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Klaus Tiemann

Publications and source records attributed to Klaus Tiemann.

At least 19 recordsLinked to original sources

Cardiac morphogenetic defects and conduction abnormalities in mice homozygously deficient for connexin40 and heterozygously deficient for connexin45.

Connexin40 (Cx40) and connexin45 (Cx45) are involved in both cardiac morphogenesis and propagation of electrical activity. We found that Cx40/Cx45 double deficiency (Cx40(-/-)/Cx45(+/-)) causes a variety of cardiac defects leading to high mortality during embryonic development and at birth. The majority of Cx40(-/-)/Cx45(+/-) embryos and postnatal mice suffered from atrioventricular septal defects. Additional cardiac abnormalities, e.g., ventricular septal defects and abnormal myocardial arrangement, occurred at lower abundance. Electrocardiograms of Cx40(-/-)/Cx45(+/+) and Cx40(-/-)/Cx45(+/-) mice revealed prolongation of P-wave, PQ interval and QRS duration compared to controls. Interestingly, in Cx40(-/-)/Cx45(+/-) mice, PQ interval and QRS duration were significantly prolonged compared to Cx40(-/-)/Cx45(+/+) mice. We conclude that the gap junctional proteins Cx40 and Cx45 have overlapping and partially compensatory functions with regard to heart morphogenesis and cardiac conduction. Cx45 might be one of the genetic modifiers that can cause variations in the phenotype of connexin40-deficient animals. Our findings may be particularly relevant for understanding molecular factors contributing to human congenital cardiac diseases.

Animals↗

Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node.

In the mammalian heart, gap junction channels between electrically coupled cardiomyocytes are necessary for impulse propagation and coordinated contraction of atria and ventricles. Recently, mouse connexin30.2 (Cx30.2) was shown to be expressed in the cardiac conduction system, predominantly in sinoatrial and atrioventricular (AV) nodes. The corresponding gap junctional channels expressed in HeLa cells exhibit the lowest unitary conductance (9 pS) of all connexin channels. Here we report that Cx30.2 slows down the propagation of excitation through the AV node. Mice expressing a LacZ reporter gene instead of the Cx30.2 coding region (Cx30.2(LacZ/LacZ)) exhibit a PQ interval that is approximately 25% shorter than in WT littermates. By recording atrial, His, and ventricular signals with intracardiac electrodes, we show that this decrease is attributed to significantly accelerated conduction above the His bundle (atrial-His interval: 27.9 +/- 5.1 ms in Cx30.2(LacZ/LacZ) versus 37.1 +/- 4.1 ms in Cx30.2(+/+) mice), whereas HV conduction is unaltered. Atrial stimulation revealed an elevated AV-nodal conduction capacity and faster ventricular response rates during induced episodes of atrial fibrillation in Cx30.2(LacZ/LacZ) mice. Our results show that Cx30.2 contributes to the slowdown of impulse propagation in the AV node and additionally limits the maximum number of beats conducted from atria to ventricles. Thus, it is likely to be involved in coordination of atrial and ventricular contraction and to fulfill a protective role toward pathophysiological states such as atrial tachyarrhythmias (e.g., atrial fibrillation) by preventing rapid conduction to the ventricles potentially associated with hemodynamic deterioration.

Animals↗

Age and gender related reference values for transthoracic Doppler-echocardiography in the anesthetized CD1 mouse.

OBJECTIVE: Doppler-echocardiography of the mouse has evolved to a commonly used technique in the past years as recent advances in imaging quality have substantially improved spatial and temporal resolution allowing the adaptation of this technique to murine models. Although mouse echocardiography is widely used, there is only little information on reference data for wild-type animals available, particularly in older mice. METHODS: We therefore established a database with echocardiographic reference-values in a large set of young (8 weeks) and older adult (52 weeks) Swiss type CD1-mice of either sex. We performed a complete Doppler-echocardiographic examination under light Ketamine-Xylazine-anesthesia. LV-mass was calculated and compared with necropsy heart weights to validate the LV-mass calculation. RESULTS: Doppler-echocardiographic measurements in mice were feasible to assess cardiac morphology and function. Sonomorphological and functional parameters hardly changed between the age of 12 and 52 weeks. Wall thickness, LV-mass and cardiac output were stable with aging. There was a good relative correlation between echocardiographically estimated LV-mass and necropsy heart weight although absolute values differed. There were no significant echocardiographic differences between male and female mice. CONCLUSIONS: The reference values established in this study can be useful in recording and quantifying pathological changes in murine models of cardiovascular diseases. There is hardly any change of cardiac function between the age of 12 and 52 weeks.

