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Isolated working hearts of 16 month old spontaneously hypertensive rats (SHR, n=8) and age matched Wistar-Kyoto (WKY, n=8) rats were exposed to 30 min global normothermic ischaemia followed by 60 min reperfusion. The hearts were routinely perfused at an afterload level of 13.3 kPa and a preload level of 1.0 kPa. The control values of left ventricular pressure, its maximal positive first derivative (dPlv/dtmax), coronary flow per gram heart tissue, and release of lactate and enzymes such as lactate dehydrogenase and aspartate aminotransferase were comparable in both groups. WKY rat hearts ejected almost twice as much perfusate per gram heart weight as the SHR hearts. In pressure-flow curves, obtained during the control period in SHR hearts, cardiac output was independent of changes in afterload, varying between 10.7 and 18.7 kPa. In contrast, in WKY rat hearts increases in afterload resulted in a progressive decrease in cardiac output. Reperfusion of the SHR hearts after 30 min of global normothermic ischaemia resulted in a poor recovery of cardiac output (13% of the control values) and dPlv/dtmax (32%) compared with the values in the WKY rat hearts (66% and 91% of the control values respectively). Reactive hyperaemia was prominent in the WKY rat hearts but completely absent in the SHR hearts. During one hour reperfusion, SHR hearts lost 3.5 times more lactate dehydrogenase and 2.5 times more aspartate aminotransferase than the WKY rat hearts. Pressure-flow curves, obtained during the reperfusion period, showed modest recovery of myocardial function of the WKY rat hearts at the lowest afterload level tested but completely depressed myocardial function of the SHR hearts at all afterload levels. Heart tissue contents of adenosine triphosphate and creatine phosphate after one hour of reperfusion were lower in the SHR than in the WKY rats, but compared with native values a comparable percentage decrease was seen in both groups of rats. [ABSTRACT FROM PUBLISHER]

An abstract of the study "Intracardiac Minipump Provides Significantly Effective Cardiac and Circulatory Support During Severe Acute Cardiogenic Shock," by K. D. Reesink and colleagues is presented.

An abstract of the study "Pericardial containment controls acute cardiac overload," by K. D. Reesink and colleagues, is presented.

Venous cannulae undergo continuous improvements to achieve better and safer venous drainage. Several cannula tests have been reported, though cannula performance during inlet obstruction has never been a test criterion. In this study, five different cannulae for proximal venous drainage were tested in a mock circulation that enabled measurement of hydraulic conductance after inlet obstruction by vessel collapse. Values for hydraulic conductance ranged from 1.11 x 10(-2) L/min/mm Hg for a Thin-Flex Single Stage Venous Cannula with an open-end lighthouse tip to 1.55 x 10(-2) L/min/mm Hg for a DLP VAD Venous Cannula featuring a swirled tip profile, showing a difference that amounts to nearly 40% of the lowest conductance value. Excessive venous drainage results in potentially dangerous high-negative venous line pressures independent of cannula design. Cannulatip design featuring swirled and grooved tip structures increases drainage capacity and enhances cannula performance during inlet obstruction.

Some patients in need of hemodynamic support do not respond to intra-aortic balloon pump (IABP) therapy. Hemodynamic stability can then be obtained by a more potent cardiac assist device, like the Impella catheter pump. Whether additional IABP support additional to Impella support can provide more optimal hemodynamic myocardial conditions is examined in this study. Seven sheep were implemented with IABP and Impella. An acute myocardial infarction was induced. Hemodynamic performance was assessed during baseline, during Impella support and IABP support individually, and during the combined Impella plus IABP support. The Impella support provided a reduction of afterload with 30% and an increase of coronary artery flow with 47%. The IABP increased coronary artery flow (13%), carotid artery flow (16%), and aortic ascending blood pressure (6%); a similar (but stronger) effect was provided when using the IABP support additional to Impella support and, respectively, increases of 33, 21, and 19% were established. The oxygen demand-supply ratio decreased by 25% due to the extra use of the IABP. A combination of IABP and Impella provides the most optimal hemodynamic myocardial conditions compared to either stand-alone support.

