Faculty Bibliography

Transcatheter aortic valve implantation (TAVI) is considered a suitable treatment for patients with severe symptomatic aortic stenosis and high operative risk. Our aim was to evaluate the effect of preprocedural and new-onset atrial fibrillation (NOAF) on mortality and stroke in patients who underwent TAVI. We performed a single-center study of 380 consecutive patients enrolled to a TAVI registry. NOAF was defined as postprocedural atrial fibrillation (AF) occurring within 30 days after the procedure. Patients were followed up for a mean of 528 ± 364 days. During follow-up, 19 (5%) new episodes of stroke occurred, of whom 6 and 18 cases occurred within 30 days and 1 year, respectively. Overall mortality during the follow-up was 68 (20%), of those 12 and 58 patients died within 30 days and 1 year, respectively. NOAF occurred in 31 (8.2%) patients and was not associated with higher stroke or mortality rates at 30 days or 1 year of follow-up. Notably, compared with patients without previous AF, patients with previous AF at baseline had increased rates of stroke and mortality at 1-year follow-up (2.1% vs 9.6%, p = 0.01, and 8.2% vs 34.9%, p <0.01; respectively). In multivariate analysis, AF at baseline but not NOAF was a significant predictor of mortality throughout the follow-up period (HR 2.2, 95% confidence interval 1.3 to 3.8, p = 0.003, and HR 1.5, 95% confidence interval 0.5 to 4.1, p = 0.390, respectively). In conclusion, previous AF at baseline but not NOAF significantly increases stroke and mortality rates after TAVI. The inclusion of AF into future TAVI risk stratification scores should be strongly considered.

Cell replacement strategies are promising interventions aiming to improve myocardial performance. Yet, the electrophysiological impact of these approaches has not been elucidated. We assessed the electrophysiological consequences of grafting of two candidate cell types, that is, skeletal myoblasts and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). The fluorescently labeled (DiO) candidate cells were grafted into the rat's left ventricular myocardium. Two weeks later, optical mapping was performed using the Langendorff-perfused rat heart preparation. Images were obtained with appropriate filters to delineate the heart's anatomy, to identify the DiO-labeled cells, and to associate this information with the voltage-mapping data (using the voltage-sensitive dye PGH-I). Histological examination revealed the lack of gap junctions between grafted skeletal myotubes and host cardiomyocytes. In contrast, positive Cx43 immunostaining was observed between donor and host cardiomyocytes in the hESC-CMs-transplanted hearts. Optical mapping demonstrated either normal conduction (four of six) or minimal conduction slowing (two of six) at the hESC-CMs engraftment sites. In contrast, marked slowing of conduction or conduction block was seen (seven of eight) at the myoblast transplantation sites. Ventricular arrhythmias could not be induced in the hESC-CM hearts following programmed electrical stimulation but were inducible in 50% of the myoblast-engrafted hearts. In summary, a unique method for assessment of the electrophysiological impact of myocardial cell therapy is presented. Our results demonstrate the ability of hESC-CMs to functionally integrate with host tissue. In contrast, transplantation of cells that do not form gap junctions (skeletal myoblats) led to localized conduction disturbances and to the generation of a proarrhythmogenic substrate.

Hypertrophic and keloid scars still are among the banes of plastic surgery. In the treatment arsenal at the disposal of the plastic surgeon, topical silicone therapy usually is considered the first line of treatment or as an adjuvant to other treatment methods. Yet, knowledge concerning its mechanisms of action, clinical efficacy, and possible adverse effects is rather obscure and sometimes conflicting. This review briefly summarizes the existing literature regarding the silicone elastomer's mechanism of action on scars, the clinical trials regarding its efficacy, a description of some controversial points and contradicting evidence, and possible adverse effects of this treatment method. Topical silicone therapy probably will continue to be the preferred first-line treatment for hypertrophic scars due to its availability, price, ease of application, lack of serious adverse effects, and relative efficacy. Hopefully, future randomized clinical trials will help to clarify its exact clinical efficacy and appropriate treatment protocols to optimize treatment results.

