Adrian Quan

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity. Due to class-wide reduction in major adverse cardiovascular events in cardiovascular outcome trials and pleiotropic actions in multiple tissues, the use of GLP-1RAs has expanded beyond metabolic diseases. Recent studies have reported GLP-1RA efficacy for the treatment of atherosclerosis, heart failure and peripheral artery disease, alongside evolving potential in chronic kidney disease. The recent discovery that GLP-1RAs can improve vascular regenerative progenitor cell flux during type 2 diabetes has uncovered a novel mechanism implicating 3 classical hallmarks of vascular aging: (1) stem cell exhaustion, (2) altered intercellular communication, and (3) chronic systemic inflammation. In this review we discuss recent evidence demonstrating that imbalances in hematopoiesis during cardiometabolic diseases intersect with the senescence-associated secretory phenotype to elevate chronic inflammation and accelerate vascular aging. With a focus on stem cells as the master regulators of regenerative processes, we integrate the activities of GLP-1RAs that shift the balance from damage accumulation to repair competence in blood vessels prematurely aged by cardiometabolic syndrome.

Aims: In the NEWTON-CABG CardioLink-5 trial, treatment with the PCSK9 inhibitor evolocumab did not improve saphenous vein graft (SVG) patency relative to placebo in post-CABG patients. This post hoc analysis investigated whether achieved month 3 LDL-C levels were related to subsequent measures of SVG patency. Methods and results: Adults (≥18 years) on moderate- to high-intensity statins and undergoing CABG surgery with ≥2 SVGs were randomized 3–21 days postoperatively to subcutaneous evolocumab 140 mg or placebo every 2 weeks for 24 months. The primary endpoint was the proportion of SVGs with ≥50% occlusion on coronary computed tomography angiography or clinically indicated invasive angiography at 24 months. Secondary efficacy outcomes included the proportion of totally occluded SVGs, the proportion of participants with ≥1 totally occluded SVG, and SVG total plaque volume. A total of 1198 SVGs were assessed (499 evaluable participants). Mean LDL-C was 2.04 mmol/L and 1.03 mmol/L at baseline and month 3, respectively. Month 3 LDL-C [odds ratio (OR) = 0.74 per 1 mmol/L decrement; P = 0.005] and LDL-C change from baseline to month 3 (OR = 0.78 per 1 mmol/L decrease; P = 0.03) were related to the primary endpoint, with lower achieved levels or greater reductions associated with improved vein outcomes. These relationships did not depend on treatment assignment (Pinteraction = 0.79 and 0.84, respectively). Conclusion: LDL-C achieved over the range in this study was associated with SVG-related angiographic outcomes, suggesting LDL-C may have some role in SVG patency. These findings emphasize the importance of adhering to cholesterol guidelines after CABG.

Background: Sodium glucose co-transport inhibitors (SGLT2i), although established heart failure (HF) therapy in acquired heart disease, are not well-studied in adult congenital heart disease (ACHD). We aimed to conduct a systematic review and meta-analysis of SGLT2i therapy in moderate or severe complexity ACHD. Methods: Five databases (Pubmed, Medline, Embase, SCOPUS, and Cochrane) were searched for peer-reviewed journal articles describing SGLT2i HF therapy in moderate or severe complexity ACHD. Outcomes included adverse clinical events, biochemical markers of HF (N-terminal pro-brain natriuretic peptide [NT-proBNP] or BNP), and imaging markers of cardiac function (global longitudinal strain [GLS] and fractional area change [FAC]). Forest plots demonstrated mean study effects as individual and pooled estimates. The impact of heterogeneity on the overall variance was evaluated. Results: The systematic review included 10 studies (n=174 patients, 60% male). SGLT2i therapy was associated with a statistically significant improvement in GLS (mean difference -1.6 [-2.4,-0.9]) but not FAC (mean difference +1.86 [-6.2,+9.9]); there was no significant post therapy change in NT-proBNP or BNP (mean difference -240 pg/mL [-516,45] and -52 pg/mL [-129,26], respectively). Heterogeneity for the pooled effects for GLS and FAC was low (I2=0%), although moderate to high for NT-proBNP and BNP (I2=47% and I2=90%, respectively). Data were insufficient for evaluation of SGLT2i impact on clinical outcomes. Conclusions: Pooled results across studies suggest that SGLT2i therapy can improve GLS among people with ACHD-HF, however the clinical implications of this observation warrant further study. Randomized controlled trials are now needed to evaluate the impact of SGLT2i therapy in ACHD.

