Impact of revascularization in patients with sustained ventricular arrhythmias, prior myocardial infarction, and preserved left ventricular ejection fraction.

BACKGROUND: The impact of revascularization on recurrent ventricular arrhythmias (VAs) in patients with coronary artery disease and relatively preserved left ventricular ejection fraction (LVEF) is unknown. OBJECTIVE: The purpose of this study was to determine the impact of revascularization on recurrent VAs or death. METHODS: A cohort study was conducted on consecutive patients with prior myocardial infarction and LVEF ≥40% presenting with a first clinical sustained VA in the absence of an acute coronary syndrome. The impact of revascularization on recurrent VAs and all-cause mortality was assessed. RESULTS: A total of 274 patients (mean age 66.1 ± 9.7 years, 85.4% male, mean LVEF 48.3% ± 7.2%) were included in the study. Eight-eight patients (32.1%) underwent coronary revascularization. During mean follow-up of 6.2 ± 5.1 years, 140 (51.1%) died or had recurrent sustained VAs or appropriate implantable-cardioverter defibrillator therapy. Revascularization was not associated with a significantly lower rate of recurrent VAs or death (multivariable hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.60-1.24, P = .43) regardless of whether it was complete or incomplete (HR 0.65, 95% CI 0.25-1.69, P = .37) or was performed by percutaneous or surgical means (HR 1.02, 95% CI 0.53-1.94, P = .96). An implantable-cardioverter defibrillator was associated with a significant reduction in mortality (HR 0.23, 95% CI 0.09-0.55, P = .001). CONCLUSION: Patients with prior myocardial infarction and LVEF ≥40% who present with sustained VAs in the absence of an acute coronary syndrome remain at high risk for recurrent VAs and all-cause death. Coronary revascularization does not systemically mitigate this risk.

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.

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.

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.

The pharmacological response of ischemia-related atrial fibrillation in dogs: evidence for substrate-specific efficacy.

OBJECTIVE: Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF. METHODS AND RESULTS: Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective. CONCLUSIONS: Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.

Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2.

Inward rectifier K(+) channels (Kir) are a significant determinant of endothelial cell (EC) membrane potential, which plays an important role in endothelium-dependent vasodilatation. In the present study, several complementary strategies were applied to determine the Kir2 subunit composition of human aortic endothelial cells (HAECs). Expression levels of Kir2.1, Kir2.2, and Kir2.4 mRNA were similar, whereas Kir2.3 mRNA expression was significantly weaker. Western blot analysis showed clear Kir2.1 and Kir2.2 protein expression, but Kir2.3 protein was undetectable. Functional analysis of endothelial inward rectifier K(+) current (I(K)) demonstrated that 1) I(K) current sensitivity to Ba(2+) and pH were consistent with currents determined using Kir2.1 and Kir2.2 but not Kir2.3 and Kir2.4, and 2) unitary conductance distributions showed two prominent peaks corresponding to known unitary conductances of Kir2.1 and Kir2.2 channels with a ratio of approximately 4:6. When HAECs were transfected with dominant-negative (dn)Kir2.x mutants, endogenous current was reduced approximately 50% by dnKir2.1 and approximately 85% by dnKir2.2, whereas no significant effect was observed with dnKir2.3 or dnKir2.4. These studies suggest that Kir2.2 and Kir2.1 are primary determinants of endogenous K(+) conductance in HAECs under resting conditions and that Kir2.2 provides the dominant conductance in these cells.

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 alpha-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.

The Kv4.2 N-terminal restores fast inactivation and confers KChlP2 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 Kvl.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 Kvl.4 subunits to display these properties and the sufficiency of the Kv4.2 N-terminal to convey them.

Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects.

Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to d-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC(50) of 106 micromol l(-1), whereas the IC(50) for IsK was 1.7 mmol l(-1). d-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. d-Sotalol had clear proarrhythmic effects, with all d-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. Effects on I(Kr) and I(Ks) were similar to those on HERG and IsK. Ranolazine blocked I(Ca) with an IC(50) of approximately 300 micromol l(-1). I(Na) was unaffected. We conclude that ranolazine inhibits I(Kr) by blocking HERG currents, inhibits I(Ca) at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike d-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I(Ca) at concentrations only slightly larger than those that inhibit I(Kr), thus producing offsetting effects on repolarization.

Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents.

