Refractory Angina Research Articles

Changes in myocardial perfusion after coronary sinus reducer implantation for refractory angina - assessment using fully automated quantitative stress perfusion cardiac MRI

Abstract Introduction Previous reports show angina improvement after Coronary Sinus Reducer (CSR) implantation [1,2]. However, the mechanistic basis remains unconfirmed. Preliminary studies using semi-quantitative metrics derived from stress perfusion cardiac MRI (CMR), have suggested improved myocardial perfusion particularly in ischaemic segments [3]. To date, assessment by fully automated quantitative myocardial perfusion CMR has not been reported. Purpose To assess the effect of CSR implantation on quantitative regional myocardial blood flow in patients with refractory angina and advanced coronary artery disease (CAD). Methods Prospective cohort study of patients undergoing CSR implantation. CMR was performed at baseline and median 7 months follow-up. Automated segmentation into a 16-segment American Heart Association model was performed to quantify segmental rest and stress myocardial blood flow (MBF, ml/min/g) and myocardial perfusion reserve (MPR). Rest MBF was corrected for heart rate by dividing by the scan heart rate and multiplying by the mean resting heart rate among all subjects. Wilcoxon matched-pairs sign rank tests were used to compare paired global and segmental perfusion values. A linear mixed-effects model with random slopes and intercepts was used to assess the relationship between baseline segmental MPR and associated change in MPR (ΔMPR) after CSR implantation. Results 12 patients (10M:2F; mean age 67) were included. Median Canadian Cardiovascular Society class was 3. Globally, there was no change in rest (P=0.90), stress MBF (P=0.34) or MPR (P=0.72) from baseline to follow-up. However, ΔMPR was related to the degree of baseline ischaemia (panel A). Segments with baseline MPR<2.45 increased in MPR whereas segments with baseline MPR ≥2.45 experienced a decrease (P=0.003, conditional R2: 0.81). In segments with MPR<2.45 (n=138), median ΔMPR was +0.18 (15.4%; P<0.0001); whereas with MPR≥2.45 (n=52) it was -0.41 (-12.7%; P=0.03; panel B). When assessed by myocardial layer, significant increases in MPR were observed in both subendocardial (+0.19 [15.6%]; P<0.0001) and subepicardial (+0.19 [12.3%]; P<0.0002) segments with baseline MPR< 2.45 (panel C). Conversely, in segments with baseline MPR≥2.45, there was a significant reduction in MPR in the subendocardium (-0.43 [-15.9%]; P=0.04) but not in the subepicardium (-0.36 [-9.90%]; P=0.08; panel D). Conclusion To our knowledge, this is the first study showing changes in quantitative myocardial perfusion after CSR implantation by fully automated inline quantitative perfusion CMR. Our analysis shows a relationship between baseline MPR and change in MPR after CSR implantation, supporting redistribution of perfusion into both subendocardial and subepicardial layers as potential mechanisms of action of CSR. Further studies are needed to confirm these preliminary results.

Angiogenic gene therapy for refractory angina: results of the epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (EXACT) phase 2 trial

