Protective role of protein kinase C epsilon activation in ischemia-reperfusion arrhythmia

PURPOSE: Ischemic heart disease carries an increased risk of malignant ventricular tachycardia (VT), fibrillation (VF), and sudden cardiac death. Protein kinase C (PKC) epsilon activation has been shown to improve the hemodynamics in hearts subjected to ischemia/reperfusion. However, very little is known about the role of epsilon PKC in reperfusion arrhythmias. Here we show that epsilon PKC activation is anti-arrhythmic and its inhibition is pro-arrhythmic. METHOD: Langendorff-perfused isolated hearts from epsilonPKC agonist (epsilonPKC activation), antagonist (epsilonPKC inhibition) transgenic (TG), and wild-type control mice were subjected to 30 min stabilization period, 10 min global ischemia, and 30 min reperfusion. Action potentials (APs) and calcium transients (CaiT) were recorded simultaneously at 37 degrees C using optical mapping techniques. The incidence of VT and VF was assessed during reperfusion. RESULTS: No VT/VF was seen in any group during the stabilization period in which hearts were perfused with Tyrode's solution. Upon reperfusion, 3 out of the 16 (19%) wild-type mice developed VT but no VF. In epsilonPKC antagonist group, in which epsilonPKC activity was downregulated, 10 out of 13 (76.9%) TG mice developed VT, of which six (46.2%) degenerated into sustained VF upon reperfusion. Interestingly, in epsilonPKC agonist mice, in which the activity of epsilonPKC was upregulated, no VF was observed and only 1 out of 12 mice showed only transient VT during reperfusion. During ischemia and reperfusion, CaiT decay was exceedingly slower in the antagonist mice compared to the other two groups. CONCLUSION: Moderate in vivo activation of epsilonPKC exerts beneficial antiarrhythmic effect vis-a-vis the lethal reperfusion arrhythmias. Abnormal CaiT decay may, in part, contribute to the high incidence of reperfusion arrhythmias in the antagonist mice. These findings have important implications for the development of PKC isozyme targeted therapeutics and subsequently for the treatment of ischemic heart diseases.     

A Case of Inappropriate Therapies for Atrial Flutter From a Subcutaneous ICD

Hypertrophic cardiomyopathy’s (HCM) association with sudden cardiac death is well recognised. The risk of sudden cardiac death is known to increase when there is a history of unexplained syncope, abnormal blood pressure response during exercise, severe left ventricular hypertrophy or a family history of unexplained death.Implantable Cardioverter Defibrillator (ICD) implantation has been widely used for primary and secondary prevention of sudden cardiac death (SCD) in people with HCM. Subcutaneous ICD (S-ICD) therapy has been developed to overcome some of the problems associated with the transvenous leads used in conventional ICDs.In this article, we report the use of S-ICD in a patient with HCM and multiple risk factors for sudden cardiac death, this device had to be extracted due to recurrent inappropriate shocks caused by over sensing of atrial flutter and failure to treat a VT episode. We are not aware of any reports of inappropriate shocks caused by atrial flutter in people with a S-ICD.     

Role of implantable cardioverter defibrillators in the treatment of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an important cardiovascular disease with sudden cardiac death as the most devastating presentation. Implantable cardioverter defibrillators (ICD) are the optimal therapy for prevention of sudden death from ventricular tachycardia or fibrillation of any cause. While there is no controversy with implanting ICDs in patients who have already survived a cardiac arrest, identifying high-risk patients for primary prevention in this disease remains a challenge. Implanting ICDs in patients with HCM is an important clinical consideration since many individuals could achieve normal or near-normal lifespans with this protection.     

ECG Marker of Adverse Electrical Remodeling Post-Myocardial Infarction Predicts Outcomes in MADIT II Study

Background

Post-myocardial infarction (MI) structural remodeling is characterized by left ventricular dilatation, fibrosis, and hypertrophy of the non-infarcted myocardium.

Objective

The goal of our study was to quantify post-MI electrical remodeling by measuring the sum absolute QRST integral (SAI QRST). We hypothesized that adverse electrical remodeling predicts outcomes in MADIT II study participants.

Methods

Baseline orthogonal ECGs of 750 MADIT II study participants (448 [59.7%] ICD arm) were analyzed. SAI QRST was measured as the arithmetic sum of absolute QRST integrals over all three orthogonal ECG leads. The primary endpoint was defined as sudden cardiac death (SCD) or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) with appropriate ICD therapies. All-cause mortality served as a secondary endpoint.

