A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5.

BACKGROUND: Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. METHODS AND RESULTS: We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. CONCLUSIONS: The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.

Blocking S1P interaction with S1P1 receptor by a novel competitive S1P1-selective antagonist inhibits angiogenesis.

Sphingosine 1-phosphate receptor type 1 (S1P(1)) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P(1) and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P(1)-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P(1) antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P(1) is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities.

Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking through the type 1 sphingosine 1-phosphate receptor (S1P(1)) and participates in many pathological conditions, including autoimmune diseases. We developed a novel S1P(1)-selective antagonist, TASP0277308, which is structurally unrelated to S1P. This antagonist competitively inhibited S1P-induced cellular responses, such as chemotaxis and receptor internalization. Furthermore, differing from previously reported S1P(1) antagonists, TASP0277308 demonstrated in vivo activities to induce lymphopenia, a block in T cell egress from the thymus, displacement of marginal zone B cells, and upregulation of CD69 expression on both T and B cells, all of which recapitulate phenotypes of S1P(1)-deficient lymphocytes. In a mouse collagen-induced arthritis model, TASP0277308 significantly suppressed the development of arthritis, even after the onset of disease. These findings provide the first chemical evidence to our knowledge that S1P(1) antagonism is responsible for immunosuppression in the treatment of autoimmune diseases and also resolve the discrepancies between genetic and chemical studies on the functions of S1P(1) in lymphocytes.

Classification and assessment of computerized diagnostic criteria for Brugada-type electrocardiograms.

BACKGROUND: Although a Brugada-type electrocardiogram (ECG) is occasionally detected in mass health screening examinations in apparently healthy individuals, the automatic computerized diagnostic criteria for Brugada-type ECGs have not been established. OBJECTIVE: This study was performed to establish the criteria for the computerized diagnosis of Brugada-type ECGs and to evaluate their diagnostic accuracy. METHODS: We examined the ECG parameters in leads V1 to V3 in patients with Brugada syndrome and cases with right bundle branch block. Based on the above parameters, we classified the ECGs into 3 types of Brugada-type ECGs, and the conditions for defining each type were explored as the diagnostic criteria. The diagnostic effectiveness of the proposed criteria was assessed using 548 ECGs from 49 cases with Brugada-type ECGs and the recordings from 192,673 cases (36,674 adults and 155,999 school children) obtained from their annual health examinations. RESULTS: The Brugada-type ST-segment elevation in V1 to V3 was classified into 3 types, types 1, 2/3, and a suggestive Brugada ECG (type S). The automatic diagnostic criteria for each type were established by the J-point amplitude, ST-segment elevation with its amplitude and configuration, as well as the T-wave morphology in leads V1 to V3. CONCLUSION: The proposed criteria demonstrated a reasonable accuracy (type 1: 91.9%, type 2/3: 86.2%, type S: 76.2%) for diagnosing Brugada-type ECG in comparison to the macroscopic diagnosis by experienced observers. Moreover, the automatic criteria had a comparable detection rate (0.6% in adults, 0.16% in children) of Brugada-type ECGs to the macroscopic inspection in the health screening examinations.

Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1-V3.

BACKGROUND: The prognosis of patients with saddleback or noncoved type (non-type 1) ST-elevation in Brugada syndrome is unknown. The purpose of this study was to clarify the long-term prognosis of probands with non-type 1 ECG and those with coved (type 1) Brugada-pattern ECG. METHODS AND RESULTS: A total of 330 (123 symptomatic, 207 asymptomatic) probands with a coved or saddleback ST-elevation > or = 1 mm in leads V(1)-V(3) were divided into 2 ECG groups-type 1 (245 probands) and non-type 1 (85 probands)-and were prospectively followed for 48.7+/-15.0 months. The absence of type 1 ECG was confirmed by drug provocation test and multiple recordings. The ratio of individuals with a family history of sudden cardiac death (14%) was lower than previous studies. Clinical profiles and outcomes were not notably different between the 2 groups (annual arrhythmic event rate of probands with ventricular fibrillation; type 1: 10.2%, non-type 1: 10.6%, probands with syncope; type 1: 0.6%, non-type 1: 1.2%, and asymptomatic probands; type 1: 0.5%, non-type 1: 0%). Family history of sudden cardiac death at age <45 years and coexistence of inferolateral early repolarization with Brugada-pattern ECG were independent predictors of fatal arrhythmic events (hazard ratio, 3.28; 95% confidence interval, 1.42 to 7.60; P=0.005; hazard ratio, 2.66; 95% confidence interval, 1.06 to 6.71; P=0.03, respectively, by multivariate analysis), although spontaneous type 1 ECG and ventricular fibrillation inducibility by electrophysiological study were not reliable parameters. CONCLUSIONS: The long-term prognosis of probands in non-type 1 group was similar to that of type 1 group. Family history of sudden cardiac death and the presence of early repolarization were predictors of poor outcome in this study, which included only probands with Brugada-pattern ST-elevation.

