Peter E. Hammer

Fluctuating Pressure-Passivity Is Common in the Cerebral Circulation of Sick Premature Infants

Cerebral blood flow pressure-passivity results when pressure autoregulation is impaired, or overwhelmed, and is thought to underlie cerebrovascular injury in the premature infant. Earlier bedside observations suggested that transient periods of cerebral pressure-passivity occurred in premature infants. However, these transient events cannot be detected reliably by intermittent static measurements of pressure autoregulation. We therefore used continuous bedside recordings of mean arterial pressure (MAP; from an indwelling arterial catheter) and cerebral perfusion [using the near-infrared spectroscopy (NIRS) Hb difference (HbD) signal) to detect cerebral pressure-passivity in the first 5 d after birth in infants with birth weight <1500 g. Because the Hb difference (HbD) signal [HbD = oxyhemoglobin (HbO2) − Hb] correlates with cerebral blood flow (CBF), we used coherence between MAP and HbD to define pressure-passivity. We measured the prevalence of pressure-passivity using a pressure-passive index (PPI), defined as the percentage of 10-min epochs with significant low-frequency coherence between the MAP and HbD signals. Pressure-passivity occurred in 87 of 90 premature infants, with a mean PPI of 20.3%. Cerebral pressure-passivity was significantly associated with low gestational age and birth weight, systemic hypotension, and maternal hemodynamic factors, but not with markers of maternal infection. Future studies using consistent serial brain imaging are needed to define the relationship between PPI and cerebrovascular injury in the sick premature infant.

Induction of atrial tachycardia and fibrillation in the mouse heart

BACKGROUND Atrial tachycardia and fibrillation in humans may be partly consequent to vagal stimulation. Induction of fibrillation in the small heart is considered to be impossible due to lack of a critical mass of > 100-200 mm2. Even with the recent progression of the technology of in vivo and in vitro mouse electrophysiological studies, few reports describe atrial tachycardia or fibrillation in mice. The purpose of this study was to attempt provocation of atrial tachyarrhythmia in mice using transvenous pacing following cholinergic stimulation. METHODS AND RESULTS In vivo electrophysiology studies were performed in 14 normal mice. A six-lead ECG was recorded from surface limb leads, and an octapolar electrode catheter was inserted via jugular vein cutdown approach for simultaneous atrial and ventricular endocardial recording and pacing. Atrial tachycardia and fibrillation were inducible in one mouse at baseline electrophysiology study and eleven of fourteen mice after carbamyl choline injection. The mean duration of atrial tachycardia was 126 +/- 384 s. The longest episode lasted 35 min and only terminated after atropine injection. Reinduction of atrial tachycardia after administration of atropine was not possible. CONCLUSION Despite the small mass of the normal mouse atria, sustained atrial tachycardia and fibrillation can be easily and reproducibly inducible with endocardial pacing after cholinergic agonist administration. This finding may contribute to our understanding of the classical theories of arrhythmogenesis and critical substrates necessary for sustaining microreentrant circuits. The techniques of transcatheter parasympathetic agonist-mediated atrial tachycardia induction may be valuable in further murine electrophysiological studies, especially mutant models with potential atrial arrhythmia phenotypes.

Transapical Transcatheter Valve-in-Valve Implantation for Deteriorated Mitral Valve Bioprostheses

