Peter Lercher

Influence of beta-blockers on melatonin release.

AbstractObjective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before.nn Methods: We performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40u2009mg (R)-propranolol, 40u2009mg (S)-propranolol, 50u2009mg (R)-atenolol, 50u2009mg (S)-atenolol, 25u2009mg (R,S)-carvedilol, 120u2009mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600u2009hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA).nn Results: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in μg): placebo 26; (R)-propranolol 24 (−7%, NS); (S)-propranolol 5 (−80%, Pu2009<u20090.001); (R)-atenolol 27 (+7%, NS); (S)-atenolol 4 (−86%, Pu2009<u20090.01); (R,S)-carvedilol 23 (−10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production.nn Conclusion: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.

Automated prediction of spontaneous termination of atrial fibrillation from electrocardiograms

An algorithm for differentiating ECGs with atrial fibrillation (AF) that will spontaneously terminate within 60 seconds from signals, where it wont, has been developed using the AF termination challenge database from physionet. The algorithm was based on the calculation of the major AF frequency by canceling out the QRS complexes and T waves from the original ECGs and then applying short time Fourier transform techniques to the remaining signals. The major AF frequency and the mean RR interval were considered for classification. Validation of the algorithm was done by sending the algorithms results for test-set-a of the AF termination challenge database to physionet. We found, that for ECGs with a low AF frequency it was more likely, that AF would terminate spontaneously than for ECGs with higher frequencies. Our algorithm was able to correctly classify 93.3% (28/30) of the signals of the test-set-a.

Managed ventricular pacing vs. conventional dual-chamber pacing for elective replacements: the PreFER MVP study: clinical background, rationale, and design

AIMSnSeveral clinical studies have shown that, in patients with intact atrioventricular (AV) conduction, unnecessary chronic right ventricular (RV) pacing can be detrimental. The managed ventricular pacing (MVP) algorithm is designed to give preference to spontaneous AV conduction, thus minimizing RV pacing. The clinical outcomes of MVP are being studied in several ongoing trials in patients undergoing a first device implantation, but it is unknown to what extent MVP is beneficial in patients with a history of ventricular pacing. The purpose of the Prefer for Elective Replacement MVP (PreFER MVP) study is to assess the superiority of the MVP algorithm to conventional pacemaker and implantable cardioverter-defibrillator programming in terms of freedom from hospitalization for cardiovascular causes in a population of patients exposed to long periods of ventricular pacing.nnnMETHODS AND RESULTSnPreFER MVP is a prospective, 1:1 parallel, randomized (MVP ON/MVP OFF), single-blinded multi-centre trial. The study population consists of patients with more than 40% ventricular pacing documented with their previous device. Approximately, 600 patients will be randomized and followed for at least 24 months. The primary endpoint comprises cardiovascular hospitalization.nnnCONCLUSIONnThe PreFER MVP trial is the first large prospective randomized clinical trial evaluating the effect of MVP in patients with a history of RV pacing.

Propafenone shows class Ic and class II antiarrhythmic effects

AIMSnPropafenone is a well-known Class Ic antiarrhythmic agent. It has the typical chemical structure of a beta-blocker, but human studies on its beta-blocking effects revealed conflicting results.nnnMETHODS AND RESULTSnTwelve healthy males received single oral doses of 600 mg propafenone and placebo according to a randomized, double-blind, placebo-controlled, cross-over protocol. Four hours following drug intake, heart rate and blood pressure were measured, and plasma concentrations of propafenone were determined at rest, during exercise and after recovery. At exercise, propafenone significantly decreased heart rate (-6%, P < 0.05), systolic blood pressure (-6%, P < 0.05), and the rate-pressure product (-11%, P < 0.05). Plasma concentrations of propafenone increased during exercise (+23%, P < 0.05) and decreased during recovery (-33%, P < 0.05).nnnCONCLUSIONnBoth effects on heart rate and blood pressure as well as the changes of plasma concentrations of propafenone during exercise represent two particular features of beta-blockers. Therefore, we conclude that propafenone is both a Class Ic and a Class II antiarrhythmic agent, and 600 mg propafenone, i.e. the dose recommended in current guidelines for cardioversion of paroxysmal atrial fibrillation, cause clinically significant beta-blockade. Thus, single oral doses of 600 mg propafenone appear also suitable for cardioversion of paroxysmal atrial fibrillation in patients with structural heart disease since beta-blockers are explicitly indicated in the treatment of both coronary artery disease and heart failure.

Exercise does not Affect Plasma Concentrations of (R)- and (S)-Carvedilol

AbstractPurpose: In vitro studies have shown that beta-blockers are taken up into and released from adrenergic cells. As a consequence, plasma concentrations of beta-blockers increase during exercise together with those of epinephrine and norepinephrine. However, effects of exercise on plasma concentrations of (R)- and (S)-carvedilol are unknown.nMethods: Twelve healthy males received oral single doses of 12.5 mg (R)-carvedilol, 12.5 mg (S)-carvedilol and 25 mg (R,S)-carvedilol in a cross-over fashion; 11 patients with essential arterial hypertension were given 25 mg (R,S)-carvedilol. Exercise was performed 3 hours following drug intake, and blood samples were taken at rest, at the end of exercise, and after 15 min of recovery. Plasma concentrations of (R)- and (S)-carvedilol were determined by HPLC.nResults: Plasma concentrations of (R)-carvedilol were 2- to 3-fold higher than those of (S)-carvedilol (p < 0.05 in all cases). Plasma concentrations of both (R)- and (S)-carvedilol remained unaffected during exercise and recovery.nConclusions: Contrary to all other beta-blockers so far investigated, exercise had no effect on plasma concentrations of (R)- and (S)-carvedilol. We conclude that neither (R)- nor (S)-carvedilol is released from adrenergic cells during exercise, a feature that clearly distinguishes carvedilol from other beta-blockers. Thus, the human organism appears to handle (R)- and (S)-carvedilol differently than other beta-adrenoceptor antagonists. This finding deserves further investigation on a molecular and cellular level in order to clarify these differences between the pharmacokinetics of carvedilol and other beta-blockers.

