Comparison of Sonazoid-Contrast­Enhanced Ultrasound and Gd­EOB­DTPA­Enhanced MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVE: This study aims to evaluate and compare the predictive accuracy of Sonazoid-contrast-enhanced ultrasound (CEUS) and Gd-EOB-DTPA-enhanced MRI for detecting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: In this single-center prospective study, we included 64 patients with histopathologically confirmed single HCC lesions. Based on post-operative pathologic data, patients were categorized into two groups: those with MVI (n = 21) and those without MVI (n = 43). The diagnostic efficacy of CEUS was compared with that of MRI in predicting MVI. RESULTS: Multifactorial analysis revealed that US features (tumor size > 4.35 cm, peritumoral enhancement, post-vascular ring enhancement, peak energy in the arterial phase of the difference between the margin area of HCC and distal liver parenchyma <-1.0 × 106 a.u), MRI features (rim enhancement, irregular tumor margin, and the halo sign) were all independent predictors of MVI (p < 0.05). The sensitivity and specificity of CEUS features in predicting MVI ranged from 61.9% to 86.4% and from 42.9% to 71.4%, respectively. For MRI features, the sensitivity and specificity ranged from 33.3% to 76.3% and from 54.7% to 90.5%, respectively. No statistically significant differences were observed in the area under the curve between CEUS and MRI (p > 0.05). Notably, peak energy of the difference showed the highest sensitivity at 86.4%, while the halo sign in MRI exhibited the highest specificity at 90.5%. CONCLUSION: Sonazoid-CEUS and Gd-EOB-DTPA-enhanced MRI demonstrate potential in predicting MVI in HCC lesions. Notably, CEUS showed higher sensitivity, whereas MRI displayed greater specificity in predicting MVI.

CEUS in prediction of early recurrence of hepatocellular carcinoma after curative resection and to stratify the risk of early recurrence: a retrospective observational study.

PURPOSE: Early recurrence (ER) after surgery is related to early death in patients with hepatocellular carcinoma (HCC) after radical resection. To explore the role of preoperative contrast-enhanced ultrasound (CEUS) in predicting ER of HCC after curative resection and to stratify the risk of ER. MATERIALS AND METHODS: This study evaluated consecutive 556 patients with HCC who were examined by CEUS during the 2 weeks before curative resection between January 2011 and December 2018. ER was defined as intrahepatic and/or extrahepatic recurrence within 2 year after resection of HCC. Univariate and logistic regression analyses were performed to identify independent risk factors for ER after surgical resection of HCC. Recurrence-free time (RFS) rates were analyzed and compared by log-rank test. RESULTS: ER occurred in 307 (55.2%) of the 556 patients. Univariate and multivariate analyses revealed that a tumor size ≥ 30 mm and satellite nodules seen on CEUS, DL(deep learning) radiomics reoccurrence score based on the frame of image with the maximum intensity of CEUS and an elevated alpha-fetoprotein level were significantly associated with ER (P < .05). Based on the number of predictors present, patients with CEUS LR-5 HCC were stratified into three risk subgroups: risk group 3 (high-risk patients, 4 predictors), risk group 2 (medium-risk patients, 2-3 predictors), and risk group 1 (low-risk patients, 0-1 predictor). The 2-year RFS rate was 19.4% in risk group 3, 40.9% in risk group 2, and 48.1% in risk group 1; the corresponding mean RFS times were 14.0 ± 2.9 months, 43.7 ± 6.6 months, and 55.5 ± 2.8 months, respectively (P < .001). CONCLUSIONS: Tumor size ≥ 30 mm and satellite nodules seen on CEUS, DL radiomics reoccurrence score based on the frame of image with the maximum intensity of CEUS and an elevated alpha-fetoprotein level can predict ER of HCC.

Dynamic contrast-enhanced ultrasonography with sonazoid predicts microvascular invasion in early-stage hepatocellular carcinoma.