Results

Adverse electrical remodeling in post-MI patients was characterized by wide QRS, increased magnitudes of spatial QRS and T vectors, J-point deviation, and QTc prolongation. In multivariable Cox regression analysis after adjustment for age, QRS duration, atrial fibrillation, New York Heart Association heart failure class and blood urea nitrogen, SAI QRST predicted SCD/VT/VF (HR 1.33 per 100 mV*ms (95%CI 1.11–1.59); P = 0.002), and all-cause death (HR 1.27 per 100 mV*ms (95%CI 1.03–1.55), P = 0.022) in both arms. No interaction with therapy arm and bundle branch block (BBB) status was found.

Conclusions

In MADIT II patients, increased SAI QRST is associated with increased risk of sustained VT/VF with appropriate ICD therapies and all-cause death in both ICD and in conventional medical therapy arms, and in patients with and without BBB. Further studies of SAI QRST are warranted.     

Ventricular arrhythmias.

Sudden cardiac death claims thousands of Canadians annually. Ventricular tachycardia and fibrillation account for up to 85% of these deaths. Identifying the patients at risk remains a major challenge. Those who have recurrent ventricular tachycardia or have been resuscitated from ventricular fibrillation are generally considered to be at highest risk. Although ventricular premature beats in the absence of previous ventricular tachycardia or fibrillation are not helpful in identifying such patients in most cases, they can indicate increased risk for sudden cardiac death in the presence of a structural cardiac abnormality, particularly recent myocardial infarction; however, the need for treatment in such cases is speculative and is being investigated. Treatment is mandatory for survivors of an episode of ventricular fibrillation and those with recurrent sustained ventricular tachycardia or torsade de pointes ventricular tachycardia. The approach to management is either invasive or noninvasive. Selection of an antiarrhythmic agent is facilitated by knowledge of some basic electrophysiologic features of the heart and of the classification of antiarrhythmic drugs. However, drug therapy has to be individualized on the basis of efficacy, left ventricular function and adverse effects or potential adverse effects of the drug. Amiodarone therapy or nonpharmacologic therapy should be considered if a suitable antiarrhythmic agent cannot be found.     

Susceptibility to ischemia-induced arrhythmias and the effect of preconditioning in the diabetic rat heart

Diabetic heart is suggested to exhibit either increased or decreased resistance to ischemic injury. Ischemic preconditioning suppresses arrhythmias in the normal heart, whereas relatively little is known about its effects in the diseased myocardium. Our objective was to investigate whether development of diabetes mellitus modifies the susceptibility to ischemia-induced arrhythmias and affects preconditioning in the rat heart. Following 1 and 9 weeks of streptozotocin-induced (45 mg/kg, i.v.) diabetes, the hearts were Langendorff-perfused at constant pressure of 70 mm Hg and subjected to test ischemia induced by 30 min occlusion of the left anterior descending (LAD) coronary artery. Preconditioning consisted of one cycle of 5 min ischemia and 10 min reperfusion, prior to test ischemia. Susceptibility to ischemia-induced arrhythmias was lower in 1-week diabetics: only 42 % of diabetic hearts exhibited ventricular tachycardia (VT) and 16 % had short episodes of ventricular fibrillation (VF) as compared to VT 100 % and VF 70 % (including sustained VF 36 %) in the non-diabetics (P<0.05). Development of the disease was associated with an increased incidence of VT (VT 92 %, not significantly different from non-diabetics) and longer total duration of VT and VF at 9-weeks, as compared to 1-week diabetics. Preconditioning effectively suppressed arrhythmias in the normal hearts (VT 33 %, VF 0 %). However, it did not provide any additional antiarrhythmic protection in the acute diabetes. On the other hand, in the preconditioned 9-weeks diabetic hearts, the incidence of arrhythmias tended to decrease (VT 50 %, transient VF 10 %) and their severity was reduced. Diabetic rat hearts are thus less susceptible to ischemia-induced arrhythmias in the acute phase of the disease. Development of diabetes attenuates increased ischemic tolerance, however, diabetic hearts in the chronic phase can benefit more from ischemic preconditioning, due to its persisting influence.     

