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Biomedical subjects

Wilhelm Haverkamp

Publications and source records attributed to Wilhelm Haverkamp.

At least 19 recordsLinked to original sources
PubMed2007

Dopamine agonists and the risk of cardiac-valve regurgitation.

BACKGROUND: Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson's disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation. METHODS: We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005. We conducted a nested case-control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis. RESULTS: Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists. CONCLUSIONS: In this study, use of the dopamine agonists pergolide and cabergoline was associated with an increased risk of newly diagnosed cardiac-valve regurgitation.

Adult↗
PubMed2006

Cardiovascular characterization of Pkd2(+/LacZ) mice, an animal model for the autosomal dominant polycystic kidney disease type 2 (ADPKD2).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2. Patients with ADPKD have an increased incidence of cardiac valve abnormalities and left ventricular hypertrophy. Systematic analyses of cardiovascular involvement have so far been performed only on genetically unclassified patients or on ADPKD1 patients, but not on genetically defined ADPKD2 patients. Even existing Pkd1 or Pkd2 mouse models were not thoroughly analyzed in this respect. Therefore, the aim of this project was the noninvasive functional cardiovascular characterization of a mouse model for ADPKD2. METHODS: Pkd2(+/LacZ) mice and wildtype controls were classified into 8 groups with respect to gender, age and genotype. In addition, two subgroups of female mice were analyzed for cardiac function before and during advanced pregnancy. Doppler-echocardiographic as well as histological studies were performed. RESULTS: Doppler-echocardiography did not reveal significant cardiovascular changes. Heart rate and left ventricular (LV) length, LV mass, LV enddiastolic and LV endsystolic diameters did not differ significantly among the various groups when comparing wildtype and knockout mice. There were no significant differences except for a tendency towards higher maximal early and late flow velocities over the mitral valve in old wildtype mice. CONCLUSIONS: Non-invasive phenotyping using ultrasound did not reveal significant cardiovascular difference between adult Pkd2(+/LacZ) and WT mice. Due to the lack of an obvious renal phenotype in heterozygous mice, it is likely that in conventional ADPKD knock out mouse models severe cardiac problems appear too late to be identified during the reduced lifespan of the animals.

Age Factors↗
PubMed2006

Optimization of cardiac resynchronization guided by Doppler echocardiography: haemodynamic improvement and intraindividual variability with different pacing configurations and atrioventricular delays.

AIMS: Cardiac resynchronization therapy (CRT) improves symptoms in heart failure patients with intraventricular conduction delay (IVCD). Different pacing modalities produce variable activation patterns and are likely to result in different haemodynamic changes. The objective of this study was to demonstrate acute haemodynamic changes with different CRT configurations. METHODS AND RESULTS: In 26 patients (left ventricular ejection fraction 22.7+/-6.1%, QRS 176+/-29 ms, New York Heart Association III/IV 18/8), a CRT device was implanted. An optimization procedure was performed including left (LVPEI) and right ventricular pre-ejection intervals, interventricular mechanical delay (IVD), left ventricular filling fraction (FTc), and myocardial performance index (MPI) during left and biventricular pacing with three different atrioventricular (AV) delays. An optimal mode and AV delay were defined. LVPEI changed from 166+/-27 to 139+/-25 ms, IVD from 49+/-19 to 6+/-18 ms, MPI from 0.98+/-0.25 to 0.62+/-0.22, and FTc from 0.42+/-0.08 to 0.51+/-0.08 (P<0.001 for all comparisons). The variability was 39+/-20 ms for LVPEI, 55+/-24 ms for IVD, 0.11+/-0.07 for FTc, and 0.35+/-0.18 for MPI. CONCLUSION: Optimized resynchronization in heart failure patients with IVCD produces marked acute improvement of the altered cardiac cycle timing. The variability of Doppler parameters with different CRT modalities underlines the necessity of individualized settings and suggests that the patients' benefit may be jeopardized without optimization.

Cardiac Pacing, Artificial↗
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

Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by IKr blockers.

