Refractory Angina Patients Research Articles

Clinical development and proof of principle testing of new regenerative vascular endothelial growth factor-D therapy for refractory angina: rationale and design of the phase 2 ReGenHeart trial

BackgroundDespite tremendous therapeutic advancements, a significant proportion of coronary artery disease patients suffer from refractory angina pectoris, that is, quality-of-life-compromising angina that is non-manageable with established pharmacological and interventional treatment...

Mobilization of Endogenous CD34+/CD133+ Endothelial Progenitor Cells by Enhanced External Counter Pulsation for Treatment of Refractory Angina.

Adult stem cell therapy via intramyocardial injection of autologous CD34+ stem cells has been shown to improve exercise capacity and reduce angina frequency and mortality in patients with refractory angina (RA). However, the cost of such therapy is a limitation to its adoption in clinical practice. Our goal was to determine whether the less costly, less invasive, and widely accessible, FDA-approved alternative treatment for RA patients, known as enhanced external counterpulsation (EECP), mobilizes endogenous CD34+ stem cells and whether such mobilization is associated with the clinical benefits seen with intramyocardial injection. We monitored changes in circulating levels of CD34+/CD133+ and CD34+/KDR+ cells in RA patients undergoing EECP therapy and in a comparator cohort of RA patients undergoing an exercise regimen known as cardiac rehabilitation. Changes in exercise capacity in both cohorts were monitored by measuring treadmill times (TT), double product (DP) scores, and Canadian Cardiovascular Society (CCS) angina scores between pre- and post-treatment treadmill stress tests. Circulating levels of CD34+/CD133+ cells increased in patients undergoing EECP and were significant (β = -2.38, p = 0.012) predictors of improved exercise capacity in these patients. CD34+/CD133+ cells isolated from RA patients could differentiate into endothelial cells, and their numbers increased during EECP therapy. Our results support the hypothesis that mobilized CD34+/CD133+ cells repair vascular damage and increase collateral circulation in RA patients. They further support clinical interventions that can mobilize adult CD34+ stem cells as therapy for patients with RA and other vascular diseases.

REGENERATE-COBRA: A phase II randomized sham-controlled trial assessing the safety and efficacy of intracoronary administration of autologous bone marrow-derived cells in patients with refractory angina

AimsThe REGENERATE-COBRA trial (NCT05711849) will assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived mononuclear cells in refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy. MethodsREGENERATE-COBRA is a single site, blinded, randomized, sham-controlled, Phase II clinical trial enrolling 110 refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy. Patients will be randomized to either autologous bone marrow derived-mononuclear cells or a sham procedure. Patients in the cell-treated arm will undergo a bone marrow aspiration and an intracoronary infusion of autologous bone marrow derived-mononuclear cells. Patients in the control arm will undergo a sham bone marrow aspiration and a sham intracoronary infusion. The trial's primary endpoint is an improvement in Canadian Cardiovascular Society (CCS) angina class by 2 classes between baseline and 6 months. Secondary endpoints include change in: CCS class at 12 months, myocardial ischemic burden (as measured by perfusion imaging) at 6 months, quality of life at 6 and 12 months (as measured by EQ-5D-5L, EQ-5D-VAS and Seattle Angina Questionnaire), angina frequency at 6 and 12 months, total exercise time (as measured by a modified Bruce protocol) and major adverse cardiovascular events at 6 and 12 months. ConclusionsThis is the first trial to assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived unfractionated mononuclear cells in symptomatic refractory angina patients who have exhausted conventional therapeutic options.

The Impact of Coronary Sinus Reducer on Arrhythmic Properties in Patients with Refractory Angina.

