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Paracrine factors from neonatal CFs alone produced significant electrophysiological changes in neonatal rat cardiomyocytes resembling those found in several cardiac pathologies.

Pedrotty DM, Klinger RY, Badie N, Hinds S, Kardashian A, Bursac N. Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay. Am J Physiol Heart Circ Physiol 295: H390 -H400, 2008. First published May 23, 2008; doi:10.1152 doi:10. /ajpheart.91531.2007controlled studies of the structural and functional interactions between cardiomyocytes and other cells are essential for understanding heart pathophysiology and for the further development of safe and efficient cell therapies. We established a novel in vitro assay composed of a large number of individual micropatterned cell pairs with reproducible shape, size, and region of cell-cell contact. This assay was applied to quantify and compare the frequency of expression and distribution of electrical (connexin43) and mechanical (N-cadherin) coupling proteins in 5,000 cell pairs made of cardiomyocytes (CMs), cardiac fibroblasts (CFs), skeletal myoblasts (SKMs), and mesenchymal stem cells (MSCs). We found that for all cell pair types, side-side contacts between two cells formed 4.5-14.3 times more often than end-end contacts. Both connexin43 and N-cadherin were expressed in all homotypic CM pairs but in only 13.4 -91.6% of pairs containing noncardiomyocytes, where expression was either junctional (at the site of cell-cell contact) or diffuse (inside the cytoplasm). CM expression was exclusively junctional in homotypic pairs but predominantly diffuse in heterotypic pairs. Noncardiomyocyte homotypic pairs exhibited diffuse expression 1.7-8.7 times more often than junctional expression, which was increased 2.6 -4.4 times in heterotypic pairs. Junctional connexin43 and N-cadherin expression, respectively, were found in 38.6 Ϯ 7.3 and 39.6 Ϯ 6.2% of CM-MSC pairs, 21.9 Ϯ 5.0 and 13.6 Ϯ 1.9% of CM-SKM pairs, and in only 3.8 -9.6% of CM-CF pairs. Measured frequencies of protein expression and distribution were stable for at least 4 days. Described studies in micropatterned cell pairs shed new light on cellular interactions relevant for cardiac function and cell therapies. micropatterning; coculture; stem cell; gap junction MYOCARDIAL INFARCTION RESULTS in an irreversible cardiomyocyte loss followed by replacement fibrosis and, often, progression to congestive heart failure. Cellular cardiomyoplasty, the transplantation of exogenous cells into the damaged heart, was recently proposed as an alternative approach for the treatment of postinfarction disease (35). Despite the initial promise of the transplantation of skeletal myoblasts and bone marrow-derived stem cells (1, 32), the latest results of double-blind placebocontrolled clinical trials have been more ambiguous (45). One main recognized obstacle to understanding the mechanisms of repair and designing more efficient therapies has been the difficulty in tracking and systematically studying the structural and functional interactions between the implanted cells and host cardiomyocytes in situ. Importantly, although a number of novel cardiogenic cell types a...

BACKGROUND The purpose of this multicenter pilot study was to: (1) determine the frequency of regional cerebral oxygen saturation (rSco2) desaturations during cardiac surgery involving cardiopulmonary bypass (CPB); (2) evaluate the accuracy of clinician-identified rSco2 desaturations compared with those recorded continuously during surgery by the near-infrared spectroscopy (NIRS) monitor; and (3) assess the effectiveness of an intervention algorithm for reversing rSco2 desaturations. METHODS Two hundred thirty-five patients undergoing coronary artery bypass graft and/or valvular surgery were enrolled at 8 US centers in this prospective observational study. NIRS (Invos™ 5100C; Covidien) was used to monitor rSco2 during surgery. The frequency and magnitude of rSco2 decrements >20% from preanesthesia baseline were documented, and the efficacy of a standard treatment algorithm for correcting rSco2 was determined. The data from the NIRS monitor were downloaded at the conclusion of surgery and sent to the coordinating center where the number of clinician-identified rSco2 desaturation events was compared with the number detected by the NIRS monitor. RESULTS The average rSco2 obtained at baseline (mean ± SD, 61% ± 11%; 99% confidence interval, 57%–65%) and during CPB (62% ± 14%; 57%–67%) was not different. However, rSco2 after separation from CPB (56% ± 11%; 53%–60%) was lower than measurements at baseline and during CPB (P < 0.001). During CPB, rSco2 desaturations occurred in 61% (99% confidence interval, 50%–75%) of patients. The area under the curve for product of magnitude and duration of the rSco2 was (mean ± SD, 145.2; 384.8% × min). Clinicians identified all patients with an rSco2 desaturation but identified only 340 (89.5%) of the 380 total desaturation events. Of the 340 clinician-identified rSco2 desaturation events, 115 resolved with usual clinical care before implementation of the treatment algorithm. For the remaining 225 events, the treatment algorithm resulted in resolution of the rSco2 desaturation in all but 18 patients. CONCLUSIONS This multicenter pilot study found that 50% to 75% of patients undergoing cardiac surgery experience one or more rSco2 desaturations during CPB. Nearly 10% of desaturation events were not identified by clinicians, suggesting that appropriate alarming systems should be adopted to alert clinicians of such events. The intervention algorithm was effective in reversing clinically identified rSco2 desaturations in the majority of events.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo. Methods After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 μg · kg−1 · min−1 for the first hour, 24 μg · kg−1 · min−1 for the second hour, and 10 μg · kg−1 · min−1 for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type. Results Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (−0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life. Conclusions Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.

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Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase upregulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.tumorigenicity ͉ smooth muscle cells ͉ vascular graft

Our study suggests that specific micro- and macrostructural features of the ventricle determine the incidence and spatiotemporal characteristics of conduction block, independent of spatial heterogeneities in ion channel expression.