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.

[Figure: see text].

Transcatheter Mitral Valve Repair in Patients With and Without Cardiac Resynchronization Therapy: The COAPT Trial.

BACKGROUND: In the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation), treatment of heart failure (HF) patients with moderate-severe or severe secondary mitral regurgitation with transcatheter mitral valve repair (TMVr) using the MitraClip plus guideline-directed medical therapy (GDMT) reduced 2-year rates of HF hospitalization and all-cause mortality compared with GDMT alone. Whether the benefits of the MitraClip extend to patients with previously implanted cardiac resynchronization therapy (CRT) is unknown. We sought to examine the effect of prior CRT in patients enrolled in COAPT. METHODS: Patients (N=614) with moderate-severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated doses of GDMT were randomized 1:1 to the MitraClip (TMVr arm) versus GDMT only (control arm). Outcomes were assessed according to prior CRT use. RESULTS: Among 614 patients, 224 (36.5%) had prior CRT (115 and 109 randomized to TMVr and control, respectively) and 390 (63.5%) had no CRT (187 and 203 randomized to TMVr and control, respectively). Patients with CRT had similar 2-year rates of the composite of death or HF hospitalization compared with those without CRT (57.6% versus 55%, P=0.32). Death or HF hospitalization at 2 years was lower with TMVr versus control treatment in patients with prior CRT (48.6% versus 67.2%, hazard ratio, 0.60 [95% CI, 0.42-0.86]) and without CRT (42.5% versus 66.9%, hazard ratio, 0.52 [95% CI, 0.39-0.69]; adjusted Pinteraction=0.23). The effects of TMVr with the MitraClip on reducing the 2-year rates of all-cause death (adjusted Pinteraction=0.14) and HF hospitalization (adjusted Pinteraction=0.82) were also consistent in patients with and without CRT as were improvements in quality-of-life and exercise capacity. CONCLUSIONS: In the COAPT trial, TMVr with the MitraClip improved the 2-year prognosis of patients with HF and moderate-severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated GDMT, regardless of prior CRT implantation. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01626079.

The effect of establishing pre-angiography thresholds on contrast utilization.

INTRODUCTION: Contrast induced nephropathy is linked to contrast utilization and strategies for minimizing renal injury are incorporated into many laboratories that perform coronary angiography. Contrast limits have been described, below which there is minimal incremental increase in the risk of renal injury. Whether a priori acknowledgement of these limits as part of a contrast "Time-Out" reduces contrast utilization has not been established. In this study, we investigate the effect of verbalizing pre-angiography and ½ time contrast thresholds on contrast utilization and associated clinical outcomes. METHODS: We retrospectively reviewed 5265 cases of coronary angiography (984 with contrast thresholds defined pre-procedure compared to 4281 without pre-defined contrast thresholds). There were two primary endpoints: (1) proportion of procedures that utilized an amount of contrast ≤ threshold, and (2) median difference between amount of contrast utilized and the contrast threshold. Secondary outcomes incorporated indices of renal function, and included changes in serum creatinine levels, eGFR, and CKD stage. RESULTS: Compared to pre-"Time-Out" group, the post-"Time-Out" group had a higher proportion of procedures with contrast ≤ stated contrast threshold (88% vs 84%, P < 0.002), and a lower amount of total contrast volume (88 mL [IQR 60-136] versus 78 mL [IQR 53-119]). The post-"Time-Out" group also had a lower incidence of any increase in post-procedure serum creatinine (45% vs 36%; P = 0.04), and a larger median decrease of pre- to post-procedure eGFR (P = 0.04). CONCLUSION: Acknowledgement of contrast threshold as part of a contrast "Time-Out" is associated with reduced overall contrast utilization, and likely minimizes risks of contrast-induced nephropathy.

Effectively Screening for Coronary Artery Disease in Patients Undergoing Orthotopic Liver Transplant Evaluation.

