The need for studies to evaluate the reproducibility of the T-wave alternans (TWA), and the rationale for a correction index of the TWA

Sudden cardiac death (SCD) due to various cardiomyopathies is currently prevented by the implantation of an automated cardioverter/defibrillator (ICD). ICD impalntation in patients who are not survivors of SCD, or have not suffered potentially lethal ventricular arrhythmias, are based on the presence of cardiomyopathy with a reduced left ventricular ejection fraction. The bulk of patients who are considered suitable for an ICD implantation and receive such devices, do not experience device therapy shocks at follow-up ("false positives"), thus creating a climate of uncertainty among patients and physicians about the soundness of our current eligibility criteria for ICDs. In addition the cost of inappropriate ICDs is staggering, and the undue exposure of "false positive" patients to complications, and hardships is disconcerting. T-wave alternans (TWA) has emerged as a possible "risk detection of SCD" technology, but its reproducibility has not been tested. Peripheral edema (extracardiac) or other cardiac mechanisms, unrelated to the degree of SCD risk, alter the amplitude, and other attributes, of the T-waves. Since TWA may be T-wave amplitude-, or other T-wave attributes-dependent (this is still a speculation), a need may be emerging for its correction by the T-wave amplitude (TWA index); such an index may enhance the reproducibility, and evaluate the true sensitivity, specificity and predictive accuracy of the TWA in detecting future victims of SCD.     

Sudden death and its predictors in myocardial infarction survivors in an Indian population

ObjectiveThis study was conducted to assess the incidence of sudden cardiac death (SCD) in post myocardial infarction patients and to determine the predictive value of various risk markers in identifying cardiac mortality and SCD.MethodsLeft ventricular function, arrhythmias on Holter and microvolt T wave alternans (MTWA) were assessed in patients with prior myocardial infarction and ejection fraction ≤ 40%. The primary outcome was a composite of cardiac death and resuscitated cardiac arrest during follow up. Secondary outcomes included total mortality and SCD.ResultsFifty-eight patients were included in the study. Eight patients (15.5%) died during a mean follow-up of 22.3 ± 6.6 months. Seven of them (12.1%) had SCD. Among the various risk markers studied, left ventricular ejection fraction (LVEF) ≤ 30% (Hazard ratio 5.6, 95% CI 1.39 to 23) and non-sustained ventricular tachycardia (NSVT) in holter (5.7, 95% CI 1.14 to 29) were significantly associated with the primary outcome in multivariate analysis. Other measures, including QRS width, heart rate variability, heart rate turbulence and MTWA showed no association.ConclusionsAmong patients with prior myocardial infarction and reduced left ventricular function, the rate of cardiac death was substantial, with most of these being sudden cardiac death. Both LVEF ≤30% and NSVT were associated with cardiac death whereas only LVEF predicted SCD. Other parameters did not appear useful for prediction of events in these patients. These findings have implications for decision making for the use of implantable cardioverter defibrillators for primary prevention in these patients.     

Is T-Wave Alternans Testing Feasible in Candidates for Prophylactic Implantable Defibrillators?

Aims

Previous studies have demonstrated that microvolt T-wave alternans (TWA) screening in patients with ischaemic and dilated cardiomyopathy is effective in identifying patients at high or low risk of sudden cardiac death. It remains unclear which percentage of potential recipients of an implantable cardioverter defibrillator (ICD) are able to perform TWA testing using an exercise protocol which is, at this moment, the golden standard. In this study, we evaluated the feasibility of TWA in the risk stratification of potential ICD recipients with ischaemic or dilated cardiomyopathy.

Methods and Results

Medical charts of 165 primary prevention ICD recipients were reviewed to decide if patients were able to perform a TWA exercise test or not. Reasons to waiver a test were: atrial fibrillation or flutter, pacemaker dependency, recent (cardiovascular) surgery (<1 month) and inability to exercise. Of the potential ICD recipients 35% had one or more of these contraindications and were therefore not suitable for testing.

Conclusion

In several studies, TWA is a promising risk stratifier for predicting sudden cardiac death; however, in our population, 35% of the potential ICD candidates could not be tested. In order to fulfil its promise as a predictor for SCD, an alternative means to measure TWA needs to be evaluated.     

