Lower Left Ventricular Pressure Research Articles

Mechanical LV support lowers diastolic LV pressure and prolongs diastolic coronary flow in the infarcted artery

Abstract Background Percutaneous left ventricular (LV) assist device provides not only circulatory support but also LV unloading. However, impact of LV unloading on coronary flow and mechanisms by which it is regulated remain unclear. We aimed to elucidate potential effects of LV unloading on coronary physiology in a pig model of myocardial infarction (MI). Methods First, six Yorkshire pigs underwent mechanical LV unloading using Impella two weeks after percutaneous MI induction. Regional blood flow (RBF) in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading (Study 1). Next, we investigated coronary flow patterns with detailed temporal information. Six Yorkshire pigs were subjected to 90-minute balloon occlusion of the middle left anterior descending artery followed by reperfusion. At 60 minutes after reperfusion, LV unloading was initiated and maintained at maximal support. LV pressure, coronary flow and pressure in the infarcted artery were simultaneously recorded. Measurements were repeated with and without LV mechanical support. Coronary wave intensity was calculated from the flow/pressure data (Study 2). Results In Study 1, RBF calculated using microsphere was significantly increased only in the infarct area, but not in the border or remote areas. In Study 2, LV unloading resulted in lower LV pressure during the whole diastolic phase and higher coronary pressure during the late diastolic phase in all animals. Coronary flow velocity was higher throughout the diastole under LV unloading. In addition, the proportion of diastole to the whole cardiac cycle was significantly prolonged with LV unloading. Accordingly, area under the curve of coronary flow was increased during diastole and also for the whole cardiac cycle. In the wave intensity analysis, the magnitude of forward wave intensity was reduced by LV unloading, suggesting that the impact of forces from the aortic side was less significant under continuous device support. The duration between backward suction and pushing waves was extended, implicating earlier relaxation and delayed contraction, further supporting prolonged diastole from the myocardial force perspective. Conclusions Mechanical LV unloading increases coronary flow by prolonging diastolic phase in the infarcted artery.

Maternal Hyperglycemia Induces Autonomic Dysfunction and Heart Failure in Older Adult Offspring.

Offspring exposed to an adverse fetal environment, such as gestational diabetes, may manifest increased susceptibility to several chronic diseases later in life. In the present study, the cardiovascular function of three different ages of offspring from diabetic rats was evaluated. Diabetes mellitus was induced in pregnant rats by a single dose of streptozotocin (50 mg/kg). The offspring from diabetic (OD) and control rats (OC) were evaluated at three different ages: 6, 12 or 18 months. In the corresponding OC groups, fasting glycemia, baseline mean arterial pressure, and sympathetic tonus increased in the OD rats at 12 (OD12) and 18 (OD18) months of age, while cardiac hypertrophy was observed in all OD groups. Cardiac function evaluation in vivo showed low left ventricular systolic pressure and+dP/dt in the OD18 rats, suggesting a systolic dysfunction. OD12 and OD18 groups showed high left ventricle end-diastolic pressure, suggesting a diastolic dysfunction. OD groups showed an age-related impairment of both baroreflex-mediated tachycardia and baroreflex-mediated bradycardia in OD12 and OD18 rats. In isolated hearts from OD18 rats, both inotropic and tachycardiac responses to increasing isoproterenol were significantly reduced compared to the corresponding OC group. These results suggest that gestational diabetes triggers the onset of hyperglycemia hypertension with impaired baroreflex sensitivity and heart failure in older age of offspring, representing important risk factors for death. Therefore, ensuring optimal glycemic control in diabetic pregnancy is important and serves as a key to preventing cardiovascular disease in the offspring in their older age.

P2: Impella Smart Assist Technology and Hemodynamics Management in Cardiogenic Shock Management

