Canadian Cardiovascular Society Research Articles

An Update on Dyslipidemia Management and Medications: A Review.

Dyslipidemia, characterized by abnormal lipid levels in the bloodstream, is a very common and underappreciated chronic disease associated with a significant cardiovascular disease burden. The management landscape for dyslipidemia has historically been static, with a sparse selection of therapeutic options. This article presents a comprehensive review of contemporary approaches to dyslipidemia management, focusing on therapeutic strategies and emerging interventions. We delineate the most current American Heart Association/American College of Cardiology & Canadian Cardiovascular Society guidelines and examine pivotal clinical trials that are shaping the contemporary approach to dyslipidemia management.

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

Percutaneous intramyocardial septal radiofrequency ablation after 5-year follow-up

ObjectiveThe objective is to evaluate the 5-year follow-up results of percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) for hypertrophic obstructive cardiomyopathy (HOCM), including clinical status, electrocardiographic and echocardiographic characteristics.Methods27 patients (age:...

The Canadian Cardiovascular Society Classification of acute atherothrombotic myocardial infarction provides a novel staging scheme based on tissue injury severity.

The Canadian Cardiovascular Society Classification of acute atherothrombotic myocardial infarction provides a novel staging scheme based on tissue injury severity.

The Significance of Equipment Availability and Anesthesia Educational Conferences to Decision-Making for EKG Lead V5 Abnormalities.

Introduction To predict postoperative myocardial infarction rates in patients who undergo noncardiac surgery, the Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management recommends assessment of brain natriuretic peptide (BNP) in certain patients. Serial troponins are measured if the BNP level is elevated. In certain cases, Revised Cardiac Risk Index (RCRI) alone does not perform well, for example, during vascular surgery. Cardiac events occur in 20% of all vascular surgery patients. The odds ratio for such events is 9.2 if ST segments were depressed by 1 mm intraoperatively (relative to the PR interval) within the first 48 hours postoperatively. Increasing the number of cables and pads from three to five for electrocardiogram (EKG) increases the sensitivity from around 30% to over 80% for ischemic events relative to a formal EKG stress test, and then the monitor continuously displays not only lead II but also lead V5. Methods Our hypothesis was that raising awareness about diagnostic and therapeutic options to reduce the risk of postoperative myocardial infarction would increase the use of five pads. We conducted open-ended surveys at six hospitals to assess the reasons for choosing three pads. In our university hospital practice, we measured a cross-sectional incidence of using three pads before and, once again, a month after an intervention during a single morning. Several resident conferences encouraged the use of five pads. Education included weekly lectures and informal discussions with other staff during surgery, demonstrating that using five pads allows interrogation of an entire 12-lead EKG. In comparison, three pads only allow viewing three leads. Results At baseline, only three pads were available in 96% of our 23 operating rooms. Five cables were available in eight of those surgeries, but two were taped off to the side. Surveys unveiled scarcity of equipment and, more importantly, disempowerment (i.e., knowing how to diagnose or when to treat ischemia). After several conferences, the prevalence of equipment availability of only three pads fell to 47%. Conclusions Education enumerated details of recognizing ischemic configurations of ST depression. Next, education revealed methods to interrupt the progression of ischemia to infarction such as elevated blood pressure and hematocrit, reducing heart rate, and calling a cardiology consultant if the anesthesiologist wishes to draw serial troponins. Barriers to implementing an enhanced recovery after surgery (ERAS) pathway began with a need for more access to manage stress tests or optimize blood pressure medications after a preoperative anesthesia evaluation. The intraoperative barrier was knowing what to do if ST depression occurs. Therefore, we began raising awareness by encouraging the addition of an element of a future ERAS pathway, adding a cost of only $1 to monitor lead V5. Future ERAS pathways can include preoperative stress tests and consults, as found in published guidelines.

Real-World Risk of Recurrent Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with LDL-C Above Guideline-Recommended Threshold: A Retrospective Observational Study.

The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels. Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up. The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively). This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk.

Evaluation of PHARM‐HF, a pharmacist‐led heart failure medication titration clinic: A pre‐post study

