Characterization and functionality of cardiac progenitor cells in congenital heart patients.

BACKGROUND: Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration. METHODS AND RESULTS: Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, <30 days), infants (age, 1 month to 2 years), and children (age, >2 to ≤13 years). C-kit(+) hCPCs were 3-fold higher in neonates than in children >2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit(+) Ki67(+) expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit(+), NKX2-5(+), NOTCH1(+), and NUMB(+) expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium-derived CPCs from all patients (n=103) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit(+), Islet-1, and supporting cells. The number of c-kit(+)-expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts. CONCLUSIONS: Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair.

Bistable switches control memory and plasticity in cellular differentiation.

Development of stem and progenitor cells into specialized tissues in multicellular organisms involves a series of cell fate decisions. Cellular differentiation in higher organisms is generally considered irreversible, and the idea of developmental plasticity in postnatal tissues is controversial. Here, we show that inhibition of mitogen-activated protein kinase (MAPK) in a human bone marrow stromal cell-derived myogenic subclone suppresses their myogenic ability and converts them into satellite cell-like precursors that respond to osteogenic stimulation. Clonal analysis of the induced osteogenic response reveals ultrasensitivity and an "all-or-none" behavior, hallmarks of a bistable switch mechanism with stochastic noise. The response demonstrates cellular memory, which is contingent on the accumulation of an intracellular factor and can be erased by factor dilution through cell divisions or inhibition of protein synthesis. The effect of MAPK inhibition also exhibits memory and appears to be controlled by another bistable switch further upstream that determines cell fate. Once the memory associated with osteogenic differentiation is erased, the cells regain their myogenic ability. These results support a model of cell fate decision in which a network of bistable switches controls inducible production of lineage-specific differentiation factors. A competitive balance between these factors determines cell fate. Our work underscores the dynamic nature of cellular differentiation and explains mechanistically the dual properties of stability and plasticity associated with the process.

A Case of Heyde's Syndrome With Subvalvular Aortic Stenosis.

Heyde's syndrome is a constellation of severe aortic stenosis, gastrointestinal arteriovenous malformations (AVMs), and an acquired von Willebrand type 2A coagulopathy resulting in moderate-to-severe gastrointestinal bleeding. Additional cardiac lesions have been observed to cause Heyde's syndrome including aortic regurgitation, mitral regurgitation, aortic/mitral valve prosthetic dysfunction, ventricular septal defects, hypertrophic cardiomyopathy, left ventricular assist devices, and extracorporeal life support devices. Repairing the cardiac lesion or removing the device decreases the incidence of gastrointestinal bleeding by normalizing the acquired von Willebrand coagulopathy and decreasing the amount of gastrointestinal AVMs likely to bleed. We describe a case of a 67-year-old woman found to have Heyde's syndrome arising from a subvalvular aortic membrane resulting in severe subaortic stenosis with no other significant cardiac lesion. She underwent successful resection of the membrane with septal myectomy, relieving the severe subaortic stenosis and resolving her anemia. Years later, she re-presented with severe gastrointestinal bleeding from gastrointestinal malformations. Early recognition of these cardiac lesions with gastrointestinal bleeds may help decrease the morbidity and mortality that Heyde's syndrome portends and provide evidence for early intervention.

Comparing downstream consequences of normal exercise stress echocardiograms and cardiac computed tomography angiography scans in patients suspected of having of obstructive coronary artery disease: a retrospective cohort study of Tricare beneficiaries.

