Canadian Cardiovascular Society Angina Research Articles

Real-World Data from the Use of Ranolazine in Patients with Stable Angina Pectoris: The RANGER Study.

Background: Although ranolazine has been available for years as a second-line treatment to reduce angina attacks in patients with stable angina pectoris, real-world data on the effectiveness, tolerability, and safety of ranolazine are limited. Methods: A non-interventional, prospective study was conducted to assess the effectiveness and safety of ranolazine. Patients eligible for enrolment had a baseline assessment between one and fourteen days after initiating ranolazine for the first time and a follow-up visit three months later. The primary endpoints comprised the weekly frequency of angina attacks, total adverse events, and ranolazine discontinuation rate. The secondary endpoints included the use of short-acting nitrates, changes on the Canadian Cardiovascular Society (CCS) angina classification score and quality of life scale score (QoL). Results: In total, 1101 patients were enrolled at 214 sites. Mean weekly angina attacks were reduced from 3.6 ± 2.9 to 0.4 ± 0.9 (p < 0.0001) and the mean weekly consumption of short-acting nitrates decreased by 1.7 ± 2.2 (p < 0.0001). CCS class and QoL were also improved (p < 0.0001). Adverse events were reported by 11 (1%) patients in total, while 2 of them (0.2%) were characterised as serious. Treatment was discontinued for various reasons in 23 patients (2.1%) after the follow-up period. Ranolazine treatment was equally effective in all subgroups tested, with larger benefits observed in patients with more frequent angina and CCS angina class III and IV. Up-titration of ranolazine during the study improved the outcomes. Conclusions: Ranolazine was well tolerated and effectively reduced angina attacks, with simultaneous improvement of the CCS class and QoL score in patients with stable angina.

Coronary Microvascular Disease Registry (CMDR): Study design and rationale

BackgroundCoronary microvascular dysfunction (CMD) is a prevalent condition among patients with cardiovascular risk factors, leading to a reduced quality of life and an increased risk of major adverse cardiovascular events. Novel invasive techniques have emerged to more accurately diagnose CMD. However, CMD's natural history remains poorly understood due to limited data. To address this knowledge gap, the Coronary Microvascular Disease Registry (CMDR) was established with the primary aim of standardizing comprehensive coronary functional testing and understanding of CMD. DesignCMDR is a prospective, multicenter registry enrolling an unlimited number of consecutive subjects who undergo comprehensive invasive hemodynamic assessment of the entire coronary arterial vasculature. Patients undergoing acetylcholine provocation test for coronary vasospasm will also be included. Follow-up assessments will be conducted at 30 days and annually for up to 5 years. The primary endpoint is Canadian Cardiovascular Society angina grade over time. Secondary endpoints, including all-cause mortality, cardiovascular death, acute myocardial infarction, stroke, hospitalizations, medication changes, and subsequent coronary interventions, will be analyzed to establish long-term safety and clinical outcomes in patients undergoing invasive CMD assessment. SummaryCMDR aims to characterize the clinical and physiologic profile of patients undergoing comprehensive invasive coronary functional testing, simultaneously providing crucial longitudinal information on the natural history and outcomes of these patients. This will shed light on CMD's course and clinical implications, which, in turn, holds the potential to significantly improve diagnostic and treatment strategies for CMD patients, ultimately leading to the enhancement of their overall prognosis and quality of life. Clinical trial registrationclinicaltrials.gov, NCT05960474

Enhanced external counterpulsation increases coronary flow reserve in coronary microvascular disease.

To investigates the outcomes of enhanced external counterpulsation (EECP) among coronary microvascular disease (CMD) patients. Coronary microvascular disease patients were separated into the EECP (n=41) and control cohorts (n=42). Prior to and following the 4-week EECP program, coronary flow reserve (CFR) was recorded using transthoracic Doppler echocardiography. The serum endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) contents were analyzed by ELISA. Quality of life (QoL) was assessed by the Seattle Angina Questionnaire (SAQ) and the Canadian Cardiovascular Society (CCS) angina class. After four weeks, CFR was substantially enhanced in the EECP versus control cohort (p<0.05). Endothelin-1 was strongly diminished whereas eNOS was considerably upregulated in the EECP cohort. EECP also enhanced patients' SAQ scores and decreased the CCS angina class. Enhanced external counterpulsation may improve CFR and enhance the CMD patient QoL.