Abstract Background Refractory or "no option" angina (RA) is a debilitating condition with increasing global prevalence. Exogenous transduction of vascular endothelial growth factor (VEGF) induces angiogenesis and improves perfusion of ischemic myocardium in preclinical studies. XC001 (AdVEGFXC1) is a novel adenoviral-5 vector expressing the three major isoforms of VEGF (-121, -165, -189) in ratios shown to enhance potency and improve safety. Purpose EXACT is a single-arm, multicenter, open-label, phase 2 trial to explore the safety, tolerability, and preliminary efficacy of trans-epicardial delivery of XC001 to improve exercise capacity and ischemic burden in RA patients. Methods Patients were required to have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy with exercise limited by angina after 90 but before 540 seconds on a modified Bruce protocol, demonstrable ischemia on stress positron emission tomography (PET) and lack revascularization options. XC001 (1x1011 viral particles) was injected directly into ischemic myocardium via surgical transthoracic epicardial access. The primary outcome was safety by adverse event monitoring. Efficacy assessments included difference from baseline to six months in total exercise time (TET), myocardial ischemia by PET, angina class, angina frequency, and quality of life. Results Thirty-two patients (mean/median ages of 64/64, 34% female) were enrolled at 13 sites between March 2021 and July 2022. Median anti-anginal use was 3, 75% had prior revascularization with CABG and 88% with PCI. Fifty-five serious adverse events (SAEs) were observed in 21 patients (66%). None were attributed to study drug. Twenty-one SAEs in 14 patients were related to the surgical procedure, all of which were expected. One non-CV death occurred in month 3 following respiratory infection (Covid) deemed unrelated to surgery or study drug. Compared to baseline, total exercise time at 6-months increased by 85.5 seconds (95% CI 31.3-139.7) [Figure 1A] while total myocardial ischemic deficit in the treated region on PET decreased by 14.4% (95% CI, 3.01–25.73) [Figure 1B]. Angina frequency and nitroglycerin use measured during a two-week diary decreased by 6.6 episodes (95% CI, 3.5–9.7) and 4.1 doses (95% CI, 1.3–6.9), respectively. Canadian Cardiovascular Society angina grade decreased from 3.1 to 1.8, mean difference 1.3 classes (95% CI, 1.0–1.6) [Figure 2] while Seattle Angina Questionnaire Frequency score improved from 41.3 to 67.4, mean difference of 26.1 (95% CI, 16.3–35.9). Conclusions VEGF gene therapy with XC001 administered via minimally invasive epicardial delivery appears safe and well tolerated. Improvements in objective and subjective measures including total exercise time, myocardial perfusion, angina frequency and quality of life support a clinically meaningful biologic effect. This therapy warrants study in larger randomized studies.

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.

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 17001: Enhancing Coronary Functional Angiography: Integrating Doppler-Based Left Circumflex Coronary Flow Reserve in Assessment

Background: Coronary microvascular dysfunction (CMD), predominantly affecting women is associated with poor outcomes and has limited diagnostic options. Coronary functional angiography (CFA) is used for diagnosing CMD in patients with refractory angina and no obstructive coronary artery disease (ANOCA). The assumption is that endothelial-independent CMD is a homogenous disease process, therefore current gold-standard for diagnosis is measure of coronary flow reserve (CFR) in the proximal left anterior descending artery (LAD). However, there is limited data on CFR in the left circumflex (LCx). Objective: Examine the benefits of measuring CFR using Doppler-tipped guide wire in LCx in addition to proximal LAD. Methods: Examined 191 ANOCA patients with Canadian Cardiovascular Society (CCS) class 3 or 4 angina despite optimal medical treatment who underwent CFA for assessment of CMD. CFR measurements were obtained using Doppler-tipped guidewire during the administration of 72 mcg of adenosine in both the proximal LAD and LCx and CFR of <2.5 was used to define CMD. Results: 191 patients underwent CFA including 91% female with a median age of 59 years (IQR: 50, 67). The correlation in CFR measurements between the proximal LAD and LCx was 0.610 (p<0.001). 149 (78%) patients had concordant results including 113 (59%) with abnormal CFRs and 36 (19%) with normal CFRs in both vessels. 12 (6%) had abnormal proximal LAD CFR and normal LCx CFR; and 30 (16%) had an abnormal LCx CFR and normal proximal LAD CFR and would have gone undiagnosed without measuring LCx CFR. Conclusion: The addition of LCx CFR measurement to the current standard CFA protocol using the Doppler guidewire improves diagnosis of CMD in patients. Further studies are needed to evaluate a comprehensive assessment of CMD including measurement of LCx CFR.

