Original Article
Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome
N Engl J Med 2010; 363:1397-1409October 7, 2010
- Abstract
Background
Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier IKs current.
Methods
We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes.
Results
Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a “ventricular,” “atrial,” or “nodal” phenotype, as evidenced by the expression of cell-type–specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in “ventricular” and “atrial” cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q–KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in IKs current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype.
Conclusions
We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.)
Media in This Article
Video
Two Videos Showing Spontaneous Contraction.
Figure 1
Generation of Pluripotent Stem Cells from Patients with Long-QT Syndrome Type 1.Article Activity
- Article
Video
Two Videos Showing Spontaneous Contraction.
The long-QT syndrome is a familial, usually autosomal dominant disease characterized by an abnormally prolonged ventricular repolarization phase and a propensity toward polymorphic ventricular tachycardia (often termed torsades de pointes) and sudden cardiac death.1-3 At least 10 different forms of the long-QT syndrome have been described, but in approximately 45% of genotyped patients, the underlying causes are mutations in the KCNQ1 (also known as KVLQT1 or Kv7.1) gene, which encodes the pore-forming alpha subunits of the channels generating IKs, an adrenergic-sensitive, slow outward potassium current.2,4,5 This form of the long-QT syndrome is designated as long-QT syndrome type 1.
Although it is believed that a reduction in IKs is the cause of the disease phenotype of long-QT syndrome type 1, this has not been established in the case of KCNQ1 channels in human cardiomyocytes. Heterologous expression systems and genetic animal models have been used to determine the underlying mechanisms of the long-QT syndrome; however, cardiac myocytes have distinct and complex electrophysiological properties, and these properties differ among species.6,7 Thus, a human cell-based system would be extremely useful for understanding the pathogenesis of the disease and for testing patient-specific therapies.8
The generation of pluripotent stem cells from human adult somatic tissues9-13 offers the opportunity to produce large numbers of patient-specific stem cells. In recent studies, investigators have been successful in deriving pluripotent stem cells from individual patients among whom there is a variety of simple and complex genetic disorders and in differentiating them into the specific cell lineages affected by the diseases.14-19 The capacity of induced human pluripotent stem cells to generate functional cardiac myocytes has been reported,20-23 but to our knowledge, the use of this approach to generate myocytes harboring a disease phenotype has not yet been shown. In this study, we generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and showed the capacity of these cells to give rise to functional cardiomyocytes that recapitulate the electrophysiological characteristics of the disorder.
Methods
Clinical History and Genetic Phenotype
During the clinical evaluation of an 8-year-old boy for attention deficit–hyperactivity disorder, an electrocardiogram showed a prolonged QT interval (QT interval corrected for heart rate [QTc], 445 msec). Sequencing of the KCNQ1 gene revealed a heterozygous single base exchange (569G→A), resulting in an R190Q missense mutation previously known to be associated with long-QT syndrome type 124-26 (Figure 1A and 1BFigure 1
Generation of Pluripotent Stem Cells from Patients with Long-QT Syndrome Type 1.). The mutation is located in the cytoplasmic loop between the transmembrane segments S2 and S3 of the KCNQ1 protein24 (Figure 1C).Subsequent screening of members of the boy's family revealed prolonged QT intervals in the 42-year-old father (QTc, 462 msec), the 39-year-old aunt (QTc, 481 msec), and the 70-year-old grandfather (QTc, 453 msec), and genetic testing showed that these family members had the same heterozygous mutation, confirming autosomal dominant inheritance in this family (Figure 1A and 1B). The father and son have thus far been asymptomatic. The grandfather and aunt have reported periods of dizziness and palpitations. All the genetically affected family members are being treated with beta-blockers.
Generation of Patient-Specific Pluripotent Stem Cells
For the generation of pluripotent stem cells, we recruited the father and son in the family affected by long-QT syndrome type 1 along with two healthy control subjects. The protocols for research involving human subjects and for stem-cell research were approved by the institutional review board and the committee charged with oversight of embryonic stem-cell research at the Technical University of Munich. All the study participants provided written informed consent.
