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Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy.

ABSTRACT: Despite the application of proven adult heart failure therapies to children with idiopathic dilated cardiomyopathy (IDC), prognosis remains poor. Clinical experience with phosphodiesterase 3 inhibitors (PDE3i) in pediatric patients with IDC, however, demonstrates improved heart failure symptoms without the increased incidence of sudden death seen in adults treated with PDE3i. We sought to determine age-related differences in PDE activity and associated intracellular signaling responsible for the efficacy and relative safety of chronic PDE3i in pediatric heart failure.cAMP levels, PDE activity, and phospholamban phosphorylation (pPLB) were determined in explanted human left ventricular myocardium (pediatric n=41; adult n=88). Adults and children with IDC (not treated with PDE3i) had lower cAMP and pPLB compared with nonfailing controls. In contrast to their adult counterparts, pediatric IDC patients chronically treated with PDE3i had elevated cAMP (P=0.0403) and pPLB (P=0.0119). In addition, total PDE- and PDE3-specific activities were not altered in pediatric IDC patients on PDE3i, whereas adult IDC patients on PDE3i demonstrated higher total PDE-specific (74.6±13.8 pmol/mg per minute) and PDE3-specific (48.2±15.9 pmol/mg per minute) activities in comparison with those of nonfailing controls (59.5±14.4 and 35.5±12.8 pmol/mg per minute, respectively).Elevated cAMP and higher pPLB may contribute to sustained hemodynamic benefits in pediatric IDC patients treated with PDE3i. In contrast, higher total PDE and PDE3 activities in adult IDC patients treated with PDE3i may perpetuate lower myocardial cAMP and pPLB levels, limiting the potential benefits of PDE3i therapy.

SUBMITTER: Nakano SJ

PROVIDER: S-EPMC4303519 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy.

Nakano Stephanie J SJ Miyamoto Shelley D SD Movsesian Matthew M Nelson Penny P Stauffer Brian L BL Sucharov Carmen C CC

Circulation. Heart failure 20141002 1

<h4>Background</h4>Despite the application of proven adult heart failure therapies to children with idiopathic dilated cardiomyopathy (IDC), prognosis remains poor. Clinical experience with phosphodiesterase 3 inhibitors (PDE3i) in pediatric patients with IDC, however, demonstrates improved heart failure symptoms without the increased incidence of sudden death seen in adults treated with PDE3i. We sought to determine age-related differences in PDE activity and associated intracellular signaling ...[more]

PMID: 25278000

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Project description:ImportanceIdiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.ObjectiveTo estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.Design, setting, and participantsA family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.ExposuresThe presence of DCM in a proband.Main outcomes and measuresFamilial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.ResultsThe study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).Conclusions and relevanceIn a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.Trial registrationClinicalTrials.gov Identifier: NCT03037632.

Project description:Background: Immune targeted therapy has become an attractive therapeutic approach for patients with dilated cardiomyopathy (DCM) recently. Genetic predisposition and gender play a critical role in immune-related responses of DCM. This study aimed to perform a bioinformatics analysis of molecular differences between male and female samples and identify immune-related ceRNA network in DCM. Methods: The gene expression microarray and clinical features dataset of GSE19303 was downloaded from the GEO. The raw data were preprocessed, followed by identification of differentially expressed genes (DEGs) between male and female DCM samples. Crucial functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A lncRNA-miRNA-mRNA network was constructed and a central module was extracted from the ceRNA network. Results: Compared with the female group, the male group benefits more from IA/IgG immunotherapy. Male patients of DCM had a significant positive correlation with the abundance of inflammatory cells (B cells, memory B cells, CD8+ Tem cells, and NK cells). Sex difference DEGs had a widespread impact on the signaling transduction, transcriptional regulation, and metabolism in DCM. Subsequently, we constructed an immune-related ceRNA network based on sex differences in DCM, including five lncRNAs, six miRNAs, and 29 mRNAs. Furthermore, we extracted a central module from the ceRNA network, including two lncRNAs (XIST and LINC00632), three miRNAs (miR-1-3p, miR-17-5p, and miR-22-3p), and six mRNAs (CBL, CXCL12, ESR1, IGF1R, IL6ST, and STC1). Among these DEGs, CBL, CXCL12, and IL6ST expression was considered to be associated with inflammatory cell infiltration in DCM. Conclusions: The identified ceRNA network and their enriched pathways may provide genetic insights into the phenotypic diversity of female and male patients with DCM and may provide a basis for development of sex-related individualization of immunotherapy.

Dataset Information

Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy.

Publications

Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy.

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