Implantation of Mouse Embryonic Stem Cell-Derived Cardiac Progenitor Cells Preserves Function of Infarcted Murine Hearts

Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart

Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

Background: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. Methods: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Results: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Conclusions: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy

Current treatments for ischemic cardiomyopathy are aimed toward minimizing the deleterious consequences of diseased myocardium. The possibility of treating heart failure by generating new myocardium and vascular tissue has been an impetus toward recent stem cell research. Mesenchymal stem cells (MSC), also referred to as marrow stromal cells, differentiate into a wide variety of lineages, including myocardial and endothelial cells. The multi-lineage potential of MSCs, their ability to elude detection by the host immune system, and their relative ease of expansion in culture make MSCs a very promising source of stem cells for transplantation. In addition, emerging experimental results with MSCs offer novel mechanistic insights into cardiac regenerative therapy in general. Here we review the characterization of MSCs, animal and human trials studying MSCs in cardiomyogenesis and vasculogenesis in postinfarct myocardium, routes of delivery, and potential mechanisms of stem cell repair

Evolution of Veterans Affairs Transcatheter Aortic Valve Replacement Program: The First 100 Patients.

BackgroundTranscatheter aortic valve replacement (TAVR) is a widely established alternative to surgery in intermediate- and high-risk patients. TAVR program development within the Veterans Affairs (VA) system has been previously described. However, national TAVR registries do not capture VA outcomes data, and few data have been reported regarding TAVR outcomes at lower-volume federal institutions. The study aim was to demonstrate the evolution of a successful VA TAVR program.MethodsA retrospective analysis was performed of the first 100 TAVR patients at San Francisco VA Medical Center. Mortality and major complications were evaluated.ResultsBetween 25th November 2013 and 31st August 2016, a total of 100 TAVR procedures was performed at the authors' institution. The mean patient age was 79.7 ± 8.7 years. Patients underwent TAVR via percutaneous-transfemoral (n = 90), surgical cutdown-transfemoral (n = 8), or transapical (n = 2) approaches. The valve systems employed were Edwards SAPIEN (n = 16), SAPIEN XT (n = 31), SAPIEN 3 (n = 23), and Medtronic CoreValve (n = 16) and CoreValve Evolut R (n = 14). The overall device success was 96%. TAVR-in-TAVR was required in the remaining 4% of patients, and was successful. All-cause procedural mortality was 1%. Complications included tamponade (1%), stroke (2%), temporary hemodialysis (1%), vascular injuries requiring intervention (4%), and permanent pacemaker implantation (14%). There were no conversions to surgical aortic valve replacement. Twenty-two (22%) patients had mild, two (2%) had moderate, and none (0%) had severe paravalvular leakage. The post-procedure aortic valve gradient by echocardiography was 8.6 ± 4.5 mmHg. Follow up was 100% complete and survival was 99%, 93%, and 89% at one, six, and 12 months, respectively.ConclusionsSuccessful outcomes were demonstrated for a VA TAVR program that compared favorably with benchmarks established by the National Transcatheter Valve Therapies Registry. These results provide a necessary transparency of TAVR outcomes at a federal institution

Midterm Durability and Structural Valve Degeneration of Transcatheter Aortic Valve Replacement in a Federal Facility

ObjectiveTranscatheter aortic valve replacement (TAVR), previously reserved for patients of intermediate to prohibitive surgical risk, has now been expanded to patients of any surgical risk with severe aortic stenosis. Bioprostheses are prone to structural valve degeneration (SVD), a progressive and multifactorial process that limits valve durability. As the population undergoing TAVR shifts toward a lower-risk and younger profile, long-term durability is a crucial determinant for patient outcomes. Our objective was to determine the incidence and risk factors of SVD at midterm follow-up in a veteran TAVR population.MethodsPatients undergoing TAVR at our federal facility were retrospectively evaluated for SVD and other endpoints with standardized consensus criteria. Multivariable Cox proportional hazards analysis was performed to evaluate risk factors for mortality and SVD.ResultsFrom 2013 to 2020, 344 patients (median age, 78 years) underwent TAVR. Survival from all-cause mortality was 91.3% at 1 year, 75.1% at 3 years, and 61.7% at 5 years. Cumulative freedom from SVD was 98.2% at 1 year, 96.5% at 3 years, and 93.7% at 5 years. All 13 patients with SVD met hemodynamic criteria, and 1 required intervention. Median time to hemodynamic SVD was 1.04 years. Independent risk factors for SVD included age (hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.86 to 0.99) and valve size (HR = 0.19, 95% CI: 0.04 to 0.89).ConclusionsSVD was evident at a low but detectable rate at 5-year follow-up. Further understanding of TAVR biomechanics as well as continued longer-term follow-up will be essential for informing patient-specific risk of SVD