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Article ; Online: The Potential of Intertwining Gene Diagnostics and Surgery for Mitral Valve Prolapse

Jasper Iske / Maximilian J. Roesel / Nikola Cesarovic / Leonard Pitts / Annabel Steiner / Leonard Knoedler / Timo Z. Nazari-Shafti / Serdar Akansel / Stephan Jacobs / Volkmar Falk / Joerg Kempfert / Markus Kofler

Journal of Clinical Medicine, Vol 12, Iss 23, p

2023 Volume 7441

Abstract: Mitral valve prolapse (MVP) is common among heart valve disease patients, causing severe mitral regurgitation (MR). Although complications such as cardiac arrhythmias and sudden cardiac death are rare, the high prevalence of the condition leads to a ... ...

Abstract	Mitral valve prolapse (MVP) is common among heart valve disease patients, causing severe mitral regurgitation (MR). Although complications such as cardiac arrhythmias and sudden cardiac death are rare, the high prevalence of the condition leads to a significant number of such events. Through next-generation gene sequencing approaches, predisposing genetic components have been shown to play a crucial role in the development of MVP. After the discovery of the X-linked inheritance of filamin A, autosomal inherited genes were identified. In addition, the study of sporadic MVP identified several genes, including DZIP1, TNS1, LMCD1, GLIS1, PTPRJ, FLYWCH, and MMP2. The early screening of these genetic predispositions may help to determine the patient population at risk for severe complications of MVP and impact the timing of reconstructive surgery. Surgical mitral valve repair is an effective treatment option for MVP, resulting in excellent short- and long-term outcomes. Repair rates in excess of 95% and low complication rates have been consistently reported for minimally invasive mitral valve repair performed in high-volume centers. We therefore conceptualize a potential preventive surgical strategy for the treatment of MVP in patients with genetic predisposition, which is currently not considered in guideline recommendations. Further genetic studies on MVP pathology and large prospective clinical trials will be required to support such an approach.
Keywords	mitral valve prolapse ; minimally invasive surgery ; genetic predisposition ; minimally invasive mitral valve reconstruction ; DZIP1 ; TNS1 ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Tramadol:Paracetamol in drinking water for treatment of post-surgical pain in laboratory mice

Jirkof, Paulin / Margarete Arras / Nikola Cesarovic

Applied animal behaviour science. 2018 Jan., v. 198

2018

Abstract: In the search for stress-free analgesia administration for laboratory mice suffering pain, oral delivery of Tramadol:Paracetamol (T:P) shows great promise. Here, we monitored the analgesic efficacy and side effects of a T:P combination administered ... ...

Abstract	In the search for stress-free analgesia administration for laboratory mice suffering pain, oral delivery of Tramadol:Paracetamol (T:P) shows great promise. Here, we monitored the analgesic efficacy and side effects of a T:P combination administered solely in the drinking water of female C57BL/6J mice after moderate-impact surgery (sham embryo transfer), using clinical and behavioral pain and recovery parameters. Animals underwent anesthesia and surgery with T:P treatment (OP+T:P), received no pain relief after surgery (OP), underwent anesthesia only with T:P treatment (An+T:P) or T:P treatment only (T:P). Indicators of pain and constraint were assessed at several time points during 24h after surgery.T:P-containing drinking water was consumed readily in amounts to assure sufficient drug levels. No obvious detrimental side effects of analgesia were observed. General condition of animals differed only slightly and non-significantly between treatment groups, with comparable post-procedural weight loss, water and food intake as well as home cage activity. Mean nest scores differed significantly between T:P and both surgery groups (p=0.002, p<0.0001) but revealed no significant difference between OP and OP+T:P groups. Nevertheless, pain scores showed significant differences between the treatment groups at 1, 3 and 6h after surgery (p=0.001, p=0.014, p=0.003). OP animals scored highest, while scores of OP+T:P animals were comparable or lower than scores of the AN+T:P group. Same was true for burrowing latency that was significantly increased in OP animals compared to An+T:P and OP+T:P (p=0.032, p=0.019), but comparable between An+T:P and OP+T:P. These results hint on a clear post-surgical pain effect after surgery that could be significantly reduced with T:P treatment towards a level of the control group receiving anesthesia and T:P only.In conclusion, we assume that orally administered T:P offers pain relief with no obvious side effects after mild-to-moderate impact surgery in female C57BL/6J mice.
Keywords	adverse effects ; analgesia ; analgesics ; anesthesia ; cages ; drinking water ; embryo (animal) ; embryo transfer ; females ; food intake ; mice ; nests ; oral administration ; pain ; weight loss
Language	English
Dates of publication	2018-01
Size	p. 95-100.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	591645-8
ISSN	0168-1591
ISSN	0168-1591
DOI	10.1016/j.applanim.2017.09.021
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Pathology and Advanced Imaging—Characterization of a Congenital Cardiac Defect and Complex Hemodynamics in a Pig

