Gernot Schram

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

The cardiac electrical system is designed to ensure the appropriate rate and timing of contraction in all regions of the heart, which are essential for effective cardiac function. Well-controlled cardiac electrical activity depends on specialized properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Cardiac electrical specialization was first recognized in the mid 1800s, but over the past 15 years, an enormous amount has been learned about how specialization is achieved by differential expression of cardiac ion channels. More recently, many aspects of the molecular basis have been revealed. Although the field is potentially vast, an appreciation of key elements is essential for any clinician or researcher wishing to understand modern cardiac electrophysiology. This article reviews the major regionally determined features of cardiac electrical function, discusses underlying ionic bases, and summarizes present knowledge of ion channel subunit distribution in relation to functional specialization.

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

Background—There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs. Methods and Results—We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42±18 to 1079±341 seconds at terminal open-chest study after tachypacing alone (P<0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117±5 to 76±6 ms (P<0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitamins C and E; however, simvastatin suppressed tachypacing-induced remodeling effects significantly, with AF duration and ERP averaging 41±15 seconds and 103±4 ms, respectively, after tachypacing with simvastatin therapy. Tachypacing downregulated L-type Ca2+-channel &agr;-subunit expression (Western blot), an effect that was unaltered by antioxidant vitamins but greatly attenuated by simvastatin. Conclusions—Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins, and constitutes a potentially interesting new pharmacological approach to preventing the consequences of atrial tachycardia remodeling.

Effects of Antiarrhythmic Drugs on Fibrillation in the Remodeled Atrium Insights Into the Mechanism of the Superior Efficacy of Amiodarone

Background—The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia. Methods and Results—Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca2+-current &agr;1c-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy. Conclusions—Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.

All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy.

OBJECTIVES This study sought to determine the impact of steroid therapy on cardiomyopathy and mortality in patients with Duchenne muscular dystrophy (DMD). BACKGROUND DMD is a debilitating X-linked disease that afflicts as many as 1 in 3,500 boys. Although steroids slow musculoskeletal impairment, the effects on cardiac function and mortality remain unknown. METHODS We conducted a cohort study on patients with DMD treated with renin-angiotensin-aldosterone system antagonists with or without steroid therapy. RESULTS Eighty-six patients, 9.1 ± 3.5 years of age, were followed for 11.3 ± 4.1 years. Seven of 63 patients (11%) receiving steroid therapy died compared with 10 of 23 (43%) not receiving steroid therapy (p = 0.0010). Overall survival rates at 5, 10, and 15 years of follow-up were 100%, 98.0%, and 78.6%, respectively, for patients receiving steroid therapy versus 100%, 72.1%, and 27.9%, respectively, for patients not receiving steroid therapy (log-rank p = 0.0005). In multivariate propensity-adjusted analyses, steroid use was associated with a 76% lower mortality rate (hazard ratio: 0.24; 95% confidence interval: 0.07 to 0.91; p = 0.0351). The mortality reduction was driven by fewer heart failure-related deaths (0% vs. 22%, p = 0.0010). In multivariate analyses, steroids were associated with a 62% lower rate of new-onset cardiomyopathy (hazard ratio: 0.38; 95% confidence interval: 0.16 to 0.90; p = 0.0270). Annual rates of decline in left ventricular ejection fraction (-0.43% vs. -1.09%, p = 0.0101) and shortening fraction (-0.32% vs. -0.65%, p = 0.0025) were less steep in steroid-treated patients. Consistently, the increase in left ventricular end-diastolic dimension was of lesser magnitude (+0.47 vs. +0.92 mm per year, p = 0.0105). CONCLUSIONS In patients with DMD, steroid therapy is associated with a substantial reduction in all-cause mortality and new-onset and progressive cardiomyopathy.

Properties, expression and potential roles of cardiac K+ channel accessory subunits: MinK, MiRPs, KChIP, and KChAP.

Over the past 10 years, cDNAs encoding a wide range of pore-forming K+-channel α-subunits have been cloned and found to result in currents with many properties of endogenous cardiac K+ channels upon homomeric expression in heterologous systems. However, a variety of remaining discrepancies have led to a search for other subunits that might be involved in the formation of native channels. Over the past few years, a series of accessory subunits has been discovered that modify current properties upon coexpression with α-subunits. One of these, the minimal K+-channel subunit minK, is essential for formation of the cardiac slow delayed-rectifier K+ current, IKs, and may also interact in functionally important ways with other α-subunits. Another, the K+-channel interacting protein KChIP appears critical in formation of native transient outward current (Ito) channels. The roles of 2 other accessory subunits, the minK-related peptide MiRP and the K+-channel accessory protein, KChAP, remain unclear. This article reviews the available knowledge regarding the accessory subunits minK, MiRP, KChIP and KChAP, dealing with their structure, effects on currents carried by coexpressed α-subunits, expression in cardiac tissues and potential physiological function. On the basis of the available information, we attempt to assess the potential involvement of these accessory K+-channel subunits in cardiac pathophysiology and in developing new therapeutic approaches.

Arrhythmogenic ionic remodeling: adaptive responses with maladaptive consequences.

Compensatory changes in ion transport mechanisms occur in response to a variety of cardiac disease processes. Recent work has demonstrated that these adaptive responses can produce the arrhythmogenic substrate for a variety of important cardiac rhythm disorders. Two important paradigms are atrial tachycardia-induced remodeling and ionic remodeling caused by congestive heart failure. Atrial tachycardia promotes cellular Ca(2)+ loading and downregulates a variety of ion channels, particularly L-type Ca(2)+ channels, thereby promoting the occurrence and maintenance of atrial fibrillation. Congestive heart failure alters the expression and function of a variety of membrane transport processes, including several K(+)-channels and key Ca(2)+-transport systems, favoring the occurrence of arrhythmogenic afterdepolarizations. An improved understanding of the mechanisms and consequences of arrhythmogenic ionic remodeling promises to lead to novel and improved therapeutic approaches.