Age Factors↗

Connexin31 cannot functionally replace connexin43 during cardiac morphogenesis in mice.

In the gastrulating mouse embryo, the gap junction protein connexin43 is expressed exclusively in cells derived from the inner cell mass, whereas connexin31 is expressed in cells of the trophoblast lineage. Since connexin43 and connexin31 do not form heterotypic gap junction channels in exogenous expression systems, such as HeLa cells and Xenopus oocytes, previous studies have suggested that the incompatibility of these two connexins could contribute to the separation of connexin43-expressing and connexin31-expressing compartments between embryo and extraembryonic tissues at gastrulation, respectively. Thus, we have generated connexin43 knock-in connexin31 mice, in which the coding region of the connexin43 gene was replaced by that of connexin31. Interbreeding of heterozygous connexin43 knock-in connexin31 mice resulted in homozygous connexin43 knock-in connexin31 mice, but none of them survived to adulthood. As these mice were born at the expected Mendelian frequency, we conclude that the reported incompatibility of connexin43 and connexin31 to form heterotypic gap junction channels does not interfere with normal embryonic development. Neonatal homozygous connexin43 knock-in connexin31 hearts showed malformation in the subpulmonary outlet of the right ventricle, similar to general connexin43-deficient mice. Electrocardiograms of neonatal hearts in homozygous connexin43 knock-in connexin31 mice revealed significantly low voltage of the QRS complex. This is in contrast to previous results from our laboratory which showed that replacement of connexin43 by connexin40 resulted in morphologically and functionally normal hearts. We conclude that connexin31 cannot functionally replace connexin43 during cardiac morphogenesis.

Animals↗

Persistence of iatrogenic atrial septal defect after pulmonary vein isolation--an underestimated risk?

BACKGROUND: According to present knowledge, pulmonary vein isolation (PVI) bears a low interventional risk and has a high feasibility. For completion of PVI, left atrial access is achieved via single or double transseptal puncture. We sought to determine the incidence and echocardiographic characteristics of persistent iatrogenic atrial septal defect (iASD) after PVI. Further objectives were to define clinical and periprocedural risk factors for the development of iASD. METHODS: Every patient admitted for PVI at our hospital was screened for eligibility for study participation. Exclusion criteria were inability for undergoing transesophageal echocardiography, preexisting atrial septal defect, open-heart surgery or another transseptal procedure during the follow-up period. Transesophageal echocardiography was performed before PVI and after 9 months. Interatrial shunt was characterized by echocardiographic parameters; right-to-left-shunting (RLS) was quantified by contrast echocardiography. RESULTS: Forty-two patients were included, 27 patients underwent PVI with single transseptal puncture and additional advancement of a second electrophysiologic catheter (group A) 15 patients underwent PVI with double transseptal puncture (group B). In 8 patients of group A, iASD persisted after the follow-up period, including 6 patients with distinct RLS. We saw no iASD in group B (P = .011, CI -0.79 to -0.11). Preprocedural pulmonary artery pressure was significantly higher in patients with iASD and accompanying RLS, compared with patients with iASD and no evidence of RLS (23.75 +/- 0.50 vs 17.59 +/- 5.82, P = .048, CI 0.048-12.27). CONCLUSION: This is the first study that demonstrates a high incidence of long-term persistent iatrogenic atrial septal defect with RLS after PVI. All interatrial shunts occurred after single transseptal puncture with passage of 2 electrophysiologic catheters into the left atrium. Increased preprocedural pulmonary artery pressure seems to promote the occurrence of RLS across iASD.

Adult↗

Paroxysmal atrial flutter caused by cardiac lymphoma.

Atrial flutter is a relatively frequent macro-reentrant tachycardia that can be caused by a variety of structural and functional atrial changes. Cardiac lymphoma is rare and usually carries a poor prognosis. It preferentially involves the right atrium. This report describes a patient with cardiac follicular B-cell lymphoma who developed paroxysmal atrial flutter. The large tumor mass created a macroscopic substrate for an area of slow conduction which is essential for atrial flutter. It also caused sinus arrest and intermittent obstruction of the tricuspid valve inlet.

