Cardiac stereotactic body radiotherapy to treat malignant ventricular arrhythmias directly affects the cardiomyocyte electrophysiology.

BACKGROUND: Promising as a treatment option for life-threatening ventricular arrhythmias, cardiac stereotactic body radiotherapy (cSBRT) has demonstrated early antiarrhythmic effects within days of treatment. The mechanisms underlying the immediate and short-term antiarrhythmic effects are poorly understood. OBJECTIVE: We hypothesize that cSBRT has a direct antiarrhythmic effect on cellular electrophysiology through reprogramming of ion channel and gap junction protein expression. METHODS: After exposure to 20 Gy of x-rays in a single fraction, neonatal rat ventricular cardiomyocytes were analyzed 24 and 96 hours postradiation to determine changes in conduction velocity, beating frequency, calcium transients, and action potential duration in both monolayers and single cells. In addition, the expression of gap junction proteins, ion channels, and calcium handling proteins was evaluated at protein and messenger RNA levels. RESULTS: After irradiation with 20 Gy, neonatal rat ventricular cardiomyocytes exhibited increased beat rate and conduction velocity 24 and 96 hours after treatment. Messenger RNA and protein levels of ion channels were altered, with the most significant changes observed at the 96-hour mark. Upregulation of Cacna1c (Cav1.2), Kcnd3 (Kv4.3), Kcnh2 (Kv11.1), Kcnq1 (Kv7.1), Kcnk2 (K2P2.1), Kcnj2 (Kir2.1), and Gja1 (Cx43) was noted, along with improved gap junctional coupling. Calcium handling was affected, with increased Ryr2 ryanodin-rezeptor 2 and Slc8a1 Na+/Ca2+ exchanger expression and altered properties 96 hours posttreatment. Fibroblast and myofibroblast levels remained unchanged. CONCLUSION: cSBRT modulates the expression of various ion channels, calcium handling proteins, and gap junction proteins. The described alterations in cellular electrophysiology may be the underlying cause of the immediate antiarrhythmic effects observed after cSBRT.

Imaging approaches for pulmonary vein isolation in patients after lobectomy or pneumonectomy: a case series.

Background: In patients who underwent pneumonectomy, pulmonary vein isolation for atrial fibrillation by catheter ablation may be complicated by the anatomical alterations caused by the surgical intervention. Pre- and peri-procedural imaging can visualize and guide the procedure to assure safety and procedural success. Case summary: This case series describes different imaging and ablation strategies in three cases from three different ablation centres with the unusually challenging and complex anatomical conditions in patients following lobectomy or pneumonectomy. Discussion: Pulmonary vein isolation in patients with previous pulmonary resection was feasible by both radiofrequency and cryocatheter ablation despite the anatomical alterations caused by the surgery. Pre- and peri-procedural imaging by cardiac computed tomography and transoesophageal echocardiography contributed to an increased understanding of the complex anatomical substrate.

In vivo cardiac pacemaker function of differentiated human mesenchymal stem cells from adipose tissue transplanted into porcine hearts.

BACKGROUND: Mesenchymal stem cells (MSC) modified by gene transfer to express cardiac pacemaker channels such as HCN2 or HCN4 were shown to elicit pacemaker function after intracardiac transplantation in experimental animal models. Human MSC derived from adipose tissue (haMSC) differentiate into cells with pacemaker properties in vitro, but little is known about their behavior after intracardiac transplantation. AIM: To investigate whether haMSC elicit biological pacemaker function in vivo after transplantation into pig hearts. METHODS: haMSC under native conditions (nhaMSC) or after pre-conditioning by medium differentiation (dhaMSC) (n = 6 pigs each, 5 × 106 cells/animal) were injected into the porcine left ventricular free wall. Animals receiving PBS injection served as controls (n = 6). Four weeks later, total atrioventricular (AV)-block was induced by radiofrequency catheter ablation, and electronic pacemaker devices were implanted for backup stimulation and heart rate monitoring. Ventricular rate and rhythm of pigs were evaluated during a follow-up of 15 d post ablation by 12-lead-ECG with heart rate assessment, 24-h continuous rate monitoring recorded by electronic pacemaker, assessment of escape recovery time, and pharmacological challenge to address catecholaminergic rate response. Finally, hearts were analyzed by histological and immunohistochemical investigations. RESULTS: In vivo transplantation of dhaMSC into the left ventricular free wall of pigs elicited spontaneous and regular rhythms that were pace-mapped to ventricular injection sites (mean heart rate 72.2 ± 3.6 bpm; n = 6) after experimental total AV block. Ventricular rhythms were stably detected over a 15-d period and were sensitive to catecholaminergic stimulation (mean maximum heart rate 131.0 ± 6.2 bpm; n = 6; P < 0.001). Pigs, which received nhaMSC or PBS presented significantly lower ventricular rates (mean heart rates 47.2 ± 2.5 bpm and 37.4 ± 3.2 bpm, respectively; n = 6 each; P < 0.001) and exhibited little sensitivity towards catecholaminergic stimulation (mean maximum heart rates 76.4 ± 3.1 bpm and 60.5 ± 3.1 bpm, respectively; n = 6 each; P < 0.05). Histological and immunohistochemical evaluation of hearts treated with dhaMSC revealed local clusters of transplanted cells at the injection sites that lacked macrophage or lymphocyte infiltrations or tumor formation. Intense fluorescence signals at these sites indicated membrane expression of HCN4 and other pacemaker-specific proteins involved in cardiac automaticity and impulse propagation. CONCLUSION: dhaMSC transplanted into pig left ventricles sustainably induced rate-responsive ventricular pacemaker activity after in vivo engraftment for four weeks. The data suggest that pre-conditioned MSC may further differentiate along a pacemaker-related lineage after myocardial integration and may establish superior pacemaker properties in vivo.

Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams.

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40-55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.

Functional characterization of zebrafish K2P18.1 (TRESK) two-pore-domain K+ channels.

The human KCNK18 gene is predominantly expressed in brain, spinal cord, and dorsal root ganglion neurons. Encoded K2P18.1K(+) channels are functionally implicated in migraine, pain and anesthesia. Data delineating the in vivo significance of K2P18.1 are still limited owing to a lack of model systems allowing for rapid, whole organism phenotypic analyses. We hypothesized that zebrafish (Danio rerio) might close this scientific gap. This work was designed to characterize the zebrafish ortholog of K2P18.1 in comparison to human K2P18.1 channels. The complete coding sequence of zKCNK18 was amplified from zebrafish cDNA. Zebrafish KCNK18 expression was assessed by in situ hybridization. Human and zebrafish K2P18.1 currents were functionally analyzed using two-electrode voltage clamp electrophysiology and the Xenopus oocyte expression system. KCNK18 mRNA is expressed in zebrafish brain and eyes. Human and zebrafish K2P18.1 proteins share 32 % identity. Zebrafish K2P18.1 channels mediate K(+)-selective background currents that stabilize the negative resting membrane potential. Functional similarities between human and zK2P18.1 currents include open rectification properties, inhibition by barium, and regulation by signaling molecules protein kinase (PK)C, PKA, and phospholipase C. In contrast to the human ortholog, zK2P18.1 exhibited reduced sensitivity to elevation of intracellular calcium levels by ionomycin and was virtually insensitive to inhibition by quinidine. Zebrafish and human K2P18.1 channels share functional and regulatory properties, indicating that the zebrafish may serve as model to assess K2P18.1 function in vivo. However, distinct differences in K2P18.1 current regulation require careful consideration when zebrafish data are extrapolated to human physiology.

The influence of endoscopic vein harvesting on outcomes after coronary bypass grafting: a meta-analysis of 267,525 patients.

In recent times, practice in cardiac surgery has shifted towards using endoscopic techniques to harvest the saphenous vein from the leg for use as a bypass graft. A paper published in the New England Journal of Medicine (NEJM) in 2009 raised concerns over increased graft occlusion rates in veins harvested endoscopically. This NEJM paper has been criticized, but has nonetheless been influential in guiding practice. We have undertaken this meta-analysis to provide evidence on the clinical outcomes of endoscopic vein harvesting (EVH), so that clinicians can make an informed judgement about whether this technique, popular as it is with patients, should still be offered. We systematically reviewed the global literature and performed a meta-analysis of clinical outcomes after endoscopic and open vein harvesting. In all outcomes, endoscopic harvesting appears to be equal, if not superior, to open harvesting. The suspicion of higher rates of vein graft occlusion was not borne out by randomized studies. When considering evidence from only randomized studies, there is no statistical difference in vein graft stenosis or occlusion between open and endoscopically harvested veins. In conclusion, EVH reduces pain and leg wound complications. At a median follow-up of 2.6 years, we found no significant difference in mortality, myocardial infarction, repeat revascularization, angina recurrence, vein graft stenosis or occlusion. Therefore, the authors support the ongoing use of endoscopic harvesting techniques.