Background: Smart Assist Impella pumps provide enhanced hemodynamic metrics via real-time assessment of aortic pressure (AoP), left ventricular pressure (LVP), cardiac output (CO) and cardiac power output (CPO). These data can constitute powerful management tools for clinicians yet information on the Smart Assist Technology algorithms and calculations remains scarce. This case reports illustrates the importance of an in-depth understanding of this newer technology to effectively manage cardiogenic shock patients on Impella support. Method: A 64yo man with cardiogenic shock supported with Impella 5.5 as a bridge to transplant had been on support for 27 days, with stable hemodynamics on P8, flowing 4.5 LPM. On day 28 patient experienced suction alarms and LVDP <-40mmHg prompting the team to reduce P level, administer fluid and attempt Impella repositioning. None of the interventions resolved the issue and consideration was given to reducing support to P2 and weaning or exchanging the Impella. The pump appeared correctly positioned by echo and hemolysis markers were negative. Careful review of patients’ data demonstrated a discrepancy between the transduced radial artery MAP at 73 mmHg and the aortic pressure measured by the Impella fiber optic sensor at 42 mmHg. This prompted a review of the LVP metric. The Impella Left ventricular pressure is calculated in real time by subtracting from the AoP the differential pressure gradient between pump outlet and inlet as derived from the motor current. An erroneous Ao signal input will result in an inaccurate LVP. Furthermore, the Impella suction alarm algorithm utilizes a sustained low LVDP as a trigger and can thus be triggered erroneously if the Ao signal is inaccurate. The suctions alarms and the low LVP were determined to be caused by drifting data feed from the Impella aortic fiber optic sensor. An Impella Ao signal bedside recalibration based on transduced MAP resolved the suction alarms. Result A drifting AoP signal resulted in an erroneous LVP measurements and subsequent suction alarms. Fiber optic technology does not require periodic calibrations once in vivo. Per IFU, the accuracy of the Ao is 1.9mmHg and the accuracy of the LV is 8.8 mmHg. In this case, the recalibration of the AO signal resolved the suction alarms and low LVP. Decision was made to not undertake an invasive pump exchange and continue supporting the patient on the implanted pump managing the metrics with daily manual recalibration. The patient was supported for an additional 17 days demonstrating optimal perfusion pressure and LV unloading and successfully underwent orthotopic heart transplant on Impella day 45. Conclusion: Impella Smart Assist technology is a powerful tool to manage patients’ hemodynamics. An in-depth understanding of the technology and its algorithms is crucial in delivering optimal patient care and preventing erroneous data feed from guiding hemodynamic management.Figure 1. Impella Smart Assist metrics. A. Stable on P8. B. Suction alarm generated by low LVDP. C. Persistent alarms despite fluid bolus and lower P level. D. Suction alarm resolved by Ao recalibrationFigure 2. LVP Calculation

Heart sound–derived systolic time intervals for atrioventricular delay optimization in cardiac resynchronization therapy

Phonocardiography (PCG) can be used to determine systolic time intervals (STIs) from ventricular pacing spike to the first heart sound (VS1) and from the first to the second heart sound (S1S2). The purpose of this study was to investigate the relations between STIs and hemodynamics during atrioventricular (AV) delay optimization of biventricular pacing (BiVP) in animals and patients. Five pigs with AV block underwent BiVP, while PCG was collected from an epicardial accelerometer. In 21 patients undergoing cardiac resynchronization therapy device implantation, PCG was recorded with a pulse generator-embedded microphone. Optimal AV delays derived from shortest VS1 and longest S1S2 were compared with AV delays derived from highest left ventricular pressure (LVP), maximal rate of rise in LVP, and stroke work. In pigs, VS1 and S1S2 predicted the AV delays with optimal hemodynamics (highest LVP, maximal rate of rise in LVP, and stroke work) by a median error of 2-28 ms, resulting in a median loss of <2% of pump function. In patients, VS1 and S1S2 predicted the optimal AV delay by errors of 32.5 and 37.5 ms, respectively, resulting in 0.2%-0.9% lower LVP and stroke work, which were reduced to 21 and 24 ms in 8 patients with a full-capture AV delay of >180 ms. During BiVP with varying AV delays, close relations exist between PCG-derived STIs and hemodynamic parameters. AV delays advised by PCG-derived STIs cause only a minimal loss of pump function compared with those based on invasive hemodynamic measurements. ClinicalTrials.gov Identifier: NCT01832493.

Mimicking Preconditioning by Vagal Stimulation. Effects on Ventricular Function in a Chronic Experimental Model