Treatment with a coronary sinus reducer (CSR) is a new therapeutic option for refractory angina patients. Preclinical studies have shown antiarrhythmic properties of coronary sinus narrowing. The possible antiarrhythmic effect of CSR implantation is unknown. This study aimed to determine the possible antiarrhythmic effects of CSR implantation as assessed by high-resolution electrocardiogram (hrECG) parameters. 24 patients from the Crossroad study randomized to either CSR treatment (n = 12) or a sham procedure (n = 12) had hrECG recorded at baseline and after 6 months. T-peak and T-end interval (TpTe) defined as the time difference between the peak amplitude of the T wave and the global end of the T wave, spatial angle between QRS complex and T axis defined as the angle between the ventricular depolarization and repolarization vectors using maximal (QRSTP) and mean (QRSTM) vector amplitudes and spatial ventricular gradient (SVG) calculated as integral of ECG voltages over the entire QRST complex were analyzed. Additionally, we analyzed parameters of QT and heart rate variability using time and frequency domain. At baseline, all analyzed parameters were comparable between both groups and heart rate remained constant. The intragroup analysis did not show any significant change in TpTe, QRSTP, QRSTM, SVG, QT, and heart rate variability at follow-up. Furthermore, intergroup comparison between CSR implantation and sham procedure also did not show any significant difference in the change of analyzed parameters. Compared to the sham procedure, CSR implantation did not demonstrate a significant impact on the arrhythmogenic substrate assessed with hrECG. Unique Identifier: NCT04121845, https://classic.clinicaltrials.gov/ct2/show/NCT04121845.

Abstract 15114: Enhanced External Counter Pulsation for Treatment of Angina With No Obstructive Coronary Artery Disease (ANOCA)

Background: Angina and no obstructive coronary artery disease (ANOCA) is associated with poor outcomes and limited treatment options. Enhanced external counterpulsation (EECP) is a non-invasive treatment that involves applying external inflatable cuffs to the lower extremities to increase blood flow during diastole (diastolic augmentation and increased preload), followed by deflation during systole (decreased afterload). Although EECP is indicated in refractory angina patients, its effectiveness in treating refractory angina in ANOCA patients is relatively unknown and limited to small case series. Objective: Assess the efficacy of EECP treatment in ANOCA patients using Canadian Cardiovascular Society (CCS) angina class, 6-minute walk test (6MWT), Duke Activity Status Index (DASI), Seattle Angina Questionnaire (SAQ), and weekly anginal episodes. Methods: We examined ANOCA patients (defined as £50% stenosis in any major epicardial vessels) with CCS class 3 or 4 angina that completed EECP treatment at 2 large centers. CCS class, 6MWT, DASI, SAQ, and weekly anginal episodes were evaluated pre- and post- EECP treatment, as data was available. A paired Student’s t-test, Wilcoxon signed-rank test, and McNemar’s test were utilized as appropriate. Results: 65 ANOCA patients (63% female; 60±11 years) that completed 35±2 EECP sessions were included. Patients were on 4±2 cardiac medications pre-EECP (78% statin, 52% ACEI/ARB, 62% BBs, 34% CCBs, 48% nitrates, and 53% ranolazine). Post-EECP, 42 patients (65%) had an improvement of 3 1 CCS angina class with 16 (25%) improving by 3 2 classes. Significant improvements in CCS angina severity, 6MWT, DASI, SAQ, and weekly anginal episodes were evident post-EECP ( Table ). Conclusion: In ANOCA patients, EECP therapy reduces CCS angina class and improves exercise tolerance. EECP should be considered in ANOCA patients with refractory angina CCS class 3 or 4 as a part of optimal medical therapy.

Abstract 17136: Prospective Cohort Study for Evaluating the Safety and Efficacy of Mobile, Motorized Enhanced Extracorporeal Counterpulsation in Refractory Angina Patients

Introduction: Enhanced external counterpulsation (EECP) therapy is a potential treatment for refractory angina, which refers to persistent symptoms despite optimal treatment. However, the immobility, cost, and lack of individualized pressure control limit the accessibility and clinical implications of EECP. To address these limitations, a new Mobile, Motorized Enhanced Counterpulsation (MECP) device has been developed. Hypothesis: To investigate efficacy of MECP in improving in angina functional class and exercise tolerance in patients with refractory angina and to validate the consistency in outcomes observed with conventional EECP treatment. Methods: This prospective study enrolled patients with symptomatic refractory angina between September 2020 and December 2022 at two tertiary centers in Korea. Baseline and post-treatment assessments included measurements of angina scale, 6-minute walking test, cardiopulmonary exercise test, and central arterial pressure. Results: The study included 71 patients (70.4% male, median age 66 years). After the 10-hour MECP treatment session, 57.7% of patients showed improvement in angina scale based on Canadian Cardiovascular Society classification, with a significant distribution change from 76.8% to 49.3% in class II and from 21.7% to 5.7% in class III (p<0.001). Furthermore, patients demonstrated an increase of 20 meters in the 6-minute walk distance after MECP treatment (464 meters vs. 484 meters, p<0.001). However, there were no statistically significant differences in the baseline characteristics of patients based on their response to MECP. Conclusion : Our study highlights the substantial benefits of MECP in relieving symptoms for patients with refractory angina and suggests its potential for broader clinical applications which merits further investigation.

