Acute Heart Failure Model Research Articles

The study of the feasibility of the tansaortic cannlation in left ventricular assist by animal experiments

Objective To approach the feasibility of using the left ventricular assist by the transaortic cannulation in the acute heart failure animal model. Methods To attempt the left ventricular assist by the transaortic carmulation in 6 acute heart failure pigs. And to observe the hemodynamie and the ultrasonic cardiogram results. Results 5 of 6 pigs finished the total procedure. All of them presented the acute heart failure status by the hemodynamic results (P 0.05). Comparing with the heart failure status, the circularory assist improved the hemo-dynamic and the biochemical results (P<0. 05). The improvement of Left Ventricular Ejection Fraction (LVEF) had also been shown by the ultrasonic cardiogram (P<0.05). Conclusion It's proved by the experiments that the transaortic cannulation didn't result in harmful effects in valves and in left ventricular function after the establishment of the acute heart failure model. This type of circulatory assist can amelio-rate the acute heart failure status in short time. Key words: Circulatory assist; Transaortic cannulation; Heart failure; Model,animal

Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation

Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.5 x 10(-5) M/kg/day) led to a significant fourfold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation. Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the AHF group, and the AHF+PP36 group two days after AHF induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group. In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the AHF group and the AHF+PP36 group. There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands' catecholamine content between the AHF group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the AHF group's animals. These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.

Smooth Muscle-Dependent Changes in Aortic Wall Dynamics during Intra-Aortic Counterpulsation in an Animal Model of Acute Heart Failure

Intra-aortic balloon pumping (IABP) may modify arterial biomechanics; however, its effects on arterial wall properties during acute cardio-depression have not yet been fully explored. This dynamical study was designed to characterize the effects of IABP on aortic wall mechanics in an in vivo animal model of acute heart failure. Aortic pressure, diameter and blood flow were measured in six anesthetized sheep with acute cardio-depression by halothane (4%), before and during IABP (1:2). Aortic characteristic impedance and aortic wall stiffness indexes were calculated. acute experimental cardio-depression resulted in a reduction in mean aortic pressure (p<0.05) and an increase in the characteristic impedance (p<0.005), incremental elastic modulus (p<0.05), stiffness index (p<0.05) and Peterson elastic modulus (p<0.05). IABP caused an increase in the cardiac output (p<0.005) and a reduction in the systemic vascular resistances (p<0.05). In addition, the aortic impedance, incremental elastic modulus, stiffness index and Peterson modulus were significantly reduced during IABP (p<0.05). Our findings show that IABP caused changes in aortic wall impedance and intrinsic wall properties, improving the arterial functional capability and the left ventricular afterload by a reduction in both. Systemic vascular resistances and aortic stiffness were also improved by means of smooth muscle-dependent mechanisms.

Computationally Managed Bradycardia Improved Cardiac Energetics While Restoring Normal Hemodynamics in Heart Failure

In acute heart failure, systemic arterial pressure (AP), cardiac output (CO), and left atrial pressure (P (LA)) have to be controlled within acceptable ranges. Under this condition, cardiac energetic efficiency should also be improved. Theoretically, if heart rate (HR) is reduced while AP, CO, and P (LA) are maintained by preserving the functional slope of left ventricular (LV) Starling's curve (S (L)) with precisely increased LV end-systolic elastance (E (es)), it is possible to improve cardiac energetic efficiency and reduce LV oxygen consumption per minute (MVO (2)). We investigated whether this hemodynamics can be accomplished in acute heart failure using an automated hemodynamic regulator that we developed previously. In seven anesthetized dogs with acute heart failure (CO < 70 mL min(-1) kg(-1), P (LA) > 15 mmHg), the regulator simultaneously controlled S (L) with dobutamine, systemic vascular resistance with nitroprusside and stressed blood volume with dextran or furosemide, thereby controlling AP, CO, and P (LA). Normal hemodynamics were restored and maintained (CO; 88 +/- 3 mL min(-1) kg(-1), P (LA); 10.9 +/- 0.4 mmHg), even when zatebradine significantly reduced HR (-27 +/- 3%). Following HR reduction, E (es) increased (+34 +/- 14%), LV mechanical efficiency (stroke work/oxygen consumption) increased (+22 +/- 6%), and MVO (2) decreased (-17 +/- 4%) significantly. In conclusion, in a canine acute heart failure model, computationally managed bradycardia improved cardiac energetic efficiency while restoring normal hemodynamic conditions.

