BackgroundAbnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium... Show moreBackgroundAbnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium to long term after MI are sparse. Histologic quantification of the small-sized cardiac nerves is challenging, and transmural analysis has not been performed.ObjectivesThis study sought to assess cardiac innervation patterns in transmural biopsy sections in a porcine reperfusion model of MI (MI-R) using a novel method for nerve quantification.MethodsTransmural biopsy sections from 4 swine (n = 83) at 3 months after MI-R and 3 controls (n = 38) were stained with picrosirius red (fibrosis) and beta-III-tubulin (autonomic nerves). Biopsy sections were classified as infarct core, border zone, or remote zone. Each biopsy section was analyzed with a custom software pipeline, allowing calculation of nerve density and classification into innervation types at the 1 × 1–mm resolution level. Relocation of the classified squares to the original biopsy position enabled transmural quantification and innervation heterogeneity assessment.ResultsCoexisting hyperinnervation, hypoinnervation, and denervation were present in all transmural MI-R biopsy sections. The innervation heterogeneity was greatest in the infarct core (median: 0.14; IQR: 0.12-0.15), followed by the border zone (median: 0.05; IQR: 0.04-0.07; P = 0.02) and remote zone (median: 0.02; IQR: 0.02-0.03; P < 0.0001). Only in the border zone was a positive linear relation between fibrosis and innervation heterogeneity observed (R = 0.79; P < 0.0001).ConclusionsThis novel method allows quantification of nerve density and heterogeneity in large transmural biopsy sections. In the chronic phase after MI-R, alternating innervation patterns were identified within the same biopsy section. Persistent innervation heterogeneity, in particular in the border zone biopsy sections, may contribute to late arrhythmogenicity. Show less
Background: Optogenetics could offer a solution to the current lack of an ambulatory method for the rapid automated cardioversion of atrial fibrillation (AF), but key translational aspects remain... Show moreBackground: Optogenetics could offer a solution to the current lack of an ambulatory method for the rapid automated cardioversion of atrial fibrillation (AF), but key translational aspects remain to be studied. Objective: To investigate whether optogenetic cardioversion of AF is effective in the aged heart and whether sufficient light penetrates the human atrial wall. Methods: Atria of adult and aged rats were optogenetically modified to express light-gated ion channels (i.e., red-activatable channelrhodopsin), followed by AF induction and atrial illumination to determine the effectivity of optogenetic cardioversion. The irradiance level was determined by light transmittance measurements on human atrial tissue. Results: AF could be effectively terminated in the remodeled atria of aged rats (97%, n = 6). Subsequently, ex vivo experiments using human atrial auricles demonstrated that 565-nm light pulses at an intensity of 25 mW/mm(2) achieved the complete penetration of the atrial wall. Applying such irradiation onto the chest of adult rats resulted in transthoracic atrial illumination as evidenced by the optogenetic cardioversion of AF (90%, n = 4). Conclusion: Transthoracic optogenetic cardioversion of AF is effective in the aged rat heart using irradiation levels compatible with human atrial transmural light penetration. Show less
Berger, F.A.; Weteringen, W. van; Sijs, H. van der; Hunfeld, N.G.M.; Bunge, J.J.H.; Groot, N.M.S. de; ... ; Gelder, T. van 2021
QTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in... Show moreQTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in critically ill patients. Critically ill patients may be more vulnerable to developing QTc prolongation, as several risk factors can be present at the same time. Therefore, it is important to know the QTc-prolonging potential of these drugs in the intensive care unit (ICU) population. The aim of this study was to assess the dynamics of the QTc interval over a 24-hour dose interval during intravenous ciprofloxacin and low-dose erythromycin treatment. Therefore, an observational study was performed in ICU patients (>= 18 years) receiving ciprofloxacin 400 mg t.i.d. or erythromycin 100 mg b.i.d. intravenously. Continuous ECG data were collected from 2 h before to 24 h after the first administration. QT-analyses were performed using high-end holter software. The effect was determined with a two-sample t-test for clustered data on all QTc values. A linear mixed model by maximum likelihood was applied, for which QTc values were assessed for the available time intervals and therapy. No evident effect over time on therapy with ciprofloxacin and erythromycin was observed on QTc time. There was no significant difference (p = 0.22) in QTc values between the ciprofloxacin group (mean 393 ms) and ciprofloxacin control group (mean 386 ms). The erythromycin group (mean 405 ms) and erythromycin control group (mean 404 ms) neither showed a significant difference (p = 0.80). In 0.6% of the registrations (1.138 out of 198.270 samples) the duration of the QTc interval was longer than 500 ms. The index groups showed slightly more recorded QTc intervals over 500 ms. To conclude, this study could not identify differences in the QTc interval between the treatments analyzed. Show less
Aims To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European... Show moreAims To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries. Methods Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. Results A total of 186 405 new DOAC users (age >= 18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). Conclusion Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH). Show less