Ventricular Tachycardia Precipitated by Short-long-short Sequence in a Patient with Implantable-cardioverter Defibrillator

Abrupt changes in heart rate, particularly short-long-short sequences in the ventricular cycle length (CL), might precede initiation of ventricular tachycardia/fibrillation (VT/VF). These changes may be facilitated or caused by pacing activity in patients with pacemakers or implantable-cardioverter defibrillators (ICDs). We describe a patient with two episodes of acquired VT precipitated by short-long-short sequences and diagnosed from the ICD recordings. In such cases, the knowledge of the device parameters is extremely important for a correct diagnosis and management.     

Simulated Interactions between a Class III Antiarrhythmic Drug and a Figure 8 Reentry

Ventricular Fibrillation is responsible for a majority of sudden cardiac death, but little is known about how ventricular tachycardia (VT) degenerates into ventricular fibrillation. Several clinical studies focused only on preventing VT with a class III antiarrhythmic drug resulted in many deaths. Our simulations investigate the interactions between an antiarrhythmic drug likely to suppress a VT and a Figure 8 reentry. A parameter AAR is introduced to increase the action potential duration and therefore simulate various Class III drugs. Simulations are ran under several conditions (phases of the reentry, values of AAR, durations). They show that a VT can be suppressed whatever the phase of the reentry but it strongly depends on the duration of the effect. It confirms that a drug which can suppress a reentry can also worsen it. It also shows a great variety of activation patterns and thus the complexity of antiarrhythmic drugs effects. Simulations also demonstrate that suppressing VT is an increasing function of AAR.     

A New Single Chamber Implantable Defibrillator with Atrial Sensing: A Practical Demonstration of Sensing and Ease of Implantation

Implantable cardioverter-defibrillators (ICDs) terminate ventricular tachycardia (VT) and ventricular fibrillation (VF) with high efficacy and can protect patients from sudden cardiac death (SCD). However, inappropriate shocks may occur if tachycardias are misdiagnosed. Inappropriate shocks are harmful and impair patient quality of life. The risk of inappropriate therapy increases with lower detection rates programmed in the ICD. Single-chamber detection poses greater risks for misdiagnosis when compared with dual-chamber devices that have the benefit of additional atrial information. However, using a dual-chamber device merely for the sake of detection is generally not accepted, since the risks associated with the second electrode may outweigh the benefits of detection. Therefore, BIOTRONIK developed a ventricular lead called the Linox^SMART S DX, which allows for the detection of atrial signals from two electrodes positioned at the atrial part of the ventricular electrode. This device contains two ring electrodes; one that contacts the atrial wall at the junction of the superior vena cava (SVC) and one positioned at the free floating part of the electrode in the atrium. The excellent signal quality can only be achieved by a special filter setting in the ICD (Lumax 540 and 740 VR-T DX, BIOTRONIK). Here, the ease of implantation of the system will be demonstrated.     

Defibrillation testing of the implantable cardioverter defibrillator: when, how, and by whom?

The implantable cardioverter-defibrillator (ICD) has become an integral part of treatment for a variety of patients with symptomatic, or at risk for, ventricular tachyarrhythmias. The ICD's effectiveness is attributed to its ability to promptly detect and terminate ventricular tachycardia (VT) and fibrillation (VF). The clinical trials that established the positive role of ICD therapy were based on patients who underwent some form of defibrillation testing at the time of implantation. Therefore, since its advent, intraoperative defibrillation testing of the ICD to assure reliable detection and termination of VT/VF has been a standard practice. But because of advances in defibrillator and lead technology, which now facilitates successful device implantation (i.e., low defibrillation energy requirement to allow for an adequate programmed safety margin) in the majority of patients, the necessity of defibrillation testing has been called into attention. Despite substantial progress, it is not altogether clear whether a wholesale abandonment of intraoperative ICD testing is appropriate at this point. We review pertinent data regarding pros and cons of ICD testing and offer a suggestion as to when, how, and who should test ICDs.     

Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo

We previously reported that alpha(2)-adrenergic receptor (alpha(2)-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses beta-adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of alpha(2)-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the beta-blocker group, 72% for the alpha(1)-blocker group, and 12.5% for the alpha(1) + beta-blockers group (unopposed alpha(2)-adrenergic activation). Direct alpha(2)-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the alpha(2)-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 +/- 1.5 and 62 +/- 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that alpha(2)-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.     

Primary prevention by implantable cardioverter defibrillators: shock proof?

In the last two decades, the focus of implantable cardioverter defibrillator {ICD} trials has mainly been on prophylactic implantation of ICDs in high-risk populations for the prevention of sudden cardiac death. In particular, prophylactic ICDs in high-risk post-MI patients with a depressed left ventricular ejection fraction has resulted in significantly improved survival. These benefits are in addition to those of optimal pharmacological therapy and ICD therapy should be considered the standard of care in these patients.     