BACKGROUND:Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels. METHODS AND RESULTS/RESULTS:To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84+/-8 ms (cycle length, 200 ms) to 154+/-13 ms (P<0.01). Margatoxin partially reversed this effect (effective refractory period, 117+/-8 ms; P<0.01). In contrast, effective refractory period did not change in nontransplanted sites (86+/-7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73+/-5 to 88+/-4 ms; P<0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results. CONCLUSIONS:Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.

OBJECTIVES/OBJECTIVE:We evaluated the ability of human embryonic stem cells (hESCs) and their cardiomyocyte derivatives (hESC-CMs) to engraft and improve myocardial performance in the rat chronic infarction model. BACKGROUND:Cell therapy is emerging as a novel therapy for myocardial repair but is hampered by the lack of sources for human cardiomyocytes. METHODS:Immunosuppressed healthy and infarcted (7 to 10 days after coronary ligation) rat hearts were randomized to injection of undifferentiated hESCs, hESC-CMs, noncardiomyocyte hESC derivatives, or saline. Detailed histological analysis and sequential echocardiography were used to determine the structural and functional consequences of cell grafting. RESULTS:Transplantation of undifferentiated hESCs resulted in the formation of teratoma-like structures. This phenomenon was prevented by grafting of ex vivo pre-differentiated hESC-CMs. The grafted cardiomyocytes survived, proliferated, matured, aligned, and formed gap junctions with host cardiac tissue. Functionally, animals injected with saline or nonmyocyte hESC derivatives demonstrated significant left ventricular (LV) dilatation and functional deterioration, whereas grafting of hESC-CMs attenuated this remodeling process. Hence, post-injury baseline fractional shortening deteriorated by 50% (from 20 +/- 2% to 10 +/- 2%) and by 30% (20 +/- 2% to 14 +/- 2%) in the saline and nonmyocyte groups while improving by 22% (21 +/- 2% to 25 +/- 3%) in the hESC-CM group. Similarly, wall motion score index and LV diastolic dimensions were significantly lower in the hESC-CM animals. CONCLUSIONS:Transplantation of hESC-CMs after extensive myocardial infarction in rats results in the formation of stable cardiomyocyte grafts, attenuation of the remodeling process, and functional benefit. These findings highlight the potential of hESCs for myocardial cell therapy strategies.

Human embryonic stem cells (hESC) are pluripotent lines that can differentiate in vitro into cell derivatives of all three germ layers, including cardiomyocytes. Successful application of these unique cells in the areas of cardiovascular research and regenerative medicine has been hampered by difficulties in identifying and selecting specific cardiac progenitor cells from the mixed population of differentiating cells. We report the generation of stable transgenic hESC lines, using lentiviral vectors, and single-cell clones that express a reporter gene (eGFP) under the transcriptional control of a cardiac-specific promoter (the human myosin light chain-2V promoter). Our results demonstrate the appearance of eGFP-expressing cells during the differentiation of the hESC as embryoid bodies (EBs) that can be identified and sorted using FACS (purity>95%, viability>85%). The eGFP-expressing cells were stained positively for cardiac-specific proteins (>93%), expressed cardiac-specific genes, displayed cardiac-specific action-potentials, and could form stable myocardial cell grafts following in vivo cell transplantation. The generation of these transgenic hESC lines may be used to identify and study early cardiac precursors for developmental studies, to robustly quantify the extent of cardiomyocyte differentiation, to label the cells for in vivo grafting, and to allow derivation of purified cell populations of cardiomyocytes for future myocardial cell therapy strategies.

Gene therapy, cell therapy, and tissue engineering are emerging as novel experimental therapeutic paradigms for a variety of cardiovascular disorders. In the current report we will review the possible implications of these emerging technologies in the field of cardiac electrophysiology. Initially, the possible role of myocardial gene and cell therapies in creating a biological alternative to electronic pacemakers for the treatment of bradyarrhythmias will be discussed. This will be followed by a description of the possible applications of using similar strategies for the treatment of common tachyarrhythmias. Finally, the electrophysiological implications of cardiac stem cell therapy for heart failure, as well as the possible in vitro applications of stem cell technology for electrophysiological studies and drug screening, will be discussed. While these emerging strategies provide a paradigm shift from conventional treatment modalities, this field is still at its infancy and several obstacles, discussed in this review, should be overcome before any clinical breakthroughs can be expected.