Exercise Training on Anginal Threshold Does Not Improve Endothelial Function in Refractory Angina Patients

Refractory angina (RA) is a chronic condition of coronary artery disease (CAD). Endothelial function (EF) measured by flow-mediated dilation (FMD) is an important prognostic marker in CAD. Exercise training is a stimulus that improves EF in CAD. However, exercise training effects on EF in RA are unknown. Therefore, we aimed to verify the effects of exercise training on EF in RA. This was a longitudinal, non-randomized clinical study, involving patients with patients limited by angina, aged 45 to 75years. Patients were prospectively allocated by convenience to either exercise trained (ET) or control group (C). Laboratory analysis, cardiopulmonary exercise test (CPET), and FMD were implemented at inclusion and after 12weeks of exercise training or clinical treatment period. Exercise training included 60minutes per session, 3 times a week, including 40minutes of aerobic exercise on anginal threshold heart rate obtained on the CPET, 15minutes of resistance training, and 5minutes of stretching. A total of 38 patients were included (mean age 60±9years, 22 men); 21 were allocated to the ET and 17 to the C group. Baseline measures showed no differences between groups. After 12weeks glycated hemoglobin and systolic blood pressure were lower in ET before than ET after (p=0.004, and p=0.05, respectively), and exercise time of the CPET was lower in ET before than ET after (p=0.002). Exercise training did not change FMD. In conclusion, exercise training performed on anginal threshold increases exercise tolerance but causes no changes in EF in patients with RA.

Effect of Coronary Sinus Reducer Implantation on Aerobic Exercise Capacity in Refractory Angina Patients—A CROSSROAD Study

Coronary sinus reducer (CSR) implantation is a new treatment option for patients with refractory angina pectoris. However, there is no evidence from a randomized trial that would show an improvement in exercise capacity after this treatment. The aim of this study was to evaluate the influence of CSR treatment on maximal oxygen consumption and compare it to a sham procedure. Twenty-five patients with refractory angina pectoris (Canadian Cardiovascular Society (CCS) class II–IV) were randomized to a CSR implantation (n = 13) or a sham procedure (n = 12). At baseline and after 6 months of follow-up, the patients underwent symptom-limited cardiopulmonary exercise testing with an adjusted ramp protocol and assessment of angina pectoris using the CCS scale and Seattle angina pectoris questionnaire (SAQ). In the CSR group, maximal oxygen consumption increased from 15.56 ± 4.05 to 18.4 ± 5.2 mL/kg/min (p = 0.03) but did not change in the sham group (p = 0.53); p for intergroup comparison was 0.03. In contrast, there was no difference in the improvement of the CCS class or SAQ domains. To conclude, in patients with refractory angina and optimized medical therapy, CSR implantation may improve oxygen consumption beyond that of optimal medical therapy.

The impact of diabetes mellitus on improvement of resting rate pressure product in patients with refractory angina undergone external counter pulsation