OBJECTIVE: Microvascular invasion (MVI) is an independent risk factor for the early recurrence and poor survival of hepatocellular carcinoma (HCC). This study aims to investigate the potential clinical value of dynamic contrast-enhanced ultrasound (DCE-ultrasound)-Sonazoid in pre-operatively assessing MVI in HCC. METHODS AND MATERIALS: This single centre prospective study included 140 patients with histopathologically confirmed single HCC lesions. Patients were classified according to the post-operative pathological information presence of MVI: MVI+ group (n = 32) and MVI- group (n = 108). All patients underwent DCE-ultrasound within 1 week before surgery. The quantitative perfusion parameters of HCC lesions, margins of HCC lesions, and distal liver parenchyma were obtained and analyzed. RESULTS: Clinicopathological (serum alpha-fetoprotein, Des-gamma-carboxyprothrombin, and pathological grade) and grayscale imaging features (tumor size) were significantly different between the MVI+ and MVI- groups (p < 0.05). Further quantitative analysis showed that when comparing the MVI+ and MVI- groups, half-decrease time and wash-out rate of HCC lesions and peak enhancement in the arterial phase of difference between the margin area of HCC and distal liver parenchyma were significantly different (p = 0.045, p = 0.035, and p = 0.023, respectively). Combining the above three quantitative parameters, the accuracy, sensitivity, specificity, positive-predictive value, and negative-predictive value were 69.3% (97/140), 37.8% (17/45), 84.3% (80/95), 53.1% (17/32), 74.1% (80/108), respectively. CONCLUSION: DCE-ultrasound with quantitative perfusion analysis has the potential to predict MVI in HCC lesions. ADVANCES IN KNOWLEDGE: DCE-ultrasound with quantitative perfusion analysis has the potential to predict MVI in HCC lesions.

Deep learning-based radiomics based on contrast-enhanced ultrasound predicts early recurrence and survival outcome in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. AIM: To predict early recurrence (ER) and overall survival (OS) in patients with HCC after radical resection using deep learning-based radiomics (DLR). METHODS: A total of 414 consecutive patients with HCC who underwent surgical resection with available preoperative grayscale and contrast-enhanced ultrasound images were enrolled. The clinical, DLR, and clinical + DLR models were then designed to predict ER and OS. RESULTS: The DLR model for predicting ER showed satisfactory clinical benefits [area under the curve (AUC)] = 0.819 and 0.568 in the training and testing cohorts, respectively), similar to the clinical model (AUC = 0.580 and 0.520 in the training and testing cohorts, respectively; P > 0.05). The C-index of the clinical + DLR model in the prediction of OS in the training and testing cohorts was 0.800 and 0.759, respectively. The clinical + DLR model and the DLR model outperformed the clinical model in the training and testing cohorts (P < 0.001 for all). We divided patients into four categories by dichotomizing predicted ER and OS. For patients in class 1 (high ER rate and low risk of OS), retreatment (microwave ablation) after recurrence was associated with improved survival (hazard ratio = 7.895, P = 0.005). CONCLUSION: Compared to the clinical model, the clinical + DLR model significantly improves the accuracy of predicting OS in HCC patients after radical resection.

Intraoperative ultrasonography of robot-assisted laparoscopic hepatectomy: initial experiences from 110 consecutive cases.

BACKGROUND: To evaluate the safety and efficacy of IOUS in robotic liver surgery and propose a standard protocol of IOUS for safe robot-assisted hepatectomy. METHODS: Between February 2015 and December 2016, liver resection was performed in 110 patients with robotic approach in Tongji Hospital. In these patients, IOUS was routinely performed. All data about demographic, surgical procedure, postoperative course were collected prospectively and analyzed. RESULTS: A four steps IOUS protocol in robotic liver surgery was proposed, including exploration, verification, guidance, and confirmation. A total of 11 additional lesions in 11 patients were detected and 7 patients accepted strategic surgical modification. No patient suffered from any single or multiple organ dysfunctions, and there were no mortalities observed. CONCLUSION: IOUS is indispensable to understand lesions and vessels in robotic liver surgery. A four-step standard protocol of IOUS is essential for safe robot-assisted hepatectomy.

Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30mmHg at rest or with provocation. There are no data on whether 30mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes. METHODS: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median follow-up period of 2.1years. RESULTS: Among 536 patients, 131 patients had resting LVOT gradients greater than 30mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients >90mmHg (HR 3.92, 95% CI 1.97-7.79) or <30mmHg (HR 2.15, 95% CI 1.08-4.29) have more events compared to those with gradients between 30 and 89mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with "benign" latent HCM (provoked gradient 30-89mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome. CONCLUSIONS: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups.

