A Deep Proteome Analysis Identifies the Complete Secretome as the Functional Unit of Human Cardiac Progenitor Cells.

RATIONALE: Cardiac progenitor cells are an attractive cell type for tissue regeneration, but their mechanism for myocardial remodeling is still unclear. OBJECTIVE: This investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), and their potential to recover injured myocardium. METHODS AND RESULTS: Adult (aCPCs) and neonatal (nCPCs) cells were derived from patients aged >40 years or <1 month, respectively, and their functional potential was determined in a rodent myocardial infarction model. A more robust in vitro proliferative capacity of nCPCs, compared with aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media was significantly more effective than nCPCs, aCPC-derived TCM, or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High-resolution accurate mass spectrometry with reverse phase liquid chromatography fractionation and mass spectrometry was used to identify proteins in the secretome of aCPCs and nCPCs, and the literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of myocardial infarction. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nCPC-derived TCM and 513 proteins in aCPC-derived TCM. The literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nCPC-derived TCM and aCPC-derived TCM, respectively. One leading candidate pathway is heat-shock factor-1, potentially affecting 8 identified pathways for nCPC-derived TCM but none for aCPC-derived TCM. To validate this prediction, we demonstrated that the modulation of heat-shock factor-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome. CONCLUSIONS: A deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.

Acute Intracardiac Thrombosis and Pulmonary Thromboembolism After Cardiopulmonary Bypass: A Systematic Review of Reported Cas.

Intracardiac thrombosis (ICT) and pulmonary thromboembolism (PE) after cardiopulmonary bypass (CPB) are life-threatening events, but pathological mechanisms are not yet well defined. The aim of this review is to provide an update of case literature of a postbypass hypercoagulable state. Case commonalities among 48 ICT/PE events included congestive heart failure (50%), platelet transfusion (37.5%), CPB duration greater than 3 hours (37.5%), and aortic injury (27.1%). Preexisting thrombophilia was rarely reported, and 16.7% had low activated clotting time, ≤400 seconds during CPB. Mortality rate was very high (85.4%), despite attempted thrombectomy and supportive therapy. Thrombolytic therapy was infrequently used (5 of 48 times), but its efficacy is questionable due to common use of antifibrinolytic therapy (77.1% of cases). Acute ICT/PE events appear to rarely occur, but common features include prolonged CPB, depressed myocardial function, major vascular injury, and hemostatic interventions. Further efforts to elucidate pathomechanisms and optimize anticoagulation during CPB and hemostatic interventions after CPB are warranted.

Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome.

Despite advances in surgical technique and postoperative care, long-term survival of children born with hypoplastic left heart syndrome (HLHS) remains limited, with cardiac transplantation as the only alternative for patients with failing single ventricle circulations. Maintenance of systemic right ventricular function is crucial for long-term survival, and interventions that improve ventricular function and avoid or defer transplantation in patients with HLHS are urgently needed. We hypothesize that the young myocardium of the HLHS patient is responsive to the biological cues delivered by bone marrow-derived mesenchymal stem cells (MSCs) to improve and preserve right ventricle function. The ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is a phase I/IIb trial designed to test whether MSC injection will be both safe and feasible by monitoring the first 10 HLHS patients for new major adverse cardiac events. If our toxicity stopping rule is not activated, we will proceed to the phase IIb component of our study where we will test our efficacy hypothesis that MSC injection improves cardiac function compared with surgery alone. Twenty patients will be enrolled in a randomized phase II trial with a uniform allocation to MSC injection versus standard surgical care (no injection). The 2 trial arms will be compared with respect to improvement of right ventricular function, tricuspid valve annulus size, and regurgitation determined by cardiac magnetic resonance and reduced mortality, morbidity, and need for transplantation. This study will establish the safety and feasibility of allogeneic mesenchymal stem cell injection in HLHS patients and provide important insights in the emerging field of stem cell-based therapy for congenital heart disease patients.

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload.