Alexandra J. Malbon / Miriam Weisskopf / Lukas Glaus / Sebastian Neuber / Maximilian Y. Emmert / Christian T. Stoeck / Nikola Cesarovic

Frontiers in Veterinary Science, Vol

A Case Report

2021 Volume 8

Abstract: Domestic pigs are widely used in cardiovascular research as the porcine circulatory system bears a remarkable resemblance to that of humans. In order to reduce variability, only clinically healthy animals enter the study as their health status is ... ...

Abstract	Domestic pigs are widely used in cardiovascular research as the porcine circulatory system bears a remarkable resemblance to that of humans. In order to reduce variability, only clinically healthy animals enter the study as their health status is assessed in entry examination. Like humans, pigs can also suffer from congenital heart disease, such as an atrial septal defect (ASD), which often remains undetected. Due to the malformation of the endocardial cushion during organ development, mitral valve defects (e.g., mitral clefts) are sometimes associated with ASDs, further contributing to hemodynamic instability. In this work, we report an incidental finding of a hemodynamically highly relevant ASD in the presence of incompetent mitral and tricuspid valves, in an asymptomatic, otherwise healthy juvenile pig. In-depth characterization of the cardiac blood flow by four-dimensional (4D) flow magnetic resonance imaging (MRI) revealed a prominent diastolic left-to-right and discrete systolic right-to-left shunt, resulting in a pulmonary-to-systemic flow ratio of 1.8. Severe mitral (15 mL/stroke) and tricuspid (22 mL/stroke) regurgitation further reduced cardiac output. Pathological examination confirmed the presence of an ostium primum ASD and found a serous cyst of lymphatic origin that was filled with clear fluid partially occluding the ASD. A large mitral cleft was identified as the most likely cause of severe regurgitation, and histology showed mild to moderate endocardiosis in the coaptation area of both atrio-ventricular valves. In summary, although not common, congenital heart defects could play a role as a cause of experimental variability or even intra-experimental mortality when working with apparently heathy, juvenile pigs.
Keywords	large animal models ; cardiovascular imaging ; congenital heart defects ; cardiovascular pathology ; atrial septal defect ; blood flow ; Veterinary medicine ; SF600-1100
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dos and don'ts in large animal models of aortic insufficiency

Miriam Weisskopf / Lukas Glaus / Nina E. Trimmel / Melanie M. Hierweger / Andrea S. Leuthardt / Marian Kukucka / Thorald Stolte / Christian T. Stoeck / Volkmar Falk / Maximilian Y. Emmert / Markus Kofler / Nikola Cesarovic

Frontiers in Veterinary Science, Vol

2022 Volume 9

Abstract: Aortic insufficiency caused by paravalvular leakage (PVL) is one of the most feared complications following transcatheter aortic valve replacement (TAVI) in patients. Domestic pigs (Sus scrofa domestica) are a popular large animal model to study such ... ...

Abstract	Aortic insufficiency caused by paravalvular leakage (PVL) is one of the most feared complications following transcatheter aortic valve replacement (TAVI) in patients. Domestic pigs (Sus scrofa domestica) are a popular large animal model to study such conditions and develop novel diagnostic and therapeutic techniques. However, the models based on prosthetic valve implantation are time intensive, costly, and often hamper further hemodynamic measurements such as PV loop and 4D MRI flow by causing implantation-related wall motion abnormalities and degradation of MR image quality. This study describes in detail, the establishment of a minimally invasive porcine model suitable to study the effects of mild-to-moderate “paravalvular“ aortic regurgitation on left ventricular (LV) performance and blood flow patterns, particularly under the influence of altered afterload, preload, inotropic state, and heart rate. Six domestic pigs (Swiss large white, female, 60–70 kg of body weight) were used to establish this model. The defects on the hinge point of aortic leaflets and annulus were created percutaneously by the pierce-and-dilate technique either in the right coronary cusp (RCC) or in the non-coronary cusp (NCC). The hemodynamic changes as well as LV performance were recorded by PV loop measurements, while blood flow patterns were assessed by 4D MRI. LV performance was additionally challenged by pharmaceutically altering cardiac inotropy, chronotropy, and afterload. The presented work aims to elaborate the dos and don'ts in porcine models of aortic insufficiency and intends to steepen the learning curve for researchers planning to use this or similar models by giving valuable insights ranging from animal selection to vascular access choices, placement of PV Loop catheter, improvement of PV loop data acquisition and post-processing and finally the induction of paravalvular regurgitation of the aortic valve by a standardized and reproducible balloon induced defect in a precisely targeted region of the aortic valve.
Keywords	large animal model ; aortic valve ; paravalvular leakage ; aortic insufficiency (AI) ; Minimally invasive ; PV loop ; Veterinary medicine ; SF600-1100
Subject code	621
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early myocardial damage (EMD) and valvular dysfunction after femur fracture in pigs