Aged↗

Echocardiographic assessment of left ventricular mass in neonatal and adult mice: accuracy of different echocardiographic methods.

Echocardiography is an established method to estimate left-ventricular mass (LVM) in mice. Accuracy is determined by cardiac size and morphology and influenced by mathematical models. We investigated accuracy of three common algorithms in three early developmental stages. High-resolution echocardiography was performed in 35 C57/BL6-mice. Therefore, two-dimensional-guided M-mode echocardiography and parasternal short- and long-axis views in B-mode were obtained. LVM was assessed in vivo applying Penn (P), Area Length (AL), and Truncated Ellipsoid (TE) algorithms and validated with histomorphometry. Regression analysis of all mice showed fair estimation of LVM assessed with M-mode-based Penn algorithm (y = 0.6*x - 0.12, r: 0.71). In contrast two-dimensional assessment of LVM revealed close linear relationship with histomorphometry (y(AL)= 1.21*x - 12.1, r: 0.88, y(TE)= 1.38*x - 2.88, r: 0.86). Bias was lowest for LVM-AL at diastole underestimating 3.2%. In concordance with the summarized data, LVM-P revealed lower regression coefficients and significant underestimation in all three subgroups. Small hearts (<50 mg, n = 12) correlated best with LVM-AL at systole. Hearts of adolescent (50-75 mg, n = 13) and adult (75-100 mg, n = 10) mice revealed close linear relationship with LVM-AL and LVM-TE at diastole. Echocardiographic assessment of LVM is feasible in hearts weighting less than 50 mg and can be estimated best in systole. Hearts weighting more than 50 mg are estimated most accurately by means of LVM-AL at diastole.

Algorithms↗

Gold-tip electrodes--a new "deep lesion" technology for catheter ablation? In vitro comparison of a gold alloy versus platinum-iridium tip electrode ablation catheter.

Gold-tip electrodes. Radiofrequency (RF) catheter ablation is widely used to induce focal myocardial necrosis using the effect of resistive heating through high-frequency current delivery. It is current standard to limit the target tissue-electrode interface temperature to a maximum of 60-70 degrees C to avoid char formation. Gold (Au) exhibits a thermal conductivity of nearly four times greater than platinum (Pt-Ir) (3.17 W/cm Kelvin vs 0.716 W/cm Kelvin), it was therefore hypothesized that RF ablation using a gold electrode would create broader and deeper lesions as a result of a better heat conduction from the tissue-electrode interface and additional cooling of the gold electrode by "heat loss" to the intracardiac blood. Both mechanisms would allow applying more RF power to the tissue before the electrode-tissue interface temperature limit is reached. To test this hypothesis, we performed in vitro isolated liver and pig heart investigations comparing lesion depths of a new Au-alloy-tip electrode to standard Pt-Ir electrode material. Mean lesion depth in liver tissue for Pt-Ir was 4.33+/-0.45 mm (n=60) whereas Au electrode was able to achieve significantly deeper lesions (5.86+/-0.37 mm [n=60; P<0.001]). The mean power delivered using Pt-Ir was 6.95+/-2.41 W whereas Au tip electrode delivered 9.64+/-3.78 W indicating a statistically significant difference (P<0.05). In vitro pig heart tissue Au ablation (n=20) increased significantly the lesion depth (Au: 4.85+/-1.01 mm, Pt-Ir: 2.96+/-0.81 mm, n=20; P<0.001). Au tip electrode again applied significantly more power (P<0.001). Gold-tip electrode catheters were able to induce deeper lesions using RF ablation in vitro as compared to Pt-Ir tip electrode material. In liver and in pig heart tissue, the increase in lesion depth was associated with a significant increase in the average power applied with the gold electrode at the same level of electrode-tissue temperature as compared to platinum material.

Animals↗

Defective epidermal barrier in neonatal mice lacking the C-terminal region of connexin43.