Abstract Funding Acknowledgements Type of funding sources: None. Background The management of coronary artery disease (CAD) has developed significantly in the last few decades. One of the therapeutic modalities that could be considered to patients with refractory angina caused by CAD is external counter pulsation (ECP). Rate pressure product (RPP) is a determinant of cardiac oxygen consumption and heart workload. It is a simple parameter that could be calculated easily by multiplying systolic blood pressure and heart rate. Increased resting RPP is associated with higher myocardial oxygen consumption and decreased cardiac efficiency. Studies that discuss factors that influence the decrease of resting RPP due to ECP procedure as a possible mechanism underlying the improvement of clinical symptoms in patients with refractory angina are still very limited. Purpose This study aimed to determine the impact of diabetes mellitus (DM) as one of most common risk factors for complex CAD and refractory angina on the decremental of resting RPP in refractory angina patients who have undergone standard 35 sessions of ECP. Methods This is a cohort retrospective study that collected data from registry of all patients who have completed 35 sessions of ECP procedures from 2018 until 2021. We compared the improvement of resting RPP after program completion and evaluated the effect of DM and blood glucose levels on the difference in resting RPP. Statistical test was performed by SPSS software for windows. Results A total of 16 patients were enrolled in this study with mean age of 65.4 years old. Subjects in this study were predominantly male (87.5%) and most of the subjects (68.8%) were diagnosed with CAD/3-vessels disease (3VD). The main risk factors found in the subjects were hypertension (75%) and DM (62.5%). All subjects underwent random blood sugar examination before starting ECP procedure with mean 122.7 mg/dL. Paired samples T-test analysis found that there was a decrease in resting RPP in subjects after undergoing ECP compared to before the procedure (7046.1 ± 1515.3 vs 8572.5 ± 1915.7; p-value <0.001). Independent samples T-test showed that the presence of DM reduced the mean decrease of resting RPP in study subjects (1034.8 ± 1122.2 vs 2345.7 ± 1167.5; p-value 0.043). Pearson correlation analysis showed that there was no significant correlation between blood sugar levels and decrease in resting RPP after ECP completion in study subjects (correlation coefficient -0.049; p-value: 0.869). Conclusion Standard 35 ECP sessions could decrease resting RPP in refractory angina patients. The improvements may contribute to the clinical benefit of ECP. However, the presence of DM can reduce the effectiveness of ECP in improving resting RPP, regardless of the blood sugar levels. These findings were probably related to cardiovascular autonomic neuropathy that were commonly found among diabetics. Further research is needed to elucidate the exact underlying mechanisms of these outcomes.

Interactive Effects of Nutrition Modification and Wet Cupping on Male Patients with Refractory Stable Angina.

ObjectivesRoutine therapies cannot control refractory stable angina, leading to a high economic burden and an impaired quality of life. Persian medicine incorporates exceptional attention to lifestyle and nutrition to prevent and treat various diseases. Previous studies have reported the analgesic and anti-inflammatory effects of wet cupping. The present study aims to determine the effects of nutrition and cupping on refractory stable angina patients.MethodsForty male patients with refractory stable angina were randomly allocated to four groups, including nutrition modification based on Persian medicine, wet cupping, nutrition modification along with wet cupping, and control. The primary outcomes were the changes in pain score using a visual analog scale and quality of life using the Seattle angina questionnaire. The secondary outcomes were changes in the exercise test and blood pressure.ResultsThe results of the present study revealed that 30 days of treatment with nutrition modification based on Persian medicine, cupping, and modified nutrition and cupping along with standard treatment for stable angina significantly increased the patient’s quality of life and exercise test results while reducing pain, and systolic and diastolic blood pressure.ConclusionApplying complementary Persian medicine methods such as nutrition modification and cupping along with the classical medical treatments may improve outcomes for refractory stable angina patients.

Intramyocardial adenoviral vascular endothelial growth factor-D∆N∆C gene therapy does not induce ventricular arrhythmias.

The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-DΔNΔC (AdVEGF-D) gene therapy (GT) to alleviate symptoms in refractory angina (RA) patients. In KAT301, 30 patients with RA were randomized to AdVEGF-D or the control group in 4:1 ratio. The treatment was found to be feasible, increasing myocardial perfusion and reducing angina symptoms at 1-year follow-up. However, there is some evidence suggesting that the intramyocardial delivery route and overexpression of (vascular endothelial growth) VEGFs might induce ventricular arrhythmias. Thus, we investigated whether intramyocardial AdVEGF-D GT increases the risk of ventricular arrhythmias in patients treated for RA. We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2years (range 6.3-10.4years) of follow-up. We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.

Efficacy of INtensive Treatment vs. Standard Treatment of COmpound DanshEn Dripping Pills in Refractory Angina Patients With Incomplete Revascularization (INCODER Study): Study Protocol for a Multicenter, Double-Blind, Randomized Controlled, Superiority Trial.