Limited therapies exist for patients with congenital heart disease (CHD) who develop right ventricular (RV) dysfunction. Bone marrow-derived mesenchymal stem cells (MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n = 5) or placebo (n = 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P < 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P < 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P < 0.0001), superior recruitment of endogenous c-kit+ cardiac stem cells to the RV (P < 0.0001) and increased proliferation of cardiomyocytes (P = 0.0009) and endothelial cells (P < 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P = 0.008), increased cardiomyocyte cross-sectional area (P = 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ß-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions.

Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome.

We have demonstrated that human neonatal cardiosphere-derived cells (CDCs) derived from the young are more regenerative due to their robust secretome. However, it is unclear how the decompensated pediatric heart impacts the functional activity of their CDCs. Our aim was to characterize the potency of pediatric CDCs derived from normal functioning myocardium of control heart disease (CHD) patients to those generated from age-matched end stage heart failure (ESHF) patients and to determine the mechanisms involved. ESHF-derived CDCs contained a higher number of c-kit(+) , Islet-1(+) , and Sca-1(+) cells. When transplanted into an infarcted rodent model, ESHF-derived CDCs significantly demonstrated higher restoration of ventricular function, prevented adverse remodeling, and enhanced angiogenesis when compared with CHD patients. The superior functional recovery of the ESHF-derived CDCs was mediated in part by increased SDF-1α and VEGF-A secretion resulting in augmented recruitment of endogenous stem cells and proliferation of cardiomyocytes. We determined the mechanism is due to the secretome directed by the heat shock response (HSR), which is supported by three lines of evidence. First, gain of function studies demonstrated that increased HSR induced the lower functioning CHD-derived CDCs to significantly restore myocardial function. Second, loss-of function studies targeting the HSR impaired the ability of the ESHF-derived CDCs to functionally recover the injured myocardium. Finally, the native ESHF myocardium had an increased number of c-kit(+) cardiac stem cells. These findings suggest that the HSR enhances the functional activity of ESHF-derived CDCs by increasing their secretome activity, notably SDF-1α and VEGF-A.

Stem cell therapy for CHD: towards translation.

Stem cell therapy has the optimistic goal of regenerating the myocardium as defined by re-growth of lost or destroyed myocardium. As applied to patients with heart failure, many confuse or limit the regenerative definition to just improving myocardial function and/or decreasing myocardial scar formation, which may not be the most important clinical outcome to achieve in this promising field of molecular medicine. Many different stem cell-based therapies have been tested and have demonstrated a safe and feasible profile in adult patients with heart failure, but with varied efficacious end points reported. Although not achieved as of yet, the encompassing goal to regenerate the heart is still believed to be within reach using these cell-based therapies in adult patients with heart failure, as the first-generation therapies are now being tested in different phases of clinical trials. Similar efforts to foster the translation of stem cell therapy to children with heart failure have, however, been limited. In this review, we aim to summarise the findings from pre-clinical models and clinical experiences to date that have focussed on the evaluation of stem cell therapy in children with heart failure. Finally, we present methodological considerations pertinent to the design of a stem cell-based trial for children with heart failure, as they represent a population of patients with very different sets of issues when compared with adult patients. As has been taught by many learned clinicians, children are not small adults!

Long-term outcomes following alemtuzumab induction in lung transplantation.

OBJECTIVES: Alemtuzumab is a commonly used induction agent for solid-organ transplantation. Its use in lung transplantation with reduced immunosuppressive regimens, however, has yet to be well characterized. METHODS: From November 2006 to March 2008, 20 consecutive lung transplantation patients received alemtuzumab induction with a reduced maintenance immunosuppression regimen. Twenty consecutive case-controls who underwent transplantation between 2005 and 2006 were treated with a standard immunosuppression regimen without induction. Outcome variables were patient survival, acute rejection, infection, and bronchiolitis obliterans syndrome. RESULTS: Mean follow-up time was 1400 days in the alemtuzumab group and 1210 days in the control group. Double lung transplantation was performed in 21 patients (12 in the alemtuzumab group and 9 in the control group). There was no difference in survival between the alemtuzumab (n = 10) and control (n = 10) groups. There was also not a significant difference in time-adjusted death based on Kaplan-Meier analysis. The mean number of any grade of rejection event per patient was not significantly different (alemtuzumab 2.3 ± 2.7 vs. control 3.2 ± 2.35; P = .22). There was a trend toward the reduced incidence of infection requiring intravenous antibiotics per patient (alemtuzumab 2.4 vs. control 3.8; P = .08). The incidence of bronchiolitis obliterans syndrome was similar in both groups (alemtuzumab 55% vs. control 70%; P = .25). CONCLUSIONS: Alemtuzumab induction with reduced immunosuppression offers a comparable 5-year survival and rejection rate compared to standard-dose immunosuppression regimen.

