Left ventricular blood flow patterns at rest and under dobutamine stress in healthy pigs.

Intracardiac blood flow patterns are affected by the morphology of cardiac structures and are set up to support the heart's pump function. Exercise affects contractility and chamber size as well as pre- and afterload. The aim of this study was to test the feasibility of four-dimensional phase contrast cardiovascular MRI under pharmacological stress and to study left ventricular blood flow under stress. 4D flow data were successfully acquired and analysed in 12 animals. During dobutamine infusion, heart rate and ejection fraction increased (82 ± 5 bpm versus 124 ± 3 bpm/46 ± 9% versus 65 ± 7%; both p < 0.05). A decrease in left ventricular end-diastolic volume (72 ± 14 mL versus 55 ± 8 mL; p < 0.05) and end-systolic volume (40 ± 15 mL versus 19 ± 6 mL; p < 0.05) but no change in stroke volume were observed. Trans-mitral diastolic inflow velocity increased under dobutamine and the trajectory of inflowing blood was directed towards the anterior septum with increased inflow angle (26 ± 5°) when compared with controls (15 ± 2°). In 5/6 animals undergoing stress diastolic vortices developed later, and in 3/6 animals vortices collapsed earlier with significantly smaller cross-sectional area during diastole. The vorticity index was not affected. Under the stress condition direct flow (% ejection within the next heart beat) increased from 43 ± 6% to 53 ± 8%. 4D MRI blood flow acquisition and analysis are feasible in pig hearts under dobutamine-induced stress. Flow patterns characterized by high blood velocity and antero-septally oriented diastolic inflow as well as decreased ventricular volumes are unfavourable conditions for diastolic vortex development under pharmacological stress, and cardiac output is increased by a rise in heart rate and directly ejected left ventricular blood volume.

Direct comparison of in vivo versus postmortem second-order motion-compensated cardiac diffusion tensor imaging.

PURPOSE: To directly compare in vivo versus postmortem second-order motion-compensated spin-echo diffusion tensor imaging of the porcine heart. METHODS: Second-order motion-compensated spin-echo cardiac diffusion tensor imaging was performed during systolic contraction in vivo and repeated upon cardiac arrest by bariumchloride without repositioning of the study animal or replaning of imaging slices. In vivo and postmortem reproducibility was assessed by repeat measurements. Comparison of helix, transverse, and sheet (E2A) angulation as well as mean diffusivity and fractional anisotropy was performed. RESULTS: Intraclass correlation coefficients for repeated measurements (postmortem/in vivo) were 0.95/0.96 for helix, 0.70/0.66 for transverse, and 0.79/0.72 for E2A angulation; 0.83/0.72 for mean diffusivity; and 0.78/0.76 for fractional anisotropy. The corresponding 95% levels of agreement across the left ventricle were: helix 14 to 18°/12 to 15°, transverse 9 to 10°/10 to 11°, E2A 15 to 20°/16 to 18°. The 95% levels of agreement across the left ventricle for the comparison of postmortem versus in vivo were 20 to 22° for helix, 13 to 19° for transverse, and 24 to 31° for E2A angulation. CONCLUSIONS: Parameters derived from in vivo second-order motion-compensated spin-echo diffusion tensor imaging agreed well with postmortem imaging, indicating sufficient suppression of motion-induced signal distortions of in vivo cardiac diffusion tensor imaging. Magn Reson Med 79:2265-2276, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Quantitative myocardial first-pass cardiovascular magnetic resonance perfusion imaging using hyperpolarized [1-13C] pyruvate.