Dermal-biopsy specimens were minced and placed on culture dishes. Fibroblasts migrating out of the explants were passaged twice and then infected with a combination of retroviruses encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC.9 After 6 days, infected cells were seeded on murine embryonic fibroblast feeders and cultured in standard human embryonic stem-cell medium until induced pluripotent stem-cell colonies appeared. Details of the study methods are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.
In Vitro Cardiac Differentiation
We differentiated induced pluripotent stem cells as embryoid bodies by detaching the stem-cell colonies from the feeder cells and maintaining them for 3 days in feeder-cell-conditioned human embryonic stem-cell medium in low attachment plates.27,28 At day 4, the medium was replaced with differentiation medium containing 20% fetal-calf serum. Embryoid bodies were plated on gelatin-coated dishes on day 7. Between days 20 and 30, areas that exhibited spontaneous contraction (indicative of cardiac differentiation) were microdissected, plated on fibronectin-coated plates, and maintained in culture in differentiation medium containing 2% fetal-calf serum. For single-cell analysis, microdissected areas were dissociated with the use of type II collagenase. Single cells were plated on fibronectin-coated slides for immunohistochemical and electrophysiological analysis.
Immunohistochemical Assessments
Immunostaining was performed according to standard protocols with the use of antibodies specific for the following: Nanog (Abcam), TRA-1-81 (BD Pharmingen), cardiac troponin T (Lab Vision), α-actinin (Sigma–Aldrich), myosin light chain 2a and myosin light chain 2v (Synaptic Systems), KCNQ1 (Abcam), and protein disulfide isomerase (Abcam). Staining was also performed for F-actin with the use of fluorescence-labeled phalloidin (Invitrogen).
Polymerase-Chain-Reaction Assays
The polymerase chain reaction (PCR) was used to amplify the mutated region of the KCNQ1 gene for sequencing. Quantitative real-time PCR was used in allelic-discrimination assays and for the assessment of expression of pluripotency genes, retroviral transgenes, and cell-lineage markers. Reverse-transcriptase (RT)–PCR was used to assay cardiomyocyte phenotype markers in single cells. Detailed methods are provided in the Supplementary Appendix; primers are listed in Table 1 in the Supplementary Appendix.
Electrophysiological Assessments
Whole-cell recordings were obtained with the use of standard patch-clamp techniques.7,29 Culture differentiation medium was used as the external bath solution. Action potentials and currents were recorded at approximately 35°C. All currents were normalized to cell capacitance.
Statistical Analysis
Data that passed tests for normality and equal variance were analyzed with the use of one-way analysis of variance followed by Tukey's test, when appropriate. The Wilcoxon signed-rank test and the Kruskal–Wallis test followed by Dunn's test were used to analyze the remaining data. Two-sided P values of less than 0.05 were considered to indicate statistical significance.
Results
Generation of Pluripotent Stem Cells
We generated pluripotent stem cells from primary fibroblasts derived from two patients with long-QT syndrome type 1 and two control subjects after retroviral transduction of the reprogramming factors. Starting at 3 weeks after viral infection, colonies with stem-cell morphologic characteristics appeared and were clonally expanded on murine embryonic fibroblasts (Figure 1D). Three clones from each subject were chosen for further characterization.
