Gerrit Eichner

Impact of age and basic heart rate on heart rate turbulence in healthy persons.

Postextrasystolic acceleration of heart rate (HR), known as HR turbulence (HRT) is attenuated in patients with coronary artery disease at increased risk of adverse events. The influence of age and basic HR on HRT have not been evaluated in a large cohort of persons. In 95 healthy individuals, HRT onset (TO) and slope (TS) were calculated from 24‐hour ambulatory electrocardiograms, as well as the turbulence timing (TT). Gender specific differences in TO and TS were compared in simple, linear, weighted regression model. The influence of age and the basic HR preceding ventricular premature contractions on HRT were examined. We found that, in men and women, TO decreases as basic HR increases (P < 0.01). In contrast, in men, TS decreased as basic HR increases, whereas in women, basic HR influenced TS only slightly (P < 0.01). A multiple, linear regression model revealed a decrease in HRT with increasing age in men. In conclusion, physiological acceleration of the HR within the first 11 beats after premature ventricular complex (VPC) was observed in >75% of healthy individuals. An accelerating HR preceding the VPC influenced HRT in men. An increasing age was associated with a decrease in HRT in men and a decrease in TO in women. These results illustrate the importance of physiological modulations of HRT when used for risk stratification, especially in older populations.

Influence of Basic Heart Rate and Sex on Heart Rate Turbulence in Healthy Subjects

Acceleration and deceleration of the heart rate after the occurrence of a ventricular premature complex is characterized as heart rate turbulence (HRT). Two parameters quantify heart rate turbulence: onset and slope. The physiological properties have not been clarified in a large cohort of persons yet. This study evaluated properties of HRT, and focused on the influence of basic heart rate and sex on HRT. Using a special protocol, 95 persons were studied prospectively. HRT and its physiological properties were determined in 95 persons using Holter ECGs. The authors found 24% with a turbulence onset 0% and 5% with a turbulence slope <2.5 ms/RRI. Mean heart rate during Holter differed significantly between women and men (745 vs 817 ms, P < 0.0001). A linear, weighted regression model revealed that an increased heart rate before a ventricular premature complex is associated with a decreased turbulence onset (P < 0.0001). Turbulence slope was attenuated by basic heart rate only in men (P = 0.0022). On the contrary, the study detected no influence of the basic heart rate on turbulence slope in women (P = 0.0015 for the comparison between women and men). Basic heart rate and sex show an influence on HRT and should be considered when using HRT for noninvasive risk stratification.

Phosphodiesterase 5 (PDE5) inhibition, ANP and NO rapidly reduce epididymal duct contractions, but long-term PDE5 inhibition in vivo does not

Contractility of the peritubular smooth muscle layer ensures the transit of immotile spermatozoa through the epididymal duct to acquire their fertilizing capacity. Atrial natriuretic peptide (ANP) and nitric oxide (NO) affect contractility via cGMP signals that are controlled by phosphodiesterases (PDEs). Sildenafil inhibits the cGMP-hydrolyzing PDE5 and thereby promotes relaxation of smooth muscle cells. While sildenafil is increasingly used in young patients for the treatment of pulmonary hypertension, virtually no knowledge exists about PDEs in the epididymis. Western blotting, immunohistochemistry and RT-PCR analyses after laser capture microdissection localized PDE5 to smooth muscle cells, but not to epithelial cells, of the epididymal duct in man and rat. Sildenafil, ANP and NO significantly slowed spontaneous contractions of rat epididymal duct segments in organ bath studies. Sildenafil effects were additive to ANP and NO. Long-term exposure to sildenafil in vivo did not change the PDE5 expression or the observed contractility pattern with the rapid relaxing response toward ANP, NO and sildenafil. Data demonstrate that PDE5 is an important member of cGMP signaling pathways regulating the finely orchestrated process of epididymal duct contractility and suggest, however, that in the epididymis side effects of therapeutically used sildenafil are unlikely.

Cre/lox-Recombinase-Mediated Cassette Exchange for Reversible Site-Specific Genomic Targeting of the Disease Vector, Aedes aegypti.

