Dalcetrapib
Adcy9 gene inactivation shrinks infarct size and preserves cardiac function after MI, but mainly when CETP is absent (Can J Cardiol 2023)
Original title: Adcy9 Gene Inactivation Improves Cardiac Function After Myocardial Infarction in Mice
Since ADCY9 gene polymorphisms influence the cardiovascular benefits of the CETP modulator dalcetrapib after acute coronary syndrome, this study tested whether Adcy9 inactivation itself could improve cardiac function after myocardial infarction, and whether this depended on CETP. Wild-type and Adcy9-inactivated (Adcy9Gt/Gt) mice, with or without a human CETP transgene, underwent permanent left anterior descending artery ligation and were followed for 4 weeks. All mice developed left ventricular hypertrophy, dilation, and systolic dysfunction, but Adcy9Gt/Gt mice showed reduced pathologic remodelling and better left ventricular function than wild-type mice, with smaller cardiomyocytes, smaller infarcts, and preserved myocardial capillary density in the infarct border zone. There was no difference between CETP-transgenic mice and CETP-transgenic Adcy9Gt/Gt mice, both showing intermediate responses, and bone marrow T and B cell counts rose significantly in Adcy9Gt/Gt mice versus other genotypes, indicating that most of the cardioprotective benefit of Adcy9 inactivation required the absence of CETP activity.
Original abstract
Background: Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity.
Methods: Wild-type (WT) and Adcy9-inactivated (Adcy9Gt/Gt) male mice, transgenic or not for human CETP (tgCETP+/-), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks. Left ventricular (LV) function was assessed by echocardiography at baseline, 1, and 4 weeks after MI. At sacrifice, blood, spleen and bone marrow cells were collected for flow cytometry analysis, and hearts were harvested for histologic analyses.
Results: All mice developed LV hypertrophy, dilation, and systolic dysfunction, but Adcy9Gt/Gt mice exhibited reduced pathologic LV remodelling and better LV function compared with WT mice. There were no differences between tgCETP+/- and Adcy9Gt/Gt tgCETP+/- mice, which both exhibited intermediate responses. Histologic analyses showed smaller cardiomyocyte size, reduced infarct size, and preserved myocardial capillary density in the infarct border zone in Adcy9Gt/Gt vs WT mice. Count of bone marrow T cells and B cells were significantly increased in Adcy9Gt/Gt mice compared with the other genotypes.
Conclusions: Adcy9 inactivation reduced infarct size, pathologic remodelling, and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.