Residual ischemia by stress CMR in stable post-STEMI patients. Association with clinical events and implications of guided revascularization

Abstract Introduction Stress cardiac magnetic resonance (sCMR) represents a gold standard approach to identify and localize myocardial ischemia. However, in the setting of stable STEMI patients, data on the prognostic implications of residual ischemia as derived from sCMR are scarce. Moreover, the association of sCMR-guided revascularization with angina class improvement and patients’ outcomes is unknown. Objectives To evaluate the implications of residual ischemia and sCMR related revascularization with prognosis and anginal symptoms of STEMI patients after the index event. Material and methods Reperfused, stable STEMI patients submitted to undergo sCMR within the first year after STEMI were included in the registry. We analyzed the association of residual ischemia and sCMR related revascularization with the occurrence of major adverse cardiac events (MACE), comprised of all-cause death, non-fatal myocardial infarction, re-admission for heart failure, or unplanned revascularization. Additionally, we explored the effect of sCMR related revascularization on angina class as derived from the Canadian Cardiovascular Society (CCS) Angina Score. A p-value &amp;lt;0.05 was considered statistically significant. Results The study group was made up of 234 patients who underwent sCMR for evaluation of non-revascularized lesions in the non-culprit arteries (n=139, 59.4%) or assessment of new onset chest pain (n=95, 40.6%). Residual ischemia was noted in a minority of patients (n=63, 26.9%), and most of them presented with mild or moderate ischemic burden (n=56, 88.9% with residual ischemia in ≤5 myocardial segments). During a median follow up of 7.49 [3.03-10.02] years, 78 (33.3%) patients presented MACE. In multivariate analysis, the extent (number of segments) of residual ischemia did not associate with MACE (HR 0.97 [0.83-1.12] per segment, p=0.65). Patients were categorized in 3 groups: Group 1 (G1, no ischemia-no revascularization, n=166), Group 2 (G2, ischemia-no revascularization, n=29), and Group 3 (G3, ischemia-revascularization, n=34). No differences in survival free from MACE were noted between these groups. Most patients (n=192, 84.6%) were in CCS Angina Score Class I before sCMR. Patients in G1 remained asymptomatic or paucisymptomatic during follow-up (CCS II-IV between 4.8 and 9%, p&amp;gt;0.05). In G3, patients were predominantly in CCS II-IV (52.9%) before sCMR, and a significant reduction in anginal symptoms was noted after revascularization (CCS II-IV between 6.5 and 12.1%, p≤0.001). Patients with ischemia on sCMR but no revascularization (G2) depicted higher proportion of patients with CCS II-IV before (24.1%) and after sCMR (13 to 19.2%, p&amp;gt;0.05). Conclusions In STEMI patients evaluated post-discharge in stable phase, residual ischemia as derived from sCMR is usually mild and does not associate with the occurrence of MACE. sCMR-guided revascularization relates to a significant and sustained improvement of anginal symptoms but not to the event rate.Survival free from MACE.Changes in CCS Angina Score.

Development, validation, and comparative analysis of a simple clinical and laboratory-based risk score system for predicting and stratifying moderate-to-severe AKI after cardiac surgery

Abstract Background Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) is prevalent and detrimental following cardiac surgery, without effective prevention. Early prediction and stratification are critical in informing appropriate care. Recent studies highlighted the predictive value of some routine laboratory markers in addition to traditional clinical variables. However, existing models suffer from complexity and practical difficulties in implementation. Purpose We aim to develop a high-performance preoperative risk score system for predicting moderate-to-severe CSA-AKI, while preserving its simplicity and utility through the integration of the most predictive and routinely accessible clinical and laboratory variables. Methods A total of 14 303 patients undergoing coronary artery bypass grafting surgery at a single institution, with comprehensive perioperative data, were included. Cohort 1 (N=9 416, 2013-2017) and cohort 2 (N=4 887, 2018-2019) were used to develop and validate a risk score system for predicting moderate-to-severe CSA-AKI, respectively, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Bootstrapped stepwise regression was employed to select the robust candidate variables for a logistic regression model (i.e., the full model), which was then simplified to a more parsimonious model. Model performance was evaluated and compared to several established models. Results The overall incidence of moderate-to-severe CSA-AKI was 3.5% in the entire cohort. Two preoperative risk scores were developed: the simple 6-variable ABC2-Surgery2 score (age, a biomarker of NT-proBNP, two clinical status variables of hypertension and preoperative critical state, and two surgery-related variables of combined surgery and on-pump surgery), and the complete 10-variable AB2C3-Surgery4 score (ABC2-Surgery2 plus an additional biomarker of blood urea nitrogen, a clinical status variable of Canadian Cardiovascular Society angina class, and two surgery-related variables of urgent surgery and previous surgery). In the validation cohort, the simple score (area under the curve, AUC 0.765) outperformed the previously established UK-AKI model (AUC 0.720), Mehta score (AUC 0.700), and Ng score (AUC 0.697), while statistically similar to the most complex 19-variable Cleveland Clinic Score (AUC 0.725). The complete score (AUC 0.777) was superior to all four models. The current score system also effectively stratified CSA-AKI with respect to requirements for vasoactive support (measured by cumulative vasoactive-inotropic score), intravenous diuretics, and renal replacement therapy, as well as in-hospital and long-term mortality. Conclusion A simple risk score system incorporating routine clinical and laboratory variables was developed to predict and stratify moderate-to-severe CSA-AKI and outperformed previous complex models. Further external validation is currently underway for generalizability.