BACKGROUND: Cytostatic agents such as anthracyclines may cause changes in the electrophysiologic properties of the heart. We hypothesized that anthracyclines facilitate life-threatening proarrhythmic side effects of cardiovascular and non-cardiovascular repolarization prolonging drugs. METHODS AND RESULTS: The electrophysiologic effects of chronic administration of doxorubicin (Dox) were studied in ten rabbits, which were treated with Dox twice a week (1.5 mg/kg i.v.). A control group (11 rabbits) was given NaCl solution. Two of ten Dox rabbits died suddenly, the remaining animals showed mild clinical signs of heart failure after a period of six weeks. Echocardiography demonstrated a decrease in ejection fraction (pre treatment: 74 +/- 23% to post treatment: 63 +/- 16% (p <0.05)). In isolated hearts, action potential duration measured by eight simultaneously recorded monophasic action potentials (MAP) was similar in Dox and control hearts. However, in Dox rabbits, administration of the I(Kr)-blocker erythromycin (150-300 microM) led to a significant greater prolongation of the mean MAP duration (63 +/- 21ms vs 29 +/- 12 ms, p <0.05) and the QT interval (100 +/- 32ms vs 58 +/- 17 ms, p <0.05) as compared to control. Moreover, I(Kr)-block led to a more marked increase of dispersion of MAP(90) in the Dox group as compared to control hearts (23 +/- 7ms vs. 9 +/- 4 ms). In the presence of hypokalemia more episodes of early afterdepolarizations and torsade de pointes occurred (p <0.05). CONCLUSION: Even during the early phase of chemotherapeutic treatment,before significant QT-prolongation is present,anthracyclines lead to an increased sensitivity to the proarrhythmic potency of I(Kr)-blocking drugs. Thus, anthracycline therapy reduces repolarization reserve and thereby represents a novel contributing factor for the development of life-threatening proarrhythmia.

Action Potentials↗
PubMed2005

Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study.

Sudden infant death syndrome (SIDS) is a frequent cause of death among infants. The etiology of SIDS is unknown and several theories, including fatal ventricular arrhythmias, have been suggested. We performed an epidemiological and genetic investigation of SIDS victims to estimate the presence of inherited long QT syndrome (LQTS) as a contributor for SIDS. Forty-one consecutively collected and unrelated SIDS cases were characterized by clinical and epidemiological criteria. We performed a comprehensive gene mutation screening with single-strand conformation polymorphism analysis and sequencing techniques of the most relevant LQTS genes to assess mutation frequencies. In vitro characterization of identified mutants was subsequently performed by heterologous expression experiments in Chinese hamster ovary cells and in Xenopus laevis oocytes. A positive family history for LQTS was suspected by mild prolonged Q-T interval in family members in 2 of the 41 SIDS cases (5%). In neither case, a family history of sudden cardiac death was present nor a mutation could be identified after thorough investigation. In another SIDS case, a heterozygous missense mutation (H105L) was identified in the N-terminal region of the KCNQ1 (LQTS 1) gene. Despite absence of this mutation in the general population and a high conservational degree of the residue H105 during evolution, electrophysiological investigations failed to show a significant difference between wild-type and KCNQ1(H105L)/minK-mediated I(Ks) currents. Our data suggest that a molecular diagnosis of SIDS related to LQTS genes is rare and that, even when an ion channel mutation is identified, this should be regarded with caution unless a pathophysiological relationship between SIDS and the electrophysiological characterization of the mutated ion channel has been demonstrated.

Age Distribution↗
PubMed2005

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole.

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.

Antipsychotic Agents↗
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

Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3.

BACKGROUND: Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated. METHODS AND RESULTS: In 11 Langendorff-perfused rabbit hearts, veratridine (0.1-0.5 microM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p<0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 microM, 92% at 0.25 microM, 208% at 0.5 microM; p<0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 microM veratridine; p<0.05). CONCLUSION: By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.

Action Potentials↗
PubMed2005

[Long QT syndrome and Brugada syndrome. Drugs, ablation or ICD?].

Long QT syndrome and Brugada syndrome are potentially fatal inherited arrhythmogenic diseases. Thanks to the contribution of molecular genetics, the genetic bases, pathogenesis, and genotype-phenotype correlation of both diseases have been progressively unveiled and shown to have an extremely high degree of genetic heterogeneity. The clinical manifestation of the diseases is also highly variable. Symptomatic patients experience ventricular tachyarrhythmias which may lead to recurrent syncope and/or sudden cardiac death. In long QT syndrome patients with syncope, therapy with beta-blockers has proven effective. When, despite beta-blocker treatment, arrhythmia-related symptoms continue to occur, an implantable cardioverter defibrillator is indicated. Such a device should also be implanted in resuscitated patients. In symptomatic patients with Brugada syndrome, the implantable cardioverter defibrillator is the only life-saving option. In asymptomatic patients with a Brugada ECG pattern, risk stratification has become of utmost importance in order to discover which patients really need definitive treatment.

Anti-Arrhythmia Agents↗
PubMed2005

[Arrhythmogenic right ventricular cardiomyopathy].

