optical-mapping-of-langendorff-perfused-rat-hearts

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 ...

Beeintr&#xE4;chtigt parasympathischen Pulssteuerung bei M&#xE4;usen mit einer Reduzierung der funktionellen G-Protein-Untereinheiten betagamma.

Acetylcholine released on parasympathetic stimulation slows heart rate through activation of muscarinic receptors on the sinus nodal cells and subsequent opening of the atrial muscarinic potassium channel (K(ACh)). K(ACh) is directly activated by G protein betagamma-subunits. To elucidate the physiological role of Gbetagamma for the regulation of heart rate and electrophysiological function in vivo, we created transgenic mice with a reduced amount of membrane-bound Gbeta protein by overexpressing nonprenylated Ggamma(2)-subunits in their hearts using the alpha-myosin heavy chain promoter. At baseline and after muscarinic stimulation with carbachol, heart rate and heart rate variability were determined with electrocardiogram telemetry in conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional Gbetagamma protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were observed in wild types. In addition, sinus node recovery time and inducibility of atrial arrhythmias were reduced in transgenic mice. Our data demonstrate in vivo that Gbetagamma plays a crucial role for parasympathetic heart rate control, sinus node automaticity, and atrial arrhythmia vulnerability.

Impaired parasympathetic heart rate control in mice with a reduction of functional G protein betagamma-subunits.

The determination of progression from afterload mismatch to myocardial failure in small animals requires invasive monitoring to assess ventricular pressure.

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

Nichtinvasive serielle Auswertung der Myokard-Mechaniker in Druck&#xFC;berlastung Hypertrophie des Herzmuskels Kaninchen.

Studies suggest that entrainment response (ER) of reentrant tachycardia to overdrive pacing can be estimated using signals from sites other than the paced site.

Estimation of entrainment response using electrograms from remote sites: validation in animal and computer models of reentrant tachycardia.

Absch&#xE4;tzung der Verschleppung Antwort mit Elektrogramme von Remote-Standorten: Validierung in der Tier-und Computer-Modelle von Reentrytachykardie.

Programmed ventricular stimulation is being performed for the provocation of ventricular arrhythmias in genetically engineered mice. Despite the high level of interest in this area of translational research, little attention has been given to differentiating between selectivity and specificity of induced ventricular tachycardia (VT) in phenotypically normal mice. We aimed to assess factors that may enhance inducibility of VT in wild-type (WT) mice. In vivo intracardiac electrophysiological studies (EPS) were performed in 230 WT mice of 4 strains. An octapolar electrode catheter was inserted into a jugular vein and advanced to the right atrium and ventricle. Baseline ventricular conduction, refractoriness, and arrhythmia inducibility were assessed using programmed electrical stimulation (PES) and burst pacing. We found that nonsustained VT (> or =4 beats) was inducible in 68/230 (30%) mice. Duration of VT was 1.6 +/- 2.4 s, and the longest episode lasted 24 s. VT inducibility differed by strain and age. Ventricular effective refractory period (VERP) was shorter in mice with inducible VT (44 +/- 12 ms) compared with noninducible mice (61 +/- 16 ms, P < 0.001). VERP increased with age (P < 0.001), albeit with strain-related variability. We conclude that nonsustained VT in WT mice is reproducibly inducible and common. Genetic background variability may predispose certain strains to a higher incidence of arrhythmia induction. EPS methods impact prevalence and specificity of inducible VT. Increased VT inducibility was seen with shorter coupling intervals and application of tightly coupled extrastimuli techniques. These factors should be carefully considered when analyzing PES and burst pacing data in murine models to minimize false positives and optimize accuracy.

Implications of ventricular arrhythmia vulnerability during murine electrophysiology studies.

Auswirkungen von ventrikul&#xE4;ren Arrhythmien Verwundbarkeit w&#xE4;hrend murine elektrophysiologischen Studien.