Réducteur de sinus coronaire : revue de littérature et enjeux autour du registre France Reducer

Coronary sinus Reducer implantation is a percutaneous technique used to treat patients suffering from refractory angina pectoris. The device narrows the coronary sinus, increases the back pressure in the myocardial venous system and forces redistribution of coronary blood flow from less ischemic subepicardium to the more ischemic subendocardium. Multiple clinical studies had proven its efficacy to alleviate myocardial ischemia and related symptoms, and to improve the quality of life of patients with refractory symptomatic chronic coronary artery disease for whom coronary revascularization is deemed unsuitable. This literature review aims to expose the device design, its mechanisms of action, and the clinical data supporting its use.Since November 2021 Reducer's reimbursement has been granted in France by the national health authority. It is the first device to be approved under a newly established reimbursement approval process. A transitional coverage is provided with opportunities for renewal before applying for full-time reimbursement. To fulfill the requirements of the National Commission for Evaluation of Medical Devices and Health Technologies, the French Society of Cardiology has been creating the France Reducer registry. This clinical registry has been collecting data from patients undergoing coronary sinus Reducer implantation regarding their clinical situation, periprocedural information, and one-year follow-up. It is crucial for the future of this emerging therapeutic option in France. To date, 215 patients from 28 centers have been included between June 2022 and September 2023.

Enhanced External Counterpulsation for the Treatment of Angina With Nonobstructive Coronary Artery Disease

Angina and nonobstructive coronary artery disease (ANOCA) is associated with poor outcomes and limited treatment options. Enhanced external counterpulsation (EECP) is a noninvasive treatment that involves applying external inflatable cuffs to the lower extremities to increase blood flow during diastole, followed by deflation during systole. Although EECP is approved for treatment in patients with refractory angina due to obstructive coronary artery disease, its effectiveness in treating patients with ANOCA with refractory angina is limited to small studies. We assessed the efficacy of EECP treatment in patients with ANOCA (defined as ≤50% stenosis in any major epicardial vessels) with refractory anginaby measuring changes in Canadian Cardiovascular Society (CCS) angina class, 6-minute walk test, Duke Activity Status Index (DASI), Seattle Angina Questionnaire 7 (SAQ7), and weekly anginal episodes pre-EECP and post-EECP treatment. A total of 101 patients with ANOCA with CCS class III/IV angina completed a full course of EECP treatment at 2 large EECP centers. In 101 patients with ANOCA the mean age (SD) of 60.6 (11.3) years and 62.4% of the cohort were women. We found significant improvements post-EECP treatment in CCS angina class (mean (SD) 3.4 (0.5) to 2.4 (2.9), p <0.001), 6-minute walk test (median 1200 (IQR 972 to 1411) to 1358 (1170 to 1600), p <0.001), DASI (mean (SD) 15.2 (11.6) to 31.5 (16.3), p <0.001), SAQ7 (mean (DS) 36.2 (24.7) to 31.5 (16.3), p <0.001), and weekly anginal episodes (mean (SD) 5.3 (3.5) to 2.4 (2.9), p <0.001). After EECP treatment, 71 patients (70.3%) had an improvement of ≥1 CCS angina class, including 33 (32.7%) patients improving by ≥2 CCS classes. In conclusion, in patients with ANOCA, EECP therapy reduces CCS angina class and improves exercise tolerance and capacity; and should be considered a part of optimal medical therapy.

Influence of enhanced external counterpulsation on endothelial function: a meta-analysis of randomized controlled trials