Background: Previous studies have shown that preischemic vagal electrostimulation (pVS) reduces acute myocardial infarctsize, without a significant improvement on ventricular function within the two-hour reperfusion period. It is unknown whichare the long-term effects of pVS on left ventricular function (LVF).Objectives: The aim of this study was to analyze whether the protective effects of brief pVS on acute infarct size improvesLVF in a chronic myocardial ischemia-reperfusion model.Methods: FVB mice were subjected to 45-minutes regional myocardial ischemia followed by 2 hours of reperfusion or 28-daypost-reperfusion follow-up with or without 10-minutes pVS. Infarct size (IS) was measured with 2,3,5-triphenyltetrazoliumchloride, and LVF was assessed by echocardiography and left ventricular catheterization.Results: Preischemic vagal stimulation reduced IS from 66.8±3.2% to 43.2±1.6% (p <0.001) at 2 hours of reperfusion, without afavorable LVF response. At 28 days, the pVS group exhibited LVF improvement, with lower left ventricular end-diastolic pressure(4.44±1 vs. 6.91±1 mmHg in the control group; p<0.05), higher ejection fraction (69.7±2.8% vs. 59.3±3.2; p<0.05), greatershortening fraction (33.4±2.23 vs. 25.8±1.8%; p<0.05) and lower isovolumic relaxation time (25±0.8 ms vs. 30.3±1.2 ms; p<0.05)Conclusions: In a mice model of myocardial ischemia and reperfusion, mimicking ischemic preconditioning by VS improvesthe chronic outcome of infarction, resulting in greater LVF recovery

Improved technical success, postnatal outcome and refined predictors of outcome for fetal aortic valvuloplasty.

Fetal aortic valvuloplasty (FAV) may prevent progression of mid-gestation aortic stenosis to hypoplastic left heart syndrome (HLHS). The aim of this study was to evaluate whether technical success and biventricular (Biv) outcome after FAV have changed from an earlier (2000-2008) to a more recent (2009-2015) era and identify pre-FAV predictors of Biv outcome. We evaluated procedural and postnatal outcomes in 123 fetuses that underwent FAV for evolving HLHS at Boston Children's Hospital between 2000 and 2015. The primary outcome measure was circulation type (Biv vs single ventricle) at the time of neonatal hospital discharge. Classification and regression tree (CART) analysis was performed to construct a stratification algorithm to predict Biv circulation based on pre-FAV fetal variables. The FAV procedure was technically successful in 101/123 (82%) fetuses, with a higher technical success rate in the more recent era than in the earlier one (49/52 (94%) vs 52/71 (73%); P = 0.003). In liveborn patients, the incidence of Biv outcome was higher in the recent than in the earlier era, both in the entire liveborn cohort (29/49 (59%) vs 16/62 (26%); P = 0.001) and in those in whom the procedure was technically successful (27/46 (59%) vs 15/47 (32%); P = 0.007). Independent predictors of Biv outcome were higher left ventricular (LV) pressure, larger ascending aorta, better LV diastolic function and higher LV long-axis Z-score. On CART analysis, fetuses with LV pressure > 47 mmHg and ascending aorta Z-score ≥ 0.57 had a 92% probability of Biv outcome (n = 24). Those with a lower LV pressure, or mitral dimension Z-score < 0.1 and mitral valve inflow time Z-score < -2 (n = 34) were unlikely to have Biv (probability of 9%). The remainder of the patients had an intermediate (∼40-60%) likelihood of Biv circulation. The proportion of patients achieving Biv outcome after FAV has increased, probably owing to an improved technical success rate and modified selection criteria. Fetal factors, including LV pressure, size of the ascending aorta and diastolic function, are associated with likelihood of Biv circulation after FAV. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Left Ventricular Diastolic Function and Characteristics in Fetal Aortic Stenosis

Fetal aortic balloon valvuloplasty (FAV) has shown promise in averting progression of midgestation aortic stenosis (AS) to hypoplastic left heart syndrome in a subset of patients. Patients who achieve biventricular circulation after FAV frequently have left ventricular (LV) diastolic dysfunction (DD). This study evaluates DD in fetuses with AS by comparing echocardiographic indices of LV diastolic function in fetuses underwent FAV (n= 20) with controls (n= 40) and evaluates for LV factors associated with DD in patients with FAV. We also compared pre-FAV and post-FAV DD variables (n= 16). Median gestational age (24weeks, range 18 to 29weeks) and fetal heart rate were similar between FAV and controls. Compared with controls, patients with FAV had universally abnormal LV diastolic parameters including fused mitral inflow E and A waves (p= 0.008), higher E velocity (p<0.001), shorter mitral inflow time (p= 0.001), lower LV lateral annulus E' (p <0.001), septal E' (p= 0.003), and higher E/E' (p <0.001) than controls. Patients with FAV had abnormal right ventricular mechanics with higher tricuspid inflow E velocity (p <0.001) and shorter tricuspid inflow time (p= 0.03). Worse LV diastolic function (lower LV E') was associated with higher endocardial fibroelastosis grade (r= 0.74, p <0.001), large LV volume (r= 0.55, p= 0.013), and sphericity (r= 0.58, p= 0.009) and with lower LV pressure by mitral regurgitation jet (r=-0.68, p <0.001). Post-FAV, fewer patients had fused mitral inflow E and A than pre-FAV (p= 0.05) and septal E' was higher (=0.04). In conclusion, fetuses with midgestation AS have evidence of marked DD. Worse DD is associated with larger, more spherical LV, with more extensive endocardial fibroelastosis and lower LV pressure.

