Rainer Schimpf

Publications (64)301.38 Total impact

• Article: Catecholaminergic polymorphic ventricular tachycardia and midventricular Takotsubo cardiomyopathy: a novel association?

  Rainer Schimpf, Jürgen Meinhardt, Martin Borggrefe, Dariush Haghi
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  ABSTRACT: Takotsubo cardiomyopathy (TTC) is a recently recognized clinical syndrome characterized by transient ventricular dysfunction in the absence of obstructive coronary artery disease. TTC primarily affects postmenopausal women; TTC in children and adolescents is only rarely reported. Furthermore, simultaneous occurrence of Takotsubo cardiomyopathy and primary electrical diseases has been previously reported in only four recent cases of female patients with congenital long QT syndrome. Here, we report the novel association of catecholaminergic polymorphic ventricular tachycardias and a midventricular type of TTC observed in a young female patient.
  Herzschrittmachertherapie & Elektrophysiologie 04/2013;
• Article: [Sudden cardiac death in the young : How can disease recognition and prevention in family members be improved?].

  Rainer Schimpf, Katrin Yen, Martin Borggrefe
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  ABSTRACT: Sudden cardiac death (SCD) in young patients (< 45 years of age) is a rare event. However, it is particularly tragic as it affects active and often otherwise healthy individuals. Furthermore, SCD may unmask an underlying congenital structural disease or channelopathy. The leading cause of SCD is coronary artery disease; however, the likelihood of an underlying congenital cardiac disease is higher in young individuals. Each SCD should therefore initiate a thorough work-up of an underlying cardiac cause, which should ideally include a molecular autopsy. Familial screening should also be initiated if a physician is years later confronted with a history of SCD in a young patient. The common aim is to prompt identification of affected family members, to include the patient in regular cardiological follow-up and if indicated to initiate prophylactic therapy to prevent further SCD. This current issue on hereditary cardio(myo)pathy will cover the main topics on familial diseases. In addition the role of molecular autopsy and molecular genetic screening is discussed.
  Herzschrittmachertherapie & Elektrophysiologie 09/2012; 23(3):149-60.
• Article: Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.

  Hector Barajas-Martínez, Dan Hu, Tania Ferrer, Carlos G Onetti, Yuesheng Wu, Elena Burashnikov, Madalene Boyle, Tyler Surman, Janire Urrutia, Christian Veltmann, Rainer Schimpf, Martin Borggrefe, Christian Wolpert, Bassiema B Ibrahim, José Antonio Sánchez-Chapula, Stephen Winters, Michel Haïssaguerre, Charles Antzelevitch
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  ABSTRACT: Adenosine triphosphate (ATP)-sensitive potassium cardiac channels consist of inward-rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9). To examine the association of mutations in KCNJ8 with Brugada syndrome (BrS) and early repolarization syndrome (ERS) and to elucidate the mechanism underlying the gain of function of ATP-sensitive potassium channel current. Direct sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch-clamp methods were used to study mutated channels expressed in TSA201 cells. The same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS probands but was absent in 430 alleles from ethnically matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole-cell patch-clamp studies showed a 2-fold gain of function of glibenclamide-sensitive ATP-sensitive potassium channel current when KCNJ8-S422L was coexpressed with SUR2A-wild type. Inside-out patch-clamp evaluation yielded a significantly greater half maximal inhibitory concentration for ATP in the mutant channels (785.5 ± 2 vs 38.4 ± 3 μM; n = 5; P <.01), pointing to incomplete closing of the ATP-sensitive potassium channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/corrected QT intervals, likely owing to their effect to induce an increase in L-type calcium channel current (I(Ca-L)). Our results support the hypothesis that KCNJ8 is a susceptibility gene for BrS and ERS and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in ATP-sensitive potassium channel current is due to reduced sensitivity to intracellular ATP.
  Heart rhythm: the official journal of the Heart Rhythm Society 04/2012; 9(4):548-55. · 4.56 Impact Factor
• Article: Early repolarization pattern is associated with ventricular fibrillation in patients with acute myocardial infarction.