Objectives Enhanced external counterpulsation (EECP) is an effective and noninvasive treatment for patients with refractory angina and chronic heart failure. However, previous studies evaluating the influence of EECP on endothelial function showed inconsistent results. This systematic review and meta-analysis was conducted to evaluate the effects of EECP on endothelial function measured by brachial artery flow-mediated dilation (FMD). Design PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched for randomized controlled trials comparing the influence of EECP versus usual care on FMD in adult population. A random-effects model incorporating the potential influence of heterogeneity was used to pool the results. Results Nineteen studies with 1647 patients were included in the meta-analysis. Compared with usual care or conventional therapy, additional treatment with EECP for 3–7 weeks was associated with a significantly improved FMD (mean difference [MD]: 1.96%, 95% confidence interval [CI]: 1.57–2.36, p < 0.001, I 2 = 52%). Subgroup analysis showed consistent results in patients with coronary artery disease and in patients with other diseases (p for subgroup difference = 0.21). Results of meta-regression analysis showed that the mean baseline FMD level was positively correlated with the influence of EECP on FMD (coefficient = 0.42, p < 0.001). Results of subgroup analysis suggested that the increment of FMD following EECP was larger in patients with baseline FMD ≥ 5% (MD: 2.69, 95% CI: 2.27–3.10, p < 0.001; I 2 = 15%) compared to those with baseline FMD < 5% (MD: 1.49, 95% CI: 1.13–1.85, p < 0.001; I 2 = 0%; p for subgroup difference < 0.001). Conclusions EECP may be effective in improving endothelial function measured by FMD.

Unlocking Promising Therapies: Drug-Eluting Stents in Medically Refractory Angina Patients With Myocardial Bridging

Myocardial bridging (MB) is a congenital variation in which a coronary artery segment tunnels through the myocardium instead of following its usual epicardial route. Although MB is usually diagnosed incidentally and has a good long-term prognosis, it can lead to complications such as angina, myocardial infarction, arrhythmias, and sudden death. This study aimed to evaluate the outcomes of drug-eluting stent (DES) implantation in patients with MB and medically refractory angina. The study included 12 patients with significant MB who did not respond to maximal medical therapy and underwent DES implantation. The patients were followed up for a mean duration of 33months. The procedural success rate was 92%, with only 1 patient experiencing acute coronary artery rupture during the procedure. During the follow-up period, none of the patients reported angina symptoms, required additional percutaneous coronary intervention, or developed stent thrombosis. One patient (8.3%) died from a non-cardiac cause. The procedure demonstrates a high procedural success rate and leads to favorable long-term outcomes, including the absence of angina symptoms and the avoidance of stent-related complications. In conclusion, this study suggests that DES implantation can serve as an effective treatment option for selected patients with medically refractory angina and significant MB.

Obstructive Sleep Apnoea as an Exacerbator of Vasospastic Angina

Little is known about the association between obstructive sleep apnoea (OSA) and vasospastic angina. The authors report the case of a 47-year-old female with vasospastic angina who had a high symptom burden despite nitroglycerine and a calcium channel blocker. After a sleep study revealed severe OSA, the patient was started on continuous positive airway pressure. Following 8 weeks of continuous positive airway pressure, the patient reported remarkable improvement in their symptoms. This case suggests an under-recognised link between OSA and vasospastic angina. While further clinical research is required, screening and treatment of OSA may be beneficial for patients with treatment refractory vasospastic angina.

Spinal cord stimulation for refractory angina pectoris: a case series

Background: Refractory angina pectoris significantly reduces the length and quality of life. One of the methods to control symptoms and improve the quality of life of patients with refractory angina pectoris is spinal cord stimulation.Objective: To evaluate the effectiveness of spinal cord stimulation in controlling anginal pain in the long-term period over a long follow-up (&gt;7 years).Methods: We retrospectively studied treatment results of 9 patients (6 men and 3 women) in the long-term follow-up from October 2012 to November 2022. Anginal pain and patients' quality of life were assessed using the visual analog scale and the Seattle Angina Questionnaire, respectively.Results: The mean follow-up was 7.33 ± 1.11 years. In the long-term postoperative period, regression of pain according to the visual analog scale was 52.3% (P = .0025). The Seattle Angina Questionnaire showed an improvement of the quality of life by 52.2% (P = .0993).Conclusion: Spinal cord stimulation allows to make control of chronic anginal pain more efficient, improve patients’ length and quality of life, and reduce the frequency and severity of disability. Received 8 December 2022. Revised 17 July 2023. Accepted 18 July 2023. Informed consent: The patient’s informed consent to use the records for medical purposes is obtained. Funding: The study did not have sponsorship. Conflict of interest: The authors declare no conflict of interest. Contribution of the authors: The authors contributed equally to this article.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.