Site-specific genome modification (SSM) is an important tool for mosquito functional genomics and comparative gene expression studies, which contribute to a better understanding of mosquito biology and are thus a key to finding new strategies to eliminate vector-borne diseases. Moreover, it allows for the creation of advanced transgenic strains for vector control programs. SSM circumvents the drawbacks of transposon-mediated transgenesis, where random transgene integration into the host genome results in insertional mutagenesis and variable position effects. We applied the Cre/lox recombinase-mediated cassette exchange (RMCE) system to Aedes aegypti, the vector of dengue, chikungunya, and Zika viruses. In this context we created four target site lines for RMCE and evaluated their fitness costs. Cre-RMCE is functional in a two-step mechanism and with good efficiency in Ae. aegypti. The advantages of Cre-RMCE over existing site-specific modification systems for Ae. aegypti, phiC31-RMCE and CRISPR, originate in the preservation of the recombination sites, which 1) allows successive modifications and rapid expansion or adaptation of existing systems by repeated targeting of the same site; and 2) provides reversibility, thus allowing the excision of undesired sequences. Thereby, Cre-RMCE complements existing genomic modification tools, adding flexibility and versatility to vector genome targeting.

Temporal dynamics of whole body residues of the neonicotinoid insecticide imidacloprid in live or dead honeybees

In cases of acute intoxication, honeybees often lay in front of their hives for several days, exposed to sunlight and weather, before a beekeeper can take a sample. Beekeepers send samples to analytical laboratories, but sometimes no residues can be detected. Temperature and sun light could influence the decrease of pesticides in bee samples and thereby residues left for analysis. Moreover, samples are usually sent via normal postal services without cooling. We investigated the temporal dynamics of whole-body residues of imidacloprid in live or dead honeybees following a single-meal dietary exposure of 41 ng/bee under various environmental conditions, such as freezing, exposure to UV light or transfer of individuals through the mail system. Immobile, “dead” looking honeybees recovered from paralysis after 48 hours. The decrease of residues in living but paralysed bees was stopped by freezing (= killing). UV light significantly reduced residues, but the mode of transport did not affect residue levels. Group feeding increased the variance of residues, which is relevant for acute oral toxicity tests. In conclusion, elapsed time after poisoning is key for detection of neonicotinoids. Freezing before mailing significantly reduced the decrease of imidacloprid residues and may increase the accuracy of laboratory analysis for pesticides.

Heart rate variability in patients suffering from structural heart disease and decreased AV-nodal conduction capacity. Insights into the formation of heart rate variability.