The genomic KCNQ1 locus was sequenced in all the induced pluripotent stem-cell clones, confirming the integrity of the locus and the absence of retroviral DNA. The expected 569G→A mutation was detected in all stem-cell clones and skin fibroblasts derived from the patients with long-QT syndrome type 1 but not in cells derived from control subjects. The presence of alkaline phosphatase activity (Figure 1E), immunoreactivity for embryonic stem-cell–associated antigens, including NANOG and TRA-1-81 (Figure 1F), reactivation of endogenous pluripotency genes (OCT3/4, SOX2, REX1, NANOG, and CRIPTO/TDGF1) (Figure 1A in the Supplementary Appendix), and silencing of retroviral transgenes (Figure 1B in the Supplementary Appendix) indicated that there had been successful reprogramming of putative induced pluripotent stem-cell clones. On spontaneous embryoid-body differentiation, all induced pluripotent stem-cell clones showed up-regulation of lineage markers representative of the three embryonic germ layers, endoderm (PDX1, SOX7, and AFP), mesoderm (CD31, DESMIN, ACTA2, SCL, MYL2, and CDH5), and ectoderm (KTR14, NCAM1, TH, and GABRR2) (Figure 2 in the Supplementary Appendix), confirming their pluripotent nature.28
Assessment of the Long-QT Syndrome Type 1 Phenotype
Using a specific differentiation protocol, we directed induced pluripotent stem cells from both affected family members and controls into the cardiac lineage (see Methods, Results, and Figure 3 in the Supplementary Appendix). Spontaneously contracting foci started to appear after approximately 12 days of differentiation (see video 1, available at NEJM.org) and were explanted and then dissociated into single cells that maintained the expression of distinct myocyte markers (Figure 2AFigure 2
Disease Phenotype of Long-QT Syndrome Type 1 Cardiac Myocytes Generated from Induced Pluripotent Stem Cells.) and spontaneous contraction (video 2). No major differences in the efficiency of differentiation into myocyte lineages were observed among the three clones from each of the four subjects (Figure 3E in the Supplementary Appendix).To assess whether the myocytes derived from induced pluripotent stem cells from patients with long-QT syndrome type 1 recapitulated the disease phenotype, we recorded the action potentials in single cells. Both spontaneously beating cells that had been dissociated from long-QT syndrome type 1 explants and those that had been dissociated from control explants responded to pacing and generated three distinct types of action potentials. These were designated as “ventricular,” “atrial,” and “nodal,” on the basis of their similarity to the action potentials of ventricular, atrial, and nodal cardiomyocytes from human fetal hearts30 (Figure 2B; for detailed classification, see Results, Discussion, and Figure 4 in the Supplementary Appendix). The classification based on action-potential properties correlated with gene-expression analysis of specific myocyte-lineage markers, as shown with the use of single-cell RT-PCR on patched cells (Figure 2B, and Figure 4 and Figure 5 in the Supplementary Appendix).
Whereas the characteristics of the action potential of “nodal” myocytes were similar between cells derived from patients with long-QT syndrome type 1 and cells derived from control subjects, the action potentials of “ventricular” and “atrial” myocytes derived from patients with long-QT syndrome type 1 were significantly longer and had a slower repolarization velocity than did those derived from controls (Figure 2B, and Table 2 and Table 3 in the Supplementary Appendix). With electrical pacing set at 1 Hz, the mean (±SE) duration of the action potential measured at 90% repolarization was 554.2±35.6 msec and 190.8±28.1 msec in “ventricular” and “atrial” myocytes, respectively, in cells derived from patients with long-QT syndrome type 1, as compared with 373.2±22.6 msec and 119.9±15.5 msec in the corresponding cells from control subjects (Figure 2B). Increasing the stimulation frequency decreased the duration of the “ventricular” myocyte action potential in both groups, with little change in other features of the action potential. However, adaptation of the action-potential duration to higher pacing frequencies was significantly less pronounced in the myocytes from the patients with long-QT syndrome type 1 than in those from the control subjects (Figure 6 in the Supplementary Appendix). The results were similar in all the clones from the two patients and in all the clones from the two healthy controls (Figure 7 in the Supplementary Appendix), suggesting that there was phenotypic homogeneity among induced pluripotent stem-cell lines from the same person and no evident difference in the disease phenotype of the cells from the two patients with long-QT syndrome type 1. Therefore, we limited our further analysis to three clones from one patient with long-QT syndrome type 1 and three clones from one control subject.