To compare overall number of downstream tests and total costs between negative exercise stress echocardiograms (ESE) or cardiac computed tomography angiography scans (CCTA) in symptomatic Tricare beneficiaries suspected of having coronary artery disease (CAD). This is a retrospective cohort study examining 651 propensity-matched patients who underwent ESE or CCTA with normal results between 2008 and 2014 at the United States' largest Department of Defense hospital. The total number of additional downstream tests over the next five years was determined. The total costs associated with each arm, inclusive of the initial test and all subsequent tests, were calculated using the 2018 Medicare Physician Fee Schedule. 18.5 percent of patients with a normal ESE result underwent some additional form of cardiac testing over the five years after initial testing compared to 12.8 percent of patients with a normal CCTA. The absolute difference in total number of downstream tests between both study groups was 5.7 percent (p = 0.03). When factoring the costs of the initial test as well as the downstream tests, the ESE group was associated with overall lower costs compared to the CCTA group, 351 United States Dollars (USD) versus 496 USD (p < 0.0001). This study demonstrates that, when compared to CCTA, ESE is associated with a higher total number of downstream tests, but overall lower total costs when chosen as initial testing strategy for suspected CAD.

Secondary Spontaneous Pneumothorax Mimicking Lung Herniation.

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for numerous pulmonary complications, including secondary spontaneous pneumothorax (SSP) and lung herniation. We describe the case of a 66-year-old female patient with severe COPD and previous lingula-sparing left upper lobectomy from adenocarcinoma who presented to the emergency department with a painful anterior chest wall mass that varied in size with respiration. This finding, in a patient with a prior history of an invasive thoracic procedure, is suggestive of lung herniation. Further investigation revealed an SSP mimicking the classic physical exam finding of a lung herniation. The patient was deemed a poor surgical candidate; therefore, talc pleurodesis was administered with resolution of the pneumothorax.

Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death.

Protein homeostatic regulators have been shown to ameliorate single, loss-of-function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes. We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol. Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator.

A novel combination of bioresorbable polymeric film and expanded polytetrafluoroethylene provides a protective barrier and reduces adhesions.

OBJECTIVE: A bioresorbable polymeric film reduces the extent and severity of postoperative adhesions in infants undergoing repeat sternotomy. Resorption of the bioresorbable polymeric film, however, leaves no barrier between the sternum and the epicardium. A sheet of expanded polytetrafluoroethylene is used by many surgeons to create a physical barrier between the sternum and the cardiac structures. We hypothesized that placing bioresorbable polymeric film beneath an expanded polytetrafluoroethylene pericardial membrane would both decrease pericardial adhesions and provide a physical barrier. METHODS: A novel combination of bioresorbable polymeric film underneath an expanded polytetrafluoroethylene membrane was tested in an established rabbit model of pericardial adhesion formation. After sternotomy, a portion of pericardium was resected and the epicardium was abraded. Rabbits (n = 36) were randomly assigned to 4 treatment groups: control group, no bioresorbable polymeric film or expanded polytetrafluoroethylene; bioresorbable polymeric film group; expanded polytetrafluoroethylene group; and bioresorbable polymeric film + expanded polytetrafluoroethylene group. At 4 weeks post-sternotomy, pericardial adhesions were scored grossly for area and density of adhesions using an established 4-point (0-3) grading system. RESULTS: The bioresorbable polymeric film group had a significant reduction in mean adhesion score compared with the control group (control = 2.86 ± 0.37 vs bioresorbable polymeric film = 0.57 ± 0.53, P < .0001) and expanded polytetrafluoroethylene group (expanded polytetrafluoroethylene = 2.75 ± 0.46 vs bioresorbable polymeric film = 0.57 ± 0.53, P < .0001). The bioresorbable polymeric film + expanded polytetrafluoroethylene group had a low adhesion profile similar to the bioresorbable polymeric film group (bioresorbable polymeric film + expanded polytetrafluoroethylene = 1.0 ± 0, vs bioresorbable polymeric film = 0.57 ± 0.53), but a considerably lower mean adhesion score than the expanded polytetrafluoroethylene group (expanded polytetrafluoroethylene = 2.75 ± 0.46, vs bioresorbable polymeric film + expanded polytetrafluoroethylene = 1.0 ± 0, P < .0001). CONCLUSIONS: Placement of bioresorbable polymeric film resulted in minimal pericardial adhesions compared with controls. The placement of bioresorbable polymeric film underneath expanded polytetrafluoroethylene at the time of sternal closure provides a novel combination to reduce the extent and severity of pericardial adhesions while providing a physical barrier between the sternum and the cardiac structures.