Ambulatory blood pressure monitoring in prepubertal idiopathic dilated cardiomyopathy children

BACKGROUND AND OBJECTIVES: Ambulatory blood pressure monitoring is recommended for several diseases in childhood; however, there are no reports about its use in the monitoring of children with dilated cardiomyopathy so far. We evaluated the pattern of ambulatory blood pressure monitoring in children with dilated cardiomyopathy and correlated it to height, weight, and body mass index. METHODS: Prepubertal children with dilated cardiomyopathy were assessed by ambulatory blood pressure monitoring. Data were collected for systolic and diastolic blood pressure. Means, for 24hours, daytime, and nighttime, dipping pattern and levels above the normal expected values were computed. RESULTS: Children with cardiomyopathy have the same blood pressure as normal kids. Weight was moderately but significantly correlated to nighttime systolic blood pressure. Children with left ventricular ejection fraction < 50% have 6% less diastolic blood pressure dipping. These same children were also receiving higher doses of carvedilol and captopril. CONCLUSIONS: Children with idiopathic dilated cardiomyopathy have the same blood pressure values and blood pressure dipping patterns on ambulatory blood pressure monitoring as normal healthy children are expected to have. Children with low left ventricular ejection pressure have lower dipping pattern.

English

Several studies indicate that some steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the effects of progesterone and its derivatives on cardiac injury ischemia/reperfusion (I/R). Therefore, in this study, a progesterone derivative was evaluated with the objective of evaluating its activity on I/R in an ischemia-reperfusion model. In addition, molecular mechanism involved in the activity of effect induced by progesterone derivative on perfusion pressure and coronary resistance was assed using the Langendorff technique by measuring left ventricular pressure in the absence or presence of mifepristone, yohimbine, ICI 118,551, atropine, methoctramine and L-NG-nittroarginine methyl esther (L-NAME). The results showed that progesterone derivative reduced infarct size compared with progesterone and control. In addition, it was also observed that the progesterone derivative significantly decreased the perfusion pressure and coronary resistance in isolated heart. Additionally, another set of data indicate that progesterone derivative produces low left ventricular pressure in a dose-dependent manner [0.001 to 100 nM]; however, this phenomenon was significantly inhibited by methoctramine (1 nM) and L-NAME (1 nM). In conclusion, these data suggest that a cardioprotective effect of progesterone derivative is through the interaction with M2 muscarinic and activation of nitric oxide synthase which may be responsible for the reduction in myocardial necrosis after ischemia and reperfusion. Key words. Progesterone derivative, ischemia/reperfusion, methoctramine and L-NG-nittroarginine methyl esther (L-NAME).

Susceptibility to cardiac ischemia/reperfusion injury modulated by an estrogen derivative

Several studies indicate that some steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the effects of the estradiol derivatives on cardiac injury ischemia/reperfusion (I/R). Therefore, in this study, an estradiol derivative was synthetized with the objective of evaluating its activity on I/R in an ischemia-reperfusion model. In addition, molecular mechanism involved in the activity of effect induced by estradiol derivative on perfusion pressure and coronary resistance was evaluated using the Langendorff technique by measuring left ventricular pressure in absence or presence of the following compounds; tamoxifen, yohimbine, ICI 118,551 and L-NAME. The results showed that estradiol derivative reduced infarct size compared with control. In addition, another results showed that the estradiol derivative significantly decrease the perfusion pressure and coronary resistance in isolated heart. Additionally, another data indicate that estradiol derivative low left ventricular pressure in a dose-dependent manner (1 × 10-9 to 1 × 10-4mmol); however, this phenomenon was significantly inhibited by tamoxifen at a dose of 1 × 10-6 mmol and L-NAME (1 × 10-6 mmol). In conclusion, these data suggest that cardioprotective effect of estradiol derivative is through the interaction with estrogen receptor and activation ofnitric oxide synthase. This phenomenon results in decrease of myocardial necrosis after ischemia and reperfusion. Key words: Estradiol derivative, ischemia/reperfusion, tamoxifen, L-NAME.

