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Paulus Kirchhof

Publications and source records attributed to Paulus Kirchhof.

At least 19 recordsLinked to original sources
PubMed2006

Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels.

In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIdelta(C) on Na(+) current (I(Na)) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIdelta(C) overexpression shifted voltage dependence of Na(+) channel availability by -6 mV (P < 0.05), and the shift was Ca(2+) dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIdelta(C) markedly increased persistent (late) inward I(Na) and intracellular Na(+) concentration (as measured by the Na(+) indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIdelta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) channels. In vivo, transgenic CaMKIIdelta(C) overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na(+) channels. This alters I(Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration). In mice, enhanced CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.

Action Potentials↗
PubMed2006

Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. METHODS AND RESULTS: Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin+/-) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P<0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin+/- hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin+/- mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. CONCLUSIONS: Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.

Aging↗
PubMed2006

[German Competence Network on Atrial Fibrillation (AFNET). A nationwide cooperation for better research and patient care].

The Atrial Fibrillation Competence Network is an interdisciplinary national research network funded by the Federal Ministry of Education and Research (BMBF). The aim of the network--founded in 2003--is to improve the treatment of atrial fibrillation, the most common clinically important arrhythmia of the heart. A decentralized patient registry has been established. This registry, which comprises the manifestation, diagnostics and therapy of atrial fibrillation in Germany, is being used as a data basis for epidemiologic clinical studies. Epidemiologic projects are being conducted to study, e.g., the prevalence of atrial fibrillation as well as the occurrence of complications. Four multicenter clinical trials have been started to optimize pharmacological treatments (ANTIPAF trial, Flec-SL trial), preventive pacing (BACE-PACE trial) and catheter-based ablation (GAP-AF trial). Other clinical projects are being conducted to study the risk of neurologic complications and to develop new diagnostic imaging techniques. Experimental basic research projects are focusing on different aspects of atrial remodeling in order to find out in which way the molecular mechanisms can be manipulated by new methods of treatment. First results are presented.

Atrial Fibrillation↗
PubMed2006

Electrocardiographic risk stratification in families with congenital long QT syndrome.

AIMS: The QT interval in the surface ECG is one of the most often used risk stratifiers in families with congenital long QT syndrome (LQTS). The best ECG lead for clinical management of LQTS families remains unclear. METHODS AND RESULTS: The predictive power of the QTc interval in all ECG leads was studied in 200 consecutive genotyped LQTS family members to identify mutation carriers (n = 103; age: 35+/-19 years) and high-risk LQTS patients (n = 16 with survived sudden cardiac arrest) using receiver operating curve (ROC) analysis (ROC = area under curve). Additionally, the risk for events (syncope and sudden cardiac arrest) was calculated for QTc decile in all individuals. The predictive power was highest in lead II and lead V5 for identifying carriers in LQTS families. These ECG leads were optimal for risk stratification (ROC range 0.83-0.87). In these leads, positive predictive value (PPV) and negative predictive value (NPV) were highest for suggested QTc cut-offs (440 and 500 ms) for identification of LQTS mutation carriers and high-risk patients (PPV between 78-81 and 73-80%, respectively). The risk for events in QTc deciles increased exponentially from 10 to 80% and was 40% for QTc > 500 ms. CONCLUSION: On the basis of these data, QTc is the best diagnostic and prognostic ECG parameter in LQTS families. A single measurement should be obtained in lead II if measurable and then in left precordial leads (preferably V5) as a second choice.

Adult↗
PubMed2006

Semi-automated 3-dimensional intracardiac echocardiography: development and initial clinical experience of a new system to guide ablation procedures.

