Behfar, Atta

Background Low body mass index ( BMI ) and serum creatinine are surrogate markers of frailty and sarcopenia. Their relationship with cause‐specific mortality in elderly patients undergoing percutaneous coronary intervention is not well studied. Methods and Results We determined long‐term cardiovascular and noncardiovascular mortality in 9394 consecutive patients aged ≥65 years who underwent percutaneous coronary intervention from 2000 to 2011. BMI and serum creatinine were divided into 4 categories. During a median follow‐up of 4.2 years (interquartile range 1.8–7.3 years), 3243 patients (33.4%) died. In the multivariable model, compared with patients with normal BMI , patients with low BMI had significantly increased all‐cause mortality (hazard ratio [ HR ] 1.4, 95% CI 1.1–1.7), which was related to both cardiovascular causes (HR 1.4, 95% CI 1.0–1.8) and noncardiovascular causes (HR 1.4, 95% CI 1.06–1.9). Compared with normal BMI , significant reduction was noted in patients who were overweight and obese in terms of cardiovascular mortality (overweight: HR 0.77, 95% CI 0.67–0.88; obese: HR 0.80, 95% CI 0.70–0.93) and noncardiovascular mortality (overweight: HR 0.85, 95% CI 0.74–0.97; obese: HR 0.82, 95% CI 0.72–0.95). In a multivariable model, in patients with normal BMI , low creatinine (≤0.70 mg/dL) was significantly associated with increased all‐cause mortality (HR 1.8, 95% CI 1.3–2.5) and cardiovascular mortality (HR 2.3, 95% CI 1.4–3.8) compared with patients with normal creatinine (0.71–1.0 mg/dL); however, this was not observed in other BMI categories. Conclusions We identified a new subgroup of patients with low serum creatinine and normal BMI that was associated with increased all‐cause mortality and cardiovascular mortality in elderly patients undergoing percutaneous coronary intervention. Low BMI was associated with increased cardiovascular and noncardiovascular mortality. Nutritional support, resistance training, and weight‐gain strategies may have potential roles for these patients undergoing percutaneous coronary intervention.

Objectives/HypothesisRadiation plays a prominent role in advanced stage head and neck tumors. Often, the radiated area includes adjacent nonmalignant mesenchymal tissue, which contains a mixture of cells that has been shown to accelerate wound healing. The purpose of this study is to determine the long‐term effect of radiation on the expansion potential of adipose‐derived stromal/stem cell (ADSC) tissue and on the ability of resident stem cells in this fraction to undergo phenotypic differentiation.Study Design/Methods: After institutional review board approval, 12 patients with a history of head and neck radiation and pending surgery were enrolled. Adipose tissue was collected from irradiated tissue (XRT) and nonirradiated tissue (NRT) sites. Mesenchymal stem cells were isolated from these populations, with subsequent assessment of cellular kinetics and differentiation potential between harvest sites.ResultsAdipose‐derived stromal/stem cells could not be isolated from XRT in six patients due to lack of in vitro cell proliferation. For the remaining six patients, overall cumulative population‐doubling time was longer for XRT relative to NRT (29.3 vs. 11.5 days; P = 0.02). However, no significant differences were observed in cell generation time or viability. When XRT and NRT ADSC fractions were grown to standardized concentrations and incubated under conditions that induce phenotypic differentiation of resident stem cells, no significant changes in chondrogenic, adipogenic, or osteogenic differentiation were observed.ConclusionThese preliminary observations suggest that irradiated ADSCs close to the surgical site undergo long‐term changes in proliferative capacity. The potential for phenotypic differentiation is retained, however, in ADSCs that survive the irradiation process.Level of Evidence2b.

Abstract Aims Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy. Methods Patients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (<35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 106 bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months. Conclusion The CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF. Trial registration: NCT01768702

PurposeThe purpose of this study was to characterize and quantitatively analyze human cardiac extracellular matrix (ECM) isolated from six different cadaveric donor hearts.Experimental designECM was isolated by decellularization of six human cadaveric donor hearts and characterized by quantifying sulfated glycosaminoglycan content (sGAG) and via PAGE. The protein content was then quantified using ECM‐targeted Quantitative conCATamers (QconCAT) by LC‐SRM analysis using 83 stable isotope labeled (SIL) peptides representing 48 different proteins. Nontargeted global analysis was also implemented using LC‐MS/MS.ResultsThe sGAG content, PAGE, and QconCAT proteomics analysis showed significant variation between each of the six patient samples. The quantitative proteomics indicated that the majority of the protein content was composed of various fibrillar collagen components. Also, quantification of difficult to remove cellular proteins represented less than 1% of total protein content, which is very low for a decellularized biomaterial. Global proteomics identified over 200 distinct proteins present in the human cardiac ECM.Conclusion and clinical relevanceIn conclusion, quantification and characterization of human myocardial ECM showed significant patient‐to‐patient variability between the six investigated patients. This is an important outcome for the development of allogeneic derived biomaterials and for increasing our understanding of human myocardial ECM composition.

Background Cardiac resynchronization therapy using bi‐ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS ‐complex. In the absence of QRS prolongation, however, device‐based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell‐based approach in the setting of narrow QRS ‐complex HF. Methods and Results Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress‐triggered dilated cardiomyopathy. In contrast to rampant end‐stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS ‐complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell‐treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony‐prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship. Conclusions In narrow QRS HF, a regenerative approach demonstrated functional and structural benefit, introducing the prospect of device‐autonomous resynchronization therapy for refractory disease.

A comparison of the biochemical, mechanical, and bioactive properties of a porcine myocardial matrix to a new human myocardial matrix and the feasibility of translating this allogeneic hydrogel to the clinic.

Background— Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results— Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Conclusions— Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.