Eingeschränkte Oszillationen der Herzfrequenz, d. h. eine reduzierte Herzfrequenzvariabilität (HRV), gehen mit einem erhöhten Mortalitätsrisiko bei Patienten mit struktureller Herzerkrankung einher. Weiterhin zeigt dieses Patientenkollektiv häufig Störungen des Erregungsleitungssystems. In wie weit bei Patienten mit struktureller Herzerkrankung und solchen Erregungsleitungsstörungen eine Analyse der Herzfrequenzvariabilität sinnvoll und aussagekräftig erscheint, wurde bisher noch nicht untersucht. In der vorliegenden Studie untersuchten wir bei 20 konsekutiven Patienten, die einer elektrophysiologischen Untersuchung zugeführt wurden, neben der HRV das genaue Zustandekommen der HRV und den Einfluss kardialer Parameter auf die HRV. Mittels eines 5 stufigen Protokolls untersuchten wir bei unseren Patienten die Zeitund Frequenzspektrum-Parameter der HRV: 1: Ruheaufnahme bei normalem Sinusrhythmus (SR1). 2: AAI-Stimulation (AAI) mit einer Frequenz von 15% oberhalb der intrinsischen Herzfrequenz. 3: VAT-Stimulation (VAT) mit einem sehr kurzen AV-Intervall. 4: DDD-Stimulation (DDD) mit einer Stimulationsfrequenz von 15% oberhalb des intrinsischen Rhythmus und einem kurzen AV-Intervall. 5: Abschlussaufnahme bei normalem Sinusrhythmus (SR2). Jede Aufnahmephase dauerte 600s und wurde in Rückenlage durchgeführt. Patienten mit höhergradigen AV-Blockierungen (II° oder III°) wurden ausgeschlossen. Die HRV-Parameter während der Phasen SR1 und SR2 zeigten keine Unterschiede. Bei funktionellem Ausschluss des AV-Knotens (VAT-Modus) war die HRV verglichen mit der SR1-Phase nicht unterschiedlich. Unter funktionellem Ausschluss des Sinusknotens (AAI-Modus) zeigte sich ein signifikanter Unterschied für SDNN und r-MSSD (p < 0,001). Auch waren die Phasen AAI und VAT signifikant verschieden (p < 0,001). Die HRV während DDD war ebenso kleiner im Vergleich zu AAI (p < 0,04). Das Vorliegen einer strukturellen Herzerkrankung, die Einschränkung der linksventrikulären Pumpleistung von < 50% sowie das Vorliegen einer nicht anhaltenden ventrikulären Tachykardie im Langzeit-EKG hatte keinen signifikanten Einfluss auf die HRV in den unterschiedlichen Phasen der Stimulation. Der mittlere Wenckebachpunkt der Patienten mit struktureller Herzerkrankung war größer als der nicht strukturell Herzkranken (437 ms vs. 350 ms, p = 0,05). Veränderungen des Wenckebachpunkts waren nicht mit einer Veränderung der HRV korreliert (p = ns). Die Herzfrequenzvariabilität ist im Wesentlichen durch die Impulsformationen des Sinusknotens bestimmt. Eine Leitungsvariabilität des AV-Knotens existiert zwar, ist jedoch unter klinischen Bedingungen vernachlässigbar. Daher kann bei Patienten mit struktureller Herzerkrankung mit oder ohne dem Vorliegen einer moderaten AV-Knoten-Überleitungsstörung die Herzfrequenzvariabilität als Teil der nicht invasiven Risikostratifikation bestimmt und bewertet werden. Attenuation of the oscillation of the heart rate, i. e. heart rate variability (HRV), is associated with an increased risk for mortality in patients with structural heart disease. Many of these patients also suffer from conduction disturbances, e. g. AV-nodal conduction delays. Whether the calculation of HRV in those patients is recommendable has not been investigated yet. Therefore, we conducted a study consisting of 20 consecutive patients in order to determine the formation of HRV, the influence of structural heart disease, the presence of a nonsustained ventricular tachycardia (VT), and a reduced ejection fraction (EF) on the HRV parameters during an elective electrophysiologic study. Time and frequency domain analysis were conducted during a period of 600 s each. We performed a special protocol consisting of five different “pacing” periods: 1) recording of normal sinus rhythm (SR1); 2) atrial pacing with a rate 15% higher than the intrinsic heart rate; 3) ventricular pacing triggered by atrial activation (VAT, with a short AV-delay of 80 ms); 4) AV-sequential pacing with an atrial rate 15% higher than the intrinsic heart rate and a very short AV delay of 80 ms (DDD); 5) normal sinus rhythm (SR2). Only patients with normal AVnodal conduction or with AV-block I° were included. The influence of a structural heart disease as well as a non-sustained VT on Holter ECG and a depressed EF on HRV parameters were analyzed using a multivariate analysis. All patients were lying in a supine position. Blood pressure was measured continuously and the frequency of breathing was controlled. No differences in HRV between the two sinus rhythm periods SR1 versus SR2 could be detected. Neither SR1 vs VAT showed a significant difference for SDNN and r-MSSD. In contrast, HRV during SR1 compared to AAI, and HRV during VAT compared to AAI were significantly different (p < 0.001). When comparing HRV during DDD, which should be zero, and AAI, we found a significantly lower SDNN and r-MSSD (1.2 ms vs 4 ms, p < 0.04). The presence of structural heart disease, a non-sustained ventricular tachycardia, a depressed ejection fraction of less than 0.50 did not reveal a significant influence on the HRV parameters (multivariate analysis). The mean Wenckebach in patients with structural heart disease tended to be greater (437 ms vs 350 ms, p = 0.05); an increase in theWenckebach was not correlated to a change in HRV parameters (p = ns). Heart rate variability derived from consecutive RR-intervals is predominantly caused by periodicity in sinusnode impulse formation. A conduction variability of the AV-node exists, but is very low. The presence of a structural heart disease, a non-sustained ventricular tachycardia on Holter ECG, as well as a depressed ejection fraction of less than 0.50 showed no significant influence on the HRV parameters. Therefore, one can apply the calculation of heart rate variability for risk stratification in patients suffering from structural heart disease and moderate AV-nodal conduction disturbances.