Abstract 1268: Small Molecule Targeting Of gβγ Reduces β-adrenergic Receptor Desensitization And Normalizes Cardiac Dysfunction In An Acute Heart Failure Model

Heart failure (HF) is a debilitating disease with poor prognosis, despite substantial therapeutic advances in the past two decades. Excess signaling through cardiac G-protein Gβγ subunits is an important component of HF pathophysiology. They recruit elevated levels of cytosolic G-protein coupled receptor kinase 2 (GRK2, a.k.a. βARK1) to agonist-stimulated β-ARs in HF, leading to chronic β-AR desensitization and down-regulation; these events are all hallmarks of HF. Previous data has suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. We recently developed a novel small molecule targeting strategy to selectively inhibit Gβγ binding interactions, and identified several Gβγ inhibitory small molecules (Bonacci et al, Science, 2006). In particular, we identified compound M119, which blocked the interaction of purified Gβγ and GRK2 in vitro. To validate this activity in a cellular setting, we isolated adult mouse cardiomyocytes, where M119 significantly reduced β-AR-mediated membrane recruitment of GRK2. Furthermore, M119 significantly enhanced both adenylyl cyclase activity and cardiomyocyte contractility at baseline and in response to β-AR agonist stimulation. Upon finding that the compound was biologically available following intraperitoneal injection in mice, we investigated whether the observed in vitro effects in isolated adult cardiomyocytes would translate to in vivo effects on cardiac function. Initial investigations were pursued in an acute pharmacologic HF model (30 mg/kg/day isoproterenol for seven days). Importantly, concurrent once daily injections of M119 normalized cardiac function, morphology and GRK2 expression in this acute HF model. Collectively, our study has identified a small molecule Gβγ inhibitor capable of reducing β-AR desensitization, thereby enhancing β-AR-mediated isolated cardiomyocyte contractility and, importantly, normalizing cardiac function and morphology in an acute HF model in vivo. Our data suggest a promising therapeutic role for small molecule inhibition of Gβγ in the treatment of HF.

Abstract 1950: Role of Superoxide, Nitric Oxide and Peroxynitrite in Doxorubicin-induced Cell Death in vitro and in vivo

Although doxorubicin (DOX) is one of the most potent antitumor agents available, its clinical use is limited because of the risk of severe cardiotoxicity often leading to irreversible congestive heart failure. Apoptotic cell death is a key component in DOX-induced cardiotoxicity, but its trigger(s) and mechanisms are poorly understood. Here, we explore the role of peroxynitrite (a reactive oxidant produced from the diffusion-controlled reaction between nitric oxide and superoxide anion) in DOX-induced cell death. Using a well-established in vivo mouse model of DOX-induced acute heart failure, we demonstrate marked increases in myocardial apoptosis (caspase-3 and 9 gene expression, caspase 3 activity, cytochrome-c release, and TUNEL), iNOS but not eNOS and nNOS expression, 3-nitrotyrosine formation and a decrease in myocardial contractility following DOX treatment. Pre-treatment of mice with peroxynitrite scavengers markedly attenuated DOX-induced myocardial cell death and dysfunction without affecting iNOS expression. DOX induced increased superoxide generation and nitrotyrosine formation in the mitochondria, dissipation of mitochondrial membrane potential, apoptosis (cytochrome-C release, annexin V staining, caspase activation, nuclear fragmentation), and disruption of actin cytoskeleton structure in cardiac-derived H9c2 cells. Selective iNOS inhibitors attenuated DOX-induced apoptosis, without affecting increased mitochondrial superoxide generation, whereas NO donors increased DOX-induced cell death in vitro . The peroxynitrite scavengers FeTMPyP and MnTMPyP markedly reduced both DOX- or peroxynitrite-induced nitrotyrosine formation and cell death in vitro , without affecting DOX-induced increased mitochondrial superoxide formation. Thus, peroxynitrite is a major trigger of DOX-induced apoptosis, and its effective neutralization can be of significant therapeutic benefit.