BACKGROUND The transcatheter valve-in-valve concept has been described for patients requiring redo valve surgery. We report our experience with transapical mitral valve-in-valve implantation. METHODS Since 2008, 301 patients were treated with transapical transcatheter valve implantation. Seven of these patients presented with a deteriorated mitral valve bioprosthesis and underwent transapical mitral valve-in-valve implantation. Median age was 79 years. Preoperatively, all patients presented in New York Heart Association functional class III. For risk estimation, The Society of Thoracic Surgeons and European System for Cardiac Operative Risk scores were used and predicted high mortality (mean ± standard error of mean: Society of Thoracic Surgeons mortality, 12.3% ± 2.1%; European System for Cardiac Operative Risk mortality, 58.0% ± 7.0%). Mean follow-up time was 93 ± 29 days, with a total of 21.6 patient-months. RESULTS Preoperatively, all patients who had deteriorated bioprostheses presented with severe regurgitation and increased transvalvular pressure gradients (maximal pressure gradient, 23.9 ± 0.9 mm Hg; mean pressure gradient, 11.3 ± 1.0 mm Hg). One patient was identified with mitral valve stenosis (effective orifice area, 0.25 cm(2)). All patients underwent successful transapical mitral valve-in-valve implantation. Sizes of previously implanted bioprostheses were 27, 29, and 31 mm; Edwards SAPIEN valves at sizes 26 and 29 mm were implanted. Postoperatively, echocardiography revealed excellent hemodynamics with no remaining mitral regurgitation in 5 patients and minimal regurgitation in 2 patients. Transvalvular pressure gradients decreased significantly (maximal pressure gradient, 13.8 ± 2.1 mm Hg; mean pressure gradient 5.7 ± 0.8 mm Hg, p < 0.05). One patient had fatal pneumonia on postoperative day 34. No patient died during further follow-up, and all patients remained in New York Heart Association class I or II. CONCLUSIONS Our results demonstrate the feasibility of transapical mitral valve-in-valve implantation for treatment of a degenerated bioprosthesis (size range, 27 to 31 mm) using the Edwards SAPIEN valve in sizes 26 and 29 mm.

Mass-Spring Model for Simulation of Heart Valve Tissue Mechanical Behavior

Heart valves are functionally complex, making surgical repair difficult. Simulation-based surgical planning could facilitate repair, but current finite element (FE) studies are prohibitively slow for rapid, clinically oriented simulations. Mass-spring (M-S) models are fast but can be inaccurate. We quantify speed and accuracy differences between an anisotropic, nonlinear M-S and an efficient FE membrane model for simulating both biaxial and pressure loading of aortic valve (AV) leaflets. The FE model incurs approximately 10 times the computational cost of the M-S model. For simulated biaxial loading, mean error in normal strains is <1% for both FE and M-S models for equibiaxial loading but increases for non-equibiaxial states for the M-S model (7%). The M-S model was less able to simulate shear behavior, with mean strain error of approximately 80%. For pressurized AV leaflets, the M-S model predicts similar leaflet dimensions to the FE model (within 2.6%), and the coaptation zone is similar between models. The M-S model simulates in-plane behavior of AV leaflets considerably faster than the FE model and with only minor differences in the deformed mesh. While the M-S model does not allow explicit control of shear response, shear does not strongly influence shape of the simulated AV under pressure.

Anisotropic mass-spring method accurately simulates mitral valve closure from image-based models

Heart valves are functionally complex, making surgical repair difficult. Simulation-based surgical planning could facilitate repair, but current finite element studies are prohibitively slow for rapid, clinically-oriented simulations. An anisotropic, nonlinear mass-spring (M-S) model is used to approximate the behavior of valve leaflets and applied to fully image-based mitral valve models to simulate valve closure for fast applications like intraoperative surgical planning. This approach is used to simulate a technique used in valve repair and to assess the role of chordae in determining the closed configuration of the valve. Direct image-based comparison is used for validation. Results of M-S model simulations showed that it is possible to build fully image-based models of the mitral valve and to rapidly simulate closure with sub-millimeter accuracy. Chordae, which are presently difficult to image, are shown to be strong determinants of closed valve shape.

Computational model of aortic valve surgical repair using grafted pericardium.

Aortic valve reconstruction using leaflet grafts made from autologous pericardium is an effective surgical treatment for some forms of aortic regurgitation. Despite favorable outcomes in the hands of skilled surgeons, the procedure is underutilized because of the difficulty of sizing grafts to effectively seal with the native leaflets. Difficulty is largely due to the complex geometry and function of the valve and the lower distensibility of the graft material relative to native leaflet tissue. We used a structural finite element model to explore how a pericardial leaflet graft of various sizes interacts with two native leaflets when the valve is closed and loaded. Native leaflets and pericardium are described by anisotropic, hyperelastic constitutive laws, and we model all three leaflets explicitly and resolve leaflet contact in order to simulate repair strategies that are asymmetrical with respect to valve geometry and leaflet properties. We ran simulations with pericardial leaflet grafts of various widths (increase of 0%, 7%, 14%, 21% and 27%) and heights (increase of 0%, 13%, 27% and 40%) relative to the native leaflets. Effectiveness of valve closure was quantified based on the overlap between coapting leaflets. Results showed that graft width and height must both be increased to achieve proper valve closure, and that a graft 21% wider and 27% higher than the native leaflet creates a seal similar to a valve with three normal leaflets. Experimental validation in excised porcine aortas (n=9) corroborates the results of simulations.