  Boris Rudic, Christian Veltmann, Esther Kuntz, Michael Behnes, Elif Elmas, Torsten Konrad, Jürgen Kuschyk, Christel Weiss, Martin Borggrefe, Rainer Schimpf
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  ABSTRACT: For years early repolarization (ER) has been considered as a benign electrocardiographic finding. However, recent reports show that ER is associated with a higher incidence of ventricular fibrillation (VF) and sudden cardiac death in patients without structural heart disease. Sporadic case studies have pointed out that ER might be related to an adverse outcome in patients with stable coronary artery disease. To evaluate the incidence of ER in patients with acute myocardial infarction complicated by VF. The study population consisted of 60 patients (80% men; mean age 61.8 ± 13.1 years) with acute myocardial infarction. Thirty consecutive patients (80% men; mean age 63.3 ± 12 years) admitted to our hospital had documented VF during myocardial infarction and were successfully resuscitated before hospital admission. A matched control group consisted of 30 patients (80% men; mean age 60.2 ± 14.2 years) with myocardial infarction without ventricular tachyarrhythmias. Twelve-lead electrocardiograms were analyzed for ER defined as J-point elevation ≥ 0.1 mV and "notching" and "slurring" of the terminal part of the QRS complex in at least 2 lateral or inferior leads. The ER pattern was observed in 18 of the 60 patients with acute myocardial infarction. Mean elevation of the J point was 0.151 ± 0.46 mV. Notching of the J wave was observed in 14 of the 18 patients and slurring in 4 of the 18 patients. ER was more common in patients with myocardial infarction complicated by VF than in patients with myocardial infarction without ventricular tachyarrhythmias (47% vs 13%; P = .005). There have been no statistical differences in the distribution of ER in the 12-lead electrocardiogram (inferior 39% vs lateral 33% vs inferolateral 28%; P >.05). Early repolarization pattern seems to be associated with ventricular tachyarrhythmias in the setting of acute myocardial infarction.
  Heart rhythm: the official journal of the Heart Rhythm Society 03/2012; 9(8):1295-300. · 4.56 Impact Factor
• Article: Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide.

  Rainer Schimpf, Christian Veltmann, Theano Papavassiliu, Boris Rudic, Turgay Göksu, Jürgen Kuschyk, Christian Wolpert, Charles Antzelevitch, Alois Ebner, Martin Borggrefe, Christian Brandt
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  ABSTRACT: The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear. Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies. Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and T(peak)-T(end) intervals were analyzed before and during rufinamide treatment. The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). T(peak)-T(end) intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed. QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.
  Heart rhythm: the official journal of the Heart Rhythm Society 01/2012; 9(5):776-81. · 4.56 Impact Factor
• Article: A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.

  Dan Hu, Hector Barajas-Martínez, Argelia Medeiros-Domingo, Lia Crotti, Christian Veltmann, Rainer Schimpf, Janire Urrutia, Aintzane Alday, Oscar Casis, Ryan Pfeiffer, Elena Burashnikov, Gabriel Caceres, David J Tester, Christian Wolpert, Martin Borggrefe, Peter Schwartz, Michael J Ackerman, Charles Antzelevitch
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  ABSTRACT: Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.
  Heart rhythm: the official journal of the Heart Rhythm Society 12/2011; 9(5):760-9. · 4.56 Impact Factor
• Article: Comparison of ventricular tachyarrhythmia characteristics in patients with idiopathic dilated or ischemic cardiomyopathy and defibrillators implanted for primary prevention.

  Florian Streitner, Juergen Kuschyk, Claudia Dietrich, Eva Mahl, Ines Streitner, Christina Doesch, Christian Veltmann, Rainer Schimpf, Christian Wolpert, Martin Borggrefe
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  ABSTRACT: Implantable cardioverter-defibrillator (ICD) therapy for primary prevention is well established in ischemic cardiomyopathy (ICM). Data on the role of ICDs in patients with dilated cardiomyopathy (DCM) and no history of ventricular tachyarrhythmia (VT/VF) are more limited. DCM patients with an impaired left ventricular ejection fraction (LVEF) still represent a low arrhythmic risk subgroup in clinical practice. ICD stored data of DCM patients with an LVEF ≤35% was compared to data of ICM patients meeting Multicenter Automatic Defibrillator Implantation Trial (MADIT) eligibility criteria. VT/VF occurrences and electrical storm (ES) events were analyzed. There were 652 patients followed for 50.9 ± 33.9 months. There were 1978 VT and 241 VF episodes analyzed in 66 out of 203 patients (32.5%) with DCM and in 118 out of 449 patients (26.3%, P = 0.209) with ICM. Freedom of appropriate ICD treatment due to VT/VF or ES events did not differ in both patient populations (log-rank, P>0.05). In patients presenting with VT/VF episodes, mean event rates were comparable in both patient populations (3.2 ± 14.1 for DCM and VT vs 3 ± 13.9 for ICM and VT [P = 0.855], 0.4 ± 1.3 for DCM and VF vs 0.4 ± 1.8 for ICM and VF [P = 0.763], and 0.2 ± 0.7 for DCM and ES vs 0.2 ± 1 for ICM and ES [P = 0.666]). DCM patients with prophylactic ICDs implanted due to heart failure and patients fulfilling MADIT criteria reveal comparable patterns of VT/VF/ES events during long-term follow-up. Incidence, mean number of events, and time to first event did not differ significantly. Findings support the current guidelines for prophylactic ICD therapy in DCM patients with heart failure.
  Clinical Cardiology 09/2011; 34(10):604-9. · 2.15 Impact Factor
• Article: From ECG to mutation: programmed ventricular stimulation providing a link to genetics of cardiac channelopathies.