Comparison of Clinical Features in Blacks Versus Whites With Hypertrophic Cardiomyopathy.

To date, there has not been a large systematic examination of the hypertrophic cardiomyopathy (HC) phenotype in blacks versus whites. In this study, we investigate differences in presentation of HC between blacks and whites. We included 441 consecutive patients with HC seen at the Johns Hopkins HC clinic in the period from February 2005 to June 2012. We compared 76 blacks for clinical presentation, electrocardiogram, exercise capacity, left ventricular morphology, and hemodynamics by echocardiography to 365 whites. Black patients with HC more often presented with abnormal electrocardiogram (93% vs 80%, p = 0.009), driven by a significant difference in repolarization abnormalities (79% vs 56%, p <0.001). Apical hypertrophy was more common in blacks (26% vs 9%, p <0.001); however, blacks had less severe systolic anterior movement of the mitral valve and had significantly lower left ventricular outflow tract gradients at rest (9 mm Hg; interquartile range [IQR] 7 to 19 vs 16 mm Hg; IQR 8 to 40, p <0.001) and during provocation (36 mm Hg; IQR 16 to 77 vs 59 mm Hg; IQR 26 to 110, p = 0.002). Despite the nonobstructive pathophysiology, blacks had lower exercise capacity (adjusted difference 1.45 metabolic equivalents [0.45 to 2.45], p = 0.005). In conclusion, blacks have an HC phenotype characterized by lower prevalence of the well-recognized echocardiographic features of HC such as systolic anterior movement of the mitral valve and left ventricular outflow tract obstruction and display worse exercise capacity.

Late gadolinium enhancement confined to the right ventricular insertion points in hypertrophic cardiomyopathy: an intermediate stage phenotype?

AIMS: To investigate whether hypertrophic cardiomyopathy (HCM) patients with late gadolinium enhancement (LGE) confined to the right ventricular insertion points (RVIP) differ phenotypically from patients without LGE or intramural LGE in the left ventricle (LV). METHODS AND RESULTS: Sixty-two HCM patients underwent cardiac magnetic resonance for quantification of LGE (% LV mass) and were classified as group (i) no-LGE (n = 18), group (ii) LGE-RVIP (n = 19), and group (iii) intramural LGE (n = 25). All patients also underwent vasodilator N-13 ammonia PET to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR), and echocardiography to measure longitudinal LV strain. LGE extent (17 ± 11% vs. 4 ± 4% vs. 0%; P < 0.001) and LV thickness (21.7 ± 3.4 vs. 18.8 ± 3.9 vs. 16.3 ± 2.8 mm; P < 0.001) were significantly greater in group 3, intermediate in group 2, and lower in group 1. In contrast, stress MBF (1.62 ± 0.44 vs. 1.90 ± 0.37 vs. 2.22 ± 0.48 mL/min/g; P < 0.001); MFR (1.92 ± 0.47 vs. 2.15 ± 0.52 vs. 2.71 ± 0.52; P < 0.001), and longitudinal LV strain (-11.4 ± 3.8 vs. -12.6 ± 3.2 vs. -14.4 ± 4.1%; P = 0.04) were lower in group 3, intermediate in group 2, and higher in group 1. CONCLUSIONS: From an imaging viewpoint, patients with LGE confined to only the RVIP appear to represent an intermediate-stage phenotype between patients with no LGE and intramural LGE in the LV.

Apparent left ventricular cavity dilatation during PET/CT in hypertrophic cardiomyopathy: Clinical predictors and potential mechanisms.

