Connexin (Cx) 43 and Cx40 are coexpressed in several tissues, including cardiac atrial and ventricular myocytes and vascular smooth muscle. It has been shown that these Cxs form homomeric͞homotypic channels with distinct permeability and gating properties but do not form functional homomeric͞heterotypic channels. If these Cxs were to form heteromeric channels, they could display functional properties not well predicted by the homomeric forms. We assessed this possibility by using A7r5 cells, an embryonic rat aortic smooth muscle cell line that coexpresses Cxs 43 and 40. Connexons (hemichannels), which were isolated from these cells by density centrifugation and immunoprecipitated with antibody against Cx43, contained Cx40. Similarly, antibody against Cx40 coimmunoprecipitated Cx43 from the same connexon fraction but only Cx40 from Cx (monomer) fractions. These results indicate that heteromeric connexons are formed by these Cxs in the A7r5 cells. The gap junction channels formed in the A7r5 cells display many unitary conductances distinct from homomeric͞homotypic Cx43 or Cx40 channels. Voltage-dependent gating parameters in the A7r5 cells are also quite variable compared with cells that express only Cx40 or Cx43. These data indicate that Cxs 43 and 40 form functional heteromeric channels with unique gating and conductance properties.Gap junction channels connect the cytoplasms of adjacent cells and provide a pathway for intercellular diffusion of ions, second messenger molecules, and small metabolites. Functional gap junction channels are formed by connexins (Cxs), a gene family with at least 14 mammalian members that are distinguished from one another by their predicted molecular weights expressed in kilodaltons (e.g., Cx43, the 43-kDa connexin). Cxs oligomerize to form connexons (hemichannels), which are defined as homomeric when the six comprising Cxs are identical or heteromeric when two or more Cxs comprise the connexon. Connexons in adjacent cells join in the extracellular space to form the functional intercellular channel, which is defined as homotypic when the Cx composition of the contributing connexons is identical or heterotypic when different.The ability of Cxs to form homomeric͞heterotypic channels has been examined in the Xenopus oocyte and HeLa cell expression systems as well as in other settings (for review, see ref. 1). Homomeric Cx43 connexons successfully dock with homomeric connexons comprised of Cxs 30.3, 37, and 45 but not with Cxs 50, 40,33,32, 31.3,31,or 26. Homomeric Cx40 connexons successfully dock with and form functional homomeric͞heterotypic channels with Cxs 37 and 45 but not with Cxs 50, 46, 43,32, 31.1,31,or 26. Clearly, there are far more incompatible than compatible combinations.The capacity of Cxs to form functional heteromeric connexons and channels has only recently received attention. Biochemical and structural tools have demonstrated the existence of heteromeric connexons comprised of Cxs 46 and 50 (2) and Cxs 32 and 26 (3). That these Cx pairs form functional hetero...

A total of 90 unrelated Chinese subjects with definite (n=69), borderline (n=15), or possible (n=6) diagnosis of ARVC and 300 age-, sex-, and ethnicity-matched healthy control subjects were recruited for gene analysis at our center. ARVC was diagnosed in all patients according to the revised diagnostic Task Force Criteria. 17 None of the control subjects had a history of cardiovascular or other systemic diseases.This study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committees of our hospital. The informed consent for the electrophysiological (EP) study and genetic testing was provided by all participants. EP study was not performed on the control subjects. Clinical EvaluationClinical evaluation including 12-lead ECG and transthoracic echocardiography was performed in all cases. Cardiovascular magnetic resonance and 24-hour Holter monitoring were performed. The EP characteristics of ARVC were assessed by EP study, and the results were correlated with genetic testing of 9 genes that have previously been reported to be related to ARVC, including plakophilin-2 (PKP2), desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP), transforming growth factor-β3 (TGFβ3), transmembrane protein 43 (TMEM43), desmin (DES), and Lamin A/C (LMNA).All clinical data were reviewed independently by 3 cardiologists with resolution of differences by consensus.Background-Although mutations of several genes are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the exact correlation between genotype and ventricular arrhythmia features remains unclear. This study was aimed to examine the possible association of the 9 known genes of ARVC with clinical and electrophysiological characteristics. Methods and Results-Ninety subjects diagnosed with ARVC who underwent electrophysiological study were recruited for screening the 9 known ARVC-causing genes. A total of 53 mutations were identified in 57 (63%) subjects. Mutation carriers had more frequent clinical ventricular tachycardia (VT; 89% versus 55%; P<0.001) and negative T waves in V 1 to V 3 (61% versus 33%; P=0.016). Subjects with plakophilin-2 (PKP2) mutations also had more frequent VT than those without mutations in PKP2. Comparison between subjects with multiple and single mutations showed that syncope occurred more often in the former group (58% versus 24%; P=0.018). VT was significantly more often induced in mutation carriers compared with noncarriers (75% versus 39%; P=0.001), as well as in PKP2 mutation carriers compared with subjects without PKP2 mutations (80% versus 48%; P=0.002). Induced VT with a rate ≥200 bpm was more often documented in mutation carriers (88% versus 54%; P=0.013), as well as in PKP2 mutation carriers (91% versus 67%; P=0.041). Conclusions-Pathogenic

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Shortening of the IVCT measured by an accelerometer is a consistent time interval change due to biventricular pacing that probably reflects more rapid acceleration of left ventricular ejection. The accelerometer may be useful to assess immediate efficacy of biventricular pacing during device implantation and optimize programmable time intervals such as AV and interventricular (VV) delays.

The feasibility of using ultrasound to induce cardiac tissue necrosis for the treatment of arrhythmias was investigated. A theoretical model was used to optimize the operating frequency for necrosis of highly perfused muscle tissue. From these simulations it appeared that frequencies from 10-15 MHz produce the deepest lesions at ultrasound intensities between 15 and 30 W/cm2. Test catheters with a planar ultrasound transducer (diameter 2.3 mm = 7 F) were also constructed and in vitro and in vivo tests with canine heart muscle were performed. Both of these tests showed that the ultrasound catheters could deliver adequate energy to necrose cardiac tissue. The in vivo lesion depths of 5-9 mm indicated that ultrasound has significant potential for cardiac ablation for the treatment of arrhythmias.