Birte Weber / Ina Lackner / Theodore Miclau / Jonathan Stulz / Florian Gebhard / Roman Pfeifer / Paolo Cinelli / Sascha Halvachizadeh / Michel Teuben / Hans-Christoph Pape / Miriam Lipiski / Nikola Cesarovic / Miriam Kalbitz

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract Musculoskeletal injuries are the most common reason for surgery in severely injured patients. In addition to direct cardiac damage after physical trauma, there is rising evidence that trauma induces secondary cardiac structural and functional ... ...

Abstract	Abstract Musculoskeletal injuries are the most common reason for surgery in severely injured patients. In addition to direct cardiac damage after physical trauma, there is rising evidence that trauma induces secondary cardiac structural and functional damage. Previous research associates hip fractures with the appearance of coronary heart disease: As 25% of elderly patients developed a major adverse cardiac event after hip fracture. 20 male pigs underwent femur fracture with operative stabilization via nailing (unreamed, reamed, RIA I and a new RIA II; each group n = 5). Blood samples were collected 6 h after trauma and the concentration of troponin I and heart-type fatty acid binding protein (HFABP) as biomarkers for EMD were measured. At baseline and 6 h after trauma, transesophageal ECHO (TOE) was performed; and invasive arterial and left ventricular blood pressure were measured to evaluate the cardiac function after femur fracture. A systemic elevation of troponin I and HFABP indicate an early myocardial damage after femur fracture in pigs. Furthermore, various changes in systolic (ejection fraction and cardiac output) and diastolic (left ventricular end-diastolic pressure, mitral valve deceleration time and E/A ratio) parameters illustrate the functional impairment of the heart. These findings were accompanied by the development of valvular dysfunction (pulmonary and tricuspid valve). To the best of our knowledge, we described for the first time the development of functional impairment of the heart in the context of EMD after long bone fracture in pigs. Next to troponin and HFABP elevation, alterations in the systolic and diastolic function occurred and were accompanied by pulmonary and tricuspid valvular insufficiency. Regarding EMD, none of the fracture stabilization techniques (unreamed nailing, reaming, RIA I and RIA II) was superior.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Zone-dependent acute circulatory changes in abdominal organs and extremities after resuscitative balloon occlusion of the aorta (REBOA)

Sascha Halvachizadeh / Ladislav Mica / Yannik Kalbas / Miriam Lipiski / Marko Canic / Michel Teuben / Nikola Cesarovic / Zoran Rancic / Paolo Cinelli / Valentin Neuhaus / Hans- Christoph Pape / Roman Pfeifer

European Journal of Medical Research, Vol 26, Iss 1, Pp 1-

an experimental model

2021 Volume 9

Abstract: Abstract Introduction Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be used in severely injured patients with uncontrollable bleeding. However, zone-dependent effects of REBOA are rarely described. We compared the short-term zone- ...