AbstractIntroductionThe PHARM‐HF clinic is a novel, pharmacist‐led medication optimization clinic for patients with heart failure with reduced ejection fraction (HFrEF). PHARM‐HF aims to achieve maximum‐tolerated HFrEF guideline‐directed medical therapy (GDMT) as outlined by the latest Canadian Cardiovascular Society heart failure guidelines.MethodsThis retrospective pre‐post study evaluated consecutive patients attending PHARM‐HF (January 2021–August 2022). The primary outcome was the modified Optimal Medication Therapy (mOMT) score, an aggregate score of HFrEF quadruple therapy. The mOMT score was categorized as suboptimal (score 0–4), acceptable (score 5–7), or optimal (score 8; all four drugs at maximum tolerated dose). Secondary outcomes included change in left ventricular ejection fraction (LVEF) from baseline to 1 year, and Kansas City Cardiomyopathy Questionnaire‐12 (KCCQ; range 0 [worst] to 100 [best]) from baseline to discharge.ResultsOf 81 included patients, median age was 68 years, 21% were female, 61% had New York Heart Association (NYHA) class 2 functional capacity, and median LVEF was 30%. Median mOMT improved from 6 (interquartile range [IQR] 4–7) at baseline to 8 (IQR 7–8) at clinic discharge (p &lt; 0.001; increase from 7% to 73% categorized as optimal). LVEF improved from a median of 30% to 38% at 1 year (p &lt; 0.001). Among 16 patients who completed the KCCQ‐12 at both time points, the score was 62 at baseline and 77 at discharge (p = 0.42).ConclusionsUptake of GDMT significantly increased from admission to discharge from the PHARM‐HF medication optimization clinic, during which other cardiovascular clinicians did not modify HFrEF medications. Furthermore, there was an improvement in LVEF at 1 year. A pilot randomized controlled trial is currently underway to guide the development of a multicenter trial to provide definitive evidence for the role of pharmacist‐led medication optimization in HFrEF.

Evaluation of Guideline-Directed Medical Therapy for Outpatients Living with Heart Failure with Reduced Ejection Fraction.

Pharmacotherapy is the cornerstone of treatment for heart failure with reduced ejection fraction (HFrEF). The Canadian Cardiovascular Society and Canadian Heart Failure Society have defined guideline-directed medical therapy (GDMT) as 4 foundational medications. Despite strong recommendations for use of GDMT in HFrEF, current practice alignment with guidelines is unknown. The primary objectives were to determine the proportion of patients for whom optimized GDMT for HFrEF was prescribed, to describe the doses of foundational medications achieved, and to describe any documented rationale limiting the optimization of GDMT. The secondary objectives were to describe documented pharmacist activities outside of scheduled multidisciplinary appointments at the heart function clinic (HFC) and to describe heart failure-related hospital encounters in 2021. A retrospective cohort study using medical records of patients with HFrEF who were receiving treatment at the Regina HFC as of December 31, 2021, was conducted. Of the 129 patients included in the study, 61 (47.3%) were prescribed optimized GDMT. Specifically, within the individual foundational medication classes, 82.2% (106/129), 80.6% (104/129), 79.1% (102/129), and 74.4% (96/129) of patients received optimized therapy with a renin-angiotensin system inhibitor, mineralocorticoid receptor antagonist, β-blocker, and sodium-glucose cotransporter 2 inhibitor, respectively. Documented rationale was not available in 35.8% (38/106) of instances of suboptimal utilization of GDMT and in 41.7% (60/144) of instances of suboptimal dosing of GDMT. The most common documented rationale for suboptimal utilization was intolerance to the medication (33.0% [35/106]), and the most common rationale for suboptimal dosing was intolerance to dose increases (57.6% [83/144]). Pharmacists documented a total of 553 patient care activities for 58.9% (76/129) of the patients, outside scheduled multidisciplinary appointments in the HFC. Sixteen patients (12.4%) had heart failure-related hospital encounters a total of 31 times in 2021. Although many patients were receiving the benefits of multidisciplinary care at the Regina HFC, there remained a treatment gap in the use of GDMT for HFrEF. These findings will be used to inform strategies to improve clinic processes, including efficient identification of patients requiring optimization of GDMT, who would benefit the most from multidisciplinary care.

Minimalistic Hybrid Approach for the Percutaneous Treatment of Coronary Chronic Total Occlusions: Midterm Follow-Up of an International Multicenter Cohort

The minimalistic hybrid approach (MHA) is a recently proposed algorithm to perform chronic total occlusion (CTO) percutaneous coronary intervention (PCI), reducing the overall invasiveness of the procedure without impacting the acute results. However, data on midterm results are lacking. This study aimed to evaluate the midterm clinical outcomes of a multicenter international cohort of CTO PCI treated according to the MHA. Data from a consecutive series of patients with a CTO who underwent PCI according to the MHA between February 2019 and March 2022 were prospectively collected in 3 European centers and retrospectively analyzed. The main outcome was the first occurrence of a major adverse cardiac event (MACE), defined as a composite outcome of all-cause death, any myocardial infarction, and target vessel revascularization, at the last follow-up available. A total of 212 patients were included. The majority of the patients were symptomatic for angina (Canadian Cardiovascular Society class 2 or 3: 63.7%) at the time of the index procedure. The mean Japanese-CTO and CASTLE scores were 2.1 ± 1.2 and 2.0 ± 1.3, respectively. Technical success (CTO open with optimal flow) was achieved in 198 patients (93.9%) and procedural success (technical success without in-hospital MACEs) in 195 (91.9%). At the last follow-up available (median 677 days), the cumulative incidence rate of MACEs was 11.5%; in particular, all-cause death was 7.4%, any myocardial infarction was 4.3%, and unplanned target vessel revascularization was 6.5%. In conclusion, the midterm results of the MHA seem to be in line with contemporary results of other CTO PCI algorithms, thus potentially validating the MHA as a valuable alternative, provided that interventionalists are already expert CTO operators and accustomed to the definitions and peculiarities of MHA.

