Emerging role of positron emission tomography (PET) imaging in cardiac surgery.

Historically, structural and anatomical imaging has been the mainstay in the diagnosis and management of cardiovascular diseases. In recent years there has been a shift toward increased use of functional imaging studies, including positron emission tomography (PET). PET is a noninvasive nuclear medicine-imaging technique that uses radiotracers to generate images of a radionucleotide distribution by detecting the physiologic substrates that emit positron radionuclides. This article will focus on the applications of PET imaging for the cardiac surgeon and highlight the collaborative nature of using PET imaging for the management of complex heart disease. We present cases that demonstrate the value of using PET imaging in the diagnosis of coronary artery disease and management of complex endocarditis, and in targeted cardiovascular therapies.

Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair.

RATIONALE: Although rare cardiomyogenesis is reported in the adult mammalian heart, whether this results from differentiation or proliferation of cardiomyogenic cells remains controversial. The tumor suppressor genes RB1 (retinoblastoma) and CDKN2a (cyclin-dependent kinase inhibitor 2a) are critical cell-cycle regulators, but their roles in human cardiomyogenesis remains unclear. OBJECTIVE: We hypothesized that developmental activation of RB1 and CDKN2a cooperatively cause permanent cell-cycle withdrawal of human cardiac precursors (CPCs) driving terminal differentiation into mature cardiomyocytes, and that dual inactivation of these tumor suppressor genes promotes myocyte cell-cycle reentry. METHODS AND RESULTS: Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes revealed that RB1 and CDKN2a are upregulated at the onset of cardiac precursor specification, simultaneously with GATA4 (GATA-binding protein 4) homeobox genes PBX1 (pre-B-cell leukemia transcription factor 1) and MEIS1 (myeloid ecotropic viral integration site 1 homolog), and remain so until terminal cardiomyocyte differentiation. In both GATA4+ hPSC cardiac precursors and postmitotic hPSC-cardiomyocytes, RB1 is hyperphosphorylated and inactivated. Transient, stage-specific, depletion of RB1 during hPSC differentiation enhances cardiomyogenesis at the cardiac precursors stage, but not in terminally differentiated hPSC-cardiomyocytes, by transiently upregulating GATA4 expression through a cell-cycle regulatory pathway involving CDKN2a. Importantly, cytokinesis in postmitotic hPSC-cardiomyocytes can be induced with transient, dual RB1, and CDKN2a silencing. The relevance of this pathway in vivo was suggested by findings in a porcine model of cardiac cell therapy post-MI, whereby dual RB1 and CDKN2a inactivation in adult GATA4+ cells correlates with the degree of scar size reduction and endogenous cardiomyocyte mitosis, particularly in response to combined transendocardial injection of adult human hMSCs (bone marrow-derived mesenchymal stromal cells) and cKit+ cardiac cells. CONCLUSIONS: Together these findings reveal an important and coordinated role for RB1 and CDKN2a in regulating cell-cycle progression and differentiation during human cardiomyogenesis. Moreover, transient, dual inactivation of RB1 and CDKN2a in endogenous adult GATA4+ cells and cardiomyocytes mediates, at least in part, the beneficial effects of cell-based therapy in a post-MI large mammalian model, a finding with potential clinical implications.

Use of an inverted On-X mitral valve in the aortic position in a resource limited setting.

Implanting an inverted aortic valve prosthesis in the mitral position has shown to be a viable solution for a small mitral annulus. We describe a case of implanting an inverted in the mitral prosthesis in the aortic position in a patient with an excessively large aortic annulus. A 46-year-old male with severe aortic insufficiency underwent aortic valve replacement during a surgical outreach program in Tegucigalpa, Honduras. Aortic valve annulus measured 30 mm on preoperative echocardiogram. An inverted On-X mechanical mitral heart valve with Conform-X sewing ring 25/33 mm was implanted with an excellent hemodynamic result and no paravalvular leak. To the best of our knowledge, this case demonstrates the first inverted mitral prosthesis implanted in the aortic valve position.

Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

RATIONALE: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. OBJECTIVE: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. METHODS AND RESULTS: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; P<0.01) and noninjected segments (-25.1 ± 7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9 ± 3.3-26.3 ± 3.5%; P=0.003) but not in noninjected scar segments (21.3 ± 2.6-23.5 ± 3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1 ± 1.2-19.9 ± 2.7%; n=18; P=0.003), versus <20% (31.7 ± 3.4-35.5 ± 3.3%; n=12; P=0.33, between-group comparison P<0.0001). CONCLUSIONS: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction.

BACKGROUND: Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit(+) cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit(+) hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI). METHODS AND RESULTS: Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo (P<0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone (P<0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P<0.01) and contractility (preload recruitable stroke work and dP/dtmax; P<0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function (P<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone (P<0.001). CONCLUSIONS: Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit(+) CSCs and MSCs that enhance cell-based therapeutic responses.

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066.

Quality improvement initiative to increase radial artery usage as a second arterial conduit in coronary artery bypass grafting.

OBJECTIVES: Use of radial artery as a second arterial graft, compared to a saphenous vein, in coronary artery bypass grafting (CABG) can improve late outcomes. However, the radial artery remains underutilized. We initiated a quality improvement (QI) initiative to increase the usage of radial artery grafts. METHODS: During our 4-month lead period, we disseminated evidence for radial artery graft usage to surgeons, developed a radial artery decision-making algorithm and adopted endoscopic harvesting. Our QI initiative was conducted over a 6-month period and included a postoperative survey of decision-making for graft selection and obstacles to radial artery usage. RESULTS: Over the 6-month study period, 247 patients received isolated CABG which included 98 (40%) with radial arteries as a second arterial graft and 144 (58%) with greater saphenous veins. Radial artery usage increased with QI initiative implementation by 67% compared to 6 months prior to the study period (60 radial arteries/252 isolated CABG, 24%) (P = 0.006). The survey response rate was 93% (231/247). Barriers to radial artery graft usage were poor quality target vessel or stenosis <80% (24%), patient age >75 years (20%), ejection fraction ≤35% (8%) and renal insufficiency/dialysis (7%). No patients experienced significant complications from radial artery harvest. CONCLUSIONS: Our institutional QI initiative was successful in (i) increasing the usage of radial artery as a second arterial graft and (ii) understanding barriers to radial artery graft usage. Implementation of a QI program can improve radial artery usage in CABG with low risk of patient morbidity from radial artery harvest.

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.

Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.

Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling.

RATIONALE: Transcatheter, intramyocardial injections of bone marrow-derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. OBJECTIVE: We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling. METHODS AND RESULTS: Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL; P=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL; P=0.06), decreased infarct size (P<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (-8.1±1.0 versus -11.4±1.3; P=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (r(2)=0.69, P=0.04) and end systolic volume (r(2)=0.83, P=0.01). CONCLUSIONS: These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.

Selective Sinus Replacement for Aortic Root Aneurysm: Durable Approach in Selected Patients.

BACKGROUND: Selective sinus replacement (SSR) allows a tailored repair approach in patients with sinus of Valsalva or asymmetric aortic root aneurysm. SSR avoids the need for coronary reimplantation for nondiseased sinuses and shortens operative time, although potential for late growth of retained sinuses exists. This study describes selection of patients and assesses operative outcomes and late root dimensions after SSR. METHODS: From 2006 to 2020, 60 patients underwent SSR at a single referral institution. Mixed effect models were used to assess trajectory of postoperative growth of remaining sinuses, adjusting for age of the patient, valve morphology, and baseline root diameter. RESULTS: Median age of the patients was 57 (interquartile range [IQR], 48-65) years. Twenty-four (40%) had a bicuspid aortic valve. Most patients (n = 55 [92%]) underwent single sinus replacement (n = 46 noncoronary, n = 9 right), whereas 5 (8%) underwent repair of both the right and noncoronary sinuses. Concomitant aortic valve replacement was performed in 15 patients (25%); aortic valve repair with internal ring annuloplasty or cusp plication was performed in 37 (62%). There was no operative death, stroke, renal failure, or respiratory failure. Median preoperative root diameter was 53 mm (IQR, 51-56 mm) vs 42 mm (IQR, 39-45 mm) at median imaging follow-up of 34 (IQR, 13-49) months. Rate of midterm root growth was 0.2 mm/y, and there were no late root reinterventions. CONCLUSIONS: For patients with sinus of Valsalva or asymmetric root aneurysm, SSR is associated with excellent operative outcomes, and midterm follow-up suggests that the technique is durable. Longer term follow-up is needed to confirm continued stability of the aortic root.

