European heart journal. Cardiovascular pharmacotherapy · 2025
Phosphodiesterase 5 and its inhibitors with ischaemic heart disease: a Mendelian randomization analysis and a real-world study.
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Xiao Jun, Zhang Naiqi, Gao Ziting, Wei Yajing, Wei Hongye, Qiu Ziyi, Sundquist Kristina, Sundquist Jan, Ji Jianguang, Huang Wuqing
Аннотация
BACKGROUND: Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.
OBJECTIVES: This study aimed to explore the relationship between genetically-predicted PDEs and ischaemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.
METHODS AND RESULTS: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers. MR analyses identified two types of PDEs, PDE5, and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD [odds ratio (OR)PDE5A = 1.22,95% confidence interval (CI) = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49] and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84).
CONCLUSION: This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischaemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.
OBJECTIVES: This study aimed to explore the relationship between genetically-predicted PDEs and ischaemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.
METHODS AND RESULTS: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers. MR analyses identified two types of PDEs, PDE5, and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD [odds ratio (OR)PDE5A = 1.22,95% confidence interval (CI) = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49] and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84).
CONCLUSION: This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischaemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.
Предметные рубрики MeSH
HumansMendelian Randomization AnalysisPhosphodiesterase 5 InhibitorsMyocardial IschemiaMaleRetrospective StudiesSwedenFemaleMiddle AgedRisk AssessmentCyclic Nucleotide Phosphodiesterases, Type 5AgedMyocardial InfarctionQuantitative Trait LociPhenotypeIncidenceGenetic Predisposition to DiseasePharmacogenomic VariantsRisk FactorsTreatment OutcomeRegistries