Abstract 67 Heterogeneous and heterocellular impact of PSCK9 on cardiac cells

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and, in the case of a gain-of-function mutation, leads to hypercholesterolemia and increased cardiovascular risk. Therefore, the PCSK9 inhibitors alirocumab and evolocumab are already used daily to prevent cardiovascular events in high-risk patients. However, the BIOSTAT-CHF study also showed a direct association between plasma PCSK9 levels and heart failure mortality. We were able to detect PCSK9 protein in both mouse and human cardiac tissue unlike skeletal muscle tissue. Therefore, we wondered whether PCSK9 has direct effects on the heterocellular heart.

Methods and results: To determine whether PCSK9 is functionally relevant to the heart, we measured contractile function and myocardial oxygen consumption (MVO2) in an isolated working heart model in PCSK9-deficient mice. Loss of PCSK9 impaired contractile function, as evidenced by a decrease in cardiac power (-32%) and cardiac output (-39%). Both MVO2 (-24%) and cardiac efficiency (-31%) were decreased, suggesting alterations in myocardial energy metabolism. Echocardiography did not detect subtle changes in systolic and diastolic cardiac function in vivo at rest. As a murine model of myocardial infarction, we performed permanent LAD ligation in PCSK9-deficient and wildtype mice. Interestingly PCSK9-deficient mice showed increased survival post-MI compared to their wildtype littermates. Mechanistically, we tested the impact of PCSK9 on isolated cardiac fibroblasts, cardiomyocytes, and bone marrow derived macrophages (BMDM) ex vivo, including functional assays and gene expression analysis. PCSK9 drives inflammation, particularly in macrophages, and has little impact of fibroblasts.

Conclusion: Beside its protective effects on atherosclerotic disease, our data suggest a high impact of PCSK9 on various cell types inside the heart under physiological and pathological conditions. Whether PCSK9 may represents a druggable target in heart disease independent of its role in controlling LDL cholesterol levels needs to be further evaluated.

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Heterogeneous and heterocellular impact of PSCK9 on cardiac cells
A. von Ehr¹, S. Rauterberg², J. Hein¹, P. Schrepf¹, T. A. Vico¹, I. Hilgendorf¹
¹Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau; ²Klinik für angeborene Herzfehler und Pädiatrische Kardiologie, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau;
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and, in the case of a gain-of-function mutation, leads to hypercholesterolemia and increased cardiovascular risk. Therefore, the PCSK9 inhibitors alirocumab and evolocumab are already used daily to prevent cardiovascular events in high-risk patients. However, the BIOSTAT-CHF study also showed a direct association between plasma PCSK9 levels and heart failure mortality. We were able to detect PCSK9 protein in both mouse and human cardiac tissue unlike skeletal muscle tissue. Therefore, we wondered whether PCSK9 has direct effects on the heterocellular heart. Methods and results: To determine whether PCSK9 is functionally relevant to the heart, we measured contractile function and myocardial oxygen consumption (MVO2) in an isolated working heart model in PCSK9-deficient mice. Loss of PCSK9 impaired contractile function, as evidenced by a decrease in cardiac power (-32%) and cardiac output (-39%). Both MVO2 (-24%) and cardiac efficiency (-31%) were decreased, suggesting alterations in myocardial energy metabolism. Echocardiography did not detect subtle changes in systolic and diastolic cardiac function in vivo at rest. As a murine model of myocardial infarction, we performed permanent LAD ligation in PCSK9-deficient and wildtype mice. Interestingly PCSK9-deficient mice showed increased survival post-MI compared to their wildtype littermates. Mechanistically, we tested the impact of PCSK9 on isolated cardiac fibroblasts, cardiomyocytes, and bone marrow derived macrophages (BMDM) ex vivo, including functional assays and gene expression analysis. PCSK9 drives inflammation, particularly in macrophages, and has little impact of fibroblasts. Conclusion: Beside its protective effects on atherosclerotic disease, our data suggest a high impact of PCSK9 on various cell types inside the heart under physiological and pathological conditions. Whether PCSK9 may represents a druggable target in heart disease independent of its role in controlling LDL cholesterol levels needs to be further evaluated.
https://dgk.org/kongress_programme/jt2023/aP1673.html