Role of R190Q-KCNQ1 in the Pathogenesis of Long-QT Syndrome Type 1
The analysis of gene expression with the use of quantitative RT-PCR and immunoblotting revealed that KCNQ1 messenger RNA and protein levels were similar between myocytes derived from subjects with long-QT syndrome type 1 and those derived from controls. In addition, there was similar allelic expression of wild-type and mutated 569G→A transcripts in explants derived from two different clones from the patient with long-QT syndrome type 1 (Figure 8 in the Supplementary Appendix). To further investigate the functional consequences of the R190Q-KCNQ1 mutation in the induced pluripotent stem-cell model, we examined the cellular distribution of the KCNQ1 protein. Immunocytochemical tests for KCNQ1 in myocytes derived from patients with long-QT syndrome type 1 revealed a reticular, intracellular expression pattern, in which KCNQ1 partially colocalized with the endoplasmic-reticulum marker protein disulfide isomerase. In contrast, in cells from control subjects, the channel subunit was enriched in the cell surface compartment (Figure 3AFigure 3
Characterization of the Role of the R190Q-KCNQ1 Mutation in the Pathogenesis of Long-QT Syndrome Type 1.). Arginine 190 of KCNQ1 is known to be part of a basic endoplasmic-reticulum retention signal.31,32 This suggests that the subcellular distribution of KCNQ1 observed in myocytes derived from patients with long-QT syndrome type 1 may be due to a trafficking defect.To confirm this hypothesis, we expressed R190Q-KCNQ1 subunits and wild-type KCNQ1 subunits in the cardiomyoblast H9c2 cell line and analyzed their subcellular localization. As was seen in the immunodetection pattern of KCNQ1 in induced pluripotent stem-cell–derived myocytes, wild-type KCNQ1 protein achieved cell-membrane targeting, whereas R190Q-KCNQ1 failed to do so (Figure 3B). Expression vectors encoding wild-type KCNQ1, fused to a yellow fluorescent protein, and R190Q-KCNQ1, fused to a cyan fluorescent protein, were then cotransfected into H9c2 cells in various ratios. The percentage of cells presenting a yellow fluorescent protein signal in a cell membrane pattern decreased as the proportion of mutant channel subunits increased, suggesting a model in which a tetrameric channel containing more than one R190Q subunit loses the ability to translocate to the cell surface compartment (Figure 3C; for details on the model, see the Methods section in the Supplementary Appendix). Analysis of fluorescence resonance energy transfer showed that the R190Q mutation did not alter the capacity of the mutant subunit to coassemble with wild-type subunits (Figure 9 in the Supplementary Appendix).33
Electrophysiological Analysis of K+ Currents
To provide further mechanistic insight into the function of the mutated KCNQ1 protein, we performed single-cell electrophysiological analysis of various repolarizing K+ currents in “ventricular” myocytes. With the use of a distinct voltage protocol that preferentially elicits the outward delayed rectifier current, IK, cardiac myocytes derived from induced pluripotent stem cells from patients with long-QT syndrome type 1, as compared with those from control subjects, showed a substantial reduction in K+ current (Figure 4AFigure 4
Electrophysiological Analysis of IK Current in Myocytes Derived from Induced Pluripotent Stem Cells from Control Subjects and from Patients with Long-QT Syndrome Type 1.).Further characterization with the use of channel blockers specific for the slow and rapid components of IK — chromanol 293B (which blocks IKs) and E4031 (which blocks IKr)34 — showed that IKs current densities in myocytes from patients with long-QT syndrome type 1, as compared with those from control subjects, were decreased, whereas IKr conductance was unaffected. At +30 mV, IKs and tail IKs were diminished by approximately 75%, suggesting that in heterozygous “ventricular” myocytes from patients with long-QT syndrome type 1, the mutant form of KCNQ1 interferes with the function of the wild-type subunit (Figure 4A). Furthermore, both activation and deactivation properties of the tail IKs current in cells from patients with long-QT syndrome type 1, as compared with cells from controls, appeared to be altered, with activation being slightly shifted toward more positive voltages (Figure 4B) and deactivation being decelerated (Figure 4C). We next analyzed the transient outward (Ito) and inward currents that function in the hyperpolarization state. As with the results for IKr, Ito and diastolic current densities did not differ between “ventricular” myocytes from patients with long-QT syndrome type 1 and those from control subjects (Figure 10 in the Supplementary Appendix), showing that there was a specific genotype–phenotype correlation.