Novel concepts in the management of angina in coronary artery disease.

Coronary artery disease remains a condition with high prevalence and detrimental effects on the quality of life of affected individuals. Its most frequent manifestation, stable angina pectoris, may be challenging to manage despite the available antianginal pharmacotherapy and adequate risk factor control, especially in subjects not amenable to revascularization. In the direction of refractory angina pectoris, several approaches have been developed over the years with varying degrees of success. Among the most recognized techniques in managing angina is enhanced external counterpulsation, which utilizes mechanical compression of the lower extremities to increase blood flow to the heart. Moving to coronary sinus reduction, it leads to an increase in coronary sinus backward pressure, ultimately augmenting myocardial blood flow redistribution to ischemic regions and ameliorating chronic angina. Clinical trial results of the above-mentioned techniques have been encouraging but are based on small sample sizes to justify their widespread application. Other interventional approaches, such as transmyocardial laser revascularization, extracorporeal shockwave myocardial revascularization, and spinal cord stimulation, have been met with either controversial or negative results, and their use is not recommended. Lastly, angiogenic therapy with targeted intramyocardial vascular endothelial growth factor injection or CD34+ cell therapy may be beneficial and warrants further investigation. In this review, we summarize the current knowledge in the field of angina management, highlighting the potential and the gaps in the existing evidence that ought to be addressed in future larger-scale, randomized studies before these techniques can be safely adapted in the clinical practice of patients with refractory angina pectoris.

The relation between atherogenic index of plasma and cardiovascular outcomes in prediabetic individuals with unstable angina pectoris

BackgroundThe atherogenic index of plasma (AIP) is a novel biomarker associated with atherosclerosis, and an important risk factor for atherosclerosis, but its relation with cardiovascular prognosis in prediabetic patients with unstable angina pectoris (UAP) is still uncertain.MethodsThis study included 1096 prediabetic patients with UAP who were subjected to follow-up for a maximum of 30 months, with cardiac death, refractory angina, and non-fatal myocardial infarction (MI) being the primary cardiovascular endpoints.ResultsA significantly increased AIP was observed for the group with primary cardiovascular endpoints. Kaplan–Meier curves corresponding to these endpoints revealed pronounced differences between these two AIP groups (Log-rank P < 0.001). Multivariate Cox proportional hazards analyses highlighted AIP as being independent related to this primary endpoint (HR 1.308, 95% CI: 1.213–1.412, P < 0.001). AIP addition to the baseline risk model improved the prediction of the primary endpoint (AUC: baseline model, 0.622, vs. baseline model + AIP, 0.739, P < 0.001).ConclusionsAIP could be used to predict cardiovascular events in prediabetic individuals with UAP.

Refractory angina pectoris: a 20-year (2003-2022) bibliometric analysis.

The increasing number of patients with refractory angina pectoris, combined with the aging population and improved survival rates among coronary heart disease patients, presents a significant challenge in contemporary cardiovascular medicine. The treatment of refractory angina has been an ongoing area of exploration, yet a comprehensive analysis of the existing literature on this topic is currently lacking. Therefore, this study aims to provide the first bibliometric analysis of publications related to refractory angina. A systematic search was conducted in the Web of Science database to identify articles related to refractory angina published between 2003 and 2022. The inclusion criteria were limited to articles and reviews written in English. CiteSpace software was utilized to conduct a collaborative network analysis of countries/regions, institutions and authors, co-occurrence analysis of keywords, and co-citation analysis of authors and references. A total of 1,386 publications were identified, with an annual publication volume exhibiting fluctuation over time. American and European countries and institutions demonstrated a leading position in terms of research output. Henry TD emerged as the most prolific researcher in the field, while Mannheimer C received the highest number of citations. The primary research hotspot within this field focused on the treatment of refractory angina, with recent emphasis on emerging treatments such as stem cell therapy and the coronary sinus reducer. A significant number of clinical trials have been conducted, with a continuous focus on patient benefits, quality of life, and survival prognosis. Significant progress has been made in the field of refractory angina pectoris in recent years. Novel treatment methods, including spinal cord stimulation, enhanced external counterpulsation, stem cell therapy, and the coronary sinus reducer, hold promising therapeutic prospects. However, further high-quality evidence-based research is essential to support these emerging interventions. Additionally, the development of comprehensive evidence-based guidelines for refractory angina treatment is crucial. Such guidelines would provide clinicians with a framework to navigate the complexities of treatment choices and optimize patient care in this challenging condition.

Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases.

Adenovirus-mediated gene therapy holds promise for the treatment of cardiovascular diseases such as refractory angina. However, potential concerns around immunogenicity and vector dissemination from the target injected tissue require evaluation. This study was undertaken to evaluate the safety and biodistribution of XC001, a replication-deficient adenovirus serotype 5 vector expressing multiple isoforms of human vascular endothelial growth factor (VEGF), following direct administration into normal rat myocardium. Animals received the buffer formulation or increasing doses of XC001 (1 × 107, 2.5 × 108 or 2.5 × 109 viral particles). Based on in-life parameters (general health, body weights, clinical pathology, serum cardiac troponin I, plasma VEGF, and gross necropsy), there were no findings of clinical concern. On Day 8, intramyocardial administration of XC001 was associated with dose-related, left ventricular myocardial inflammation at injection sites, resolving by Day 30. XC001 DNA was not detected in blood at any time but was present at Day 8 around the site of injection and to a much lesser extent in the spleen, liver, and lungs, persisting at low levels in the heart and spleen until at least Day 91. These findings demonstrate that intramyocardial injection of XC001 is supported for use in human studies.

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.

Baseline Left Ventricle Longitudinal Strain as a Predictor for Clinical Improvement Following Coronary Sinus Reducer Implantation

Coronary sinus narrowing device (reducer) implantation has emerged as an effective treatment to improve the quality of life and functional capacity in patients suffering from disabling refractory angina. Left ventricle global longitudinal strain (LV-GLS) is a useful tool for early diagnosis of subclinical cardiac injury and an independent predictor for coronary artery disease. We aimed to investigate whether LV-GLS could help predict clinical improvement after coronary sinus reducer implantation. LV-GLS assessments were performed at baseline and 6months after reducer implantation in consecutive patients treated for refractory angina. Patients were divided into 2 groups based on reduced (<17% absolute value) or preserved baseline LV-GLS. Clinical improvement was defined as an increase of ≥25m in the 6-minute walk test (6MWT) at follow-up. Overall, 41 patients were included, 31 in the reduced LV-GLS group and 10 in the preserved LV-GLS group. The mean age was 68±8years, with only 2 female patients (5%). Baseline characteristics did not differ significantly between the 2 groups. Univariable analysis revealed that LV-GLS was the only significant predictor for 6MWT improvement. Baseline preserved LV-GLS reduced the likelihood of 6MWT improvement by 82% (odds ratio 0.18 [0.04 to 0.83], p=0.029). A significant increase in 6MWT (307±97m to 343±92m, p=0.017) was observed in the reduced LV-GLS group, compared with a decrease in the preserved LV-GLS group (378±86m to 361±123m, p=0.651). In conclusion, reduced LV-GLS may serve as a marker for potential clinical improvement in patients with refractory angina treated with reducer. Larger clinical trials are needed to establish its role.

Anti-anginal effects of empagliflozin in patients with type 2 diabetic and refractory angina; A randomized, double-blind placebo-controlled trial (EMPT-angina trial)

Anti-anginal effects of empagliflozin in patients with type 2 diabetic and refractory angina; A randomized, double-blind placebo-controlled trial (EMPT-angina trial)

EXACT Trial: Results of the Phase 1 Dose-Escalation Study.

New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown. In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses. Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2. URL: https://www. gov; Unique identifier: NCT04125732.