BACKGROUND: Apparent left ventricular cavity dilatation (LVCD) in patients with hypertrophic cardiomyopathy (HCM) is an incompletely understood phenomenon. We aimed at investigating its clinical predictors and potential mechanisms. METHODS: Sixty one HCM patients underwent N-13-ammonia PET for visual evaluation of LVCD, transient ischemic dilatation (TID) index, myocardial blood flow (MBF), coronary flow reserve (CFR), and regional myocardial perfusion (rMP). TID index was also derived at 2-4 and 15-20 minutes. RESULTS: Visual LVCD and quantitative TID (>1.13 abnormal) agreement were excellent (k 0.91; P < .0001). LVCD-positive (n = 32) patients had greater LV thickness (2.26 ± 0.59 vs 1.92 ± 0.41 cm; P = .005), but lower stress MBF (1.66 ± 0.42 vs 2.07 ± 0.46 mL/minute/g; P < .0001), and CFR (1.90 ± 0.46 vs 2.46 ± 0.69; P < .0001) than LVCD-negative (n = 29) patients. Abnormal rMP was present in 31/32 LVCD-positive but only 12/29 (P < .0001) LVCD-negative. TID index was higher at 2-4 (1.30 ± 0.13) than at 15-20 minutes (1.27 ± 0.12; P = .001) in LVCD-positive, whereas it was the same (1.04 ± 0.07 vs 1.04 ± 0.07; P = .9) in LVCD-negative. In multivariate analysis, global peak MBF, abnormal rMP, and LV thickness were the best predictors of LVCD. CONCLUSION: Apparent LVCD is a common finding in HCM, intimately related to abnormal myocardial perfusion, globally impaired vasodilator flow reserve, and degree of hypertrophy. In addition to regional and/or diffuse subendocardial ischemia, some degree of true LV chamber dilatation may also contribute to the occurrence of apparent LVCD in HCM.

Ultrasound-guided percutaneous microwave ablation treatment of initial recurrent hepatocellular carcinoma after hepatic resection: long-term outcomes.

This study aimed to evaluate the long-term outcomes after percutaneous microwave ablation (MWA) for patients with initial recurrent hepatocellular carcinoma (HCC) measuring ≤5 cm in diameter after hepatectomy. From May 2005 to December 2011, 89 patients with 116 initial recurrent HCCs after hepatectomy treated with percutaneous MWA were included in the study. One mo after MWA, the complete ablation rate was 91.0% (81/89). At 1, 3, 5 and 7 y, the respective overall and recurrence-free survival rates after percutaneous MWA were 73.3%, 53.7%, 39.6% and 17.3% and 58.5%, 26.4%, 22.0% and 11.0%. The cumulative incidence of local tumor progression (LTP) and the intra-hepatic distant recurrence (IDR)-free survival rates after MWA were 9.1%, 14.6%, 18.3% and 18.3% and 62.9%, 32.3%, 26.9% and 13.5% at 1, 3, 5 and 7 y, respectively. The multivariate analysis indicated that multiple tumors (p = 0.006), a poor Child-Pugh score (p = 0.003), serum α-fetoprotein (AFP) >100 ng/mL (p = 0.002), and MWA treatment failure (p = 0.000) were risk factors that significantly affected overall survival, and MWA treatment failure (p = 0.000) was a risk factor that significantly affected IDR-free survival. In conclusion, percutaneous MWA is an effective therapeutic technique for initial recurrent HCC measuring ≤5 cm in diameter after hepatectomy.

Exercise heart rates in patients with hypertrophic cardiomyopathy.

The exercise heart rate (HR) profile and its relation to cardiac function and arrhythmias were investigated in patients with hypertrophic cardiomyopathy (HC). Chronotropic response (CR) and heart rate recovery (HRR) were computed during and after treadmill exercise testing in 273 patients with HC and 95 age-matched healthy controls. Patients with HC had higher prevalence of chronotropic incompetence and lower HRR1-5min compared with controls. Exercise capacity, diastolic function (assessed by E/e') and left atrial volume index were associated with HRR1min and CR in HC. Septal myectomy was associated with reduction in chronotropic incompetence but did not affect HRR1min. In conclusion, impaired CR and HRR1min are associated with advanced disease and do not appear to be independent clinical markers indicating high-risk status in HC. Improving CR by titrating doses of negative chronotropic agents, myectomy, and atrial pacing may be useful to increase exercise capacity in patients with HC.

Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans.