Automated and manufacturer independent assessment of the battery status of implanted cardiac pacemakers by electrocardiogram analysis

According to international standards, cardiac pacemakers have to indicate the status of their batteries upon magnet application by specific stimulation patterns. The purpose of this study has been to assess whether this concept can be used as a basis for automated and manufacturer independent examination of the depletion level of pacemakers in the framework of a collaborative telemedical pacemaker follow-up system. A prototype of such a system was developed and tested in a real clinical environment. Electrocardiograms (ECGs) were recorded during magnet application and automatically processed to extract the specific stimulation patterns. The results were used to assign each signal a corresponding pacemaker status: ok, replace or undefined, based on the expected behavior of the devices as specified by the manufacturer. The outcome of this procedure was compared to the result of an expert examination, resulting in a positive predictive value of 100% for the detection of ECGs indicating pacemaker status ok. The method can, therefore, be utilized to quickly, safely and manufacturer neutrally classify cases into the categories ok and needs further checking, which - in a telemedical setting - may be used to increase the efficiency of pacemaker follow-up procedures in the future.

Long-term reverse remodeling by cardiac resynchronization therapy with MultiPoint Pacing: A feasibility study of noninvasive hemodynamics–guided device programming

BACKGROUNDnCardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint Pacing [MPP]) improves acute hemodynamics and chronic outcomes in comparison to conventional biventricular pacing (BiV), though MPP programming questions persist.nnnOBJECTIVESnIn this multicenter feasibility study, we evaluated the feasibility of using noninvasive systolic blood pressure (SBP) to guide MPP programming and assessed the chronic 6-month echocardiographic CRT response.nnnMETHODSnPatients implanted with MPP-enabled CRT-defibrillator devices underwent noninvasive hemodynamic assessment (finger arterial pressure) during a pacing protocol that included atrial-only pacing and various BiV and MPP configurations. Each configuration was repeated 4 times, alternating with a reference pacing configuration, to calculate the SBP difference relative to reference (ΔSBP). CRT configurations with the greatest ΔSBP were programmed. An independent core laboratory analyzed baseline and 6-month echocardiograms, with CRT response defined as a 6-month reduction in LV end-systolic volume ≥ 15%.nnnRESULTSnForty-two patients (71% male; LV ejection fraction 30.3% ± 7.5%; QRS duration 161 ± 19 ms; 26% had ischemic cardiomyopathy) were enrolled in 4 European centers. Relative to atrial-only pacing, the best BiV and best MPP configurations produced significant SBP elevations of 3.1 ± 4.2 (P < .01) and 4.1 ± 4.1 mm Hg (P < .01), respectively (BiV vs MPP; P < .01). Greater SBP elevations were associated with the best MPP compared with the best BiV configurations in 29 of 37 patients completing the pacing protocol (78%). Of MPP-programmed patients completing the 6-month follow-up visit, 23 of 27 (85%) were classified as CRT responders (6-month reduction in LV end-systolic volume 37.0% ± 13.6%).nnnCONCLUSIONnAcute noninvasive hemodynamics after CRT device implantation predominantly favored MPP over BiV programming. MPP programming guided by noninvasive hemodynamics resulted in positive LV structural remodeling.

Oral loading of propafenone: restoring its role before restoring rhythm—authors’ reply

We wish to thank Martignani et al. 1 for their critical Letter to the Editor according to our article recently published in Europace 2 where they question our proposal that propafenone should not be generally excluded from cardioversion of paroxysmal atrial fibrillation in patients with structural heart disease. Recent 2016 European Society of Cardiology Guidelines for the Management of Atrial Fibrillation 3 support the use of propafenone for acute pharmacological cardioversion in patients with new onset of atrial fibrillation. However, their restriction that propafenone should only be given to patients without structural heart disease3 particularly bases on CAST (the Cardiac Arrhythmias Suppression Trial ), …

A randomized controlled clinical trial of pacemaker follow-up in clinic and by telemedical interpretation of the pacemakers' magnet mode

We assessed a two-stage follow-up procedure for cardiac pacemakers, where in-clinic follow-ups were partly replaced by telemedical follow-ups. This was compared with the standard follow-up regime (in-clinic follow-up only). The new procedure required an electronic patient record, a telemedical follow-up unit for recording ECGs while the pacemaker was temporarily set to magnet mode, an ECG processing unit, and a reviewing and reporting unit. A total of 177 (86 female) patients were randomized to the control group and 182 (98 female) patients to the telemedicine group. In the telemedicine group, 234 telemedical follow-ups were performed. Out of these, 68 required an additional in-clinic follow-up, while 166 were sufficient for assessing the pacemakers working status. During the study, there were 19 deaths in the telemedicine group and 20 in the control group. There was no significant difference between the two groups(Pu2009=u20090.40). The probability that an individual patient’s pacemaker would not to be replaced over time was analysed in a similar way to the Kaplan-Meier survival function. Fewer pacemakers were replaced in the telemedicine group (14) than in the control group (18), but the difference was not significant (Pu2009=u20090.26). We conclude that alternating telemedical and in-clinic follow-ups brings no additional risks for patients. The follow-up procedure is feasible and interpretation of the pacemakers’ magnet effect provides an easy-to-use, manufacturer-independent method of assessing the pacemakers’ working status. This should reduce the patient load on pacemaker centres and decrease the overall costs of pacemaker therapy.