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder that is characterized by localized or diffuse atrophy of predominantly right ventricular myocardium with subsequent replacement by fatty and fibrous tissue. Arrhythmias of right ventricular origin are the main clinical manifestation. Affected patients present with ventricular premature beats and nonsustained or sustained ventricular tachycardia demonstrating a left bundle branch block pattern. However, since ventricular tachycardia may also degenerate into ventricular fibrillation, sudden death may be the first manifestation of ARVC.In recent years, ARVC has been more and more recognized as an important and frequent cause of ventricular tachyarrhythmias and sudden cardiac death, particularly in young patients and athletes, with apparently normal hearts. Evidence of the disease is found in 30-50% of family members. ARVC is a genetically heterogeneous disease. The diagnosis is based on electrocardiographic abnormalities and the identification of regional or global right ventricular dysfunction and fibrolipomatosis. Although several potentially causative genes have been identified, currently, genetic testing is not part of the routine diagnostic work-up.An implantable cardioverter-defibrillator is indicated in selected high-risk patients with ARVC (i. e., patients with life-threatening ventricular tachycardia or survivors of sudden cardiac death). The clinical course of the disease is often characterized by progression. In individual patients heart transplantation may become necessary.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up.

OBJECTIVES: The purpose of this study was to evaluate retrospectively a single-center experience with the use of ICDs in patients with long QT syndrome (LQTS) concerning outcome, complications, and optimal programming. BACKGROUND: Use of implantable cardioverter-defibrillator (ICD) in patients with congenital LQTS is controversial but is generally accepted in high-risk patients. METHODS: We enrolled 27 symptomatic patients with LQTS undergoing ICD therapy (QTc 540 +/- 64 ms(1/2); 85% female, 63% cardiac arrest; 33% syncope despite beta-blockers; 4% with severe phenotype) and 81 genotyped patients with LQTS undergoing conventional drug therapy (28 LQT1, 39 LQT2, 1 LQT3, 13 LQT5). During a mean follow-up of 65 +/- 34 months, one death occurred in the ICD group that was not LQTS related. A total of 178 appropriate shocks were observed in 10/27 patients (37%), mostly in survivors of cardiac arrest (in 58% of cardiac arrest patients vs. in 20% of non-cardiac arrest patients). RESULTS: In a logistic regression analysis, only QTc interval (121/178 shocks (68%) for QTc > 500 ms(1/2)) and "survived cardiac arrest" were prognostic for ICD shocks. In 30% of patients in the ICD group, multiple shocks occurred and could be reduced after increase of antibradycardia pacing rate, adding beta-blocker therapy, or starting the rate-smoothing algorithm (average 7.1 shocks before to 0.75 shocks after additional intervention annually). CONCLUSION: ICD therapy is a safe and useful tool in high-risk patients with LQTS. QTc interval and cardiac arrest survivors were prognostic factors for appropriate ICD shocks. The results of this large single-center experience suggest that beta-blockers should always be added to ICD therapy. In addition, some patients might benefit from additional antibradycardia pacing, prolonged detection time, and a rate-smoothing algorithm to prevent recurrent episodes.

Adolescent↗
PubMed2005

True right bundle branch block masking the typical ECG in Brugada syndrome.

A patient with a family history of sudden cardiac death and a structurally normal heart presented with a resting ECG intermittently displaying a saddle-type Brugada-ECG, which could be reproducibly converted to a coved-type ECG pattern suggestive of Brugada syndrome. However, no ST-segment changes occurred in the presence of a true right bundle branch block (RBBB) in the same patient. In consideration of the inalienable diagnostic criterion of dynamic ECG abnormalities in the right precordial leads in Brugada syndrome, setting the diagnosis in patients with true RBBB may be unattainable.

Adult↗
PubMed2005

Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death.

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from the market or restricted use of antipsychotics, such as sultopride, droperidol, sertindole or thioridazine. Reviewing the available data shows that all antipsychotics tested affect the cardiac potassium channel, with the concentration that produces 50% inhibition (IC50) ranging from 1 nmol/L (haloperidol) to 6 micromol/L (olanzapine). Experimental in vitro or in vivo electrophysiological studies have shown a dose-dependent increase in the duration of the action potential with various degrees of indicators of serious arrhythmogenicity. However, this does not always translate clinically into an increased duration of the QT interval or increased risk of torsade de pointes or sudden death in clinical trials or pharmacoepidemiological studies. In turn, QT prolongation in clinical trials does not always translate to an increased risk of torsade de pointes or sudden death. The reasons for these apparent discrepancies are unclear and could be related to insufficiently powered field studies, low plasma and tissue drug concentrations with reference to in vitro data or drug effects on other receptors or ion channels that have a protective effect. Alternatively, risks that were not apparent from preclinical or clinical data could be related to the use of the drug in high-risk patients, metabolic interactions or other factors that would only be encountered in large postmarketing populations. The assessment of cardiovascular safety, both preclinical and during premarketing clinical trials, needs to be supported by appropriately powered pharmacoepidemiology studies.

Animals↗