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Repolarization alternans has been considered a strong marker of electrical instability. The objective of this study was to investigate the hypothesis that ischemia-induced contrasting effects on the kinetics of membrane voltage and intracellular calcium transient (CaiT) can explain the vulnerability of the ischemic heart to repolarization alternans. Ischemia-induced changes in action potential (AP) and CaiT resulting in alternans were investigated in perfused Langendorff guinea pig hearts subjected to 10–15 min of global no-flow ischemia followed by 10–15 min of reperfusion. The heart was stained with 100 μl of rhod-2 AM and 25 μl of RH-237, and AP and CaiT were simultaneously recorded with an optical mapping system of two 16 × 16 photodiode arrays. Ischemia was associated with shortening of AP duration (D) but delayed upstroke, broadening of peak, and slowed decay of CaiT resulting in a significant increase of CaiT-D. The changes in APD were spatially heterogeneous in contrast to a more spatially homogeneous lengthening of CaiT-D. CaiT alternans could be consistently induced with the introduction of a shorter cycle when the upstroke of the AP occurred before complete relaxation of the previous CaiT and generated a reduced CaiT. However, alternans of CaiT was not necessarily associated with alternans of APD, and this was correlated with the degree of spatially heterogeneous shortening of APD. Sites with less shortening of APD developed alternans of both CaiT and APD, whereas sites with greater shortening of APD could develop a similar degree of CaiT alternans but slight or no APD alternans. This resulted in significant spatial dispersion of APD. The study shows that the contrasting effects of ischemia on the duration of AP and CaiT and, in particular, on their spatial distribution explain the vulnerability of ischemic heart to alternans and the increased dispersion of repolarization during alternans.

Mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure (HF) are undefined.The purpose of this study was to elucidate VT/VF mechanisms in HF by using a computational-clinical approach.In 53 patients with HF and 18 control patients, we established the relationship between low-amplitude action potential voltage alternans (APV-ALT) during ventricular pacing at near-resting heart rates and VT/VF on long-term follow-up. Mechanisms underlying the transition of APV-ALT to VT/VF, which cannot be ascertained in patients, were dissected with multiscale human ventricular models based on human electrophysiological and magnetic resonance imaging data (control and HF).For patients with APV-ALT k-score1.7, complex action potential duration (APD) oscillations (≥2.3% of mean APD), rather than APD alternans, most accurately predicted VT/VF during long-term follow-up (+82%; -90% predictive values). In the failing human ventricular models, abnormal sarcoplasmic reticulum (SR) calcium handling caused APV-ALT (1 mV) during pacing with a cycle length of 550 ms, which transitioned into large magnitude (100 ms) discordant repolarization time alternans (RT-ALT) at faster rates. This initiated VT/VF (cycle length400 ms) by steepening apicobasal repolarization (189 ms/mm) until unidirectional conduction block and reentry. Complex APD oscillations resulted from nonstationary discordant RT-ALT. Restoring SR calcium to control levels was antiarrhythmic by terminating electrical alternans.APV-ALT and complex APD oscillations at near-resting heart rates in patients with HF are linked to arrhythmogenic discordant RT-ALT. This may enable novel physiologically tailored, bioengineered indices to improve VT/VF risk stratification, where SR calcium handling and spatial apicobasal repolarization are potential therapeutic targets.

The rate of repolarization (RRepol) and so the duration of the cardiac action potential are determined by the balance of inward and outward currents across the cardiac membrane (net ionic current). Plotting action potential duration (APD) as a function of the RRepol reveals an inverse non-linear relationship, arising from the geometric association between these two factors. From the RRepol-APD relationship, it can be observed that a longer action potential will exhibit a greater propensity to shorten, or prolong, for a given change in the RRepol (i.e. net ionic current), when compared with one that is initially shorter. This observation has recently been used to explain why so many interventions that prolong the action potential exert a greater effect at slow rates (reverse rate-dependence). In this article, we will discuss the broader implications of this simple principle and examine how common experimental observations on the electrical behaviour of the myocardium may be explained in terms of the RRepol-APD relationship. An argument is made, with supporting published evidence, that the non-linear relationship between the RRepol and APD is a fundamental, and largely overlooked, property of the myocardium. The RRepol-APD relationship appears to explain why interventions and disease with seemingly disparate mechanisms of action have similar electrophysiological consequences. Furthermore, the RRepol-APD relationship predicts that prolongation of the action potential, by slowing repolarization, will promote conditions of dynamic electrical instability, exacerbating several electrophysiological phenomena associated with arrhythmogenesis, namely, the rate dependence of dispersion of repolarization, APD restitution, and electrical alternans.

Cardiac electrical alternans is a period-2 dynamical behavior with alternating long and short action potential durations (APD) that often precedes dangerous arrhythmias associated with cardiac arrest. Despite the importance of alternans, many current ordinary differential equations models of cardiac electrophysiology do not produce alternans, thereby limiting the use of these models for studying the mechanisms that underlie this condition. Because delay differential equations (DDEs) commonly induce complex dynamics in other biological systems, we investigate whether incorporating DDEs can lead to alternans development in cardiac models by studying the Fox et al. canine ventricular action potential model. After suppressing the alternans in the original model, we show that alternans can be obtained by introducing DDEs in the model gating variables, and we quantitatively compare the DDE-induced alternans with the alternans present in the original model. We analyze the behavior of the voltage, currents, and gating variables of the model to study the effects of the delays and to determine how alternans develops in that setting, and we discuss the mathematical and physiological implications of our findings. In future work, we aim to apply our approach to induce alternans in models that do not naturally exhibit such dynamics.

