Citations

ABSTRACT Mutations in genes encoding ion channels have increasingly been identified to cause disease conditions collectively termed channelopathies. Recognizing the molecular basis of an ion channel disease has provided new opportunities for screening, early diagnosis, and therapy of such conditions. This synopsis provides an overview of progress in the identification of molecular defects in inwardly rectifying potassium (Kir) channels. Structurally and functionally distinct from other channel families, Kir channels are ubiquitously expressed and serve functions as diverse as regulation of resting membrane potential, maintenance of K + homeostasis, control of heart rate, and hormone secretion. In humans, persistent hyperinsulinemic hypoglycemia of infancy, a disorder affecting the function of pancreatic β cells, and Bartter's syndrome, characterized by hypokalemic alkalosis, hypercalciuria, increased serum aldosterone, and plasma renin activity, are the two major diseases linked so far to mutations in a Kir channel or associated protein. In addition, the weaver phenotype, a neurological disorder in mice, has also been associated with mutations in a Kir channel subtype. Further genetic linkage analysis and full understanding of the consequence that a defect in a Kir channel would have on disease pathogenesis are among the priorities in this emerging field of molecular medicine.—Abraham, M. R., Jahangir, A., Alekseev, A. E., Terzic, A. Channelopathies of inwardly rectifying potassium channels. FASEB J . 13, 1901–1910 (1999)

ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. KATP channels have been implicated in the shortening of the action potential duration and the cellular loss of K+ that occurs during metabolic inhibition. KATP channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATPi) is the main regulator of KATP channels. ATPi has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg2+, to maintain the activity of KATP channels (presumably through an enzymatic reaction). KATP channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATPi-induced inhibition of channel opening or induce KATP channels to open. How nucleotides will affect KATP channels depends on the state of the channel. K+ channel-opening drugs are pharmacological agents that enhance KATP channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. KATP channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP-binding protein, antagonizes the ATPi-induced channel closure. Understanding the molecular mechanisms that underlie KATP channel regulation should prove essential to further define the function of KATP channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the KATP channel has now become available, it is anticipated that major progress in the KATP channel field will be achieved.

The failing ventricular myocardium is characterized by reduction of high-energy phosphates and reduced activity of the phosphotransfer enzymes creatine kinase (CK) and adenylate kinase (AK), which are responsible for transfer of high-energy phosphoryls from sites of production to sites of utilization, thereby compromising excitation-contraction coupling. In humans with chronic atrial fibrillation (AF) unassociated with congestive heart failure (CHF), impairment of atrial myofibrillar energetics linked to oxidative modification of myofibrillar CK has been observed. However, the bioenergetic status of the failing atrial myocardium and its potential contribution to atrial electrical instability in CHF have not been determined. Dogs with ( n = 6) and without ( n = 6) rapid pacing-induced CHF underwent echocardiography (conscious) and electrophysiological (under anesthesia) studies. CHF dogs had more pronounced mitral regurgitation, higher atrial pressure, larger atrial area, and increased atrial fibrosis. An enhanced propensity to sustain AF was observed in CHF, despite significant increases in atrial effective refractory period and wavelength. Profound deficits in atrial bioenergetics were present with reduced activities of the phosphotransfer enzymes CK and AK, depletion of high-energy phosphates (ATP and creatine phosphate), and reduction of cellular energetic potential (ATP-to-ADP and creatine phosphate-to-Cr ratios). AF duration correlated with left atrial area ( r = 0.73, P = 0.01) and inversely with atrial ATP concentration ( r = −0.75, P = 0.005), CK activity ( r = −0.57, P = 0.054), and AK activity ( r = −0.64, P = 0.02). Atrial levels of malondialdehyde, a marker of oxidative stress, were significantly increased in CHF. Myocardial bioenergetic deficits are a conserved feature of dysfunctional atrial and ventricular myocardium in CHF and may constitute a component of the substrate for AF in CHF.

Background —Previous studies of atrial flutter have found linear block at the crista terminalis; this was thought to predispose the patient to the arrhythmia. More recent observations, however, have demonstrated crista conduction. We sought to characterize the posterior boundary of atrial flutter. Methods and Results —Patients with counterclockwise flutter (n=20), clockwise flutter (n=3), or both (n=5) were studied using two 20-pole catheters. Biplane fluoroscopy determined catheter positions. During counterclockwise flutter, craniocaudal activation occurred along the entire lateral and posterior right atrial walls. Septal activation proceeded caudocranially. In all patients, a line of block was seen in the posteromedial (sinus venosa) right atrium; this was manifested by the presence of double potentials where the upward and downward activations collided. Anatomic location was confirmed by intracardiac echocardiography in 9 patients. In patients with clockwise flutter, the line of block and double potentials were seen in the same location during counterclockwise flutter, but the activation sequence around the line of block was reversed. Pacing near the site of double potentials during sinus rhythm excluded a fixed line of block, and premature atrial complexes demonstrated functional block with manifest double potentials. In 2 patients, posterior ectopy organized to subsequently initiate isthmus-dependent atrial flutter. Conclusions —(1) A functional line of block is seen at the posteromedial (sinus venosa region) right atrium during counterclockwise and clockwise atrial flutter. (2) All lateral wall right atrial activation can be uniform during flutter, without linear block or double potentials in the region of the crista terminalis. (3) Activation at the site of posteromedial right atrial functional block can organize to subsequently initiate isthmus-dependent atrial flutter.

