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

The Application of Head-Up Tilt Test to Diagnose Hemodynamic Type of Orthostatic Intolerance in Children Aged Between 3 and 5 Years

Objectives: The head-up tilt test (HUTT) is a useful tool to assess autonomic function and to reproduce neurally mediated reflex. In this study, we evaluated the use of HUTT in pediatric patients aged 3–5 years with orthostatic intolerance.Materials and Methods: The medical history and HUTT records of 345 (180 males, aged from 3 to 5 years) cases of patients who complained of symptoms of orthostatic intolerance and who visited the Syncope Ward, Children's Medical Center, The Second Xiangya Hospital, Central South University from January 2003 to December 2019, were reviewed retrospectively.Results: Seventy-nine (22.9%) cases had positive responses to complete HUTT (basic HUTT and sublingual nitroglycerin HUTT), while 29 (8.4%) cases had positive responses if only basic HUTT was performed. Sublingual nitroglycerin provocation significantly increased the positive rate of the test (x2= 27.565, P < 0.001). The most frequent hemodynamic response to HUTT was vasoinhibitory type vasovagal syncope (12.2%), Syncope (28.7%), and dizziness (22.6%) were the most common symptoms. Eight cases discontinued the test due to intolerable symptoms without severe adverse events occurring.Conclusions: HUTT was safe and well-tolerated and could be used to diagnose the hemodynamic type of orthostatic intolerance in children aged 3–5 years.

Comparative analysis of cost–effectiveness between isosorbide-5-mononitrate and isosorbide: a retrospective real-world evaluation

Aim: The cost–effectiveness of isosorbide-5-mononitrate (5-ISMN) and isosorbide dinitrate (ISDN) in real-world use in patients with coronary heart disease (CHD; either angina pectoris or myocardial infarction) was retrospectively compared. Method: In this retrospective real-world evaluation, patients with established CHD satisfying the following criteria were selected from information system of two tertiary hospitals in China: with pharmacy claiming for at least one injection of 5-ISMN or ISDN between July 2008 and May 2017; and, CHD patients. By using propensity score matching (PSM), we compared clinical aspects of efficacy, safety, length of hospital stay and cost during hospitalization between 5-ISMN and ISDN group. All data were processed by R statistical package v.2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Result: Of 5609 patients selected, 4047 received 5-ISMN and 1562 received ISDN. After PSM, we acquired 1555 pairs based on balancing of age, sex, insurance and comorbidities on admission. The frequency (4.2 ± 6.6-times vs 6.5 ± 9.5-times; p < 0.05) and total dosage (47.5 ± 153.4 vs 136.4 ± 261.0 mg; p < 0.05) of sublingual nitroglycerin use decreased and hypotension incidence lowered (8.0 vs 13.0%; p < 0.05) in 5-ISMN group compared with ISDN group. Hospital stay (16.0 ± 11.3 days vs 17.7 ± 13.2; p < 0.05) and hospitalization expenditure ([the ratio of cost in the study to the average hospitalization cost in the city] [odds ratio: 2.5 vs 2.6; p < 0.05]) were reduced in 5-ISMN group as with that of ISDN group. Moreover, the main component of hospitalization cost was medical consumables and medications in both the groups. Conclusion: In the present retrospective real-world evaluation, by using PSM analysis, we found that newer injection agent of 5-ISMN was associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization expenditure related to its comparator ISDN in patients with established CHD. Further evaluation and clinical experience are need in different circumference for the usage of ISDN.