A mathematical model of the arterial baroreflex was developed and used to assess the stability of the reflex and its potential role in producing the low-frequency arterial blood pressure oscillations called Mayer waves that are commonly seen in humans and animals in response to decreased central blood volume. The model consists of an arrangement of discrete-time filters derived from published physiological studies, which is reduced to a numerical expression for the baroreflex open-loop frequency response. Model stability was assessed for two states: normal and decreased central blood volume. The state of decreased central blood volume was simulated by decreasing baroreflex parasympathetic heart rate gain and by increasing baroreflex sympathetic vaso/venomotor gains as occurs with the unloading of cardiopulmonary baroreceptors. For the normal state, the feedback system was stable by the Nyquist criterion (gain margin = 0.6), but in the hypovolemic state, the gain margin was small (0.07), and the closed-loop frequency response exhibited a sharp peak (gain of 11) at 0.07 Hz, the same frequency as that observed for arterial pressure fluctuations in a group of healthy standing subjects. These findings support the theory that stresses affecting central blood volume, including upright posture, can reduce the stability of the normally stable arterial baroreflex feedback, leading to resonance and low-frequency blood pressure waves.

Resonance in a mathematical model of baroreflex control: arterial blood pressure waves accompanying postural stress.

Resonance in einem mathematischen Modell des Baroreflex Steuerung: arterielle Blutdruck Wellen begleiten Haltungssch&#xE4;den Stress.

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins. Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal's natural life. Perfusion of hearts with fluorescently labeled lec-tin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding re-cipient rat cardiomyocytes. Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy.

Cardiac conduction through engineered tissue.

Bei Kindern kann Unterbrechung des Herzens Atrioventrikul&auml;rer (AV) Elektrische Leitverm&ouml;gen w&auml;hrend der Schwangerschaft durch angeborene Defekte, chirurgische Eingriffe und m&uuml;tterlichen Autoimmunkrankheiten entstehen. Komplette AV-Reizleitungs wird in der Regel durch Implantation einer elektronischen Herzschrittmacher-Ger&auml;ts behandelt, obwohl langfristige Therapie in der p&auml;diatrischen Patienten Tempo hat erhebliche Komplikationen. Als ersten Schritt zur Entwicklung einer Ersatz-Behandlung implantierten wir technische Gewebe-Konstrukte in Rattenherzen eine alternative AV Leitverm&ouml;gen Weg zu erstellen. Wir fanden, dass skelettartiger Muskel-abgeleitete Zellen in die Konstrukte nachhaltige elektrische Kopplung durch best&auml;ndige Ausdruck und Funktion L&uuml;cke Kreuzung Proteine ausgestellt. Mit Fluoreszenz-in Situ-Hybridisierung und Polymerase-Kettenreaktion-Analysen, zeigten die myogener Zellen in die Konstrukte in der AV-Nut der implantierten Herzen f&uuml;r die Dauer des nat&uuml;rlichen Lebens des Tieres zu &uuml;berleben. Perfusion der Herzen mit Leuchtstoff beschriftetem Lec-Zinn gezeigt, dass implantierten Gewebe wurde vascularized Paraffinschnitten &uuml;berpr&uuml;ft das Vorhandensein von Proteinen wichtig, Elektromechanische Integration myogener Zellen mit den umliegenden R&uuml;ck-chrichtigen Ratte Cardiomyocytes. Schlie&szlig;lich belegen mit optische Zuordnung und elektrophysiologischen Analysen, wir permanent AV-Leitung durch das Implantat in einem Drittel der Empf&auml;nger Tiere. Unsere Experimente bieten ein Beweis-des-Prinzip, die Gewebe-Konstrukte des Saatguts kann als eine elektrische Kanal fungieren und letztlich eine Ersatz-Behandlung, um konventionelle Tempo Therapie bieten kann.

Kardiale W&auml;rmeleitung durch ver&auml;nderte Gewebe.

Previous studies have demonstrated that alterations in myocardial structure, consistent with tissue and sarcomere disruption as well as myofibril dissociation, occur after myocardial ischemia and reperfusion. In this study we determine the onset of these structural changes and their contribution to electrical conduction.

Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion.