To the Editor, I read with great interest the study by Hojo et al. [1], published in the Journal, about a 74-year-old woman with bouts of polymorphic ventricular tachycardia (PVT) in the setting of Takotsubo syndrome (TTS) who was found to be hypokalemic and had prominent T-wave and J-wave electrical alternans, and mechanical alternans. The following are some thoughts and questions for the authors’ kind consideration: (1) It is conceivable that TTS came first, as the authors propose, followed by J-wave and T-wave alternans, and QTc interval prolongation, which led to PVT, with perhaps some further facilitation caused by the underlying hypokalemia. However, it is also possible that the patient had bouts of PVT precipitated by the underlying hypokalemia (although later hypokalemia was not associated with electrocardiographic repolarization changes), J-wave and T-wave alternans, and QTc interval prolongation, which in turn led to the physical stress that triggered the TTS. (2) Why did the patient’s hypokalemia take 56 h to control? Was there any reason that larger potassium infusions, of course under close potassium blood level monitoring, were not implemented? (3) The mechanical alternans could have been a phenomenon previously encountered in association with T-wave alternans and in the absence of heart failure, or could have been an epiphenomenon of the precipitated left ventricular failure due to TTS. (4) Although this patient’s hypokalemia was attributed to the hydrocortisone “she had taken for pituitary adrenal insufficiency after surgery for a pituitary tumor” [1], it is conceivable that hypokalemia was also further aggravated by the underlying circulating catecholamines (particularly epinephrine), and thus poorly responded to the potassium infusion. Both, TTS [2] and hypokalemia [3], [4] have been shown to be mediated by specific β2-adrenoreceptor stimulation.

© 2015, Springer-Verlag Berlin Heidelberg. Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A2A receptor (A2AR) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs-protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 ± 0.1 to 0.6 ± 0.1 Hz; p

We present a bifurcation analysis of electrical alternans in the two-current Mitchell-Schaeffer (MS) cardiac-cell model using the theory of \(\delta \)-decidability over the reals. Electrical alternans is a phenomenon characterized by a variation in the successive Action Potential Durations (APDs) generated by a single cardiac cell or tissue. Alternans are known to initiate re-entrant waves and are an important physiological indicator of an impending life-threatening arrhythmia such as ventricular fibrillation. The bifurcation analysis we perform determines, for each control parameter \(\tau \) of the MS model, the bifurcation point in the range of \(\tau \) such that a small perturbation to this value results in a transition from alternans to non-alternans behavior. To the best of our knowledge, our analysis represents the first formal verification of non-trivial dynamics in a numerical cardiac-cell model.

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure-response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. (c) 2012 Elsevier Inc. All rights reserved.

Electrical alternans is a broad term that describes alternate-beat variation in the direction, amplitude and duration of any component of the ECG wave-form. It is associated with cardiac tamponade, serious ventricular arrhythmias, and sudden death. We present the clinical case of a 77-year-old female with electrical alternans, from which a diagnosis of cardiac tamponade was established.

Alternans of the ventricular electrogram (VEGM) during ventricular tachycardia (VT) is a rare cause of ventricular undersensing by an implantable cardioverter-defibrillator (ICD). This report describes a patient with a St. Jude ICD who exhibited sustained monomorphic VT associated with surface QRS alternans, alternating cycle lengths, alternans of the VEGM causing intermittent undersensing of the smaller component, and intermittent 2:1 counting of ventricular intervals during 1:1 sensing in response to the ICD detection algorithm. VEGM undersensing was corrected noninvasively simply by programming the threshold start from 62.5% to 50% which increased the sensitivity based on the amplitude of the VEGM. This maneuver did not affect the satisfactory and stable defibrillation threshold.

The Brugada syndrome is a genetic disease (mutation of the SCN5A gene) that predisposes to syncope and life-threatening sudden cardiac death. The case highlights the importance of recognizing hyperkalemia, as potential triggers of the acquired Brugada sign with electrical alternans.

Cardiac electrical alternans, characterized by a beat-to-beat alternation in action potential waveform, is a naturally occurring phenomenon, which can occur at sufficiently fast pacing rates. Its presence has been putatively linked to the onset of cardiac reentry, which is a precursor to ventricular fibrillation. Previous studies have shown that closed-loop alternans control techniques that apply a succession of externally-administered cycle perturbations at a single site provide limited spatially-extended alternans elimination in sufficiently large cardiac substrates. However, detailed experimental investigations into the spatial dynamics of alternans control have been restricted to Purkinje fiber studies. A complete understanding of alternans control in the more clinically relevant ventricular tissue is needed. In this paper, we study the spatial dynamics of alternans and alternans control in arterially perfused canine right ventricular preparations using an optical mapping system capable of high-resolution fluorescence imaging. Specifically, we quantify the spatial efficacy of alternans control along 2.5 cm of tissue, focusing on differences in spatial control between different subregions of tissue. We demonstrate effective control of spatially-extended alternans up to 2.0 cm, with control efficacy attenuating as a function of distance. Our results provide a basis for future investigations into electrode-based control interventions of alternans in cardiac tissue.

We present a case of a 59-year-old man with acute abdominal pain and progressive shortness of breath. A focused assessment with sonography for trauma scan showed free fluid in the hepatorenal recess and in the recto-uterine recess. Later, due to clinical deterioration and the differential possibility of a pulmonary embolism or aortic dissection, a CT scan was performed which revealed large pericardial effusion. This, together with a dilated vena cava inferior and portal system, raised the suspicion of cardiac tamponade. The diagnosis was confirmed by transthoracic echocardiography (TTE). In retrospect, the ECG at admission showed a sinus tachycardia, low-voltage QRS complexes and a total electrical alternans corresponding with the swinging heart seen on TTE. An electrical alternans on ECG is an important diagnostic clue but is often missed, causing an unnecessary delay to proper diagnostic and therapeutic measures.