IntroductionPatients with incomplete revascularization (ICR) tend to develop refractory angina despite optimal medical therapy. The Compound Danshen Dripping Pills (CDDP) is a widely used antianginal drug in China and is shown to significantly alleviate myocardial ischemia. Previous studies showed dose-efficacy tendency when increasing doses of CDDP. This study aims to investigate the efficacy and safety of intensive doses of CDDP in patients with refractory angina with ICR.Methods and AnalysisThe INCODER study is a multicenter, double-blind, randomized controlled, superiority trial. We plan to recruit 250 patients aged 18–85 years with a diagnosis of refractory angina with ICR. Patients will be randomized (1:1) to intensive treatment group (CDDP 20 pills three times per day) or standard treatment group (10 pills CDDP and 10 pills placebo three times per day). Patients will have a 6-week medication period and be followed up every 2 weeks. The primary endpoint is the change of total exercise time from baseline to week 6 as assessed by cardiopulmonary exercise testing (CPET). Secondary endpoints include changes in the frequency of angina, Canadian Cardiovascular Society angina class, nitroglycerin use, Seattle Angina Questionnaire scores, peak oxygen uptake (VO2 peak) and other parameters as measured by CPET, and the levels of plasma C-reactive protein, homocysteine, and N-terminal pro-B-type natriuretic peptide. Safety events related to CDDP use will be monitored.Ethics and DisseminationThe research had been approved by the Clinical research and laboratory animal ethics committee of the First Affiliated Hospital, Sun Yat-sen University ([2019]65). The results will be reported through peer-reviewed journals, seminars, and conference presentations.Trial Registration Numberwww.chictr.org.cn (ChiCTR2000032384). Registered on 27 April 2020.

Efficacy of coronary sinus reducer implantation in patients with chronic total occlusion of the right coronary artery.

Clinical efficacy of coronary sinus reducer (CSR) in refractory angina (RA) patients with ischemia due to the chronic total occlusion (CTO) of the right coronary artery (RCA) remains unknown. To evaluate the efficacy of CSR implantation in RA patients with CTO RCA and compare them to CSR recipients with left coronary artery (LCA) ischemia. Consecutive patients with CTO RCA from 2 centers were prospectively included and compared to patients with LCA ischemia. All patients underwent evaluation of angina severity and quality of life (QoL) at baseline and after 12 months. In a subgroup of CTO RCA patients, stress cardiac magnetic resonance (CMR) imaging was also performed. Twenty-two patients with CTO RCA and predominant inferior and/or inferoseptal wall ischemia (the CTO RCA group) were compared to 24 patients with predominant anterior, lateral, and/or anteroseptal wall ischemia (the LCA group). While the Canadian Cardiovascular Society (CCS) anginascore mean (SD) improved in the CTO RCA group from 2.73 (0.46) to 1.82 (0.73) (P <0.001) and in the LCA group from 2.67 (0.57) to 1.92 (0.72) (P <0.001), there was no intergroup difference (P = 0.350). Significant improvement in all domains of the Seattle Angina Questionnaire was observed. Stress CMR did not show a significant reduction of ischemic inferior and/or inferoseptal segments, however, improvements in the transmurality index (P = 0.03) and the myocardial perfusion reserve index in segments with inducible ischemia (P = 0.03) were observed in the CTO RCA group. In CTO RCA patients, CSR implantation alleviated angina symptoms and improved QoL. The extent of improvement was comparable to that observed in patients with LCA ischemia.

Safety and effectiveness of enhanced external counterpulsation (EECP) in refractory angina patients: A systematic reviews and meta-analysis.

Enhanced external counterpulsation (EECP) is believed to be a non-invasive treatment for coronary artery disease and angina. The aim of this study was to determine the safety and effectiveness of EECP in refractory angina patients through a systematic reviews and meta-analysis. We conducted a comprehensive search of the literature published on PubMed, Cochrane library, Scopus, ScienceDirect, Trip Database and Google Scholar databases using appropriate keywords and specific strategy with no time limit. Having selected and screened the studies based on the defined inclusion and exclusion criteria and evaluating their quality based on the Cochrane checklist. For the meta-analysis,the Mantel-Haenszel method or the generic Inverse Variance was used. Analyses were done with Review Manager 5.2 software. A number of 299 studies were initially reviewed and finally, seventeen studies were included in the meta-analysis based on the inclusion and exclusion criteria. Also, thirteen outcomes were analyzed and the results of meta-analysis in twelve outcomes including (Systolic Blood Pressure (7 studies), Diastolic Blood Pressure (7 studies), Pulse Pressure (4 studies), Mean Arterial Pressures (4 studies), Heart Rate (6 studies), Angina episodes (7 studies), Walking distance (2 studies),Canadian Cardiovascular Society classification (6 studies), Flow-Mediated Dilation (3 studies), Daily Nitrate Usage (4 studies), Exercise Treadmill Test-Time (2 studies), ST-segment depression (2 studies)demonstrated a significant clinical advantage in the EECP treatment effectiveness in patients with angina. No significant difference was observed regarding EECP usefulness (P = 0.18) in the outcome of brachial artery diameter (2 studies). Based on the meta-analysis, the results indicate the safety and effectiveness of EECP in patients with angina pectoris and indicate the usefulness of this treatment in these patients. In general, the authors believe that the general conclusion in this regard requires some studies with a large sample size and a control group assignment.