Fr&uuml;here Studien haben bewiesen, dass Ver&auml;nderungen in der myokardialen Struktur, mit Gewebe und Sarkomer St&ouml;rung sowie Muskelfibrille Dissoziation, nach myokardialen Isch&auml;mie und Reperfusion auftreten. In dieser Studie ermitteln wir den Beginn dieser strukturellen Ver&auml;nderungen und ihren Beitrag zur elektrischen Leitung.

Verringerung und Neuverteilung der L&uuml;cke und Adherens Junction-Proteine nach Isch&auml;mie und Reperfusion.

We propose a mathematical model to describe the hemodynamic changes induced by a venous occlusion in a human limb. These hemodynamic changes, which include an increase in blood volume, a reduction in blood flow, and modifications to the oxygen saturation of hemoglobin, can all be measured noninvasively with near-infrared spectroscopy (NIRS). To test the model, we have performed NIRS measurements on the human forearm, specifically on the brachioradialis muscle, during venous occlusion induced by a pneumatic cuff inflated around the upper arm to pressures within the range 10-60 mmHg. We have found a good agreement between parameters measured by NIRS (total hemoglobin concentration and hemoglobin saturation) and the corresponding model parameters (capacitor voltage and arterial/capillary branch current). In particular, model and experiment indicate that the time constant for blood accumulation during venous occlusion (approximately 73-79 s) is much slower than the time constant for blood drainage following cuff release (approximately 5 s). These results indicate that this mathematical model can be a valuable analytical tool to characterize, optimize, and further develop diagnostic measurement schemes that use venous occlusion approaches.

Mathematical model for the hemodynamic response to venous occlusion measured with near-infrared spectroscopy in the human forearm.

Wir schlagen ein mathematisches Modell zur Beschreibung der h&auml;modynamischen Ver&auml;nderungen induziert durch eine ven&ouml;se Thrombose in einer menschlichen Gliedma&szlig;en. Diese h&auml;modynamischen Ver&auml;nderungen, darunter eine Erh&ouml;hung im Blutvolumen, eine Verringerung der Durchblutung und &Auml;nderungen an die Sauerstoffs&auml;ttigung des H&auml;moglobins, k&ouml;nnen alle Bauteilqualit&auml;t mit Nah-Infrarot Spektroskopie (NIRS) gemessen werden. Um das Modell zu testen, haben wir NIRS-Messungen f&uuml;r die menschlichen Unterarm, speziell auf der Brachioradialis Muskel, w&auml;hrend ven&ouml;se Thrombose induziert durch einen pneumatischen Manschette um den Oberarm Druck innerhalb der Bereich 10-60 MmHg aufgepumpt ausgef&uuml;hrt. Wir haben ein gutes Abkommen zwischen Parametern gemessen an NIRS (Gesamt-H&auml;moglobin-Konzentration und H&auml;moglobin S&auml;ttigung) und die entsprechenden Modellparameter (Kondensator-Spannung und arterielle/Kapillare Filiale aktuelle) gefunden. Insbesondere Modell und Experiment zeigen, dass die Zeitkonstante f&uuml;r Blut Akkumulation w&auml;hrend ven&ouml;se Thrombose (ca. 73-79-s) ist viel langsamer als die Zeitkonstante f&uuml;r Blut-Ableitung nach einer Manschette Freisetzung (ca. 5 s). Diese Ergebnisse zeigen, dass dieses mathematischen Modells eine wertvolle Analyse-Tool sind zu charakterisieren, Optimierung und Weiterentwicklung der diagnostischen Messung-Schemata, die ven&ouml;se Thrombose Ans&auml;tze verwenden.

Mathematisches Modell f&uuml;r die h&auml;modynamische Reaktion auf ven&ouml;se Thrombose mit Nah-Infrarot-Spektroskopie in der menschlichen Unterarm gemessen.

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.

Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants.