Aortic and Mitral Valve Infective Endocarditis Caused by Gemella sanguinis.

We present a case of infective endocarditis (IE) of the aortic valve, mitral valve, and aortomitral curtain caused by Gemella sanguinis. The patient was an otherwise healthy 53-year-old male without significant risk factors for infective endocarditis in his medical history. Due to the extent of the infective endocarditis and the rapid deterioration of his clinical condition, which included respiratory failure and severe heart failure, the patient was treated with urgent surgery (a Commando operation where both the aortic and mitral valves were replaced and the aortomitral curtain was reconstructed), broad-spectrum antibiotics, and aggressive postoperative measures such as venovenous (VV) extracorporeal membrane oxygenation (ECMO). This is the first reported case where the aortic valve, mitral valve, and aortomitral curtain were affected by G. sanguinis.

Can Robotic-Assisted Surgery Overcome the Risk of Mortality in Cardiac Reoperation?

OBJECTIVE: A robotic-assisted approach potentially has many advantages for cardiac reoperation, which include sternum-sparing and three-dimensional visualization leading to precise adhesiolysis and excellent exposure in a limited field. METHODS: We retrospectively reviewed our patients undergoing robotic cardiac reoperation (redo group) from July 2013 to April 2017 at our institution and compared with our patients undergoing standard robotic surgery (nonredo group). In the reoperative cases, a thoracoscope was inserted through a 5-mm port placed away from the previous scar. Another 5-mm port was inserted under direct vision to make space for one or two robotic arms, and further precise dissection was performed robotically. RESULTS: A total of 486 patients underwent robotic-assisted cardiac surgery. There were 36 patients who had one or more previous cardiac surgeries (42 surgeries). Although the mean operative and cardiopulmonary bypass time were longer in the redo group (median = 351 minutes vs. 289 minutes and 219 minutes vs. 178 minutes, P < 0.05, respectively), cardiac arrest time was similar between two groups. The redo group had a higher incidence of postoperative prolonged ventilation (16.7% vs. 6.9%, P = 0.046) and pneumonia (11.1% vs. 0.2%, P < 0.001). The 30-day mortality was 2.8% (1/36) in the redo group and similar to that in the nonredo group (1.3%, P = 0.419). CONCLUSIONS: Robotic cardiac reoperation is feasible with acceptable clinical outcomes including a low mortality rate similar to standard robotic surgery in our hands. Robotic assistance may have the potential to minimize morbidity and mortality.

CC1 Emergent Endovascular Repair of a Ruptured Descending Thoracic Aortic Aneurysm in an Arresting Patient.

OBJECTIVE: Our goal was to present a case of emergent endovascular repair of a ruptured descending aortic aneurysm in an actively arresting patient. PATIENT: The patient was a 75-year-old woman with a known history of a 6.5-cm descending thoracic aortic aneurysm with acute onset of back pain and syncope. A computed tomographic angiogram revealed disruption of the descending thoracic aorta and a mediastinal hematoma. The patient was taken emergently to the operating room. During induction, the patient developed pulseless electrical activity arrest, and cardiopulmonary resuscitation was promptly initiated. The bilateral groins were prepped and draped, and an emergent cutdown was made to gain access to the femoral artery. Wire access of the aortic arch was obtained via a 6F micropuncture sheath, over which a 45- × 45- × 20-mm covered endograft was introduced. Using fluoroscopic guidance alone without angiography, the endograft was rapidly deployed proximally to the level of the distal aortic arch using calcification as a landmark (Fig. CC1-1). Immediately after deployment, the patient regained a pulse, and cardiopulmonary resuscitation was discontinued for a total of 30 minutes of continuous compressions. A right thoracotomy was then performed for evacuation of the hemothorax and ligation of the torn intercostal arteries. The patient was cooled to 35 degrees Celsius for 24 hours post-arrest and a lumbar drain was placed postoperatively. The patient thereafter regained all neurological and end-organ function and at the 6-month follow-up has had no progression of her aneurysm (Fig. CC1-1). CONCLUSIONS: Rapid introduction and deployment of a descending thoracic aortic endograft for a ruptured descending aortic aneurysm is safe and effective in an arresting patient.

