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Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.

ABSTRACT: Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocyte transplantation, thereby potentially preventing dilative remodeling and progression to heart failure.Assessment of transport stability, long-term survival, structural organization, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction model.We constructed EHMs from human embryonic stem cell-derived cardiomyocytes and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). One month after ischemia/reperfusion injury, EHMs were implanted onto immunocompromised rat hearts to simulate chronic ischemia. Bioluminescence imaging showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving ?25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs, -6.7±1.4% versus control, -10.9±1.5%; n>12; P=0.05), we observed no difference between EHMs containing viable and nonviable human cardiomyocytes in this chronic xenotransplantation model (n>12; P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring.EHM transplantation led to high engraftment rates, long-term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic myocardial infarction model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation.

SUBMITTER: Riegler J

PROVIDER: S-EPMC4679370 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.

Riegler Johannes J Tiburcy Malte M Ebert Antje A Tzatzalos Evangeline E Raaz Uwe U Abilez Oscar J OJ Shen Qi Q Kooreman Nigel G NG Neofytou Evgenios E Chen Vincent C VC Wang Mouer M Meyer Tim T Tsao Philip S PS Connolly Andrew J AJ Couture Larry A LA Gold Joseph D JD Zimmermann Wolfram H WH Wu Joseph C JC

Circulation research 20150819 8

<h4>Rationale</h4>Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocyte transplantation, thereby potentially preventing dilative remodeling and progression to heart failure.<h4>Objective</h4>Assessment of transport stability, long-term survival, structural organization, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction model.<h4>Methods and results</h4>We constructed ...[more]

PMID: 26291556

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Project description:BackgroundAlthough silent myocardial infarction (SMI) accounts for about one-half of the total number of myocardial infarctions (MIs), the risk of heart failure (HF) among patients with SMI is not well established.ObjectivesThe purpose of this study was to examine the association of SMI and clinically manifested myocardial infarction (CMI) with HF, as compared with patients with no MI.MethodsThis analysis included 9,243 participants from the ARIC (Atherosclerosis Risk In Communities) study who were free of cardiovascular disease at baseline (ARIC visit 1: 1987 to 1989). SMI was defined as electrocardiographic evidence of MI without CMI after the baseline until ARIC visit 4 (1996 to 1998). HF events were ascertained starting from ARIC visit 4 until 2010 in individuals free of HF before that visit.ResultsBetween ARIC visits 1 and 4, 305 SMIs and 331 CMIs occurred. After ARIC visit 4 and during a median follow-up of 13.0 years, 976 HF events occurred. The incidence rate of HF was higher in both CMI and SMI participants than in those without MI (incidence rates per 1,000 person-years were 30.4, 16.2, and 7.8, respectively; p < 0.001). In a model adjusted for demographics and HF risk factors, both SMI (hazard ratio [HR]: 1.35; 95% confidence interval [CI]: 1.02 to 1.78) and CMI (HR: 2.85; 95% CI: 2.31 to 3.51) were associated with increased risk of HF compared with no MI. These associations were consistent in subgroups of participants stratified by several HF risk predictors. However, the risk of HF associated with SMI was stronger in those younger than the median age (53 years) (HR: 1.66; 95% CI: 1.00 to 2.75 vs. HR: 1.19; 95% CI: 0.85 to 1.66, respectively; overall interaction p by MI type <0.001).ConclusionsSMI is associated with an increased risk of HF. Future research is needed to examine the cost effectiveness of screening for SMI as part of HF risk assessment, and to identify preventive therapies to improve the risk of HF among patients with SMI.

