Dr Paul Wang: Welcome to the monthly podcast, On the Beat, for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor in chief, with some of the key highlights from this month's issue.

In our first paper, Leroy Joseph and associates examined whether an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm, by an NADPH oxidase 2, NOX2-dependent mechanism.

In mice on high fat diets, they found that saturated fat activates NOX, whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity in ventricular tachycardia, VT inducibility in perfused hearts. Pharmacologic inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high saturated fat diet and resulted in less inducible VT. On the other hand, high saturated fat diet activates calcium calmodulin dependent protein kinase in the heart, which contributes to abnormal calcium handling, promoting arrhythmia. This work suggests that a molecular mechanism links cardiac metabolism to arrhythmia and it suggest that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.

In our next paper, Misha Regouski and associates examined whether the relationship between endurance exercise and atrial fibrillation, or AF, is dependent on atrial myopathy. They examined six cardiac specific TGFβ1 transgenic and six wild type goats. Pacemakers were implanted in all animals for continuous arrhythmia monitoring and AF inducibility. AF inducibility was evaluated using five separate ten second bursts of atrial pacing. At baseline sustained AF greater than 30 seconds was induced with 10 seconds of atrial pacing in 4 out of 6 transgenic goats, compared to zero out of six wild type controls, P less than 0.05. No spontaneous AF was observed at baseline, three months of progressive endurance exercise up to 90 minutes at 4.5 miles per hour was performed. The authors observed that between two to three months of exercise, three out of six transgenic animals developed self-terminating spontaneous atrial fibrillation compared to zero out of six wild type animals, (P less than 0.05). There was an increase in AF inducibility in both transgenic and wild type animals during the first two months of exercise with partial normalization at three months.

These changes in AF susceptibility were associated with a decrease in circulating micro RNA 21 and micro RNA 29 during the first two months of exercise, with partial normalization three months in both transgenic and wild type animals. The authors concluded that endurance exercise appears to increase inducible AF secondary to altered expression of key profibrotic biomarkers that is independent of the presence of an atrial myopathy.

In our next paper, Seokhun Yang and associates examined whether there is an association between lifetime exposure to endogenous sex hormone, and incident atrial fibrillation, or AF, in subsequent ischemic stroke. They studied nearly five million natural postmenopausal women aged 40 years or greater without prior history of AF and with breast cancer. The primary end point was incident AF and the secondary end point was subsequent ischemic stroke once AF is developed. During the mean follow up of 6.3 years, shorter total reproductive years (<30 years) was associated with 7% increased risk of AF after adjusting for confounding variables. Adjusted hazard ratio, 1.07. Risk of AF declined progressively with every five-year increment in total reproductive years. P for trend less than 0.001. However, the prolonged, two years or greater use of hormone replacement therapy after menopause was paradoxically associated with a 3% increase in AF risk. (Adjusted ratio 1.03).

For the secondary endpoint analysis, the risk of ischemic stroke after AF development significantly decreased with each five-year increment in total reproductive years with less than 30 years as a reference. (Adjusted hazard ratio 0.93, for 30 to 34 years 0.84, for 35 to 39 years is 0.88, for 40 years or greater. P for trend less than 0.001) the authors concluded that women with natural menopause shortened lifetime exposure to endogenous sex hormone, that is, shorter total reproductive years, was significantly associated with a higher risk of AF and subsequent ischemic stroke. In contrast, prolonged exogenous hormone replacement therapy increased the risk of incident AF.

In our next paper, Stephan Hohmann and associates examine the accuracy of electrocardiographic imaging, ECGi, in a closed chest porcine model. A total of 109 endocardial and nine epicardial locations were paced in nine pigs. ECGi predicted the correct chamber of origin in 85% of atrial and 92% of ventricular sites. Lateral locations were predicted in the correct chamber more often than septal location. (97% versus 79% P=0.01) Absolute distances in space between true and predicted pacing locations were 20.7 millimeters.