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.

Quantity and quality of shared decision making incorporation across major international cardiology guidelines

Abstract Background/Introduction Shared decision-making (SDM) is a key component of the provision of ethical care, but prior reviews have indicated that clinical practice guidelines poorly promote and facilitate SDM. Purpose To identify and characterize all pharmacotherapy recommendations integrating SDM within contemporary cardiovascular guidelines using a novel classification system. Methods The American College of Cardiology (ACC), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC) digital guideline libraries (2012–2022) were searched for current guidelines, or subsequent updates, that included at least one pharmacotherapy recommendation. We identified all pharmacotherapy recommendations for each guideline. Recommendations that incorporated SDM were rated according to a novel Supporting Higher Patient Autonomy in Recommendations (SHARE) rating framework – which evaluates the quality of SDM incorporation based on directness (1-3; assessing whether SDM was incorporated directly and impartially into the recommendation’s text) and facilitation (A-D; assessing whether decision aids or quantified benefits/harms were provided). Results From 65 guidelines and updates, 2,655 recommendations (35% of total) addressed pharmacotherapy. Of these recommendations, 171 (6%) incorporated SDM. By category, general cardiology guidelines contained the highest proportion of pharmacotherapy recommendations incorporating SDM (10%), whereas heart failure and myocardial disease contained the least (3%). The proportion of pharmacotherapy recommendations incorporating SDM was comparable across societies (ACC: 8%, CCS: 9%, ESC: 5%), with no trend for change over time. Only 5/171 (3%) of SDM recommendations met SHARE grade 1A (impartial recommendations for SDM supported by a decision aid), whereas 63% were SHARE grade 3D (SDM mentioned only in supporting text and without any tools or information to facilitate SDM). Conclusions Across guidelines published by three cardiovascular societies over the last decade, few recommendations incorporated SDM in any form, and even fewer adequately facilitated SDM. Guidelines should move away from merely advocating for consideration of patient preferences, and toward facilitating meaningful engagement in SDM.

Treatment of microvascular angina with the coronary sinus reducer: a first experience

Abstract The Coronary Sinus Reducer (CSR) is an hourglass-shaped device approved for the treatment of refractory angina. Its percutaneous implantation in the coronary sinus leads to a retrograde increase in venous pressure, which is thought to improve capillary recruitment and perfusion to the ischemic myocardium. No data is however available on the use of the CSR to treat microvascular angina, an increasingly recognized but still poorly understood condition. In this preliminary study, we evaluated the efficacy of the CSR in a small cohort of patients with non-obstructive disease. We screened consecutive patients from the prospective COMPLEX registry that received a CSR for refractory angina between June 2018 and November 2022. Inclusion criteria were the absence of obstructive coronary artery disease (&amp;lt;50% narrowing in all coronary arteries, or a negative intracoronary fractional flow reserve test) and no prior history of revascularization. Endpoints were angina and dyspnea symptoms, evaluated with the Canadian Cardiovascular Society (CCS) and the New York Hearth Association (NYHA) scores respectively, procedural success rate, and major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, cardiovascular death, acute coronary syndromes (ACS) and heart failure (HF) hospitalizations. We ultimately enrolled 8 patients; 6 (75%) were females and mean age was 67.8±9.9 years. Their baseline characteristics are further depicted in table 1. Microvascular dysfunction was invasively confirmed in 5 (62.5%) patients; mean index of microvascular resistance (IMR) was 32.8±15.7 and mean coronary flow reserve (CFR) was 1.7±0.7. In one patient, reduced global CFR (1.4) was evident on cardiac magnetic resonance examination. At baseline, mean CCS class was 2.9±0.6, NYHA class 2±0.9, and number of antianginal drugs 2.6±1.6. Procedural success was 100%, with only one patient experiencing a procedure-related complication (sternocleidomastoid muscle hematoma requiring no intervention). At a median follow-up of 647.5 days (IQR 132-732), mean CCS class was 1.5±0.8, NYHA class 1.9±0.9 and number of antianginal drugs 1.9±1.1. All patients improved by ≥1 CCS class and 3 (37.5%) by ≥2 CCS classes. No MACE was observed. To the best of our knowledge, we present the first report of CSR implantation for the treatment of microvascular angina. Our positive results are particularly promising given the paucity of treatment options currently available for the condition, but larger studies are needed to confirm these findings.table 1figure 1