Hemodynamic Support With the Pulsatile Catheter Pump in a Sheep Model of Acute Heart Failure

This study was aimed to mimic clinical heart failure (HF) conditions and to assess the effect of pulsatile catheter (PUCA) pump support on hemodynamics and tissue perfusion in a sheep model of acute HF. In 14 sheep, HF was induced by partial occluding the middle left circumflex coronary artery combined with pacemaker-induced tachycardia. PUCA pump was then activated to support the HF for 3 h. Hemodynamic parameters were recorded at baseline, HF, and then every 30 min during experiments. Blood samples were taken in carotid artery (CA), pulmonary artery (PA), and coronary sinus (CS) for the determination of oxygen saturation (SO2) and lactate concentration as markers of tissue perfusion. Results showed that HF model was induced successfully in 10 sheep and failed in four sheep due to refractory ventricular fibrillation. PUCA pump support was successful in seven out of 10 sheep for 3 h. Three cases failed due to technical problems. After HF (n = 10), cardiac output (CO) was decreased from 3.7 +/- 0.5 to 2.0 +/- 0.5 L/min (P < 0.001). Mean arterial pressure (MAP) was lowered from 116.1 +/- 14.2 to 68.1 +/- 14.7 mm Hg (P < 0.001). In seven sheep supported with PUCA pump, MAP rose from 68.9 +/- 15.2 to 94.7 +/- 14.7 mm Hg (P = 0.005), systolic blood pressure increased from 86.6 +/- 17.0 to 112.6 +/- 17.1 mm Hg (P = 0.009), and diastolic blood pressure increased from 57.7 +/- 12.6 to 79.9 +/- 13.9 mm Hg (P = 0.011). CO remained at about 2.0 L/min. SO2 in CA, PA, and CS decreased significantly after HF (P < 0.001), with an increase after support (compared with HF, P < 0.001, 0.066 and 0.114, respectively). Lactate concentrations increased gradually in CA, PA, and CS toward the end of experiments without difference among different sampling sites. This HF model in sheep is simple, easy to manipulate, reproducible and reflecting clinical HF conditions. PUCA pump can maintain the hemodynamic status for 3 h in this acute HF model.

Decreased mortality in a rat model of acute postinfarction heart failure

Introduction The rat model of postinfarction heart failure (HF) has been very valuable in experimental cardiology. One disadvantage of this model is the very high acute mortality (70–80%). The aim of this study was to evaluate whether measures of intensive cardiac care applied to rats with acute myocardial infarction (MI) would reduce mortality. Methods Male Sprague–Dawley rats weighing ∼300 g were used. The animals were randomized into two groups. The intensive care group (IC) n = 20 and conventional care group (CC) n = 20. Experimental MI was induced by ligation of the left coronary artery producing large anterolateral MI. Animals in the IC group received isoflurane anesthesia and respiratory support postoperatively. The heart rhythm was monitored continuously and ventricular arrhythmias were treated with amiodarone and cardioversion. Results Mortality rate within 24 h was 4/20 (20%) in the IC group and 14/20 (70%) in the CC group ( p < 0.01). This represents a 3.5-fold reduction in acute mortality rate. Conclusions The use of amiodarone, respiratory support, isoflurane gas anesthesia, and electrical cardioversion of malignant arrhythmias are simple and effective measures to reduce mortality in rats with acute MI and HF. Improving survival rates increases cost-efficiency and ethical acceptance of this important experimental HF model.

Therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET‐1?NOS and oxidative stress in rats

AbstractCPU 86017, a derivative of berberine, was administered to rats in which acute and chronic heart failure was induced by left coronary artery ligation for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+ CPU 86017 (80?40 and 20 mg/kg, ig) and CAL+ captopril (60 mg/kg, ig). In the acute model, the systolic parameters of LVSP and LV+dp/dtmax as well as the diastolic parameters of LVEDP and LV‐dp/dtmin improved significantly on pretreatment of CPU 86017 (80 mg/kg). Reductions in elevated serum CPK?LDH?MDA?GOT?GPT?infarcted area and blood viscosity were also significant (P &lt; 0.01). In the chronic model, CPU 86017 (80 mg/kg) preserved the systolic parameters of LVSP and LV+dp/dtmax and the diastolic function of the LVEDP and LV‐dp/dtmin. CPU 86017 completely suppressed elevated plasma ANP and ET‐1, serum and tissue iNOS?NO and MDA, whereas the decreased SOD was improved. CPU 86017 and captopril improved cardiac failure performance and regressed cardiac remodeling in CHF by reducing tissue weight index: lung weight/body weight (BW), right ventricular weight/BW, and left ventricular weight/BW. CPU 86017 exerted beneficial actions in cardiac performance in models of both acute and chronic heart failure, mainly by suppressing ET‐1, iNOS, and oxidative stress in infarcted tissue. Drug Dev Res 63:22–32, 2004. © 2004 Wiley‐Liss, Inc.

Detection of regional changes in protein levels in the in vivo canine model of acute heart failure following ischemia-reperfusion injury: functional proteomics studies.

In this study, we demonstrate the use of proteomics to detect regional differences in protein levels between the reperfused ischemic zone (IZ) and the nonischemic zone (NIZ) of dog hearts which were subjected to in vivo ischemia-reperfusion injury. Using the two-dimensional gel electrophoresis (2-DE) technique, we identified five proteins that were differentially expressed in the IZ versus NIZ: (1) the alpha subunit of ATP synthase isoform precursor was decreased 1.71-fold; (2) creatine kinase M chain was decreased 1.72-fold; (3) NAD+-isocitrate dehydrogenase, alpha subunit was increased 8.34-fold; (4) ATP synthase D chain, mitochondrial was increased 3.02-fold; (5) ventricular myosin light chain-1 was decreased 2.02-fold. Additionally, we found that the level of actin was decreased 2.6-times in the IZ compared to the NIZ on Western blot analysis but was unchanged on 2-DE.

Effects of direct mechanical ventricular assistance on regional myocardial function in an animal model of acute heart failure.

Direct mechanical ventricular assistance (DMVA) improves hemodynamics in failing hearts without complications associated with a blood/device interface. Epicardial Doppler displacement transducers provide exact measurements of tissue displacement and regional myocardial function (RMF). An in vivo porcine model of acute heart failure was used to examine the effects of DMVA on RMF, which have not been reported before. In 8 anesthetized pigs cardiac output (CO), left ventricular pressure (LVP), aortic blood pressure (BP), systolic contractility (dp/dt max), and systolic wall thickening fraction (WT%) were measured. A multichamber pump system (IMPS) surrounding the left ventricle was implanted and the measurements were repeated. Then acute heart failure was induced by beta-blockade, resulting in a decline of all measured parameters to more than 30% compared to baseline values. In the further course of the experiment, repeated measurements were taken at several intervals with and without DMVA by the implanted device. The IMPS implantation caused no significant hemodynamic changes. Under conditions of acute heart failure DMVA improved LVP (46 +/- 7 to 81 +/- 9 mm Hg), dp/dt max (532 +/- 207 to 744 +/- 361 mm Hg/s), CO (1.5 +/- 0.1 to 1.9 +/- 0.5 L/min) and WT% (19 +/- 7% to 32 +/- 8%). Left ventricular myocardium not directly assisted by external pressure application showed improved regional myocardial function during DMVA. We conclude that DMVA is capable of improving hemodynamics due to extrinsic compression. It also enhances the remaining myocardial function of the failing heart, which might lead to myocardial recovery. These synergistic effects are considered responsible for the high efficiency shown by the IMPS in previous investigations.