Abstract 13176: Impact Of Cardiac Shock Wave Therapy On Myocardial Perfusion And Left Ventricular Ejection Fraction In Patient With Angina: A Meta-analysis

Introduction: Cardiac shock wave therapy (CSWT) using low-intensity shock waves is a non-invasive therapeutic option in the management of chronic refractory angina. This meta-analysis aimed to review the available studies on CSWT and observe its anti-anginal efficacy. Methods: PubMed, Embase, Cochrane, ClinicalTrials.gov, and Google Scholar were searched for studies evaluating the efficacy of CSWT in patients with refractory angina from January 1, 2000, until March, 2021. The primary outcome was the assessment of left ventricular ejection fraction (LVEF) before and after CWST. The secondary outcome was myocardial perfusion before and after CSWT. The analysis was performed using a random-effects-model using the Mantel-Haenszel method and results presented as 95% confidence interval using STATA version 15.1 software. Results: Twenty-four studies (20 observational and 4 Controlled Trails) with a total of 503 patients were included in the meta-analysis. The mean age was 64.92 ± 9 years and 25% were females. In patients undergoing CSWT, left ventricular ejection fraction improved significantly in patients undergoing CSWT (SMD: 0.31, 95% CI: 0.14 to 0.48, P = 0.0003, I 2 = 41%, Figure 1B). Likewise, myocardial perfusion improved significantly in patients undergoing CSWT (SMD: 0.74, 95% CI: 0.39 to 1.090, P = &lt;0.05, I 2 = 84%, Figure 1A). Conclusions: Based on our results, CSWT is a promising noninvasive modality for the management of refractory angina in patients with stable coronary artery disease and on optimal medical therapy.

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36–2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Son of a Lesser God: The Case of Cell Therapy for Refractory Angina.

In the last decades, various non-pharmacological solutions have been tested on top of medical therapy for the treatment of patients affected by refractory angina (RA). Among these therapeutics, neuromodulation, external counter-pulsation and coronary sinus constriction have been recently introduced in the guidelines for the management of RA in United States and Europe. Notably and paradoxically, although a consistent body of evidence has proposed cell-based therapies (CT) as safe and salutary for RA outcome, CT has not been conversely incorporated into current international guidelines yet. As a matter of fact, published randomized controlled trials (RCT) and meta-analyses (MTA) cumulatively indicated that CT can effectively increase perfusion, physical function and well-being, thus reducing angina symptoms and drug assumption in RA patients. In this review, we (i) provide an updated overview of novel non-pharmacological therapeutics included in current guidelines for the management of patients with RA, (ii) discuss the Level of Evidence stemmed from available clinical trials for each recommended treatment, and (iii) focus on evidence-based CT application for the management of RA.

Efficacy of coronary sinus Reducer in patients with refractory angina and diabetes mellitus.

Coronary sinus Reducer (CSR) implantation is currently recommended to relieve angina in patients with refractory symptoms despite optimal medical therapy and maximally achievable revascularization. The impact of diabetes mellitus on outcome after CSR implantation is at present unknown. We aimed to explore the impact of CSR in refractory angina patients with diabetes mellitus. Data from consecutive patients undergoing CSR implantation at four different centres between 2014 and 2018 were included. Patients were divided according to the presence or absence of diabetes mellitus. Primary objective of this analysis was to evaluate the clinical response to CSR implantation defined as an improvement of ≥ 1 classes of the Canadian Cardiovascular Society (CCS) Classification. A total of 219 patients were included, 116 (53%) of whom had diabetes mellitus. The median age of the population was 69years and 167 patients (76%) were male. There were no significant differences between groups of patients with and without diabetes mellitus with respect to CCS class at baseline (p value = 0.32) and at follow-up (p = 0.75). Over a median follow-up of 393 [224-1004] days, 84 (72%) of the patients with diabetes mellitus met the primary outcome, similarly to those without diabetes mellitus (p = 0.28). Fifty-three patients (24%) did not have an improvement in CCS class and no one experienced worsening of angina. CSR implantation was equally effective in improving angina symptoms among patients with refractory angina and diabetes mellitus compared to patients without diabetes mellitus.