BACKGROUND: Kir2 subunits are believed to underlie the cardiac inwardly rectifying current I(K1). The subunit composition of native I(K1) currents is uncertain, and it has been suggested that heteromultimer formation may play a role. METHODS: We studied Ba(2+) block of homo- and heteromeric Kir2 channels in Xenopus oocytes and compared the properties observed to those of human cardiac I(K1) in cells isolated from myocardial biopsies of normal human hearts. RESULTS: Homomeric expression of Kir2.1 and Kir2.3 produced currents with similar Ba(2+) sensitivities (e.g. IC(50) at -120 mV: 16.2+/-3.4, n=11 and 18.5+/-2.1, n=10, respectively), but these were less sensitive to Ba(2+) than native I(K1) (4.7+/-0.5 microM, n=10, P=0.001, P<0.001, respectively) and had different Ba(2+) blocking kinetics from cardiac I(K1). Kir2.2 sensitivity was similar to cardiac I(K1) (e.g., 2.8+/-0.4 microM, Kir2.2, n=9, vs. 4.7+/-0.5 microM for I(K1)), but the blocking kinetics of Kir2.2 were faster than those of I(K1). Currents resulting from co-expression of Kir2 subunits had similar Ba(2+) sensitivities and blocking kinetics among groups and were similar to I(K1) in both Ba(2+) sensitivity (e.g., IC(50) at -120 mV: 4.5+/-1.0, 2.5+/-0.5, and 2.3+/-0.4 microM for co-injected Kir2.1/2.2, n=6, Kir2.1/2.3, n=5, and Kir2.2/2.3, n=4, respectively) and blocking kinetics. CONCLUSION: Co-injection of Kir2 subunits results in currents with Ba(2+) blocking properties different from homomeric Kir2 expression but similar to cardiac I(K1). These observations suggest that a substantial proportion of native I(K1) may result from heteromultimer formation among diverse Kir2 family subunits.

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

1. 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. 2. The experiments were performed at 37 degrees C on COS7 cells using the whole-cell configuration of the patch-clamp technique. 3. Flecainide and quinidine inhibited Kv4.2WT currents in a concentration-dependent manner (IC(50)=23.6+/-1.1 and 12.0+/-1.4 microMat +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. 4. These results point to an important role for S6 valines at positions 402 and 404 in mediating voltage-dependent block by quinidine and flecainide.

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 alpha1c-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.

Properties of potassium currents in Purkinje cells of failing human hearts.

Cardiac Purkinje fibers play an important role in cardiac arrhythmias, but no information is available about ionic currents in human cardiac Purkinje cells (PCs). PCs and midmyocardial ventricular myocytes (VMs) were isolated from explanted human hearts. K(+) currents were evaluated at 37 degrees C with whole cell patch clamp. PCs had clear inward rectifier K(+) current (I(K1)), with a density not significantly different from VMs between -110 and -20 mV. A Cs(+)-sensitive, time-dependent hyperpolarization-activated current was measurable negative to -60 mV. Transient outward current (I(to)) density was smaller, but end pulse sustained current (I(sus)) was larger, in PCs vs. VMs. I(to) recovery was substantially slower in PCs, leading to strong frequency dependence. Unlike VM I(to), which was unaffected by 10 mM tetraethylammonium, Purkinje I(to) was strongly inhibited by tetraethylammonium, and Purkinje I(to) was 10-fold more sensitive to 4-aminopyridine than VM. PC I(sus) was also reduced strongly by 10 mM tetraethylammonium. In conclusion, human PCs demonstrate a prominent I(K1), a time-dependent hyperpolarization-activated current, and an I(to) with pharmacological sensitivity and recovery kinetics different from those in the atrium or ventricle and compatible with a different molecular basis.

Kir2.4 and Kir2.1 K(+) channel subunits co-assemble: a potential new contributor to inward rectifier current heterogeneity.

Heteromeric channel assembly is a potential source of physiological variability. The potential significance of Kir2 subunit heterotetramerization has been controversial, but recent findings suggest that heteromultimerization of Kir2.1-3 may be significant. This study was designed to investigate whether the recently described Kir2.4 subunit can form heterotetramers with the important subunit Kir2.1, and if so, to investigate whether the resulting heterotetrameric channels are functional. Co-expression of either dominant negative Kir2.1 or Kir2.4 subunits in Xenopus oocytes with either wild-type Kir2.1 or 2.4 strongly decreased resulting current amplitude. To examine physical association between Kir2.1 and Kir2.4, Cos-7 cells were co-transfected with a His(6)-tagged Kir2.1 subunit (Kir2.1-His(6)) and a FLAG-tagged Kir2.4 subunit (Kir2.4-FLAG). After pulldown with a His(6)-binding resin, Kir2.4-FLAG could be detected in the eluted cell lysate by Western blotting, indicating co-assembly of Kir2.1-His(6) and Kir2.4-FLAG. Expression of a tandem construct containing covalently linked Kir2.1 and 2.4 subunits led to robust current expression. Kir2.1-Kir2.4 tandem subunit expression, as well as co-injection of Kir2.1 and Kir2.4 cRNA into Xenopus oocytes, produced currents with barium sensitivity greater than that of Kir2.1 or Kir2.4 subunit expression alone. These results show that Kir2.4 subunits can co-assemble with Kir2.1 subunits, and that co-assembled channels are functional, with properties different from those of Kir2.4 or Kir2.1 alone. Since Kir2.1 and Kir2.4 mRNAs have been shown to co-localize in the CNS, Kir2.1 and Kir2.4 heteromultimers might play a role in the heterogeneity of native inward rectifier currents.

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.