Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04125732.

Predictors of mitral valve haemodynamics after mitral valve repair for degenerative mitral regurgitation.

OBJECTIVE: Intraoperative predictors of functional mitral valve (MV) stenosis after surgical repair of mitral regurgitation (MR) caused by prolapse remain poorly characterised. This study evaluated the effect of annuloplasty size on postoperative MV haemodynamics during exercise and evaluated predictors of MV hemodynamics. METHODS: 104 patients were randomly assigned to leaflet resection or preservation for surgical repair of MR in the Canadian Mitral Research Alliance CardioLink-2 study. In this post hoc analysis, we compared MV haemodynamics between the two surgical groups and examined the relationship between annuloplasty size and MV haemodynamics 1 year after repair in the combined groups. Echocardiograms were performed at baseline and intraoperatively. Exercise transthoracic echocardiography was performed 1 year postoperatively. Multivariable linear regression analysis was used to identify predictors of exercise MV gradients at follow-up. RESULTS: Mean age of participants was 65±10 years, and 83% were male. Median annuloplasty size was 34 (IQR 32-36). Dividing by the median, 48 (46%) had annuloplasty size of <34 mm and 56 (54%) had ≥34 mm. Mean and peak exercise gradients at 1 year were 11±5 mm Hg and 22±9 mm Hg in <34, and 6±3 mm Hg and 14±5 mm Hg in ≥34 (p<0.001). Rate of residual MR was similar in both groups. In multivariable analyses, annuloplasty size of ≥34 mm was associated with lower mean and peak exercise gradients at 12 months, after adjustment for repair type, age, sex, heart rate and body surface area (ß -4.1, 95% CI -6 to -3, p<0.001, and ß -7 95% CI -10 to -4, p<0.001, respectively). Intraoperative mean and peak MV gradients by transesophageal echocardiography independently predicted mean and peak resting and exercise gradients at follow-up (p<0.001). Similar results were obtained in both leaflet resection and preservation. CONCLUSION: Annuloplasty size of ≥34 mm is associated with a 4 and 7 mm Hg reduction in mean and peak exercise MV gradients, respectively, 1 year post MV repair regardless of the repair strategy used. Intraoperative TEE MV gradients predict exercise MV gradients 1 year post repair. TRIAL REGISTRATION NUMBER: NCT02552771.

Anticoagulation for rheumatic mitral stenosis, INVICTUS in perspective.

PURPOSE OF REVIEW: Rheumatic mitral stenosis (MS) while declining in high- and middle-income countries, continues to be a major cause of death and disability in low-income countries. Although the nonvitamin-K antagonist oral anticoagulants (NOACs) have essentially supplanted vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation (AF), their efficacy for stroke prevention in patients with rheumatic MS and AF has not been widely studied until recently. The purpose of this review is to provide a succinct synopsis of the current anticoagulation recommendations for patients with native and prosthetic heart valve disease, with a specific focus on patients with rheumatic MS. RECENT FINDINGS: The INVICTUS trial was the first large randomized evaluation of a NOAC vs. VKA in approximately 4600 patients with moderate to severe rheumatic MS and AF. The primary outcome of stroke, systemic embolization, myocardial infarction, vascular and all-cause death, VKA treated patients exhibited lower event rates (including mortality) compared to rivaroxaban. We discuss and contextualize these findings as they relate to the broader use of anticoagulants in patients with valvular heart disease, with and without concomitant AF. SUMMARY: VKA remains the standard of care for patients with moderate to severe rheumatic MS who have concomitant AF. Rates of stroke in anticoagulated patients with rheumatic MS and AF are lower than what is traditionally held, while nonstroke related deaths remain the most common mechanism of mortality.

Adapting the Admissions Interview During COVID-19: A Comparison of In-Person and Video-Based Interview Validity Evidence.