The efficacy of coronary sinus reduction in refractory angina: A meta-analysis

Abstract Objectives Refractory angina is a frequent complain of patients with coronary artery disease. Its management is challenging despite the available pharmacological approaches. Interventional approaches have also been attempted, with coronary sinus reduction (CSR) being the main treatment option. Purpose This meta-analysis aimed to assess the efficacy of CSR in improving symptoms and cardiovascular endpoints in patients with refractory angina. Methods We searched the Pubmed database till 26/2/2023 for studies assessing the impact of CSR in refractory angina. The primary outcome of interest was the improvement in Canadian Cardiovascular Society (CCS) category by at least one class. Secondary outcomes included the implantation success, the proportion of patients improving by at least two CCS classes, as well as the rates of new myocardial infarction/percutaneous coronary intervention and mortality at follow-up. Results The literature search resulted in 190 studies. After screening of title/abstract/full-text, a total of 10 studies (1400 patients) were included in the meta-analysis. The median follow-up was 12.8 months (range: 4-24 months). High rates of implantation success (97%, 95% confidence interval (CI) 95%-98) were reported. Improvement by at least one CCS class was reported by 77% (95% CI 73%-81%). Improvement by at least two CCS classes was seen in 41% (95% CI 36%-47%). The proportion of patients exhibiting a new myocardial infarction/percutaneous coronary intervention was 7% (95% CI 3%-16%), while the mortality rate was 7% (95% CI 3%-14%). Conclusion Coronary sinus reduction is a procedure accompanied by high success rates, and is effective in improving symptoms in a considerable proportion of patients with refractory angina.

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.

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&amp;lt;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&amp;lt;2.45 (n=138), median ΔMPR was +0.18 (15.4%; P&amp;lt;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&amp;lt;0.0001) and subepicardial (+0.19 [12.3%]; P&amp;lt;0.0002) segments with baseline MPR&amp;lt; 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.

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.

Does ischaemia testing predict worse adverse outcomes in ANOCA patients?

Abstract Background Following the recent ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) it was revealed that the extent of ischaemia was not associated with an increased risk for adverse outcomes after adjustment for coronary artery disease (CAD) severity. How the extent of ischemia applies to outcomes for patients with stable angina without obstructive CAD is unknown. Purpose To determine if the presence of ischaemia impacted on 3-year clinical outcomes (mortality and readmission) in patients with Angina and Non-Obstructive Coronary Arteries (ANOCA). Methods ANOCA was defined as those presenting with chest pain symptoms consistent with angina and undergoing an elective angiogram. All consecutive ANOCA (stenosis &amp;lt;50%) enrolled in the CADOSA (Coronary Angiogram Database of South Australia) Registry between 2012-2018 were included. CADOSA captures all public hospital patients undergoing coronary angiography. Results Among 8,932 symptomatic patients undergoing elective angiography, 1,169 patients (60±11 years, 59% female) with ANOCA underwent ischaemic stress testing prior to angiography. Of these patients, 185 (16%) had no evidence of ischaemia (ANOCA ischaemia negative), and 984 (84%) had documented evidence of ischaemia (ANOCA ischaemia positive). The ANOCA ischaemic negative patients (relative to the ANOCA ischaemic positive patients) were (a) younger (58±11 vs 61±11, p&amp;lt;0.05), (b) in the year preceding diagnostic angiography, more often presented to the emergency department with chest pain (36% vs 21%, p&amp;lt;0.05) and required hospital admission (28% vs 14%, p&amp;lt;0.05), and (c) had more disabling angina, as assessed by the Canadian Cardiovascular Society Score (CCSS; CCSC-IV 19% vs 13%, p&amp;gt;0.05). At 3-year post-angiography follow-up, (i) cardiac mortality was similar (ANOCA negative 0% vs ANOCA positive 0.1%, p&amp;gt;0.05), but the ANOCA negative patients were more likely to present to the emergency department (26% vs 14%, p&amp;lt; 0.05) and require hospital readmission (18% vs 8%), compared to the ANOCA positive patients. Conclusion Patients with ANOCA and negative ischaemic testing have more disabling symptoms, with frequent emergency department presentations and readmissions, compared to those with a positive ischaemic test. Hence the presence of ischaemia on stress testing is not predictive of clinical outcomes and further investigation is required to identify predictors of outcomes in ANOCA.

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.