A Physical Heart Failure Simulation System Utilizing the Total Artificial Heart and Modified Donovan Mock Circulation.

With the growth and diversity of mechanical circulatory support (MCS) systems entering clinical use, a need exists for a robust mock circulation system capable of reliably emulating and reproducing physiologic as well as pathophysiologic states for use in MCS training and inter-device comparison. We report on the development of such a platform utilizing the SynCardia Total Artificial Heart and a modified Donovan Mock Circulation System, capable of being driven at normal and reduced output. With this platform, clinically relevant heart failure hemodynamics could be reliably reproduced as evidenced by elevated left atrial pressure (+112%), reduced aortic flow (-12.6%), blunted Starling-like behavior, and increased afterload sensitivity when compared with normal function. Similarly, pressure-volume relationships demonstrated enhanced sensitivity to afterload and decreased Starling-like behavior in the heart failure model. Lastly, the platform was configured to allow the easy addition of a left ventricular assist device (HeartMate II at 9600 RPM), which upon insertion resulted in improvement of hemodynamics. The present configuration has the potential to serve as a viable system for training and research, aimed at fostering safe and effective MCS device use.

Remodeling an infarcted heart: novel hybrid treatment with transmyocardial revascularization and stem cell therapy.

Transmyocardial revascularization (TMR) has emerged as an additional therapeutic option for patients suffering from diffuse coronary artery disease (CAD), providing immediate angina relief. Recent studies indicate that the volume of surgical cases being performed with TMR have been steadily rising, utilizing TMR as an adjunctive therapy. Therefore the purpose of this review is to provide an up-to-date appreciation of the current state of TMR and its future developmental directions on CAD treatment. The current potential of this therapy focuses on the implementation of stem cells, in order to create a synergistic angiogenic effect while increasing myocardial repair and regeneration. Although TMR procedures provide increased vascularization within the myocardium, patients suffering from ischemic cardiomyopathy may not benefit from angiogenesis alone. Therefore, the goal of introducing stem cells is to restore the functional state of a failing heart by providing these cells with a favorable microenvironment that will enhance stem cell engraftment.

Reliability of the Thoratec HeartMate II flow measurements and alarms in the presence of reduced or non-existent flow.

INTRODUCTION: The Thoratec Corporation has over 10,000 patients registered as recipients of the HeartMate II left ventricular assist device (LVAD) worldwide. Although it has undoubtedly prolonged the lifespan of heart failure patients, the most recognized risk associated with these devices is the development of thrombus. In the presence of a small or developing clot, the HeartMate II display module and system monitor indicate that there is a decrease in pump flow, adjusts its pump power and is accompanied by audible and visual alarms when flow rates drop below a fixed threshold established by Thoratec. In contrast, when thrombus completely inhibits flow through the device, the display module and system monitor have failed in previous case studies to indicate that flow has reduced to zero and do not produce any corresponding alarms. METHODS: To test the efficacy of the HeartMate II alarms, a cardiovascular simulation tank was used to reproduce the hemodynamics of a typical heart failure patient. The hemodynamics were then improved by the addition of the HeartMate II LVAD and different partial and complete occlusions were applied to the inlet and outlet of the HeartMate II pump. CONCLUSIONS: Partially occluding the inflow and/or outflow of the HeartMate II did display changes in flow and presented with alarms when flow was estimated to be below 2.5 L/min; however, complete occlusion of the inflow and/or outflow failed to produce any alarms or accurately measured changes in flow.

Functional aortic stiffness: role of CD4(+) T lymphocytes.