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Ventricular tachyarrhythmias are the most common cause of sudden cardiac death (SCD); a healed myocardial infarction increases the risk of SCD. We determined the contribution of specific repolarization abnormalities to ventricular tachyarrhythmias in a postinfarction model of SCD. For our methods, we used a postinfarction canine model of SCD, where an exercise and ischemia test was used to stratify animals as either susceptible (VF(+)) or resistant (VF(-)) to sustained ventricular tachyarrhythmias. Our results show no changes in global left ventricular contractility or volumes occurred after infarction. At 8-10 wk postmyocardial infarction, myocytes were isolated from the left ventricular midmyocardial wall and studied. In the VF(+) animals, myocyte action potential (AP) prolongation occurred at 50 and 90% repolarization (P < 0.05) and was associated with increased variability of AP duration and afterdepolarizations. Multiple repolarizing K(+) currents (I(Kr), I(to)) and inward I(K1) were also reduced (P < 0.05) in myocytes from VF(+) animals compared with control, noninfarcted dogs. In contrast, only I(to) was reduced in VF(-) myocytes compared with controls (P < 0.05). While afterdepolarizations were not elicited at baseline in myocytes from VF(-) animals, afterdepolarizations were consistently elicited after the addition of an I(Kr) blocker. In conclusion, the loss of repolarization reserve via reductions in multiple repolarizing currents in the VF(+) myocytes leads to AP prolongation, repolarization instability, and afterdepolarizations in myocytes from animals susceptible to SCD. These abnormalities may provide a substrate for initiation of postmyocardial infarction ventricular tachyarrhythmias.     

PREVENTION-ACHD: PRospEctiVE study on implaNTable cardioverter-defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease; Rationale and Design

Background

Many adult congenital heart disease (ACHD) patients are at risk of sudden cardiac death (SCD). An implantable cardioverter-defibrillator (ICD) may prevent SCD, but the evidence for primary prevention indications is still unsatisfactory.

Study Design

PREVENTION-ACHD is a prospective study with which we aim to prospectively validate a new risk score model for primary prevention of SCD in ACHD patients, as well as the currently existing guideline recommendations. Patients are screened using a novel risk score to predict SCD as well as current ICD indications according to an international Consensus Statement. Patients are followed up for two years. The primary endpoint is the occurrence of SCD and sustained ventricular arrhythmias. The Study was registered at ClinicalTrials.gov (NCT03957824).

Conclusion

PREVENTION-ACHD is the first prospective study on SCD in ACHD patients. In the light of a growing and aging population of patients with more severe congenital heart defects, more robust clinical evidence on primary prevention of SCD is urgently needed.

     

Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus

ABSTRACT: BACKGROUND: Many patients who survive a myocardial infarction (MI) remain at risk of sudden cardiac death despite revascularization and optimal medical treatment. We used the modified moving average (MMA) method to assess the utility of T-wave alternans (TWA) and heart rate turbulence (HRT) as risk markers in MI patients with or without diabetes mellitus (DM). METHODS: We prospectively enrolled 248 consecutive patients: 96 with MI (post-MI patients); 77 MI with DM (post-MI + DM patients); 75 controls without cardiovascular disease (group control). Both TWA and HRT were measured on ambulatory electrocardiograms (AECGs). HRT was assessed by two parameters [BOX DRAWINGS LIGHT HORIZONTAL] turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO [GREATER-THAN OR EQUAL TO]0% and TS [LESS-THAN OR EQUAL TO]2.5 ms/R-R interval were met. The endpoint was cardiac mortality. RESULTS: TWA values differed significantly between MI and controls. Post-MI + DM patients had higher TWA values than post-MI patients (58 [PLUS-MINUS SIGN] 21 muV VS 52 [PLUS-MINUS SIGN] 18 muV, P = 0.029). Impaired HRT--increased TO and decreased TS were observed in MI patients with or without DM. During follow-up of 578 [PLUS-MINUS SIGN] 146 days, cardiac death occurred in ten patients and three of them suffered sudden cardiac death (SCD). Multivariate analysis determined that a HRT-positive outcome [HR (95% CI): 5.01, 1.33--18.85; P = 0.017], as well as the combination of abnormal TWA ([GREATER-THAN OR EQUAL TO]47 muV) and positive HRT had significant association with the endpoint [HR (95% CI): 9.08, 2.21--37.2; P = 0.002)]. CONCLUSION: This study indicates that AECGs-based TWA and HRT can predict cardiac mortality in MI patients with or without DM. Combined analysis TWA and HRT may be a convenient and useful method of identifying patients at high risk for cardiovascular death.     