Scoping review of percutaneous mechanical aspiration for valvular and cardiac implantable electronic device infective endocarditis.

BACKGROUND: Percutaneous mechanical aspiration (PMA) of intravascular vegetations is a novel strategy for management of patients with infective endocarditis (IE) who are at high risk of poor outcomes with conventional cardiac surgery. However, clear indications for its use as well as patient outcomes are largely unknown. OBJECTIVES: To conduct a scoping review of the literature to summarize patient characteristics and outcomes of those undergoing PMA for management of IE. METHODS: Two independent reviewers screened abstracts and full text for inclusion and independently extracted data. DATA SOURCES: MEDLINE, Embase, and Web of Science. STUDY ELIGIBILITY CRITERIA: Studies published until February 21, 2023, describing the use of PMA for management of patients with cardiac implantable electronic device (CIED) or valvular IE were included. ASSESSMENT OF RISK OF BIAS: As this was a scoping review, risk of bias assessment was not performed. METHODS OF DATA SYNTHESIS: Descriptive data was reported. RESULTS: We identified 2252 titles, of which 1442 abstracts were screened, and 125 full text articles were reviewed for inclusion. Fifty-one studies, describing a total of 294 patients who underwent PMA for IE were included in our review. Over 50% (152/294) of patients underwent PMA to debulk cardiac implantable electronic device lead vegetations prior to extraction (152/294), and 38.8% (114/294) of patients had a history of drug use. Patient outcomes were inconsistently reported, but few had procedural complications, and all-cause in-hospital mortality was 6.5% (19/294). CONCLUSIONS: While PMA is a promising advance in the care of patients with IE, higher quality data regarding patient outcomes are needed to better inform the use of this procedure.

Tailored approach and outcomes of aortic arch reconstruction after acute type A dissection repair.

OBJECTIVE: After limited root/ascending with or without hemiarch repair for acute type A aortic dissection (ATAAD), 20% to 30% of patients require distal reintervention, frequently for arch pathology. In this report, we describe an institutional algorithm for arch management after previous limited ATAAD repair and detail operative and long-term outcomes. METHODS: From August 2005 to April 2021, 71 patients status post previous limited ATAAD repair underwent reoperative arch repair involving zones 1 to 3 for aneurysmal degeneration of residual arch dissection including complete cervical debranching with zone 0/1 thoracic endovascular aortic repair in 6 (8%), open total arch in 13 (18%), type I hybrid arch repair in 23 (32%), and type II/III hybrid arch repair in 29 (41%). RESULTS: Mean age was 59 ± 12 years; time from index ATAAD repair to reoperation was 4 (interquartile range, 2-9) years. There were 2 (2.8%) in-hospital deaths and 2 (2.8%) postdischarge deaths within 30 days of surgery. Three patients suffered stroke (4.2%) and 2 (2.8%) had acute renal failure requiring dialysis. Overall Kaplan-Meier survival was 78%, 70%, and 58% at 1, 3, and 5 years, respectively. Institutional experience appeared to play a significant role in early and late outcomes, because there have been no operative mortalities in the past 9 years and improved survival of 87% versus 66%, 79% versus 58%, and 79% versus 40% at 1, 3, and 5 years in comparisons of the past 9 years with the previous era (P = .01). CONCLUSIONS: Aneurysmal degeneration of residual arch dissection after limited ATAAD repair presents a complex reoperative challenge. An algorithmic operative approach tailored to patient anatomy and comorbidities yields excellent early and late outcomes, which continue to improve with increasing institutional experience.

Initial Management Strategy and Long-Term Outcomes in 186 Cases of Spontaneous Coronary Artery Dissection.