The immune system is suggested to be essential in vascular remodeling and stiffening. To study the dependence upon lymphocytes in vascular stiffening, we compared an angiotensin II-model of vascular stiffening in normal C57BL/6J mice with lymphocyte-deficient RAG 1(-/-) mice and additionally characterized the component of vascular stiffness due to vasoconstriction vs. vascular remodeling. Chronic angiotensin II increased aortic pulse wave velocity, effective wall stiffness, and effective Young's modulus in C57BL/6J mice by three-fold but caused no change in the RAG 1(-/-) mice. These functional measurements were supported by aortic morphometric analysis. Adoptive transfer of CD4(+) T helper lymphocytes restored the angiotensin II-mediated aortic stiffening in the RAG 1(-/-) mice. In order to account for the hydraulic vs. material effects of angiotensin II on pulse wave velocity, subcutaneous osmotic pumps were removed after 21 days of angiotensin II-infusion in the WT mice to achieve normotensive values. The pulse wave velocity (PWV) decreased from three- to two-fold above baseline values up to 7 days following pump removal. This study supports the pivotal role of the CD4(+) T-lymphocytes in angiotensin II-mediated vascular stiffening and that angiotensin II-mediated aortic stiffening is due to the additive effect of active vascular smooth muscle vasoconstriction and vascular remodeling.

Effect of lysyl oxidase inhibition on angiotensin II-induced arterial hypertension, remodeling, and stiffness.

It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, ß -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young's modulus. The increase in effective Young's modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN.

Physiological characterization of the SynCardia total artificial heart in a mock circulation system.

The SynCardia total artificial heart (TAH) has emerged as an effective, life-saving biventricular replacement system for a wide variety of patients with end-stage heart failure. Although the clinical performance of the TAH is established, modern physiological characterization, in terms of elastance behavior and pressure-volume (PV) characterization has not been defined. Herein, we examine the TAH in terms of elastance using a nonejecting left ventricle, and then characterize the PV relation of the TAH by varying preload and afterload parameters using a Donovan Mock Circulatory System. We demonstrate that the TAH does not operate with time-varying elastance, differing from the human heart. Furthermore, we show that the TAH has a PV relation behavior that also differs from that of the human heart. The TAH does exhibit Starling-like behavior, with output increasing via preload-dependent mechanisms, without reliance on an alteration of inotropic state within the operating window of the TAH. Within our testing range, the TAH is insensitive to variations in afterload; however, this insensitivity has a limit, the limit being the maximum driving pressure of the pneumatic driver. Understanding the physiology of the TAH affords insight into the functional parameters that govern artificial heart behavior providing perspective on differences compared with the human heart.

Dodecafluoropentane emulsion elicits cardiac protection against myocardial infarction through an ATP-Sensitive K+ channel dependent mechanism.

PURPOSE: Dodecafluoropentane emulsion (DDFPe) is a perfluorocarbon with high oxygen dissolving, transport, and delivery capacity that may offer the potential to limit ischemic injury prior to clinical reperfusion. Here we investigated the cardiac protective potential of DDFPe in a mouse model of myocardial infarction. METHODS: Myocardial infarction was initiated by permanent ligation of the left anterior descending (LAD) coronary artery. Mice were administered vehicle or 5-hydroxydecanoate (5-HD) intravenously 10 min before LAD occlusion followed by a single intravenous administration of vehicle or DDFPe immediately after occlusion. Heart tissue and serum samples were collected 24 after LAD occlusion for measurement of infarct size and cardiac troponin I (cTnI) levels, respectively. RESULTS: DDFPe treatment reduced infarct size by approximately 72% (36.9 ± 4.2% for vehicle vs 10.4 ± 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h. Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8). Pretreatment with 5-HD, a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) inhibitor, blocked the reduction in infarct size (29.2 ± 4.4% for 5-HD vs 35.4 ± 7.4% for 5-HD+DDFPe; p = 0.48; n = 6-8) and serum cTnI levels (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD+DDFPe; p = 0.86; n = 6-8) by DDFPe. CONCLUSION: Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection.

Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening.

Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Three-month-old male C57BL/6J mice were treated with IL-2/mAbCD25 concomitantly with continuous infusion of angiotensin type 1 receptor agonist, [Val(5)]angiotensin II. Our results indicate that the IL-2/mAbCD25 complex effectively induced Treg phenotype expansion by 5-fold in the spleens with minimal effects on total CD4(+) and CD8(+) T-lymphocyte numbers. The IL-2/mAbCD25 complex inhibited angiotensin II-mediated aortic collagen remodeling and the resulting stiffening, analyzed with in vivo pulse wave velocity and effective Young's modulus. Furthermore, the IL-2/mAbCD25 complex suppressed angiotensin II-mediated Th17 responses in the lymphoid organs and reduced gene expression of IL-17 as well as T cell and macrophage infiltrates in the aortic tissue. This study provides data that support the protective roles of Tregs in vascular stiffening and highlights the use of the IL-2/mAbCD25 complex as a new potential therapy in angiotensin II-related vascular diseases.