Myocardial biopsies are an increasingly important tool to unravel the molecular mechanisms of cardiac disease. We evaluate a novel minimally invasive trans-thoracic approach for left-ventricular (LV) intra-mural biopsies, which enables repetitive individual sampling in adult dogs. Forty three generally anaesthesised dogs were studied during sinus rhythm (SR, control) and multiple times after the induction of volume overload hypertrophy (complete atrioventricular block [AVB]). Through a small cutaneous incision, an automatic biopsy needle was advanced into the apicolateral LV, guided by fluoroscopy. Electrocardiography (ECG), LV pressure and echocardiography served to monitor the procedure. One hundred eighty-eight intra-mural LV biopsies were obtained in 82 serial experiments (usually SR, 1, 2 and 6 weeks AVB) with a maximum of 8 repeated biopsies. All biopsies ( approximately 10 mm(3)) were suitable for simultaneous application of different cell-biological (light and electron microscopy, immunohistochemistry) and molecular techniques (PCR, Western blotting). In chronic experiments, repeated biopsy sampling did not influence haemodynamics, mechanics, electrocardiographic parameters or myocardial remodelling during SR or AVB. The rate of significant complications was as low as 4% of experiments. Minimally invasive sampling of LV needle biopsies enables serial assessment of myocardial remodelling using different molecular techniques in individual animals. The technique is safe and has no long-term effects on cardiac function or structure.

The objective of this study was to investigate venous collapse (VC) related to venous drainage during the use of an extracorporeal life support circuit. A mock circulation was built containing a centrifugal pump and a collapsible vena cava model to simulate VC under controlled conditions. Animal experiments were performed for in vivo verification. Changing pump speed had a different impact on flow during a collapsed and a distended caval vein in both models. Flow measurement in combination with pump speed interventions allows for the detection and quantitative assessment of the degree of VC. Additionally, it was verified that a quick reversal of a VC situation could be achieved by a two-step pump speed intervention, which also proved to be more effective than a straightforward decrease in pump speed.

Background: The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects. Experimentally, AVE0118 has been antiarrhythmic against some specific ventricular arrhythmias., Objectives: The purpose of this study was to investigate the proarrhythmic and antiarrhythmic effects of AVE0118 in anesthetized dogs with chronic complete AV block, known for a high proclivity for torsades de pointes (TdP)., Methods: AVE0118 was administered intravenously as a fast infusion (0.5 mg/kg/5 min) and a slow infusion (3 or 10 mg/kg/60 min). Dofetilide was given to induce TdP. ECG and monophasic action potentials were recorded. Short-term beat-to-beat variability (STV) of the left ventricular monophasic action potential duration (MAPD) was calculated. We examined whether AVE0118 (1) caused ventricular proarrhythmia (both infusions), (2) prevented dofetilide-induced TdP (slow infusion + dofetilide after 30 minutes), and (3) abolished TdP (fast infusion)., Results: At 0.55 +/- 0.10 microg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD(50) and MAPD(90) were significantly increased by 26% +/- 9% and 10% +/- 5%, respectively (P <.05 vs baseline). At 1.9 +/- 0.5 microg/mL and 6.1 +/- 1.2 microg/mL (30 minutes of 3 or 10 mg/kg/h), AVE0118 did not induce TdP (0/6 and 0/4) nor prevent dofetilide-induced TdP (6/6 and 2/2). Dofetilide significantly increased all repolarization parameters, including STV from 2.1 +/- 0.4 ms to 4.6 +/- 1.8 ms (P <.05 vs baseline), which were not changed by AVE0118 (to 2.1 +/- 0.3 ms after 30 minutes). Rapid infusion of AVE0118 did not suppress dofetilide-induced TdP., Conclusion: In the anesthetized chronic complete AV block dog, the atrial-specific drug AVE0118 is free of TdP and has no antiarrhythmic properties against dofetilide-induced torsades de pointes.

Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive IKs. Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the time course of molecular alterations underlying IKs downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to beta-adrenergic receptor (beta-AR) stimulation., Methods and Results: Serial left-ventricular (LV) biopsies were collected from anesthetized dogs during sinus rhythm (SR; control) and at 3, 7 and 30 days of AVB. KCNQ1 mRNA and protein decreased within 3 days (protein expression 58 +/- 10% of control), remaining low thereafter. beta1-AR mRNA and protein decreased more gradually to 53 +/- 8% at 7 days. In chronic-AVB LV myocytes, IKs -tail density was reduced: 1.4 +/- 0.3 pA/pF versus 2.6 +/- 0.4 pA/pF in controls. beta-A enhancement of IKs was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. beta-A early afterdepolarizations were induced in 4 of 13 chronic-AVB cells, but not in controls. In intact conscious dogs, isoproterenol shortened QTc at SR (by -8 +/- 3% from 295 ms), left it unaltered at 3 days AVB (+1 +/- 3% from 325 ms) and prolonged QTc at 30 days (+6 +/- 3% from 365 ms)., Conclusions: Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of beta1-AR expression. Downregulation and blunted beta-A activation of IKs contribute to the loss of beta-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy.