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 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 18770: Understanding Patients’ Characteristics and Coronary Microvasculature: Early Insights From First US Coronary Microvascular Dysfunction Registry

Introduction: Coronary angiography falls short in accurately evaluating the coronary microcirculation. Fortunately, a new comprehensive invasive hemodynamic assessment method, which uses coronary flow reserve (CFR) and the index of microvascular resistance (IMR), provides enhanced diagnostic capabilities. Objective: We present our early real-world experience with invasive hemodynamic assessment of the coronary microvasculature in symptomatic patients with non-obstructive coronary artery disease (CAD) from the first US Coronary Microvascular Disease Registry (CMDR). Methods: The CMDR is a prospective, multi-center, standardized registry of patients with angina and non-obstructive CAD who underwent invasive hemodynamic assessment of the coronary microvasculature using the Coroventis CoroFlow Cardiovascular System (Abbott Laboratories, Chicago, Illinois). Comprehensive assessments, including resting full-cycle ratio (RFR), fractional flow reserve (FFR), CFR, and IMR, were performed on all patients. Results: The first 156 patients enrolled in the CMDR were analyzed; their mean age was 62.4 years and 65.6% were female. A substantial proportion (31.8%) of patients presented with a Canadian Cardiovascular Society Angina Score of 3 or 4. CMD was diagnosed in 39 of 154 patients (25.3%), with mean RFR of 0.89±0.43, mean FFR of 0.93±0.08, mean CFR of 1.8±0.9, and mean IMR of 36.26±19.23. None of the patients experienced in-hospital adverse events. Conclusions: Early results from CMDR patients show that invasive hemodynamic assessment of the coronary microvasculature is safe and effective for suspected CMD. Tailored medical therapy for microvascular angina was provided to diagnosed CMD patients. With ongoing patient enrollment, the CMDR aims to contribute valuable insights to the growing evidence base for CMD.

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.

Elevated Serum Total Bilirubin Might Indicate Poor Coronary Conditions for Unstable Angina Pectoris Patients beyond as a Cardiovascular Protector.

Serum total bilirubin (STB) is recently more regarded as an antioxidant with vascular protective effects. However, we noticed that elevated STB appeared in unstable angina pectoris (UAP) patients with diffused coronary lesions. We aimed to explore STB's roles in UAP patients, which have not been reported by articles. 1120 UAP patients were retrospectively screened, and 296 patients were finally enrolled. They were grouped by Canadian Cardiovascular Society (CCS) angina grades. The synergy between PCI with TAXUS stent and cardiac surgery score (SYNTAX score) and corrected thrombolysis in myocardial infarction flow count (CTFC) were adopted to profile coronary features. The results showed that STB, mean platelet volume (MPV), hs-CRP, fasting blood glucose (FBG), red blood cell width (RDW), and CTFC elevated significantly in the CCS high-risk group. STB (B = 0.59, 95% CI: 0.39-0.74, P < 0.01) and MPV (B = 0.86, 95% CI: 0.42-1.31, P < 0.01) could indicate SYNTAX score changes for these patients. STB (≥21.7 μmol/L) could even indicate a coronary slow flow condition (AUC: 0.88, 95% CI: 0.84-0.93, P < 0.01). Moreover, UAP patients with elevated STB had a lower event-free survival rate by the Kaplan-Meier curve. STB ≥21.7 μmol/L could reflect a poor coronary flow status and indicate 1-year poor outcomes for these patients (HR: 2.01, 95% CI: 1.06-3.84, P < 0.01). Elevated STB in UAP patients has a close relationship with changes in SYNTAX score. STB (over 21.7 μmol/L) could even indicate a coronary slow flow condition and poor outcomes for the UAP patients.