Coronary artery disease (CAD) is prevalent in patients with end-stage liver disease and associated with poor outcomes when undergoing orthotopic liver transplantation (OLT); however, noninvasive screening for CAD in this population is less sensitive. In an attempt to identify redundancy, we reviewed our experience among patients undergoing CAD screening as part of their OLT evaluation between May 2009 and February 2014. Demographic, clinical, and procedural characteristics were analyzed. Of the total number of screened patients (n = 132), initial screening was more common via stress testing (n = 100; 75.8%) than coronary angiography (n = 32; 24.2%). Most with initial stress testing underwent angiography (n = 52; 39.4%). Among those undergoing angiography, CAD was common (n = 31; 23.5%). Across the entire cohort the number of traditional risk factors was linearly associated with CAD, and those with two or more risk factors were found to have CAD by angiography 50% of the time (OR 1.92; CI 1.07-3.44, p = 0.026). Our data supports that CAD is prevalent among pre-OLT patients, especially among those with 2 or more risk factors. Moreover, we identified a lack of uniformity in practice and the need for evidence-based and standardized screening protocols.

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).

Regional and overall aortic function in nondiabetic individuals with insulin resistance and normal glucose tolerance.

CONTEXT: Insulin resistance is associated with altered vascular function in diabetes. OBJECTIVE: The objective of the study was to define the overall and regional aortic function as well as the changes of aortic function over time in nondiabetic individuals with insulin resistance and a normal oral glucose tolerance test (OGTT). DESIGN: This was a cross-sectional and longitudinal analysis with 12 months follow-up. SETTING: The setting of the study was in primary care. PATIENTS: Nondiabetic individuals (n = 181, mean age 42 ± 8 y) with a normal OGTT and insulin resistance as defined by the insulin sensitivity index (ISI) participated in the study. INTERVENTIONS: ISI was estimated from serial measurements of plasma insulin and glucose during an iv glucose tolerance test. Ascending and abdominal aortic distensibility (AoD) and stiffness index-ß (AoSI) were assessed using echocardiography. Carotid-to-femoral artery pulse wave velocity (PWVc-f; an index of overall aortic function) was measured from carotid and femoral arteries Doppler flow velocities recorded simultaneously with an electrocardiogram. Associations between ISI, AoD, AoSI, and PWVc-f were assessed using linear regression analyses and ANOVA. Differences between baseline and 12 months were compared using a paired t test. MAIN OUTCOME MEASURES: AoD and AoSI associations as well as changes over a 12-month period in relation to ISI were measured. RESULTS: Ascending AoD (P = .01) and ascending AoSI (P = .025) were significantly associated with ISI; in contrast, abdominal AoD and AoSI and PWVc-f did not. Changes in AoD, AoSI, and PWVc-f over time were more prominent in individuals with low ISI compared with those with high ISI. CONCLUSIONS: The significant associations between ISI and aortic function suggest that insulin resistance may affect the cardiovascular system, even when OGTT is normal.

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.

Factors determining left atrial kinetic energy in patients with chronic mitral valve disease.

BACKGROUND: Increased left atrial (LA) work is a major contributor to LA fatigue, LA failure and atrial fibrillation in patients with mitral stenosis (MS) and mitral valvular regurgitation (MVR). The present study was undertaken to define factors that determine LA work in patients with chronic mitral valve disease. PATIENTS AND METHODS: Peak left atrial kinetic energy (LAKE)was used as an index of LA work in 14 patients with MS, 14 with MVR, and 19 normal subjects matched for age and gender with MS and MVR patients. LA stroke volume and ejection fraction were measured from the biplane area-length method using echo techniques. Peak LAKE was obtained from the formula 1/2 mv2, where m = LA stroke volume x 1.06 (blood's specific gravity) and v = transmitral Doppler A-wave velocity. RESULTS: Stepwise regression analysis often clinical and echocardiographic parameters demonstrated that in MS, mitral valve area (r2 = 0.43) and LA maximal volume (r2 = 0.62), in MVR, only LA maximal volume (r2 = 0.42) contributed independently to LAKE. LAKE was greater in MS and MVR compared to control subjects while LA ejection fraction was similar in all groups. CONCLUSIONS: It is concluded that LA work is markedly increased in patients with chronic mitral valve disease. Increased LA work in chronic mitral valve disease may contribute to LA fatigue, LA failure, and atrial fibrillation.