Objective: A new pulsatile extracorporeal life support (pECLS) system has entered the market. We wanted to investigate what potential advantages pECLS may have over current non-pulsatile systems (NPS). Our research was focused on the pump's functional interaction with the left ventricle and the coronary circulation., Methods: Extensive hemodynamic measurements were performed during asynchronous and synchronous pECLS in 10 calves. The two extremes regarding LV afterload, namely systolic arrival (SA) and diastolic arrival (DA) of the pump pulse were studied., Results: SA was associated with increased oxygen consumption (+57%) and decreased diastolic coronary perfusion (-43%). DA increased left ventricular output (DA: 4.5+/-2.4 l/min vs SA: 3.5+/-2.2 l/min), LV ejection fraction (+10%), and ventricular efficiency (+17%). Mean aortic pressure and mean coronary flow were only marginally affected by pulse incidence. Systolic impairment was more pronounced with higher bypass flows. These results indicate that myocardial working conditions can be optimized by phasing pECLS ejection into cardiac diastole., Conclusion: We conclude that during pECLS, myocardial working conditions can be improved by avoidance of systolic impairment. Synchronously counterpulsating pECLS could be a more economic and versatile alternative to NPS or NPS combined with intra-aortic balloon pumping. The potential benefits of synchronously counterpulsating pECLS over the current alternatives remain to be investigated.

Right-sided circulatory failure (RSCF) is a serious complication in 15-30% of patients receiving a left ventricular assist device (LVAD). It is hypothesized that left ventricular support which lacks physiologic properties predisposes to RSCF. An integral computer simulation and experimental validation protocol was performed. The results suggest that with conventional insensitive left ventricular support right-sided circulatory function is compromised, which may form a substrate for the onset or progress of RSCF. Feedback control of the LVAD could provide a means to counter this problem. A control concept for the LVAD which aims to preserve right-sided circulatory function, while supporting peripheral perfusion, is proposed

Objective: We investigated whether in vivo closed-chest left ventricular pressure-volume measurements would yield similar values for LV hemodynamics compared with open-chest PV measurements under several anesthetics., Methods: The right common carotid of C57Bl/6 mice was cannulated with a combined pressure-conductance catheter and inserted retrogradely into the left ventricle in the closed-chest model. The open-chest model consisted of an abdominal approach involving the opening of the thoracic cavity by transverse opening of the diaphragm and ventricular catheterization by apical stab. Measurements were performed under urethane or pentobarbital intraperitoneal injection anesthesia., Results: Cardiac function in the open-chest model was characterized by larger ejection fraction and stroke volume with a leftward shift in ventricular volume compared to the closed-chest model. Further observed characteristics include low end-systolic pressure and arterial-ventricular coupling mismatch in the open-chest model. Arrhythmias were not detected in either model., Conclusion: Murine cardiac function determination via open-chest or closed-chest protocols is sensitive, reproducible and comparable. The choice for open- or closed-chest pressure-volume measurements in mice depends on the aims of the study.

The quantification of mechanical interventricular asynchrony (IVA) was investigated. In 12 dogs left bundle branch block (LBBB) was induced by radio frequency ablation. Left ventricular (LV) and right ventricular (RV) pressures were recorded before and after induction of LBBB and during LBBB + LV apex pacing at different atrioventricular (AV) delays. Four IVA measures were validated using computer simulations on experimentally obtained pressure signals. The most robust measure for IVA was the time delay between the upslope of the LV and RV pressure signals (DeltaT(up)), estimated by cross correlation. The induction of experimental LBBB decreased DeltaT(up) from -6.9 +/- 7.0 ms (RV before LV) to -33.9 +/- 7.6 ms (P < 0.05) in combination with a significant decrease of LV maximal first derivative of pressure development over time (dP/dt(max)). During LV apex pacing, DeltaT(up) increased with decreasing AV delay up to +20.9 +/- 14.6 ms (P < 0.05). Interventricular resynchronization (DeltaT(up) = 0 ms) significantly improved LV dP/dt(max) by 15.1 +/- 5.9%. QRS duration increased significantly after induction of LBBB but did not change during LV apex pacing. In conclusion, DeltaT(up) is a reliable measure of mechanical IVA, which adds valuable information concerning the nature of asynchronous activation of the ventricles.