Protective Action of Beta-Blockade
Since fatal arrhythmias are precipitated by increased sympathetic tone in patients with long-QT syndrome type 1,3,35 we tested whether adrenergic stimulation can affect the phenotype of long-QT syndrome type 1 cardiomyocytes derived from pluripotent stem cells. First, we analyzed the effect of catecholamines on the duration of the action potential in paced “ventricular” myocytes. At 2 Hz, isoproterenol induced approximately a 20% reduction in the interval between 30% and 90% repolarization of the action potential in control myocytes, whereas in cells from patients with long-QT syndrome type 1 this interval was almost unaffected (Figure 5AFigure 5
Adrenergic Modulation and Protective Effect of Beta-Blockade in Control and Long-QT Syndrome Type 1 “Ventricular” Myocytes.). Accordingly, IKs was markedly enhanced by adrenergic stimulation in “ventricular” myocytes from control subjects, and the increase was significantly smaller in cells from patients with long-QT syndrome type 1, suggesting that defective responsiveness to adrenergic challenge is due to an abnormal IKs current (Figure 5B).36 We further investigated the effect of isoproterenol on spontaneously beating myocytes. In cells from control subjects, isoproterenol had a positive chronotropic effect accompanied by a shortening of the duration of the action potential, resulting in a 30% reduction in the ratio of the action-potential duration at 90% repolarization to the action-potential interval. In contrast, in myocytes from patients with long-QT syndrome type 1, this ratio was increased by 15%, thereby exacerbating the long-QT syndrome type 1 phenotype and increasing the risk of arrhythmic events (Figure 5C). In fact, under conditions of adrenergic stress, six of nine “ventricular” myocytes from patients with long-QT syndrome type 1 developed early afterdepolarizations (4.1±1.5 early afterdepolarizations per 20 sec, with 9.2±2.1% of the beats affected by early afterdepolarizations), whereas none of the eight cells from control subjects did. Pretreatment with propranolol, a nonselective beta-blocker, substantially blunted the effect of isoproterenol in myocytes from both control subjects and patients with long-QT syndrome type 1 (0.6±0.3 early afterdepolarizations per 20 sec, with 1.7±0.8% of the beats affected), thus protecting the diseased cells from catecholamine-induced tachyarrhythmia due to impaired rate adaptation of the action potential (Figure 5C).
Discussion
Since the initial reports on induced human pluripotent stem-cell technology were published, several patient-specific induced pluripotent stem-cell lines for neurodegenerative and metabolic disorders have been developed.14,16,18,19,37 Establishing reliable models of human disease in such cells has remained challenging, owing to difficulties in directing cell differentiation and in identifying disease-related mechanisms. In this study, we reprogrammed fibroblasts derived from members of a family with autosomal-dominant long-QT syndrome type 1 and used these induced pluripotent stem cells to generate patient-specific cardiomyocytes. These myocytes showed expression of specific markers and electrophysiological characteristics that suggested that the reprogramming process did not affect the ability of the cells to function normally. Furthermore, we observed disease-specific abnormalities in the duration of the action potential, the action-potential rate adaptation, and IKs currents, owing to an R190Q-KCNQ1 trafficking defect, as well as vulnerability to catecholaminergic stress.
To date, insights into the pathogenesis of the long-QT syndrome have come primarily from heterologous expression systems and genetic animal models. Depending on the cell type used, both haploinsufficiency and dominant negative effects have been postulated as the mechanism of disease associated with the R190Q mutation.24-26 In our induced pluripotent stem-cell model of long-QT syndrome type 1, a reduction in IKs current density by approximately 75%, combined with subcellular localization, showed that the R190Q mutant suppresses channel trafficking to the plasma membrane in a dominant negative manner. Owing to differences among species in the channels that generate the main cardiac repolarizing currents, none of the available mouse models of the long-QT syndrome fully emulate the human disease phenotype. Recently, transgenic rabbit models of long-QT syndrome type 1 and long-QT syndrome type 2 have been engineered by means of overexpression of dominant negative pore mutants of the human genes KCNQ1 and KCNH2.38 In these animals, both transgenes caused a down-regulation of the complementary IKr and IKs currents. In contrast, no alterations in repolarizing currents other than in IKs were observed in patient-specific myocytes derived from persons with the R190Q-KCNQ1 mutation associated with long-QT syndrome type 1. This discrepancy, which may be mutant-dependent or model-dependent, shows the importance of alternative systems in which human genetic disorders can be studied in the physiologic and disease-causing contexts on a patient-specific level.