Biphasic change of tau (τ) in mice as arterial load acutely increased with phenylephrine injection.

BACKGROUND: Diastolic dysfunction is the hemodynamic hallmark of hypertensive heart disease. Tau (τ) has been used to describe left ventricle relaxation. The relationship between τ and afterload has been controversial. Our goal was to demonstrate this relationship in mice, because genetically-modified mouse models have been used extensively for studies in cardiovascular diseases. METHODS: Increased arterial load was produced by phenylephrine administration (50 µg/kg iv) (n = 10). A series of pressure-volume loops was recorded with a Millar conductance catheter in vivo as the left ventricle pressure reached the maximum. The arterial load was expressed as Ea (effective arterial elastance). Tau values were computed using three mathematical methods: τWeiss, τGlantz, and τLogistic. RESULTS: A correlation plot between τ and Ea showed a biphasic relationship a flat phase I and an inclined phase II. The existence of an inflection point was proved mathematically with biphasic linear regression. Pressure-volume area (PVA), a parameter linearly related to myocardial O2 consumption (MVO2), was found to be directly proportional to Ea. The plot of τ versus PVA was also biphasic. CONCLUSION: We concluded that a small increase of the arterial load by phenylephrine increased PVA (index of MVO2) but had little effect on τ. However, after an inflection point, further increase of arterial load and PVA resulted in the linear increase of τ.

Leptin's regulation of obesity-induced cardiac extracellular matrix remodeling.

Obesity-induced remodeling of cardiac extracellular matrix (ECM) leads to myocardial fibrosis and ultimately diastolic dysfunction. Leptin, an adipocyte hormone, is emerging as a novel mechanistic link between obesity and heart diseases. Despite the known essential role of leptin in hepatic and renal fibrosis, the in vivo effects of leptin on cardiac ECM remodeling remain unclear. Our objective was to define the role of leptin as a key mediator of pro-fibrogenic responses in the heart. In vitro administration of leptin to primary cardiofibroblasts resulted in significant stimulation of pro-collagen Iα ( 1 ) and a decrease in pro-matrix metalloproteinase (MMP)-8, -9 and -13 gene expressions at 24 h. To study the in vivo pro-fibrotic effect, leptin was administrated to C57BL/6 and leptin-deficient ob/ob mice for 8 weeks. With exogenous leptin ob/ob mice displayed passive diastolic filling dysfunction, coincided with significant increase in myocardial collagen compared with ob/ob controls. We also observed a marked stimulation of pro-collagen IIIα ( 1 ) and suppression of pro-MMP-8, TIMP-1 and -3 gene expressions in leptin-treated ob/ob mice. Our findings suggest pro-fibrotic effects of leptin in the heart, primarily through the predominance of collagen synthesis over degradation.

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice.

Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers - T-cell receptor Vß peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.

T lymphocyte regulation of lysyl oxidase in diet-induced cardiac fibrosis.

Left ventricular diastolic dysfunction is an important predictor of prognosis and mortality of heart failure. Increased left ventricular stiffness can be associated with excessive myocardial fibrosis and increased cross-linked collagen by the enzyme lysyl oxidase (LOX). These cardiac extracellular matrix (ECM) remodeling processes are affected by T-lymphocyte function and phenotype. We sought to examine the role of T lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice, devoid of functional T lymphocytes, and wild-type (WT) C57BL/6 were treated with a high-fat high-simple carbohydrate (HFHSC) diet for 12 months. HFHSC-fed WT mice demonstrated a significant increase in the catalytic activity of myocardial LOX compared with respective controls. These changes coincided with a marked increase in ECM collagen cross-linking and impaired diastolic filling pattern. However, induction of LOX was minimal in the SCID mice compared with the WT group. Correspondingly fibrillar cross-linked collagen concentrations and diastolic dysfunction were less prominent in the SCID mice compared with the WT group. Our results suggest a role for T lymphocytes in this dietary induction of diastolic dysfunction through modulation of LOX-dependent collagen maturation.