COVID-19 physical distancing limited many medical schools' abilities to conduct in-person interviews for the 2020 admissions cycle. The University of Toronto (U of T) Temerty Faculty of Medicine was already in the midst of its interview process, with two-thirds of applicants having completed the in-person modified personal interview (MPI). As the university and surrounding region were shut down, the shift was made in the middle of the application cycle to a semisynchronous video-based MPI interview (vMPI) approach. U of T undertook the development, deployment, and evaluation of the 2 approaches mid-admissions cycle. Existing resources and tools were used to create a tailored interview process with the assistance of applicants. The vMPI was similar in content and process to the MPI: a 4-station interview with each station mapped to attributes relevant to medical school success. Instead of live interviews, applicants recorded 5-minute responses to questions for each station using their own hardware. These responses were later assessed by raters asynchronously. Out of 627 applicants, 232 applicants completed the vMPI. Validity evidence was generated for the vMPI and compared with the MPI on the internal structure, relationship to other variables, and consequential validity, including applicant and interviewer acceptability. Overall, the vMPI demonstrated similar reliability and factor structure to the MPI. As with the MPI, applicant performance was predicted by nonacademic screening tools but not academic measures. Applicants' acceptance of the vMPI was positive. Most interviewers found the vMPI to be acceptable and reported confidence in their ratings. Continuing physical distancing concerns will require multiple options for admissions committees to select medical students. The vMPI is an example of a customized approach that schools can implement and may have advantages for selection beyond the COVID-19 pandemic. Future evaluation will examine additional validity evidence for the tool.

Right Ventricular Mass 12 Years after Osteosarcoma: Multimodality Imaging with Pathologic Correlation.

The authors report a 27-year-old woman with a remote left femoral osteosarcoma and amputation above the left knee who presented with a large right ventricular mass. Initial evaluation with thoracic CT was inconclusive regarding thrombus versus tumor, but metastatic osteosarcoma was suggested by findings at transthoracic echocardiography, cardiac CT, and cardiac MRI. The patient underwent tumor debulking, and osteosarcoma was confirmed with pathologic examination. She responded to chemotherapy, which resulted in reduction in size of the residual right ventricular tumor and of a few pulmonary metastases. Following induction chemotherapy, patient remains well undergoing maintenance therapy with an oral tyrosine kinase inhibitor. Keywords: CT, Echocardiography, MR Imaging, Intraoperative, Cardiac, Heart, Right Ventricle, Imaging Sequences, Metastases, Oncology Supplemental material is available for this article. © RSNA, 2021.

Effect of Continuous Electrocardiogram Monitoring on Detection of Undiagnosed Atrial Fibrillation After Hospitalization for Cardiac Surgery: A Randomized Clinical Trial.

Importance: Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is associated with adverse outcomes. Whether POAF persists beyond discharge is not well defined. Objective: To determine whether continuous cardiac rhythm monitoring enhances detection of POAF among cardiac surgical patients during the first 30 days after hospital discharge compared with usual care. Design, Setting, and Participants: This study is an investigator-initiated, open-label, multicenter, randomized clinical trial conducted at 10 Canadian centers. Enrollment spanned from March 2017 to March 2020, with follow-up through September 11, 2020. As a result of the COVID-19 pandemic, enrollment stopped on July 17, 2020, at which point 85% of the proposed sample size was enrolled. Cardiac surgical patients with CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female sex) score greater than or equal to 4 or greater than or equal to 2 with risk factors for POAF, no history of preoperative AF, and POAF lasting less than 24 hours during hospitalization were enrolled. Interventions: The intervention group underwent continuous cardiac rhythm monitoring with wearable, patch-based monitors for 30 days after randomization. Monitoring was not mandated in the usual care group within 30 days after randomization. Main Outcomes and Measures: The primary outcome was cumulative AF and/or atrial flutter lasting 6 minutes or longer detected by continuous cardiac rhythm monitoring or by a 12-lead electrocardiogram within 30 days of randomization. Prespecified secondary outcomes included cumulative AF lasting 6 hours or longer and 24 hours or longer within 30 days of randomization, death, myocardial infarction, ischemic stroke, non-central nervous system thromboembolism, major bleeding, and oral anticoagulation prescription. Results: Of the 336 patients randomized (163 patients in the intervention group and 173 patients in the usual care group; mean [SD] age, 67.4 [8.1] years; 73 women [21.7%]; median [interquartile range] CHA2DS2-VASc score, 4.0 [3.0-4.0] points), 307 (91.4%) completed the trial. In the intent-to-treat analysis, the primary end point occurred in 32 patients (19.6%) in the intervention group vs 3 patients (1.7%) in the usual care group (absolute difference, 17.9%; 95% CI, 11.5%-24.3%; P < .001). AF lasting 6 hours or longer was detected in 14 patients (8.6%) in the intervention group vs 0 patients in the usual care group (absolute difference, 8.6%; 95% CI, 4.3%-12.9%; P < .001). Conclusions and Relevance: In post-cardiac surgical patients at high risk of stroke, no preoperative AF history, and AF lasting less than 24 hours during hospitalization, continuous monitoring revealed a significant increase in the rate of POAF after discharge that would otherwise not be detected by usual care. Studies are needed to examine whether these patients will benefit from oral anticoagulation therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02793895.

