Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy

Lichter, Justin G.; Carruth, Eric D.; Mitchell, Chelsea; Barth, Andreas S.; Aiba, Takeshi; Kass, David A.; Tomaselli, Gordon F.; Bridge, John H.B.; Sachse, Frank B.

doi:10.1016/j.yjmcc.2014.03.012

Cited by 36 publications

(33 citation statements)

References 36 publications

(66 reference statements)

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“…However, CRT had also specific metabolic effects such as activation of substrate utilization, amino acid and energy metabolism. CRT also improves metabolomics environment which is associated with a delta change in LVEF, as a evidence of improved heart performance similar to other reports 18, 43, 52, 54 . Although post-CRT metabolomic profile improved significantly, many metabolite levels have not been restored to the normal range, indicating existence of resynchronization independent metabolic disturbances associated with HF 49, 50, 53 .…”

Section: Discussionsupporting

confidence: 88%

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Cardiac Resynchronization Therapy Induces Adaptive Metabolic Transitions in the Metabolomic Profile of Heart Failure

Nemutlu

Zhang

et al. 2015

Journal of Cardiac Failure

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Background Heart failure (HF) is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT). The aim of this study was to determine the metabolomic signature in HF and its prognostic value for the response to CRT. Methods This prospective study consisted of 24 patients undergoing CRT for advanced HF and 10 control patients who underwent catheter ablation for supraventricular arrhythmia but not CRT. Blood samples were collected before and 3 months after CRT. Metabolomic profiling of plasma samples was performed using gas chromatography–mass spectrometry and nuclear magnetic resonance. Results The plasma metabolomic profile was altered in the HF patients, with a distinct panel of metabolites, including Krebs cycle and lipid, amino acid, and nucleotide metabolism. CRT improved the metabolic profile. The succinate/glutamate ratio, an index of Krebs cycle activity, improved from 0.58±0.13 to 2.84±0.60 (P<.05). The glucose/palmitate ratio, an indicator of the balance between glycolytic and fatty acid metabolism, increased from 0.96±0.05 to 1.54±0.09 (P<.01). Compared with the nonresponders to CRT, the responders had a distinct baseline plasma metabolomic profile, including higher isoleucine, phenylalanine, leucine, glucose, and valine levels and lower glutamate levels at baseline (P<.05). Conclusion CRT improves plasma metabolomic profile of HF patients indicating harmonization of myocardial energy substrate metabolism. CRT responders may have a favorable metabolic profile as a potential biomarker for predicting CRT outcome.

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Section: Discussionsupporting

confidence: 88%

“…Cardiac dyssynchrony affects many systems ranging from gene expression, ion channels, sarcomeres, mitochondrial energy metabolism and metabolic pathways 41–43 . CRT improves chamber mechano-energy efficiency, reducing morbidity and mortality of HF patients 13–15, 44 .…”

Section: Discussionmentioning

confidence: 99%

Cardiac Resynchronization Therapy Induces Adaptive Metabolic Transitions in the Metabolomic Profile of Heart Failure

Nemutlu

Zhang

et al. 2015

Journal of Cardiac Failure

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“…A targeted next-generation sequencing approach allowed the identification of a novel α-actinin-2 variant associated with midapical hypertrophic cardiomyopathy and juvenile-onset atrial fibrillation [24]. One study showed remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy [25]. Only a few studies have reported the structural remodeling of the sarcomeric cytoskeleton in AF patients.…”

Section: Discussionmentioning

confidence: 99%

Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Zhang

Zhang²,

Tang³

et al. 2016

Cardiology

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Objectives: Atrial ﬁbrosis, a marker of atrial structural remodeling, plays a critical role in atrial ﬁbrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β₁ (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF. Methods: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting. Results: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05). Conclusions: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

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“…It is interesting to speculate that similarly to LV assist device, the CRT treatment also affects cardiac myocardium by direct effect on myocardial metabolism [22,26,27]. It may affect heart muscle metabolism towards utilization of long chain fatty acids or better utilization of glucose.…”

Section: Discussionmentioning

confidence: 99%

Metabolic syndrome is associated with different clinical outcome after cardiac resynchronization therapy in patients with ischemic and non-ischemic cardiomyopathy

et al. 2016

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Background: Although association of metabolic syndrome (MS) and ischemic heart disease is strongly established, it is not known whether presence of MS may differently influence clinical responses to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the associations between obesity and metabolic features and the clinical outcome after cardiac resynchronization with defibrillator therapy (CRT-D), compared to an implantable cardioverter defibrillator (ICD). Methods: The risk of heart failure (HF) or death and death alone was evaluated in 829 non--obese patients, 156 obese patients without MS, and 277 obese patients with MS (all with left bundle branch block), who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).Results: Obese patients with MS (HR 0.50, p = 0.002), obese patients without MS (HR 0.57, p = 0.077), and non-obese patients (HR 0.48, p < 0.001 (HR 0.11, p < 0.001), whereas obese patients without MS had no reduction (HR 0.98, p = 0.951; interaction p < 0.001). The reverse was observed in ischemic cardiomyopathy patients: obese patients with MS had no reduction in the risk of HF/death (HR 0.80, p = 0.402), while obese patients without MS showed a significant reduction in the risk of events (HR 0.15, p = 0.011; interaction p = 0.036). Similar trends were observed for the endpoint of death. (Cardiol J 2016; 23, 3: 344-351) ) had a similar risk reduction of HF/death in response to CRT-D therapy when compared to ICD patients. However, among those with non-ischemic cardiomyopathy, obese patients with MS experienced a 90% reduction for HF/death Conclusions: Presence of MS differentiates the response to CRT in obese patients with ischemic and non-ischemic etiology for HF.

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Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy

Cited by 36 publications

References 36 publications

Cardiac Resynchronization Therapy Induces Adaptive Metabolic Transitions in the Metabolomic Profile of Heart Failure

Cardiac Resynchronization Therapy Induces Adaptive Metabolic Transitions in the Metabolomic Profile of Heart Failure

Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Metabolic syndrome is associated with different clinical outcome after cardiac resynchronization therapy in patients with ischemic and non-ischemic cardiomyopathy

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