Respiratory artifact in the electrocardiogram usually indicates labored breathing due to compromised cardiac or pulmonary function. This case series illustrates that correlating the presence and characteristics of respiratory artifact with the ECG morphology and with changes in heart rate frequently allows us to reach specific clinical diagnoses.

Cardiac tamponade as an initial manifestation of undifferentiated connective tissue diseases (UCTD) is extremely rare, with only one case reported in literature thus far. We describe here, a case of a middle-aged man who presented with symptoms of fatigue, exertional dyspnea and orthopnea. His physical exam was significant for anasarca, elevated JVP and pulsus paradoxus. Chest X-ray showed pleural effusions and cardiomegaly, electrocardiogram revealed electrical alternans and a transthoracic echocardiogram demonstrated massive pericardial effusion with hemodynamic compromise. There was clear evidence of tamponade on right heart catheterization. All common causes of pericardial effusion were assiduously excluded before working up the patient for connective tissue disorders, which revealed a high antinuclear antibody titer (1:160), grossly elevated SSA, SSB antibodies and increased C-reactive protein levels (13.04 mg/dl). Patient had no signs or symptoms suggestive of systemic sclerosis (xerophthalmia or xerostomia) and did not meet criteria for any other known connective tissue diseases. He was therefore diagnosed with UCTD, and successfully treated with colchicine after emergency pericardiocentesis. This case presents UCTD as a rare cause of cardiac tamponade and large pericardial effusions and suggests that colchicine can be used to treat UCTD-associated effusions. These patients once diagnosed, are at risk of developing known connective tissue diseases within 5 years of disease onset and should be followed up in clinic periodically.

Cardiac electrical alternans is an alternating rhythm in the electrical properties of the heart, such as cellular action potential duration, conduction velocity, and/or intracellular calcium (Ca) concentrations. These alternations can initiate reentrant arrhythmias and can also break up ongoing reentry, creating ventricular fibrillation. Alternans can take several forms. The alternation in time can be uniform in space (concordant alternans) or can have regions that are out of phase with other regions (discordant alternans). Alternans can be driven by voltage instabilities (involving electrical restitution) or by Ca instabilities. In addition, the relation between voltage and Ca can be positive or negative. Anatomical factors can play a role in generating spatially discordant alternans, but there is also a critical role for instabilities that are dynamically generated and can only be understood as the response of a nonlinear medium to periodic excitation. This is especially true of spatially discordant alternans, the most deadly form. We will review the role of factors such as action potential duration, conduction velocity, and Ca, which interact with each other to produce alternans. Simulations of cardiac conduction support these conclusions, as do experiments in a variety of animal and human preparations.

Electrical alternans, a beat-to-beat alternation in the electrocardiogram or electrogram, is frequently seen during the first few minutes of acute myocardial ischemia, and is often immediately followed by malignant cardiac arrhythmias such as ventricular tachycardia and ventricular fibrillation. As ischemia progresses, higher-order periodic rhythms (e.g., period-4) can replace the period-2 alternans rhythm. This is also seen in modelling work on a two-dimensional (2-D) sheet of regionally ischemic ventricular muscle. In addition, in the experimental work, ventricular arrhythmias are overwhelmingly seen only after the higher-order rhythms arise. We investigate an ionic model of a strand of ischemic ventricular muscle, constructed as a 3-cm-long 1-D cable with a centrally located 1-cm-long segment exposed to an elevated extracellular potassium concentration ([K(+)](o)). As [K(+)](o) is raised in this "ischemic segment" to represent one major effect of ongoing ischemia, the sequence of rhythms {1:1--2:2 (alternans)--2:1} is seen. With further increase in [K(+)](o), one sees higher-order periodic 2N:M rhythms {2:1--4:2--4:1--6:2--6:1--8:2--8:1}. In a 2N:M cycle, only M of the 2N action potentials generated at the proximal end of the cable successfully traverse the ischemic segment, with the remaining ones being blocked within the ischemic segment. Finally, there is a transition to complete block {8:1--2:0--1:0} (in an n:0 rhythm, all action potentials die out within the ischemic segment). Changing the length of the ischemic segment results in different rhythms and transitions being seen: e.g., when the ischemic segment is 2 cm long, the period-6 rhythms are not seen; when it is 0.5 cm long, there is a 3:1 rhythm interposed between the 2:1 and 1:0 rhythms. We discuss the relevance of our results to the experimental observations on the higher-order rhythms that presage reentrant ischemic ventricular arrhythmias.

Electrical alternans, defined as a beat-to-beat change in the duration of the excited phase of cardiac cells, is among the known precursors of sudden cardiac death. It may appear as concordant (all the tissue presenting the same phase of oscillation) or discordant (with out-of-phase regions distributed among tissue). Spatially discordant alternans can lead to unidirectional block that initiates reentry and ventricular fibrillation. The role played by tissue heterogeneities and heart rate changes in their initiation remains, however, unclear. We study the mechanisms for initiation of spatially discordant alternans by numerical simulations of an ionic model spatially distributed in a one-dimensional cable and in an anatomical model of the rabbit heart. The effects of CV-restitution, ectopic beats, and the role of spatial gradients of electrical restitution properties are investigated. In homogeneous tissue, the origin of discordant alternans may be dynamical, through CV-restitution, or due to a localized change in the pacing period. We also find that a sudden change of stimulation rate can initiate discordant alternans in the presence of a spatial gradient of APD-restitution without necessitating CV-restitution. The mechanism of, and the conditions for, initiation are determined based on an iterated map analysis of beat to beat changes of APD. This analysis leads to the definition of a vulnerable window for initiation of discordant alternans. Moreover, the pattern of spatially discordant alternans is found to change slowly over several beats following initiation, as reflected in ECG recordings.