  Rainer Schimpf, Martin Borggrefe
  Heart rhythm: the official journal of the Heart Rhythm Society 08/2011; 8(10):1553-4. · 4.56 Impact Factor
• Article: Long-term follow-up of patients with short QT syndrome.

  Carla Giustetto, Rainer Schimpf, Andrea Mazzanti, Chiara Scrocco, Philippe Maury, Olli Anttonen, Vincent Probst, Jean-Jacques Blanc, Pascal Sbragia, Paola Dalmasso, Martin Borggrefe, Fiorenzo Gaita
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  ABSTRACT: The aim of this study was to investigate the clinical characteristics and the long-term course of a large cohort of patients with short QT syndrome (SQTS). SQTS is a rare channelopathy characterized by an increased risk of sudden death. Data on the long-term outcome of SQTS patients are not available. Fifty-three patients from the European Short QT Registry (75% males; median age: 26 years) were followed up for 64 ± 27 months. A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an implantable cardioverter defibrillator, and 12 patients received long-term prophylaxis with hydroquinidine (HQ), which was effective in preventing the induction of ventricular arrhythmias. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2 already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1 had syncope. Nonsustained polymorphic ventricular tachycardia was recorded in 3 patients. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events occurred in patients receiving HQ. SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up.
  Journal of the American College of Cardiology 08/2011; 58(6):587-95. · 14.16 Impact Factor
• Article: Sudden cardiac death in a patient with lamin A/C mutation in the absence of dilated cardiomyopathy or conduction disease.

  Philipp Ehlermann, Stephanie Lehrke, Theano Papavassiliu, Benjamin Meder, Martin Borggrefe, Hugo A Katus, Rainer Schimpf
  Clinical Research in Cardiology 02/2011; 100(6):547-51. · 2.95 Impact Factor
• Article: Predictors of electrical storm recurrences in patients with implantable cardioverter-defibrillators.

  Florian Streitner, Juergen Kuschyk, Christian Veltmann, Eva Mahl, Claudia Dietrich, Rainer Schimpf, Christina Doesch, Ines Streitner, Christian Wolpert, Martin Borggrefe
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  ABSTRACT: To determine prevalence and predictors of electrical storm recurrences (ES-Rs) in patients with implantable cardioverter-defibrillators (ICDs) as electrical storms (ESs) represent serious clinical events carrying a high risk of mortality. Single-centre study analysing data of consecutive patients receiving an ICD between 1993 and 2008. Electrical storm was defined as ≥ 3 separate ventricular tachyarrhythmic (VT/VF) episodes ≤ 24 h. Nine hundred and fifty-five patients [mean left ventricular ejection fraction (LVEF) 35.7 ± 15.6%] were prospectively followed for 54.2 ± 35.5 months. In 274 of 955 patients (28.7%), 2871 VT/VF episodes were observed. One hundred and fifty-three ES episodes occurred in 63 of 955 patients (6.6%). Thirty-two of 63 patients (50.8%) experienced ≥ 2 ES episodes. Twenty-six of 32 patients (81.2%) with ES-Rs experienced the second ES episode within 1 year after the initial event. Cox regression analysis identified an LVEF ≤ 30% (OR 2.2; 95% CI 1.021-4.856; P = 0.044) and a patient's age >65 years (OR 3.5; 95% CI 1.207-10.176; P = 0.021) to be predictive for ES-Rs. Patients with angiotensin-converting enzyme (ACE) inhibitor therapy were less likely to experience ES-Rs (OR 0.39; 95% CI 0.187-0.817; P = 0.013). Electrical storm events are not rare in a 'real-world' patient population with ICDs (6.6% in 4.5 years). The risk for ES-Rs, especially within the first year after the initial event, is high. Left ventricular ejection fraction ≤ 30%, age >65 years, and a lack of ACE inhibitor therapy are independent predictors of ES-R.
  Europace 12/2010; 13(5):668-74. · 1.98 Impact Factor
• Article: Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.