Thoracoscopic Sympathectomy for Refractory Electrical Storm After Coronary Artery Bypass Grafting.

We report a patient with refractory electrical storm after coronary artery bypass grafting who was successfully treated with thoracoscopic sympathectomy. Cardiac arrest with ventricular tachycardia occurred on postoperative day 2, and the patient required emergency support with venoarterial extracorporeal membrane oxygenation. Frequent episodes of ventricular tachycardia prevented cardiac recovery and weaning from mechanical circulatory support. A percutaneous left stellate ganglion block initially demonstrated successful prevention of ventricular tachycardia, and definitive sympathetic denervation was achieved by a left thoracoscopic sympathectomy. The patient remained in normal sinus rhythm and gained recovery of baseline ventricular function, permitting successful decannulation and weaning of inotropic support.

Transmitral Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy.

BACKGROUND: Intrinsic abnormalities of the mitral valve are common in patients with hypertrophic cardiomyopathy and may need to be addressed at operation. METHODS: Consecutive patients undergoing transmitral septal myectomy were retrospectively reviewed. The ventricular septum was exposed through a left atriotomy, and the anterior leaflet of the mitral valve was detached from its annulus. An extended myectomy was performed to the base of the papillary muscles. After myectomy, the anterior leaflet was reattached and concomitant mitral valve repair or replacement was performed. In some cases, we performed a modified anterolateral commissural closure suture, which served to reposition the lateral aspect of the anterior leaflet out of the left ventricular outflow tract ("curtain stitch"). RESULTS: Twenty patients who underwent this procedure were identified (70% women; mean age 63 years). Mitral regurgitation was moderate in 55% and severe in 40%. Preoperative peak left ventricular outflow tract gradient was 92 ± 43 mm Hg. Mitral valve repair (n = 11) or replacement (n = 9) was performed. Predischarge transthoracic echocardiography demonstrated a left ventricular outflow tract gradient of 10 ± 5 mm Hg. There was no operative mortality. Follow-up was 100% complete and averaged 22 ± 25 months. No patient required reoperation, and there was no recurrence of left ventricular outflow tract obstruction or mitral regurgitation greater than mild. CONCLUSIONS: Potential advantages of transmitral myectomy include a panoramic view of the septum and mitral subvalvular apparatus and the ability to simultaneously address mitral valve pathology. Consideration should be given to using the transmitral approach to septal myectomy as the preferred approach for the surgical treatment of hypertrophic cardiomyopathy.

Programmatic and Surgeon Specialization Improves Mortality in Isolated Coronary Bypass Grafting.

BACKGROUND: Throughout surgery, specialization in a procedure has been shown to improve outcomes. Currently, there is no evidence for or against subspecialization in coronary surgery. Tasked with the goal of improving outcomes after isolated coronary artery bypass grafting (CABG), our institution sought to determine whether the development of a subspecialized coronary surgery program would improve morbidity and mortality. METHODS: All isolated CABG operations at a single institution were retrospectively examined in two distinct periods, 2002 to 2013 and 2013 to 2016, before and after the implementation of a subspecialized coronary surgery program. Improved policies included leadership and subspecialization of a program director, standardization of surgical technique and postoperative care, and monthly multidisciplinary quality review. Outcomes were collected and compared. RESULTS: Between 2002 and 2013, 3,256 CABG operations were done by 16 surgeons, the most frequent surgeon doing 33%. Between 2013 and 2016, 1,283 operations were done by 10 surgeons, 70% by the coronary program director. CABGs done in the specialized era had shorter bypass and clamps times and increased use of bilateral internal mammary arteries. Blood transfusion and complication rates, including permanent stroke and prolonged ventilation, were significantly decreased after implementation of the coronary program. Likewise, overall operative mortality (2.67% vs 1.48%, p = 0.02) was significantly reduced. CONCLUSIONS: Subspecialization in CABG and dedicated coronary surgery programs may lead to faster operations, increased use of bilateral internal mammary arteries, fewer complications, and improved survival after isolated CABG.