Noninvasive serial evaluation of myocardial mechanics in pressure overload hypertrophy of rabbit myocardium

Background: The determination of progression from afterload mismatch to myocardial failure in small animals requires invasive monitoring to assess ventricular pressure. Objective: We sought to (1) validate the noninvasive determination of blood pressure using optical plethysmography, and (2) determine the time course and progression from afterload mismatch to myocyte failure in neonatal rabbits with coarctation (aortic banding at 7–10 days of life) compared to normal rabbits. Methods and Results: Comparison of continuous arterial pressure determined by optical plethysmography with high-fidelity intraarterial recording was performed in nine animals. An accuracy of 5.9 ± 4.7 and 9.2 ± 6.9 mm Hg for systolic and diastolic blood pressure was noted. Fourier analysis confirmed similar frequency components. Simultaneous transthoracic echocardiography and optical plethysmography were serially performed in 33 banded and 13 control animals. Load-dependent and -independent measures of myocardial function were obtained. Midwall contractility, initially normal, showed a gradual significant deterioration (0.22 ± 1.68 [week 3] to −1.36 ± 1.24 [week 6]; Z-scores). Conclusions: This novel noninvasive method for determination of myocardial mechanics allows for serial evaluation of cardiac function and the determination of the time course from compensated hypertrophy to myocyte failure.Hintergrund: Zur Bestimmung des linksventrikulären Drucks bei kleinen Tieren bedarf es des invasiven Monitorings. Diese Parameter sind erforderlich, um die Progression von pathologischer Nachlasterhöhung bis hin zum myokardialen Versagen messen zu können. Ziel: In dieser Studie soll in neonatalen Kaninchen mit Aortenkoarktation (Banding der Aorta descendens im Alter von 7–10 Tagen) zum einen die nichtinvasive Bludruckmessung mittels optischer Plethysmographie validiert und zum anderen der zeitliche Verlauf der Progression von pathologischer Nachlasterhöhung bis hin zum myokardialen Versagen erfasst werden. Methodik und Ergebnisse: Kontinuierliche invasive Messungen des arteriellen Blutdrucks und nichtinvasive Bludruckmessung mittels optischer Plethysmographie wurden bei insgesamt neun Tieren durchgeführt und miteinander verglichen. Eine Messungenauigkeit von 5,9 ± 4,7 und 9,2 ± 6,9 mm Hg für systolischen bzw. diastolischen Bludruck wurde ermittelt und konnte des Weiteren durch eine Fourier-Analyse bestätigt werden. Transthorakale Echokardiographie mit simultaner optischer Plethysmographie wurde bei insgesamt 33 operierten und 13 Kontrolltieren durchgeführt, wobei nachlastabhängige und -unabhängige Parameter der Myokardfunktion erhoben wurden. Initial war die Kontraktilität der Myokardwandmitte normal, verschlechterte sich bei den Tieren mit Aortenkoarktation aber im zeitlichen Verlauf (0,22 ± 1,68 [Alter: 3 Wochen], −1,36 ± 1,24 [Alter: 6 Wochen]; Z-Scores). Diese neue nichtinvasive Methode zur Bestimmung der Myokardmechanik ermöglicht die Durchführung wiederholter Untersuchungen, um die sich verändernde Kontraktilität bei progressiver linksventrikulärer Hypertrophie – angefangen bei der kompensierten Myokardhypertrophie bis hin zum terminalen Herzversagen – im zeitlichen Verlauf zu verfolgen. Schlussfolgerungen: Die Etablierung eines Tiermodells zur Untersuchung der Myokardmechanik von kompensierter Hypertrophie bis zum Myokardversagen kann als Grundlage zur Testung besserer Therapieverfahren dienen, die dann auch Eingang in die klinische Praxis finden würden.