CardioWest temporary total artificial heart.

BACKGROUND: The CardioWest temporary total artificial heart (TAH-t) replaces both native ventricles of the heart and is more beneficial for a select group of patients than most other typical ventricular assist devices (VADs). This review will expand on the current literature and highlight the chronology of this device. The CardioWest TAH-t has been implanted in over 715 patients at 30 multiple institutional centers worldwide as a bridge-to-transplant (BTT) since 1993. The mechanical flow dynamics of the device are manufactured and designed differently from other traditional VADs, allowing increased outputs and normal filling pressures, allowing for sufficient organ and tissue perfusion and dramatic recoveries, allowing patients to return to an almost normal quality of life. RESULTS: There was a 79% survival to transplant achievement in the protocol group who received the TAH-t versus a 46% in the control group (P < 0.001). Furthermore, there was a 70% survival rate at one year in the protocol group versus 31% in the control group (P < 0.001). The one- and five-year survival rates after transplantation were 69% and 34%, respectively, in the control group and 86% and 64%, respectively, in the protocol group. CONCLUSION: It is evident that the advancement of modern engineering and medicine has made way for a reliable and durable device that provides a promising future in the field of end-stage heart failure.

Truncation of titin's elastic PEVK region leads to cardiomyopathy with diastolic dysfunction.

RATIONALE: The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region. OBJECTIVE: The purpose of this study was to investigate the contribution of titin's proline-glutamate-valine-lysine (PEVK) region to biomechanics and growth of the heart. METHODS AND RESULTS: We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element. CONCLUSIONS: Titin's PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.

Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome.

Metabolic syndrome (MetS) represents an increased risk of cardiovascular disease. Although its individual components adversely affect cardiac structure and function, the extent to which multiple components of MetS affect the cardiac extracellular matrix (ECM) has not been well characterized. Lysyl oxidase (LOX) is one of the cardiac ECM-modifying enzymes that catalyze the formation of collagen cross-linking. Our objective was to define the effect of diet-induced MetS on the LOX enzyme. MetS was induced in male C57BL/6 mice by administrating a high-fat, high-simple carbohydrate diet for 6 mo. Gene expression was determined by real-time PCR. The cardiac protein expression and enzymatic activity of LOX were measured. The severity of fibrosis was assessed by histology and hydroxylproline assay. Cardiac diastolic function was assessed by in vivo analysis of the pressure-volume relationship. LOX, matrix metalloproteinases, and their tissue inhibitors were analyzed, and of these three, LOX was most significantly changed in the MetS mice. Despite the blunted gene expression of LOX isoforms, MetS mice demonstrated a significant upregulation of bone morphogenetic protein-1. Correspondingly, there was an increase in the ratio of protein expression of mature to proenzyme LOX by 25.9%, enhanced LOX activity by 50.0%, and increased cardiac cross-linked collagen compared with the controls. This fibrotic response coincided with a marked increase in end-diastolic pressure, increased left ventricular stiffness, and impaired diastolic filling pattern. Our data signify that diet-induced MetS alters the remodeling enzymes, mainly LOX, thereby altering ECM structure by increasing the amount of cross-linking and inducing diastolic dysfunction.

IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice.

Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.

Lusitropic effects of dobutamine in young and aged mice in vivo.