Early Operation in Patients With Mitral Valve Infective Endocarditis and Acute Stroke Is Safe.

BACKGROUND: To determine if preoperative embolic stroke is associated with an increased risk of postoperative stroke among patients undergoing early operation for mitral valve (MV) infective endocarditis (IE), we compared outcomes among patients presenting with and without acute stroke. METHODS: From 2003 to 2015, 243 consecutive patients underwent surgery for active MV IE. Patients were categorized into 2 groups: 72% (174 of 243 patients) with no preoperative acute stroke (clinical, radiographic or both) and 28% (69 of 243 patients) with stroke. Both preoperative and postoperative strokes were confirmed in all patients with brain computed tomography or magnetic resonance imaging and comprehensive examination by a neurologist. RESULTS: Among patients presenting with stroke, 33% (23 of 69 patients) were asymptomatic and had only positive imaging findings. The median time from admission to operation was 5 days. The overall rate of new postoperative stroke was 4% (10 of 243 patients). The rate of postoperative stroke was not different between the 2 groups: 4% (7 of 174 patients) among patients with no preoperative stroke and 4% (3 of 69 patients) with stroke (p = 0.9). One patient developed a hemorrhagic conversion of an acute infarct. Operative mortality was 7% (13 of 174 patients) among patients with no preoperative stroke and 7% (5 of 69 patients) among patients with stroke (p = 0.9). CONCLUSIONS: MV surgery for IE and acute stroke can be performed early with a low risk of postoperative neurologic complications. When indicated, surgical intervention for MV IE complicated by acute stroke should not be delayed.

Interstage Weight Gain Is Associated With Survival After First-Stage Single-Ventricle Palliation.

BACKGROUND: Low birth and operative weight have been identified as risk factors for death after first-stage single-ventricle palliation. We hypothesize that weight gain after the first-stage operation is associated with transplant-free interstage survival to admission for the second-stage operation. METHODS: We used historical data from the National Pediatric Cardiology Quality Improvement Collaborative database to conduct a longitudinal study to assess the association between weight gain and transplant-free interstage survival. The primary predictor was weight gain. The primary outcome was transplant-free survival. We constructed a repeated-measures logistic regression model using the general estimating equation method to examine the association between weight gain and transplant-free interstage survival. RESULTS: The study population included 1,501 infants who were discharged alive from the first-stage single-ventricle palliation between June 2008 and January 2015. Patients who underwent a hybrid operation (n = 132) or were lost to follow-up (n = 11) were excluded. Transplant-free interstage survival was 90% (1,228 of 1,358). The mean weight gain was 2.5 (SD, 1.0) kg. Adjusted for age at the time of each measurement, the number of measurements, age at discharge from the first-stage operation, sex, diagnosis, postoperative arrhythmia, postoperative complications, and discharge antibiotic therapy, each 100-g increase in weight was associated with an odds ratio of transplant-free interstage survival of 1.03 (95% confidence limit, 1.01, 1.05). CONCLUSIONS: After first-stage single-ventricle palliation, interstage weight gain is significantly associated with transplant-free interstage survival.

Cardiac Progenitor Cells Enhance Neonatal Right Ventricular Function After Pulmonary Artery Banding.