BACKGROUND: The feasibility of absolute myocardial blood flow quantification and suitability of hyperpolarized [1-13C] pyruvate as contrast agent for first-pass cardiovascular magnetic resonance (CMR) perfusion measurements are investigated with simulations and demonstrated in vivo in a swine model. METHODS: A versatile simulation framework for hyperpolarized CMR subject to physical, physiological and technical constraints was developed and applied to investigate experimental conditions for accurate perfusion CMR with hyperpolarized [1-13C] pyruvate. Absolute and semi-quantitative perfusion indices were analyzed with respect to experimental parameter variations and different signal-to-noise ratio (SNR) levels. Absolute myocardial blood flow quantification was implemented with an iterative deconvolution approach based on Fermi functions. To demonstrate in vivo feasibility, velocity-selective excitation with an echo-planar imaging readout was used to acquire dynamic myocardial stress perfusion images in four healthy swine. Arterial input functions were extracted from an additional image slice with conventional excitation that was acquired within the same heartbeat. RESULTS: Simulations suggest that obtainable SNR and B0 inhomogeneity in vivo are sufficient for the determination of absolute and semi-quantitative perfusion with ≤25% error. It is shown that for expected metabolic conversion rates, metabolic conversion of pyruvate can be neglected over the short duration of acquisition in first-pass perfusion CMR. In vivo measurements suggest that absolute myocardial blood flow quantification using hyperpolarized [1-13C] pyruvate is feasible with an intra-myocardial variability comparable to semi-quantitative perfusion indices. CONCLUSION: The feasibility of quantitative hyperpolarized first-pass perfusion CMR using [1-13C] pyruvate has been investigated in simulations and demonstrated in swine. Using an approved and metabolically active compound is envisioned to increase the value of hyperpolarized perfusion CMR in patients.

Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity-selective excitation.

BACKGROUND: A velocity-selective binomial excitation scheme for myocardial first-pass perfusion measurements with hyperpolarized 13C substrates, which preserves bolus magnetization inside the blood pool, is presented. The proposed method is evaluated against gadolinium-enhanced 1H measurements in-vivo. METHODS: The proposed excitation with an echo-planar imaging readout was implemented on a clinical CMR system. Dynamic myocardial stress perfusion images were acquired in six healthy pigs after bolus injection of hyperpolarized 13C urea with the velocity-selective vs. conventional excitation, as well as standard 1H gadolinium-enhanced images. Signal-to-noise, contrast-to-noise (CNR) and homogeneity of semi-quantitative perfusion measures were compared between methods based on first-pass signal-intensity time curves extracted from a mid-ventricular slice. Diagnostic feasibility is demonstrated in a case of septal infarction. RESULTS: Velocity-selective excitation provides over three-fold reduction in blood pool signal with a two-fold increase in myocardial CNR. Extracted first-pass perfusion curves reveal a significantly reduced variability of semi-quantitative first-pass perfusion measures (12-20%) for velocity-selective excitation compared to conventional excitation (28-93%), comparable to that of reference 1H gadolinium data (9-15%). Overall image quality appears comparable between the velocity-selective hyperpolarized and gadolinium-enhanced imaging. CONCLUSION: The feasibility of hyperpolarized 13C first-pass perfusion CMR has been demonstrated in swine. Comparison with reference 1H gadolinium data revealed sufficient data quality and indicates the potential of hyperpolarized perfusion imaging for human applications.

Protective effects of new femoral reaming techniques (Reamer irrigator aspirator, RIA I and II) on pulmonary function and posttraumatic contusion (CT morphology) - results from a standardized large animal model.

INTRODUCTION: The effects of reaming for preparation of intramedullary fixation in long bone fractures have been widely studied. We compared pulmonary and systemic effects between conventional reaming with reamer irrigator aspirator and unreamed nailing in an acute porcine trauma model with a standardized femur fracture. MATERIALS AND METHODS: In a standardized porcine model, (moderate blunt chest trauma, abdominal injury and femoral shaft fracture), the femur was submitted to intramedullary nailing after resuscitation and normalization of pulmonary function. The treatment groups included 3 reamer types (Group RFN: conventional reaming with Synream; group RIA1; reamer irrigator aspirator, version 2005; group RIA 2; reamer irrigator aspirator, version 2019) and were compared to unreamed femoral nailing (Group UFN). Pulmonary function measurements included arterial partial carbon-dioxide pressure (paCO2 [kPa]) (baseline, post reaming, 2,4,6 h) and volumetric measures of contusion in chest computer tomography (CT) (at 6 hrs.). Systemic inflammatory response was measured at baseline and every second hour until six hours after trauma. RESULTS: This study included 24 male animals, mean weight 50.76 ± 4.1 kg n = 6 per group). Group RFN developed a significantly higher partial CO2 (pCO2) at one hour after reaming when compared with all other groups (7.4 ± 0.4 kPa versus 5.4 ± 0.6 RIA 1, 5.6 ± 0.4 RIA 2, and 5.5 ± 0.5 UFN, p < 0.001), along with a had lower pO2 (12.3 ± 1.3 kPa versus 17.2 ± 1.9 RIA 1, 17.4 ± 1.6 RIA 2, and 16.4 ± 0.7 UFN, p < 0.001) and the degree of pulmonary hyperdense changes in the CT analysis was higher in RFN (485.2 ± 98.5 cm3 versus 344.4 ± 74.4 cm3 RIA 1 and 335.2 ± 58.1 cm3 RIA 2, p < 0.01). The inflammatory reaction was lowest in both RIA groups when compared with group RFN or UFN (p < 0.001). CONCLUSION: Both RIA 1 and RIA 2 protect the lung from reaming induced dysfunction and have no systemic inflammatory effects, while the negative effects were more sustained after reamed or unreamed nailing. Both RIA 1 and RIA II appear to be of value in terms of a Safe Definitive Surgery (SDS) strategy.

