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Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.

ABSTRACT: Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG).Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57+/-5 versus 39+/-4 and 65+/-6 versus 48+/-4 muL, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium.Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

SUBMITTER: Pokreisz P

PROVIDER: S-EPMC3791110 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.

Pokreisz Peter P Vandenwijngaert Sara S Bito Virginie V Van den Bergh An A Lenaerts Ilse I Busch Cornelius C Marsboom Glenn G Gheysens Olivier O Vermeersch Pieter P Biesmans Liesbeth L Liu Xiaoshun X Gillijns Hilde H Pellens Marijke M Van Lommel Alfons A Buys Emmanuel E Schoonjans Luc L Vanhaecke Johan J Verbeken Erik E Sipido Karin K Herijgers Paul P Bloch Kenneth D KD Janssens Stefan P SP

Circulation 20090112 3

<h4>Background</h4>Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG).<h4>Methods and result ...[more]

PMID: 19139381

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Project description:ObjectivesYoung patients account for about half of ST-segment elevation myocardial infarction (STEMI) patients and display a unique risk profile compared with old patients. Whether these differences are related to disparities in ventricular remodeling remains unknown. This study aimed to evaluate age-related differences in ventricular remodeling after primary percutaneous coronary intervention (PPCI) for STEMI.MethodsIn this observational study, consecutive STEMI patients between October 2019 and March 2021 who underwent serial cardiovascular magnetic resonance at index admission (3 to 7 days) and 3 months after PPCI were enrolled. Adverse remodeling was defined as ≥ 10% enlargement in left ventricular end-diastolic volume index (LVEDVi), while reverse remodeling was defined as a decrease in left ventricular end-systolic volume index (LVESVi) of more than 10%.ResultsA total of 123 patients were included and grouped into young (< 60 years, n = 71) and old (≥ 60 years, n = 52) patients. Despite generally similar baseline structural and infarct characteristics, LVESVi significantly decreased only in old patients during follow-up (p = 0.034). The incidence of adverse remodeling was higher (49.3% vs 30.8%, p = 0.039), while the incidence of reverse remodeling was lower (31.0% vs 53.8%, p = 0.011) in young compared with old patients. Younger age (< 60 years) was associated with a significantly higher risk of adverse remodeling (adjusted OR 3.51, 95% CI 1.41-8.74, p = 0.007) and lower incidence of reverse remodeling (adjusted OR 0.42, 95% CI 0.18-0.97, p = 0.046).ConclusionsIn STEMI patients undergoing PPCI, young patients are at a higher risk of adverse remodeling and less probably develop reverse remodeling than old patients. Equal or more attention should be paid to young patients with STEMI compared with their older counterparts.Key points• In STEMI patients undergoing PPCI, young patients displayed unfavorable remodeling compared with old patients. • Young patients are at a higher risk of adverse remodeling and less probably develop reverse remodeling than old patients. • Equal or more attention should be paid to young patients compared with their older counterparts.

Dataset Information

Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.

Publications

Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.

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