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Regenerative Therapy Prevents Heart Failure Progression in Dyssynchronous Nonischemic Narrow QRS Cardiomyopathy.

ABSTRACT: Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF. Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress-triggered dilated cardiomyopathy. In contrast to rampant end-stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS-complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell-treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony-prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship. In narrow QRS HF, a regenerative approach demonstrated functional and structural benefit, introducing the prospect of device-autonomous resynchronization therapy for refractory disease.

SUBMITTER: Yamada S

PROVIDER: S-EPMC4599402 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Regenerative Therapy Prevents Heart Failure Progression in Dyssynchronous Nonischemic Narrow QRS Cardiomyopathy.

Yamada Satsuki S Arrell D Kent DK Martinez-Fernandez Almudena A Behfar Atta A Kane Garvan C GC Perez-Terzic Carmen M CM Crespo-Diaz Ruben J RJ McDonald Robert J RJ Wyles Saranya P SP Zlatkovic-Lindor Jelena J Nelson Timothy J TJ Terzic Andre A

Journal of the American Heart Association 20150511 5

<h4>Background</h4>Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF.<h4>Methods and results</h4>Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress-tr ...[more]

PMID: 25964205

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Project description:ObjectivesIn patients with nonischemic dilated cardiomyopathy (NIDCM), native T1, partition coefficient (λGd), and extracellular volume fraction (ECV) mapping may offer prognostic values beyond late gadolinium enhancement (LGE), by scaling the range of myocardial changes.BackgroundIn patients with NIDCM, LGE is seen in 30% of patients and it indicates adverse prognosis.MethodsThe study mapped 6 anatomical locations using all 4 cardiac magnetic resonance (CMR) tissue-characterizing methods and associated with outcome. The authors performed T1 mapping of the myocardium and the blood pool, before and serially after contrast injection, using a Look-Locker cine gradient-echo technique to obtain T1 and the corresponding reciprocal R1 values. λGd values were derived from the slopes of the least-squares regression lines for myocardial versus blood R1, then adjusted to serum hematocrit to yield ECV.ResultsConsecutive 240 NIDCM patients (49 ± 16 years of age; 38% women) underwent CMR for cardiac function, LGE, native T1, λGd, and ECV. After a median of 3.8 years, 36 (15%) experienced major adverse cardiac events (MACE), including 22 heart failure hospitalizations and 14 deaths. Nonischemic LGE was detected in 34%, whereas ECV was elevated (≥1 location) in 58%. Comparing the 4 methods, mean ECV and λGd both demonstrated strong association with MACE (both p < 0.001). In contrast to native T1 and LGE, ECV values from all 6 locations were associated with MACE and death, with the anteroseptum being the most significant (p < 0.0001). The number of abnormal ECV locations correlated linearly with annual MACE rates (p = 0.0003). Mean ECV was the only predictor to enter a prognostic model that contained age, sex, New York Heart Association functional class, and left ventricular ejection fraction. For every 10% increase, mean ECV portended to a 2.8-fold adjusted increase risk to MACE (p < 0.001).ConclusionsIn this study of patients with NIDCM, mapping the myocardial extent of abnormality using ECV offers prognostication toward heart failure outcomes incremental to LGE or native T1 mapping.