Heart rate variability in patients suffering from structural heart disease and decreased AV-nodal conduction capacity

Eingeschränkte Oszillationen der Herzfrequenz, d. h. eine reduzierte Herzfrequenzvariabilität (HRV), gehen mit einem erhöhten Mortalitätsrisiko bei Patienten mit struktureller Herzerkrankung einher. Weiterhin zeigt dieses Patientenkollektiv häufig Störungen des Erregungsleitungssystems. In wie weit bei Patienten mit struktureller Herzerkrankung und solchen Erregungsleitungsstörungen eine Analyse der Herzfrequenzvariabilität sinnvoll und aussagekräftig erscheint, wurde bisher noch nicht untersucht. In der vorliegenden Studie untersuchten wir bei 20 konsekutiven Patienten, die einer elektrophysiologischen Untersuchung zugeführt wurden, neben der HRV das genaue Zustandekommen der HRV und den Einfluss kardialer Parameter auf die HRV. Mittels eines 5 stufigen Protokolls untersuchten wir bei unseren Patienten die Zeitund Frequenzspektrum-Parameter der HRV: 1: Ruheaufnahme bei normalem Sinusrhythmus (SR1). 2: AAI-Stimulation (AAI) mit einer Frequenz von 15% oberhalb der intrinsischen Herzfrequenz. 3: VAT-Stimulation (VAT) mit einem sehr kurzen AV-Intervall. 4: DDD-Stimulation (DDD) mit einer Stimulationsfrequenz von 15% oberhalb des intrinsischen Rhythmus und einem kurzen AV-Intervall. 5: Abschlussaufnahme bei normalem Sinusrhythmus (SR2). Jede Aufnahmephase dauerte 600s und wurde in Rückenlage durchgeführt. Patienten mit höhergradigen AV-Blockierungen (II° oder III°) wurden ausgeschlossen. Die HRV-Parameter während der Phasen SR1 und SR2 zeigten keine Unterschiede. Bei funktionellem Ausschluss des AV-Knotens (VAT-Modus) war die HRV verglichen mit der SR1-Phase nicht unterschiedlich. Unter funktionellem Ausschluss des Sinusknotens (AAI-Modus) zeigte sich ein signifikanter Unterschied für SDNN und r-MSSD (p < 0,001). Auch waren die Phasen AAI und VAT signifikant verschieden (p < 0,001). Die HRV während DDD war ebenso kleiner im Vergleich zu AAI (p < 0,04). Das Vorliegen einer strukturellen Herzerkrankung, die Einschränkung der linksventrikulären Pumpleistung von < 50% sowie das Vorliegen einer nicht anhaltenden ventrikulären Tachykardie im Langzeit-EKG hatte keinen signifikanten Einfluss auf die HRV in den unterschiedlichen Phasen der Stimulation. Der mittlere Wenckebachpunkt der Patienten mit struktureller Herzerkrankung war größer als der nicht strukturell Herzkranken (437 ms vs. 350 ms, p = 0,05). Veränderungen des Wenckebachpunkts waren nicht mit einer Veränderung der HRV korreliert (p = ns). Die Herzfrequenzvariabilität ist im Wesentlichen durch die Impulsformationen des Sinusknotens bestimmt. Eine Leitungsvariabilität des AV-Knotens existiert zwar, ist jedoch unter klinischen Bedingungen vernachlässigbar. Daher kann bei Patienten mit struktureller Herzerkrankung mit oder ohne dem Vorliegen einer moderaten AV-Knoten-Überleitungsstörung die Herzfrequenzvariabilität als Teil der nicht invasiven Risikostratifikation bestimmt und bewertet werden. Attenuation of the oscillation of the heart rate, i. e. heart rate variability (HRV), is associated with an increased risk for mortality in patients with structural heart disease. Many of these patients also suffer from conduction disturbances, e. g. AV-nodal conduction delays. Whether the calculation of HRV in those patients is recommendable has not been investigated yet. Therefore, we conducted a study consisting of 20 consecutive patients in order to determine the formation of HRV, the influence of structural heart disease, the presence of a nonsustained ventricular tachycardia (VT), and a reduced ejection fraction (EF) on the HRV parameters during an elective electrophysiologic study. Time and frequency domain analysis were conducted during a period of 600 s each. We performed a special protocol consisting of five different “pacing” periods: 1) recording of normal sinus rhythm (SR1); 2) atrial pacing with a rate 15% higher than the intrinsic heart rate; 3) ventricular pacing triggered by atrial activation (VAT, with a short AV-delay of 80 ms); 4) AV-sequential pacing with an atrial rate 15% higher than the intrinsic heart rate and a very short AV delay of 80 ms (DDD); 5) normal sinus rhythm (SR2). Only patients with normal AVnodal conduction or with AV-block I° were included. The influence of a structural heart disease as well as a non-sustained VT on Holter ECG and a depressed EF on HRV parameters were analyzed using a multivariate analysis. All patients were lying in a supine position. Blood pressure was measured continuously and the frequency of breathing was controlled. No differences in HRV between the two sinus rhythm periods SR1 versus SR2 could be detected. Neither SR1 vs VAT showed a significant difference for SDNN and r-MSSD. In contrast, HRV during SR1 compared to AAI, and HRV during VAT compared to AAI were significantly different (p < 0.001). When comparing HRV during DDD, which should be zero, and AAI, we found a significantly lower SDNN and r-MSSD (1.2 ms vs 4 ms, p < 0.04). The presence of structural heart disease, a non-sustained ventricular tachycardia, a depressed ejection fraction of less than 0.50 did not reveal a significant influence on the HRV parameters (multivariate analysis). The mean Wenckebach in patients with structural heart disease tended to be greater (437 ms vs 350 ms, p = 0.05); an increase in theWenckebach was not correlated to a change in HRV parameters (p = ns). Heart rate variability derived from consecutive RR-intervals is predominantly caused by periodicity in sinusnode impulse formation. A conduction variability of the AV-node exists, but is very low. The presence of a structural heart disease, a non-sustained ventricular tachycardia on Holter ECG, as well as a depressed ejection fraction of less than 0.50 showed no significant influence on the HRV parameters. Therefore, one can apply the calculation of heart rate variability for risk stratification in patients suffering from structural heart disease and moderate AV-nodal conduction disturbances.