Introduction: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. Methods:Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1 = 220 (or 240) ms immediately followed by 30 test-beats at S2 = 200 ms. This S1–S2 protocol was repeated for S2 = 190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. Results:Physiologically relevant inhibition (IC20) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (Ceff). At the highest achievable levels, fluoxetine (20-fold Ceff) and citalopram (28-fold Ceff) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold Ceff, but did not increase electrical alternans at the highest achievable dose (3.1-fold Ceff). Discussion:These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.

The extensive development of detailed mathematical models of cardiac myocyte electrophysiology in recent years has led to a proliferation of models, including many that model the same animal species and specific region of the heart and thus would be expected to have similar properties. In this paper we review and compare two recently developed mathematical models of the electrophysiology of canine ventricular myocytes. To clarify their similarities and differences, we also present studies using them in a range of preparations from single cells to two-dimensional tissue. The models are compared with each other and with new and previously published experimental results in terms of a number of their properties, including action potential morphologies; transmembrane currents during normal heart rates and during alternans; alternans onsets, magnitudes, and cessations; and reentry dynamics of spiral waves. Action potential applets and spiral wave movies for the two canine ventricular models are available online as supplemental material. We find a number of differences between the models, including their rate dependence, alternans dynamics, and reentry stability, and a number of differences compared with experiments. Differences between models of the same species and region of the heart are not unique to these canine models. Similar differences can be found in the behavior of two models of human ventricular myocytes and of human atrial myocytes. We provide several possible explanations for the differences observed in models of the same species and region of the heart and discuss the implications for the applicability of models in addressing questions of mechanism in cardiac electrophysiology.

Microvolt T-wave alternans (TWA) increases acutely prior to ventricular tachycardia (VT) or ventricular fibrillation (VF) in computer simulations and animal models, suggesting that TWA may provide a warning for VT/VF in patients with an implantable cardioverter-defibrillator (ICD).The purposes of this study were to develop a method for analyzing TWA recorded from ICD electrograms (EGMs) and to evaluate the degree of concordance between EGM TWA and TWA recorded from the surface ECG.We developed a software program to measure EGM TWA in the frequency domain and then used simulated EGMs to determine the effects of ICD signal processing, electrical noise, and variation in the EGM fiducial point on the recorded amplitude and K score (signal-to-noise ratio) of TWA. We then applied this method to analyze TWA simultaneously using both surface ECGs and ICD EGMs during incremental pacing in 25 ICD patients. Pacing modes and EGM sources were varied in repeated trials. EGMs with dynamic range adjusted to achieve a large T wave were telemetered to a digital Holter recorder and measured offline. ECG TWA was analyzed using a commercial system. A positive (+) ECG test had sustained alternansor=1.9 microV with K scoreor=3. Stored EGMs were reviewed for VT/VF during a 6-month follow-up period.Simulations demonstrated that the EGM method accurately identified TWAor=10 microV. Overall, 10 (40%) patients had at least one ECG TWA+ test and 15 patients (60%) had no ECG TWA+ tests. The maximum value of TWA was greater in EGMs than in ECGs (median 64 microV vs 2.2 microV, P.0001). EGM TWA was greater in ECG TWA+ tests than in ECG TWA- tests (169 +/- 175 microV vs 71 +/- 61 microV, P.001). Using a sustained EGM TWA threshold of 30 microV, EGM TWA was concordant with ECG TWA in 63 (84%) of 75 analyzed tests (P.0001) and predicted ECG TWA results with 85% sensitivity and 84% specificity. Both ECG and EGM TWA predicted VT/VF during follow-up (ECG: P = .006; EGM: P = .035).The amplitude of TWA is at least 10 times greater on ICD EGMs than on surface ECGs. EGM and ECG TWA have substantial concordance and comparable predictive value for spontaneous VT/VF. These observations support the hypothesis that ECG and EGM TWA detect the same electrical alternans phenomenon.

Instability in the intracellular Ca2+ handling system leading to Ca2+ alternans is hypothesized to be an underlying cause of electrical alternans. The highly coupled nature of membrane voltage and Ca2+ regulation suggests that there should be reciprocal effects of membrane voltage on the stability of the Ca2+ handling system. We investigated such effects using a mathematical model of the cardiac intracellular Ca2+ handling system. We found that the morphology of the action potential has a significant effect on the stability of the Ca2+ handling system at any given pacing rate, with small changes in action potential morphology resulting in a transition from stable nonalternating Ca2+ transients to stable alternating Ca2+ transients. This bifurcation occurs as the alternans eigenvalue of the system changes from absolute value 1. These results suggest that the stability of the intracellular Ca2+ handling system and the occurrence of Ca2+ alternans are not dictated solely by the Ca2+ handling system itself, but are also modulated to a significant degree by membrane voltage (through its influence on sarcolemmal Ca2+ currents) and, therefore, by all ionic currents that affect membrane voltage.

A combination of pericardial effusion with cardiac tamponade and superior vena caval syndrome is an unusual first presentation of carcinoma of lung, although cardiac involvement is often a late finding in widespread malignancy. Clinical identification can be difficult ante-mortem. Accurate diagnosis and prompt intervention are necessary to prevent adverse outcomes. Decisions regarding treatment must take into account the clinical presentation and echocardiographic findings. Echocardiography-guided pericardiocentesis with catheter drainage and/or pericardial window is the primary treatment strategy of choice for most large or hemodynamically significant effusions. New cardiac symptoms or classic findings of cardiac tamponade should prompt aggressive investigation. We present a case of adenocarcinoma of the lung that initially presented as pericardial effusion with tamponade and superior vena cava syndrome. The patient had all the clinical features of tamponade such as pulsus paradoxus, tachycardia, elevated jugular venous pressure, hypotension, and electrical alternans on surface electrocardiography. The findings were confirmed on echocardiography and computed tomography of chest, both of which allowed for rapid confirmation of the presence of an effusion and compression of the superior vena cava. The existing literature on the subject is succinctly reviewed.