Early and late effects of iron deficiency on heart and baroreflex function

Iron deficiency (ID) induces cardiac and neural alterations, such as cardiac hypertrophy and apoptosis, electron transport dysfunction, and brain mitochondrial disruption. Cardiac norepinephrine (NE) depletion suggests chronically high sympathetic nervous system (SNS) traffic to the heart. Thus, ID would be expected to affect heart function and blood pressure, and our previous experiments have shown baroreflex alterations after 4 weeks of ID.HYPOTHESES(1) Chronic high SNS output initially leads to a hyperfunctional heart with higher left ventricular pressure (LVP) and heart rates (HR) at each mean arterial pressure (MAP), and (2) eventual depletion of NE, along with heart apoptosis and debility, is coincident with reduced LVP and HR at all MAP.METHODSRats were fed control (CN) or ID diets for 2 or 4 weeks. Baroreflex experiments were conducted using ramp (before and after atropine) and steady state protocols. Hearts were excised for Langendorff experiments to obtain LVP at set flow rates.RESULTSHematocrit verified ID (p ≤ 0.05); heart mass verified hypertrophy. Baroreflex preliminary data suggests higher HR at all MAP at 2 weeks, but lower HR after 4 weeks; experiments continue at time of writing. Langendorff data indicates higher LVP with ID at 2 weeks, but lower LVP after 4 weeks.CONCLUSIONChanges with ID are adaptive at 2 weeks but pathological after 4 weeks. Supported by WY INBRE (LC4090).

Linking Cellular Energetics to Local Flow Regulation in the Heart

A mathematical model has been developed to explain the metabolic and energetic responses induced by abnormal routes of cardiac excitation. For example, in left bundle branch block (LBBB), both glucose uptake and flow are reduced in the septal region, similar to the situation in dogs paced at the right ventricular outflow tract. In these conditions the septum is activated early, the sarcomere lengths shorten rapidly against low left ventricular (LV) pressure, and the blood flow to the interventricular septum diminishes. In contrast, the work load and the blood flow increases in the later-activated LV free wall. To provide a logical, quantitatively appropriate representation, the model links: (1) the processes of excitation-contraction coupling; (2) regional ATP utilization for force development at the cross-bridge, for ion pumping, and for cell maintenance; (3) the regulation of demands on local fatty acid and glucose metabolism for ATP generation by glycolysis and oxidative phosphorylation; and (4) feedback regulation of blood flow to supply substrate and oxygen. The heart is considered as a cylinder composed of two parts: an early-activated region and a late-activated region in tandem, but activated separately with the time delay representing the time for excitation to spread from septum to free wall. The same model equations and parameter sets are used for the two regions. The contraction of the early-activated region stretches the other region, with the result that the early-stimulated region has diminished oxygen requirements compared to those found with simultaneous stimulation. The late-activated region has increased work and increased oxygen consumption, as seen in the intact heart. Integrating the modeling of cardiac energy metabolism with local blood flow regulation and capillary-tissue substrate exchange provides a quantitative description, an hypothesis formulated to stimulate further experimentation to test its validity. The hypothesis "explains" observations of contraction and metabolism in LBBB, but whether this concept can be extended to explain the normal flow heterogeneity in the heart remains unknown.

Bactericidal/permeability increasing protein attenuates the myocardial inflammation/dysfunction that occurs with burn complicated by subsequent infection

Intubation and mechanical ventilation after burn contribute to pneumonia-related infection. Although postburn presence or absence of endotoxin has been described, inactivation of Toll-like receptor 4 signaling has been shown to improve postburn organ function, suggesting that LPS participates in burn-related susceptibility to infection. We hypothesized that bactericidal/permeability-increasing protein (rBPI) given postburn would attenuate myocardial inflammation/dysfunction associated with postburn septic challenge given 7 days postburn. Rats were given burn over 40% total body surface area, lactated Ringer 4 ml.kg(-1).% burn(-1); burns received either vehicle or rBPI, 1 mg.kg(-1).h(-1) for 48 h postburn. Postburn day 7, subgroups of burns and shams were given intratracheal Klebsiella pneumoniae, 4 x 10(6) CFU to produce burn complicated by sepsis; additional sham and burn subgroups received intratracheal vehicle to produce sham sepsis. Vehicle-treated groups: 1) sham burn + sham sepsis 2) sham burn + sepsis, 3) burn + sham sepsis, 4) burn + sepsis. rBPI-treated groups: 5) sham burn + sham sepsis, 6) sham burn + sepsis, 7) burn + sham sepsis, 8) burn + sepsis. Cardiomyocyte cytokine secretion and myocardial function were studied 24 h after septic challenge, postburn day 8. Pneumonia-related infection 8 days after vehicle-treated burn produced myocyte cytokine secretion (pg/ml), indicated by increased myocyte TNF-alpha, 549 +/- 46; IL-1beta, 50 +/- 8; IL-6, 286 +/- 3 levels compared with levels in sham myocytes (TNF-alpha, 88 +/- 11; IL-1beta, 7 +/- 1; IL-6, 74 +/- 10; P < 0.05). Contractile dysfunction was evident from lower left ventricular pressure +/-dP/dt values in this group compared with sham. rBPI attenuated myocyte cytokine responses to septic challenge and improved contractile function, suggesting that burn-related mobilization of microbial-like products contribute to postburn susceptibility to infection.