  Elena Burashnikov, Ryan Pfeiffer, Héctor Barajas-Martinez, Eva Delpón, Dan Hu, Mayurika Desai, Martin Borggrefe, Michel Häissaguerre, Ronald Kanter, Guido D Pollevick, [......], Gi-Byoung Nam, Roberto Robles, Rainer Schimpf, Dwight D Stapleton, Sami Viskin, Stephen Winters, Christian Wolpert, Samuel Zimmern, Christian Veltmann, Charles Antzelevitch
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  ABSTRACT: L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.
  Heart rhythm: the official journal of the Heart Rhythm Society 12/2010; 7(12):1872-82. · 4.56 Impact Factor
• Article: Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2.

  Jonathan M Cordeiro, Guillermo J Perez, Nicole Schmitt, Ryan Pfeiffer, Vladislav V Nesterenko, Elena Burashnikov, Christian Veltmann, Martin Borggrefe, Christian Wolpert, Rainer Schimpf, Charles Antzelevitch
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  ABSTRACT: Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = -53.1 ± 1.13 mV and -60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.
  Canadian Journal of Physiology and Pharmacology 12/2010; 88(12):1181-90. · 1.95 Impact Factor
• Article: Spontaneous type 1 electrocardiographic pattern is associated with cardiovascular magnetic resonance imaging changes in Brugada syndrome.

  Theano Papavassiliu, Christian Veltmann, Christina Doesch, Dariusch Haghi, Tjeerd Germans, Stefan O Schoenberg, Albert C van Rossum, Rainer Schimpf, Joachim Brade, Christian Wolpert, Martin Borggrefe
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  ABSTRACT: Patients with Brugada syndrome (BrS) and a spontaneous type 1 ECG are considered to be at greater increased risk for sudden cardiac death than are patients with an abnormal ECG only after administration of sodium channel blockers and therefore represent a more severe phenotype. Thus, it can be hypothesized that in the presence of a more severe electrical phenotype, structural and functional changes are more likely expected because electrical changes can play a causal role in producing structural changes. The purpose of this study was to investigate whether the different ECG manifestations in patients with BrS are associated with structural changes detected by cardiovascular magnetic resonance imaging. Cardiovascular magnetic resonance imaging was performed on 69 consecutive patients with proven BrS and 30 healthy controls. Twenty-six patients had a spontaneous diagnostic type 1 BrS ECG; the remainder had a type 1 response to ajmaline provocation. Left and right ventricular volumes and dimensions were assessed and compared with respect to ECG pattern. The right ventricular outflow tract area was significantly enlarged in patients with a spontaneous type 1 ECG compared to patients with a nondiagnostic resting ECG or controls (11 cm(2), 9 cm(2), and 9 cm(2), respectively, P < .05). Patients with a spontaneous type 1 BrS ECG revealed significantly lower left ventricular ejection fraction than did patients with a nondiagnostic resting ECG and controls (56 ± 5 vs 59 ± 5 vs 60 ± 4, respectively, P < .05) and significantly lower right ventricular ejection fraction (54 ± 5 vs 59 ± 5, P = .001) as well as end-systolic volumes compared to controls (34 ± 9 mL/m(2) vs 28 ± 79 mL/m(2), P = .02). Patients with a spontaneous type 1 BrS ECG reveal significantly functional and morphological alterations in both the left and right ventricles compared to patients with basal nondiagnostic ECG or controls.
  Heart rhythm: the official journal of the Heart Rhythm Society 12/2010; 7(12):1790-6. · 4.56 Impact Factor
• Article: Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2

