Boris Schmitt

Pulmonary Vascular Resistance, Collateral Flow, and Ventricular Function in Patients With a Fontan Circulation at Rest and During Dobutamine Stress

Background—The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood. Methods and Results—Using an MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance and aortopulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (end-systolic pressure-volume relation), and diastolic compliance (end-diastolic pressure-volume relation) in 10 patients with a Fontan circulation at rest and during dobutamine stress. Pulmonary and ventricular pressures were measured invasively and synchronized with velocity-encoded MRI-derived pulmonary and aortic blood flows and cine MRI-derived ventricular volumes. Pulmonary vascular resistance and end-systolic and end-diastolic pressure-volume relations were then determined. Aortopulmonary collateral flow was calculated as the difference between aortic and pulmonary flow. Compared to rest, dobutamine caused a small increase in mean pulmonary pressures (P<0.05). Collateral flow was significantly augmented (P<0.001) and contributed importantly to an increase in pulmonary flow (P<0.01). Pulmonary vascular resistance decreased significantly (P<0.01). Dobutamine did not increase stroke volumes significantly despite slightly enhanced contractility (end-systolic pressure-volume relation). Active early relaxation (&tgr;) was inconspicuous, but the end-diastolic pressure-volume relation shifted upward, indicating reduced compliance. Conclusions—In patients with a Fontan circulation, aortopulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate, but decreased diastolic compliance was identified as an important component of ventricular dysfunction.

Repair of anomalous origin of the left coronary artery from the pulmonary artery in infants and children

OBJECTIVE Although mortality after direct aortic reimplantation for anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) has significantly decreased, many questions remain unanswered. METHODS Between 1986 and June 2010, we operated on 27 consecutive pediatric patients with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). All patients underwent reestablishment of a dual coronary system with direct aortic reimplantation of the left coronary artery into the aorta. Postoperative extracorporeal mechanical circulatory support was necessary in 7 cases. In all 7 patients, hemodynamic stability was achieved after 4 to 10 days of support. Mitral valve repair was performed in 9 patients with severe mitral valve incompetence and resulted in stable mitral valve function during follow-up as long as 19 years. RESULTS There were no early or late deaths. During follow-up (3 months-17.5 years), both early and late improvement of myocardial function was observed in all patients. Reduced left ventricular regional function late after successful surgical correction of ALCAPA was related to the presence of left ventricular myocardial scar tissue, as detected by magnetic resonance imaging. CONCLUSIONS Despite the absence of early and late mortality, the long-term prognosis for patients after reimplantation of ALCAPA into the aorta is not clear. Scars and perfusion deficits of the left ventricle may not be detected by standard echocardiographic evaluation of global left ventricular function and therefore may be underestimated. We therefore recommend lifelong surveillance of these patients, including magnetic resonance imaging.

Pulmonary Vascular Resistance, Collateral Flow and Ventricular Function in Fontan Patients at Rest and During Dobutamine Stress

Background—The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood. Methods and Results—Using an MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance and aortopulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (end-systolic pressure-volume relation), and diastolic compliance (end-diastolic pressure-volume relation) in 10 patients with a Fontan circulation at rest and during dobutamine stress. Pulmonary and ventricular pressures were measured invasively and synchronized with velocity-encoded MRI-derived pulmonary and aortic blood flows and cine MRI-derived ventricular volumes. Pulmonary vascular resistance and end-systolic and end-diastolic pressure-volume relations were then determined. Aortopulmonary collateral flow was calculated as the difference between aortic and pulmonary flow. Compared to rest, dobutamine caused a small increase in mean pulmonary pressures (P<0.05). Collateral flow was significantly augmented (P<0.001) and contributed importantly to an increase in pulmonary flow (P<0.01). Pulmonary vascular resistance decreased significantly (P<0.01). Dobutamine did not increase stroke volumes significantly despite slightly enhanced contractility (end-systolic pressure-volume relation). Active early relaxation (&tgr;) was inconspicuous, but the end-diastolic pressure-volume relation shifted upward, indicating reduced compliance. Conclusions—In patients with a Fontan circulation, aortopulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate, but decreased diastolic compliance was identified as an important component of ventricular dysfunction.

Integrated Assessment of Diastolic and Systolic Ventricular Function Using Diagnostic Cardiac Magnetic Resonance Catheterization Validation in Pigs and Application in a Clinical Pilot Study