More than 97% of mice in which the C-terminal region of connexin43 (Cx43) was removed (designated as Cx43K258stop) die shortly after birth due to a defect of the epidermal barrier. The abnormal expression of Cx43K258stop protein in the uppermost layers of the epidermis seems to perturb terminal differentiation of keratinocytes. In contrast to Cx43-deficient mice, neonatal Cx43K258stop hearts show no lethal obstruction of the right ventricular outflow tract, but signs of dilatation. Electrocardiographies of neonatal hearts reveal repolarization abnormalities in 20% of homozygous Cx43K258stop animals. The very rare adult Cx43K258stop mice show a compensation of the epidermal barrier defect but persisting impairment of cardiac function in echocardiography. Female Cx43K258stop mice are infertile due to impaired folliculogenesis. Our results indicate that the C-terminally truncated Cx43K258stop mice lack essential functions of Cx43, although the truncated Cx43 protein can form open gap junctional channels.

Animals↗

Establishment of an orthotopic tumour model for hepatocellular carcinoma and non-invasive in vivo tumour imaging by high resolution ultrasound in mice.

BACKGROUND/AIMS: In this study we established an orthotopic tumour model for hepatocellular carcinoma and evaluated a non-invasive high resolution ultrasound technique for diagnosis and follow-up of intrahepatic HCC. METHODS: Orthotopic liver tumours were induced by intrahepatic tumour cell injection of 10(5) Hepa129 hepatoma cells. Tumour establishment and growth were assessed by explorative laparotomy, ultrasound technique and hepatectomy one and two weeks after tumour cell implantation. Tumour establishment was confirmed histologically in liver sections. RESULTS: Our results show that the Hepa129 hepatoma cell line is suitable for orthotopic tumour establishment and that tumours can be diagnosed correctly by ultrasound imaging in all cases as confirmed by explorative laparotomy, hepatectomy and cross-sections. Tumour diameters obtained by explorative laparotomy correlated significantly with diameters assessed by ultrasound (r=0.7; P<0.0001). Tumour burden was slightly overestimated (1.2-fold) by ultrasound one week after tumour induction and relative tumour extensions increased 1.7-fold and 1.8-fold within one week as determined by subsequent explorative laparotomy or ultrasound imaging, respectively. CONCLUSIONS: These data demonstrate in a systematic study that ultrasound imaging can be used as a reliable tool to detect and to follow up orthotopic liver tumours in this tumour model in mice.

Animals↗

Vascular flow and perfusion imaging with ultrasound contrast agents.

Current techniques for imaging ultrasound (US) contrast agents (UCA) make no distinction between low-velocity microbubbles in the microcirculation and higher-velocity microbubbles in the larger vasculature. A combination of radiofrequency (RF) and Doppler filtering on a low mechanical index (MI) pulse inversion acquisition is presented that differentiates low-velocity microbubbles (on the order of mm/s) associated with perfusion, from the higher-velocity microbubbles (on the order of cm/s) in larger vessels. In vitro experiments demonstrate the ability to separate vascular flow using both harmonic and fundamental Doppler signals. Fundamental and harmonic Doppler signals from microbubbles using a low-MI pulse-inversion acquisition are compared with conventional color Doppler signals in vivo. Due to the lower transmit amplitude and enhanced backscatter from microbubbles, the in vivo signal to clutter ratios for both the fundamental (-11 dB) and harmonic (-4 dB) vascular flow signals were greater than with conventional power Doppler (-51 dB) without contrast agent. The processing investigated here, in parallel with conventional pulse-inversion processing, enables the simultaneous display of both perfusion and vascular flow. In vivo results demonstrating the feasibility and potential utility of the real-time display of both perfusion and vascular flow using US contrast agents are presented and discussed.

Algorithms↗

In vitro and in vivo studies on continuous echo-contrast application strategies using SonoVue in a newly developed rotating pump setup.

With emerging imaging strategies for contrast sonography (CS), there is a rising demand for the precise control of ultrasound (US) contrast agent delivery. Constant delivery minimizes artefacts and improves efficacy. The aim of this study was to evaluate the physical properties of the new contrast agent SonoVue and to evaluate the feasibility and accuracy of a new infusion approach using an automated infusion system for contrast agitation and delivery of echo-contrast agents. In vitro testing of infusion properties of SonoVue were performed in a capillary phantom mimicking tissue perfusion. Nonagitated standard infusion setups were compared with hand agitation and the new pump system with respect to possible artefacts, constancy of contrast effect and efficacy. In three volunteers, the new pump system was tested for constancy of contrast in large vessels. Without continuous agitation, continuous infusion of SonoVue resulted in bolus-like signal-intensity curves, along with substantial imaging artefacts. Additionally, homogenization of SonoVue significantly improved efficacy (p < 0.0001). No significant differences were found between hand agitation and homogenization by the new pump. In clinical settings, constant agitation using the new pump resulted in constant signal conditions in the carotid artery 3.72 +/- 0.46 units (U) after 5 min. Continuous agitation of SonoVue is mandatory for quantitative approaches. By the new infusion technique, CS could be performed for a reasonably long time period and efficacy is significantly improved (p < 0.0001). The new infusion technique might thereby allow routine application of constant infusion scenarios in clinical CS.

