Charles Jia-Yin Hou

Electrophysiologic Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes

Antiarrhythmic drugs that exert their therapeutic effects primarily by delaying cardiac repolarization and prolonging the QT interval have, in recent years, become the favored drug treatment for life-threatening ventricular arrhythmias. Such drugs are presumed to have greater clinical effectiveness and a lower risk profile than more traditional antiarrhythmic drugs, which primarily slow the action potential conduction velocity and prolong the QRS duration [1, 2]. Although agents that prolong the QT interval may be useful in treating arrhythmia, they may also provoke a unique form of proarrhythmia called torsade de pointes [3, 4]. Torsade de pointes (twisting of points) is a characteristic form of polymorphic ventricular tachycardia in which the mean electrical axis of the QRS complex within any single electrocardiographic lead appears to twist around the isoelectric line [3]. Quinidine is the most widely used antiarrhythmic drug that can induce torsade de pointes; the reported incidence of torsade de pointes in patients receiving quinidine is 1% to 8% [5]. Antiarrhythmic drugs such as procainamide, disopyramide, and sotalol may also cause torsade de pointes, although amiodarone, which also prolongs the QT interval, is much less likely to do so [6, 7]. However, torsade de pointes is more than simply an unusual cardiac curiosity; numerous noncardiac agents or conditions may also precipitate it. The acquired and hereditary long QT interval syndromes and the form of polymorphic ventricular tachycardia associated with them have now become a model of the ways in which identifiable cellular electrophysiologic abnormalities can cause clinical cardiac arrhythmia. With the development of new cellular and molecular biological techniques, the cellular mechanisms of these syndromes are now the subject of renewed research interest. In this review, we 1) classify the forms of the long QT interval syndromes; 2) discuss proposed explanations of the cellular electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes; 3) outline the causes of the acquired long QT interval syndromes, placing particular emphasis on torsade de pointes caused by antiarrhythmic drugs; 4) briefly review the hereditary long QT interval syndromes and torsade de pointes; and 5) summarize the available short- and long-term treatment options for the acquired and hereditary long QT interval syndromes. Classification of the Long QT Interval Syndromes and Torsade de Pointes As seen in Figure 1, the QT interval recorded on the surface electrocardiogram corresponds to the relatively isoelectric plateau phase of the action potential. The broad T wave is inscribed as a result of the rapid repolarization occurring nonsimultaneously throughout the ventricles. The QT interval is prolonged by any agent or condition that delays repolarization in the ventricular cells. Various agents and conditions cause these long QT interval syndromes (Table 1) and initiate the characteristic torsade de pointes tachyarrhythmia (Figure 2). Table 1. Classification and Causes of the Long QT Interval Syndromes Figure 1. Relation between phases of the cardiac action potential and the surface electrocardiogram. Figure 2. Electrocardiogram showing the typical short-long-short RR interval initiation sequence triggering an episode of torsade de pointes. The long QT interval syndromes have been classified as acquired or hereditary on the basis of the conditions that appear to trigger the polymorphic ventricular tachycardia associated with the syndromes. The acquired long QT interval syndromes are also typically classified as pause-dependent because the torsade de pointes associated with them generally occurs at slow heart rates or in response to short-long-short RR interval sequences. The hereditary long QT interval syndromes are typically considered adrenergic-dependent because the torsade de pointes associated with them is generally triggered by adrenergic activation or enhancement of sympathetic nervous system tone [5]. However, the acquired and hereditary syndromes overlap somewhat; adrenergic-dependent forms are more likely to occur in response to pauses or short-long-short RR interval sequences or during slow heart rates. As seen in Table 1, causes of the acquired long QT interval syndromes include antiarrhythmic drugs, severe bradycardia, electrolyte disturbances (notably hypokalemia), various nonantiarrhythmic drugs, and numerous unrelated clinical disorders. The hereditary long QT interval syndromes include the Jervell and Lange-Nielsen syndrome [8], which is associated with congenital deafness, and the Romano-Ward syndrome [9, 10], in which hearing is normal. As mentioned above, initiation of the acquired, pause-dependent form of torsade de pointes often (although not invariably [11]) involves a short-long-short RR interval sequence [5]. As seen in Figure 2, a premature ventricular depolarization closely coupled