Intramural Purkinje cell network of sheep ventricles as the terminal pathway of conduction system.

To identify the anatomical basis for cardiac electrical signal conduction, particularly seeking the intramural terminals of conduction pathway within the ventricles, sheep hearts were examined compared with human hearts utilizing the characteristic morphology of Purkinje cells as a histological marker. In 15 sheep and five human autopsies of noncardiac death, prevalence of Purkinje or Purkinje-type cells were histologically examined in the atrioventricular node, its distal conduction pathway, the interventricular septum, and the right- and left-ventricular free walls. Myocardial tissue cleavages were examined in the transmural sections (along cardiac base-to-apex axis) obtained from the septum and ventricular free walls. Serial histological sections through virtually the entirety of the septum in selected sheep were used as the basis of a three-dimensional reconstruction of the conduction pathway, particularly of the intramural Purkinje cell network. Purkinje cells were found within the mural myocardium of sheep ventricles whereas no intramural Purkinje-type cell was detected within the human ventricles. In the sheep septum, every intramural Purkinje cell composed a three-dimensional network throughout the mural myocardium, which proximally connected to the subendocardial extension of the bundle branches and distally formed an occasional junction with ordinary working myocytes. The Purkinje-cell network may participate in the ventricular excitation as the terminal conduction pathway. Individual connections among the Purkinje cells contain the links of through-wall orientation which would benefit the signal conduction crossing the architectural barriers by cleavages in sheep hearts. The myocardial architectural changes found in diseased hearts could disrupt the network links including those with transmural orientation. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.

Reentrant ventricular tachycardia originating in the right ventricular outflow tract: slow conduction identified by right coronary artery ostium pacing.

A case of reentrant ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT) is described. An electrophysiological study revealed that programmed stimulation from the right ventricle apex induced 2 types of VT with similar left bundle branch block configuration and inferior axis. Yet, VT cycle length (CL) was different; one was stable, sustained VT with a CL of 360 ms and the other was hemodynamically intolerable VT with a CL of 330 ms. Similarly for both VTs, perfect pace mapping was obtained at the anterior septum beneath the pulmonary valve in the RVOT, and exits of both VTs were very close. Entrainment mapping during stable VT was performed and the anterior septum RVOT was designated as the exit for the stable VT. Intriguingly, entrainment pacing from the ostium of the right coronary artery showed that the post-pacing interval was identical to VTCL. The stimulus to QRS interval was very long (340 ms) during entrainment with concealed fusion, and the right coronary artery ostium was therefore consistent with the VT reentry circuit inner loop or the upper portion of the VT reentry circuit exit. These findings suggest that the stable VT reentry circuit had a slow conduction zone from the ostium of the right coronary artery to the exit in the anterior septum RVOT. When radiofrequency catheter ablation was performed at the 2 exits of the anterior septum RVOT, both VTs then could not be induced.

[Brugada syndrome].

Brugada syndrome is characterized by the right bundle branch block type electrocardiogram (ECG) with ST-segment elevation and ventricular fibrillation (Vf) attack in patients without obvious heart disease. Its background is considered to be the genetic Na channelopathy. The coved type is a typical morphology and is classified into type 1 in the European Society of Cardiology (ESC). In general, the coved type and the saddel-back type (type 2, 3 in the ESC) are interchangeable, and the latter is more frequently detected clinically. For diagnosis of the Brugada syndrome, confirmation of the type 1 morphology is needed. Administration of Na channel blocker, pilsicainide, is a sensitive test for confirmation of the type 1. When the type 1 has one of 7 items recommended by the ESC, the patient is diagnosed with Brugada syndrome. ECG finding alone is classified into patient with Brugada type ECG. As there is no reliable medical treatment, implantation of a cardioverter defibrillator is indicated in patients with Brugada syndrome, and observation alone in those with Brugada type ECG.

Discrimination of Brugada syndrome patients from individuals with the saddle-back type ST-segment elevation using a marker of the standard 12-lead electrocardiography.