A comparative study was conducted to evaluate the feasibility of a fiber-optic sensor in invasive blood pressure measurements. Static and wide-bandwidth stimuli were offered to the fiber-optic, Millar, Baxter, and Sentron devices to measure static transfer function and transient response. Animal experiments focused on offset drift, dynamic accuracy, and electromagnetic sensitivity. Compared to the Millar, Sentron, and Baxter devices, the fiber-optic sensor had a near-identical static transfer function. Gain and offset errors were < 3.4% and < 0.25%, respectively. Hysteresis nonlinearity was < 0.1%. The dynamic accuracy of the fiber-optic system matched that of the Millar and Sentron systems. Time delay was < 1 msec. Maximum rate of change was > 30,000 mm Hg/sec and bandwidth was 0-150 Hz minimum. Offset drift was 0.6 +/- 0.03 mm Hg. Application of diathermy highlighted the fiber-optic sensor's excellent electromagnetic disturbance rejection. The fiber-optic system appears to be a reliable, high-fidelity pressure monitor in demanding clinical environments., (Copyright 2002 Wiley-Liss, Inc.)

When treating severe cardiac failure with dynamic cardiomyoplasty, knowledge about the optimal way of stimulating the latissimus dorsi (LD) muscle is of obvious importance. We evaluated a new stimulation protocol in four goats using in situ electrical stimulation of the left LD muscle. Stimulation was started using a burst of two pulses with an interpulse interval of 100 msec for 50 bursts/min. The number of pulses was increased every 2 weeks concomitant with a decrease in interpulse interval. This resulted after 12 weeks in 60 bursts/min using bursts of six pulses with an interpulse interval of 20 msec after 12 weeks. Force measurements, which were done every 2 weeks, showed an early decrease in contraction and relaxation speed as reflected in the ripple (= interstimulus amplitude/peak force amplitude measured at 10 Hz). Fatigue resistance increased significantly within 4 weeks of conditioning as indicated by preservation of force, positive dF/dt, and negative dF/dt. Full preservation of these variables was seen even during a 1-hour fatigue test at the end of the conditioning period. Skeletal muscle enzyme activity as an indicator of muscle damage showed a significant rise in creatine kinase enzyme activity only on the first day following the start of LD stimulation. LD muscle biopsies revealed almost complete transformation to type I muscle fibers with a significant increase in capillary/fiber ratio when compared to the nonstimulated LD muscle. However, some biopsies, in particular near the electrodes, did show some signs of skeletal muscle damage. Contraction characteristics of the fully transformed LD muscles were tested by increasing the number of bursts of six pulses from 50/min to 100/min. Interpulse intervals of 20 and 33 msec were used. These tests revealed that maximal force, positive dF/dt, and negative dF/dt was reached with 50 bursts/min using a six pulse burst with interpulse intervals of 20 msec.

Objective: The value of intravenous imipramine in creating a reversible model of short term heart failure was evaluated in anaesthetised dogs., Methods: Acute effects of imipramine were studied in 11 dogs using invasive haemodynamic pressure measurements and two dimensional echo evaluation., Results: After a 30 min imipramine infusion (7.5 mg.kg-1.h-1), positive left ventricular dP/dtmax decreased from 1368(SEM 108) to 909(119) mm Hg.s-1 (p < 0.05), left ventricular end diastolic pressure increased from 8(1) to 12(2) mm Hg (p < 0.05), while left ventricular pressure decreased from 106(4) to 87(6) mm Hg (p < 0.05). Cessation of imipramine administration resulted within 60 min in partial restoration of cardiac function. This deterioration and subsequent recovery was also demonstrated with echocardiographic measurements, which showed a decrease in ejection fraction from 54(3)% to 28(2)% (p < 0.05). During administration of imipramine neither significant electrophysiological changes nor supraventricular/ventricular arrhythmias were seen. Repeated infusions of imipramine in three anaesthetised dogs with a two week interval showed the reproducibility of the haemodynamic effects and the recovery of ventricular function. Since the model was developed to evaluate the use of cardiomyoplasty in heart failure, the effect of imipramine was also evaluated on latissimus dorsi muscle contraction. Administration of imipramine did not affect skeletal muscle force development at the dosage used to create heart failure., Conclusions: This model can be used to produce short term reversible heart failure in anaesthetised animals to test the efficacy of supportive interventions like dynamic cardiomyoplasty, intra-aortic balloon pumping, and mechanical cardiac assist devices.

