Do we need a map to get through the maze?
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Atrial Fibrillation↗
Biomedical subjects
Richard B Schuessler
Publications and source records attributed to Richard B Schuessler.
Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning.
Electrical uncoupling of cardiac myocytes during ischemia is delayed by ischemic preconditioning. This presumably adaptive response may limit development of arrhythmia substrates. To elucidate responsible mechanisms, we studied isolated, perfused rat hearts subjected to a standard preconditioning protocol of 3 cycles of 3 minutes of global no-flow ischemia each followed by 5 minutes of reperfusion before a 30-minute interval of ischemia. Changes in coupling were monitored by measuring whole-tissue resistance. Changes in phosphorylation and subcellular distribution of connexin43 (Cx43) were defined by quantitative immunoblotting and confocal microscopy. Preconditioning caused a 34% decrease in the maximal rate of uncoupling and delayed the time to plateau in uncoupling. Dephosphorylation of Cx43, known to occur during uncoupling induced by ischemia, was dramatically decreased in preconditioned hearts. Translocation of Cx43 from gap junctions to the cytosol, also known to occur during ischemia, was reduced by >5-fold in preconditioned hearts. The KATP channel blockers glybenclamide and 5-hydroxydecanoate prevented these effects in preconditioned hearts, whereas the KATP channel agonist diazoxide mimicked these effects in nonpreconditioned hearts. Intracellular translocation of Cx43 was blocked, but Cx43 dephosphorylation was not blocked during ischemia in preconditioned hearts treated with the PKC inhibitors chelerythrine and calphostin C. Uncoupling during ischemia was accelerated by PKC and KATP channel inhibition. Thus, delayed uncoupling in preconditioned hearts is likely related to diminished dephosphorylation and intracellular redistribution of Cx43 during prolonged ischemia. Both of these effects are regulated by activation of KATP channels, whereas PKC plays a role in internalization of Cx43.
Animals↗
Cardiac ischemia activates calcium-independent phospholipase A2beta, precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition.
Murine myocardium contains diminutive amounts of calcium-independent phospholipase A2 (iPLA2) activity (<5% that of human heart), and malignant ventricular tachyarrhythmias are infrequent during acute murine myocardial ischemia. Accordingly we considered the possibility that the mouse was a species-specific knockdown of the human pathologic phenotype of ischemiainduced lethal ventricular tachyarrhythmias. Transgenic mice were generated expressing amounts of iPLA2beta activity comparable to that present in human myocardium. Coronary artery occlusion in Langendorff perfused hearts from transgenic mice resulted in a 22-fold increase in fatty acids released into the venous eluent (29.4 nmol/ml in transgenic versus 1.35 nmol/ml of eluent in wild-type mice), a 4-fold increase in lysophosphatidylcholine mass in ischemic zones (4.9 nmol/mg in transgenic versus 1.1 nmol/mg of protein in wild-type mice), and malignant ventricular tachyarrhythmias within minutes of ischemia. Neither normally perfused transgenic nor ischemic wild-type hearts demonstrated these alterations. Pretreatment of Langendorff perfused transgenic hearts with the iPLA2 mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL) just minutes prior to induction of ischemia completely ablated fatty acid release and lysolipid accumulation and rescued transgenic hearts from malignant ventricular tachyarrhythmias. Collectively these results demonstrate that ischemia activates iPLA2beta in intact myocardium and that iPLA2beta-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.
Animals↗
Physiological consequences of bipolar radiofrequency energy on the atria and pulmonary veins: a chronic animal study.
BACKGROUND: Alternative energy sources have been proposed for the transvenous and surgical treatment of atrial fibrillation. This study examined the physiologic consequences of a novel energy source, bipolar radiofrequency energy, in a chronic animal model in order to determine its ability to produce transmural lesions on the beating heart. METHODS: Five dogs underwent baseline pacing from the following target areas: right and left atrial appendage, superior and inferior vena cavae, and right and left pulmonary veins. A cuff of atrial myocardium, proximal to the target tissue was clamped and ablated between the arms of the bipolar radiofrequency energy device. Tissue conductance was used as a transmural indicator. After ablation, the pacing protocol was repeated. Baseline and postablation pulmonary vein flows were measured. Animals were survived for 30 days, and permanent electrical isolation was evaluated by pacing, epicardial mapping, and histology. RESULTS: Mean ablation time was 5.0 +/- 1.8 seconds and mean peak tissue temperature was 46.7 degrees C +/- 2.8 degrees C. All lesions (30/30) acutely and permanently isolated atrial tissue. There was no change in pulmonary vein flow. Mapping studies with pacing of atrial tissue on both sides of the lesion confirmed isolation. Histology demonstrated that all lesions were linear, continuous, and transmural with no thrombus formation or stenosis. CONCLUSIONS: Bipolar radiofrequency energy rapidly produced permanent transmural linear lesions on the beating heart. Measurement of tissue conductance reliably predicted transmural lesions. This new technology may enable the development of a less invasive, surgical approach to atrial fibrillation.
Animals↗
The Cox maze III procedure for atrial fibrillation: long-term efficacy in patients undergoing lone versus concomitant procedures.