Improving the Data Quality of Untargeted Metabolomics through a Targeted Data-Dependent Acquisition Based on an Inclusion List of Differential and Preidentified Ions.

Metabolomics based on high-resolution mass spectrometry has become a powerful technique in biomedical research. The development of various analytical tools and online libraries has promoted the identification of biomarkers. However, how to make mass spectrometry collect more data information is an important but underestimated research topic. Herein, we combined full-scan and data-dependent acquisition (DDA) modes to develop a new targeted DDA based on the inclusion list of differential and preidentified ions (dpDDA). In this workflow, the MS1 datasets for statistical analysis and metabolite preidentification were first obtained using full-scan, and then, the MS/MS datasets for metabolite identification were obtained using targeted DDA of quality control samples based on the inclusion list. Compared with the current methods (DDA, data-independent acquisition, targeted DDA with time-staggered precursor ion list, and iterative exclusion DDA), dpDDA showed better stability, higher characteristic ion coverage, higher differential metabolites' MS/MS coverage, and higher quality MS/MS spectra. Moreover, the same trend was verified in the analysis of large-scale clinical samples. More surprisingly, dpDDA can distinguish patients with different severities of coronary heart disease (CHD) based on the Canadian Cardiovascular Society angina classification, which we cannot distinguish through conventional metabolomics data collection. Finally, dpDDA was employed to differentiate CHD from healthy control, and targeted metabolomics confirmed that dpDDA could identify a more complete metabolic pathway network. At the same time, four unreported potential CHD biomarkers were identified, and the area under the receiver operating characteristic curve was greater than 0.85. These results showed that dpDDA would expand the discovery of biomarkers based on metabolomics, more comprehensively explore the key metabolites and their association with diseases, and promote the development of precision medicine.

Understanding Patient Characteristics and Coronary Microvasculature: Early Insights from the Coronary Microvascular Disease Registry

Coronary angiography has limitations in accurately assessing the coronary microcirculation. A new comprehensive invasive hemodynamic assessment method utilizing coronary flow reserve (CFR) and the index of microvascular resistance (IMR) offers improved diagnostic capabilities. This study aimed to present early real-world experience with invasive hemodynamic assessment of the coronary microvasculature in symptomatic patients with nonobstructive coronary artery disease (CAD) from the Coronary Microvascular Disease Registry, which is a prospective, multi-center registry that standardized the evaluation of patients with angina and nonobstructive CAD who underwent invasive hemodynamic assessment of the coronary microvasculature using the Coroventis CoroFlow Cardiovascular System. All patients underwent comprehensive invasive hemodynamic assessment. Analysis was performed on the first 154 patients enrolled in the Coronary Microvascular Disease Registry; their mean age was 62.4years and 65.6% were female. A notable proportion of patients (31.8%) presented with a Canadian Cardiovascular Society Angina Score of 3 or 4. Coronary microvascular dysfunction was diagnosed in 39 of 154 patients (25.3%), with mean fractional flow reserve of 0.89±0.43, mean resting full cycle ratio of 0.93±0.08, mean CFR of 1.8±0.9, and mean IMR of 36.26±19.23. No in-hospital adverse events were reported in the patients. This study demonstrates the potential of invasive hemodynamic assessment using CFR and IMR to accurately evaluate the coronary microvasculature in patients with nonobstructive CAD. These findings have important implications for improving the diagnosis and management of coronary microvascular dysfunction, leading to more targeted and effective therapies for patients with microvascular angina.