Our data provide clear evidence that the pathogenesis of the R190Q mutation can be modeled in myocyte lineages generated from pluripotent stem cells derived from patients with long-QT syndrome type 1. Moreover, our findings suggest that there may be alternative approaches to the development of candidate drugs, such as compounds to promote the delivery of the mutant to the plasma membrane or IKs activators. The observed protective effects of beta-blockade show that it is possible to investigate the therapeutic action of medications for treating human cardiac disease in vitro with the use of patient-specific cells. This approach is particularly attractive because of the pluripotent nature of these cells and the potentially unlimited number of induced cardiomyocytes available for high-throughput drug development.
Even though the incidence of the long-QT syndrome is only 1 case per 2500 live births, this syndrome provides a platform for showing the suitability of induced pluripotent stem-cell technology as a means of exploring disease mechanisms in human genetic cardiac disorders. Larger sets of long-QT syndrome cell lines harboring different channel mutations will be needed to further validate the disease phenotype and compare pathogenetic mechanisms in diverse forms of the disease. Clinically, the severity of manifestations of the long-QT syndrome varies among family members, and incomplete penetrance exists.39 However, we did not observe any phenotypic differences in the prolongation of the action potential between the myocytes from our two patients, a finding that is probably due to the similarity of the clinical phenotype in these cases.
In summary, we derived pluripotent stem cells from patients with long-QT syndrome type 1 and directed them to differentiate into cardiac myocytes. As compared with myocytes derived in a similar fashion from healthy controls, cells from patients with long-QT syndrome type 1 exhibited prolongation of the action potential, altered IKs activation and deactivation properties, and an abnormal response to catecholamine stimulation, with a protective effect of beta-blockade, thus showing that induced pluripotent stem-cell models can recapitulate aspects of genetic cardiac diseases.
Supported by grants from the European Research Council (Marie Curie Excellence Team Grant, MEXT-23208), the German Research Foundation (Research Unit 923 and La 1238 3-1/4-1), and the German Ministry for Education and Research (01 GN 0826).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org
Drs. Moretti, Bellin, and Welling contributed equally to this article.
This article (10.1056/NEJMoa0908679) was published on July 21, 2010, at NEJM.org.
We thank Takashi Kitamura and Shinya Yamanaka for providing viral vectors through Addgene; Jacques Barhanin for KCNE1 and wild-type and mutant (R190Q) KCNQ1 complementary DNAs; Stefan Engelhardt and Andrea Ahles for the fluorescent β1-receptor fusion construct; Diana Grewe, Christina Scherb, and Sabine Teuber for their technical assistance in cell culture and immunohistochemical assessments; and especially the members of the family affected by long-QT syndrome type 1 and the healthy volunteers who provided us with skin-biopsy specimens for the reprogramming.
Source Information
From the Cardiology Division, First Department of Medicine (A.M., M.B., C.B.J., J.T.L., L.B.-F., T.D., A.G., M.S., D.S., A.S., K.-L.L.), and the Plastic Surgery Department (C.H.), Klinikum rechts der Isar; the Cardiology Department, German Heart Center Munich (A.M., M.B., C.B.J., J.T.L., L.B.-F., T.D., A.G., M.S., D.S., A.S., K.-L.L.); and the Institute of Pharmacology and Toxicology (A.W., F.H.) — all at the Technical University of Munich, Munich, Germany.
Address reprint requests to Dr. Laugwitz at the Cardiology Division, First Department of Medicine and German Heart Center Munich, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str., 22, D-81675 Munich, Germany, or at klaugwitz@med1.med.tum.de.
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