  Jonathan M. Cordeiro, Guillermo J. Perez, Nicole Schmitt, Ryan Pfeiffer, Vladislav V. Nesterenko, Elena Burashnikov, Christian Veltmann, Martin Borggrefe, Christian Wolpert, Rainer Schimpf, Charles Antzelevitch
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  ABSTRACT: Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = -53.1 ± 1.13 mV and -60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.Le syndrome du QT long (SQTL) est une anomalie héréditaire caractérisée par un allongement des intervalles (espace QT) QT et par des arythmies potentiellement mortelles. Des mutations dans 12 gènes différents ont été associées au SQTL. Ici, nous décrivons une patiente atteinte d'un SQTL, porteuse d'une mutation dans KCNQ1 et d'un polymorphisme dans KCNQ2. Le propositus (MMRL0362), une femme âgée de 32 ans, a présenté de multiples extrasystoles et une syncope. Son ECG (QTc = 518 ms) a montré une morphologie de type LQT2 dans les dérivations V4-V6 et de type LQT1 dans les dérivations V1-V2. L'ADN génomique a été isolé des lymphocytes. Toutes les jonctions exons et introns de 7 gènes de prédisposition au SQTL ont été amplifiées et séquencées. Les variations détectées ont annoncé une nouvelle mutation faux-sens (V110I) dans KCNQ1 et un polymorphisme commun dans KCNH2 (K897T). Nous avons exprimé des canaux Kv7.1 V110I ou TS dans les cellules CHO-K1 cotransfectées avec KCNE1, puis effectué une analyse en patch clamp. Nous avons aussi utilisé la technique du patch clamp pour examiner des canaux Kv1.1 K897T ou TS. Les relations courant-tension (I-V) pour V110I ont montré une diminution significative des densités des courants en cours de développement ou de queue comparativement à celles des courants TS aux potentiels >+20 mV (p < 0,05; n = 8 cellules, chaque groupe), ce qui laisse supposer une diminution des courants IKs. Les canaux K897T-Kv1.1 ont subi une diminution significative de la densité du courant de queue comparativement à celle du courant Kv11.1-TS aux potentiels >+10 mV. Fait intéressant, la disponibilité des canaux évaluée en utilisant un protocole à 3 impulsions a été légèrement plus élevée pour K897T que pour TS (V0,5 = -53,1 ± 1,13 mV et -60,7 ± 1,15 mV pour K897T et TS, respectivement; p < 0,05). La comparaison des relations I-V n'a révélé aucune différence dans les propriétés de rectification des canaux TS et K897T. En conclusion, nous avons décrit une patiente porteuse d'une mutation perte de fonction dans KCNQ1 et un polymorphisme perte de fonction dans KCNH2.
  Canadian Journal of Physiology and Pharmacology 11/2010; 88(12):1181-1190. · 1.95 Impact Factor
• Article: J-wave syndromes caused by repolarization or depolarization mechanisms a debated issue among experimental and clinical electrophysiologists.

  Martin Borggrefe, Rainer Schimpf
  Journal of the American College of Cardiology 02/2010; 55(8):798-800. · 14.16 Impact Factor
• Article: Risk stratification in electrical cardiomyopathies.

  Christian Veltmann, Rainer Schimpf, Martin Borggrefe, Christian Wolpert
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  ABSTRACT: Electrical cardiomyopathies contain the long QT syndrome (LQTS), the short QT syndrome (SQTS), the Brugada syndrome, and the catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients diagnosed with an electrical cardiomyopathy have an increased risk of syncope and sudden cardiac death (SCD). Usually, we are dealing with young patients or even children. The prevalence of these diseases is low. No large prospective randomized studies exist with respect to outcome based on different clinical and genetic parameters. Thus, risk stratification in these patients is based on retrospective data from single- or multicenter registries.The implantable cardioverter defibrillator is the only reliable therapy in patients with Brugada syndrome and SQTS, as no pharmacological therapy has been proven to prevent SCD. In LQTS and CPVT, the primary therapy relies on beta-blockers. In high-risk patients, the ICD is indicated.In all electrical diseases, risk stratification is based on the clinical phenotype, including the electrocardiogram, the history of unexplained or disease-related syncope, and sudden cardiac arrest. In LQTS and CPVT, demographic data like age and gender are important factors for risk stratification. The genotype contributes to risk stratification only in LQTS and CPVT.Patients with electrical cardiomyopathies have to be risk-stratified individually based on the data and the current guidelines available.
  Herz 11/2009; 34(7):518-27. · 0.92 Impact Factor
• Article: Prevention of inappropriate ICD shocks in patients with Brugada syndrome.

