Dual Variation in SCN5A and CACNB2b Underlies the Development of Cardiac Conduction Disease without Brugada Syndrome

Background: Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood. Methods: Direct sequencing was performed in a family with cardiac conduction disease. Wild‐type (WT) and mutant channels were expressed in TSA201 cells for electrophysiological study. Green fluorescent protein (GFP)‐fused WT or mutant genes were used to assess channel trafficking. Results: A novel SCN5A mutation, P1008S, was identified in all family members displaying first‐degree atrioventricular block, but not in unaffected family members nor in 430 reference alleles. Peak P1008S current was 11.77% of WT (P < 0.001). Confocal microscopy showed that WT channels tagged with GFP were localized on the cell surface, whereas GFP‐tagged P1008S channels remained trapped in intracellular organelles. Trafficking could be rescued by incubation at room temperature, but not by incubation with mexiletine (300 μM) at 37°C. We also identified a novel polymorphism (D601E) in CACNB2b that slowed inactivation of L‐type calcium current (I_Ca,L), significantly increased total charge. Using the Luo‐Rudy action potential (AP) model, we show that the reduction in sodium current (I_Na) can cause loss of the right ventricular epicardial AP dome in the absence but not in the presence of the slowed inactivation of I_Ca,L. Slowed conduction was present in both cases. Conclusions: Our results suggest genetic variations leading to a loss‐of‐function in I_Na coupled with a gain of function in I_Ca,L may underlie the development of cardiac conduction disease without BrS. (PACE 2010; 33:274–285)     

Diagnostic evaluation of a synthetic peptide derived from a novel antigen B subunit as related to other available peptides and native antigens used for serology of cystic hydatidosis

A synthetic peptide (GU4) derived from an antigen B (AgB) subunit was serologically compared with crude antigen (HCFA); immunopurified AgB and antigen 5 (Ag5), and two other synthetic peptides, for diagnosis of human cystic hydatidosis. GU4 was derived from the sequence of AgB/2, the novel AgB subunit described by us. The other two peptides: 65 (AgB mimotope) and 89–122 (Ag5 mimotope), were described by others. Antigens B and 5 showed higher diagnostic sensitivity than corresponding peptides. All sera reacting with peptides 89–122 and GU4 also reacted with 65. The latter provided three to four times higher sensitivity than the former two peptides, but 30% lower specificity. The diagnostic efficiency of AgB (82%) was higher than those of Ag5 (74%) and HCFA (71%). Interestingly, 89–122 only reacted with hydatid sera, some of which did not react with AgB. Considering positive those reacting with 89–122 or AgB, sensitivity increases from 77% (with AgB) to 82% (combined), while specificity is the same as with AgB (86%). Our results suggest that hydatid serology may be improved by: a) combining several defined antigens (including synthetic peptides), b) design of new E. granulosus-specific mimotopes, which react with the false negative sera (16/90; 18%).     

Conversion Rates of Induced Versus Spontaneous Ventricular Tachycardia by a Third Generation Cardioverter Defibrillator

Seventy consecutive patients received the first VENTAK PRx pulse generators (Cardiac Pacemakers, Inc.) implanted in the United States. This multiprogrammable device has therapeutic options that include: (1) antitachycardia pacing; (2) low energy cardioversion; (3) defihrillation shocks; and (4) bradycardia pacing. There were 60 males and 10 females with a mean age of 65.3 ± 9.4 years. The anatomical diagnoses were coronary artery disease in 55 patients, cardiomyopathy in 7 patients, congenital heart disease in 2 patients, and miscellaneous disease in the remaining 6 patients. Thirty-six percent had a history of sudden cardiac death and 90% had documented monomorphic ventricular tachycardia. The mean ejection fraction was 32.7%± 12.2%. Thirty-three (49.3%) had an ejection fraction ≤ 30%. Electrophysiological testing was done preimplant, predischarge, and 1 to 2 months postimplant to define a specific electrical therapy and evaluate the efficacy of the device. Two hundred ninety-three of 367 (80%) episodes of induced ventricular tachycardia were successfully terminated by the VENTAK PRx programmed for antitachycardia pacing. There were 1,794 total therapy episodes for spontaneous ventricular tachycardia; 91% (1,641 episodes) were terminated by antitachycardia pacing and 153 episodes were converted by shocks during a minimal 6-month follow-up per patient. We conclude that documentation of a successful antitachycardia pacing modality in the electrophysiology laboratory predicts conversion of spontaneous episodes of ventricular tachycardia. Furthermore, antitachycardia pacing by the VENTAK PRx can terminate the majority of episodes of ventricular tachycardia.     

Some Aspects of Human and Canine Macroscopic Pancreas Innervation

Both vagus nerves and the celiae ganglion complex are the main source of the pancreatic gland innervation. In both man and dog there is a distinct difference in the number of fibers ending in the different segments of the gland. In the former, the macroscopic innervation is primarily concentrated in the pancreas head and isthmus. In the latter most of the nerves enter through the upper part of the right limb (uncinate process). Both vagus nerves send direct fibers to the gland but in most of the nerves, that course in general along the different branches of the celiac and mesenteric arteries, the parasympathetic and adrenergic fibers are intermingled. The anterior hepatic plexus, continued down by the gastroduodenal, completes a nervous circle, at the lower edge of the pancreas, with the branches arising from the splenic plexus. In human pancreas most of the nerves, with the exception of the branches given off by the gastroduodenal network, enter the gland by its periphery, either through its superior or inferior border. The gastroduodenal plexus is the pathway for the duodenopancreatic and the duodenogastric are reflexes and for the "pancreatic type" of pain triggered by some posterior penetrating duodenal ulcers.     

Erythropoietin Excretion in Normal Man

Levels of erythropoietin have been consistently demonstrated in urine collections from healthy adult males using a modification of the polycythemic mouseassay. This method is stable and reproducible, and it provides assay animalswith low background erythropoiesis. Six hour collections of urine can be concentrated without apparent loss of activity and the entire daily excretion canbe used in the assay. Quantitation has been achieved by comparing theresponse to a concentrate of normal urine directly to a linear dose/responsecurve of erythropoietin standard B. Based on 6 hour urine collections, erythropoietin excretion in the subjects tested averaged 4.0 units of erythropoietinstandard B (range 1.2-9.5). In addition to wide unexplained variations inresults seen from day to day, the data indicate that a diurnal pattern ofexcretion of the hormone may exist.

Submitted on October 26, 1965 Accepted on January 1, 1966