Towards a better risk stratification for sudden cardiac death in patients with structural heart disease

With the introduction of the implantable cardioverter defibrillator (ICD), patients can be protected against sudden cardiac death (SCD) due to ventricular arrhythmia (VA). Guidelines have been drawn up for selecting patients for primary and secondary prophylaxis. However, most ICD recipients today who receive an ICD for primary prevention will not experience a life-threatening VA requiring antitachypacing or shock therapy. Better risk stratification is desirable with efficacy, costs and complication rate in mind. An overview is presented of widely accepted and potentially valuable risk markers and the role they may play in better identifying candidates for ICD therapy. (Neth Heart J 2009;17:101–6.)     

Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release

Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.     

Reduced susceptibility to ventricular tachyarrhythmias in rats selectively bred for high aerobic capacity

Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Human epidemiological studies and experimental work with animals indicate that regular physical activity is associated with reductions in cardiovascular disease (CVD) risk factors and sudden cardiac death. Similarly, artificial selection of rats for high aerobic treadmill-running capacity (high-capacity runners; HCR) has been shown to reduce CVD risk factors relative to rats selected as low-capacity runners (LCR). Therefore, we tested the hypothesis that HCR, relative to LCR rats, would be less susceptible to ischemia-reperfusion-mediated ventricular tachyarrhythmias. To test this hypothesis, we measured the susceptibility to ventricular tachyarrhythmias produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious LCR and HCR rats. Results document a significantly lower incidence of ventricular tachyarrhythmias in HCR (3 of 11, 27.3%) relative to LCR (6 of 7, 85.6%) rats. The decreased susceptibility to tachyarrhythmias in HCR rats was associated with a reduced cardiac metabolic demand during ischemia (lower rate-pressure product and ST segment elevation) as well as a wider range for the autonomic control of heart rate. The HCR and LCR represent a unique substrate for evaluation of the mechanisms underlying ischemia-mediated cardiac arrhythmogenesis.     

Ventricular tachycardia prediction in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death

Clinical data analysis of 83 patients with implantable cardioverter-defibrillators (ICDs) for sudden cardiac death (SCD) primary prevention has been done. We revealed 5 parameters associated with the detection of life-threatening ventricular arrhythmias. These parameters formed the basis for constructing a logistic regression model. The model makes it possible to obtain the probability of occurrence of a specific event depending on the severity of the predictive parameters and the degree of its influence (risk of true ventricular arrhythmias detection). Estimating the potential risk of the life-threatening arrhythmias, individual programming options are required in implantable cardioverter-defibrillators (ICDs) to reduce the amount of unnecessary electrotherapy, as well as more accurate monitoring of the patient's drug therapy.     

Cardiac ischemia activates calcium-independent phospholipase A2beta,precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition

Murine myocardium contains diminutive amounts of calcium-independent phospholipase A2 (iPLA2) activity (<5% that of human heart), and malignant ventricular tachyarrhythmias are infrequent during acute murine myocardial ischemia. Accordingly we considered the possibility that the mouse was a species-specific knockdown of the human pathologic phenotype of ischemiainduced lethal ventricular tachyarrhythmias. Transgenic mice were generated expressing amounts of iPLA2beta activity comparable to that present in human myocardium. Coronary artery occlusion in Langendorff perfused hearts from transgenic mice resulted in a 22-fold increase in fatty acids released into the venous eluent (29.4 nmol/ml in transgenic versus 1.35 nmol/ml of eluent in wild-type mice), a 4-fold increase in lysophosphatidylcholine mass in ischemic zones (4.9 nmol/mg in transgenic versus 1.1 nmol/mg of protein in wild-type mice), and malignant ventricular tachyarrhythmias within minutes of ischemia. Neither normally perfused transgenic nor ischemic wild-type hearts demonstrated these alterations. Pretreatment of Langendorff perfused transgenic hearts with the iPLA2 mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL) just minutes prior to induction of ischemia completely ablated fatty acid release and lysolipid accumulation and rescued transgenic hearts from malignant ventricular tachyarrhythmias. Collectively these results demonstrate that ischemia activates iPLA2beta in intact myocardium and that iPLA2beta-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.     