Rank transformations in Kernel density estimation

We introduce and study a kernel density estimator which takes into account not only the local information contained in the data, but also their global structure given through the ranks. The approach allows for an adaptive choice of the smoothing parameters which avoids estimation of higher order derivatives. Our methodology also leads to a new isoperimetric problem which seems to be of independent interest. While in traditional kernel smoothing efficiency is obtained by choosing proper kernels, this role is now played by appropriate rank transformations.

Low testosterone in ApoE/LDL receptor double-knockout mice is associated with rarefied testicular capillaries together with fewer and smaller Leydig cells

The testis as a site for atherosclerotic changes has so far attracted little attention. We used the apolipoprotein E (ApoE)/low density lipoprotein (LDL) receptor deficient mouse model (KO) for atherosclerosis (20, 40, 60 and 87-week-old) to investigate whether Leydig cells or the capillary network are responsible for reduced serum testosterone levels previously observed in extreme ages of this model. In KO mice, overall testosterone levels were reduced whereas the adrenal gland-specific corticosterone was increased excluding a general defect of steroid hormone production. In addition to micro-CT investigations for bigger vessels, stereology revealed a reduction of capillary length, volume and surface area suggesting capillary rarefaction as a factor for diminished testosterone. Stereological analyses of interstitial cells demonstrated significantly reduced Leydig cell numbers and size. These structural changes in the testis occurred on an inflammatory background revealed by qPCR. Reduced litter size of the KO mice suggests hypo- or infertility as a consequence of the testicular defects. Our data suggest reduced testosterone levels in this atherosclerosis model might be explained by both, rarefication of the capillary network and reduced Leydig cell number and size. Thus, this study calls for specific treatment of male infertility induced by microvascular damage through hypercholesterolemia and atherosclerosis.

Kader—An R Package for Nonparametric Kernel Adjusted Density Estimation and Regression

In a series of three papers published from 2011 through 2013, Stute and coauthors introduced a fully data-adaptive nonparametric kernel method for pointwise univariate density estimation and likewise for regression estimation. For density estimation a robustified version of this adaptive method was also provided and the pointwise method was extended to an \(L_2\)-approach. Here, an R package is presented that implements (so far) parts of those methods. This package is a first attempt to narrow the gap between the theoretical derivation of the methods and their availability for practical applications.