OBJECTIVES This study sought to develop and validate a method for the integrated analysis of systolic and diastolic ventricular function. BACKGROUND An integrated approach to assess ventricular pump function, myocontractility (end-systolic pressure-volume relationship [ESPVR]), and diastolic compliance (end-diastolic pressure-volume relation [EDPVR]) is of high clinical value. Cardiac magnetic resonance (CMR) is well established for measuring global pump function, and catheterization-combined CMR was previously shown to accurately measure ESPVR, but not yet the EDPVR. METHODS In 8 pigs, the CMR technique was compared with conductance catheter methods (gold standard) for measuring the EDPVR in the left and right ventricle. Measurements were performed at rest and during dobutamine administration. For CMR, the ESPVR was estimated with a single-beat approach by synchronizing invasive ventricular pressures with cine CMR-derived ventricular volumes. The EDPVR was determined during pre-load reduction from additional volume data that were obtained from real-time velocity-encoded CMR pulmonary/aortic blood flow measurements. Pre-load reduction was achieved by transient balloon occlusion of the inferior vena cava. The stiffness coefficient beta was calculated by an exponential fit from the EDPVR. After validation in the animal experiments, the EDPVR was assessed in a pilot study of 3 patients with a single ventricle using identical CMR and conductance catheter techniques. RESULTS Bland-Altman tests showed good agreement between conductance catheter-derived and CMR-derived EDPVR. In both ventricles of the pigs, dobutamine enhanced myocontractility (p < 0.01), increased stroke volume (p < 0.01), and improved diastolic function. The latter was evidenced by shorter early relaxation (p < 0.05), a downward shift of the EDPVR, and a decreased stiffness coefficient beta (p < 0.05). In contrast, in the patients, early relaxation was inconspicuous but the EDPVR shifted left-upward and the stiffness constant remained unchanged. The observed changes in diastolic function were not significantly different when measured with conductance catheter and CMR. CONCLUSIONS This novel CMR method provides differential information about diastolic function in conjunction with parameters of systolic contractility and global pump function.

Transcatheter creation of an aortopulmonary shunt in an animal model.

The surgical creation of an aortopulmonary shunt is an important tool in the therapy of complex congenital heart defects. We report on a transcatheter approach to establish an aortopulmonary shunt in piglets.

Methylprednisolone and Tacrolimus Prevent Hypothermia-Induced Endothelial Dysfunction

BACKGROUND Hypothermia is used to preserve organs for transplantation and is the oldest method to protect organs during complex pediatric cardiac surgery. Loss of tissue function and tissue edema are common complications in children undergoing corrective cardiac surgery and heart transplantation. The present study was designed to examine the effects of methylprednisolone and tacrolimus on endothelial cell function and morphology after deep hypothermia and rewarming. METHODS Human umbilical vein endothelial cells were pre-treated with methylprednisolone or tacrolimus, or both, incubated within a specially designed bioreactor or in monolayers, and then exposed to a dynamic cooling and rewarming protocol. Immunocytochemistry, time-lapse video microscopy, cell permeability and adherence assays, and Western blot analysis were performed. RESULTS Confluent endothelial cells exposed to hypothermia displayed elongated cell shapes with intercellular gap formation, increased endothelial cell-layer permeability, and loss in adherence. Upon rewarming, however, endothelial cell integrity was restored. Opening and closing of intercellular gaps was dependent on extracellular signal-regulated kinase 1 and 2 (ERK 1/2) activation and connexin 43 expression. The combined treatment with methylprednisolone and tacrolimus inhibited these hypothermia-induced changes. CONCLUSIONS These results suggest that methylprednisolone and tacrolimus inhibit hypothermia-induced endothelial gap formation by phosphorylated ERK 1/2 inhibition and connexin 43 stabilization. Application of combined drugs that affect multiple targets may therefore be considered as a possible new therapeutic strategy to prevent endothelial dysfunction after hypothermia and rewarming.

Three-dimensional alignment of the aggregated myocytes in the normal and hypertrophic murine heart

Several observations suggest that the transmission of myocardial forces is influenced in part by the spatial arrangement of the myocytes aggregated together within ventricular mass. Our aim was to assess, using diffusion tensor magnetic resonance imaging (DT-MRI), any differences in the three-dimensional arrangement of these myocytes in the normal heart compared with the hypertrophic murine myocardium. We induced ventricular hypertrophy in seven mice by infusion of angiotensin II through a subcutaneous pump, with seven other mice serving as controls. DT-MRI of explanted hearts was performed at 3.0 Tesla. We used the primary eigenvector in each voxel to determine the three-dimensional orientation of aggregated myocytes in respect to their helical angles and their transmural courses (intruding angles). Compared with controls, the hypertrophic hearts showed significant increases in myocardial mass and the outer radius of the left ventricular chamber (P < 0.05). In both groups, a significant change was noted from positive intruding angles at the base to negative angles at the ventricular apex (P < 0.01). Compared with controls, the hypertrophied hearts had significantly larger intruding angles of the aggregated myocytes, notably in the apical and basal slices (P < 0.001). In both groups, the helical angles were greatest in midventricular sections, albeit with significantly smaller angles in the mice with hypertrophied myocardium (P < 0.01). The use of DT-MRI revealed significant differences in helix and intruding angles of the myocytes in the mice with hypertrophied myocardium.