BACKGROUND: Pre-interventional three-dimensional (3D) reconstruction of the heart by CT or MRI provides important information on cardiac anatomy for electrophysiological interventions. However, updates of 3D-imaging modalities with high soft-tissue contrast are not available during ablation procedures. OBJECTIVE: We describe the development and first clinical testing of a close to real-time visualization of cardiac anatomy by intracardiac echocardiography (ICE). METHODS: An electronic phased-array 5-10 MHz ICE-catheter (AcuNav/Siemens/64 elements) was inserted via a straightened femoral vein sheath (12F) and placed in the right atrium in 5 pigs. A custom-made prototype stepper motor allowed automatic rotation around the longitudinal axis from 90 degrees to 360 degrees in 2-5 degrees steps. For every plane 2D images of a complete cardiac cycle were acquired, triggered by respiration and ECG. The ultrasound images were digitized and 3D-reconstruction was performed by a prototype software. After experimental validation the system was tested in 6 patients during electrophysiological studies. RESULTS: From a single location in the right atrium, 3D-acquisition and reconstruction of both atria and ventricles with good image quality were achieved within 3-5 minutes. Doppler-mode facilitated identification of the great vessels including the pulmonary veins and their entry into the heart. 3D-visualization of ablation catheters was also possible in all patients and pigs. CONCLUSION: Semi-automated 3D intracardiac echocardiography from a single site inside the right atrium provides the electrophysiologist with a detailed image of both atria and ventricles with repeated updates of the cardiac anatomy.

Animals↗
PubMed2006

G-CSF/SCF reduces inducible arrhythmias in the infarcted heart potentially via increased connexin43 expression and arteriogenesis.

Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model. G-CSF/SCF improved cardiac output after myocardial infarction. Although G-CSF/SCF led to a twofold increased, potentially proarrhythmic homing of bone marrow (BM)-derived cells to the area of infarction, <1% of these cells adopted a cardial phenotype. Inducibility of ventricular tachycardias during programmed stimulation was reduced 5 wk after G-CSF/SCF treatment. G-CSF/SCF increased cardiomyocyte diameter, arteriogenesis, and expression of connexin43 in the border zone of the infarction. An enhanced expression of the G-CSF receptor demonstrated in cardiomyocytes and other cell types of the infarcted myocardium indicates a sensitization of the heart to direct influences of this cytokine. In addition to paracrine effects potentially caused by the increased homing of BM-derived cells, these might contribute to the therapeutic effects of G-CSF.

Animals↗
PubMed2005

A trial of self-adhesive patch electrodes and hand-held paddle electrodes for external cardioversion of atrial fibrillation (MOBIPAPA).

AIMS: External electrical cardioversion is the method of choice to terminate persistent atrial fibrillation. Whether the type of shock electrode affects cardioversion success is not known. We tested whether hand-held steel electrodes improve cardioversion outcome with monophasic or biphasic shocks when compared with adhesive patch electrodes. METHODS AND RESULTS: Two hundred and one consecutive patients with persistent atrial fibrillation (147 male, mean age 63+/-1 years, duration of atrial fibrillation 6.3+/-1 months) were randomly assigned to cardioversion using either a sinusoidal monophasic or a truncated exponential biphasic shock wave form. The first half of patients were cardioverted using adhesive patch electrodes, the second half using hand-held steel paddle electrodes, and all patients using an anterior-posterior electrode position. Paddle electrodes successfully cardioverted 100/104 patients (96%) and patch electrodes 85/97 patients (88%, P=0.04). This effect was comparable to that of biphasic shocks: biphasic shocks cardioverted 102/104 patients (98%) and monophasic shocks 83/97 patients (86%, P=0.001). A beneficial effect of paddle electrodes was observed for both shock wave forms. After cross-over from an ineffective monophasic to a biphasic shock, cardioversion was successful in 198/201 (98.5%) patients. Unsuccessful cardioversion after cross-over (3/201 patients) only occurred with patch electrodes (P=0.07). CONCLUSION: Hand-held paddle electrodes increase success of external cardioversion of atrial fibrillation in this trial. This increase is of similar magnitude as the increase in cardioversion success achieved with biphasic shocks. A combination of biphasic shocks, paddle electrodes, and an anterior-posterior electrode position renders outcome of external cardioversion almost always successful (104/104 patients in this trial).

Atrial Fibrillation↗
PubMed2005

Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation.