with the last normal QRS complex is followed by a long pause after extrasystole that precedes another closely coupled premature ventricular depolarization, which constitutes the first beat of the tachycardia [5, 12, 13]. The tachycardia has a rate of 150 to 250 beats/min and is usually self-terminating. It is usually nonsustained and produces either no symptoms or only mild symptoms of presyncope, but it can occasionally degenerate into ventricular fibrillation that may be fatal. Although the initiation of torsade de pointes in patients with the hereditary long QT interval syndromes does not require pauses or bradycardia, adrenergic activation or enhanced sympathetic nervous system tone does appear to be necessary to produce the bizarre QT or QTU prolongation characteristic of this form of the disorder. Cellular Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes Normal Cardiac Action Potential The action potential of the ventricular or Purkinje fiber (Figure 1) results from the transmembrane movement of ions through channels in the cell membrane. The normal resting potential of most cardiac cells is about 80 to 90 mV. Membrane depolarization results from the net influx of positive charges (inward current) and repolarization occurs secondary to the net efflux of positive charges (outward current). The major ion currents responsible for the action potential in ventricular and Purkinje fibers are listed in Table 2. During diastole (phase 4), the membrane remains polarized near the K+ equilibrium potential ( 90 mV) because the inward rectifier K+ current (IK1) is normally the only current of significant magnitude activated at this membrane potential. In Purkinje fibers, diastolic depolarization results from a combination of the decay of the outward delayed rectifier current (IK) and the activation of the inward pacemaker current (If) and the inward Na+ background leak current (INa-B). The rapid upstroke of the action potential (phase 0) results from the inward fast Na+ and L- and T-type Ca2+ currents (INa, ICa-L, and ICa-T). Initial repolarization immediately after the overshoot (phase 1) is mediated by activation of the transient outward current (ITO) carried by K+ ions. The plateau (phase 2) results from a balance between inward currents, primarily the slowly decaying ICa-L and possibly the electrogenic Na+-Ca2+ exchange current (INaCa) [14] and the outward currents IK and ITO.Repolarization (phase 3) develops as the outward currents, especially I (K), overwhelm the decaying inward currents. An inward window current is responsible for the repetitive depolarizations at plateau levels of potential that are characteristic of early afterdepolarizations (see below). This current appears to be generated by the slow inactivation of ICa-L [15] and INa [16]. Table 2. Major Ion Currents Underlying the Cardiac Action Potential* Role of Early Afterdepolarizations in the Genesis of Prolongation of the QT Interval and Torsade de Pointes The study of torsade de pointes is confounded by the transient nature of the condition and the unpredictability of its occurrence and because it generally cannot be induced by programmed electrical stimulation during electrophysiologic study [17, 18]. Thus, animal studies form the basis for the current understanding of this arrhythmia. It is believed that prolongation of the QT interval and torsade de pointes are caused by early afterdepolarizations, defined as single or repetitive depolarizations or oscillations of the transmembrane voltage, that occur at low levels of membrane potential because of a failure of normal, complete membrane repolarization (Figures 3 and 4). Early afterdepolarizations may occur during the plateau phase (phase 2 early afterdepolarizations) or the early rapid repolarization phase (phase 3 early afterdepolarizations) of the action potential (Figures 3 and 4) [19, 20]. Because these afterdepolarizations delay repolarization, they may result in significant prolongation of the QT interval. Figure 3. Schematic drawing illustrating transmembrane action potentials from a Purkinje fiber, a ventricular muscle fiber, and a surface electrocardiogram. dotted line dotted line Although direct evidence that early afterdepolarizations cause torsade de pointes is lacking, considerable indirect evidence supports this hypothesis. Specifically, conditions that induce early afterdepolarizations initiate torsade de pointes [21, 22], especially at slow heart rates [23], and conditions that suppress early afterdepolarizations prevent torsade de pointes [24]. Furthermore, endocardial monophasic action potential signals (which reflect transmembrane electrical activity generated by action potentials) recorded under clinical and experimental conditions have shown that torsade de pointes is associated with voltage deflections resembling early afterdepolarizations [25, 26]. Early afterdepolarizations probably arise from the Purkinje fibers rather than from working myocardial cells because interventions that induce e