Percutaneous pulmonary valve replacement using completely tissue-engineered off-the-shelf heart valves : Six-month in vivo functionality and matrix remodelling in sheep

AIMS The objective was to implant a stented decellularised tissue-engineered heart valve (sdTEHV) percutaneously in an animal model, to assess its in vivo functionality and to examine the repopulation and remodelling of the valvular matrix by the recipients autologous cells. METHODS AND RESULTS Prototypes of sdTEHV were cultured in vitro, decellularised and percutaneously implanted into the pulmonary position in 15 sheep. Functionality was assessed monthly by intracardiac echocardiography (ICE). Valves were explanted after eight, 16 or 24 weeks and analysed macroscopically, histologically and by electron microscopy. Implantation was successful in all animals. Valves showed normal pressure gradients throughout the study. Due to a suboptimal design with small coaptation area, stent ovality led to immediate regurgitation which continuously increased during follow-up. Analyses revealed complete endothelialisation and rapid cellular repopulation and remodelling of the entire matrix. Valves were free from endocarditis, calcification and graft rejection. CONCLUSIONS sdTEHV can be safely implanted percutaneously. The fast autologous recellularisation and the extensive matrix remodelling demonstrate the valves potential as a next-generation percutaneous prosthesis with the capacity for tissue self-maintenance and longevity. Regurgitation may be prevented by valve design optimisation.

Heterogeneity of Regional Function and Relation to Ventricular Morphology in Patients With Fontan Circulation

The relation between underlying ventricular morphology and regional function in patients with Fontan circulation remains unclear. The aim of this study was to compare regional function and its heterogeneity in patients with tricuspid atresia (TA), biventricular apex-forming morphology (BiV), and controls. Nineteen patients (median age 12 years) with Fontan circulation who presented consecutively were prospectively enrolled and compared with age- and heart rate-matched controls. Most patients were in New York Heart Association class I (63%). Longitudinal systolic strain (S), systolic strain rate (SRsys), and early diastolic strain rate (SRdia) peaks were obtained from 6 ventricular segments, and a coefficient of variation by segment was calculated as a measure of regional heterogeneity. Systolic S, SRsys and SRdia peaks were decreased at the right and left lateral walls in both patient groups compared with controls (p ≤0.001 for all). Patients with TA had higher systolic S and SRsys in the middle of the right lateral wall than those with BiV morphology (p = 0.009 and p = 0.001, respectively). The mean coefficients of variation assessed by S and SRsys were similar in controls and patients with TA but lower in those with BiV than in controls and patients with TA (p <0.001 and p = 0.01, respectively). The mean coefficient of variation assessed by SRdia was greater only in patients with BiV than in controls (p = 0.001). In conclusion, patients with Fontan circulation have more heterogeneous systolic and early diastolic regional function than healthy control subjects, and patients with TA have better systolic regional function in the middle of the right lateral wall and less systolic heterogeneity than patients with BiV morphology.

Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model

Computational modeling–inspired heart valve designs guide tissue remodeling and ensure long-term functionality in tissue-engineered heart valves in sheep. Modeling remodeling Patients with valvular heart disease such as aortic stenosis (narrowing of the aortic valve in the heart) receive artificial or bioprosthetic valve replacements, but these have limited longevity and cannot grow with younger patients. Emmert et al. used computational modeling to design tissue-engineered heart valves from polymer scaffolds seeded with vascular cells. After 4 weeks of bioreactor culture, the grafts were decellularized before transcatheter implantation in sheep as pulmonary valve replacements. Nine of the 11 grafts remained functional up to 1 year later. Computational modeling predicted that valve leaflets would shorten in vivo during dynamic remodeling before reaching equilibrium, which was confirmed in the sheep. This work suggests that tissue engineering strategies should incorporate computational simulation to lead to more successful outcomes and more predictable clinical translation. Valvular heart disease is a major cause of morbidity and mortality worldwide. Current heart valve prostheses have considerable clinical limitations due to their artificial, nonliving nature without regenerative capacity. To overcome these limitations, heart valve tissue engineering (TE) aiming to develop living, native-like heart valves with self-repair, remodeling, and regeneration capacity has been suggested as next-generation technology. A major roadblock to clinically relevant, safe, and robust TE solutions has been the high complexity and variability inherent to bioengineering approaches that rely on cell-driven tissue remodeling. For heart valve TE, this has limited long-term performance in vivo because of uncontrolled tissue remodeling phenomena, such as valve leaflet shortening, which often translates into valve failure regardless of the bioengineering methodology used to develop the implant. We tested the hypothesis that integration of a computationally inspired heart valve design into our TE methodologies could guide tissue remodeling toward long-term functionality in tissue-engineered heart valves (TEHVs). In a clinically and regulatory relevant sheep model, TEHVs implanted as pulmonary valve replacements using minimally invasive techniques were monitored for 1 year via multimodal in vivo imaging and comprehensive tissue remodeling assessments. TEHVs exhibited good preserved long-term in vivo performance and remodeling comparable to native heart valves, as predicted by and consistent with computational modeling. TEHV failure could be predicted for nonphysiological pressure loading. Beyond previous studies, this work suggests the relevance of an integrated in silico, in vitro, and in vivo bioengineering approach as a basis for the safe and efficient clinical translation of TEHVs.