AIMS: Atrial fibrillation (AF) shortens the atrial action potential and the atrial refractory period. These changes promote persistence of AF. Pharmacological prolongation of atrial action potential duration (APD) may therefore help to prevent recurrent AF. In addition to prolonging APD, sodium channel blockers may prevent AF by inducing post-repolarization refractoriness (PRR). We studied whether two antiarrhythmic drugs (sotalol, flecainide) prolong APD or induce PRR in the fibrillating human atrium. METHODS: In 12 patients with persistent AF (11 male, 58 +/- 5 yrs, 27 +/- 7 months duration of AF), we recorded monophasic action potentials from the right atrial appendage and inferior right atrium at baseline and 15 minutes after intravenous administration of sotalol (1.5 mg/kg) or flecainide (2 mg/kg). APD and effective refractory periods (ERP) were determined. RESULTS: Both drugs prolonged APD90 during AF (flecainide from 109 +/- 7 ms to 137 +/- 10 ms, sotalol from 108 +/- 6 ms to 131 +/- 8 ms, both p < 0.05 vs. baseline). Sotalol prolonged ERP in parallel to APD (from 119 +/- 8 ms to 139 +/- 8 ms, p < 0.05). Flecainide induced PRR by prolonging ERP more than APD90 (from 134 +/- 9 ms to 197 +/- 28 ms, p < 0.05 vs. baseline and vs. sotalol). CONCLUSIONS: Flecainide and sotalol prolong the atrial action potential during atrial fibrillation in humans. In addition, flecainide induces atrial PRR. These electrophysiological effects may reduce AF recurrences and prevent their persistence.

Action Potentials↗
PubMed2005

Arrhythmogenic right ventricular cardiomyopathy. Antiarrhythmic drugs, catheter ablation, or ICD?

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of sudden cardiac death and ventricular tachyarrhythmias in young, apparently healthy individuals and athletes. Myocardial atrophy with subsequent fibrofatty replacement predominantly affects right ventricular myocardium and results in global and regional dysfunction as well as areas of slow conduction and dispersion of refractoriness which are prerequisites for reentrant ventricular tachyarrhythmias. Patients affected with ARVC should be excluded from competitive sports and vigorous training. To provide optimal treatment, a detailed diagnostic evaluation and risk stratification are mandatory. Tailored treatment strategies aim at the suppression or effective termination of recurrent ventricular tachyarrhythmias and prevention of sudden death by antiarrhythmic drug therapy, catheter ablation, or implantation of a cardioverter defibrillator (ICD). Antiarrhythmic drugs may be used as a stand-alone treatment to suppress ventricular tachycardia (VT) recurrences in patients with ARVC and low risk of sudden death. Sotalol (preferred) or amiodarone in combination with beta-blockers showed the highest efficacy rates. In patients at higher risk, an ICD should be implanted and antiarrhythmic drugs be used only as an adjunct to prevent or suppress frequent VT recurrences and ICD discharges. Catheter ablation using conventional or electroanatomic mapping techniques yields good acute results for eliminating the targeted arrhythmia substrate. However, during the progressive long-term course of ARVC, VT recurrences from new arrhythmia foci are frequent and therefore limit the curative value of catheter ablation. In patients with frequent VT recurrences and ICD discharges, however, catheter ablation plays an important role as a palliative and adjunctive treatment option for arrhythmia suppression. ICD therapy has been increasingly used for secondary and also primary prevention of sudden death in patients with ARVC. In secondary prevention, the ICD has shown to improve the long-term prognosis of patients at high risk of sudden death by effective termination of life-threatening recurrences of ventricular tachyarrhythmias. However, adequate lead placement may be difficult and lead-related complications during long-term follow-up must be taken into account. The role of ICD therapy for primary prevention of sudden death in ARVC is not yet adequately defined. Ongoing international registries will provide important additional data to improve risk stratification and refine treatment algorithms in order to select the best individual treatment for arrhythmia suppression and prevention of sudden death in patients with ARVC.

Anti-Arrhythmia Agents↗
PubMed2005

Gender differences in cardiac arrhythmias.