TAVR for severe aortic stenosis and papillary fibroelastoma in a high-risk setting.

Papillary fibroelastomas (PFE) are rare benign cardiac tumours mainly originating on aortic and mitral valvular surfaces. Management is individualised, but most recommend surgical excision due to thromboembolic risk. We report a 75-year-old man with symptomatic severe aortic stenosis compounded by PFE. Redo sternotomy aortic valve replacement was deferred in favour of the trans-apical (TAVR) approach. This report highlights, for the first time, the application of TAVR as a strategy for aortic valve stenosis and PFE to mitigate risk posed by injury to patent internal mammary arterial graft in close proximity to the manubrium, and complications due to the patient's multiple comorbidities.

Randomized, Controlled Trial Comparing Mitral Valve Repair With Leaflet Resection Versus Leaflet Preservation on Functional Mitral Stenosis: The CAMRA CardioLink-2 Study.

BACKGROUND: Equipoise exists between the use of leaflet resection and preservation for surgical repair of mitral regurgitation caused by prolapse. We therefore performed a randomized, controlled trial comparing these 2 techniques, particularly in regard to functional mitral stenosis. METHODS: One hundred four patients with degenerative mitral regurgitation surgically amenable to either leaflet resection or preservation were randomized at 7 specialized cardiac surgical centers. Exclusion criteria included anterior leaflet or commissural prolapse, as well as a mixed cause for mitral valve disease. Using previous data, we determined that a sample size of 88 subjects would provide 90% power to detect a 5-mm Hg difference in mean mitral valve gradient at peak exercise, assuming an SD of 6.7 mm with a 2-sided test with α=5% and 10% patient attrition. The primary end point was the mean mitral gradient at peak exercise 12 months after repair. RESULTS: Patient age, proportion who were female, and Society of Thoracic Surgeons risk score were 63.9±10.4 years, 19%, and 1.4±2.8% for those who were assigned to leaflet resection (n=54), and 66.3±10.8 years, 16%, and 1.9±2.6% for those who underwent leaflet preservation (n=50). There were no perioperative deaths or conversions to replacement. At 12 months, moderate mitral regurgitation was observed in 3 subjects in the leaflet resection group and 2 in the leaflet preservation group. The mean transmitral gradient at 12 months during peak exercise was 9.1±5.2 mm Hg after leaflet resection and 8.3±3.3 mm Hg after leaflet preservation (P=0.43). The participants had similar resting peak (8.3±4.4 mm Hg versus 8.4±2.6 mm Hg; P=0.96) and mean resting (3.2±1.9 mm Hg versus 3.1±1.1 mm Hg; P=0.67) mitral gradients after leaflet resection and leaflet preservation, respectively. The 6-minute walking distance was 451±147 m for those in the leaflet resection versus 481±95 m for the leaflet preservation group (P=0.27). CONCLUSIONS: In this adequately powered randomized trial, repair of mitral prolapse with either leaflet resection or leaflet preservation was associated with similar transmitral gradients at peak exercise at 12 months postoperatively. These data do not support the hypothesis that a strategy of leaflet resection (versus preservation) is associated with a risk of functional mitral stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier NCT02552771.

Learning curve predictors for minimally invasive mitral valve surgery; how far should the rabbit hole go?

OBJECTIVE: To analyze predictors that influence the learning curve of minimally invasive mitral valve surgery (MIMVS). METHODS: Patients who underwent MIMVS between March 2010 to March 2015 were retrospectively analyzed. Predictive factors that influence the learning curve were analyzed. RESULTS: One hundred and five patients were included in the analysis. Cardiopulmonary bypass (CPB) time in minutes was 158.72 ± 40.98 and the aortic cross-clamp (ACC) time in minutes was 114.48 ± 27.29. There were three operative mortalities, one stroke and five >2+ mitral regurgitation. ACC time in minutes was higher in the low logistic Euroscore II (LES) group (LES < 5% = 118.42 ± 27.94) versus (LES ≥ 5 = 88.66 ± 22.26), P < .05 while creatinine clearance in µmol/L was higher in the LES < 5% group (LES < 5% = 84.32 ± 33.7) versus (LES ≥ 5% = 41.66 ± 17.14), (P < .05). One patient from each group required chest tube insertion for pleural effusion P < .05. The cumulative sum analysis (CUSUM) for the first 25 patients had CPB and ACC times that reached the upper limits. Between 25 to 64 patients the curve remained stable while with the introduction of reoperations and complex surgical procedures the CUSUM reached the upper limits. CONCLUSIONS: The learning curve is affected by many factors but this should not desist surgeons from approaching this technique. The introduction of high-risk patients in clinical practice should be carefully measured based on surgeon experience.