Capillaries↗

Intratumoral immunization with tumor RNA-pulsed dendritic cells confers antitumor immunity in a C57BL/6 pancreatic murine tumor model.

Pancreatic tumors lack adequate recruitment of immunocompetent cells, especially dendritic cells (DCs). We have shown previously that coculturing of natural killer-like T cells with DCs transfected with pancreatic tumor cell line-derived RNA reverses pancreatic carcinoma cell resistance by directly triggering natural killer-like T lymphocytes in vitro. In the present study, we tested triggering of specific T lymphocytes in vivo by using an immunocompetent mouse strain (C57BL/6). Syngenic, bone marrow-derived DCs were pulsed with tumor RNA derived from the pancreatic cell line PANC02. This cell line is a ductal pancreatic adenocarcinoma and shows high resistance to every known class of clinically active antitumor agent. PANC02 cells were implanted orthotopically via ultrasound guidance and led to pancreatic tumor formation in all of the mice. Thereafter, tumor RNA-pulsed DCs were injected intratumorally. Intratumoral administration of tumor RNA-pulsed DCs induced significantly more potent protective immunity than s.c. or i.v. administration. It was significantly more effective than administration with unpulsed DCs or DCs pulsed with a control tumor RNA derived from a lymphomatous cell line (EL4). The antitumor effect was caused by induction of antigen-specific T lymphocytes as shown by additional in vitro studies. These results favor intratumoral injection of tumor RNA-pulsed DCs for immunotherapy of pancreatic cancer.

Animals↗

Echoscintigraphy: a new imaging modality for the reduction of color blooming and acoustic shadowing in contrast sonography.

The purpose of this study was to develop and evaluate a new imaging modality (echoscintigraphy) to reduce color blooming and acoustic shadowing in contrast sonography. After injection of various amounts (700 to 40,000 bubbles/mL) of the echo contrast agent SH-U 563A into a flow phantom, artificial vessels were insonated in the intermittent harmonic-power Doppler imaging (H-PDI) mode. The receive gain was varied from 50% to 75%. The cross-sectional area (CSA) of the tube was assessed using a new summation algorithm (echoscintigraphy) and a conventional single-frame analysis (S-FA) of the H-PDI-signals. Echoscintigraphy is based on the recording and summation of low-intensity signals that are emitted during the ultrasound (US)-induced destruction of microbubbles. Application of the summation algorithm at low-contrast concentration allowed a gain-independent automatic calculation of the CSA at medium and high gain settings. Using the S-FA method, the assessment of the vessel diameter and the CSA was gain-dependent and allowed correct measurements only from 60% to 65% gain. At a high receive-gain and high contrast concentration, S-FA resulted in an overestimation of the CSA up to 35.5%. Echoscintigraphy allows correct display of contrast-filled vessels over a wide range of gain settings at low contrast concentrations, where S-FA does not adequately display echo contrast. Thus, echoscintigraphy minimizes artefacts resulting from color blooming and acoustic shadowing.

Algorithms↗

Increasing myocardial contraction and blood pressure in C57BL/6 mice during early postnatal development.