Objective: The restitution mechanism has been the focus of attention as the possible mechanism behind ventricular fibrillation (VF). However, its contribution in chronic ischemic heart has not been established. Methods: We investigated chronic ischemic dogs with occlusion of left anterior descending artery. Sixty unipolar electrograms were simultaneously recorded from an entire cardiac surface. Activation-recovery intervals (ARIs) and QRST deflection area (AQRST) were measured during constant atrial pacing. The ischemic dogs were divided into two groups, five dogs in VF(+) group or seven dogs in VF(−) group, according to VF occurrence by programmed electrical stimulation. Results: When investigating ARI dispersions on an epicardium, there was no difference between VF(+) and VF(−) groups. The relationship between ARIs and diastolic intervals was quantified as an electrical restitution curve. The slopes of the ARI restitution curve for the anterior left ventricle in VF(+) dogs were significantly steeper than those of VF(−) dogs. The amplitude of AQRST alternans were significantly greater in VF(+) dogs than VF(−) dogs. Conclusions: Combined observation of steep restitution slopes and increased electrical alternans supported the restitution mechanism as being involved in the arrhythmia. Dynamic restitution properties and not static single-beat ARI dispersion may play an important role in the VF arrhythmia in the chronic ischemic heart.

Suppression of electrical alternans may be antiarrhythmic. Our previous computer simulations have suggested that increasing the rapid component of the delayed rectifier K+current ( IKr) suppresses alternans. To test this hypothesis, IKrin isolated canine ventricular myocytes was increased by infection with an adenovirus containing the gene for the pore-forming domain of IKr[human ether-a-go-go gene (HERG)]. With the use of the perforated or whole cell patch-clamp technique, action potentials recorded at different pacing cycle lengths (CLs) were applied to the myocytes as the command waveforms. HERG infection markedly increased peak IKrduring the action potential (from 0.54 ± 0.03 pA/pF in control to 3.60 ± 0.81 pA/pF). Rate-dependent alterations of peak IKrwere similar for freshly isolated myocytes and HERG-infected myocytes. In both cell types, IKrincreased when CL decreased from 1,000 to 500 ms and then decreased progressively as CL decreased further. During alternans at CL = 170 ms, peak IKrwas larger for the short than for the long action potential for both groups, but the difference in peak IKrwas larger for HERG-infected myocytes. The voltage at which peak IKroccurred was significantly less negative in HERG-infected myocytes, in association with shifts of the steady-state voltage-dependent activation and inactivation curves to less negative potentials. Pacing at short CL induced stable alternans in freshly isolated myocytes and in cultured myocytes without HERG infection, but not in HERG-infected myocytes. These data support the idea that increasing IKrmay be a viable approach to suppressing electrical alternans.

We examine the utility of the action potential (AP) duration (APD) restitution curve slope in predicting the onset of electrical alternans when electrotonic and memory effects are considered. We develop and use two ionic cell models without memory that have the same restitution curve with slope >1 but different AP shapes and, therefore, different electrotonic effects. We also study a third cell model that incorporates short-term memory of previous cycle lengths, so that it has a family of S1-S2 restitution curves as well as a dynamic restitution curve with slope >1. Our results indicate that both electrotonic and memory effects can suppress alternans, even when the APD restitution curve is steep. In the absence of memory, electrotonic currents related to the shape of the AP, as well as conduction velocity restitution, can affect how alternans develops in tissue and, in some cases, can prevent its induction entirely, even when isolated cells exhibit alternans. When short-term memory is included, alternans may not occur in isolated cells, despite a steep APD restitution curve, and may or may not occur in tissue, depending on conduction velocity restitution. We show for the first time that electrotonic and memory effects can prevent conduction blocks and stabilize reentrant waves in two and three dimensions. Thus we find that the slope of the APD restitution curve alone does not always well predict the onset of alternans and that incorporating electrotonic and memory effects may provide a more useful alternans criterion. A Data Supplement containing movies and JAVA applets is available online at http://ajpheart.physiology.org/cgi/content/full/00747.2003/DC1 .

Electrical alternans is a pattern of variation in the shape of the ECG waveform that appears on an every-other-beat basis. In humans, alternation in ventricular repolarization, namely, repolarization alternans, has been associated with increased vulnerability to ventricular tachycardia/ventricular fibrillation and sudden cardiac death. This study investigates the utility of implantable cardioverter defibrillator electrograms to estimate repolarization alternans preceding a tachyarrhythmic event. It is demonstrated that microvolt-level repolarization alternans is present prior to an arrhythmic event, and one can record low-amplitude-noise signals that can be used to obtain reliable estimates of repolarization alternans. This study eventually may lead to new methods that would prevent the onset of malignant tachyarrhythmias.