Intramural coronary length correlates with symptoms in patients with anomalous aortic origin of the coronary artery.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) from the opposite sinus of Valsalva is a rare congenital anomaly with the potential for myocardial ischemia and sudden death. This review evaluated our series of AAOCA patients, who underwent coronary artery unroofing, to test our hypothesis that the intramural length of the anomalous coronary artery correlates with symptoms. METHODS: A retrospective analysis of symptoms, preoperative imaging (computed tomography and magnetic resonance imaging), intraoperative assessment, perioperative course, and follow-up were reviewed. RESULTS: From 2005 to 2010, 27 patients (70% male) underwent surgical AAOCA repair. Mean age was 14.3±12 (range, 6 to 52) years. In 25 patients with right AAOCA, 14 had chest pain and 4 had syncope. Both patients with left AAOCA had chest pain. AAOCA unroofing was done in 25 and side-to-side anastomosis in 2. The intramural coronary artery length measured intraoperatively correlated with preoperative symptoms (symptoms=10±3.58 mm, no symptoms=5.2±1.5 mm, p<.002), as did preoperative imaging measurements (symptoms=7.8±2.8 mm, no symptoms=5.3±0.8 mm, p<.001). Preoperative imaging strongly predicted the intraoperative measurement (r=0.81, p=0.00001). There were no deaths, significant morbidity, or recurrence of symptoms. CONCLUSIONS: Coronary unroofing for AAOCA is a safe method of enlarging the coronary orifice and eliminating the intramural course. Symptomatic patients had a longer intramural course than asymptomatic patients, as assessed by preoperative imaging and intraoperative measurements. These results may have important clinical implications in determining indications for operation.

Coarctation of the aorta: midterm outcomes of resection with extended end-to-end anastomosis.

BACKGROUND: We began using the technique of resection with extended end-to-end anastomosis for infants and children with coarctation of the aorta in 1991. The purpose of this review is to evaluate the midterm outcomes of this technique, specifically determining the incidence of and risk factors for transcatheter or surgical reintervention. METHODS: A retrospective analysis of the cardiac surgery database was performed to identify all patients who had a diagnosis of coarctation of the aorta with or without ventricular septal defect and had resection with extended end-to-end anastomosis from 1991 to 2007. Perioperative course and follow-up with physical examination, echocardiogram, and cardiology evaluation were obtained. RESULTS: From 1991 through 2007, 201 patients had repair of coarctation of the aorta with resection with extended end-to-end anastomosis. The median age was 23 days, and the median weight was 4.0 kg. Surgical approach was by left thoracotomy in 157 patients (78%) with a mean cross-clamp time of 18 +/- 4 minutes. Median sternotomy approach was used in 44 patients (22%) to repair a hypoplastic transverse aortic arch (n = 16) or because of associated ventricular septal defect (n = 28) with a mean circulatory arrest time of 14 +/- 9 minutes. Early mortality occurred in 4 patients (2.0%). Three patients (1.5%) required early arch revision: 2 intraoperatively and 1 on postoperative day 1. Follow-up data were available for 182 patients (91%) with a mean follow-up of 5.0 +/- 4.3 years (908 patient-years). Reinterventions (n = 8; 4.0%) included three balloon angioplasties and five reoperations; 75% of the reinterventions occurred in the first postoperative year. Hypoplastic transverse aortic arch was not a risk factor for reintervention (p = 0.36), but was a risk factor for mortality (p = 0.039). Aberrant right subclavian artery was the only risk factor for recoarctation (p = 0.007). CONCLUSIONS: Repair of coarctation of the aorta with resection with extended end-to-end anastomosis has a low early mortality, effectively addresses transverse arch hypoplasia, and at midterm follow-up has a low rate of reintervention for recurrent coarctation.