Importance of preserving the apex and plication of the base in left ventricular volume reduction surgery

Objective: Volume reduction surgery for dilated cardiomyopathy has not yielded predictable outcomes. The purpose of this study was to clarify the efficacy of modified volume reduction surgery in preserving the left ventricular apex and reducing the left ventricular diameter at the base to maintain fiber continuity. Methods: Heart failure was induced with propranolol in 12 dogs, and the animals were randomized into 2 groups. In one group the left ventricular wall was plicated between the 2 papillary muscles from the middle to the apex (apex-sacrificing volume reduction surgery, group A, n = 6), and in the other group plication was done from the base to the middle (apex-sparing volume reduction surgery, group B, n = 6). Left ventricular function was then compared between the groups by using echocardiography and sonomicrometry crystals. Results: After volume reduction surgery, the fractional area change at the base in group B was greater than that in group A (40% ± 3% vs 27% ± 4%, P =.003). Cardiac output in group B was better than that in group A (2.5 ± 0.2 vs 1.8 ± 0.2 L/min, P =.023). Left ventricular end-diastolic pressure in group A was higher than that in group B (16 ± 2 vs 8 ± 1 mm Hg, P =.001). Fractional shortening in the long axis, as assessed by means of sonomicrometry, was better in group B than in group A. Conclusions: Apex-sparing volume reduction surgery capable of maintaining left ventricular fiber continuity provided better left ventricular function in both the systolic and diastolic phases than apex-sacrificing volume reduction surgery in the acute heart failure model. This modification might improve the results of left ventricular volume reduction surgery.J Thorac Cardiovasc Surg 2003;125:669-77

Coronary microembolization.

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. However, it does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction; in milder forms the result can be embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. This review summarizes the available morphological evidence for coronary microembolization in patients who died from coronary artery disease, most notably from sudden death, and then goes on to address the experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and heart failure. Finally, the review presents the available clinical evidence for coronary microembolization in patients, highlights its key features (ie, arrhythmias, contractile dysfunction, infarctlets and reduced coronary reserve) and addresses its prevention by mechanical protection devices and glycoprotein IIb/IIIa antagonism.

A new approach to assist postoperative heart failure in an animal model: juxta-aortic counterpulsation.

Aortic counterpulsation is a useful technique frequently used in postcardiotomy heart failure. An acute heart failure model in open chest sheep was chosen to evaluate hemodynamic improvement with a counterpulsation balloon pump in juxta-aortic position. This was achieved with a manufactured Dacron prosthesis and a balloon pump placed between the prosthesis and the aorta. Juxta-aortic balloon pump counterpulsation in acute experimental heart failure resulted in a significant improvement of hemodynamic parameters: increase of cardiac output (from 0.86 +/- 0.04 to 1.29 +/- 0.09 L/min, p < 0.05) and cardiac index (from 0.03 +/- 0.01 to 0.04 +/- 0.01 L/min per kg, p < 0.05), and decrease of systemic vascular resistance (from 89.76 +/- 6.69 to 66.56 +/- 6.02 mm Hg/L per min, p < 0.05). The extent of aortic diastolic pressure change evaluated through the diastolic and systolic areas beneath the aortic pressure curve (DABAC/SABAC) index before cardiac failure induction showed a significant increase compared with unassisted values (from 0.81 +/- 0.10 to 1.12 +/- 0.09, p < 0.05). Assisted values of DABAC/SABAC index after heart failure induction also showed a significant increase compared with unassisted values (from 0.78 +/- 0.21 to 1.17 +/- 0.38, p < 0.05). Treatment of experimental acute heart failure by juxta-aortic balloon pump counterpulsation allows an effective hemodynamic improvement in open chest sheep.