Project description:Background: Development of advanced heart failure (HF) symptoms is the most common adverse pathway in hypertrophic cardiomyopathy (HCM) patients. Currently, there is a limited ability to identify HCM patients at risk of HF. Objectives: In this study, we present a machine learning (ML)-based model to identify individual HCM patients who are at high risk of developing advanced HF symptoms. Methods: From a consecutive cohort of HCM patients evaluated at the Tufts HCM Institute from 2001 to 2018, we extracted a set of 64 potential risk factors measured at baseline. Only patients with New York Heart Association (NYHA) functional class I/II and LV ejection fraction (LVEF) by echocardiography >35% were included. The study cohort (n = 1,427 patients) was split into three disjoint subsets: development (50%), model selection (10%), and independent validation (40%). The least absolute shrinkage and selection operator was used to select the most influential clinical variables. An ensemble of ML classifiers, including logistic regression, was used to identify patients with high risk of developing a HF outcome. Study outcomes were defined as progression to NYHA class III/IV, drop in LVEF below 35%, septal reduction procedure, and/or heart transplantation. Results: During a mean follow-up of 4.7 ± 3.7 years, advanced HF occurred in 283 (20% out of 1,427) patients. The model features included patients' sex, NYHA class (I or II), HCM type (i.e., obstructive or not), LV wall thickness, LVEF, presence of HF symptoms (e.g., dyspnea, presyncope), comorbidities (atrial fibrillation, hypertension, mitral regurgitation, and systolic anterior motion), and type of cardiac medications. The developed risk stratification model showed strong differentiation power to identify patients at advanced HF risk in the testing dataset (c-statistics = 0.81; 95% confidence interval [CI]: 0.76, 0.86). The model allowed correct identification of high-risk patients with accuracy 74% (CI: 0.70, 0.78), sensitivity 80% (CI: 0.77, 0.83), and specificity 72% (CI: 0.68, 0.76). The model performance was comparable among different sex and age groups. Conclusions: A 5-year risk prediction of progressive HF in HCM patients can be accurately estimated using ML analysis of patients' clinical and imaging parameters. A set of 17 clinical and imaging variables were identified as the most important predictors of progressive HF in HCM.

Project description:BackgroundCardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored.Methods and resultsAdult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K(+) current (I(K1)), delayed rectifier K(+) current (I(K)), and transient outward K(+) current (I(to)) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I(K1) and I(K) but not I(to), consistent with trends in the changes in steady state K(+) channel mRNA and protein levels. DHF reduced the peak inward Ca(2+) current (I(Ca)) density and slowed I(Ca) decay in lateral compared with anterior cells, whereas CRT restored peak I(Ca) amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca(V)1.2 (alpha1C) mRNA or protein expression, but reduced Ca(V)beta2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca(2+) ATPase and increased Na(+)-Ca(2+) exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca(2+) ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT.ConclusionsCRT partially restores DHF-induced ion channel remodeling and abnormal Ca(2+) homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

Project description:AimsOur previous studies suggested that the complement system was critical in the prognosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The acylation-stimulating protein (ASP), generated through the alternate complement pathway, was reported to regulate lipogenesis and triglyceride storage. This study aimed to investigate the role of ASP in predicting adverse cardiac events in an ARVC cohort.Methods and resultsWe enrolled 111 ARVC patients and 106 healthy volunteers, and measured their plasma ASP levels using enzyme-linked immunosorbent assays. Plasma ASP levels were significantly higher in the ARVC patients than in the healthy controls (2325.22 ± 20.08 vs. 2189.75 ± 15.55, P < 0.001), with a similar trend observed in the myocardial explant assay. Spearman correlation analysis indicated plasma ASP level associated with cardiac structural (right ventricular internal dimension, P = 0.006) and functional remodelling (left ventricular ejection fraction, P = 0.002) in ARVC patients. The ARVC patients were followed up for an average of 17.79 ± 1.09 months. Heart failure-associated events (HFAEs) were defined as heart transplantation, on a cardiac transplant list, or death due to end-stage heart failure. Plasma ASP levels in patients with HFAEs were significantly higher than in those without clinical events (2486.03 ± 26.70 vs. 2268.83 ± 23.51, P < 0.001) or those with malignant arrhythmic events (2486.03 ± 26.70 vs. 2297.80 ± 60.46, P = 0.008). LASSO (least absolute shrinkage and selection operator) and multivariable Cox regression analyses showed the ASP level (HR = 1.004, 95% CI [1.002,1.006], P = 0.002) was an independent predictor for adverse HFAEs in ARVC patients. The spline-fitting procedure was applied to illustrate the HFAE-free probabilities at different time points.ConclusionsOur results suggest that plasma ASP may be a useful biomarker in prediction of adverse HF-associated events in ARVC patients.

Dataset Information

Regenerative Therapy Prevents Heart Failure Progression in Dyssynchronous Nonischemic Narrow QRS Cardiomyopathy.

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Regenerative Therapy Prevents Heart Failure Progression in Dyssynchronous Nonischemic Narrow QRS Cardiomyopathy.

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