Zone-dependent acute circulatory changes in abdominal organs and extremities after resuscitative balloon occlusion of the aorta (REBOA): an experimental model.

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 to the same occlusion, whereas local microcirculation in extremities appeared to be unaffected by short-time REBOA, regardless of the zone of occlusion.

Early myocardial damage (EMD) and valvular insufficiency result in impaired cardiac function after multiple trauma in pigs.

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.

Early myocardial damage (EMD) and valvular dysfunction after femur fracture in pigs.

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.

Reaming of femoral fractures with different reaming irrigator aspirator systems shows distinct effects on cardiac function after experimental polytrauma.

Cardiac injuries are recorded after multiple trauma and are associated with a poor patient outcome. Reaming prior to locked intramedullary nailing is a frequently used technique to stabilize femoral diaphysis fractures. However, in polytraumatized patients, complications such as fat emboli and acute respiratory distress syndrome have been associated with reaming. The reaming irrigator aspirator (RIA) system provides concomitant irrigation and suction of the intramedullary contents, and should, therefore, reduce reaming-associated complications. The aim of the study was to investigate cardiac function after multiple trauma with regard to two different RIA devices (RIAI vs RIAII). 15 male pigs were included in the study. Pigs received either sham treatment or multiple trauma (chest trauma, femur fracture, liver laceration, and hemorrhagic shock), followed by intramedullary nailing after reaming with either the RIAI or RIAII system (RIAII: reduced diameter of the reamer, improved control of irrigation and suction). Cardiac function was assessed by transesophageal echocardiography and systemic inflammation as well as local cardiac damage examined. Pigs of both treatment groups showed impaired cardiac function, valvular insufficiency, and cardiac damage. Systemic inflammation and local cardiac alterations were observed which might contribute to early myocardial damage in vivo. Multiple trauma including long-bone fracture and subsequent intramedullary reaming induces cardiac dysfunction and valvular insufficiency, which might be linked to both mechanical cardiac injury and increased systemic inflammation. 6 hours after trauma there are less differences between RIAI and RIAII treatment with regard to post-traumatic cardiac consequences in multiple injured pigs, indicating no beneficial effect of RIAII over RIAI.

Establishing a pre-clinical growing animal model to test a tissue engineered valved pulmonary conduit.

BACKGROUND: Many valvular pathologies of the heart may be only sufficiently treated by replacement of the valve if a reconstruction is not feasible. However, structural deterioration, thrombosis with thromboembolic events and infective endocarditis are commonly encountered complications over time and often demand a re-operation. In congenital heart disease the lack of small diameter valves with the potential to grow poses additional challenges and limits treatment options to homo- or xenograft implants. METHODS: In this study, a chronic sheep model (24 months follow-up), a self-constructed valved conduit was created out of a tissue engineered (TE) patch (CorMatrix® Cardiovascular, Inc, USA) and implanted in orthotopic right ventricular (RV)-pulmonary artery (PA) position. Thereafter, the sheep were regularly monitored by clinical, laboratory and echocardiographic examinations to evaluate cardiac function and the implanted RV-PA-conduit. DISCUSSION: Here, we summarize the study protocol and our experiences during the perioperative phase and the follow up period and explain how we constructed a valved conduit out of a commercially available TE patch. TRIAL REGISTRATION: License number: ZH 284/14.

Complement Activation and Organ Damage After Trauma-Differential Immune Response Based on Surgical Treatment Strategy.