Postmortem mRNA Expression Patterns in Left Ventricular Myocardial Tissues and Their Implications for Forensic Diagnosis of Sudden Cardiac Death

Sudden cardiac death (SCD), which is primarily caused by lethal heart disorders resulting in structural and arrhythmogenic abnormalities, is one of the prevalent modes of death in most developed countries. Myocardial ischemia, mainly due to coronary artery disease, is the most common type of heart disease leading to SCD. However, postmortem diagnosis of SCD is frequently complicated by obscure histological evidence. Here, we show that certain mRNA species, namely those encoding hemoglobin A1/2 and B (Hba1/2 and Hbb, respectively) as well as pyruvate dehydrogenase kinase 4 (Pdk4), exhibit distinct postmortem expression patterns in the left ventricular free wall of SCD subjects when compared with their expression patterns in the corresponding tissues from control subjects with non-cardiac causes of death. Hba1/2 and Hbb mRNA expression levels were higher in ischemic SCD cases with acute myocardial infarction or ischemic heart disease without recent infarction, and even in cardiac death subjects without apparent pathological signs of heart injuries, than control subjects. By contrast, Pdk4 mRNA was expressed at lower levels in SCD subjects. In conclusion, we found that altered myocardial Hba1/2, Hbb, and Pdk4 mRNA expression patterns can be employed as molecular signatures of fatal cardiac dysfunction to forensically implicate SCD as the primary cause of death.     

Influence of heart rate and sympathetic stimulation on arrhythmogenic T wave alternans

We determined the temporal stability of T wave alternans (TWA) during constant rate stimulation and the dependence of alternans on heart rate (HR) and beta-adrenergic stimulation. Although it is established that exercise can provoke microvolt-level TWA in patients at risk for reentrant ventricular arrhythmias, the mechanisms underlying TWA in humans are not well understood. Specifically, the temporal stability of alternans at any given HR and the influence of HR vs. sympathetic activation on alternans remain unclear. TWA was measured during prolonged fixed-rate atrial pacing at multiple cycle lengths (CLs) in 10 subjects referred for electrophysiological testing and in 14 additional subjects in whom atrial pacing was performed at identical pacing CLs with and without isoproterenol. During constant CL stimulation, TWA amplitude oscillated significantly over time (typically by 10 microV) in a quasiperiodic fashion with periodicity of approximately 2-3 min. Alternans amplitude was strongly dependent on HR but not on adrenergic stimulation. There was a patient-specific threshold HR over which alternans appeared. At higher HR, alternans amplitude increased and oscillations were less prominent. Adrenergic stimulation was required to produce TWA that was not already elicited by moderate elevation of HR in only 2 of 14 (14%) patients. In conclusion, TWA 1) fluctuates spontaneously over 2-3 min and 2) increases monotonically with increased HR (without a major adrenergic contribution in most patients). These data suggest that increased HR rather than sympathetic activation is responsible for arrhythmogenic microvolt-level TWA measured during exercise.     

Electroacupuncture decreases the susceptibility to ventricular tachycardia in conscious rats by reducing cardiac metabolic demand

Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Clinical observations and experimental work with animals suggest that acupuncture may have therapeutic effects for individuals with coronary heart disease, certain arrhythmias, and myocardial ischemia. Therefore, we tested the hypothesis that electroacupuncture reduces the susceptibility to ischemia-reperfusion-mediated ventricular tachyarrhythmias. To test this hypothesis, we measured the susceptibility to ventricular tachyarrhythmias produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious rats under two experimental conditions: 1) control and 2) with electroacupuncture. Acupuncture was simulated by electrically stimulating the median nerves, corresponding to the Jianshi-Neiguan [pericardial meridian (P) 5-6] acupoints. Results document a significantly lower incidence of ventricular tachyarrhythmias with electroacupuncture (2 of 8, 25%) relative to control (14 of 14, 100%) rats. The decreased susceptibility to tachyarrhythmias with electroacupuncture was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST-segment elevation) during ischemia.     

Acute volume overload elevates T-wave alternans magnitude.