The effect of external counterpulsation on angiopoietin-1 and angiopoietin-2 levels in nondiabetic patients with refractory angina

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Health Research and Development of the Ministry of Health of Indonesia. Background External counterpulsation (ECP) is a noninvasive therapy that employs external compression on the lower extremities to augment coronary perfusion pressure. Numerous studies reported that ECP possesses potential benefits in enhancing the angiogenesis process by promoting expressions of several growth factors. Nondiabetic patients are believed to be more reliable in portraying the angiogenesis process. Unfortunately, the effect of ECP on angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) as angiogenesis markers has not been elucidated. Purpose The objective of this study is to evaluate the effect of ECP on Ang-1 and Ang-2 levels in nondiabetic patients with refractory angina. Methods This is a randomised, double-blind, sham-controlled clinical trial. Nondiabetic patients with refractory angina, who were not contraindicated to ECP therapy, were enrolled and randomised into ECP or sham groups. The treatment consisted of optimal medical therapy plus 35 sessions of ECP or sham, with an hour duration for each session. The pressure applied was up to 300 mmHg in the ECP group, while only 75 mmHg in the sham group. Subjective symptoms, laboratory, echocardiographic, and functional capacity parameters were measured before and after 35 sessions of treatment. Appropriate statistical tests were performed and a p-value of &amp;lt;0.05 was considered statistically significant. Results A total of 26 nondiabetic patients with refractory angina were enrolled and randomised into ECP (n=11) and sham (n=15) groups. All patients successfully followed every treatment session until the 35th session. The baseline characteristics were comparable between the two groups (p&amp;gt;0.05). After 35 sessions, there were increases in Ang-1 median levels in both ECP (1663.4 pg/ml versus 891.6 pg/ml, p=0.477) and sham groups (1577.0 pg/ml versus 1295.0 pg/ml, p=0.496). The Ang-2 median levels after the treatments were slightly lower in ECP (2849.5 pg/ml versus 2902.3 pg/ml, p=0.594), while higher in sham groups (2728.3 pg/ml versus 2376.2 pg/ml, p=0.826). Meanwhile, the ECP group also showed an improvement in the Canadian Cardiovascular Society (CCS) angina class from class III to class I/II in 18% (2 out of 11) patients, while in the sham group only 13% (2 out of 15) patients. Interestingly, the ECP group seemed to elicit a noticeable increase in Ang-1 median levels and a decrease in Ang-2 median levels. However, the effects of ECP shown in this study were not statistically significant (p&amp;gt;0.05). Conclusion The ECP group exhibited a higher trend of increase in Ang-1 level compared to the sham group. The Ang-2 level was slightly lowered in the ECP group, while increased in the sham group. Although it was not statistically significant, the increasing trend in the Ang-1 level may provide an additional understanding of the ECP angiogenic effects. Therefore, further studies to validate these results are warranted.

P321 NEOVASC REDUCER IMPLANTATION AS A USEFUL THERAPEUTIC CHANCE IN REFRACTORY ANGINA

Abstract Refractory angina is a clinical condition caused by myocardial ischemia inadequately controlled by medical therapy and coronary revascularization. Emblematic case of this condition concerns a 72–year–old man with chronic coronary syndrome (percutaneous transluminal coronary angioplasty [PTCA] + drug–eluting stent [DES] on the proximal portion of the left main coronary artery [LMCA] in 2009 and PTCA + 2 overlapping DES on the proximal portion of the right coronary artery [RCA] in 2017) who accessed in the emergency room for unstable angina. The patient‘s past medical history was positive for repeated hospitalizations for unstable angina: in particular, was registered an admission in 2019 with angiographic evidence of intermediate stenosis 30% at the mid–distal tract of LMCA and good distant outcome of previously implanted stents on LMCA and RCA, and a further admission in 2021 with coronary evidence overlapping the previous one. In both hospitalizations, medical therapy optimization was carried out by adding also 2nd–line drugs to the antianginal therapy with Bisoprolol 2.5 mg and Amlodipine 5 mg such as transdermal Nitroglycerin 15 mg, Ranolazine 750 mg bis in die, and subsequently Trimetazidine 20 mg ter in die during the first and second hospitalizations, respectively. In the context of this re–hospitalization, coronarography was repeated again with evidence of unchanged angiographic picture from the previous one (2021) and, in view of the refractoriness of the anginal symptoms, was placed an indication for Neovasc Reducer device implantation. This device creates a pressor gradient in the coronary sinus, determining a redistribution of blood flow from the subepicardial areas to the ischemic subendocardial areas. Therefore, by performing jugular venous access we engaged the coronary sinus with 6F diagnostic catheter then by mother and child technique we placed the 9F guide catheter advancing as distally as possible in the coronary sinus and finally we implanted the Neovasc Reducer device (4 atm for 60‘‘), obtaining a good final angiographic result. At 6–month follow–up, the patient experienced symptomatic improvement, in particular he improved by 2 Canadian Cardiovascular Society (CCS) angina classes. The Neovasc Reducer device, by improving quality of life and reducing the need for hospitalizations for unstable angina, is a viable therapeutic strategy in patients angina unresponsive to medical therapy and coronary revascularization.