Next-generation screening of disease-related metabolomic phenotypes requires monitoring of both metabolite levels and turnover rates. Stable isotope18O-assisted31P nuclear magnetic resonance (NMR) and mass spectrometry uniquely allows simultaneous measurement of phosphometabolite levels and turnover rates in tissue and blood samples. The18O labeling procedure is based on the incorporation of one18O into Pifrom [18O]H2O with each act of ATP hydrolysis and the distribution of18O-labeled phosphoryls among phosphate-carrying molecules. This enables simultaneous recording of ATP synthesis and utilization, phosphotransfer fluxes through adenylate kinase, creatine kinase, and glycolytic pathways, as well as mitochondrial substrate shuttle, urea and Krebs cycle activity, glycogen turnover, and intracellular energetic communication. Application of expanded18O-labeling procedures has revealed significant differences in the dynamics of G-6-P[18O] (glycolysis), G-3-P[18O] (substrate shuttle), and G-1-P[18O] (glycogenolysis) between human and rat atrial myocardium. In human atria, the turnover of G-3-P[18O], which defects are associated with the sudden death syndrome, was significantly higher indicating a greater importance of substrate shuttling to mitochondria. Phosphometabolomic profiling of transgenic hearts deficient in adenylate kinase (AK1−/−), which altered levels and mutations are associated to human diseases, revealed a stress-induced shift in metabolomic profile with increased CrP[18O] and decreased G-1-P[18O] metabolic dynamics. The metabolomic profile of creatine kinase M-CK/ScCKmit−/−-deficient hearts is characterized by a higher G-6-[18O]P turnover rate, G-6-P levels, glycolytic capacity, γ/β-phosphoryl of GTP[18O] turnover, as well as β-[18O]ATP and β-[18O]ADP turnover, indicating altered glycolytic, guanine nucleotide, and adenylate kinase metabolic flux. Thus,18O-assisted gas chromatography-mass spectrometry and31P NMR provide a suitable platform for dynamic phosphometabolomic profiling of the cellular energetic system enabling prediction and diagnosis of metabolic diseases states.

Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.

Background— Right ventricular pacing increases the risk of heart failure in adults with structural heart disease. The impact of prolonged right ventricular pacing in adults without structural heart disease is not fully characterized and may depend on interactions of pacing with abnormal substrate predisposing to ventricular dysfunction. Methods and Results— We assessed the effect of right ventricular pacing in patients who underwent pacemaker implantation for isolated congenital atrioventricular block between 1964 and 2005. To assess for immunologic contribution to cardiac dysfunction, outcomes were compared between patients with (Ab + ) and without (Ab − ) antinuclear antibody during adulthood and an age- and sex-matched Olmsted County, Minnesota, population. Of 103 patients (mean±SD age, 32±19 years), 18 were Ab + . Long-term survival free of new heart failure after pacemaker implantation in isolated congenital atrioventricular block patients was worse than in the matched population ( P <0.001). This difference was attributable to the development of heart failure in 12 Ab + patients (67%; P <0.001), without differences between Ab − patients (2%) and the matched population (2%; P =0.7). Compared with baseline, at last follow-up, left ventricular ejection fraction did not decline in Ab − (53±9% to 57±12%) but decreased in Ab + (52±10% to 38±12%; P =0.03) patients. Survival was similar in Ab − patients and the Minnesota population (98%; P =0.7) but worse in Ab + patients (79%; P <0.01). Conclusions— The natural history of patients with isolated congenital atrioventricular block who require pacing depends upon their antibody status. Antinuclear antibody status was a predictor for the development of heart failure and death. Long-term right ventricular pacing alone does not appear to be associated with development of heart failure, deterioration in ventricular function, or reduced survival in Ab − isolated congenital atrioventricular block patients.

Background— Outflow tract ventricular tachycardia originating above the semilunar valves has been reported in a small number of studies. Discrete potentials in the great arteries (above the semilunar valves) have been rarely described in patients undergoing electrophysiology evaluation and radiofrequency ablation for ventricular arrhythmias. The mechanisms of these discrete potentials in the great arteries and the utility of such potentials in guiding radiofrequency ablation are unknown. Methods and Results— Twelve patients with outflow tract ventricular arrhythmia originating above the semilunar valves with discrete arterial potentials were studied. The clinical characteristics, properties of the arterial potentials, electrophysiological evaluation and ablation, and short- and long-term outcomes were reviewed. Of the twelve patients, 8 (67%) were women. The patients’ average age was 41�14 years. The average ejection fraction was 0.52�0.16 (range: 0.16 to 0.75). Contact mapping in the great artery demonstrated discrete near-field electrograms that were separate from far-field ventricular electrograms in all patients (8 above the pulmonary valve and in 4 the aortic valve). One or more of the following electrophysiological characteristics, supportive of an arrhythmogenic substrate, were observed in 10 of 12 patients: (1) A fixed or reproducibly variable pattern of discrete potential–ventricular arrhythmia relationship was present at baseline or during pacing; (2) the discrete potential–ventricular electrogram relationship during sinus rhythm was the reverse of that during the ventricular arrhythmia; (3) during sustained ventricular tachycardia, spontaneous variation of the ventricular (V-V) cycle length was preceded by a similar variation of arterial spike potential–spike potential cycle length; and (4) ablation guided by the discrete arterial potential successfully eliminated the clinical arrhythmia. Ablation was successful in these patients. In the remaining 2 patients, the potentials were believed to be bystanders. Over 10�4 months (range: 5 to 32 months) of follow-up, there have been no recurrences of the premature ventricular complex or ventricular arrhythmia. Conclusions— Discrete potentials are present in the great arteries of a select group of patients with outflow tract ventricular tachycardia originating above the semilunar valves. When an arrhythmogenic relationship can be demonstrated, discrete potentials are useful in guiding ablation within the great vessels, despite significant anatomic complexity.