BACKGROUND: In the clinical situation, the saddle-back (S-B) type is more frequently detected than the coved type. In the present study, the discrimination of Brugada syndrome from the S-B type individuals using a marker of the standard 12-lead electrocardiography (ECG) was attempted. METHODS AND RESULTS: The study group consisted of 55 individuals with the S-B type in whom pilsicainide provocation test (PLC test) was carried out. The time from the onset of the QRS wave in lead V(2) (IV (2)) to the peak of the late R-like wave in the QRS wave (PV(2)), and the time from IV(2) to the offset of the QRS wave in lead V(5) (EV(5)) were measured. The coved type was induced by the PLC test in 29 cases (N-C group), but not in the remaining 26 cases (N-N group). The (IV(2) -PV(2)) - (IV(2) - EV(5)) value before the PLS test was greater in the N-C group than in the N-N group. The negative predictive value of ;(IV(2) - PV(2)) - (IV(2) - EV(5)) > or =0' was 76.4% for the prediction of a positive PLC test. CONCLUSIONS: A ;(IV(2) - PV(2)) - (IV(2) - EV(5)) > or =0' is a useful ECG marker for the discrimination of Brugada syndrome in the S-B type individuals.

Continuous administration of nicorandil decreases QT dispersion during the chronic phase of acute myocardial infarction.

We previously reported that continuous intravenous (IV) administration of nicorandil (NIC) inhibits QT dispersion (QTd). However, no prior study has evaluated the efficacy of NIC when administered orally to acute myocardial infarction (AMI) patients following continuous IV administration. Thirty patients with anteroseptal infarction in whom revascularization was performed successfully within 6 hours of AMI onset were included in the study and assigned to one of 3 groups: group A (continuous IV administration of NIC), group B (continuous IV and oral administration of NIC), and group C (no treatment with NIC). After 24 hours, QTd in groups A and B was significantly decreased compared to QTd in group C (P < 0.01) (group A, 58.1; group B, 58.2; and group C, 81.3). The QTd obtained 3 months later was significantly shorter in group B subjects who were orally administered NIC, and QTd before percutaneous coronary intervention (PCI) was restored in group A, in which no NIC had been administered orally [group A, 66.7; group B, 54.1; and group C, 73.9; P < 0.05 (group A versus group B) and P < 0.01 (group B versus group C)]. The effects were evaluated by comparing different routes of administration. Continuous IV and subsequent oral administration of NIC inhibited prolongation of QTd, suggesting that these effects may prevent the occurrence of cardiac events during both the acute and chronic phases of AMI.

Molecular and electrophysiological differences in the L-type Ca2+ channel of the atrium and ventricle of rat hearts.

BACKGROUND: Many pathological conditions induce electrical remodeling, possibly through intracellular Ca2+ overload, but the currently available L-type Ca2+ channel blockers may be detrimental because of their global negative inotropic effects. METHODS AND RESULTS: To determine whether the L-type Ca2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of alpha2delta-2 (Cacna2d2) was more abundantly expressed in the atrium (approximately 5-fold) than in the ventricle. In contrast, alpha1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the alpha1C (Cacna1c) (Cav1.2) protein was decreased (approximately 0.5-fold) and that of alpha2 delta-1 (Cacna2d1) was increased (approximately 2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle. CONCLUSION: These results indicate that in the rat heart the L-type Ca2+ channel differs between the atrium and ventricle with regard to gene expression and electrophysiological properties.

Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias.

Population pharmacokinetics (PK) of a sodium channel-blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed-effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS-like elevation of ST-segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant (P < .01) covariates of weight-normalized systemic clearance of pilsicainide. Patients who showed a BrS-like ECG pattern after the drug administration also showed a significantly (P < .01) greater prolongation in His-Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug-induced BrS-like ECG morphology may be associated with augmented ECG responses to pilsicainide.

Automated detection of Brugada-type electrocardiogram using diagnostic criteria of the European Society of Cardiology and the American Heart Association.

