Fractional Flow Reserve versus Angiography-Guided Management of Coronary Artery Disease: A Meta-Analysis of Contemporary Randomised Controlled Trials.

Background and Aims: Randomised controlled trials (RCTs) comparing outcomes after fractional flow reserve (FFR)-guided versus angiography-guided management for obstructive coronary artery disease (CAD) have produced conflicting results. We investigated the efficacy and safety of an FFR-guided versus angiography-guided management strategy among patients with obstructive CAD. Methods: A systematic electronic search of the major databases was performed from inception to September 2022. We included studies of patients presenting with angina or myocardial infarction (MI), managed with medications, percutaneous coronary intervention, or bypass graft surgery. A meta-analysis was performed by pooling the risk ratio (RR) using a random-effects model. The endpoints of interest were all-cause mortality, MI and unplanned revascularisation. Results: Eight RCTs, with outcome data from 5077 patients, were included. The weighted mean follow up was 22 months. When FFR-guided management was compared to angiography-guided management, there was no difference in all-cause mortality [3.5% vs. 3.7%, RR: 0.99 (95% confidence interval (CI) 0.62−1.60), p = 0.98, heterogeneity (I2) 43%], MI [5.3% vs. 5.9%, RR: 0.93 (95%CI 0.66−1.32), p = 0.69, I2 42%], or unplanned revascularisation [7.4% vs. 7.9%, RR: 0.92 (95%CI 0.76−1.11), p = 0.37, I2 0%]. However, the number patients undergoing planned revascularisation by either stent or surgery was significantly lower with an FFR-guided strategy [weighted mean difference: 14 (95% CI 3 to 25)%, p =< 0.001]. Conclusion: In patients with obstructive CAD, an FFR-guided management strategy did not impact on all-cause mortality, MI and unplanned revascularisation, when compared to an angiography-guided management strategy, but led to up to a quarter less patients needing revascularisation.

IGFBP-1 in Cardiometabolic Pathophysiology-Insights From Loss-of-Function and Gain-of-Function Studies in Male Mice.

We have previously reported that overexpression of human insulin-like growth factor binding protein (IGFBP)-1 in mice leads to vascular insulin sensitization, increased nitric oxide bioavailability, reduced atherosclerosis, and enhanced vascular repair, and in the setting of obesity improves glucose tolerance. Human studies suggest that low levels of IGFBP-1 are permissive for the development of diabetes and cardiovascular disease. Here we seek to determine whether loss of IGFBP-1 plays a causal role in the predisposition to cardiometabolic disease. Metabolic phenotyping was performed in transgenic mice with homozygous knockout of IGFBP-1. This included glucose, insulin, and insulin-like growth factor I tolerance testing under normal diet and high-fat feeding conditions. Vascular phenotyping was then performed in the same mice using vasomotor aortic ring studies, flow cytometry, vascular wire injury, and angiogenesis assays. These were complemented with vascular phenotyping of IGFBP-1 overexpressing mice. Metabolic phenotype was similar in IGFBP-1 knockout and wild-type mice subjected to obesity. Deletion of IGFBP-1 inhibited endothelial regeneration following injury, suggesting that IGFBP-1 is required for effective vascular repair. Developmental angiogenesis was unaltered by deletion or overexpression of IGFBP-1. Recovery of perfusion following hind limb ischemia was unchanged in mice lacking or overexpressing IGFBP-1; however, overexpression of IGFBP-1 stimulated hindlimb perfusion and angiogenesis in insulin-resistant mice. These findings provide new insights into the role of IGFBP-1 in metabolic and vascular pathophysiology. Irrespective of whether loss of IGFBP-1 plays a causal role in the development of cardiometabolic disorders, increasing IGFBP-1 levels appears effective in promoting neovascularization in response to ischemia.

Insulin-like growth factor binding proteins and angiogenesis: from cancer to cardiovascular disease.

Angiogenesis is a tightly regulated activity that is vital during embryonic development and for normal physiological repair processes and reproduction in healthy adults. Pathological angiogenesis is a driving force behind a variety of diseases including cancer and retinopathies, and inhibition of angiogenesis is a therapeutic option that has been the subject of much research, with several inhibitory agents now available for medical therapy. Conversely, therapeutic angiogenesis has been mooted as having significant potential in the treatment of ischemic conditions such as angina pectoris and peripheral arterial disease, but so far there has been less translation from lab to bedside. The insulin-like growth factor binding proteins (IGFBP) are a family of seven proteins essential for the binding and transport of the insulin-like growth factors (IGF). It is being increasingly recognised that IGFBPs have a significant role beyond simply modulating IGF activity, with evidence of both IGF dependent and independent actions through a variety of mechanisms. Moreover, the action of the IGFBPs can be stimulatory or inhibitory depending on the cell type and environment. Specifically the IGFBPs have been heavily implicated in angiogenesis, both pathological and physiological, and they have significant promise as targeted cell therapy agents for both pathological angiogenesis inhibition and therapeutic angiogenesis following ischemic injury. In this short review we will explore the current understanding of the individual impact of each IGFBP on angiogenesis, and the pathways through which these effects occur.

The insulin like growth factor and binding protein family: Novel therapeutic targets in obesity & diabetes.

BACKGROUND: Recent changes in nutrition and lifestyle have provoked an unprecedented increase in the prevalence of obesity and metabolic disorders. Recognition of the adverse effects on health has prompted intense efforts to understand the molecular determinants of insulin sensitivity and dysglycemia. In many respects, actions of insulin-like growth factors (IGFs) mirror those of insulin in metabolic regulation. Unlike insulin, however, the bioactivity of IGFs is regulated by a family of seven high-affinity binding proteins (IGFBPs) which confer temporospatial modulation with implications for metabolic homeostasis. In addition, evidence is accumulating that IGF-independent actions of certain of the IGFBPs can directly modulate insulin sensitivity. SCOPE OF REVIEW: In this review, we discuss the experimental data indicating a critical role for IGF/IGFBP axis in metabolic regulation. We highlight key discoveries through which IGFBPs have emerged as biomarkers or putative therapeutic targets in obesity and diabetes. MAJOR CONCLUSIONS: Growing evidence suggests that several components of the IGF-IGFBP system could be explored for therapeutic potential in metabolic disorders. Both IGFBP-1 and IGFBP-2 have been favorably linked with insulin sensitivity in humans and preclinical data implicate direct involvement in the molecular regulation of insulin signaling and adiposity respectively. Further studies are warranted to evaluate clinical translation of these findings.