Image-based mass-spring model of mitral valve closure for surgical planning

Surgical repair of the mitral valve is preferred in most cases over valve replacement, but replacement is often performed instead due to the technical difficulty of repair. A surgical planning system based on patient-specific medical images that allows surgeons to simulate and compare potential repair strategies could greatly improve surgical outcomes. In such a surgical simulator, the mathematical model of mechanics used to close the valve must be able to compute the closed state quickly and to handle the complex boundary conditions imposed by the chords that tether the valve leaflets. We have developed a system for generating a triangulated mesh of the valve surface from volumetric image data of the opened valve. We then compute the closed position of the mesh using a mass-spring model of dynamics. The triangulated mesh is produced by fitting an isosurface to the volumetric image data, and boundary conditions, including the valve annulus and chord endpoints, are identified in the image data using a graphical user interface. In the mass-spring model, triangle sides are treated as linear springs, and sides shared by two triangles are treated as bending springs. Chords are treated as nonlinear springs, and self-collisions are detected and resolved. Equations of motion are solved using implicit numerical integration. Accuracy was assessed by comparison of model results with an image of the same valve taken in the closed state. The model exhibited rapid valve closure and was able to reproduce important features of the closed valve.

On the design of an interactive, patient-specific surgical simulator for mitral valve repair

Surgical repair of the mitral valve is a difficult procedure that is often avoided in favor of less effective valve replacement because of the associated technical challenges facing non-expert surgeons. In the interest of increasing the rate of valve repair, an accurate, interactive surgical simulator for mitral valve repair was developed. With a haptic interface, users can interact with a mechanical model during simulation to aid in the development of a surgical plan and then virtually implement the procedure to assess its efficacy. Sub-millimeter accuracy was achieved in a validation study, and the system was successfully used by a cardiac surgeon to repair three virtual pathological valves.

Optical Mapping of Langendorff-perfused Rat Hearts

Optical mapping of the cardiac surface with voltage-sensitive fluorescent dyes has become an important tool to investigate electrical excitation in experimental models that range in scale from cell cultures to whole-organs([1, 2]). Using state-of-the-art optical imaging systems, generation and propagation of action potentials during normal cardiac rhythm or throughout initiation and maintenance of arrhythmias can be visualized almost instantly([1]). The latest commercially-available systems can provide information at exceedingly high spatiotemporal resolutions and were based on custom-built equipment initially developed to overcome the obstacles imposed by more conventional electrophysiological methods([1]). Advancements in high-resolution and high-speed complementary metal-oxide-semiconductor (CMOS) cameras and intensely-bright, light-emitting diodes (LEDs) as well as voltage-sensitive dyes, optics, and filters have begun to make electrical signal acquisition practical for cardiovascular cell biologists who are more accustomed to working with microscopes. Although the newest generation of CMOS cameras can acquire 10,000 frames per second on a 16,384 pixel array, depending on the type of sample preparation, long-established fluorescence acquisition technologies such as photodiode arrays, laser scanning systems, and cooled charged-coupled device (CCD) cameras still have some distinct advantages with respect to dynamic range, signal-to-noise ratio, and quantum efficiency([1, 3]). In the present study, Lewis rat hearts were perfused ex vivo with a crystalloid perfusate (Krebs-Henseleit solution) at 37 degrees C on a modified Langendorff apparatus. After a 20 minute stabilization period, the hearts were intermittently perfused with 11 mMol/L 2,3-butanedione monoxime to eliminate contraction-associated motion during image acquisition. For optical mapping, we loaded hearts with the fast-response potentiometric probe di-8-ANEPPS([4]) (5 microMol/L) and briefly illuminated the preparation with 475+/-15 nm excitation light. During a typical 2 second period of illumination, >605 nm light emitted from the cardiac preparation was imaged with a high-speed CMOS camera connected to a horizontal macroscope. For this demonstration, hearts were paced at 300 beats per minute with a coaxial electrode connected to an isolated electrical stimulation unit. Simultaneous bipolar electrographic recordings were acquired and analyzed along with the voltage signals using readily-available software. In this manner, action potentials on the surface of Langendorff-perfused rat hearts can be visualized and registered with electrographic signals.