Mild gender-specific differences in myocellular and invasive electrophysiology have been described recently. Importantly, the QT interval is slightly prolonged in women, when compared to men. In men atrial fibrillaton, preexcitation and ventricular tachycardia are found more often. Modifications of the cellular "milieu" come from hormonal factors and the autonomous nervous system. The interaction of theses influences with regional cellular factors will help us in the future to analyze gender-specific factors of arrhythmogenesis and develop treatment and prevention strategies.

Arrhythmias, Cardiac↗
PubMed2005

Targeted pharmacological reversal of electrical remodeling after cardioversion--rationale and design of the Flecainide Short-Long (Flec-SL) trial.

Persistent atrial fibrillation (AF) causes relevant mortality and cardiovascular and noncardiovascular morbidity. Therefore, maintenance of sinus rhythm is an important clinical goal, especially when the patient is symptomatic, despite the fact that current treatment strategies are not sufficient to completely prevent recurrent AF. In addition to underlying atrial disease that predisposes to AF, AF in itself induces structural and electrical adaptations ("electrical remodeling" and "structural remodeling"). Underlying disease processes and parts of structural remodeling are not always reversible. Electrical remodeling, in contrast, is reversed by a few weeks of maintenance of sinus rhythm under experimental conditions. This corresponds to the period when most of the recurrent episodes of AF occur after cardioversion. Antiarrhythmic drugs that prolong the atrial action potential can assist in the prevention of recurrent AF by promoting the reversal of electrical remodeling. Such drugs, which are currently used over long periods after cardioversion, may only be needed until the physiological action potential duration is restored, for example, during the first few weeks after cardioversion of persistent AF. This treatment concept that we call "targeted pharmacological reversal of electrical remodeling" would limit both cost and drug-induced side effects of antiarrhythmic drug therapy after cardioversion. The Flec-SL trial, ISECTN62728743, therefore tests the main hypothesis that targeted pharmacological reversal of electrical remodeling by short-term antiarrhythmic drug therapy for 4 weeks after cardioversion is not inferior to standard long-term antiarrhythmic drug therapy for the prevention of recurrent AF after cardioversion in a parallel group, randomized, multicenter, open, blinded end point analysis design. Based on its effectiveness and pharmacokinetic profile, flecainide is used to test the study hypothesis. The trial uses daily transtelephonic electrocardiographic monitoring for all patients and will be conducted within the German Atrial Fibrillation Competence NETwork (AFNET) to facilitate inclusion of patients from electrophysiologically oriented cardiology centers, ordinary hospitals, and office-based physicians.

Anti-Arrhythmia Agents↗
PubMed2004

Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice.

The transcriptional activation mediated by cAMP-response element (CRE) and transcription factors of the CRE-binding protein (CREB)/CRE modulator (CREM) family represents an important mechanism of cAMP-dependent gene regulation possibly implicated in detrimental effects of chronic beta-adrenergic stimulation in end-stage heart failure. We studied the cardiac role of CREM in transgenic mice with heart-directed expression of CREM-IbDeltaC-X, a human cardiac CREM isoform. Transgenic mice displayed atrial enlargement with atrial and ventricular hypertrophy, developed atrial fibrillation, and died prematurely. In vivo hemodynamic assessment revealed increased contractility of transgenic left ventricles probably due to a selective up-regulation of SERCA2, the cardiac Ca(2+)-ATPase of the sarcoplasmic reticulum. In transgenic ventricles, reduced phosphorylation of phospholamban and of the CREB was associated with increased activity of serine-threonine protein phosphatase 1. The density of beta(1)-adrenoreceptor was increased, and messenger RNAs encoding transcription factor dHAND and small G-protein RhoB were decreased in transgenic hearts as compared with wild-type controls. Our results indicate that heart-directed expression of CREM-IbDeltaC-X leads to complex cardiac alterations, suggesting CREM as a central regulator of cardiac morphology, function, and gene expression.

Animals↗
PubMed2004

Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin.

