section: Phosphorylation Sites Of the Cardiac-specific N2bus Elementmentioning

confidence: 99%

Section: Phosphorylation Sites Of the Pevk Domainmentioning

confidence: 99%

Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes

2017

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“…However, conventional heart failure therapy is ineffective or frankly harmful in this condition, and currently, there is no demonstrated beneficial treatment. With this in mind, a very early and provocative report by Tschope describes the experience with CCM in two patients with symptomatic HFpEF [60]. Endomyocardial biopsies and exercise testing were performed in both cases before and after CCM.…”

Section: Device Therapy For Heart Failurementioning

confidence: 99%

“…CCM therapy upregulated phosphorylated titin, with similar improvement in troponin 3 and myosin light chain 2 [60]. CCM resulted in a reduction in cardiac fibrosis as evidenced by decreased collagen expression by over 20 %.…”

Section: Device Therapy For Heart Failurementioning

confidence: 99%

Cardiac contractility modulation: a novel approach for the treatment of heart failure

Abi‐Samra¹,

Gutterman

2016

Heart Fail Rev

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Heart failure is a major health problem worldwide and, despite effective therapies, is expected to grow by almost 50 % over the next 15 years. Five-year mortality remains high at 50 % over 5 years. Because of the economic burden and large impact on quality of life, substantial effort has focused on treatments with multiple medical (beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB), aldosterone antagonists, and combination of ARB/neprilysin blockers, ivabradine) and device therapies (ICD, CRT) which have been implemented to reduce disease burden and mortality. However, in the past decade only two new medical therapies and no devices have been approved by the US FDA for the treatment of heart failure. This review highlights the preclinical and clinical literature, and the implantation procedure, related to a relatively new therapeutic device for heart failure; cardiac contractility modulation (CCM). CCM delivers a biphasic high-voltage bipolar signal to the RV septum during the absolute refractory period, eliciting an acute increase in global contractility, and chronically producing a sustained improvement in quality of life, exercise tolerance, and heart failure symptoms. The technology is used commercially in Europe with nearly 3000 patients implanted worldwide. Indications include patients with reduced EF and normal or slightly prolonged QRS duration, thus filling an important therapeutic gap among the 2/3 of patients with heart failure who do not meet criteria for CRT. The mechanism by which CCM provides benefit can be seen at the cellular level where improved calcium handling (phosphorylation of phospholamban, upregulation of SERCA-2A), reversal of the fetal myocyte gene program associated with heart failure, and reverse remodeling are observed. Recent retrospective studies indicate a long-term mortality benefit. A pivotal randomized controlled study is currently being completed in the USA. CCM appears to be an effective, safe technology for the treatment of heart failure with reduced ejection fraction.

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“…The action of increase in contraction force appears to be mediated by reversing the molecular remodeling associated with heart failure and restore the expression of several calcium handling proteins [10][11][12]. It has also been reported that CCM has a favorable effect on cardiac remodeling by echocardiography and histological assessment and normalizes expressions of key cytoskeleton proteins and matrix metalloproteinase (MMPs) [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

Zhang

Dang

et al. 2016

Cell Physiol Biochem

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Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. Methods: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were measured by western blot analysis. Results: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were down regulated. Conclusion: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-β1/Smad3 signaling pathway in CHF rabbits.

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Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF

Cited by 47 publications

References 14 publications

Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes

Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes

Cardiac contractility modulation: a novel approach for the treatment of heart failure

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

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