Improvement of angina after treating focal coronary artery disease undetected in resting conditions.

A 65-year-old woman without cardiovascular risk factors presented with stable angina Canadian Cardiovascular Society (CCS) Class II. The 7-item Seattle Angina Questionnaire (SAQ-7) indicated frequent angina, moderate physical limitation, and low quality of life for a summary score of 50/100. Coronary CT and invasive angiography revealed severe stenosis in the mid-left anterior descending (LAD) coronary artery with a minimum lumen area (MLA) of 0.9 mm2 and mixed plaque (Figures 1A and B). Intravascular ultrasound (IVUS) confirmed small MLA and 84% plaque burden (Figure 1A, right panels). The resting full-cycle ratio (RFR) was negative (0.93), whereas fractional flow reserve (FFR) was positive (0.75) with a focal pressure step-up in the pullback curve as quantified by a high pullback pressure gradient (PPG) index of 0.79 (Figures 1C and D). The patient underwent percutaneous coronary intervention (PCI) with one drug-eluting stent (Figure 1E). Post-PCI IVUS confirmed good stent expansion. Post-PCI FFR increased to 0.92 without residual focal pressure gradients in the pullback curve (Figure 1F), and normal microcirculation function demonstrated by a coronary flow reserve (CFR) of 7.8 and index of microvascular resistance (IMR) of 16 (Figure 1G). RFR remained unchanged at 0.94. The SAQ-7 at 1-year follow-up showed complete symptoms resolution and improvement in all domains (Figure 1H). A symptomatic patient with obstructive focal epicardial disease yet a negative resting index experienced relief from angina after PCI. This case highlights the usefulness of a comprehensive physiological assessment in cases considered for revascularization, particularly with focal lesions.

Therapeutic Neovascularization for Refractory Angina-Are We Any Closer?

Therapeutic Neovascularization for Refractory Angina-Are We Any Closer?

Proangiogenic Growth Factor Therapy for the Treatment of Refractory Angina: A Meta-analysis

<h2>Abstract</h2><h3>Background</h3> Refractory angina (RFA; limiting angina despite optimal medical therapy) is a growing, global problem, with limited treatment options. Therefore, we conducted a systematic review of randomized controlled trials (RCTs) to evaluate the effect of proangiogenic growth factor therapy (in the form of vascular growth factors delivered either as recombinant proteins or gene therapy) in patients with RFA ineligible for revascularization. <h3>Methods</h3> We performed a meta-analysis (PROSPERO: CRD42018107283) of RCTs as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. A comprehensive search of the PubMed, CENTRAL, Embase, Cochrane, ClinicalTrials.gov and Google Scholar databases, as well as scientific session abstracts, were performed. The pooled outcomes included major adverse cardiac events (MACE), mortality, myocardial perfusion, and indices of angina severity (Canadian Cardiovascular Society angina class [CCS] and exercise tolerance). A prespecified subgroup analysis was performed for delivery method, vector, and protein type. The standardized mean difference (SMD) or odds ratio (OR) was calculated to assess relevant outcomes. We assessed heterogeneity using the χ² and I² tests. <h3>Results</h3> We included 16 RCTs involving 1607 patients (1052 received proangiogenic growth factor therapy and 555 received a placebo or optimal medical therapy). Our analysis showed a significant decreased risk of MACE (OR, 0.72; 95% confidence interval [CI], 0.55-0.93) and significantly improved CCS class (SMD, −0.55; 95% CI, −1.10 to 0.00), but not mortality (OR, 0.66; 95% CI, 0.28-1.54) or exercise tolerance (SMD, 0.47; 95% CI, −0.14 to 1.09), in treated patients compared to those in the control group. <h3>Conclusions</h3> Proangiogenic growth factor therapy is a promising treatment option for RFA, with beneficial effects seen on MACE and CCS class. The results of ongoing trials are needed before it can be considered for clinical practice.

