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Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy.

ABSTRACT: Background: Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the "gold standard" pressure unloading therapy. Methods: Abdominal aortic banding was performed for 6 or 12 weeks. Sham operated animals served as controls. Pressure unloading was induced by removing the aortic constriction after week 6. The animals were treated from week 7 to 12, with 10 mg/kg/day cinaciguat or with placebo p.o., respectively. Cardiac function and morphology were assessed by left ventricular pressure-volume analysis and echocardiography. Additionally, key markers of myocardial hypertrophy, fibrosis, nitro-oxidative stress, apoptosis and cGMP signaling were analyzed. Results: Pressure unloading effectively reversed LVH, decreased collagen accumulation and provided protection against oxidative stress and apoptosis. Regression of LVH was also associated with a full recovery of cardiac function. In contrast, chronic activation of the sGC enzyme by cinaciguat at sustained pressure overload only slightly influenced pre-established hypertrophy. However, it led to increased PKG activity and had a significant impact on interstitial fibrosis, nitro-oxidative stress and apoptosis. Amelioration of the pathological structural alterations prevented the deterioration of LV systolic function (contractility and ejection fraction) and improved myocardial stiffness. Conclusion: Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners.

SUBMITTER: Ruppert M

PROVIDER: S-EPMC6331535 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy.

Ruppert Mihály M Korkmaz-Icöz Sevil S Li Shiliang S Brlecic Paige P Németh Balázs Tamás BT Oláh Attila A Horváth Eszter M EM Veres Gábor G Pleger Sven S Grabe Niels N Merkely Béla B Karck Matthias M Radovits Tamás T Szabó Gábor G

Frontiers in physiology 20190108

<b>Background:</b> Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the "gold standard" pressure unloading therapy. <b>Methods:</b ...[more]

PMID: 30670980

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Project description:Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic G?q overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in G?q hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic G?q overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium.

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

Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy.

Publications

Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy.

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