The introduction of proprotein convertase subtilisin/Kexin type 9 (PSCK9) inhibitors has transformed the approach to low-density lipoprotein cholesterol lowering in the prevention of atherosclerotic cardiovascular disease. This paper aims to determine the longer-term impact of these interventions on major adverse cardiovascular events (MACE) and all-cause mortality. A systematic search of major databases was conducted to identify randomised controlled trials comparing PCSK9 inhibitors with a placebo. Studies were included if they reported cardiovascular events with a follow-up duration greater than 12 months. Frequentist, Bayesian meta-analysis, and trial sequential analysis were utilised to assess the efficacy of PCSK9 inhibitors in reducing MACE. Amongst 11 studies encompassing 52,372 patients, statistically significant reductions were observed in rates of myocardial infarction (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.68 to 0.89, p < 0.01, I2 = 20%), coronary revascularisation (RR 0.83; 95% CI 0.75 to 0.91, p < 0.01, I2 = 9.1%) and ischemic stroke (RR 0.76; 95% CI 0.66 to 0.87, p < 0.01, I2 = 0%) amongst patients on PCSK9 inhibitors compared to placebo based on random-effects meta-analysis. Trial sequential analysis and Bayesian analysis supported these results, with posterior probabilities that PCSK9 inhibitors improve outcomes for myocardial infarction, coronary revascularisation, and ischemic stroke of 83.8%, 82.9%, and 69.4%, respectively. No statistically significant effect was observed for the other outcomes. This meta-analysis demonstrates significant reductions in the rate of myocardial infarction, coronary revascularisation, and ischemic stroke. Further benefits may emerge with longer-term follow-up and alternate methods of targeting PCSK9.
Mechanotransduction is essential for cardiovascular physiology, enabling cells to sense and respond to mechanical forces such as shear stress, stretch, pressure, and extracellular matrix deformation. Among mechanosensitive ion channels, PIEZO1 and PIEZO2 have emerged as critical regulators of cardiovascular mechanobiology. These large trimeric ion channels convert mechanical stimuli into calcium-dependent electrochemical signals that regulate vascular development, endothelial homeostasis, cardiac remodeling, inflammatory activation, and blood pressure control. Recent advances in structural biology, electrophysiology, and molecular genetics have substantially improved understanding of PIEZO channel architecture, mechanogating mechanisms, and downstream signaling pathways. In the cardiovascular system, PIEZO1 functions prominently in endothelial cells, cardiomyocytes, fibroblasts, erythrocytes, and vascular smooth muscle cells, where dysregulated signaling contributes to hypertension, fibrosis, cardiac hypertrophy, ischemic injury, and vascular inflammation. This review summarizes current knowledge of PIEZO-mediated cardiovascular mechanotransduction, emphasizing structural mechanisms, physiological functions, disease implications, and therapeutic potential. Emerging computational approaches, including artificial intelligence and machine learning-assisted electrophysiology, are also discussed as promising tools for advancing mechanobiological research, multiscale modeling, and precision cardiovascular medicine.