Spontaneous coronary artery dissection (SCAD) is a rare but important nonatherosclerotic cause of acute coronary syndrome. Indications for revascularization and long-term outcomes of SCAD remain areas of active investigation. We report our experience with initial management strategy and long-term outcomes in SCAD. We reviewed all patients treated at our institution from 1996-2021 with a SCAD diagnosis. Demographics, comorbidities, clinical presentations, angiography findings, and management strategies were obtained by chart review. The primary outcome was a composite of cardiac death, recurrent/progressive SCAD, subsequent diagnosis of congestive heart failure, or subsequent/repeat revascularization after the initial management. Unadjusted Kaplan-Meier survival analysis was performed. Of 186 patients with a SCAD diagnosis treated at our institution, 149 (80%) were female. Medical management was the initial treatment in 134 (72.0%) patients, percutaneous coronary intervention (PCI) in 43 (23.1%), and coronary artery bypass grafting in 9 (4.8%). Surgery/PCI intervention was associated with younger age (38.8 vs 47.7 years, P = 0.01), ST elevation myocardial infarction on presentation (67.0% vs 34.0%, P < 0.001), lower ejection fraction (45.0% vs 55.0%, P = 0.002), and left anterior descending coronary artery dissection (75.0% vs 51.0%, P = 0.006). Ten-year freedom from our composite outcome was similar between revascularized patients and those managed with medical therapy (P = 0.36). Median follow-up time was 4.5 years. SCAD in the setting of ST elevation myocardial infarction, left anterior descending coronary artery involvement, or decreased cardiac function suggests greater ischemic insult and was associated with initial percutaneous or surgical revascularization. Despite worse disease on initial presentation, long-term outcomes of patients undergoing revascularization are similar to medically managed patients with SCAD.

Infarct exclusion repair of postmyocardial infarction ventricular septal rupture with a hybrid patch and septal occluder device compared with patch only.

Objective: We developed a hybrid technique for repairing post-myocardial infarction (MI) ventricular septal defect (VSD) that combines infarct exclusion with patch and a nitinol-mesh septal occluder device (SOD) to provide a scaffold to support the damaged septal wall. Here, we compare outcomes of patients with post-MI VSD repaired using patch only or hybrid patch/SOD. Methods: Patients undergoing post-MI VSD repair at our institution from 2013 to 2022 who received patch alone or patch/SOD repair were analyzed. Primary outcome was survival to hospital discharge. Clinical outcomes and echocardiograms were also analyzed. Results: Over a 9-year period, 24 patients had post-MI VSD repair at our institution with either hybrid patch/SOD (n = 10) or patch only repair (n = 14). VSD size was 18 ± 5.8 mm for patch/SOD and 17 ± 4.6 mm for patch only. In the patch/SOD repair cohort, average size of SOD implant was 23.6 ± 5.6 mm. Mild left ventricular dysfunction was present prerepair and was unchanged postrepair in both groups; however, moderate-to-severe right ventricular (RV) dysfunction was common in both groups before repair. RV function worsened or persisted as severe in 10% of hybrid versus 54% of patch-only patients postrepair. Tricuspid annular systolic excursion and RV:left ventricle diameter ratio, quantitative metrics of RV function, improved after patch/SOD repair. No intraoperative mortality occurred in either group. Postoperative renal, hepatic, and respiratory failure requiring tracheostomy was common in both groups. Survival to hospital discharge in both cohorts was 70%. Conclusions: Post-MI VSD repair with patch/SOD has comparable short-term outcomes with patch alone. Addition of a SOD to patch repair provides a scaffold that may enhance the repair of post-MI VSD with patch exclusion.

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.

An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.

The efficacy and safety of gene-therapy strategies for indications like tissue damage hinge on precision; yet, current methods afford little spatial or temporal control of payload delivery. Here, we find that tissue-regeneration enhancer elements (TREEs) isolated from zebrafish can direct targeted, injury-associated gene expression from viral DNA vectors delivered systemically in small and large adult mammalian species. When employed in combination with CRISPR-based epigenome editing tools in mice, zebrafish TREEs stimulated or repressed the expression of endogenous genes after ischemic myocardial infarction. Intravenously delivered recombinant AAV vectors designed with a TREE to direct a constitutively active YAP factor boosted indicators of cardiac regeneration in mice and improved the function of the injured heart. Our findings establish the application of contextual enhancer elements as a potential therapeutic platform for spatiotemporally controlled tissue regeneration in mammals.

Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts.

BACKGROUND: The optimal delivery route to enhance effectiveness of regenerative therapeutics to the human heart is poorly understood. Direct intra-myocardial (IM) injection is the gold standard, however, it is relatively invasive. We thus compared targeted IM against less invasive, catheter-based intra-coronary (IC) delivery to porcine myocardium for the acute retention of nanoparticles using cardiac magnetic resonance (CMR) imaging and viral vector transduction using qPCR. METHODS: Ferumoxytol iron oxide (IO) nanoparticles (5 ml) were administered to Yorkshire swine (n = 13) by: (1) IM via thoracotomy, (2) catheter-based IC balloon-occlusion (BO) with infusion into the distal left anterior descending (LAD) coronary artery, (3) IC perforated side-wall (SW) infusion into the LAD, or (4) non-selective IC via left main (LM) coronary artery infusion. Hearts were harvested and imaged using at 3T whole-body MRI scanner. In separate Yorkshire swine (n = 13), an adeno-associated virus (AAV) vector was similarly delivered, tissue harvested 4-6 weeks later, and viral DNA quantified from predefined areas at risk (apical LV/RV) vs. not at risk in a potential mid-LAD infarct model. Results were analyzed using pairwise Student's t-test. RESULTS: IM delivery yielded the highest IO retention (16.0 ± 4.6% of left ventricular volume). Of the IC approaches, BO showed the highest IO retention (8.7 ± 2.2% vs. SW = 5.5 ± 4.9% and LM = 0%) and yielded consistent uptake in the porcine distal LAD territory, including the apical septum, LV, and RV. IM delivery was limited to the apex and anterior wall, without septal retention. For the AAV delivery, the BO was most efficient in the at risk territory (Risk: BO = 6.0 × 10-9, IM = 1.4 × 10-9, LM = 3.2 × 10-10 viral copies per µg genomic DNA) while all delivery routes were comparable in the non-risk territory (BO = 1.7 × 10-9, IM = 8.9 × 10-10, LM = 1.2 × 10-9). CONCLUSIONS: Direct IM injection has the highest local retention, while IC delivery with balloon occlusion and distal infusion is the most effective IC delivery technique to target therapeutics to a heart territory most in risk from an infarct.

Stent Graft-induced Aortic Wall Injury: Incidence, Risk Factors, and Outcomes.

BACKGROUND: Stent graft-induced new entry has been described in thoracic endovascular aortic repair for aortic dissection. The incidence of stent graft-induced aortic wall injury (SAWI) related to iatrogenic injury in nondissections is incompletely described. We describe incidence, risk factors, and outcomes of SAWI. METHODS: All post-thoracic endovascular aortic repair computed tomography angiograms (January 2005 to December 2018) were reviewed for radiographic evidence of SAWI. Endograft-induced aortic dissections were likewise considered SAWI. Patient characteristics, time to SAWI, and need for reintervention were noted. Cox proportional hazards modeling was used to identify risk factors for SAWI. RESULTS: Within the study cohort (n = 430), 38 patients (9%) had SAWI during a median follow-up of 2.3 years (interquartile range, 4.8); 42% (n = 16) were proximal, 53% (n = 20) distal, and 5% (n = 2) both proximal and distal. Nine (23%) were distal intimal flap injuries in dissection cases, thus subclassifying them as stent graft-induced new entry. Twenty-nine percent of SAWI (n = 11) required reintervention. Of these, 45% (n = 5) were open, and 55% (n = 6) were endovascular. Thoracic endovascular aortic repair for acute dissection had a higher incidence of SAWI development (hazard ratio 4.6; 95% confidence interval, 2.4 to 9; P < .001) as compared with other indications. Use of devices with proximal bare springs or barbs was also associated with increased SAWI incidence (hazard ratio 5.3; 95% confidence interval, 2.6 to 11.0; P < .001). CONCLUSIONS: The rate of SAWI after thoracic endovascular aortic repair is low (9%), but nearly one third will require reintervention. Thoracic endovascular aortic repair in the setting of acute dissection and use of devices with proximal bare springs or barbs were associated with an increased incidence of SAWI.