Dronedarone for Recurrent Ventricular Tachycardia: A Real Alternative?

Sustained ventricular tachycardia (VT) is an important cause of morbidity and sudden death in patients with dilated cardiomyopathy. Although ICD effectively terminate VT episodes and improve survival, shocks reduce quality of life, and episodes of VT predict increased risk of heart failure and death despite effective therapy. Patients suffering recurrent VT episodes remain a challenge. Antiarrhytmic therapy reduces VT episodes, but it is associated with serious adverse events, and disappointing efficacy. Catheter ablation has emerged as an important option to control recurrent VT, but major procedure-related complications, and even death, are still issues to concern. And even with these armamentaria, some patients still have recurrent VT episodes and ICD shocks. We report on a patient with non-ischemic dilated cardiomyopathy and recurrent ventricular tachycardia resistant to multiple antiarrhytmic agents, in whom dronedarone was effective in completely suppressing ventricular tachycardia episodes.     

Bundle branch reentrant ventricular tachycardia

Bundle branch reentrant (BBR) tachycardia is an uncommon form of ventricular tachycardia (VT) incorporating both bundle branches into the reentry circuit. The arrhythmia is usually seen in patients with an acquired heart disease and significant conduction system impairment, although patients with structurally normal heart have been described. Surface ECG in sinus rhythm (SR) characteristically shows intraventricular conduction defects. Patients typically present with presyncope, syncope or sudden death because of VT with fast rates frequently above 200 beats per minute. The QRS morphology during VT is a typical bundle branch block pattern, usually left bundle branch block, and may be identical to that in SR. Prolonged His-ventricular (H-V) interval in SR is found in the majority of patients with BBR VT, although some patients may have the H-V interval within normal limits. The diagnosis of BBR VT is based on electrophysiological findings and pacing maneuvers that prove participation of the His- Purkinje system in the tachycardia mechanism. Radiofrequency catheter ablation of a bundle branch can cure BBR VT and is currently regarded as the first line therapy. The technique of choice is ablation of the right bundle. The reported incidence of clinically significant conduction system impairment requiring implantation of a permanent pacemaker varies from 0% to 30%. Long-term outcome depends on the underlying cardiac disease. Patients with poor systolic left ventricular function are at risk of sudden death or death from progressive heart failure despite successful BBR VT ablation and should be considered for an implantable cardiovertor-defibrillator.     

Intrinsic anti-tachycardia pacing terminated ventricular tachycardia resistant to traditional anti-tachycardia pacing

Implantable cardioverter-defibrillators (ICDs) serve to reduce the risk of sudden death; however, ICD shocks worsen patient prognosis. Therefore, attempts have been made to terminate life-threatening arrhythmias without ICD shocks. A 71-year-old man with non-ischemic cardiomyopathy, who previously underwent cardiac resynchronization therapy-defibrillator (CRT-D) placement, was hospitalized for ventricular tachyarrhythmia (VT) that was refractory to traditional anti-tachycardia pacing (ATP). Endocardial and epicardial ablation failed to prevent VT recurrence. Since the CRT-D battery was exhausted, it was replaced with a Cobalt? XT HF CRT-D (Medtronic, Minneapolis, MN, USA), and the intrinsic ATP (iATP) algorithm was employed. Although VT recurred frequently, recurrent VTs were terminated by the iATP, which created a conduction block in the circuit without VT acceleration or shock. This is the first reported case wherein an iATP algorithm was effective against VT resistant to traditional anti-tachycardia pacing. This novel ATP algorithm has the potential to terminate refractory VT without ICD shocks and provide a better prognosis.     

Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia

Background

It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K⁺ current (I_Kr) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I_Kr increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF.

Methodology/Principal Findings

We examined the effects of serum of HF patients on recombinant I_Kr recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I_Kr tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia.

Conclusions/Significance

Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF.     

Approach to the asymptomatic patients with Brugada syndrome

Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of coved-type ST segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD) as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). Data from large patient studies and a meta-analysis of previous reports have shown that patients with a history of syncope or SCD and a spontaneous type 1 Brugada type ECG are at high risk for SCD. However, risk stratification of asymptomatic patients with Brugada type ECG is still a challenge. In particular, the use of electrophysiological study (EPS) for risk stratification remains controversial. Although some investigators have reported the possibility of use of EPS for distinguishing between high- and low-risk patients with Brugada type ECG, no precise predictor of risk for SCD in asymptomatic patients has yet been determined. The approach to treatment of these patients is thus still unclear. Large clinical prospective studies with uniform diagnostic criteria and protocols for EPS as well as extended follow-up periods of over ten years are required for prediction of SCD.     