Pericardial and thoracic peri-aortic adipose tissues contribute to systemic inflammation and calcified coronary atherosclerosis independent of body fat composition, anthropometric measures and traditional cardiovascular risks

BACKGROUND Coronary atherosclerosis has traditionally been proposed to be associated with several cardiovascular risk factors and anthropometric measures. However, clinical data regarding the independent value of visceral adipose tissue in addition to such traditional predictors remains obscure. MATERIALS AND METHODS We subsequently studied 719 subjects (age: 48.1±8.3 years, 25% females) who underwent multidetector computed tomography (MDCT) for coronary calcium score (CCS) quantification. Baseline demographic data and anthropometric measures were taken with simultaneous body fat composition estimated. Visceral adipose tissue of pericardial and thoracic peri-aortic fat was quantified by MDCT using TeraRecon Aquarius workstation (San Mateo, CA). Traditional cardiovascular risk stratification was calculated by metabolic (NCEP ATP III) and Framingham (FRS) scores and high-sensitivity CRP (Hs-CRP) was taken to represent systemic inflammation. The independent value of visceral adipose tissue to systemic inflammation and CCS was assessed by utilizing multivariable regression analysis. RESULTS Of all subjects enrolled in this study, the mean values for pericardial and peri-aortic adipose tissue were 74.23±27.51 and 7.23±3.69ml, respectively. Higher visceral fat quartile groups were associated with graded increase of risks for cardiovascular diseases. Both adipose burdens strongly correlated with anthropometric measures including waist circumference, body weight and body mass index (all p<0.001). In addition, both visceral amount correlates well with ATP and FRS scores, all lipid profiles and systemic inflammation marker in terms of Hs-CRP (all p<0.001). After adjustment for baseline variables, both visceral fat were independently related to Hs-CRP levels (all p<0.05), but only pericardial fat exerted independent role in coronary calcium deposit. CONCLUSION Both visceral adipose tissues strongly correlated with systemic inflammation beyond traditional cardiovascular risks and anthropometric measures, though only pericardial fat exerted independent role in coronary calcium deposit. Our data suggested that visceral adipose tissue may thus contribute to systemic inflammation and play an independent role in the pathogenesis of atherosclerosis.

Localization of the origin of the atrioventricular junctional rhythm induced during selective ablation of slow-pathway conduction in patients with atrioventricular node reentrant tachycardia