The effect of external counterpulsation on intrinsic myocardial function evaluated by speckle tracking echocardiography in refractory angina patients: a randomized controlled trial.

External Counterpulsation (ECP) is one of the therapeutic options in patients with refractory angina inadequately controlled by medical, interventional, or surgical therapy. The 2D Speckle Tracking Echocardiography (2D-STE) method is considered superior in assessing clinical improvement. We would like to evaluate any improvement ofmyocardial intrinsic function using 2D-STE in patients underwent standard ECP protocol (35 sessions). We conducted a double-blind randomized controlled trial. Patients with refractory angina who could not be revascularized conventionally were randomized into two groups: (1) the ECP group (300mmHg) and (2) the Sham/control group (75mmHg). ECP standard therapy was given for 35 sessions (1h/day/session). The 2D-STE data, including longitudinal strain and post systolic index (PSI) were obtained before and after therapy. 43 subjects were analyzed, with 22 subjects in ECP group and 21 control subjects (Sham group). A homogenous baseline strain was found either globally (12.42 ± 4.55 vs 12.00 ± 4.92 [-%]; P = 0.774) or segmentally/regionally (12.63 (0.01-25.16) vs 12.43 (0.01-27.20) [-%]; P = 0.570). There was no statistically significant improvement between groups in the left ventricle longitudinal strain globally (P = 0.535) and segmentally/regionally (P = 0.434). PSI parameters showed improvement in the ECP group (P = 0.049), and segments with PSI ≥ 20% seemed to improve longitudinal strains in the ECP group after therapy (P = 0.042). In conclusion, 35 ECP therapy sessions did not improve either global or segmental/regional left ventricular mechanical function in patients with refractory angina.However, the mechanical function of myocardial segments with PSS tends to improve after ECP therapy.

51. ENHANCED EXTERNAL COUNTERPULSATION REDUCES BLOOD PRESSURE IN REFRACTORY ANGINA PECTORIS PATIENTS; A SYSTEMATIC REVIEW AND META-ANALYSIS

Refractory angina patients often coexist with hypertension. Uncontrolled hypertension increased the risk of major adverse cardiac event (MACE) and target-organ damage. Enhanced External Counterpulsation (EECP) is a non-invasive treatment that is beneficial in refractory angina pectoris patients. Hemodynamic benefits of EECP to peripheral blood pressure are observed but not yet established. We systematically review the available evidence of the efficacy of EECP in addressing systolic and diastolic blood pressure (SBP and DBP) in refractory angina pectoris patients. We conducted a literature search in MEDLINE and ResearchGate from its inception to January 2021. We included studies that reported SBP and DBP measurement at baseline and after EECP treatment in refractory angina patients. We conducted a meta-analysis of weighted mean differences from baseline to post-intervention for SBP and DBP. We identified 22 studies from 17 articles (n = 1564) consisting of 12 articles EECP only and six articles EECP vs control. Within EECP group, EECP treatment significantly reduce SBP by 6.7 mmHg (MD −6.77, 95%CI −9.09 to −4.45, p = &lt;0.00001, I 2 = 71%) and DBP by 3 mmHg (MD −3.03, 95%CI −4.07 to −2, p = &lt;0.00001, I 2 = 49%). Between-group, EECP treatment compared to control could reduce SBP by 9.1 mmHg (MD −9.15, 95%CI −15.75 to −2.56, p = 0.007, I 2 = 80%) and SBP by 2.6 mmHg (MD −2.68, 95%CI −5.52 to −0.17, p = 0.07, I 2 = 63%). Conclusion: EECP treatment provides additional benefits that reduce SBP and DBP in refractory angina pectoris patients to support controlling hypertension and reduce the risk of MACE and target-organ damage.