COMPARISON OF NONPULSATILE VERSUS PULSATILE ECLS (TPL-STM)

PURPOSE OF STUDY The study was designed to compare the safety and efficacy of Korean pulsatile ECLS (Twin Pulse Life Support system: TPLSTM) to those of nonpulsatile ECLS. METHODS USED An acute heart failure model was constructed in twelve piglets by using a pulmonary artery banding technique. The animals were divided into two groups: In group I, a centrifugal pump (Medtronic, co.) was used as a control (n = 6). In group II, a dual-pulse ECLS (TPLS) system was used as an experiment (n=6). The bypass circuit contained a membrane oxygenator, and the right atrium and the aorta were bypassed for two hours under 2 L/min of pump flow. SUMMARIZED RESULTS Pulmonary artery banding lowered systolic blood pressure to 60 mmHg or less. During the bypass, systolic pressure was maintained 103±20 mmHg in group I and 103±20 mmHg in group II (P=NS). Central venous pressure was 8±3 mmHg in group I and 7±5 mmHg in group II (p=NS). The plasma free hemoglobin level showed 19±9 mg% in group I and 15±2 mg% in group II. The peak pressure at the inlet of a membrane oxygenator was 190 mmHg in group I and 230 mmHg in group II. Systemic oxygenation throughout the bypass period was not different between the groups. We believe the Korean dual-pulsatile system (TPLSTM) can be safely applied as an ECLS for the treatment of acute heart failure.

Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters

Background: The TO-2 hamster is an animal model of dilated cardiomyopathy (DCM). It has genetic and clinical features in common with humans who carry the gene deletion or mutation of the δ-sarcoglycan (SG) gene, a component in dystrophin-related proteins (DRP). DRP stabilise the sarcolemma during cardiac contraction. We performed in vivo gene therapy of the TO-2 hamster, whose heart is defective in all four SG proteins, to determine its potential as a model for therapy for DCM. In addition to the hereditary origin, heart failure is aggravated by treatment with catecholamines and ameliorated by the administration of some kinds of β-antagonist both in humans and in TO-2 hamsters. Methods: Gene therapy for DCM was achieved by supplementing the δ-SG gene with rAAV vector and intramurally delivering rAAV-δ-SG into the cardiac apex and left ventricle. Results: This treatment resulted in: (i) a sustained and non-pathogenic expression of both the transcript and transgene of δ-SG and all other SG proteins; (ii) improvement to both morphological and physiological deterioration; and (iii) rescued prognosis compared with untreated TO-2 hamsters, and TO-2 hamsters transfected with reporter gene alone. Another acute heart-failure model was prepared by high-dose isoproterenol treatment in Wistar rats, which resulted in: (i) translocation of dystrophin, but not δ-SG, from the cardiac sarcolemma to the myoplasm; and (ii) fragmentation of dystrophin, probably due to the activation of endogenous protease(s) or proteasome(s) that contributed to muscular dystrophy-like degeneration occurring specifically in cardiomyocytes. Conclusions: Both the TO-2 hamster and the isoproterenol-treated Wistar rat models commonly experience disruption of dystrophin or DRP. Targeting the responsible gene with the use of a potent vector may provide a novel strategy for the treatment of advanced heart failure.

Coronary microembolization

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction; however, in milder forms it may result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. The present report summarizes the available morphologic evidence for coronary microembolization in patients who died of coronary artery disease, especially sudden death. The report then goes on to address the experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and heart failure. Finally, the report presents the available clinical evidence for coronary microembolization, highlights its key features-arrhythmias, contractile dysfunction, infarctlets and reduced coronary reserve-and addresses prevention by mechanical protection devices and glycoprotein IIb/IIIa antagonism. Copyright © 2001 by W.B. Saunders CompanyProgress in Cardiovascular Diseases, Vol. 44, No. 3, (November/December) 2001: pp 217-230

Hemodynamic effects of helium vs carbon dioxide pneumoperitoneum in an experimental model of acute heart failure

Background The systemic absorption of carbon dioxide (CO2) during abdominal insufflation can lead to hypercarbia and acidosis, which contribute to the systemic hemodynamic effects of the pneumoperitoneum (PnP). In several animal and clinical studies, the use of helium (He) as a substitute for CO2 prevented the development of hypercarbia. One of the common comorbid conditions in which the use of a CO2 PnP may cause adverse effects is heart failure. The aim of our study was to evaluate and compare the hemodynamic effects of CO2 and He PnP in an animal model of acute heart failure (AHF).