During radiofrequency catheter ablation of slow atrioventricular node pathway conduction in patients with atrioventricular node reentrant tachycardia, an atrioventricular junction rhythm is frequently observed. The origin and relation to ablation success of this junctional rhythm was examined in this study. By using standard intracardiac electrophysiology techniques, we studied the radiofrequency energy-induced atrioventricular junctional rhythm in 43 consecutive patients with atrioventricular node reentrant tachycardia undergoing selective ablation of slow-pathway conduction. The frequency of atrioventricular junctional activity was correlated with successful and unsuccessful attempts at ablation of slow-pathway conduction. Also, we compared the sequence of retrograde atrial activation of radiofrequency energy-induced atrioventricular junctional beats in a subgroup of 22 patients with the retrograde activation sequence observed during pacing from the right ventricular apex and the site of successful ablation of slow-pathway conduction. A total of 201 radiofrequency-energy applications was delivered in 43 patients with > or = 5 atrioventricular junctional beat(s) induced during 110 (55%) of 201 ablation attempts. Atrioventricular junctional activity was noted during 98% of successful ablations but only 43% of the unsuccessful attempts (sensitivity, 98%; specificity, 57%; negative predictive value, 99%). The mean time to appearance of atrioventricular junctional beats was 8.8 +/- 4.1 sec (mean +/- SD) after the onset of radiofrequency-energy application. In 22 (100%) of 22 patients in whom detailed atrial mapping was performed, the retrograde atrial activation sequence of the radiofrequency-induced atrioventricular junctional beats was earliest in the anterior atrial septum, identical to that seen during pacing from the right ventricular apex. Earliest retrograde atrial activation was at the posterior septum in all patients during pacing from the successful ablation site, a markedly different activation pattern compared with that seen during either radiofrequency ablation or ventricular pacing. Whereas the occurrence of atrioventricular junctional activity during radiofrequency ablation does not necessarily herald a successful ablation of slow atrioventricular node pathway conduction, its absence strongly suggests that the energy is being applied in an unsuccessful fashion. Furthermore, it appears that radiofrequency energy-induced atrioventricular junctional beats originate not from the endocardium in contact with the ablating catheter tip but instead appear to exit remotely from the anterior atrial septal region. This finding supports the existence of specialized tissues in the atrioventricular junction that preferentially transmit the effects of radiofrequency energy to an anterior exit site, possibly identical to the atrial exit site of the retrograde fast atrioventricular node conduction pathway.

Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-deficient Mice: Simvastatin Exacerbates the Reduction

We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male apolipoprotein E (apoE)-deficient mice were made diabetic by streptozotocin. Three weeks later, the animals were treated with simvastatin for 2 weeks. The expression of aortic gap junctions in the non-diabetic (n=10), untreated diabetic (n=10), and simvastatin-treated diabetic animals (n=6) was analyzed. There was a >4-fold increase in serum cholesterol level and >50% increase in plaque areas in the diabetic mice, regardless of simvastatin treatment. Western blotting of aortae showed reduced expression of connexin37 (Cx37) and Cx40 in the diabetic mice, which were further decreased in the simvastatin-treated diabetic mice. Immunoconfocal microscopy showed that endothelial gap junctions made of Cx37 and Cx40 were both reduced in the untreated diabetic mice compared with the non-diabetic mice (decrease: Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrease in treated diabetic vs non-diabetic: Cx37, 61%; Cx40, 79%; both p<0.01; decrease in treated diabetic vs untreated diabetic: Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were decreased in the endothelium of plaque surface. Cx43 appeared in the medial layer and inner layer of the intima. All three connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice, streptozotocin-induced diabetes is associated with downregulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the downregulation.

Late Development of Renal Arteriovenous Fistula Following Gunshot Trauma A Case Report

A 43-year-old man presenting with symptoms of congestive heart failure, cardiomegaly, and impaired left ventricular (LV) function was diagnosed as having a huge left renal arteriovenous (AV) fistula. The AV fistula might be attributed to a gunshot wound suffered during his military service twenty years ago. Percutaneous transcatheter arterial embolization utilizing multiple spring coils in conjunction with cyanoacrylic glue success fully occluded the fistula, with subsequent improvement of LV function and reduction of LV size on his serial echocardiographic follow-up.

Is the Fascicle of Left Bundle Branch Involved in the Reentrant Circuit of Verapamil‐Sensitive Idiopathic Left Ventricular Tachycardia?