BACKGROUND: For the last decade, the Cox maze III procedure has been available for the treatment of atrial fibrillation. It is unknown whether the operation has similar efficacy in patients with lone atrial fibrillation compared with that in patients with atrial fibrillation associated with coronary, valve, or congenital heart disease. This study examined the long-term outcome of patients who underwent this procedure either as a lone operation or as a concomitant procedure. METHODS: From 1988 to 2001, 198 patients underwent a Cox maze III procedure; 112 were lone operations, and 86 were concomitant procedures. Major complications included renal failure, reoperation for bleeding, mediastinitis, stroke, and balloon pump insertion. Follow-up was performed by means of mail and telephone questionnaires with both the patients and their cardiologists. All patients who had any history of arrhythmia or who were taking medication had their rhythm documented by means of electrocardiography. RESULTS: The lone operation group was significantly younger (51.3 +/- 10.5 vs 58.8 +/- 9.9 years) and had a higher male/female ratio (4:1 vs 2:1). There was no difference in operative mortality between groups (1.8% vs 1.2%). At a follow-up of 5.4 +/- 2.9 years, 96.6% (172/178) of all patients were free of atrial fibrillation. There was no difference between the lone operation and concomitant procedure groups (95.9% vs 97.5%). CONCLUSION: The Cox maze III procedure has equivalent operative risk and long-term efficacy in patients undergoing both lone operations and concomitant procedures. The Cox maze III procedure remains the standard against which alternative procedures for atrial fibrillation must be judged.
Adult↗
Abnormal sinus node function in clinical arrhythmias.
To understand abnormal sinus node function in clinical atrial arrhythmias, it is essential to understand the normal function of the sinus node. Much of our understanding of the sinus node comes from work done in rabbits. In small animals, the node is a thin structure and can be modeled in two dimensions. However, in canines and humans, the node is a more complex structure completely surrounded by myocytes. Recent data suggest that the node may be insulated from the surrounding atrial myocytes, except at a limited number of exit sites. A model of the node with discrete exit sites explains how atrial activation can be initiated from multiple sites simultaneously. Within the node there may exist specialized pathways that explain the complex conduction within the node. Multiple cell types, with different intrinsic rates, combined with the nonuniform distribution of autonomic receptors, provide a basis for understanding the dynamics of heart rate control and the initiation of atrial activation. In addition, this model of the sinus node provides a framework to propose novel mechanisms underlying various atrial arrhythmias, such as atrial premature depolarizations or sinus node reentry.
Action Potentials↗
Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation.
BACKGROUND: A number of genetic polymorphisms have been shown to regulate the production and secretion of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interferon (IFN)-gamma, interleukin (IL)-6, and IL-10. Several of these genetic polymorphisms have been shown to be associated with either acute or chronic rejection of kidney, liver, and heart allografts and with development of allograft fibrosis after lung transplantation. The aim of this study was to assess the effect of these genetic polymorphisms on the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Genetic polymorphisms were detected by means of polymerase chain reaction in 93 lung allograft recipients for functional polymorphisms in the TNF-alpha (-308), TGF-beta1 (+869 and +915), IL-6 (-174), IFN-gamma (+874), and IL-10 (-1082, -819, and -592) genes. Then, a correlation between BOS development and the presence of these cytokine genotypes was determined using Kaplan-Meier actuarial analysis. RESULTS: A significant correlation was detected between the presence of high-expression polymorphisms of the IL-6 and IFN-gamma genes and BOS development after lung transplantation (P =0.045 and 0.039, respectively). Also, patients with high-expression polymorphisms in both genes developed BOS significantly earlier than patients with low-expression polymorphisms in one or both genes, suggesting a synergistic effect of the alleles during BOS pathogenesis (P =0.016). No correlation was detected between polymorphisms of the TNF-alpha, TGF-beta1, and IL-10 genes and development of BOS after lung transplantation. CONCLUSIONS: The presence of high-expression polymorphisms at position -174 of the IL-6 gene and position +874 of the IFN-gamma gene significantly increases the risk for BOS development after lung transplantation.
Bronchiolitis Obliterans↗
Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction.
Gene-targeting in mice is a powerful tool to define molecular mechanisms of ischemic heart disease that determine infarct size, postinfarct left ventricular (LV) remodeling, and arrhythmogenesis. Coronary ligation in mice is becoming a widely used model of myocardial infarction (MI), but the pathophysiologic consequences of MI in mice and its relevance to human MI have not been fully elucidated. To characterize structural and functional changes during evolving MI, we analyzed 2-dimensional-based reconstruction of the left ventricle by noninvasive echocardiography obtained 1 day and 1 week after surgical ligation of the left anterior descending coronary artery in mice. Sequential 2-dimensional short-axis cineloops of the left ventricle were used to measure LV mass, and LV volumes at end-diastole and end-systole. Echocardiographic infarct size was estimated by measuring the volume of akinetic LV segments. Histologic infarct size was measured by planimetry of 9 transverse sections of each heart. There was close correlation between the 2 methods (31% +/- 20% of LV mass and 34% +/- 17% of LV area, respectively; y =.83x + 7.9, r = 0.96, P <.01). LV volumes at end diastole increased significantly between 1 day and 1 week (51 +/- 17 microL vs 78 +/- 46 microL, respectively, P <.05). The relative change in LV volumes at end diastole varied as a function of infarct size (r = 0.93, P <.01). LV mass and the extent of hypertrophy of noninfarcted segments also varied with infarct size (r = 0.92, P <.01; r = 0.90, P <.01, respectively). Thus, echocardiography is an accurate noninvasive tool for determination of infarct size and quantitative characterization of postinfarct remodeling in the mouse model of MI. Alterations in cardiac structure and function after coronary ligation in mice closely resemble pathophysiologic changes in human ischemic heart disease.