ß-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC(403)) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male αMHC(403) transgenic mice (at t-5 weeks, -12 weeks, and -24 weeks) and 10 HCM patients from the same family with a ß-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (αMHC(403)) were examined at ages -5 weeks, -12 weeks, and -24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59±0.06 vs. 0.64±0.05 vs. 0.69±0.11 mm, P<0.01) and anterior wall thickness (0.58±0.1 vs. 0.62±0.07 vs. 0.80±0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain (-22%±4% vs. -20%±3% vs. -19%±3%, P=0.03), global longitudinal strain (-19%±3% vs. -17%±2% vs. -16%±3%, P=0.001) and E/A ratio (1.9±0.3 vs. 1.7±0.3 vs. 1.4±0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53±6 years), and 2nd generation (n=4; mean age 32±8 years). Septal thickness (2.2±0.9 vs. 1.4±0.1 cm, P<0.05), left atrial (LA) volume (62±16 vs. 41±5 mL, P=0.03), E/A ratio (0.77±0.21 vs. 1.1±0.1, P=0.01), E/e' ratio (25±10 vs. 12±2, P=0.03), global left ventricular (LV) strain (-14%±3% vs. -20%±3%, P=0.01) and global LV early diastolic strain rate (0.76±0.17 s(-1) vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In ß-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC(403) transgenic mouse model closely recapitulates human disease.

Comparison of clinical presentation, left ventricular morphology, hemodynamics, and exercise tolerance in obese versus nonobese patients with hypertrophic cardiomyopathy.

Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics, and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index [BMI] ≥30 kg/m(2)) and 154 nonobese (BMI <30 kg/m(2)) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p = 0.04) and chest pain (p = 0.002) and had greater prevalence of hypertension (p = 0.008). LV posterior wall thickness (p = 0.01) but not the septal wall (p ≥0.21) was significantly greater in obese patients, resulting in an increased LV mass index (p = 0.003). No significant differences in LV systolic and diastolic functions were observed, but obesity was associated with higher LV stroke volume (p = 0.03), inducible LV outflow tract gradients (p = 0.045), and chance of developing LV outflow tract obstruction during stress (p = 0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (ß = 0.15, p = 0.02) and LV mass index (ß = 0.18, p = 0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance, and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.

Relationship of delayed enhancement by magnetic resonance to myocardial perfusion by positron emission tomography in hypertrophic cardiomyopathy.

BACKGROUND: Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy. METHODS AND RESULTS: Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09±0.44 versus 1.78±0.34 cm; P=0.03). Stress myocardial blood flow (2.25±0.46 versus 1.78±0.43 mL/min per gram; P=0.01) and coronary flow reserve (2.78±0.32 versus 2.01±0.52; P<0.001) were significantly lower in DE-positive patients. Summed difference score (7.3±6.6 versus 0.9±1.4; P<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (P<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities. CONCLUSIONS: We found a close relationship between DE by CMR and microvascular function in most of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in hypertrophic cardiomyopathy patients.

Hyaluronic acid-human blood hydrogels for stem cell transplantation.

Tissue engineering-based approaches have the potential to improve stem cell engraftment by increasing cell delivery to the myocardium. Our objective was to develop and characterize a naturally-derived, autologous, biodegradable hydrogel in order to improve acute stem cell retention in the myocardium. HA-blood hydrogels (HA-BL) were synthesized by mixing in a 1:1(v/v) ratio, lysed whole blood and hyaluronic acid (HA), whose carboxyl groups were functionalized with N-hydroxysuccinimide (NHS) to yield HA succinimidyl succinate (HA-NHS). We performed physical characterization and measured survival/proliferation of cardiosphere-derived cells (CDCs) encapsulated in the hydrogels. Hydrogels were injected intra-myocardially or applied epicardially in rats. NHS-activated carboxyl groups in HA react with primary amines present in blood and myocardium to form amide bonds, resulting in a 3D hydrogel bound to tissue. HA-blood hydrogels had a gelation time of 58±12 s, swelling ratio of 10±0.5, compressive and elastic modulus of 14±3 and 1.75±0.6 kPa respectively. These hydrogels were not degraded at 4 wks by hydrolysis alone. CDC encapsulation promoted their survival and proliferation. Intra-myocardial injection of CDCs encapsulated in these hydrogels greatly increased acute myocardial retention (p=0.001). Epicardial application of HA-blood hydrogels improved left ventricular ejection fraction following myocardial infarction (p=0.01). HA-blood hydrogels are highly adhesive, biodegradable, promote CDC survival and increase cardiac function following epicardial application after myocardial infarction.