Abstract	Abstract Introduction Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be used in severely injured patients with uncontrollable bleeding. However, zone-dependent effects of REBOA are rarely described. We compared the short-term zone- and organ-specific microcirculatory changes in abdominal organs and the extremity during occlusion of the aorta in a standardized porcine model. Methods Male pigs were placed under general anesthesia, for median laparotomy to expose intra-abdominal organs. REBOA placement occurred in Zone 1 (from origin left subclavian artery to celiac trunk), Zone 2 (between the coeliac trunk and most caudal renal artery) and Zone 3 (distal most caudal renal artery to aortic bifurcation). Local microcirculation of the intra-abdominal organs were measured at the stomach, colon, small intestine, liver, and kidneys. Furthermore, the right medial vastus muscle was included for assessment. Microcirculation was measured using oxygen-to-see device (arbitrary units, A.U). Invasive blood pressure measurements were recorded in the carotid and femoral artery (ipsilateral). Ischemia/Reperfusion (I/R)-time was 10 min with complete occlusion. Results At baseline, microcirculation of intra-abdominal organs differed significantly (p < 0.001), the highest flow was in the kidneys (208.3 ± 32.9 A.U), followed by the colon (205.7 ± 36.2 A.U.). At occlusion in Zone 1, all truncal organs showed significant decreases (p < 0.001) in microcirculation, by 75% at the colon, and 44% at the stomach. Flow-rate changes at the extremities were non-significant (n.s). During occlusion in Zone 2, a significant decrease (p < 0.001) in microcirculation was observed at the colon (− 78%), small intestine (− 53%) and kidney (− 65%). The microcirculatory changes at the extremity were n.s. During occlusion in Zone 3, truncal and extremity microcirculatory changes were n.s. Conclusion All abdominal organs showed significant changes in microcirculation during REBOA. The intra-abdominal organs react differently ...
Keywords	REBOA ; Abdominal organ perfusion ; Shock ; Trauma ; Resuscitative balloon occlusion of the aorta ; Polytrauma ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative analysis of cardiac mechano-energetics in isolated hearts supported by pulsatile or rotary blood pumps

Marcus Granegger / Young Choi / Benedikt Locher / Philipp Aigner / Emanuel J. Hubmann / Frithjof Lemme / Nikola Cesarovic / Michael Hübler / Martin Schweiger

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract The previously more frequently implanted pulsatile blood pumps (PBPs) showed higher recovery rates than the currently preferred rotary blood pumps (RBPs), with unclear causality. The aim of this study was to comparatively assess the capability ... ...

Abstract	Abstract The previously more frequently implanted pulsatile blood pumps (PBPs) showed higher recovery rates than the currently preferred rotary blood pumps (RBPs), with unclear causality. The aim of this study was to comparatively assess the capability of PBPs and RPBs to unload the left ventricle and maintain cardiac energetics as a possible implication for recovery. An RBP and a heartbeat synchronized PBP were alternately connected to isolated porcine hearts. Rotational speed of RBPs was set to different support levels. For PBP support, the start of ejection was phased to different points during the cardiac cycle, prescribed as percentage delays from 0% to 90%. Cardiac efficiency, quantified by the ratio of external work over myocardial oxygen consumption, was determined. For RBP support, higher degrees of RBP support correlated with lower left atrial pressures (LAP) and lower cardiac efficiency (r = 0.91 ± 0.12). In contrast, depending on the phase delay of a PBP, LAP and cardiac efficiency exhibited a sinusoidal relationship with the LAP minimum at 90% and efficiency maximum at 60%. Phasing of a PBP offers the possibility to maintain a high cardiac efficiency and simultaneously unload the ventricle. These results warrant future studies investigating whether optimized cardiac energetics promotes functional recovery with LVAD therapy.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early myocardial damage (EMD) and valvular insufficiency result in impaired cardiac function after multiple trauma in pigs

Birte Weber / Ina Lackner / Meike Baur / Florian Gebhard / Roman Pfeifer / Paolo Cinelli / Sascha Halvachizadeh / Michel Teuben / Hans-Christoph Pape / Armin Imhof / Miriam Lipiski / Nikola Cesarovic / Miriam Kalbitz

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 12

Abstract: Abstract One third of multiple trauma patients present abnormal echocardiographic (ECHO) findings. Therefore, ECHO diagnostic after trauma is indicated in case of hemodynamic instability, shock, after chest trauma and after cardiac arrest. 20 male pigs ... ...

Abstract	Abstract One third of multiple trauma patients present abnormal echocardiographic (ECHO) findings. Therefore, ECHO diagnostic after trauma is indicated in case of hemodynamic instability, shock, after chest trauma and after cardiac arrest. 20 male pigs underwent multiple trauma. Blood samples were collected 4 and 6 h after trauma and concentrations of heart-type fatty acid binding protein (HFABP) as a biomarker for EMD were measured. Myocardial damage was evaluated by scoring Hematoxylin–Eosin stained sections. At baseline, 3 and 6 h after trauma, transesophageal ECHO (TOE) was performed, invasive arterial and left ventricular blood pressure were measured to evaluate the cardiac function after multiple trauma. Systemic HFABP concentrations were elevated, furthermore heart injury score in multiple trauma animals was increased determining EMD. A significant decrease of blood pressure in combination with a consecutive rise of heart frequency was observed. Ongoing depression of mean arterial pressure and diastolic blood pressure were accompanied by changes in ECHO-parameters indicating diastolic and systolic dysfunction. Furthermore, a valvular dysfunction was detected. In this study complex myocardial and valvular impairment after multiple trauma in pigs has been observed. Therefore, detection of EMD and progressive valvular dysfunction might be crucial and therapeutically relevant.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Computed Tomography-based evaluation of porcine cardiac dimensions to assist in pre-study planning and optimized model selection for pre-clinical research

