PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates

Sammour, Yasser; DeZorzi, Christopher; Austin, Bethany A.; Borkon, A. Michael; Everley, M.P.; Fendler, Timothy J.; Khumri, Taiyeb M.; Lawhorn, S.L.; Nassif, Michael E.; Vodnala, Deepthi; Magalski, Anthony; Kao, Andrew; Sperry, Brett W.

doi:10.1016/j.cardfail.2021.02.018

Cited by 18 publications

(9 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evolocumab (a PCSK9 inhibitor) is a novel lipid-lowering drug that has been shown to decrease the incidence of myocardial infarction and stroke (49). In addition, Evolocumab has also been used in heart transplantation recipient on a small scale (25,50,51). Here, we found that Evolocumab, similar with Pcsk9 knockout, reduced allograft vasculopathy in hPCSK9 mice.…”

Section: Discussionmentioning

confidence: 64%

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

et al. 2022

View full text Add to dashboard Cite

BackgroundGraft vascular disease (GVD), which limits the long-term survival of patients after solid-organ transplantation, is associated with both immune responses and nonimmune factors, including dyslipidemia. Recent studies have shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a U.S. Federal Drug Administration-approved treatment for hyperlipidemia, reduces cardiovascular events, regulates inflammatory responses, and enhances the efficacy of immune checkpoint therapy in cancer treatment through a cholesterol-independent mechanism. However, whether targeting PCSK9 is a potential therapeutic strategy for GVD remains unknown.MethodsSerum samples and grafts were harvested from male mice undergoing abdominal aortic transplantation. The pathological alterations in the aortic grafts were detected by hematoxylin and eosin staining, Verhoeff’s Van Gieson staining, and Masson staining. Inflammatory cell infiltration and proinflammatory cytokine expression in the aortic grafts were detected by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The regulatory effects of PCSK9 on vascular smooth muscle cell (VSMC) migration and proliferation were examined by transwell, EdU, and western blot assays. The effect of Evolocumab, a PCSK9 inhibitor, on GVD in humanized PCSK9 mice was also evaluated.ResultsPCSK9 was upregulated in the serum, grafts, and liver of mice in the allograft group subjected to abdominal aortic transplantation. Pcsk9 knockout significantly reduced vascular stenosis, the intimal hyperplasia area and collagen deposition. Pcsk9 depletion also inhibited macrophage recruitment and the mRNA expression of proinflammatory cytokines in aortic grafts. Furthermore, Pcsk9 knockout suppressed the migration and proliferation of VSMCs, which was related to the inhibition of NLRP3 inflammasome activation. Meanwhile, Evolocumab significantly ameliorated GVD in humanized PCSK9 mice.ConclusionPCSK9 is upregulated in a mouse model of GVD, and Pcsk9 knockout reduces vascular occlusion, suggesting that PCSK9 may be a promising target for the treatment of GVD.

show abstract

Section: Discussionmentioning

confidence: 64%

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The availability of proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) may be of use. Some studies have already provided data supporting their efficacy and short-term safety in cardiac transplant recipients [54,55]. As a result, although more information about PCSK9i safety in heart transplant patients is needed, those with FH may benefit from early initiation of this therapy.…”

Section: Discussionmentioning

confidence: 99%

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Salgado

Díaz‐Molina

Cuesta‐Llavona

et al. 2023

JCM

View full text Add to dashboard Cite

Heart transplantation remains the gold standard for the treatment of advanced heart failure (HF). Identification of the etiology of HF is mandatory, as the specific pathology can determine subsequent treatment. Early identification of familial hypercholesterolemia (FH), the most common genetic disorder associated with premature cardiovascular disease, has a potential important impact on clinical management and public health. We evaluated the genetic information in the genes associated with FH in a cohort of 140 heart-transplanted patients. All patients underwent NGS genetic testing including LDLR, APOB, and PCSK9. We identified four carriers of rare pathogenic variants in LDLR and APOB. Although all four identified carriers had dyslipidemia, only the one carrying the pathogenic variant LDLR c.676T>C was transplanted due to CAD. Another patient with heart valvular disease was carrier of the controversial LDLR c.2096C>T. Two additional patients with non-ischemic dilated cardiomyopathy were carriers of variants in APOB (c.4672A>G and c.5600G>A). In our cohort, we identified the genetic cause of FH in patients that otherwise would not have been diagnosed. Opportunistic genetic testing for FH provides important information to perform personalized medicine and risk stratification not only for patients but also for relatives at concealed high cardiovascular risk. Including the LDLR gene in standard NGS cardiovascular diagnostics panels should be considered.

show abstract

“…Some cases reported that patients after heart transplantation treated with PCSK9i had no serious adverse reactions during the follow-up period ( 7 , 12 ). In another study of 65 patients taking PCSK9i after heart transplantation, four cases withdrew from the study due to adverse reactions: increased CK, severe abdominal pain, headache, shortness of breath, and joint pain ( 13 ). Nevertheless, there are few experiences of PCSK9i therapy in kidney transplant patients.…”

Section: Discussionmentioning

confidence: 99%

PCSK9 inhibitors in a renal transplant patient complicated with hepatitis B: A case report and literature review

Li²,

Lin³

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Lipid metabolism disorders are recognized to be one of the most frequent complications of renal transplantation, while dyslipidemia and chronic kidney disease (CKD) are strong risk factors for arteriosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are novel lipid-lowering drugs, the safety and efficacy of which are yet to be confirmed in transplanted patients. There have been several small-sample studies using PCSK9i in patients after heart transplantation, while fewer cases use PCSK9i after kidney transplantation. We report a case of a renal transplant recipient complicated with hepatitis B treated with PCSK9i, which achieved a remarkable lipid-lowering efficacy, and no significant adverse effects were found during the follow-up.

show abstract

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates

Cited by 18 publications

References 7 publications

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

PCSK9 inhibitors in a renal transplant patient complicated with hepatitis B: A case report and literature review

Contact Info

Product

Resources

About