Showing papers by "Paulus Kirchhof published in 2006"

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

Abstract: In heart failure (HF), Ca2+/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 CaMKIIδC on Na+ current (INa) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδC overexpression shifted voltage dependence of Na+ channel availability by –6 mV (P < 0.05), and the shift was Ca2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2–related inhibitory peptide [AIP] or KN93). CaMKIIδC markedly increased persistent (late) inward INa 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 CaMKIIδC overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na+ channels. In vivo, transgenic CaMKIIδC 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 INa gating to reduce availability at high heart rate, while enhancing late INa (which could prolong action potential duration). In mice, enhanced CaMKIIδC activity predisposed to VT. Thus, CaMKII-dependent regulation of Na+ channel function may contribute to arrhythmogenesis in HF.

Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice

Abstract: 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 ...

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

Abstract: 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.

Electrocardiographic risk stratification in families with congenital long QT syndrome.

Abstract: 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.

Primary prevention of sudden cardiac death

Abstract: Sudden cardiac death (SCD) causes more than 300 000 deaths per annum in Europe, with the same number occurring in the United States, according to current estimations.1,2 This amounts to a death toll of 1–1.5 per 1000 people per year in the industrialised world.w1 In low-income regions of the world, the estimations are less valid. These estimates are based on clinical definitions of “sudden” and “cardiac”. “Sudden” implies that death occurred unexpectedly and that the sequence of events that led to death occurred within a short time span, usually one hour before death. It is generally assumed that the patient was in a stable condition before the sudden and lethal event. “Cardiac” implies that the primary pathology occurred in the heart. This is usually confirmed by the absence of other lethal diseases upon inspection and, whenever available, autopsy. At times, signs of acute myocardial infarction or of acute heart failure can substantiate the assumption of “cardiac” death. Within the limitations of such a definition, it is generally assumed that the majority (85%) of SCD victims die of ventricular tachyarrhythmias, usually in the form of ventricular fibrillation (VF).1 The remaining SCD victims die either of bradyarrhythmias or of acute pump failure. SCD urgently requires primary prevention because the first clinical event is often fatal, especially in patients with ventricular tachyarrhythmias. Patients with acute bradyarrhythmias often retain a basal circulation—for example, due to ventricular escape rhythms. Thereby, the appropriate treatment (often a pacemaker) can usually be deployed in time to prevent irreversible organ damage when a sudden bradyarrhythmia occurs. VF, in contrast, results in a rapid and complete loss of blood circulation. If left untreated, this condition results in irreversible organ (most notably brain) damage after a few minutes.1 Even in regions of the world with highly …

Approach to wide complex tachycardias in patients without structural heart disease

Abstract: The correct diagnosis of a wide complex tachycardia (WCT)—QRS duration > 120 ms—remains a challenge despite numerous established criteria for the differentiation of ventricular from supraventricular tachycardia (SVT) with aberrant conduction. Making the correct diagnosis is important for the acute as well as long term management of patients with WCT. The objective of the present review is to discuss the major causes as well as clinical and electrophysiologic criteria of WCT (table 1) in patients without structural heart disease. View this table: Table 1 Causes of wide complex tachycardias (WCTs) in patients without structural heart disease Broad categories of WCTs include ventricular tachycardia (VT), SVT with abnormal intraventricular conduction, and ventricular paced rhythms. A lack of underlying structural heart disease does neither exclude a VT nor imply a benign prognosis. However, if a patient has had similar episodes during previous years, SVT is more likely than VT. Termination of a tachycardia by the Valsalva manoeuvre or adenosine injection also suggests a supraventricular origin, although some VT can also be terminated by these manoeuvres (for example, fascicular VT). A WCT in a patient who is alert and haemodynamically stable is not necessarily of supraventricular origin. The clinical presentation depends on the haemodynamic consequences it produces. These depend partly on tachycardia rate, the degree of myocardial dysfunction, the circumstances and suddenness of initiation, and autonomic factors. Physical examination in a patient presenting with WCT may indicate haemodynamic distress (low blood pressure, heart failure or cardiogenic shock). When cardiac output and blood pressure are maintained and/or when the tachycardia is short lived, the arrhythmia may present as palpitations, breathlessness or just discomfort. Intraventricular conduction delay can result from heart rate changes, as well as from fixed pathological lesions in the conduction system. In patients with pre-existing or “fixed” (present during the normal baseline rhythm) bundle branch block (BBB), …

Hypertension begets hypertrophy begets atrial fibrillation? Insights from yet another sheep model.

Abstract: Atrial fibrillation (AF) affects approximately two million patients in the USA and an equal number in Europe and increases morbidity and mortality in affected patients and population worldwide. Although acute conversion of AF to sinus rhythm can be achieved in almost all patients, therapeutic options to maintain sinus rhythm (repeated cardioversions, anti-arrhythmic drugs, catheter ablation, or surgical procedures) are often ineffective. Understanding the different mechanisms that contribute to AF may guide us towards a more effective ‘rhythm control’ therapy. Arterial hypertension, found in 65–70% of AF patients1,2 but only in 25–50% of the population,3 is the most common co-morbidity found in AF registries in Germany and Europe. Although this suggests a causal link between hypertension and AF, the mechanisms by which hypertension predisposes to AF are not well understood. Electrical, structural, and ultrastructural changes usually concur in the atria before AF develops. Some of the electrical changes that precipitate AF, shortening of the atrial action potential and refractory period and/or local conduction disturbances, have been delineated in detail during the past decade. The underlying pathophysiological concept of electrical remodelling (AF-induced shortening of atrial refractoriness) stems from studies in … *Corresponding author: Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitatsklinikum Munster, D-48129 Munster, Germany. Tel: +49 251 8345185; fax: +49 251 8347864. E-mail address : kirchhp{at}uni-muenster.de