Knowledge of the developmental changes of cardiovascular parameters in the genetic background of a mouse strain is important for understanding phenotypic changes in transgenic or knockout mouse models for heart disease. We studied arterial blood pressure and myocardial contractility in mice of the common background strain C57BL/6, aged 21 days [postnatal day 21 (P21)] to 580 days. Heart rate increased during maturation from 396 beats/min at P21 to 551 beats/min at postnatal day 50 (P50), and mean arterial blood pressure increased in parallel from 86 to 110 mmHg and remained constant afterward. Echocardiographically determined left ventricular myocardial wall dimensions (R = 0.79, P < 0.0001) and left ventricular mass calculated using the area-length algorithm correlated strongly with histomorphometrical measurements (R = 0.93, P < 0.001). Sarcomere shortening records from isolated ventricular myocytes used as a measure for myocardial contractility revealed a negative shortening-frequency relation under a pacing frequency of 2 Hz and a positive relation above 2 Hz. Shortening amplitudes recorded from P21 myocytes were smaller, and the shortening-frequency relation was less steep than in adult myocytes. A stimulation pause was followed by a negative "staircase" at pacing frequency of < or =6 Hz and a positive staircase at > or =6 Hz. P21 myocytes developed positive staircases at 8 and 10 Hz, and adult myocytes also developed them at 6 Hz. Blood pressure increase during maturation until P50 may originate from increasing single cardiomyocyte contractility.

Aging↗

Cellular cardiomyoplasty improves survival after myocardial injury.

BACKGROUND: Cellular cardiomyoplasty is discussed as an alternative therapeutic approach to heart failure. To date, however, the functional characteristics of the transplanted cells, their contribution to heart function, and most importantly, the potential therapeutic benefit of this treatment remain unclear. METHODS AND RESULTS: Murine ventricular cardiomyocytes (E12.5-E15.5) labeled with enhanced green fluorescent protein (EGFP) were transplanted into the cryoinjured left ventricular walls of 2-month-old male mice. Ultrastructural analysis of the cryoinfarction showed a complete loss of cardiomyocytes within 2 days and fibrotic healing within 7 days after injury. Two weeks after operation, EGFP-positive cardiomyocytes were engrafted throughout the wall of the lesioned myocardium. Morphological studies showed differentiation and formation of intercellular contacts. Furthermore, electrophysiological experiments on isolated EGFP-positive cardiomyocytes showed time-dependent differentiation with postnatal ventricular action potentials and intact beta-adrenergic modulation. These findings were corroborated by Western blotting, in which accelerated differentiation of the transplanted cells was detected on the basis of a switch in troponin I isoforms. When contractility was tested in muscle strips and heart function was assessed by use of echocardiography, a significant improvement of force generation and heart function was seen. These findings were supported by a clear improvement of survival of mice in the cardiomyoplasty group when a large group of animals was analyzed (n=153). CONCLUSIONS: Transplanted embryonic cardiomyocytes engraft and display accelerated differentiation and intact cellular excitability. The present study demonstrates, as a proof of principle, that cellular cardiomyoplasty improves heart function and increases survival on myocardial injury.

Animals↗

Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing.

OBJECTIVE: Atrial fibrillation (AF) as an "indicator arrhythmia" for enhanced atrial vulnerability in mouse hearts has not yet been systematically examined. We therefore evaluated a transesophageal rapid atrial stimulation protocol for the induction of AF in C57Bl/6 mice. METHODS: 40 C57Bl/6 mice (19 female and 21 male; 5.2 +/- 2.1 months; 18 - 27 g) were examined by closed chest transesophageal atrial stimulation. Baseline ECG and electrophysiological parameters, AF-inducing stimulation cycle length (CL) and AF duration were analyzed. RESULTS: The surface ECG demonstrated a significantly faster heart rate in female mice (R-R: 138.7 +/- 19.9 ms versus 150.5 +/- 15.7 ms, P < 0.05). AF was inducible in 90 % of the population and not inducible in 4 mice, all female (21 % in this subgroup). Mean induction CL was 27.4 +/- 7.3 ms. Mean AF duration was 26.9 +/- 42.6 s before spontaneous termination. In a subgroup of 4 female and 4 male mice (mean age 7.5 months), successive testing of AF induction showed a range of higher susceptibility to AF at stimulus amplitudes of 3.0 - 4.0 mA and stimulation CLs between 15 - 25 ms. AF induction was observed to be constantly reproducible in the individual animals. No correlation to pacing stimulus length and amplitude was found. CONCLUSIONS: This study demonstrates that it is possible to reproducibly induce self-terminating AF and supraventricular arrhythmias in mice by transesophageal atrial burst stimulation. The presented method allowing serial testings of the same animal can be a useful tool in further investigations with transgenic mice and might be helpful in the characterization of underlying genetic or molecular mechanisms of AF.

Animals↗