Introduction: Progressive heart failure and ventricular fibrillation are major causes of death in patients with chronic heart failure. Mechanical alternans (pulsus alternans) has been observed in patients with severe congestive heart failure. Visible T wave alternans occasionally is a precursor of ventricular fibrillation. We investigated the occurrence of both cardiac alternans in 94 patients with chronic heart failure. Methods and Results: Mean left ventricular ejection fraction (LVEF) of the study population was 35 ± 10%. Mechanical alternans was detected in left ventricular pressure during diagnostic cardiac catheterization. Only sustained mechanical alternans was included in the study. Visible T wave alternans, not microvolt alternans, was noted on standard surface ECG. Cardiac alternans was examined at rest, during physiologic tachycardia, and during stepwise dobutamine loading (2–4–8 μg/kg/min). Prevalences of mechanical and electrical alternans were 19.1% and 4.4% at rest, 45.5% and 8.0% during physiologic tachycardia, and 62.1% and 9.5% under dobutamine loading. Overall, 70 patients (74.5%) showed mechanical alternans and 10 patients (10.6%) showed T wave alternans. T wave alternans always appeared with large mechanical alternans. Among patients with mechanical alternans, cases with T wave alternans showed lower LVEF than those without (27.5 ± 4.4 and 35.1 ± 10.2, P < 0.002). Conclusion: Visible T wave alternans was detectable in patients with chronic heart failure, especially under tachycardia or catecholamine exposure. Investigating mechanical and mechanoelectrical alternans may bring new insights into the management of patients with chronic heart failure. (J Cardiovasc Electrophysiol, Vol. 15, pp. 295-299, March 2004)

Sudden cardiac death, secondary to ventricular fibrillation (VF), remains the leading cause of death in many developed countries. Substantial experimental and theoretical support exists for the idea that VF is caused by spiral wave re-entry. The initiation and subsequent break-up of spiral waves have been linked to electrical alternans, a phenomenon typically associated with a steeply sloped restitution relationship. Interventions that reduce the slope of the restitution relationship have been shown to prevent the induction of VF and to terminate existing VF in experimental models. These results suggest that electrical restitution may be a promising new target for antiarrhythmic therapies.

The electrical restitution curve (ERC) traditionally describes the recovery of action potential duration (APD) as a function of the interbeat interval or, more correctly, the diastolic interval (DI). Often overlooked in modeling studies, the normal ventricular ERC is triphasic, starting with a steep initial recovery at the shortest DIs, a transient decline, and a final asymptotic rise to a plateau phase reached at long DIs. Recent studies have proposed that it would be advantageous to lower the slope of the ERC by drug intervention, as this might reduce the potential for electrical alternans and ventricular fibrillation. This review discusses the pros and cons of a flat versus steep slope of the ERC and draws attention to mechanisms thatjustify the (physiologically) steep slope, rather than a flat slope, as a better design against arrhythmias. Five potential mechanisms are discussed, which allows for a different interpretation of the effect of the slope on arrhythmogenicity. The most important appears to be the physiologic rate adaptive shortening of APD that, by reciprocal lengthening of the DI, allows the subsequent APD to move more quickly from the steep initial ERC phase onto the flat phase. A less steep initial ERC phase would protract the transition toward more fully recovered APD and, in fact, may perpetuate electrical alternans. The triphasic ERC time course in normal myocardium cannot be explained by or fitted to single exponentials or single ion channel recovery kinetics. A simple tri-ionic model is suggested that may help explain the shape of the ERC at various repolarization levels and place APD recovery into perspective with intracellular calcium recycling and recovery of contractile force.

Right atrial monophasic action potentials were recorded before and after 60 minutes of rapid atrial pacing (pacing cycle length (CL); 127 +/- 10 ms) in 12 closed-chest dogs. The right atrial (RA) monophasic action potential (MAP) duration at 90% repolarization (RAMAPD) was measured at CLs of 400 ms and 250 ms. CL-dependent changes in RAMAPD (CL 400 ms - 250 ms) before and after rapid atrial pacing were 24 +/- 1 ms and 16 +/- 5 ms, respectively (p 5 minutes) was induced in 1 of 12 dogs at a pacing CL of 130 ms before rapid atrial pacing and in 4 of 12 dogs at a pacing CL of 135 +/- 17 ms after rapid atrial pacing. Onset of AF was always preceded by the RAMAPD alternans. Sixty minutes of rapid atrial pacing leads to diminution of rate adaptation of atrial action potential duration (APD) and appearance of APD alternans of greater magnitude at longer CL, both of which may contribute to the initiation and perpetuation of AF during its early phase.

The phenomenon of a 2:1 bundle branch block is reported during atrioventricular (AV) nodal reentrant tachycardia, sinus tachycardia, atrial fibrillation, and atrial flutter. A 2:1 bundle branch block is attributed to first- and second-degree bundle branch block, linking, electrical alternans, aberrancy, or supernormal conduction. However, the same phenomenon has not been reported in AV reentrant tachycardia. Herein, we report the case of a 52-year-old man presenting with orthodromic atrioventricular reentrant tachycardia with a 2:1 right bundle branch block.

Pulsus alternans was observed in a child with left ventricular dysfunction secondary to systemic hypertension. The Echo-Doppler of supravalvular aorta and a simultaneous electrocardiographic trace (ECG) clearly demonstrated the mechanism of an apparent abrupt halving of pulse frequency compared with the ECG, similar to an electromechanical dissociation 2: 1. Besides the extreme pulsus alternans, a P wave and a PP cycle length change were also observed. Both mechanical and electrical alternans disappeared with afterload reduction by nitroprusside treatment.

Although alternans of action potential duration (APD) is a robust feature of the rapidly paced canine ventricle, currently available ionic models of cardiac myocytes do not recreate this phenomenon. To address this problem, we developed a new ionic model using formulations of currents based on previous models and recent experimental data. Compared with existing models, the inward rectifier K+ current ( I K1) was decreased at depolarized potentials, the maximum conductance and rectification of the rapid component of the delayed rectifier K+ current ( I Kr) were increased, and I Kr activation kinetics were slowed. The slow component of the delayed rectifier K+current ( I Ks) was increased in magnitude and activation shifted to less positive voltages, and the L-type Ca2+ current ( I Ca) was modified to produce a smaller, more rapidly inactivating current. Finally, a simplified form of intracellular calcium dynamics was adopted. In this model, APD alternans occurred at cycle lengths = 150–210 ms, with a maximum alternans amplitude of 39 ms. APD alternans was suppressed by decreasing I Ca magnitude or calcium-induced inactivation and by increasing the magnitude of I K1, I Kr, or I Ks. These results establish an ionic basis for APD alternans, which should facilitate the development of pharmacological approaches to eliminating alternans.