The objective of this study was to determine whether acute volume loading elevates T-wave alternans (TWA) in dogs with structurally normal hearts. TWA predicts sudden cardiac arrest in patients with left ventricular dysfunction and congestive heart failure. However, volume load and ventricular stretch may themselves precipitate arrhythmias. It is unclear to what extent volume load causes TWA. In six male mongrel dogs [25.8 kg (SD 4.2)] under general anesthesia, we measured TWA during progressive atrial pacing to 160 beats/min. Pacing was performed at baseline, at the midpoint and peak of a saline infusion designed to induce acute CHF, and then during diuresis. Dog 1 was hypothermic throughout the protocol and excluded from analysis. For dogs 2-6, 102 ml/kg (SD 30) were infused over 315 min (SD 50), causing pulmonary capillary wedge pressure to rise from 9.6 (SD 3.5) to 21.2 mmHg (SD 1.6) (P < 0.01), and heart rate variability to fall (P < 0.01). TWA magnitude (Valt) rose in all dogs with volume load (P < 0.001). Compared with baseline, TWA at peak infusion had higher magnitude [Valt 3.4 (SD 1.95) vs. 0.5 muV (SD 0.35); P = 0.011] and occurred at lower heart rates [128 (SD 6) vs. 151 beats/min (SD 12); P = 0.008]. Net volume load was linearly related to Valt (P < 0.01), with each 10 ml/kg net volume load increasing Valt by 0.23 muV. Acute volume overload elevates TWA in normal canine hearts. Although dramatic, however, this effect may contribute clinically to abnormal TWA only in patients with marked volume overload. Future studies should examine the interaction of fluid overload, myocardial disease, and arrhythmia susceptibility.     

Loss of cadherin-binding proteins β-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis

Arrhythmic right ventricular cardiomyopathy (ARVC) is a hereditary heart muscle disease that causes sudden cardiac death (SCD) in young people. Almost half of ARVC patients have a mutation in genes encoding cell adhesion proteins of the desmosome, including plakoglobin (JUP). We previously reported that cardiac tissue-specific plakoglobin (PG) knockout (PG CKO) mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, β-catenin (CTNNB1), showed increased association with the gap junction protein connexin43 (Cx43) in PG CKO hearts. To determine whether β-catenin is required to maintain cardiac conduction in the absence of PG, we generated mice lacking both PG and β-catenin specifically in the heart (i.e., double knockout [DKO]). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD. Loss of the cadherin linker proteins resulted in dissolution of the intercalated disc (ICD) structure. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Finally, ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous lethal ventricular arrhythmia in the DKO mice. In conclusion, these studies demonstrate that the N-cadherin-binding partners, PG and β-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart.     

Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study

Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with (n = 12) and without (n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater (P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater (P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.     

Compression entropy contributes to risk stratification in patients with cardiomyopathy.

Sudden cardiac death (SCD) is a leading cause of mortality with an incidence of 3 million cases per year worldwide. Therapies for patients who have survived an SCD episode or have a high risk of developing lethal ventricular arrhythmia are well established and depend mainly on risk stratification. In this study we investigated the suitability of the non-linear measure compression entropy (Hc) for improved risk prediction in cardiac patients. We recorded 24-h Holter ECG for 300 patients with congestive heart failure (CHF). During a mean follow-up period of 12 months, 32 patients died due to a cardiac event. Hc depends on the compression parameters window length w and buffer length b, which were optimised by analysing a subgroup of patients. Compression entropies based on the beat-to-beat interval (BBI) were subsequently calculated and compared with standard heartrate variability parameters. Statistical analysis revealed significant differences between high- and low-risk CHF patients in standard HRV measures, as well as compression entropy based on the BBI (cardiac death, p = 0.005; SCD, p = 0.02). In conclusion, the implementation of non-linear compression entropy analysis in multivariate analysis seems to be useful for enhanced risk stratification of cardiac death, especially SCD, in ischaemic cardiomyopathy patients.     

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.     

Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction

Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G protein-coupled receptor kinase-2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 h after coronary artery ligation in the dog. We previously demonstrated that the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1 h before the onset of ischemia, and this was associated with significant cardioprotection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine whether a clinical window exists following the onset of ischemia for such a protective effect. The treatment of six dogs with the selective proteasome inhibitor bortezomib 1 h after the surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against the loss of GRK2 at 24 h. There was no significant increase of heat shock protein 70(72) in the EBZ of bortezomib-treated animals compared with control. There was a striking absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that is highly predictive of sudden cardiac deaths (SCDs) during electrocardiogram monitoring of the first 24 h in the bortezomib-treated animals in contrast with nontreated infarcted animals. There were no SCDs in the 6 treated animals (0%) and five SCDs in the 14 control animals (36%). Assay of whole blood proteasome activity demonstrated the expected decrease over the 24-h observation period. These data support the concept that proteasome inhibition within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.