The diagnostic criteria of Brugada syndrome were reported from the European Society of Cardiology (ESC) and the American Heart Association in 2002. We examined the automated detection of Brugada-type electrocardiogram (ECG) on 12-lead ECG analysis program by modifying ESC criteria and evaluated it. In ESC criteria, Brugada-type ECG was classified into 3 types of ST-segment abnormalities of V1 to V3 leads. We modified these criteria and determined automated detection criteria as follows: type 1: STj>or=0.2 mV and STj>ST1>ST2 and T<0 mV; type 2: STj>or=0.2 mV and STj>STmin>or=0.1 mV and T>0 mV and T<1.8xR' and Sor=0.2 mV and 0.1 mV>STmin>0 mV and T>0 mV and T<1.8xR' and S>or=3.0 mV; STj, ST1, and ST2 are amplitude of the ST segment (STj: J point, ST1: J point +40 milliseconds, ST2: J point +80 milliseconds). We evaluated these criteria with 97 ECGs from 27 patients, which are diagnosed as Brugada syndrome in university hospital. Brugada-type ECGs were detected correctly in 85 of total 97 ECGs (sensitivity, 88.7%, type 1: 32/32, type 2: 50/61, type 3: 4/4). As compared with 5 cardiologists interpretation of Brugada-type ECGs, computer classified incorrectly in 20 ECGs (type 1: 2, type 2: 17, type 3: 1) in 21,524 cases.

Tests of the homogeneous nucleation theory with molecular-dynamics simulations. I. Lennard-Jones molecules.

Two kinds of the homogeneous nucleation theory exist at the present: the classical nucleation theory and the semiphenomenological model. To test them, we performed molecular-dynamics (MD) simulations of nucleation from vapor to liquid with 5000-20,000 Lennard-Jones-type molecules. Simulations were done for various values of supersaturation ratios (from 2 to 10) and temperatures (from 80 to 120 K). We compared the size distribution of clusters in MD simulations with those in the theoretical models because the number density of critical clusters governs the nucleation rate. We found that the semiphenomenological model achieves excellent agreements in size distributions of the clusters with all MD simulations we done. The classical theory underestimates the number density of the clusters in the temperature range of 80-100 K, but overestimates in 100-120 K. The semiphenomenological model also predicts well the nucleation rate in MD simulations, while the classical nucleation theory does not. Our results confirmed the validity of the semiphenomenological model for Lennard-Jones-type molecules.

Clinical significance of electrocardiography recordings from a higher intercostal space for detection of the brugada sign.

BACKGROUND: The significance of higher intercostal space electrocardiography (HICS ECG) for the detection of the Brugada sign was investigated. METHODS AND RESULTS: The subjects consisted of 113 cases (108 males, 5 females; mean age, 57+/-17 years) with incomplete right bundle branch block type QRS morphology and ST-segment elevation (>0.10 mV) in the right precordial leads. Obvious structural heart disease was not observed in any of the subjects. The V(1-3) leads of the standard 12-lead ECG and the HICS ECG were recorded in the supine position, and the amplitude of the terminal portion of the QRS (J-point) and ST-segment (80 ms from the J-point) were measured. In the HICS ECG, there was an increase in the area in which the Brugada sign was detectable (47 leads to 66 leads), and in cases with the Brugada sign, the amplitude of the J-point increased. CONCLUSIONS: The HICS ECG may be helpful for the detection of the Brugada sign.

New holter monitoring analysis system: a calculation of the lead vectors.

BACKGROUND: A new system of synthesizing a 12-lead electrocardiogram (Syn-ECG) with practically identical waveforms to the standard 12-lead ECG (Stn-ECG) from 3-channel ECGs recorded by Holter monitoring has been developed. METHODS AND RESULTS: The study group comprised 16 healthy individuals and 13 patients with abnormal ECGs. The bipolar eV1, eV5 and eVF leads were recorded using digital Holter monitoring and nine Syn-ECGs, corresponding to each lead of the Stn-ECG, were synthesized. The 9 ECGs consisted of a theoretical Syn-ECG and 8 Syn-ECGs positioned around the theoretical Syn-ECG at 3 cm intervals on the Frank's image surface. Of the 9 ECGs, the Syn-ECG with the maximum product of the cross-correlation coefficient of the QRS wave and that of the T wave, was automatically selected as the optimal Syn-ECG. The amplitude data from the QRS wave, R wave, T wave, and ST level, and also the amplitude ratio of the R wave, T wave to the QRS wave, were significantly well correlated between the Syn-ECG and Stn-ECG. CONCLUSIONS: A practically identical ECG morphology, comparable with a Stn-ECG, was successfully created using this system.

Transvenous catheter cryoablation of the atrioventricular node and visual assessment of freezing of cardiac tissue using intracardiac echocardiography.