Junctin is a transmembrane protein of the cardiac junctional sarcoplasmic reticulum (SR) that binds to the ryanodine receptor, calsequestrin, and triadin 1. This quaternary protein complex is thought to facilitate SR Ca2+ release. To improve our understanding of the contribution of junctin to the regulation of SR function, we examined the age-dependent effects of junctin overexpression in the atrium of 3-, 6-, and 18-wk-old transgenic mice. The ratio of atrial weight and body weight was unchanged between junctin-overexpressing (JCN) and wild-type (WT) mice at all ages investigated (n=6-8). The protein expression of triadin 1 was decreased starting in 3-wk-old JCN atria (by 69%), whereas the expression of the ryanodine receptor was diminished in 6- (by 48%) and 18-wk-old (by 57%) JCN atria compared with age-matched WT atria. Force of contraction was decreased by 35% in 18-wk-old JCN compared with age-matched WT left atrial muscle strips, which was accompanied by a prolonged time of relaxation (48.1 +/- 0.9 vs. 44.2 +/- 0.8 ms, respectively, n=6-8, P <0.05). The spontaneous beating rate of isolated right atria was higher in 18-wk-old JCN mice compared with age-matched WT mice (389 +/- 10 vs. 357 +/- 6 beats/min, respectively, n=6-8, P <0.05). Heart rate was lower by 9% in telemetric ECG recordings in 18-wk-old JCN mice during stress tests. Three-week-old JCN atria exhibited a higher potentiation of force of contraction at rest pauses of 30 s (by 13%) and of 300 s (by 35%), suggesting increased SR Ca2+ content. This was consistent with the higher force of contraction in 3-wk-old JCN atria (by 29%) compared with age-matched WT atria (by 10%) under the administration of caffeine. We conclude that in 3-wk-old atria, junctin overexpression was associated with a reduced expression of triadin 1 resulting in a higher SR Ca2+ load without changes in contractility or heart rate. In 6-wk-old JCN atria, the compensatory downregulation of the ryanodine receptor may offset the effects of junctin overexpression. Finally, the progressive decrease in ryanodine receptor density may contribute to the decreased atrial contractility and lower heart rate during stress in 18-wk-old JCN mice.

Aging↗
PubMed2004

Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors.

OBJECTIVE: An increased expression of adenosine receptors is a promising target for gene therapy aimed at protecting the myocardium against ischemic damage, but may alter cardiac electrophysiology. We therefore studied the effects of heart-directed overexpression of A(3) adenosine receptors (A(3)ARs) at different gene doses on sinus and atrio-ventricular (AV) nodal function in mice. METHODS AND RESULTS: Mice with heart-specific overexpression of A(3)AR at high (A(3)(high)) or low (A(3)(low)) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving A(3)(high) mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia-tachycardia syndrome (minimal heart rate A(3)(high) 217+/-25*; WT 406+/-21 beats/min, all values as mean+/-S.E.M., n=7 per genotype, *p<0.05). Exercise attenuated bradycardia in A(3)(high) mice (maximal heart rate A(3)(high) 650+/-13*; WT 796+/-13 beats/min) and first-degree AV nodal block was present (PQ interval A(3)(high) 36+/-4*; WT 23+/-5 ms). Isolated hearts showed complete heart block (10/17 A(3)(high)* vs. 1/17 WT). Atrial bradycardia and AV block were already present 3 weeks after birth. Doppler echocardiography revealed atrial dysfunction and progressive atrial enlargement that was moderate at 3 and 8 weeks, and progressed at 12 and 21 weeks of age (all p<0.05 vs. WT). Atrial contractility and sarcoendoplasmic Ca(2+) ATPase (SERCA) 2a protein expression were reduced in isolated left A(3)(high) atria at the age of 14 weeks. Fibrosis was present in left A(3)(high) atria at 14 weeks, but not at 5 weeks of age. A(3)(low) mice had first-degree AV block without arrhythmias or structural changes. CONCLUSIONS: Heart-directed overexpression of A(3)AR resulted in gene dose-dependent AV block and pronounced sinus nodal dysfunction in vivo. Profound bradycardia heralded atrial and ventricular dilatation, dysfunction, and fibrosis. In contrast to A(1) adenosine receptors (A(1)AR), the effects of A(3)AR overexpression were attenuated during exercise. This may have implications for the physiology of sinus nodal regulation and for therapeutic attempts to increase the expression of adenosine receptors.

Animals↗