Background: The complement system is part of the innate immunity, is activated immediately after trauma and is associated with adult respiratory distress syndrome, acute lung injury, multiple organ failure, and with death of multiply injured patients. The aim of the study was to investigate the complement activation in multiply injured pigs as well as its effects on the heart in vivo and in vitro. Moreover, the impact of reamed vs. non-reamed intramedullary nailing was examined with regard to the complement activation after multiple trauma in pigs. Materials and Methods: Male pigs received multiple trauma, followed by femoral nailing with/without prior conventional reaming. Systemic complement hemolytic activity (CH-50 and AH-50) as well as the local cardiac expression of C3a receptor, C5a receptors1/2, and the deposition of the fragments C3b/iC3b/C3c was determined in vivo after trauma. Human cardiomyocytes were exposed to C3a or C5a and analyzed regarding calcium signaling and mitochondrial respiration. Results: Systemic complement activation increased within 6 h after trauma and was mediated via the classical and the alternative pathway. Furthermore, complement activation correlated with invasiveness of fracture treatment. The expression of receptors for complement activation were altered locally in vivo in left ventricles. C3a and C5a acted detrimentally on human cardiomyocytes by affecting their functionality and their mitochondrial respiration in vitro. Conclusion: After multiple trauma, an early activation of the complement system is triggered, affecting the heart in vivo as well as in vitro, leading to complement-induced cardiac dysfunction. The intensity of complement activation after multiple trauma might correlate with the invasiveness of fracture treatment. Reaming of the femoral canal might contribute to an enhanced "second hit" response after trauma. Consequently, the choice of fracture treatment might imply the clinical outcome of the critically injured patients and might be therefore crucial for their survival.

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

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.

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

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.

Differential Leaflet Remodeling of Bone Marrow Cell Pre-Seeded Versus Nonseeded Bioresorbable Transcatheter Pulmonary Valve Replacements.

This study showed that bone marrow mononuclear cell pre-seeding had detrimental effects on functionality and in situ remodeling of bioresorbable bisurea-modified polycarbonate (PC-BU)-based tissue-engineered heart valves (TEHVs) used as transcatheter pulmonary valve replacement in sheep. We also showed heterogeneous valve and leaflet remodeling, which affects PC-BU TEHV safety, challenging their potential for clinical translation. We suggest that bone marrow mononuclear cell pre-seeding should not be used in combination with PC-BU TEHVs. A better understanding of cell-scaffold interaction and in situ remodeling processes is needed to improve transcatheter valve design and polymer absorption rates for a safe and clinically relevant translation of this approach.

Transplantation of Autologous Dermo-Epidermal Skin Substitutes in a Pig Model.

Due to its similarity of skin anatomy and physiology, the pig appears to be a well-suited animal model for preclinical studies of skin analog transplantations. The choice of the location of the skin defect and appropriate postoperative measures are essential for the protection of the transplanted graft. This protocol describes in detail a porcine skin transplantation model including peri- and postoperative measures taken to improve and refine the study outcome.

Reintroducing Heart Sounds for Early Detection of Acute Myocardial Ischemia in a Porcine Model - Correlation of Acoustic Cardiography With Gold Standard of Pressure-Volume Analysis.

BACKGROUND: Acoustic cardiography is a hybrid technique that couples heart sounds recording with ECG providing insights into electrical-mechanical activity of the heart in an unsupervised, non-invasive and inexpensive manner. During myocardial ischemia hemodynamic abnormalities appear in the first minutes and we hypothesize a putative diagnostic role of acoustic cardiography for prompt detection of cardiac dysfunction for future patient management improvement. METHODS AND RESULTS: Ten female Swiss large white pigs underwent permanent distal coronary occlusion as a model of acute myocardial ischemia. Acoustic cardiography analyses were performed prior, during and after coronary occlusion. Pressure-volume analysis was conducted in parallel as an invasive method of hemodynamic assessment for comparison. Similar systolic and diastolic intervals obtained with the two techniques were significantly correlated [Q to min dP/dt vs. Q to second heart sound (r 2 = 0.9583, p < 0.0001), PV diastolic filling time vs. AC perfusion time (r 2 = 0.9686, p < 0.0001)]. Indexes of systolic and diastolic impairment correlated with quantifiable features of heart sounds [Tau vs. fourth heart sound Display Value (r 2 = 0.2721, p < 0.0001) cardiac output vs. third heart sound Display Value (r 2 = 0.0791 p = 0.0023)]. Additionally, acoustic cardiography diastolic time (AUC 0.675, p = 0.008), perfusion time (AUC 0.649, p = 0.024) and third heart sound Display Value (AUC 0.654, p = 0.019) emerged as possible indicators of coronary occlusion. Finally, these three parameters, when joined with heart rate into a composite joint-index, represent the best model in our experience for ischemia detection (AUC 0.770, p < 0.001). CONCLUSION: In the rapidly evolving setting of acute myocardial ischemia, acoustic cardiography provided meaningful insights of mechanical dysfunction in a prompt and non-invasive manner. These findings should propel interest in resurrecting this technique for future translational studies as well as reconsidering its reintroduction in the clinical setting.