Animals↗
Chronic transmural atrial ablation by using bipolar radiofrequency energy on the beating heart.
BACKGROUND: Recently, there has been renewed interest in the development of minimally invasive procedures to treat atrial fibrillation. Unipolar radiofrequency catheters are plagued by poor results, in part because of their inability to produce transmural lesions. This study tested the ability of bipolar radiofrequency energy to create chronic transmural lesions on the beating heart that isolated atrial myocardium. METHODS: Five sheep underwent a right thoracotomy. Baseline pacing was performed from the following targeted areas: right atrial appendage, superior vena cava, inferior vena cava, and right pulmonary veins. A cuff of atrial myocardium around the targeted tissue was clamped between the 2 arms of the device. Radiofrequency energy was delivered at 750 mA and continued until the tissue conductance between the electrodes reached a stable minimum level. After ablation, pacing was used to document tissue isolation. The animals survived for 30 days. RESULTS: Twenty circumferential lesions were produced at the initial operation. The mean ablation time was 9.3 +/- 4.0 seconds, and the mean peak temperature was 48.4 degrees C +/- 6.4 degrees C. All lesions acutely and chronically isolated the targeted tissue. Trichrome staining showed that all lesions were transmural. There were no instances of pulmonary vein stenosis or thrombosis. CONCLUSIONS: Bipolar radiofrequency energy can produce permanent transmural linear lesions on the beating heart. Online measurement of tissue conductance reliably predicted lesion transmurality. This new technology may enable surgeons to perform a curative minimally invasive operation for atrial fibrillation on the beating heart.
Animals↗
Epicardial ablation on the beating heart: progress towards an off-pump maze procedure.
BACKGROUND: The treatment of atrial fibrillation with unipolar radiofrequency (RF) catheter ablation techniques has been fraught with difficulty. This study was designed to evaluate the potential advantages of bipolar RF energy and its ability to create transmural linear lesions on the beating heart. METHODS: A right thoracotomy was performed on eight adult sheep. A bipolar RF device was inserted and targeted tissue was clamped between the instrument arms. Ablation was performed on the beating heart. Energy was delivered until the tissue conductance between the two electrodes became constant. RESULTS: A total of 30 lesions were performed. Average ablation time for all lesions was 9.2+/-3.9 seconds with a mean peak temperature of 48.7+/-5.8 OC. Pacing studies demonstrated 100%(30/30) isolation and staining showed that all lesions were transmural. CONCLUSIONS: Epicardially delivered bipolar RF energy was able to reproducibly isolate atrial myocardium. As opposed to other energy sources, lesions were always transmural and can be created within seconds. On-line measurement of conductance correlates with lesion transmurality. This technology has the potential to perform a beating heart MAZE procedure.
Animals↗
Spontaneous and inducible ventricular arrhythmias after myocardial infarction in mice.
INTRODUCTION: Remodeling of gap junctions has been implicated in development of ventricular arrhythmias following myocardial infarction (MI) but the specific contribution of reduced electrical coupling is not known. We addressed this question using hearts from mice heterozygous for a connexin43 null allele (Cx43(+/-)). METHODS: To determine whether Cx43-deficient mice exhibit increased spontaneous ventricular arrhythmias in the setting of chronic ischemic heart disease, radiofrequency transmitters were implanted in wild-type and Cx43(+/-) mice 2 days or 9 weeks after left anterior descending coronary artery ligation or sham operations. ECGs were recorded from unanesthetized, unrestrained mice 1 and 10 weeks after MI. Isolated, perfused hearts excised 1 and 10 weeks after MI were subjected to programmed electrical stimulation to induce arrhythmias. RESULTS AND CONCLUSIONS: Hearts with infarcts exhibited more spontaneous and inducible arrhythmias, but there was no significant difference between wild-type and Cx43-deficient mice. Fewer hearts exhibited spontaneous ventricular tachycardia (VT) in vivo than were inducible in vitro, suggesting that structural and functional substrates for inducible VT in isolated hearts may not be sufficient for initiation and maintenance of sustained VT in vivo. Previous studies have shown that Cx43-deficient mice exhibit more VT than wild-type mice during acute regional ischemia. Mice with MI exhibit increased arrhythmias. However, reduced coupling in Cx43-deficient mice does not significantly enhance spontaneous or inducible VT after MI.
Animals↗