Mohammad H Mustafa

Background: Heart failure (HF) is a progressive clinical syndrome marked by the heart’s inability to maintain sufficient cardiac output, resulting in fatigue, dyspnea, venous congestion, and systemic hypoperfusion¹. Globally, HF affects over 26 million people and leads to an estimated $31 billion in healthcare expenditures annually¹^, ². Although current treatments primarily target symptom relief and comorbidities, they do not adequately address the molecular mechanisms driving disease progression². One emerging target of interest is Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a protease originally studied for its role in hepatic LDL receptor degradation and cholesterol metabolism³. However, recent evidence suggests PCSK9 may also regulate cardiomyocyte mitochondrial function and structural integrity independent of lipid pathways³⁻⁶.

Methods: An initial literature review was conducted using PubMed and Google Scholar using keywords “(PSCK9)”, “(PCSK9) AND (Heart Failure)”, “(PCSK9) AND (Heart)” and relevant studies discussing the interaction of PCSK9 within the cardiovascular system were selected. Several experimental models were observed to investigate the role of PCSK9 in HF. A foundational study used wild-type (WT), global PCSK9 knockout (KO), liver-specific KO, and PCSK9/LDLR double KO mice to assess cardiac function through echocardiography, exercise testing, and cardiac metabolic assays⁶. Another study utilized cardiomyocyte-specific PCSK9 KO (CM-KO) mice to evaluate mitochondrial bioenergetics, myocardial structure, and gene expression changes over time⁴. Investigators employed histological analysis, contractile function tests, transmission electron microscopy, and transcriptomic profiling. Additional in vitro and in vivo studies examined PCSK9 secretion in hepatocytes using DRP1 (dynamin-related protein 1) inhibition via mdivi-1, and CRISPR/Cas9-mediated gene deletion to assess the link between mitochondrial fission and PCSK9 expression⁷. To counteract mitochondrial dysfunction, a study overexpressed the ubiquitin ligase FBXL4 in obese, HF-prone mice and assessed outcomes including mitochondrial integrity, cardiac geometry, and diastolic function⁵. Finally, a nested case-control study analyzed PCSK9 variants in human populations using UK Biobank data to determine clinical relevance⁸.

Results: Global and CM-specific PCSK9 KO mice demonstrated hallmark features of HF, including increased cardiac fibrosis, ventricular dilation, reduced cardiac reserve, and elevated cardiomyocyte apoptosis⁴,⁶. Notably, liver-specific PCSK9 deletion did not replicate these findings, suggesting a non-hepatic, LDLR-independent mechanism⁶. Transcriptomic data from CM-KO mice revealed downregulation of mitochondrial pathways such as oxidative phosphorylation, fatty acid β-oxidation, the TCA cycle, and amino acid metabolism, while glycolysis remained unaffected⁴. In hepatocytes, DRP1 inhibition via mdivi-1 led to a 74% reduction in PCSK9 secretion, a finding confirmed by CRISPR/Cas9 deletion of DRP1, which reduced secretion by 66%⁷. DRP1 inhibition also promoted efferocytosis and protected against mitochondrial dysfunction under metabolic stress. FBXL4 overexpression restored mitochondrial structure and improved diastolic function by antagonizing DRP1-induced fission in cardiomyocytes⁵. However, in the human study, PCSK9 variants did not show significant association with heart failure incidence, suggesting possible species-specific differences or compensatory mechanisms⁸.

Conclusion: PCSK9 plays a critical role in maintaining mitochondrial and structural integrity of cardiomyocytes, independent of its cholesterol-regulating function. Animal studies indicate that PCSK9 deficiency contributes to mitochondrial dysfunction and HF progression through altered metabolic and structural remodeling. Novel therapeutic approaches targeting mitochondrial dynamics, such as DRP1 inhibition or FBXL4 overexpression, offer potential in preventing HF. Further research is essential to validate whether enhances of PCSK9 expression and/or function can prevent HF progression in patients.

Works Cited

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