Aged individuals have impaired diastolic relaxation-lusitropic function. Dobutamine, a selective B1-adrenergic agonist, is used to augment systolic cardiac function at the termination of cardiopulmonary bypass (CPB). However, our question is whether dobutamine will also enhance the lusitropic function in the aged individual. The myocyte mechanism for the rate of ventricular relaxation is dependent on the velocity of calcium removal from the myocyte contractile elements by sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), which is regulated by an inhibitory protein, phospholamban (PLB). Ventricular tissues harvested from young (4 month) and aged (20 months) mice were analyzed to compare the protein levels of SERCA2a and PLB with immunoblot and gene expression for PLB with reverse-transcriptase-polymerase chain reaction. The molecular analyses were compared with in vivo left ventricular function in the young and old mice before and during an intravenous infusion of dobutamine (5 microg/kg/min). The SERCA2a levels were not different between the groups; however, there was a 2-fold increase in PLB in the aged group compared with the young group (p < .05). The gene expression for PLB was increased by 5-fold in the aged group compared with the young group (p < .01). There were significant differences between the young and aged groups related to the lusitropic parameters, tau and dP/dt(min), and dobutamine infusion increased these parameters in the aged group to that of the young group. This report supports the concept that altered PLB levels correspond with the respective lusitropic function and that dobutamine administration in the aged group increased lusitropic function that was comparable with the young group. Because the patient population requiring CPB is aging, these data suggest that the use of dobutamine at the terminal phase of CPB is warranted to increase systolic and diastolic function.

Myocardial cytokine IL-8 and nitric oxide synthase activity during and after resuscitation: preliminary observations in regards to post-resuscitation myocardial dysfunction.

AIM: Increases in serum cytokines have been reported after successful resuscitation from prolonged ventricular fibrillation (VF). Pro-inflammatory cytokines can stimulate inducible nitric oxide synthase (iNOS) to produce excessive levels of nitric oxide (NO). High levels of both myocardial inflammatory cytokines and nitric oxide levels can depress myocardial contractile function. We hypothesized that myocardial pro-inflammatory cytokines and iNOS activity would increase following successful resuscitation from prolonged ventricular fibrillation cardiac arrest, and that such increases would parallel the development of post-resuscitation myocardial dysfunction. METHODS: Ventricular fibrillation cardiac arrest was induced in seven domestic swine (25+/-5 kg). After 10 min of untreated VF, the animals were defibrillated and resuscitated. Left ventricular (LV) systolic and diastolic function measurements, serum samples (arterial and coronary sinus) for IL-8 cytokine quantification, and LV myocardial biopsies were collected before, during, and after resuscitation. Quantification of myocardial endothelial (eNOS) and inducible (iNOS) nitric oxide synthase protein levels were determined using immunoblot analyses and protein localization was examined using immunohistochemistry. RESULTS: Post-resuscitation LV systolic and diastolic functions were depressed while increases in both coronary sinus IL-8 levels and myocardial iNOS activity were found. Compared to pre-arrest baseline, levels of iNOS protein increased during VF (p < or = 0.05) and continued to increase throughout the post-resuscitation study period of 6 h (p < or = 0.05). CONCLUSIONS: Myocardial inflammatory cytokines and iNOS activity increase during and after prolonged cardiac arrest and successful resuscitation. These increases correspond to the well described decrease in LV function post-resuscitation.

Insulin binding to the cardiopulmonary bypass biomaterials.

Hyperglycemia associated with cardiopulmonary bypass (CPB) is an independent predictor of morbidity and mortality. One suggested cause of hyperglycemia during CPB is a decline of serum insulin concentrations. Since plasma C-proteins are not reduced during CPB -suggesting that pancreatic insulin secretion is not affected - the reduction of insulin concentrations is hypothesized to be due to the binding of the insulin protein to the CPB biomaterials. The hypothesis of this study is that insulin binds to the CPB polyvinyl chloride (PVC) tubing and that selected bio-coatings inhibit this process. Human insulin was diluted to a physiologic concentration of 30 microU/mL in saline and exposed to four types of sterile PVC tubing, namely: uncoated, Terumo X-coated, Medtronic Carmeda, and Cobe SMARx T for 30 minutes at 37 degrees C. Insulin concentrations were determined with ELISA. The recovered insulin concentrations were found to be 9.3 +/- 0.6 microU/mL in the uncoated (control), 17.7 +/- 1.9 microU/mL in the X-coating, 17.9 +/- 1.1 microU/mL in the Carmeda, and 14.28 +/- 0.17 microU/mL in the SMARxT coated tubing. These data support the hypothesis that the insulin binding to the PVC tubing can be reduced by 48% and up to 35% with X-coating and Carmeda, and SMARxT coating, respectively. Therefore, the use of coated CPB systems is justified to reduce CPB-associated hyperglycemia.