Attenuated natriuretic response to adrenomedullin in experimental heart failure

Background: The recently discovered vasodilating and positive inotropic peptide, adrenomedullin (ADM), has strong natriuretic actions. ADM-induced natriuresis is caused by an increase in glomerular filtration rate and a decrease in distal tubular sodium reabsorption. Although ADM is activated in human and experimental heart failure, the role of ADM in the kidney in heart failure remains undefined. Methods and Results: The present study was performed to determine the renal hemodynamic and urinary excretory actions of exogenously administered ADM in a canine model of acute heart failure produced by rapid ventricular pacing. Experimental acute heart failure was characterized by a decrease in cardiac output and an increase in pulmonary capillary wedge pressure with an increase in plasma ADM concentration. Intrarenal infusion of ADM (1 and 25 ng/kg/min) induced an increase in urinary sodium excretion in the normal control dogs (change in urinary sodium excretion [ΔUNaV], +94.5 μEq/min during 1 ng/kg/min ADM infusion and +128.1 μEq/min during 25 ng/kg/min ADM infusion). In the acute heart failure dogs, intrarenal ADM infusion resulted in an attenuated increase in urinary sodium excretion (ΔUNaV, +44.8 μEq/min during 1 ng/kg/min ADM infusion and +51.8 μEq/min during 25 ng/kg/min ADM infusion). Both glomerular and tubular actions of ADM were attenuated in the acute heart failure group compared with responses in the normal control group. Conclusion: The present study shows that the renal natriuretic responses to ADM are markedly attenuated in experimental acute heart failure. This study provides insight into humoral mechanisms that may promote sodium retention in heart failure via a renal hyporesponsiveness to natriuretic actions of ADM.

Maximizing hemodynamic effectiveness of biventricular assistance by direct cardiac compression studied in ex vivo and in vivo canine models of acute heart failure

Objective: Direct cardiac compression improves effective ventricular contractility. However, associated reductions in filling volumes and increases in arterial pressure occurring at the onset of direct cardiac compression limit the degree to which cardiac output is augmented. We tested the hypothesis that active preload and afterload control maximizes the hemodynamic effectiveness of direct cardiac compression. Methods and results: Studies in isolated canine hearts loaded with a computer-controlled volume servo system that mimicked heart failure were used to clearly define the hemodynamic effects of direct cardiac compression. Immediately on initiation of direct cardiac compression, ventricular end-diastolic pressure and volume decreased substantially, arterial pressure increased, but stroke volume did not change significantly. When end-diastolic pressure was restored to about 20 mm Hg, stroke volume doubled; decreasing afterload resistance further increased stroke volume by about 30%. Such load adjustments were then tested in vivo in a canine model of acute heart failure induced by coronary artery microembolizations titrated to decrease cardiac output to 33% ± 9% of control as end-diastolic pressure rose to 20.6 ± 2.2 mm Hg. Direct cardiac compression decreased end-diastolic pressure to 11.4 ± 2.6 mm Hg while increasing cardiac output from 0.8 ± 0.2 to 1.4 ± 0.5 L/min (to only ~55% of normal). Restoring end-diastolic pressure to 19.6 ± 2.2 mm Hg by infusions of saline solution increased cardiac output to 1.9 ± 0.5 L/min. Afterload reduction (nitroprusside), while maintaining end-diastolic pressure at 19.8 ± 1.3 mm Hg, increased cardiac output to its baseline, 2.8 ± 1.1 L/min. Conclusions: Direct cardiac compression significantly improves ventricular pumping capacity and can restore cardiac output to about 60% of normal in the setting of acute heart failure. When combined with active preload and afterload manipulations, direct cardiac compression can restore cardiac output to normal. (J Thorac Cardiovasc Surg 2000;120:379-86)