Cardiac electrical alternans is a state of alternation between long and short action potentials and is frequently associated with harmful cardiac conditions. Different dynamic mechanisms can give rise to alternans; however, many cardiac models based on ordinary differential equations are not able to reproduce this phenomenon. A previous study showed that alternans can be induced by the introduction of delay differential equations (DDEs) in the formulations of the ion channel gating variables of a canine myocyte model. The present work demonstrates that this technique is not model-specific by successfully promoting alternans using DDEs for five cardiac electrophysiology models that describe different types of myocytes, with varying degrees of complexity. By analyzing results across the different models, we observe two potential requirements for alternans promotion via DDEs for ionic gates: (i) the gate must have a significant influence on the action potential duration and (ii) a delay must significantly impair the gate's recovery between consecutive action potentials.

Cardiac arrhythmias, such as atrial fibrillation (AF), require an arrhythmogenic focus (ectopic activity) and transient or permanent tissue inhomogeneity (conduction heterogeneity). Electrical and calcium alternans in atrial tissue represent a risk factor for the occurrence of AF. The aims of our study were to determine characteristics of the development of Ca transient (CaT) alternans in coupled pairs of atrial myocytes and the relationship between cellular atrial alternans and occurrence of AF episodes in the perfused intact heart. Atrial cell pairs isolated from rabbit hearts were field stimulated at increasing rates until CaT alternans occurred. The CaT alternans usually initiated in one cell first. Alternans in the second cell rarely occurred simultaneously (3/11 pairs), but rather started at higher frequencies (5/11 pairs), or did not occur at all (3/11pairs). Stimulation with angiotensin (Ang II) lowered the pacing threshold for CaT alternans (from 1.71±0.08 to 1.49±0.14 Hz) and enhanced the degree of alternans (increased alternans ratio), presumably through activation of IP3 receptor-induced Ca release. Under control conditions cell pairs spontaneously switched between periods of concordant and discordant CaT alternans. Concordant and discordant CaT alternans between cell pairs led to intercellular heterogeneity in the CaT amplitude resulting in beat-to-beat intercellular Ca gradients. Ang II further enhanced these intercellular Ca gradients. In Langendorff perfused rabbit hearts pacing-induced electrical alternans were recorded with atrial bipolar electrograms and multielectrode mapping of the epicardial surface. The data revealed a high temporal correlation between atrial alternans and episodes of AF: atrial electrical alternans in form of atrial T wave alternans triggered AF episodes, and AF induced by a burst pacing protocol was followed by episodes of atrial T wave alternans. Ang II perfusion enhanced tissue-wide atrial T wave variability, suggesting enhanced electrical tissue heterogeneity and possibly discordant alternans at tissue level.

In hypothyroid patients pericardial effusion occurs with an increased incidence. Usually, this liquid accumulates in small or moderate amount and is rich in mucopolysaccarides and cholesterol. The aim of our study was to establish if there is any correlation between the severity of the thyroid disorder, expressed by the levels of TSH and the amount of pericardial effusion and its evolution. Material and method: We studied 192 patients with overt and subclinical hypothyroidism, admitted in the Clinic of Endocrinology between 2010 and 2013. All subjects had endocrinologic and cardiology evaluations, including echocardiography, in order to asses the presence and amount of pericardial effusion. Results: We found an increased incidence of pericarditis, especially in patients with overt hypothyroidism and a very significant correlation between the amount of pericardial effusion and the levels of TSH. The pericardial fluid, independent of its amount, regressed under hormone replacement therapy so that no surgical intervention was needed. A peculiar aspect, found in patients with overt hypothyroidism, was a thickened pericardium caused probably, by long lasting or/and repeated pericarditis. Conclusion: in hypothyroidism, the incidence and amount of pericardial effusion correlates with the severity of the disease and regresses slowly, under hormonal replacement therapy. In some cases, with long lasting hypothyroidism, chronic pericarditis develops. Introduction In hypothyroid patients, pericardial effusion represents a common finding (1, 2). The incidence of pericarditis in patients with mild hypothyroidism ranges from 3% to 6%, but in those with severe deficiency, the incidence raises to 30% or even 80%. However, pericardial effusion has also been associated with subclinical hypothyroidism (3). Hypothyroidism induces accumulation of effusions in various body cavities including peritoneum, pericardium, pleura, middle ear, uvea, joints and scrotum. These are exudates and the incriminated pathophysiological mechanism is an increase in the volume of distribution of albumin, with extravasation of hygroscopic mucopolysaccarides into the body cavities, combined with increased permeability and decreased lymphatic clearance, associated with increased retention of salt and water (4, 5). In hypothyroidism, the pericardial effusion contains high levels of cholesterol. Methodology We studied 192 patients with hypothyroidism, admitted in the Clinic of Endocrinology of the County Emergency Hospital Timisoara, in a period of 3 years, January 2010 – January 2013. The study was approved by the ethics committee of the hospital and all patients gave their consent. The study group contained 169 women and 23 men, aged between 21 and 79 years (mean age = 54.27 + 21.5 years). All patients were first evaluated by an endocrinologist, with hormonal determinations (thyroid stimulating hormone TSH, free thyroxin FT4, free triiodothyroxin FT3) and sonography, in order to establish the etiology and severity of thyroid disorder. Subsequently, they underwent cardiologic evaluation: physical examination, ECG, chest x-ray and echocardiography, done with an Acuson Sequoia C512 echocardiograph. We established by echocardiography the presence and amount of pericardial effusion with its hemodynamic consequences, eventually the signs of tamponade. A particular aspect, noticed in some cases, was the presence of a thick, hyperreflecting pericardium. Results From the 192 patients included in our study, 156 (81.25%) had overt hypothyroidism and 36 (18.75%) subclinical disease (SHT). Because of the inhomogeneity of patients with overt hypothyroidism we divided them into two categories: 77 subjects (49.35%) with severe thyroid insufficiency (STI), with TSH levels > 70 μmol/ml and FT4 ˂ 6 pmol/ml, and 79 (50.64%) patients with moderate forms of clinical hypothyroidism (MCHT). In our patients, pericarditis had an insidious onset, evolved without significant hemodynamic manifestations, and echocardiography was the primary method of diagnosis. Suggestive EKG findings were microvolt, ST segment changes, negative T waves and electrical alternans. The results of the laboratory examinations are presented in table 1. Except for patients with prolonged hypothyroidism, pericardial effusion was detected in a minor or moderate amount, symptoms were minimal and alleviated with hormonal replacement therapy. Occasionally, pericardial effusion was substantial with cardiomegaly on chest X-ray and echocardiography revealed signs of tamponade. Patients with overt hypothyroidism had the highest incidence of pericarditis: from the 77 subjects with STI, 59 (76.62 %) had pericardial effusions, of which 37 (62.71%) were small, 16 (27.11%) moderate and only 6 (10.16%) large, with signs of tamponade; from the 79 patients with MCHT, 22 (27.84%) had pericarditis: 15 (68.18%), small, 5 (22.72%) moderate and in 2 cases (9.09%) large. In patients with SHT, only 8 (22.22%) had pericardial effusion, but 6 (75%) had mild forms and 2 (25%) moderate ones, see fig.1. Table 1: Results of laboratory examinations