In conscious dogs with chronic atrioventricular (AV) block, we recently demonstrated that flunarizine is effective against ouabain-induced arrhythmias (triggered activity resulting from delayed afterdepolarizations, DADs) but fails to suppress spontaneous ventricular tachycardias (VT) occurring 24 h after left anterior descending coronary artery occlusion (abnormal automaticity). Neither does flunarizine affect normal automaticity, which suggests that flunarizine could be used as a clinical tool to recognize cardiac arrhythmias based on triggered activity. To elucidate further the arrhythmia mechanism-specific action of flunarizine, we investigated (a) its hemodynamic and electrophysiologic effects in 6 anesthetized dogs, (b) its ability to prevent pacing-induced VT 7 days after myocardial infarction (reentry) in 9 anesthetized animals, and (c) its effect on premature escape beats (PEBs) in 9 conscious dogs with chronic AV block. PEBs are probably caused by DADs. Flunarizine decreased systemic blood pressure (p less than 0.01), and left ventricular dP/dt (p less than 0.01), but did not affect AH or HV internal, QRS duration, QT time, or the effective refractory period of either AV node or right ventricle over a wide range of (paced) cycle lengths. Flunarizine decreased the inducibility of PEBs by 42% (p less than 0.01), but not that of the reentrant VT in any of the 6 inducible dogs. Therefore, we conclude that although flunarizine has no electrophysiologic effects in normal heart, it prevents induction of PEBs. The inability of flunarizine to prevent induction of reentrant VT confirms the mechanism-specific action of flunarizine against triggered activity.

The effect of cooling to 25 degrees C on myocardial metabolism was studied during four periods of global ischemia (10 minutes each) followed by 15 minutes of reperfusion in dogs on cardiopulmonary bypass. Systemic and heart temperature at normothermia (group N, 34 degrees C; n = 15) was compared with general hypothermia (group H, 25 degrees C; n = 16). Before and at the end of each aortic crossclamp period in small myocardial biopsy specimens the adenosine triphosphate, creatine phosphate, inorganic phosphate, glycogen, and lactate content was analyzed. Also, lactate and inorganic phosphate were measured in the coronary effluents during the repetitive periods of reperfusion. Hemodynamic function was not different at 60 minutes after cardiopulmonary bypass compared with pre-cardiopulmonary bypass values, and was not different between the groups N and H. The tissue content of adenosine triphosphate and glycogen decreased progressively during the experimental period, resulting in slightly depressed values in both groups at the end of cardiopulmonary bypass. Pronounced effects of ischemia and reperfusion on tissue content of creatine phosphate, inorganic phosphate, and lactate were observed after each period of ischemia. The net decrease in tissue creatine phosphate content was not different between groups N and H (41 +/- 4 versus 38 +/- 4 mumol.gm-1 dry weight; mean +/- standard error of the mean) after 10 minutes of ischemia. However, during ischemia the net inorganic phosphate increase in myocardial tissue was significantly higher in group H (70 +/- 7 mumol.gm-1) than in group N (44 +/- 3 mumol.gm-1). These findings do not support the notion that myocardial protection is improved during hypothermia. Moreover, quantitatively the release of inorganic phosphate and lactate did not correlate with the amount accumulated in the myocardial tissue during the preceding periods of ischemia. The release appeared to be temperature dependent, that is, significantly reduced at 25 degrees C. The present data demonstrate why clinical outcome is satisfactory in both surgical procedures, when in general the periods of aortic crossclamping do not exceed 10 minutes each and the reperfusion periods in between the ischemic episodes last about 15 minutes. Besides, the findings indicate that hypothermia is not strictly necessary under these circumstances.