Brugada disease: chronology of discovery and paternity. Preliminary observations and historical aspects

The Brugada disease, the last clinico-cardiologic entity described in the 20th century, initially called right bundle branch block syndrome with ST segment elevation from V1 to V2 or V3 and sudden cardiac death, is genetically determined in a dominant autosomal mode, and it affects the alpha subunit of the Na+ channel by alteration of chromosome 3 and mutation in the SCN5A gene. In clinical diagnosis the mentioned electrocardiographic pattern in a patient without structural heart disease and positivity in pharmacological tests are considered major criteria. As minor criteria, the following are considered: positive family history, presence of syncope with unknown origin, documented episode of VT/VF, inducibility in electrophysiologic study and positivity of genetic study. The long-standing technology of ECG, with more than a century of existence, remains as the supplementary method with highest value in diagnosis, and currently new electrocardiographic criteria are suggested, which indicate high risk of VF. Natural history indicates a somber diagnosis in symptomatic patients with a high index of arrhythmic SCD secondary to very fast polymorphic ventricular tachycardia bursts, which degenerate into VF. Asymptomatic individuals with only a Brugada-type electrocardiographic pattern have a low risk. The prognosis seems to depend more on clinical facts, since a positive electrophysiologic study has an accuracy of just around 50%. We propose that this entity should be promoted to the category of disease, since it has a characteristic set of signs and symptoms, and an identified genetic defect.     

The role of prostaglandins in the antiarrhythmic effect of ischemic preconditioning

The role of prostaglandins in the antiarrhythmic effect of ischemic preconditioning (IP) was investigated in pentobarbital-anesthetized rats. In 5 unpreconditioned control rats, 30 min of occlusion of the left coronary artery elicited ventricular tachycardia (VT) and fibrillation (VF), with an average duration of VT and VF of 51 +/- 6 and 43 +/- 4 s, respectively. Frequent ventricular premature beats (VPBs; average 1,249 +/- 145) were also documented in these animals. Thirty minutes of reperfusion after the prolonged coronary occlusion in these animals caused more severe arrhythmias, including irreversible VF. In animals pretreated with IP (n = 5), which was achieved by 3 cycles of 3 min of occlusion followed by 5 min of reperfusion, 30 min of coronary artery occlusion caused neither VT nor VF, but occasional VPBs (average 2 +/- 1, p < 0.001 vs. control). Only occasional VPBs were observed during 30 min of reperfusion in this group. In animals pretreated with indomethacin (1 mg/kg i.v., n = 5) followed by IP, prolonged ischemia and reperfusion led to frequent VPBs but no VT or VF. The average number of VPBs during ischemia and reperfusion in this indomethacin-treated group was less than that of the controls but greater than the IP-only group (p < 0.01). In conclusion, prostaglandins appear to play a role in the protective effect of IP against VPBs during acute ischemia and reperfusion.     

Preclinical assessment of antiarrhythmic drugs

The morbidity statistics for the United States alone would suggest that there are 400,000 victims each year who succumb to sudden coronary death, which suggests that there is a need for the development of pharmacological interventions capable of preventing ventricular fibrillation (VF) in patients identified as being at high risk. A major deficiency in this area of experimental investigation is the lack of an animal model that would permit preclinical studies to identify potentially useful therapeutic agents. We have developed an experimental canine model of sudden coronary death in which VF occurs in the chronically injured heart that is subjected to a period of transient ischemia in a coronary region remote from the site of a previous myocardial infarction. The experimental model is subject to the induction of ventricular tachyarrhythmias in response to programmed electrical stimulation, thereby permitting the investigator to correlate the effectiveness of a pharmacological agent in preventing electrically induced arrhythmias with its potential to prevent the development of VF in response to ischemia at a site remote from a previous infarct. Thus, acute myocardial ischemia at a site distant from a previous myocardial infarction enhances the likelihood of primary VF in the conscious dog. This model of sudden coronary death may stimulate more closely the clinical state in humans and might serve as an appropriate model for the study of electrophysiological mechanisms associated with the development of VF and for the evaluation of potential antifibrillatory drugs.