  Christian Veltmann, Juergen Kuschyk, Rainer Schimpf, Florian Streitner, Nina Schoene, Martin Borggrefe, Christian Wolpert
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  ABSTRACT: In Brugada syndrome implantable cardioverter defibrillator (ICD) therapy is associated with a high rate of inappropriate therapies, mainly due to supraventricular tachyarrhythmias (SVT) (2.7-14.1%/year). Aim of the present study was to evaluate a single ventricular fibrillation (VF) detection zone with a high cut-off rate with respect to prevention of inappropriate ICD shock due to SVT and safety of this programming. Sixty-one consecutive patients (mean age 42.6 +/- 12.9 years; 41 males) diagnosed with Brugada syndrome and implanted with an ICD were included. ICDs were prospectively programmed with a single VF detection zone and a cut-off rate of 222 beats/minute (bpm). A maximum of six shocks with the maximal shock energy were programmed. The minimal follow-up was 1 year. During a follow-up of 47.6 +/- 23.1 months seven patients (2.91%/year) received appropriate ICD shocks. No patient suffered from syncope or died. Five patients (2.07%/year) received inappropriate ICD shocks: four patients due to T-wave oversensing and only one patient (0.4%/year) due to SVT (atrial fibrillation with a ventricular rate of >222 bpm). Programming of a single, high-rate VF zone in patients with Brugada syndrome and an implanted defibrillator is safe. Such programming may be associated with reduced inappropriate defibrillator discharges. A single detection zone with a high VF cut-off rate can be recommended in patients with Brugada syndrome.
  Clinical Research in Cardiology 09/2009; 99(1):37-44. · 2.95 Impact Factor
• Article: Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.

  Christian Veltmann, Christian Wolpert, Frederic Sacher, Philippe Mabo, Rainer Schimpf, Florian Streitner, Joachim Brade, Florence Kyndt, Juergen Kuschyk, Herve Le Marec, Martin Borggrefe, Vincent Probst
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  ABSTRACT: The diagnostic type I ECG in Brugada syndrome (BS) is often concealed and fluctuates between the diagnostic and non-diagnostic pattern. Challenge with intravenous ajmaline is used to unmask the diagnostic Brugada ECG. The aim of this study was to evaluate the safety of the test and to identify predictors for the response to an intravenous ajmaline challenge. In four tertiary referral centres, 677 consecutive patients underwent an intravenous ajmaline challenge for diagnosis or exclusion of BS in accordance with the recommendations of the Brugada consensus conferences. Two hundred and sixty-two ajmaline challenges (39%) were positive. Male gender, familial BS, sudden cardiac arrest (SCA), first-degree AV-block, basal saddleback type ECG, and basal right bundle branch block were identified as predictors for a positive ajmaline challenge. A predictor for negative ajmaline test was the absence of ST-segment elevation at baseline. Six of 12 patients who had experienced SCA, and five of 25 patients with a familial sudden death exhibited a positive response to ajmaline. Only one patient (0.15%) developed sustained ventricular tachyarrhythmias (ventricular fibrillation) during ajmaline challenge, which was terminated by a single external defibrillator shock. Ajmaline challenge is a safe procedure to unmask the electrocardiographic pattern of BS. Electrocardiographic and clinical parameters were identified to predict patients' response to ajmaline. The results of this study guide the clinician in which setting an ajmaline challenge is an appropriate diagnostic step.
  Europace 08/2009; 11(10):1345-52. · 1.98 Impact Factor
• Article: Channelopathies: Brugada syndrome, long QT syndrome, short QT syndrome, and CPVT.

  Rainer Schimpf, Christian Veltmann, Christian Wolpert, Martin Borggrefe
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  ABSTRACT: In approximately 10-20% of all sudden deaths, no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachyarrhythmias (CPVT). The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases, specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli, or increased vagal tone. Young, otherwise healthy individuals are likely to be involved in sports activity. Therefore, special attention has to be given to advise these patients. Competitive sports and vigorous exercise are contraindications in almost all patients. Even recreational exercise may have to be avoided in phenotypically overt patients or silent gene carriers depending on the underlying disease.
  Herz 07/2009; 34(4):281-8. · 0.92 Impact Factor