IMPROvE-CED Trial: Intracoronary Autologous CD34+ Cell Therapy for Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Non-Obstructive Coronary Arteries

Background: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with no-obstructive CAD (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary (IC) autologous CD34+ cell therapy for CED. Methods: Twenty NOCAD patients with invasively-diagnosed CED and persistent angina despite maximally-tolerated medical therapy (MTMT) underwent baseline exercise stress test (EST), GCSF-mediated CD34+ cell-mobilization, leukapheresis, and selective 1x105 CD34+ cells/kg infusion into LAD. Invasive CED evaluation and EST were repeated 6-months after cell infusion. Primary endpoints were safety and effect of IC autologous CD34+ cell therapy on CED at 6-months follow-up. Secondary endpoints were change in CCS angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire (SAQ) scores, and exercise time at 6-months. Change in CED was compared to that of 51 historic-control NOCAD patients treated with MTMT alone. Results: Mean age was 52{plus minus}13 years, 75% women. No death, myocardial infarction, or stroke occurred. IC CD34+ cell infusion improved microvascular CED [% acetylcholine-mediated coronary blood flow increased from 7.2 (-18.0-32.4) to 57.6 (16.3-98.3) %, p=0.014], decreased CCS angina class (3.7{plus minus}0.5 to 1.7{plus minus}0.9, Wilcoxon signed-rank test p=0.00018) and sublingual nitroglycerin use/day [1 (0.4-3.5) to 0 (0-1), Wilcoxon signed-rank test p=0.00047], and improved all SAQ scores with no significant change in exercise time at 6-months follow-up. Historic-control patients had no significant change in CED. Conclusion: A single IC autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Clinical Trial Registration: NCT03471611

Anxiety Disorders Are Associated With Coronary Endothelial Dysfunction in Women With Chest Pain and Nonobstructive Coronary Artery Disease

Background Anxiety disorders are the most prevalent mental disorders and are an emerging risk factor for coronary artery disease and its complications. We determine the relationship between having a clinical diagnosis of an anxiety disorder and coronary endothelial dysfunction (CED) using invasive coronary reactivity testing across both sexes. Methods and Results Patients presenting with chest pain and nonobstructive coronary artery disease (stenosis <40%) at coronary angiography underwent an invasive assessment of CED. Patients were categorized as having a clinical diagnosis of an anxiety disorder at the time of coronary angiography by chart review. The frequency of CED was compared between patients with versus without an anxiety disorder and after stratifying patients by sex. Between 1992 and 2020, 1974 patients (mean age, 51.3 years; 66.2% women) underwent invasive coronary reactivity testing, of which 550 (27.9%) had a documented anxiety disorder at the time of angiography. There was a significantly higher proportion of patients with any type of CED in those with an anxiety disorder in all patients (343 [62.7%] versus 790 [56.4%]; P =0.011) that persisted in women but not in men. After adjusting for covariables, anxiety was significantly associated with any CED among all patients (odds ratio [95% CI], 1.36 [1.10–1.68]; P =0.004), and after stratifying by sex in women but not in men. Conclusions Anxiety disorders are significantly associated with CED in women presenting with chest pain and nonobstructive coronary artery disease. Thus, CED may represent a mechanism underpinning the association between anxiety disorders and coronary artery disease and its complications, highlighting the role of anxiety as a potential therapeutic target to prevent cardiovascular events.