The exact reentrant circuit of the verapamil‐sensitive idiopathic left VT with a RBBB configuration remains unclear. Furthermore, if the fascicle of left bundle branch is involved in the reentrant circuit has not been well studied. Forty‐nine patients with verapamil‐sensitive idiopathic left VT underwent electrophysiological study and RF catheter ablation. Group I included 11 patients (10 men, 1 woman; mean age 25 ± 8 years) with left anterior fascicular block (4 patients), or left posterior fascicular block (7 patients) during sinus rhythm. Group II included 38 patients (29 men, 9 women; mean age 35 ± 16 years) without fascicular block during sinus rhythm. Duration of QRS complex during sinus rhythm before RF catheter ablation in group I patients was significant longer than that of group II patients (104 ± 12 vs 95 ± 11 ms, respectively, P = 0.02). Duration of QRS complex during VT was similar between group I and group II patients (141 ± 13 vs 140 ± 14 ms, respectively, P = 0.78). Transitional zones of QRS complexes in the precordial leads during VT were similar between group I and group II patients. After ablation, the QRS duration did not prolong in group I or group II patients (104 ± 11 vs 95 ± 10 ms, P = 0.02); fascicular block did not occur in group II patients. Duration and transitional zone of QRS complex during VT were similar between the two groups, and new fascicular block did not occur after ablation. These findings suggest the fascicle of left bundle branch may be not involved in the antegrade limb of reentry circuit in idiopathic left VT. (PACE 2003; 26:1986–1992)

Predictors of 1-year outcomes in the Taiwan Acute Coronary Syndrome Full Spectrum Registry.

BACKGROUND/PURPOSE Evidence-based guidelines have been formulated for optimal management of acute coronary syndrome (ACS). The Taiwan ACS Full Spectrum Registry aimed to evaluate the ACS management and identify the predictors of clinical outcomes of death/myocardial infarction/stroke 1 year post hospital discharge. METHODS Three thousand and eighty confirmed ACS patients enrolled in this registry were followed up for 1 year at 3-month intervals. Patient data on medical interventions as well as clinical events were recorded and analyzed by descriptive statistics. RESULTS One-year mortality among patients with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina was 6.1%, 10.1%, and 6.2%, respectively. Use of secondary preventive therapies was suboptimal throughout the follow-up phase, especially dual antiplatelet therapy, which fell from 74.8% patients at discharge to 24.9% patients at 1-year follow-up. The odds of an adverse incidence of death/myocardial infarction/stroke 1 year after discharge was significantly reduced in patients receiving aspirin and clopidogrel for ≥9 months and was consequently higher in patients in whom dual antiplatelet therapy was discontinued or prescribed for <9 months. Chronic renal failure, in-hospital bleeding, a diagnosis of NSTEMI, and antiplatelet therapy discontinuation had a negative association with 1-year outcomes, whereas the use of drug-eluting stents and antiplatelet agents, clopidogrel and aspirin, were predictors of positive outcomes. CONCLUSION There is a significant deviation from evidence-based guidelines in ACS management in Taiwan as reported in other countries. Policy adherence, especially with regard to dual antiplatelet therapy may hold the key to long-term favorable outcomes and improved survival rates in ACS patients in Taiwan.

Sequential endovascular coil embolization for a traumatic cervical vertebral AV fistula

An arteriovenous (AV) fistula involving the cervical vertebral artery is rare. Iatrogenic injury from percutaneous puncture and penetrating wounds are the most common causes. Symptoms include tinnitus and the presence of a pulsatile mass with a thrill. Conservative treatment with coil embolization and preservation of the vertebral artery is an alternative to surgical intervention. We report a patient who developed an AV fistula involving the vertebral artery and internal jugular vein following surgical repair of a stab wound to the neck. The sequential endovascular coil embolism was performed with subsequent successful occlusion of fistula. No neurological deficit developed during or after intervention. This approach appears to be a safe method in the treatment of vertebral AV fistula.Catheter Cardiovasc Interv 2003;60:267–269. ©2003 Wiley‐Liss, Inc.

