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.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

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Hybrid Coronary Revascularization for the Treatment of Multivessel Coronary Artery Disease: A Multicenter Observational Study.

BACKGROUND: Hybrid coronary revascularization (HCR) combines minimally invasive surgical coronary artery bypass grafting of the left anterior descending artery with percutaneous coronary intervention (PCI) of non-left anterior descending vessels. HCR is increasingly used to treat multivessel coronary artery disease that includes stenoses in the proximal left anterior descending artery and at least 1 other vessel, but its effectiveness has not been rigorously evaluated. OBJECTIVES: This National Institutes of Health-funded, multicenter, observational study was conducted to explore the characteristics and outcomes of patients undergoing clinically indicated HCR and multivessel PCI for hybrid-eligible coronary artery disease, to inform the design of a confirmatory comparative effectiveness trial. METHODS: Over 18 months, 200 HCR and 98 multivessel PCI patients were enrolled at 11 sites. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) (i.e., death, stroke, myocardial infarction, repeat revascularization) within 12 months post-intervention. Cox proportional hazards models were used to model time to first MACCE event. Propensity scores were used to balance the groups. RESULTS: Mean age was 64.2 ± 11.5 years, 25.5% of patients were female, 38.6% were diabetic, and 4.7% had previous stroke. Thirty-eight percent had 3-vessel coronary artery disease, and the mean SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score was 19.7 ± 9.6. Adjusted for baseline risk, MACCE rates were similar between groups within 12 months post-intervention (hazard ratio [HR]: 1.063; p = 0.80) and during a median 17.6 months of follow-up (HR: 0.868; p = 0.53). CONCLUSIONS: These observational data from this first multicenter study of HCR suggest that there is no significant difference in MACCE rates over 12 months between patients treated with multivessel PCI or HCR, an emerging modality. A randomized trial with long-term outcomes is needed to definitively compare the effectiveness of these 2 revascularization strategies. (Hybrid Revascularization Observational Study; NCT01121263).

Cardiac repair and regeneration: the Rubik's cube of cell therapy for heart disease.

Acute ischemic injury and chronic cardiomyopathies damage healthy heart tissue. Dead cells are gradually replaced by a fibrotic scar, which disrupts the normal electromechanical continuum of the ventricular muscle and compromises its pumping capacity. Recent studies in animal models of ischemic cardiomyopathy suggest that transplantation of various stem cell preparations can improve heart recovery after injury. The first clinical trials in patients produced some encouraging results, showing modest benefits. Most of the positive effects are probably because of a favorable paracrine influence of stem cells on the disease microenvironment. Stem cell therapy attenuates inflammation, reduces apoptosis of surrounding cells, induces angiogenesis, and lessens the extent of fibrosis. However, little new heart tissue is formed. The current challenge is to find ways to improve the engraftment, long-term survival and appropriate differentiation of transplanted stem cells within the cardiovascular tissue. Hence, there has been a surge of interest in pluripotent stem cells with robust cardiogenic potential, as well as in the inherent repair and regenerative mechanisms of the heart. Recent discoveries on the biology of adult stem cells could have relevance for cardiac regeneration. Here, we discuss current developments in the field of cardiac repair and regeneration, and present our ideas about the future of stem cell therapy.

Routine intraoperative completion angiography after coronary artery bypass grafting and 1-stop hybrid revascularization results from a fully integrated hybrid catheterization laboratory/operating room.

OBJECTIVES: This study sought to report our experience with a routine completion angiogram after coronary artery bypass surgery (CABG) and simultaneous (1-stop) percutaneous coronary intervention (PCI) at the time of CABG performed in the hybrid catheterization laboratory/operating room. BACKGROUND: The value of a routine completion angiogram after CABG and 1-stop hybrid CABG/PCI remains unresolved. METHODS: Between April 2005 and July 2007, 366 consecutive patients underwent CABG surgery, with (n = 112) or without (n = 254) concomitant 1-stop PCI (hybrid), all with completion angiography before chest closure. Among the 112 1-stop hybrid CABG/PCI patients, 67 (60%) underwent a planned hybrid procedure based on pre-operative assessment, whereas 45 (40%) underwent open-chest PCI (unplanned hybrid) based on intraoperative findings. RESULTS: Among the 796 CABG grafts (345 left internal mammary artery, 12 right internal mammary artery/radial, and 439 veins), 97 (12%) angiographic defects were identified. Defects were repaired with either a minor adjustment of the graft (n = 22, 2.8%), with intraoperative open-chest PCI (unplanned hybrid, n = 48, 6%) or with traditional surgical revision (n = 27, 3.4%). Hybrid patients had clinical outcomes similar to standard CABG patients. CONCLUSIONS: Routine completion angiography detected 12% of grafts with important angiographic defects. One-stop hybrid coronary revascularization is reasonable, safe, and feasible. Combining the tools of the catheterization laboratory and operating room greatly enhances the options available to the surgeon and cardiologist for patients with complex coronary artery disease.

Estradiol increases platelet aggregation in Pl(A1/A1) individuals.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor is a key mediator of platelet aggregation and intracoronary thrombosis. Studies have suggested that hormone replacement therapy (HRT) may increase coronary events in postmenopausal women. OBJECTIVES: We sought to characterize the relationship between the estrogen concentration expected in HRT and platelet aggregation. DESIGN AND RESULTS: Platelet aggregation studies were performed using epinephrine on 30 healthy individuals (15 Pl(A1/A1) and 15 Pl(A1/A2)) before and after incubation with beta-estradiol (E2) (10(-11) mol/L). The effect of E2 10(-11) mol/L on Pl(A1/A1) platelets demonstrated a significant increase (P = .03) in aggregation compared with baseline. In contrast, with the same concentration of E2, aggregation of Pl(A1/A2) platelets decreased significantly compared with baseline (P < .0001). CONCLUSIONS: Estrogen concentration similar to that expected in HRT resulted in an increase in platelet aggregation in Pl(A1/A1) individuals, but not in Pl(A1/A2) individuals. The data may provide further insight for the increase in coronary events seen in HRT clinical trials and suggest that further evaluation is needed to better define the role of pharmacogenetics in HRT.