Project description:AimsNew-onset atrial fibrillation (NOAF) complicating acute myocardial infarction (AMI) has been associated with poor survival, but the clinical implication of NOAF on heart failure (HF) is still not well characterized. We aimed to investigate the relationship between NOAF complicating AMI and HF hospitalization.Methods and resultsAdult AMI patients identified in the New-Onset Atrial Fibrillation Complicating Acute Myocardial Infarction in Shanghai registry who, discharged alive, had complete echocardiography and follow-up data from February 2014 to March 2018 were included. Patients were divided according to the presence of NOAF. The outcome measures were HF hospitalization and death during the observational period (until 10 April 2019). Cox proportional hazard models were performed in the whole population and propensity score-matched (PSM) cohort to assess the adjusted hazard ratio (HR) and 95% confidence interval (CI). Overall, 2075 patients (mean age: 65.2 ± 12.3 years, 77.3% were men) with AMI were analysed, of whom 228 (11.0%) developed NOAF. Advanced age, admission HF (Killip II-IV), impaired renal function, decreased left ventricular ejection fraction, increased heart rate, and left atrial enlargement were independent predictors of NOAF. Over a median observational period of 2.7 years, the annual incidence rates of HF hospitalization were 18.4% and 2.8% for patients with NOAF and sinus rhythm, respectively. After adjustment for confounders, NOAF was significantly associated with HF hospitalization (HR: 3.14, 95% CI: 2.30-4.28, P < 0.001). Similar results were obtained when accounting for the competing risk of all-cause death (subdistribution HR: 3.06, 95% CI: 2.18-4.30, P < 0.001) or from the PSM cohort (HR: 2.82, 95% CI: 1.99-4.00, P < 0.001). Patients with persistent NOAF (HR: 5.81, 95% CI: 3.59-9.41) were at significantly higher risk of HF hospitalization when compared with those with transient one (HR: 2.61, 95% CI: 1.84-3.70, P interaction = 0.008). Although post-MI NOAF was significantly related to cardiovascular death (annual incidence rates for NOAF and sinus rhythm were 9.4% and 2.3%, respectively; HR: 1.97, 95% CI: 1.36-2.85, P < 0.001), such an association was attenuated when HF hospitalization (modelled as a time-varying covariate) and antithrombotic treatment were adjusted (HR: 1.37, 95% CI: 0.92-2.02, P = 0.121).ConclusionsIn patients with AMI, NOAF is strongly associated with an increased long-term risk of HF hospitalization. Our findings suggest that strengthened secondary prevention of HF should be considered in this high-risk population.

Project description:AimsThe aim of this study is to investigate the association between adherence to beta-blocker treatment after a first acute myocardial infarction (AMI) and long-term risk of heart failure (HF) and death.Methods and resultsAll patients admitted for a first AMI included in the nationwide Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies register between 2005 and 2010 were eligible (n = 71 638). After exclusion of patients who died in-hospital, patients with previous HF, patients with unknown left ventricular ejection fraction (EF), and patients who died during the first year after the index event, 38 608 patients remained in the final analysis. Adherence to prescribed beta-blockers was determined for 1 year after the index event using the national registry for prescribed drugs and was measured as proportion of days covered, the ratio between the numbers of days covered by the dispensed prescriptions and number of days in the period. As customary, a threshold level for proportion of days covered ≥80% was used to classify patients as adherent or non-adherent. At discharge 90.6% (n = 36 869) of all patients were prescribed a beta-blocker. Among 38 608 1 year survivors, 31.1% (n = 12 013) were non-adherent to beta-blockers. Patients with reduced EF with and without HF were more likely to remain adherent to beta-blockers at 1-year compared with patients with normal EF without HF (NEF). Being married/cohabiting and having higher income level, hypertension, ST-elevation MI, and percutaneous coronary intervention were associated with better adherence. Adherence was independently associated with lower all-cause mortality [hazard ratio (HR) 0.77, 95% confidence interval [CI] 0.71-0.84] and a lower risk for the composite of HF readmission/death, (HR 0.83, 95% CI 0.78-0.89, P value <0.001) during the subsequent 4 years of follow up. These associations were favourable but less apparent in patients with HFNEF and NEF.ConclusionsNearly one in three AMI patients was non-adherent to beta-blockers within the first year. Adherence was independently associated with improved long-term outcomes; however, uncertainty remains for patients with HFNEF and NEF.

Dataset Information

Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.

Publications

Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.

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