Effect of Cardiac Resynchronization Therapy on Myocardial Fibrosis and Relevant Cytokines in a Canine Model With Experimental Heart Failure

Wang, Jingfeng; Gong, Xue; Chen, Haiyan; Qin, Shengmei; Zhou, Nan; Su, Yangang; Ge, Junbo

doi:10.1111/jce.13171

Cited by 19 publications

(18 citation statements)

References 30 publications

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“…Such changes were accompanied by left ventricular reverse remodelling, a reversal of the HF‐induced left ventricular dilatation . Newer studies now also provide molecular mechanism of these favourable changes, indicating restoration of left ventricular cardiomyocyte diameter, suppression of collagen deposition, and most importantly, down‐regulation of transforming growth factor (TGF)‐β 1 cytokines linked to lower levels of the matrix glycoprotein, osteopontin, required for the activation of fibroblasts upon TGF‐β 1 stimulation . As we know from large clinical trials, however, LVEF is linked to HF risk as a continuum up to an LVEF of 45%; therefore it is conceivable that the aforementioned benefits would be present in those with a higher ejection fraction, as indicated in our current analysis.…”

Section: Discussionmentioning

confidence: 99%

Long‐term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction

Kutyifa

Vermilye

Solomon

et al. 2018

European J of Heart Fail

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Aims Despite our prior report suggesting heart failure (HF) risk reduction from cardiac resynchronization therapy with defibrillator (CRT‐D) in mild HF patients with higher left ventricular ejection fraction (LVEF > 30%), data on mortality benefit in this cohort are lacking. We aimed to assess long‐term mortality benefit from CRT‐D in mild HF patients by LVEF > 30%. Methods and results Among 1274 patients with mild HF and left bundle branch block enrolled in MADIT‐CRT, we analysed long‐term effects of CRT‐D vs. implantable cardioverter defibrillator (ICD) therapy only, and reverse remodelling to CRT‐D (left ventricular end‐systolic volume percent change ≥ median at 1 year), on all‐cause mortality and HF for the LVEF ≤ 30% and LVEF > 30 subgroups using Kaplan–Meier and Cox analyses. During long‐term follow‐up, CRT‐D vs. ICD was associated with reduction in all‐cause mortality in both patients with LVEF > 30% and LVEF ≤ 30% [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.25–0.85, P = 0.036 vs. HR 0.69, 95% CI 0.49–0.98, P = 0.013, interaction P = 0.261]. The efficacy of CRT‐D vs. ICD only to reduce HF was similar in those with LVEF above and below 30% (HR 0.36, 95% CI 0.35–0.61, P < 0.001 vs. HR 0.46, 95% CI 0.35–0.61, P < 0.001; interaction P = 0.342). Patients with CRT‐D‐induced reverse remodelling had significant mortality reduction when compared to ICD, with either LVEF > 30% or LVEF ≤ 30% (HR 0.17 and 0.39), but no mortality benefit was seen in patients with less reverse remodelling. HF events, however, were reduced in both CRT‐D‐induced high and low reverse remodelling vs. ICD only, in both LVEF subgroups. Conclusions In MADIT‐CRT, left bundle branch block patients with higher LVEF (> 30%) derive long‐term mortality benefit from CRT‐D when exhibiting significant reverse remodelling. Clinical Trial registration: http://ClinicalTrials.gov ID NCT00180271, NCT01294449, and NCT02060110

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Section: Discussionmentioning

confidence: 99%

Long‐term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction

Kutyifa

Vermilye

Solomon

et al. 2018

European J of Heart Fail

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“…TGF- β 1 plays multiple regulatory roles in fibrosis remodeling through smad's dependent pathway in many diseases [ 21 ]. During HF or myocardial ischemia, TGF- β 1 signaling can induce fibrosis of cardiac fibroblasts and promote the synthesis of collagen and fibronectin, finally promoting myocardial fibrosis [ 22 ]. In the present study, H 9 C 2 cells were transfected with miRNA-132 mimics and miRNA-132 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