Neue Antiarrhythmika in der Therapie des Vorhofflimmerns

Abstract: Die vergangenen zehn Jahre haben einen rasanten Zuwachs in unserem Verstandnis von den Mechanismen, die dem Vorhofflimmern zugrunde liegen, gebracht. Nach dem Einsetzen von Vorhofflimmern treten bereits innerhalb kurzer Zeit elektrophysiologische und strukturelle Veranderungen (Remodeling) auf, die die Progredienz dieser Rhythmusstorung masgeblich verstarken. Die Entwicklung neuer Therapieansatze verfolgt drei Ziele, namlich 1. Verhinderung von Remodeling, insbesondere von strukturellem Remodeling, 2. Verbesserung von zugelassenen Antiarrhythmika hinsichtlich Wirksamkeit und Nebenwirkungsprofil, und 3. Entwicklung von Vorhof- bzw. Pathologie-selektiven Antiarrhythmika, um ventrikulare proarrhythmische Effekte zu vermeiden. In der vorliegenden Ubersicht werden die Pathophysiologie und das elektrische Remodeling bei Vorhofflimmern erortert. Nachfolgend werden die Eigenschaften neuer, speziell fur die Therapie des Vorhofflimmerns entwickelter antiarrhythmischer Substanzen im Einzelnen diskutiert.

[New antiarrhythmic drugs for therapy of atrial fibrillation: II. Non-ion channel blockers].

Abstract: During the last ten years we have made substantial progress in our understanding of the underlying mechanisms of atrial fibrillation. The high rate associated alterations in electrical and structural properties of the atria, referred to as atrial remodeling, promote the progression of atrial fibrillation. The development of new therapeutic approaches addresses three different directions: (i) prevention of atrial remodeling, especially of structural remodeling; (ii) increase of long-term efficacy of currently used drugs and improvement of their side-effect profile; and (iii) design of atria- and pathology-specific antiarrhythmic drugs without concomitant proarrhythmic effects in the ventricles. The current review outlines the pathophysiology of atrial fibrillation and focuses on electrical remodeling. The properties of new antiarrhythmic drugs for atrial fibrillation are discussed in detail.

Anticoagulation with atrial fibrillation

Abstract: Atrial fibrillation is associated with a relevant risk for ischemic stroke: Observational studies suggest that one in four to five strokes is due to atrial fibrillation. Depending on the risk profile of an individual patient, the yearly risk for a stroke is between 2% and 14%. Continuous oral anticoagulation is indicated if atrial fibrillation is accompanied by at least one additional risk factor for thromboembolic complications. This recommendation is supported by several large randomized trials. Due to their low therapeutic range, vitamin K antagonists (phenprocoumon, warfarin, and others), the most commonly used oral anticoagulants, require regular anticoagulation monitoring. If well-controlled (international normalized ratio 2-3, in elderly patients preferably 2-2.5), oral anticoagulation prevents more than half of ischemic strokes related to atrial fibrillation, while bleeding complications are rare. In the follow-up of low risk patients (CHADS2-Score 0), oral anticoagulation becomes necessary when risk factors for thromboembolic complications develop. If a stroke occurs during oral anticoagulation and an INR>2 in a patient with atrial fibrillation, other causes than thromboembolic events should be considered. New anticoagulants--especially direct thrombin antagonists--are currently evaluated in clinical trials and may in the future facilitate anticoagulation in patients with atrial fibrillation.

Das Kompetenznetz Vorhofflimmern (AFNET)

Abstract: Das Kompetenznetz Vorhofflimmern ist ein interdisziplinares bundesweites Forschungsnetzwerk, das vom Bundesministerium fur Bildung und Forschung (BMBF) gefordert wird. Ziel des 2003 gegrundeten Netzwerks ist es, die Diagnose und Behandlung von Vorhofflimmern, der haufigsten klinisch bedeutsamen Herzrhythmusstorung, zu verbessern. In einem zentralen Patientenregister wird eine Bestandsaufnahme zur Manifestation, Diagnostik und Therapie von Vorhofflimmern in Deutschland durchgefuhrt. Dieses Register dient als Datenbasis fur epidemiologische und klinische Studien. Epidemiologische Projekte untersuchen z.B. die Pravalenz von Vorhofflimmern sowie Komplikationen dieser Rhythmusstorung. Vier multizentrische klinische Studien zur Optimierung der medikamentosen Behandlung (ANTIPAF-Studie, Flec-SL-Studie), der praventiven Schrittmachertherapie (BACE-PACE-Studie) sowie der Katheterablation (GAP-AF-Studie) wurden gestartet. In weiteren klinischen Projekten werden das Risiko neurologischer Komplikationen untersucht und neue bildgebende Verfahren entwickelt. Experimentelle Projekte der Grundlagenforschung befassen sich mit unterschiedlichen Aspekten des atrialen Remodelings und versuchen aufzuklaren, wie die molekularen Mechanismen durch neue Behandlungsansatze beeinflussbar sind. Erste Ergebnisse werden hier vorgestellt. Schlusselworter:

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

Abstract: 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.