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Reverse remodeling in Dilated Cardiomyopathy: Insights and future perspectives.

ABSTRACT: Dilated Cardiomyopathy (DCM) has been classically considered a progressive disease of the heart muscle that inexorably progresses towards refractory heart failure, ventricular arrhythmias and heart transplant. However, the prognosis of DCM has significantly improved in the past few years, mostly as the result of successful therapy-induced reverse remodeling. Reverse remodeling is a complex process that involves not only the left ventricle, but also many other cardiac structures and it is now recognized both as a measure of therapeutic effectiveness and as an important prognostic tool. Nevertheless, several aspects of reverse remodeling remain unclear, including the best timing for its quantification, its predictors and its interaction with individual genetic backgrounds. In this review, we summarize our current understanding of reverse remodeling in patients with DCM and provide practical recommendations for the clinical management of this challenging patient population.

SUBMITTER: Merlo M

PROVIDER: S-EPMC5988485 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Reverse remodeling in Dilated Cardiomyopathy: Insights and future perspectives.

Merlo M M Caiffa T T Gobbo M M Adamo L L Sinagra G G

International journal of cardiology. Heart & vasculature 20180308

Dilated Cardiomyopathy (DCM) has been classically considered a progressive disease of the heart muscle that inexorably progresses towards refractory heart failure, ventricular arrhythmias and heart transplant. However, the prognosis of DCM has significantly improved in the past few years, mostly as the result of successful therapy-induced reverse remodeling. Reverse remodeling is a complex process that involves not only the left ventricle, but also many other cardiac structures and it is now rec ...[more]

PMID: 29876504

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Project description:BackgroundWhen β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca(2+)-ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.Methods and resultsForty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β1-selective), metoprolol+doxazosin (β1/α1), or carvedilol (β1/β2/α1). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β1-adrenergic signaling.ConclusionsIn addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β1-adrenergic receptor gene network.Clinical trial registrationURL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.

Project description:Background: The prognosis of pediatric dilated cardiomyopathy (PDCM) is highly variable, ranging from death to cardiac function recovery. Left ventricular reverse remodeling (LVRR) represents a favorable prognosis in PDCM. Disturbance of lipid metabolism is associated with the change of cardiac function, but no studies have examined lipidomics data and LVRR. Methods: Discovery analyses were based on 540 targeted lipids in an observational, prospective China-AOCC (An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China) study. The OPLS-DA and random forest (RF) analysis were used to screen the candidate lipids. Associations of the candidate lipids were examined in Cox proportional hazards regression models. Furthermore, we developed a risk score comprising the significant lipids, with each attributed a score of 1 when the concentration was above the median. All significant findings were replicated in a validation set of the China-AOCC study. Results: There were 59 patients in the discovery set and 24 patients in the validation set. LVRR was observed in 27 patients (32.5%). After adjusting for age, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD) z-score, lysophosphatidic acids (LysoPA) 16:0, LysoPA 18:2, LysoPA 18:1, and LysoPA 18:0 were significantly associated with LVRR in the discovery set, and hazard ratios (HRs) were 2.793 (95% CI, 1.545-5.048), 2.812 (95% CI, 1.542-5.128), 2.831 (95% CI, 1.555-5.154), and 2.782 (95% CI, 1.548-5.002), respectively. We developed a LysoPA score comprising the four LysoPA. When the LysoPA score reached 4, LVRR was more likely to be observed in both sets. The AUC increased with the addition of the LysoPA score to the LVEDD z-score (from 0.693 to 0.875 in the discovery set, from 0.708 to 0.854 in the validation set) for prediction of LVRR. Conclusions: Serum LysoPA can predict LVRR in PDCM patients. When the LysoPA score was combined with the LVEDD z-score, it may help in ascertaining the prognosis and monitoring effects of anti-heart failure pharmacotherapy.

Dataset Information

Reverse remodeling in Dilated Cardiomyopathy: Insights and future perspectives.

Publications

Reverse remodeling in Dilated Cardiomyopathy: Insights and future perspectives.

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