Miriam Lipiski / Matthias Eberhard / Thea Fleischmann / Sascha Halvachizadeh / Beate Kolb / Francesco Maisano / Mareike Sauer / Volkmar Falk / Maximilian Y. Emmert / Hatem Alkadhi / Nikola Cesarovic

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 11

Abstract: Abstract The pig (Sus Scrofa Domestica) is an accepted model for preclinical evaluation of prosthetic heart valves and trans-catheter implantation techniques. Understanding porcine cardiac dimensions through three-dimensional computed tomography (CT), ... ...

Abstract	Abstract The pig (Sus Scrofa Domestica) is an accepted model for preclinical evaluation of prosthetic heart valves and trans-catheter implantation techniques. Understanding porcine cardiac dimensions through three-dimensional computed tomography (CT), increases preclinical study success, leading to higher cost efficiency and to the observance of the obligation to the 3 R principles. Cardiac CT images of twenty-four Swiss large white pigs were segmented; aortic root, mitral valve, pulmonary trunk, tricuspid valve, as well as the aorto-mitral angle and left atrial height were analyzed. Correlation coefficient (r) was calculated in relation to body weight. In Swiss large white pigs, valvular dimensions, length of the pulmonary artery and ascending aorta as well as left atrial height correlate with body weight. Coronary ostia heights and aorto-mitral angle size can be neglected in animal size selection; no changes were found for either of the two parameters with increasing body weight.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural alterations and inflammation in the heart after multiple trauma followed by reamed versus non-reamed femoral nailing.

Meike Baur / Birte Weber / Ina Lackner / Florian Gebhard / Roman Pfeifer / Paolo Cinelli / Sascha Halvachizadeh / Michel Teuben / Miriam Lipiski / Nikola Cesarovic / Hans-Christoph Pape / Miriam Kalbitz

PLoS ONE, Vol 15, Iss 6, p e

2020 Volume 0235220

Abstract: Background Approximately 30,000 patients with blunt cardiac trauma are recorded each year in the United States. Blunt cardiac injuries after trauma are associated with a longer hospital stay and a poor overall outcome. Organ damage after trauma is linked ...

Abstract	Background Approximately 30,000 patients with blunt cardiac trauma are recorded each year in the United States. Blunt cardiac injuries after trauma are associated with a longer hospital stay and a poor overall outcome. Organ damage after trauma is linked to increased systemic release of pro-inflammatory cytokines and damage-associated molecular patterns. However, the interplay between polytrauma and local cardiac injury is unclear. Additionally, the impact of surgical intervention on this process is currently unknown. This study aimed to determine local cardiac immunological and structural alterations after multiple trauma. Furthermore, the impact of the chosen fracture stabilization strategy (reamed versus non-reamed femoral nailing) on cardiac alterations was studied. Experimental approach 15 male pigs were either exposed to multiple trauma (blunt chest trauma, laparotomy, liver laceration, femur fracture and haemorrhagic shock) or sham conditions. Blood samples as well as cardiac tissue were analysed 4 h and 6 h after trauma. Additionally, murine HL-1 cells were exposed to a defined polytrauma-cocktail, mimicking the pro-inflammatory conditions after multiple trauma in vitro. Results After multiple trauma, cardiac structural changes were observed in the left ventricle. More specifically, alterations in the alpha-actinin and desmin protein expression were found. Cardiac structural alterations were accompanied by enhanced local nitrosative stress, increased local inflammation and elevated systemic levels of the high-mobility group box 1 protein. Furthermore, cardiac alterations were observed predominantly in pigs that were treated by non-reamed intramedullary reaming. The polytrauma-cocktail impaired the viability of HL-1 cells in vitro, which was accompanied by a release of troponin I and HFABP. Discussion Multiple trauma induced cardiac structural alterations in vivo, which might contribute to the development of early myocardial damage (EMD). This study also revealed that reamed femoral nailing (reamed) is associated with more prominent immunological cardiac alterations compared to nailing without reaming (non-reamed). This suggests that the choice of the initial fracture treatment strategy might be crucial for the overall outcome as well as for any post-traumatic cardiac consequences.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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