Zerebralen Blut flie&szlig;en Druck-Passivit&auml;t f&uuml;hrt, wenn Druck Selbstregelung beeintr&auml;chtigt ist oder Sie &uuml;berw&auml;ltigt, und wird gedacht, um zerebrovaskul&auml;re Verletzung in die vorzeitige S&auml;ugling zugrunde liegen. Fr&uuml;here Schreibmappe Beobachtungen vorgeschlagen, dass vor&uuml;bergehende Perioden der zerebralen Druck-Passivit&auml;t bei Fr&uuml;hgeborenen aufgetreten ist. Jedoch werden nicht diese vor&uuml;bergehende Ereignisse durch intermittierende statische Messungen der Druck Selbstregelung zuverl&auml;ssig erkannt. Daher verwendet wir kontinuierliche Schreibmappe Aufnahmen des mittleren arteriellen Druck (Karte; aus einer Innewohnung arterielle Katheter) und zerebrale Perfusion [mit den Nah-Infrarot Spektroskopie (NIRS) Hb Unterschied (HbD) Signal), zerebrale Druck-Passivit&auml;t in der ersten 5D nach der Geburt bei S&auml;uglingen mit Geburtsgewicht zu erkennen &lt; 1500 g. Da die Hb Unterschied (HbD) Signal [HbD = Oxyhemoglobin (HbO2) - Hb] korreliert mit zerebralen Blutflusses (CBF), verwendeten wir Koh&auml;renz zwischen Karte und HbD, um Druck-Passivit&auml;t zu definieren. Wir messen die Pr&auml;valenz von Druck-Passivit&auml;t &uuml;ber einen Druck-passiv-Index (PPI), definiert als der Anteil der 10-min-Epochen mit erheblichen Niederfrequenz-Koh&auml;renz zwischen der Karte und HbD-Signale. Druck-Passivit&auml;t ist aufgetreten in 87 90 Fr&uuml;hgeborene mit einem Mittelwert PPI 20,3 %. Zerebrale Druck-Passivit&auml;t war deutlich in Zusammenhang mit niedrigem Gestationsalter und Geburtsgewicht, systemische Hypotonie und m&uuml;tterlichen h&auml;modynamischen Faktoren, aber nicht mit Markern der m&uuml;tterlichen Infektion. Zuk&uuml;nftige Studien mit konsistenten serielle Gehirn Bildgebung sind notwendig, definieren Sie die Beziehung zwischen PPI und zerebrovaskul&auml;re Verletzungen in den Kranken vorzeitige S&auml;ugling.

Schwankenden Druck-Passivit&auml;t ist &uuml;blich in der zerebralen Zirkulation des Kranken Fr&uuml;hgeborenen.

Duchenne-Muskeldystrophie (DMD) ist eine progressive Muskelentspannung-Krankheit verursacht durch Mutationen im Dystrophin-gen. Kardiomyopathie, Reizleitungsst&ouml;rungen und ventrikul&auml;re Arrhythmien sind erhebliche Komplikationen dieser Krankheit. Die Mdx (5cv)-Maus tr&auml;gt eine Dystrophin-Mutation und veranschaulicht einen schwereren Ph&auml;notyp als die klassischen Mdx-Maus.

Kardiale elektrophysiologische Eigenschaften von Mdx (5cv) Mausmodell der Duchenne-Muskeldystrophie.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by mutations in the dystrophin gene. Cardiomyopathy, conduction abnormalities, and ventricular arrhythmias are significant complications of this disease. The mdx ( 5cv ) mouse carries a dystrophin mutation and demonstrates a more severe phenotype than the classic mdx mouse.

Cardiac electrophysiological characteristics of the mdx ( 5cv ) mouse model of Duchenne muscular dystrophy.

Complete heart block is a significant clinical problem that can limit the quality of life in affected children. To understand the pathophysiology of this condition and provide for development of novel therapies, we sought to establish a large animal model of permanent, pacemaker-dependent atrioventricular block (AVB) that mimics the size and growth characteristics of pediatric patients.

Development of an ovine model of pediatric complete heart block.

Komplette Herzblock ist ein bedeutendes Klinisches Problem, das Verbesserung der Lebensqualit&auml;t bei betroffenen Kindern einschr&auml;nken. Um die Pathophysiologie der Erkrankung zu verstehen und bieten f&uuml;r die Entwicklung neuartiger Therapien, wollten wir eine gro&szlig;e Tiermodell f&uuml;r dauerhafte, Herzschrittmacher-abh&auml;ngige AV-Block (AVB) zu etablieren, das die Gr&ouml;&szlig;e und das Wachstum Merkmale der p&auml;diatrischen Patienten nachahmt.