Relation of Carotid Artery Diameter With Cardiac Geometry and Mechanics in Heart Failure With Preserved Ejection Fraction

Background Central artery dilation and remodeling are associated with higher heart failure and cardiovascular risks. However, data regarding carotid artery diameter from hypertension to heart failure have remained elusive. We sought to investigate this issue by examining the association between carotid artery diameter and surrogates of ventricular dysfunction. Methods and Results Two hundred thirteen consecutive patients including 49 with heart failure and preserved ejection fraction (HFpEF), 116 with hypertension, and an additional 48 healthy participants underwent comprehensive echocardiography and tissue Doppler imaging. Ultrasonography of the common carotid arteries was performed for measurement of intima‐media thickness and diameter (CCAD). Cardiac mechanics, including LV twist, were assessed by novel speckle‐tracking software. A substantial graded enlargement of CCAD was observed across all 3 groups (6.8±0.6, 7.7±0.73, and 8.7±0.95 mm for normal, hypertension, and HFpEF groups, respectively; ANOVA P<0.001) and correlated with serum brain natriuretic peptide level (R2=0.31, P<0.001). Multivariable models showed that CCAD was associated with increased LV mass, LV mass‐to‐volume ratio (β‐coefficient=10.9 and 0.11, both P<0.001), reduced LV longitudinal and radial strain (β‐coeffficient=0.81 and −3.1, both P<0.05), and twist (β‐coefficient=−0.84, P<0.05). CCAD set at 8.07 mm as a cut‐off had a 77.6% sensitivity, 82.3% specificity, and area under the receiver operating characteristic curves (AUROC) of 0.86 (95% CI 0.80 to 0.92) in discriminating HFpEF. In addition, CCAD superimposed on myocardial deformation significantly expanded AUROC (for longitudinal strain, from 0.84 to 0.90, P of ΔAUROC=0.02) in heart failure discrimination models. Conclusions Increased carotid artery diameter is associated with worse LV geometry, higher brain natriuretic peptide level, and reduced contractile mechanics in individuals with HFpEF.

The normal limits, subclinical significance, related metabolic derangements and distinct biological effects of body site-specific adiposity in relatively healthy population.

Background The accumulation of visceral adipose tissue that occurs with normal aging is associated with increased cardiovascular risks. However, the clinical significance, biological effects, and related cardiometabolic derangements of body-site specific adiposity in a relatively healthy population have not been well characterized. Materials and Methods In this cross-sectional study, we consecutively enrolled 608 asymptomatic subjects (mean age: 47.3 years, 27% female) from 2050 subjects undergoing an annual health survey in Taiwan. We measured pericardial (PCF) and thoracic peri-aortic (TAT) adipose tissue volumes by 16-slice multi-detector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA) and related these to clinical characteristics, body fat composition (Tanita 305 Corporation, Tokyo, Japan), coronary calcium score (CCS), serum insulin, high-sensitivity C-reactive protein (Hs-CRP) level and circulating leukocytes count. Metabolic risk was scored by Adult Treatment Panel III guidelines. Results TAT, PCF, and total body fat composition all increased with aging and higher metabolic scores (all p<0.05). Only TAT, however, was associated with higher circulating leukocyte counts (ß-coef.:0.24, p<0.05), serum insulin (ß-coef.:0.17, p<0.05) and high sensitivity C-reactive protein (ß-coef.:0.24, p<0.05). These relationships persisted after adjustment in multivariable models (all p<0.05). A TAT volume of 8.29 ml yielded the largest area under the receiver operating characteristic curve (AUROC: 0.79, 95%CI: 0.74–0.83) to identify metabolic syndrome. TAT but not PCF correlated with higher coronary calcium score after adjustment for clinical variables (all p<0.05). Conclusion In our study, we observe that age-related body-site specific accumulation of adipose tissue may have distinct biological effects. Compared to other adiposity measures, peri-aortic adiposity is more tightly associated with cardiometabolic risk profiles and subclinical atherosclerosis in a relatively healthy population.