The Role of miRNA-132 against Apoptosis and Oxidative Stress in Heart Failure

Liu

Tong

Chen

et al. 2018

BioMed Research International

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Objective To explore the effect of microRNA-132 of heart failure and provide theoretical guidance for clinical treatment of heart failure (HF). Methods Peripheral blood was collected from HF patients. RT-qPCR was used to determine microRNA-132 expression. Mouse models of heart failure were established. Color Doppler ultrasound was utilized to measure the changes of cardiac function. HE and Masson staining were applied to observe pathological changes of the myocardium. After H9C2 cells were transfected with microRNA-132, MTT assay was employed to detect the stability of H9C2 cells. ELISA was used to measure the levels of oxidative stress factors. Western blot assay and RT-qPCR were utilized to determine the expression of Bax, Bcl-2, TGF-β1, and smad3. Results MicroRNA-132 expression was downregulated in HF patients' blood. After establishing mouse models of HF, cardiac function obviously decreased. HE staining revealed the obvious edema and hypertrophy of cardiomyocytes. Masson staining demonstrated that cardiomyocytes were markedly fibrotic. After microRNA-132 transfection and H9C2 cell apoptosis induced by H2O2, antioxidant stress and antiapoptotic ability of the H9C2 cells obviously increased. TGF-β1 and smad3 expression remarkably diminished. Conclusion Overexpression of microRNA-132 dramatically increased the antioxidant stress and antiapoptotic ability of H9C2 cells and decreased the expression of TGF-β1 and smad3.

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“…mechano-electric feedback). [ 18 ] Besides restoring cardiomyocyte size, there is improvement in kinetics of intracellular calcium cycling through up regulation of SERCA, RyR, and sodium-calcium exchanger levels in patients responding to CRT while no significant change is observed in nonresponders [ 1 , 2 ]. Furthermore, Aiba et al demonstrated in an animal model of LV dyssynchrony, a reduction in inward rectifier potassium current and delayed rectifier potassium current, which was associated with APD prolongation [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mechanical coordination of left ventricle (LV) with long-term cardiac resynchronization therapy (CRT) has been shown to reverse LV structural and molecular remodeling in cardiomyopathy patients with wide left bundle branch block (LBBB) and LV dysfunction. In particular, sarcomeric proteins, sarcoplasmic reticulum calcium ATPase 2α (SERCA) and ryanodine receptor (RyR) levels are restored, resulting in augmentation of excitation-contraction coupling and intracellular calcium cycling [ 1 , 2 ]. In addition, restoration of electric LV conduction direction may reverse chronic LBBB-related action potential duration (APD) heterogeneity arising from long-term cardiac memory [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Reduced T wave alternans in heart failure responders to cardiac resynchronization therapy: Evidence of electrical remodeling

et al. 2018

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BackgroundT-wave alternans (TWA), a marker of electrical instability, can be modulated by cardiac resynchronization therapy (CRT). The relationship between TWA and heart failure response to CRT has not been clearly defined.Methods and resultsIn 40-patients (age 65±11 years, left ventricular ejection-fraction [LVEF] 23±7%), TWA was evaluated prospectively at median of 2 months (baseline) and 8 months (follow-up) post-CRT implant. TWA-magnitude (Valt >0μV, k≥3), its duration (d), and burden (Valt ·d) were quantified in moving 128-beat segments during incremental atrial (AAI, native-TWA) and atrio-biventricular (DDD-CRT) pacing. The immediate and long-term effect of CRT on TWA was examined. Clinical response to CRT was defined as an increase in LVEF of ≥5%. Native-TWA was clinically significant (Valt ≥1.9μV, k≥3) in 68% of subjects at baseline. Compared to native-TWA at baseline, DDD-CRT pacing at baseline and follow-up reduced the number of positive TWA segments, peak-magnitude, longest-duration and peak-burden of TWA (44±5 to 33±5 to 28±4%, p = 0.02 and 0.002; 5.9±0.8 to 4.1±0.7 to 3.8±0.7μV, p = 0.01 and 0.01; 97±9 to 76±8 to 67±8sec, p = 0.004 and <0.001; and 334±65 to 178±58 to 146±54μV.sec, p = 0.01 and 0.004). In addition, the number of positive segments and longest-duration of native-TWA diminished during follow-up (44±5 to 35±6%, p = 0.044; and 97±9 to 81±9sec, p = 0.02). Clinical response to CRT was observed in 71% of patients; the reduction in DDD-CRT paced TWA both at baseline and follow-up was present only in responders (interaction p-values <0.1).ConclusionLong-term CRT reduces the prevalence and magnitude of TWA. This CRT induced beneficial electrical remodeling is a marker of clinical response after CRT.

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Effect of Cardiac Resynchronization Therapy on Myocardial Fibrosis and Relevant Cytokines in a Canine Model With Experimental Heart Failure

Abstract: By means of coordinating LV dyssynchrony, cellular and molecular reverse remodeling relevant to fibrosis inhibition could also be invoked by CRT.

Cited by 19 publications

References 30 publications

Long‐term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction

Long‐term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction

The Role of miRNA-132 against Apoptosis and Oxidative Stress in Heart Failure

Reduced T wave alternans in heart failure responders to cardiac resynchronization therapy: Evidence of electrical remodeling

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