Entwicklung eines Schafe Modells der p&auml;diatrischen komplette Herzblock.

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.

Mass-spring model for simulation of heart valve tissue mechanical behavior.

Herzklappen sind funktional Komplex, chirurgische Reparatur erschwert. Simulationsbasierte Operationsplanung Reparatur erleichtern k&ouml;nnte, aber aktuelle finite Elemente (FE) Studien sind untragbar langsam f&uuml;r schnelle, klinisch orientierte Simulationen. Masse-Feder (M-S) Modelle sind schnell aber ungenau sein k&ouml;nnen. Wir quantifizieren, Geschwindigkeit und Genauigkeit Unterschiede zwischen einem anisotropen, nichtlineare M-S und ein effizientes FE-Membran-Modell f&uuml;r beide biaxialen simulieren und Druck beladen der Aortenklappe (AV)-Merkbl&auml;tter. Die FE-Modelle Bergen etwa 10 Mal die computational Kosten f&uuml;r das M-S-Modell. F&uuml;r simulierte biaxialen laden, meine Fehler im normalen Belastungen ist &lt; 1 % FE und M-S Modelle f&uuml;r Equibiaxial laden sondern erh&ouml;ht f&uuml;r nicht-Equibiaxial Zust&auml;nde f&uuml;r das M-S-Modell (7 %). Das M-S-Modell konnte weniger Scherung Verhalten, mittlere Belastung Fehler von rund 80 % zu simulieren. Unter Druck stehende AV-Prospekte das M-S-Modell vorhersagt &auml;hnliche Brosch&uuml;re Abmessungen dem FE-Modell (max. 2,6 %) und die Coaptation-Zone ist zwischen Modellen vergleichbar. Das M-S-Modell simuliert in der Ebene Verhalten der AV-Merkbl&auml;tter betr&auml;chtlich schneller als das FE-Modell und mit nur kleinen Unterschieden im deformierten Mesh. W&auml;hrend das M-S-Modell keine explizite Kontrolle der Scherung Antwort zul&auml;sst, beeinflusst scher Form des simulierten AV unter Druck nicht stark.

Article	Year
Impaired parasympathetic heart rate control in mice with a reduction of functional G protein betagamma-subunits. American journal of physiology. Heart and circulatory physiology\| PubMed ID: 11788391	2002
Noninvasive serial evaluation of myocardial mechanics in pressure overload hypertrophy of rabbit myocardium. Herz\| PubMed ID: 12616321	2003
Estimation of entrainment response using electrograms from remote sites: validation in animal and computer models of reentrant tachycardia. Journal of cardiovascular electrophysiology\| PubMed ID: 12625610	2003
Implications of ventricular arrhythmia vulnerability during murine electrophysiology studies. Physiological genomics\| PubMed ID: 12888626	2003
Resonance in a mathematical model of baroreflex control: arterial blood pressure waves accompanying postural stress. American journal of physiology. Regulatory, integrative and comparative physiology\| PubMed ID: 15718393	2005
Cardiac conduction through engineered tissue. The American journal of pathology\| PubMed ID: 16816362	2006
Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion. The Annals of thoracic surgery\| PubMed ID: 16996956	2006
Mathematical model for the hemodynamic response to venous occlusion measured with near-infrared spectroscopy in the human forearm. IEEE transactions on bio-medical engineering\| PubMed ID: 17405365	2007
Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatric research\| PubMed ID: 17515873	2007
Cardiac electrophysiological characteristics of the mdx ( 5cv ) mouse model of Duchenne muscular dystrophy. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing\| PubMed ID: 17940855	2007
Development of an ovine model of pediatric complete heart block. The Journal of surgical research\| PubMed ID: 21227467	2011
Mass-spring model for simulation of heart valve tissue mechanical behavior. Annals of biomedical engineering\| PubMed ID: 21350891	2011

Peter E. Hammer

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