In the next paper, Ayelet Shapira-Daniels and associates examine the lesion formation produced by a novel expandable lattice electrode radio frequency, RF catheter with an expanded lattice electrode in a larger surface area. The eight French bi-directional irrigated catheter (Sphere-9 Affera Inc) has a nine-millimeter spherical lattice tip with an effective surface area 10-fold larger than standard linear catheter. In 11 ex vivo bovine hearts unipolar ablation lattice produce deeper lesions at 60, 30 and 126 application duration. 6.7 versus 4.8 millimeters. 8.3 versus 5.3 millimeters and 10.0 versus 6.2 millimeters respectively. (P less than or equal 0.001) In five porcine hearts bipolar ablation was compared between the catheters. T max 60 degrees centigrade versus 40 Watts, 60 seconds bipolar lesions were deeper, 15.8 versus 10.5 millimeters, (P less THA 0.001) and we're more likely to be transmural (80% versus 0% P equals 0.002) in vivo lattice produced deeper lesions, 10.5 versus 6.5 millimeters. (P less than or equal to 0.001) Tissue temperature at seven millimeters was higher with lattice. (P less than 0.001) The steam pop occurrence was lower with lattice. (4% versus 18% P equals 0.01) (in vivo, 0% versus 14.2% P equals 0.13) the authors concluded that this novel RF system produces larger ventricle lesions compared to standard irrigated catheters and at a lower risk of tissue overheating.

In our next paper, Jinlin Zhang and associates used an ultra-high-density mapping system to identify the characteristics and precise mechanisms of atrial tachycardia with cycle length alternans. They identified seven atrial tachycardias with alternating cycle length in a total of 478 atrial tachycardias from two institutions mapped with an ultra-high-density mapping system. Activation maps were performed for long cycle length (289 milliseconds; mapping points 21,520) in short cycle length, (251 milliseconds; mapping points, 17,594) separately. The authors classified atrial tachycardias with cycle length alternans into two types. Type one: There existed two potential loops with different routes. Cycle length alternans resulted from an intermittently 2:1 conducting block within the channel of the smaller loop. Type two: Cycling alternans resulted from different conduction velocity through two closely spaced gaps within preexisting linear lesions. Catheter ablation successfully terminated all seven atrial tachycardias.

In our next paper Marine Cacheux and associates examine the role of stromal interaction molecule one STIM1, a calcium sensor that regulates cardiac hypertrophy by triggering store operated calcium entry on arrhythmias. Binding to phospholamban STIM1 increases sarcoplasmic reticulum calcium load independent of store operated calcium entry. They hypothesize that STIM1 controls electrophysiological function in arrhythmias in the adult heart. Inducible myocyte restricted STIM1 knockdown was achieved in adult mice. STIM1 knocked down mice (n=23) exhibited poor survival compared to STIM control (n=22). In Cre recombinase control (n=11) with greater than 50% mortality after only eight days of cardiomyocyte restricted STIM1 knock down. STIM1 knock down but not STIM1 control or CRE recombinase control hearts exhibited increased arrhythmias, such as frequent ectopy to pacing induced VTVF. There was decreased conduction velocity, increased action potential duration heterogeneity in STEM one knocked down mice. These features however, were comparable in VTVF positive and VTVF negative hearts.

They also uncovered a marked increase in the magnitude of action potential duration alternans during rapid pacing and the emergence of a spatially discordant alternans profile in STIM1 knock down hearts. Unlike conduction velocity slowing and actual potential duration of heterogeneity, the magnitude of action potential alternatives was greater. (80%, P less than 0.05 in VTVF positive versus VTVF negative STIM1 knock down hearts) The authors concluded that an adult murine model with inducible and myocyte specific STIM1 depletion. The regulation of spatially discord alternans was mediated by STIM1.

In our next paper Charlotte Houck and associates examined arrhythmia mechanisms and procedural and long-term outcomes in pediatric congenital heart disease patients undergoing catheter ablation. The authors studied 232 patients, (11.7 years, 33.5 kilograms). The most common diagnoses were Ebstein's anomaly (n=44), septal defects (n=39) and single ventricle (n=36).

Arrhythmia Mechanisms included atrioventricular reentry tachycardia (n=104 in 90 patients), atrioventricular nodal reentry tachycardia (n=33 in 29 patients). Twin atrioventricular nodal tachycardia (n=3 in two patients), macroreentrant atrial tachycardia (n=59 in 56 patients). Focal atrial tachycardia (n=33 in 25 patients). Ventricular ectopy (n=10 in eight patients) and ventricul