We investigated the use of a catheter-based cryoablation system on atrioventricular (AV) junction ablation in dogs. In five dogs, the cryoablation catheter was introduced to the AV junction area in order to create transient high degree or complete AV block. Cryo-freezing energy was applied by lowering the temperature to -75 degrees C for five minutes as a single cycle. This cycle was repeated until significant impairment of the AV conduction appeared. Transient high degree and complete AV block was obtained in all five dogs without any adverse effects. The iceball formation was identified by intracardiac echocardiography. Ablation of the AV junction is effective with several freeze-thaw cycles using a transvenous catheter cryoablation system.

Brugada syndrome-like ST-segment elevation increase exacerbated by vomiting.

The patient was a 53 year-old male who had 3 syncopal episodes over a 6-month period. In the electrophysiological study, ventricular fibrillation (VF) was repeatedly induced by the ventricular extrastimulus method. Intravenous pilsicainide was administered, and the J-point and ST-segment in the right precordial leads became slightly elevated just following drug administration. Five min later, the patient experienced severe nausea and then vomited twice, at which point the electrocardiogram (ECG) showed increased elevation of the J-point and ST-segment. These ECG changes recovered to normal 30 min later. The cause of his syncope was strongly suspected to be related to the VF associated with Brugada syndrome. An interesting aspect of this case was the particular type of J-point and ST-segment elevation that was induced when the patient experienced nausea and vomiting. It is proposed that this phenomenon originated from the vagal stimulation associated with the nausea and vomiting.

123I-MIBG myocardial scintigraphy in patients with "takotsubo" cardiomyopathy.

UNLABELLED: The clinical characteristics of reversible left ventricular dysfunction due to "takotsubo" cardiomyopathy have been described, but the origin of this condition remains unclear. This study investigated (123)I-metaiodobenzlguanidine ((123)I-MIBG) myocardial scintigraphy in patients with takotsubo cardiomyopathy. METHODS: Eight consecutive patients with takotsubo cardiomyopathy were studied. Left ventricular wall motion was monitored by echocardiography until wall motion normalized. (123)I-MIBG myocardial scintigrams were performed within 3 d of admission (0 mo) and after the improvement of left ventricular dysfunction (3 mo). Early images were obtained at 30 min after radioisotope injection and delayed images were obtained after 4 h. The heart-to-mediastinum ratio (H/M ratio) and the washout rate were calculated. RESULTS: The mean left ventricular ejection fraction improved significantly (from 42.8% +/- 8.7% to 66.5% +/- 7.9%; P < 0.0001) and normalized after 19.4 +/- 5.4 hospital days. The early H/M ratio was significantly higher than the late ratio at 0 mo (2.16 +/- 0.25 vs. 1.89 +/- 0.24, respectively; P < 0.05), but not at 3 mo. The washout rate was significantly greater at 0 mo than at 3 mo (39.1% +/- 10.2% vs. 25.4% +/- 6.3%, respectively; P < 0.05). CONCLUSION: In patients with takotsubo cardiomyopathy, initial (123)I-MIBG myocardial scintigraphy depicted a unique pattern of ventricular asynergy and indicated the existence of cardiac sympathetic hyperactivity, although coronary blood flow was maintained. These findings strongly suggest that takotsubo cardiomyopathy could be caused by neurogenic myocardial stunning.

Left ventricular rupture associated with Takotsubo cardiomyopathy.

A 70-year-old woman was admitted to the hospital with chest discomfort after quarreling with her neighbors. Electrocardiography revealed ST-segment elevation in leads I, II, III, aVL, aVF, and V2 through V6. Coronary angiography demonstrated normal arteries, but left ventriculography showed apical akinesis and basal hyperkinesis. Takotsubo cardiomyopathy was diagnosed on the basis of these characteristic findings. The creatine kinase and creatine kinase-MB concentrations were elevated at admission and reached maximum levels 6 hours after admission. The plasma level of brain natriuretic peptide was 10.7 pg/mL (reference range, <18.4 pg/mL) on the first hospital day. ST-segment elevation in leads I, II, III, aVL, aVF, and V2 through V6 persisted at 72 hours after admission. On the third hospital day, sudden rupture of the left ventricle occurred, and despite extensive resuscitation efforts, the patient died. Takotsubo cardiomyopathy presents in a manner similar to that of acute myocardial infarction, but ventricular systolic function usually returns to normal within a few weeks. To our knowledge, this is the first reported case of fatal left ventricular rupture associated with takotsubo cardiomyopathy. We suggest that takotsubo cardiomyopathy may be a newly recognized cause of sudden cardiac death.