A novel hybrid strategy of drug coated balloon and stent for coronary bifurcation lesions

Background. Provisional side branch (SB) stenting strategy is the default approach for the majority of bifurcation lesions, but outcomes of SB is suboptimal. Though drug coated balloon (DCB) improving SB outcomes attracts an increasing attention, sequence of DCB hasn’t yet been determined. We presented a novel hybrid strategy of DCB and stent for bifurcation lesions. Methods. With lesion preparation, DCB was persistently inflated in SB kissing with main branch (MB) stent deployment and balloon post-dilation of the bifurcation core. Proximal optimization technique was performed strictly not exceeding the bifurcation. Procedural and clinical adverse events were evaluated. Canadian Cardiovascular Society (CCS) angina classification was assessed at baseline and clinical follow-up. Results. Fourteen patients undergoing the hybrid technique from August 2020 to July 2021 were enrolled. The technique was successfully performed in all patients without rewiring or SB compromise. Minimal lumen diameter of SB increased from 0.60 ± 0.40 mm to 2.1 ± 0.2 mm while the percent stenosis decreased from 72.4 ± 17.9% to 19.6 ± 4.7%. In addition, intravascular ultrasound indicated comparable stent symmetry index and incomplete stent apposition between proximal and distal segments of stent. No further intervention was performed, and mean fractional flow reserve of SB (n = 12) was 0.88 ± 0.05. No major adverse cardiac events was noted in hospital and 12-month follow up. The mean CCS angina score was reduced by 84% (2.2 vs 0.4, p < .001). Conclusion. The hybrid strategy facilitates treatment of DCB and stent for bifurcation lesions, which appears to be feasible and acceptable in a short-term follow-up.

A Systematic Review of CD34+ Stem Cell Therapy as an Innovative and Efficient Treatment for the Management of Refractory Angina.

Despite optimal medical treatment, many individuals suffering from severe coronary artery disease are not suitable candidates for further revascularization. Therapeutic angiogenesis has attracted continuous interest to increase myocardial perfusion. Cell therapy using autologous stem cells expressing Cluster of Differentiation 34 plus (CD34+) offers a special therapeutic choice for individuals with refractory angina, seeing as CD34+ stem cells can restore microcirculation. We searched PubMed, PubMed Central (PMC), and Google Scholar to find the relevant articles to write this systematic review about the role of CD34+ stem cell therapy in the management of refractory angina. Additionally, we provided a brief explanation of CD34+ cells and their mechanism of action. Along with the positive finding of other trials, a recent open-label, single-center intracoronary CD34+ cell therapy for the treatment of coronary endothelial dysfunction in patients with angina and nonobstructive coronary arteries (IMPROvE-CED) clinical trial published in 2022 concluded improvement in coronary blood flow, a significant reduction in daily as-needed sublingual nitroglycerin use and improvement in Canadian Cardiovascular Society (CCS) angina class were observed after autologous CD34+ cell treatment. In conclusion, refractory angina management and overall prognosis may be revolutionized once this treatment is approved.

Growth factor for therapeutic angiogenesis in ischemic heart disease: A meta-analysis of randomized controlled trials.

Aim: This study was designed to systematically evaluate the effects of growth factor (GF) for therapeutic angiogenesis on ischemic heart disease (IHD) by pooling the results of randomized controlled trials (RCTs). Methods and Results: PubMed, EMBASE, and CENTRAL databases were searched from inception to October 2022. RCTs, investigating the effects of GF therapy on IHD, were included. The risk bias of included study was assessed according to Cochrane tool. Weighted mean difference (WMD), calculated with fixed effect model or random effect model, was used to evaluate the effects of GF therapy on left ventricular ejection fraction (LVEF) and Canadian Cardiovascular Society (CCS) angina class. Relative risk (RR) was used to evaluate the effects of GF therapy on all-cause mortality, major adverse cardiovascular events (MACE) and revascularization. Meta-analysis, meta-regression analysis and publication bias analysis were performed by RevMan 5.3 or Stata 15.1 software. Twenty-nine studies involving 2899 IHD patients (1,577 patients in GF group and 1,322 patients in control group) were included. Compared with the control group, GF therapy did not reduce all-cause mortality (RR: 0.82; 95% CI: 0.54-1.24; p = 0.341), MACE [(RR: 0.83; 95% CI: 0.61-1.12; p = 0.227), revascularization (RR: 1.27, 95% CI: 0.82-1.96, p = 0.290) and CCS angina class (WMD: -0.08, 95% CI: -0.36 to 0.20, p = 0.560). However, GF therapy could increase LVEF during short-term follow-up (<1year). Conclusion: GF for therapeutic angiogenesis was beneficial for increasing LVEF during short-term follow-up (<1year), however, the therapy was not efficacious in decreasing all-cause mortality, MACE and revascularization.