Transcatheter aortic valve-in-ring implantation: feasibility in an acute, preclinical, pilot trial.

OBJECTIVES: The HAART ring device has been introduced as a novel strategy to facilitate aortic valve repair. This rigid, elliptical device aims to restore normal leaflet configuration and to provide annular stabilization in the setting of aortic regurgitation. The goal of this preclinical study is to evaluate the in vivo feasibility of 'aortic valve-in-ring' transcatheter aortic valve replacement (TAVR). METHODS: Six animals {landrace pigs, 87.6 [standard deviation (SD) 4.5] kg} underwent HAART ring implantation (5 cases #19 mm and 1 case #21 mm) via full sternotomy with cardiopulmonary bypass. Seven transfemoral TAVR implantations were performed with the Medtronic EvolutR prosthesis to assess the sizing and outcome (5 cases #23 mm, 1 case #26 mm and 1 case #29 mm). RESULTS: TAVR implantation was successful in 6 of 7 attempts. Post-dilatation was performed in 1 case without damage of the ring or the valve. One embolization occurred due to oversizing (EvolutR valve 29 mm in HAART ring 19 mm). No clinically relevant postimplantation gradient [7.6 (SD 4.0) mmHg] or regurgitation was detected by invasive and echocardiographic measurements. Postoperative computed tomography scans revealed good device configuration. CONCLUSIONS: Transcatheter aortic valve-in-ring implantation of a self-expandable TAVR into a rigid aortic annuloplasty ring after aortic valve repair appears feasible. Proper sizing and correct depth of implantation are crucial.

Human cell-derived tissue-engineered heart valve with integrated Valsalva sinuses: towards native-like transcatheter pulmonary valve replacements.

Transcatheter valve replacement indication is currently being extended to younger and lower-risk patients. However, transcatheter prostheses are still based on glutaraldehyde-fixed xenogeneic materials. Hence, they are prone to calcification and long-term structural degeneration, which are particularly accelerated in younger patients. Tissue-engineered heart valves based on decellularized in vitro grown tissue-engineered matrices (TEM) have been suggested as a valid alternative to currently used bioprostheses, showing good performance and remodeling capacity as transcatheter pulmonary valve replacement (TPVR) in sheep. Here, we first describe the in vitro development of human cell-derived TEM (hTEM) and their application as tissue-engineered sinus valves (hTESVs), endowed with Valsalva sinuses for TPVR. The hTEM and hTESVs were systematically characterized in vitro by histology, immunofluorescence, and biochemical analyses, before they were evaluated in a pulse duplicator system under physiological pulmonary pressure conditions. Thereafter, transapical delivery of hTESVs was tested for feasibility and safety in a translational sheep model, achieving good valve performance and early cellular infiltration. This study demonstrates the principal feasibility of clinically relevant hTEM to manufacture hTESVs for TPVR.

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism.

Background and Purpose: Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS ≥ 16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of inflammatory biomarkers. One of these is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction, remain unknown. Experimental Approach: Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analyzed regarding viability, apoptosis, calcium handling, metabolic alterations, and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb ®300 was tested with recombinant Midkine or plasma from multiply injured patients. Key Results: Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling in vitro. CytoSorb®300 filtration reduced Midkine concentration ex vivo and in vitro depending on the dosage. Conclusion and Implications: Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes in vitro. Further examinations are required to determine whether the application of CytoSorb®300 filtration in patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac disfunction.