A 66-year-old man sought medical care at the hospital due to severe chest pain lasting for 24 hours. The patient was aware of being hypertensive and was a smoker. Without any prior symptom, he started to have severe chest pain and sought emergency medical care after about 24 hours, due to pain persistence. At physical examination (August 13, 2005, 10 PM) he had a heart rate of 90 bpm and blood pressure of 110/70 mmHg. Lung examination showed no alterations. Heart assessment showed a systolic murmur in the lower left sternal border and mitral area. The initial electrocardiogram (August 13, 2005, 22 h) showed HR of 100 bpm, sinus rhythm, 1st-degree atrioventricular block (PR 240 ms), low-voltage QRS complexes in the frontal plane, QRS complex electrical alternans and extensive ongoing anterior wall infarction (QS V1 to V6, ST elevation in the same leads and QS in the inferior wall, II, III and aVF) (Figure 1). Figure 1 ECG: low QRS voltage in the frontal plane, electrical alternans of QRS complexes, electrically inactive lower wall area and extensive ongoing myocardial infarction. Acetylsalicylic acid by oral route and 5 mg of intravenous metoprolol were administered. The patient had bradycardia and cardiorespiratory arrest in pulseless electrical activity, reversed after five minutes. He developed hypotension and peripheral hypoperfusion and was transferred to InCor (The Heart Institute). On admission he had received heparin and continuous intravenous norepinephrine. BP was 60/30 mmHg. The ECG (August 13, 2005, 11:36 PM) disclosed heart rate of 116 bpm, junctional escape rhythm with sinus arrest and atrial extrasystoles); low-voltage QRS complex in the frontal plane, extensive ongoing anterior acute myocardial infarction, inactive area in the inferior wall; presence of ST elevation at V1 to V5 and ST depression in leads I, II and aVF; ST elevation in aVR (Figure 2). Figure 2 ECG: low QRS voltage in the frontal plane, electrically inactive lower wall area and anterior myocardial infarction with increased ST elevation, still with positive T waves, "hyperacute phase of myocardial infaction". Coronary angiography was indicated, which disclosed anterior interventricular branch occlusion and images suggestive of intracoronary thrombus, lesion of 70% in the circumflex artery, 50% in the right coronary artery and 70% in the ostium of the right posterior descending branch. Angioplasty was performed with stent implant in the anterior interventricular artery, but distal flow was not restored. This was followed by cardiac arrest in asystole, which did not respond to treatment and the patient died.

Alternans is the periodic beat-to-beat short–long alternation in action potential duration (APD), which is considered to be a precursor of ventricular arrhythmias and sudden cardiac death. In extended cardiac tissue, electrical alternans can be either spatially concordant (SCA, all cells oscillate in phase) or spatially discordant (SDA, cells in different regions oscillate out of phase). SDA gives rise to an increase in the spatial dispersion of repolarization, which is thought to be proarrhythmic. In this paper, we investigated the effect of two aspects of short term memory (STM) ( α , τ ) and their interplay with conduction velocity (CV) restitution on alternans formation using numerical simulations of a mapping model with two beats of memory. Here, α quantifies the dependence of APD restitution on pacing history and τ characterizes APD accommodation, which is an exponential change of APD over time once basic cycle length (BCL) changes. Our main findings are as follows: In both single cell and spatially coupled homogeneous cable, the interplay between α and τ affects the dynamical behaviors of the system. For the case of large APD accommodation ( τ ≥ 290 ms ) , increase in α leads to suppression of alternans. However, if APD accommodation is small ( τ ≤ 250 ms ) , increase in α leads to appearance of additional alternans region. On the other hand, the slope of CV restitution does not change the regions of alternans in the cable. However, steep CV restitution leads to more complicated dynamical behaviors of the system. Specifically, SDA instead of SCA are observed. In addition, for steep CV restitution and sufficiently large τ , we observed formations of type II conduction block ( CB 2 ) , transition from type I conduction block ( CB 1 ) to CB 2 , and unstable nodes.