BACKGROUND: C-kit+ cardiac progenitor cells (CPCs) have been shown to be safe and effective in large-animal models and in an early-phase clinical trial for adult patients with ischemic heart disease. However, CPCs have not yet been evaluated in a preclinical model of right ventricular (RV) dysfunction, which is a salient feature of many forms of congenital heart disease. METHODS: Human c-kit+ CPCs were generated from right atrial appendage biopsy specimens obtained during routine congenital cardiac operations. Immunosuppressed Yorkshire swine (6 to 9 kg) underwent pulmonary artery banding to induce RV dysfunction. Thirty minutes after banding, pigs received intramyocardial injection into the RV free wall with c-kit+ CPCs (1 million cells, n = 5) or control (phosphate-buffered saline, n = 5). Pigs were euthanized at 30 days postbanding. RESULTS: Banding was calibrated to a consistent rise in the RV-to-systemic pressure ratio across both groups (postbanding: CPCs = 0.76 ± 0.06, control = 0.75 ± 0.03). At 30 days postbanding, the CPCs group demonstrated less RV dilatation and a significantly greater RV fractional area of change than the control group (p = 0.002). In addition, measures of RV myocardial strain, including global longitudinal strain and strain rate, were significantly greater in the CPCs group at 4 weeks relative to control (p = 0.004 and p = 0.01, respectively). The RV free wall in the CPCs group demonstrated increased arteriole formation (p < 0.0001) and less myocardial fibrosis compared with the control group (p = 0.02). CONCLUSIONS: Intramyocardial injection of c-kit+ CPCs results in enhanced RV performance relative to control at 30 days postbanding in neonatal pigs. This model is important for further evaluation of c-kit+ CPCs, including long-term efficacy.

Veno-Venous Extracorporeal Membrane Oxygenation Use in the Treatment of Bleomycin Pulmonary Toxicity.

Pulmonary toxicity is a devastating complication of bleomycin chemotherapy. This insult is likely exacerbated by the free radical injury induced by high inspired oxygen content, which is required to support these patients. Traditional treatment consists of high-dose corticosteroids. We report the case of a 45-year-old man who developed bleomycin pulmonary toxicity, which failed to respond to treatment with high-dose corticosteroids. We used protective mechanical ventilatory settings while supported on veno-venous extracorporeal membrane oxygenation using a bicaval dual-lumen, single cannula system to allow for lung recovery. This case demonstrates the feasibility of using veno-venous extracorporeal membrane oxygenation to treat bleomycin pulmonary toxicity in a patient who has failed traditional therapy.

Intracoronary Stem Cell Delivery to the Right Ventricle: A Preclinical Study.

Clinical protocols for stem cell-based therapies are currently under development for patients with hypoplastic left heart syndrome. An ideal cell delivery method should have minimal safety risks and provide a wide distribution of cells to the nonischemic right ventricle (RV). However, the optimal strategy for stem cell delivery to the RV has yet to be explored in a preclinical model, necessary for a hypoplastic left heart syndrome trial. Human c-kit+ cardiac stem cells (CSCs) were delivered to healthy Yorkshire swine through the proximal right coronary artery with a stop and reflow technique. The effect of premedication with antiarrhythmic (AA) medications in this model was retrospectively reviewed, with the primary outcome of survival 2 hours after infusion. A group underwent CSC delivery to the RV without prophylactic AA medication (no AA, n = 7), whereas the second group was premedicated with a loading dose and intravenous infusion of amiodarone and lidocaine (AA, n = 13). Cardiac biopsies were obtained from each chamber to ascertain the biodistribution of CSCs. Survival was significantly greater in the prophylactic AA group compared with the group without AA (13/13 [100%] vs 1/7 [14.3%], P < 0.0001). Cardiac arrest during balloon inflation was the cause of death in each of the nonmedicated animals. In the premedicated group, 9 (69.2%) pigs experienced transient ST segment changes in the precordial leads during CSC delivery, which resolved spontaneously. Most c-kit+ CSCs were distributed to lateral segments of the RV free wall, consistent with the anatomical course of the right coronary artery (lateral RV, 19.2 ± 1.5 CSCs/field of view vs medial RV, 10.4 ± 1.3 CSCs/field of view, P < 0.0001). Few c-kit+ CSCs were identified in the right atrium, septum, or left ventricle. Prophylactic infusion of AA enhances survival in swine undergoing intracoronary delivery of human c-kit+ CSCs to the RV. Additionally, intracoronary delivery results in a limited biodistribution of c-kit+ CSCs within the RV. Human clinical protocols can be optimized by requiring infusion of AA medications before cell delivery.