Background and Aims: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major atherosclerotic cardiovascular events in individuals living with either diabetes or obesity. Since the turnover of vascular regenerative (VR) stem and progenitor cells has been demonstrated to modulate vessel repair and atherothrombotic risk, this study aimed to determine the effect of the GLP-1RA semaglutide on the levels of circulating VR cells. Methods: SEMA-VR CardioLink-15 was a randomized translational trial of usual care vs semaglutide for 6 months in 46 participants with either type 2 diabetes and/or obesity plus atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors. Vascular regenerative cells were enumerated using multi-parametric flow cytometry for high aldehyde dehydrogenase activity (ALDHhi) and lineage-specific cell surface marker expression. The primary endpoint was the 6-month change in VR cell content. Results: Compared with usual care (n = 24), semaglutide (n = 22) led to a greater increase in the number of VR cells [high aldehyde dehydrogenase 1A1 activity and low side scatter (ALDHhiSSClow): +0.8% vs +34.8%; P = .036], pan-haematopoietic myeloid progenitors (ALDHhiSSClowCD45+: +2.8% vs +40.1%; P = .017), and endothelial precursors (ALDHhiSSClowCD34+ CD133+ CD45−: −2.3% vs +66.2%; P = .037) from baseline. Semaglutide also decreased granulocyte precursors (ALDHhiSSChi: +0.3% vs −50.8%; P = .002), particularly those expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Semaglutide down-regulated serum proteins over-represented in pro-inflammatory tumour necrosis factor and interleukin signalling pathways. Conclusions: In people living with either type 2 diabetes or obesity plus ASCVD risk, semaglutide increased circulating VR cell content while reducing pro-inflammatory granulocyte precursors and cytokine production. Collectively, these findings suggest that semaglutide may improve endogenous progenitor cell–mediated blood vessel repair processes.

Aims: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD); however, the relationship between Lp(a) and the capacity for vascular repair remains unclear. Depletion of vascular regenerative (VR) progenitor cells has been shown to be a novel indicator of compromised vascular repair in people living with cardiometabolic disorders. The purpose of this study was to determine if elevated levels of Lp(a) modify VR cell content properties. Methods and results: The cross-sectional, multi-site Lipoprotein(a) and Vascular Regenerative Cell Content CardioLink-16 [Lp(a)-VRCE] study enrolled 40 individuals—20 with Lp(a) ≥100 nmol/L and 20 with Lp(a) <100 nmol/L. Isolated peripheral blood mononuclear cells were analysed by multi-parameter flow cytometry. VR progenitor cells were identified based on high aldehyde dehydrogenase (ALDH) activity, in combination with primitive vs. mature lineage-specific cell surface markers. The Lp(a) ≥100 nmol/L group exhibited baseline characteristic differences compared with the Lp(a) <100 nmol/L group such as lower estimated glomerular filtration rate (86.9 vs. 100.1 mL/min/1.73 m2), lower total cholesterol (4.0 vs. 4.8 mmol/L), greater statin use (90 vs. 60%), and a higher prevalence of ASCVD (60 vs. 25%). The Lp(a) ≥100 nmol/L group had lower frequencies of pro-angiogenic ALDHhiSSClowCD133+ (P = 0.0008) and ALDHhiSSClowCD34+CD133+ (P = 0.005) progenitor cells with pro-angiogenic secretory function. Compared with those in the Lp(a) <100 nmol/L group, individuals in the Lp(a) ≥100 nmol/L group demonstrated a higher frequency of M1-polarized pro-inflammatory monocytes (ALDHhiSSCmidCD86+CD163−; P = 0.007) and a lower frequency of ALDHhiSSChiCD49d+ granulocyte precursor cells (P = 0.04) that are involved in vessel repair. Conclusion: In this translational study, people with an Lp(a) ≥100 nmol/L had fewer VR cells and more pro-inflammatory polarized monocyte precursor cells than those with Lp(a) levels <100 nmol/L. These findings suggest that vessel repair activities may be compromised in individuals with elevated Lp(a) levels. Registration: Lp(a)-VRCE ClinicalTrials.gov: NCT06626659

In this post hoc subanalysis of 92 individuals living with T2D and at high cardiovascular risk, the authors summarize the differences in circulating vascular regenerative (VR) progenitor cell content between those on GLP-1RA therapy, on SGLT2 inhibitor without GLP-1RA therapy, and on neither therapy. Those on GLP-1RA therapy demonstrated greater circulating VR progenitor cell content and reduced proinflammatory granulocyte precursor content. These results offer novel mechanistic insights into the cardiometabolic benefits associated with GLP-1RA therapy.