A Systematic Review and Meta-Analysis of del Nido Versus Conventional Cardioplegia in Adult Cardiac Surgery.

OBJECTIVE: Del Nido cardioplegia (DC) has been used extensively in pediatric cardiac surgery but the efficacy and safety in adults remains uncertain. Our objective was to perform a systematic review and meta-analysis comparing DC and blood cardioplegia (BC) in our primary endpoint of 30-day or in-hospital mortality as well as other efficacy and safety endpoints. METHODS: Both MEDLINE and EMBASE were searched from 1996 to 2017 for studies comparing DC and BC. Data were extracted by 2 independent investigators and aggregated in a random effects model. RESULTS: One randomized controlled trial (n = 89), 7 adjusted (n = 1,104), and 5 unadjusted observational studies (n = 717) were included. There was no difference in in-hospital mortality between DC and BC (relative risk:0.67, 95% confidence interval [CI]: 0.22, 2.07; P = 0.49). DC reduced cardioplegia volume requirements (mean difference [MD]:-1.1 L, 95% CI, -1.6, -0.6; P < 0.0001), aortic cross-clamp time (MD: -8 minutes, 95% CI, -12, -3; P = 0.0004), and cardiopulmonary bypass (CPB) times (MD: -8 minutes, 95% CI, -14, -3; P = 0.03). DC reduced troponin release (standardized MD: -0.3, 95% CI, -0.5, -0.1; P = 0.001). In-hospital outcomes of stroke, atrial fibrillation, acute kidney injury/dialysis, low cardiac output state, blood transfusion, reoperation rate, postoperative left ventricular EF, intensive care unit length of stay (LOS), and in-hospital LOS were comparable between groups. CONCLUSIONS: DC is a safe alternative to BC in routine adult cardiac surgery. Its use is associated with reduction in CPB and aortic cross-clamp times and may potentially offer improved myocardial protection.

Pulmonary Artery Catheter Knotted in the Tricuspid Valve Apparatus Requiring Surgery With Cardiopulmonary Bypass: A Case Report.

Placement of a pulmonary artery catheter (PAC) is associated with complications such as entrapment or knotting. PAC entrapment in the heart, vena cava, or pulmonary artery is serious, potentially life-threatening, particularly if they are unrecognized. We present a patient with a PAC knot after aortic valve replacement. Interventional radiology (IR) determined that the catheter may have lodged in the tricuspid valve. Surgical exploration requiring cardiopulmonary bypass revealed that the PAC had passed through the tricuspid valve orifice and knotted itself around the anterior leaflet chordal structure. The catheter was unknotted, with the patient subsequently recovering without long-term sequelae.

Palliative Surgical Resection of an Extensive Metastatic Cardiac Myxofibrosarcoma.

Herein, we report a rare case of metastatic secondary cardiac myxofibrosarcoma in a 33-year-old female patient. The tumor infiltrated the right lung and was extending into the heart via the right superior pulmonary vein. The patient who initially presented with a stroke was found to be at a high risk of recurrent embolic events and therefore was managed successfully surgically with a complex joint thoracic and cardiac tumor resection. This case illustrates that, in the setting of an extensive metastatic myxofibrosarcoma, an aggressive palliative surgical resection can be successfully performed to improve quality of life.

Anterior mediastinal mass 4 years after type A aortic dissection.

A 47-year-old male who previously underwent emergency surgery for type A aortic dissection presented to the emergency department 4 years later with acute chest pain radiating to his back and a significant drop in hemoglobin. Clinical presentation was concerning for aortic graft failure, but imaging revealed a large (6.0 × 3.2 × 12.8 cm3) soft tissue mediastinal mass that was not present 4 years before. Pathologic analysis revealed a rare thymic cyst with a hemorrhagic component. This was a challenging case from diagnostic and operative perspectives, involving the expertise of both cardiac and thoracic surgical teams.