Effects of flecainide and quinidine on Kv4.2 currents: voltage dependence and role of S6 valines

The effects of flecainide and quinidine were studied on wild‐type Kv4.2 channels (Kv4.2WT), channels with deletion of the N‐terminal domain (N‐del) and channels with mutations in the valine residues located at positions 402 and 404 in the presence (V[402,404]I) or in the absence (N‐del/V[402,404]I) of the N‐terminus. The experiments were performed at 37°C on COS7 cells using the whole‐cell configuration of the patch‐clamp technique. Flecainide and quinidine inhibited Kv4.2WT currents in a concentration‐dependent manner (IC50=23.6±1.1 and 12.0±1.4 μMat +50 mV, respectively), similar to their potency for the rest of the constructs at the same voltage. In Kv4.2WT channels, flecainide‐ and quinidine‐induced block increased as channel inactivation increased. In addition, the inhibition produced by quinidine, but not by flecainide, increased significantly at positive test potentials. Similar effects were observed in N‐del channels. However, in V[402,404]I and N‐del/V[402,404]I channels, the voltage dependence of block by both quinidine and flecainide was lost, without significant modifications in potency at +50 mV. These results point to an important role for S6 valines at positions 402 and 404 in mediating voltage‐dependent block by quinidine and flecainide.

Electrocardiographic and electrophysiological predictors of atrioventricular block after transcatheter aortic valve replacement

BACKGROUND Electrophysiological predictors of atrioventricular (AV) block after transcatheter aortic valve replacement (TAVR) are unknown. OBJECTIVE We sought to assess the value of electrophysiology study before and after TAVR. METHODS Seventy-five consecutive pacemaker-free patients undergoing TAVR at the Montreal Heart Institute were prospectively studied. RESULTS Eleven patients (14.7%) developed AV block during the index hospitalization and 3 (4.0%) after hospital discharge over a median follow-up of 1.4 years (interquartile range 0.6-2.1 years). AV block developed in 5 of 6 patients with preprocedural right bundle branch block (83.3%), 8 of 30 patients with new-onset left bundle branch block (LBBB; 26.7%), and 1 of 7 patients with preexisting LBBB (14.3%). In multivariate analysis that considered all patients, the delta-HV interval (HV interval after TAVR minus HV interval before TAVR) was the only factor independently associated with AV block. In the subgroup of patients with new-onset LBBB, the postprocedural HV interval was strongly associated with AV block. By receiver operating characteristic analysis, a delta-HV interval of ≥13 ms predicted AV block with 100.0% sensitivity and 84.4% specificity and an HV interval of ≥65 ms predicted AV block with 83.3% sensitivity and 81.6% specificity. In multivariate analysis, the HV interval after TAVR (hazard ratio 1.073 per ms; 95% confidence interval 1.029-1.119; P = .001) was also independently associated with all-cause mortality. CONCLUSION A prolonged delta-HV interval (≥13 ms) is strongly associated with AV block after TAVR. In patients with new-onset LBBB after TAVR, a postprocedural HV interval of ≥65 ms is likewise predictive of AV block.

The Kv4.2 N-terminal restores fast inactivation and confers KChIP2 modulatory effects on N-terminal-deleted Kv1.4 channels

The N-terminal end of the subunits of the voltage-gated K+ channel Kv1.4 is essential for their rapid N-type inactivation, but removal of the entire Kv4.2 N-terminus slows inactivation only moderately. In this study, we investigated the effect of substituting the Kv4.2 N-terminal for that of Kv1.4 subunits. Despite the minor role of the Kv4.2 N-terminal in Kv4.2 inactivation and the limited degree of amino acid identity between Kv1.4 and Kv4.2 N-terminals, attachment of the Kv4.2 N-terminal to inactivation-deficient, N-terminal-deleted Kv1.4 subunits restored rapid inactivation. The Kv4.2 N-terminal/N-deleted Kv1.4 chimeric construct had inactivation kinetics like those of Kv4.2, inactivation voltage-dependence resembling Kv1.4 and recovery from inactivation substantially faster than wild-type Kv1.4. Acceleration of reactivation appeared to be due to the ability of chimeric channels to recover from inactivation without passing through the open state. Co-expression of wild-type Kv1.4 with the K+ channel interacting protein-2 (KChIP2) did not alter Kv1.4 properties, but co-expression of KChIP2 with Kv4.2 N-terminal/N-deleted Kv1.4 chimeric subunits significantly increased current expression and slowed inactivation without altering the rate of recovery from inactivation. We conclude that substitution of the Kv4.2 N-terminal for that of Kv1.4 transfers a variety of properties of Kv4.2, including inactivation time-dependence, accelerated recovery from inactivation and interaction with KChIP2, to Kv1.4, indicating the ability of Kv1.4 subunits to display these properties and the sufficiency of the Kv4.2 N-terminal to convey them.

Ventricular septal rupture and right ventricular free wall dissection after inferior myocardial infarction: a case report and review of the literature.

Ventricular septal rupture (VSR) with dissection of the right ventricular free wall is an extremely rare complication after inferior myocardial infarction. Mortality is 100% without surgical treatment. The optimal surgical strategy remains unclear because of the limited number of cases, but repair of VSR alone might be equally effective as repair of VSR and right ventricular free wall reconstruction. Transesophageal echocardiography is an important adjunct to transthoracic echocardiography to establish the diagnosis.