Experimental periodontal disease triggers coronary endothelial dysfunction in middle-aged rats: preventive effect of a prebiotic β-glucan

This study aimed to verify the hypothesis that periodontal disease contributes to endothelial dysfunction in the coronary arteries of middle-aged rats. Besides we evaluated the effects of a prebiotic (β-glucan isolated from Saccharomyces cerevisiae) in preventing vascular dysfunction. The sample comprised young (sham and induced to periodontal disease) and middle-aged rats (sham, periodontal disease, sham-treated and periodontal disease-treated), at 12 and 57 weeks, respectively. The treated-groups received daily doses of β-glucan (50 mg/kg) orally (gavage) for four weeks, and periodontal disease was induced in the last two weeks by ligature. A myograph system assessed vascular reactivity. The expression of eNOS, COX-1, COX-2, p47 phox, gp91phox, NFKB-p65, p53, p21, p16 was quantified by Western blotting. Serum hydroperoxide production was measured by the FOX-2 method. IL-1β, IL-10, and TNF-α levels were evaluated by spectroscopic ultraviolet-visible analysis. Periodontal disease in middle-aged rats was associated with reduced acetylcholine-induced relaxations of coronary artery rings affecting the endothelium-dependent hyperpolarization (EDH)- and the nitric oxide (NO)-mediated relaxations. The endothelial dysfunction was related to eNOS downregulation, increased IL-1β, TNF-α pro-inflammatory cytokines and also upregulation of NADPH oxidase, and COXs, inducing cell cycle inhibitory pathways, including the p53/p21 and the p16. Treatment with β-glucan effectively reduced bone loss in periodontal disease and delayed endothelial dysfunction in the coronary artery. Our data show that yeast β-glucan ingestion prevented oxidative stress, pro-inflammatory markers synthesis, and prevented eNOS reduction induced by periodontal disease in middle-aged rats. These results suggest that β-glucan has a beneficial effect on the coronary vascular bed.

Coronary endothelial function

The assessment of coronary endothelial function has profound importance in terms of diagnostic and prognostic significance in patients with both obstructive and non-obstructive coronary artery disease. Endothelial dysfunction may take place in both epicardial coronary arteries as well as in the coronary microcirculation. Epicardial coronary endothelial dysfunction can be detected in the catheterization laboratory with abnormal vascular responses to endothelial-dependent physiological or pharmacological stimuli, and is characteristically a precursor to the initial processes of atherosclerotic coronary disease. This chapter discusses coronary endothelial physiology, the prevalence of endothelial dysfunction, how to evaluate coronary endothelial function, and the prognosis for patients with endothelial dysfunction.

Abstract 17182: Coronary Endothelial Dysfunction in Humans is Associated With Elevated Expression of Clonal Hematopoiesis of Indeterminate Potential

Introduction: Recent evidence has demonstrated that Clonal Hematopoiesis of Indeterminate Potential (CHIP) increases the risk of cardiovascular events. However, the exact role played by CHIP in early stages of coronary atherosclerosis, characterized by coronary endothelial dysfunction remains to be elucidated. Hypothesis: The current study was designed to test the hypothesis that the presence of CHIP in peripheral blood cells is associated with coronary endothelial dysfunction and increased levels of inflammatory markers. Methods: Next generation sequencing was used to detect mutations among patients who had coronary endothelial dysfunction and control group (normal coronary endothelial function). Endothelial dysfunction was defined by ≥ 20% decrease in coronary artery diameter or ≤50% increase in blood flow in response to acetylcholine injection compared to baseline. Plasma cytokine levels of Interleukin (IL)-6 and IL-8 were also assessed. Results: Clonal hematopoiesis relevant gene mutations were found in 1 out of 64 patients with normal endothelial function (1.5%) and 11 out of 119 cases in the endothelial dysfunction group (9.2%) (P = 0.04) with ASXL1 (Additional sex combs-like 1) being the most frequent gene (4.2%) mutated. Cytokine analysis demonstrated that mutations in ASXL1, DNMT3A (DNA methyltransferase 3A) and TET2 (Ten-eleven-translocation-2) in the endothelial dysfunction group were associated with increased levels of IL-6 and IL-8 (P = 0.001, P = 0.003; respectively). Conclusions: The current study supports a potential role for CHIP in mechanisms of coronary artery disease starting at early stage of atherosclerosis. Furthermore, enhanced expression levels of IL-6 and IL-8 seem to be related to mutations in DNMT3A, ASXL1 and TET2 genes, more than other gene mutations relevant CHIP.