The Effects of Early Excision and Grafting on Myocardial Inflammation and Function after Burn Injury

Sepsis is a frequent complication of burn injury despite absence of confirmed infection. Numerous investigators have proposed that the burn wound itself is a primary stimulus for postburn inflammation, and that early excision of the burn wound attenuates the hypermetabolic and inflammatory responses to burn injury. However, others have suggested that aggressive fluid resuscitation and correction of postburn fluid and electrolyte deficits should be the primary focus of intervention in the first 24 hours postburn. This present study determined whether excision and grafting of the burned wound within 30 minutes after injury abrogated myocardial inflammation and contractile defects that occur after burn injury. In group 1, Sprague Dawley rats were given a third-degree burn over 20% total body surface area (TBSA), whereas rats in group 2 had burns over 30% TBSA and no wound excision. Rats in groups 3 and 4 had burn over 20% and 30% TBSA, respectively, followed by-wound excision and grafting (WE/G) within 30 minutes after completing burn injury. Group 5 included sham burn with no excision, whereas rats in groups 6 and 7 included shams that had either 20% or 30% normal skin excised and grafted to provide appropriate surgical controls. All rats received lactated Ringer's (4 mL/kg/% burn or percent wound excision). Twenty-four hours postburn, hearts were perfused (Langendorff) to assess ventricular function; myocytes were isolated to examine cytokine secretion and Ca2+/Na+ homeostasis. Burn in the absence of wound excision produced myocardial inflammation and contractile defects as indicted by a lower left ventricular pressure and lower rate of left ventricular pressure rise (+dP/dt) and fall (-dP/dt) response to maximal increases in preload or perfusate Ca2+ compared with responses measured in sham hearts. WE/G within 30 minutes after burn injury reduced myocyte secretion of proinflammatory cytokines and improved left ventricular pressure and +/-dP/dt responses to inotropic challenge. Cutaneous burn injury and the loss of the skin barrier function contribute, in part, to the myocardial inflammation which, in turn, contributes to myocardial contractile dysfunction that is characteristic of major burn injury.

Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma.

Whereas controversial, several studies have suggested that nitric oxide (NO) alters cardiac contractility via cGMP, peroxynitrite, or poly(ADP ribose) synthetase (PARS) activation. This study determined whether burn-related upregulation of myocardial inducible NO synthase (iNOS) and NO generation contributes to burn-mediated cardiac contractile dysfunction. Mice homozygous null for the iNOS gene (iNOS knockouts) were obtained from Jackson Laboratory. iNOS knockouts (KO) as well as wild-type mice were given a cutaneous burn over 40% of the total body surface area by the application of brass probes (1 x 2 x 0.3 cm) heated to 100 degrees C to the animals' sides and back for 5 s (iNOS/KO burn and wild-type burn). Additional groups of iNOS KO and wild-type mice served as appropriate sham burn groups (iNOS/KO sham and wild-type sham). Cardiac function was assessed 24 h postburn by perfusing hearts (n = 7-10 mice/group). Burn trauma in wild-type mice impaired cardiac function as indicated by the lower left ventricular pressure (LVP, 67 +/- 2 mmHg) compared with that measured in wild-type shams (94 +/- 2 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dtmax, 1,620 +/- 94 vs. 2,240 +/- 58 mmHg/s, P < 0.001), and a lower rate of LVP fall (-dP/dtmax, 1,200 +/- 84 vs. 1,800 +/- 42 mmHg/s, P < 0.001). Ventricular function curves confirmed significant contractile dysfunction after burn trauma in wild-type mice. Burn trauma in iNOS KO mice produced fewer cardiac derangements compared with those observed in wild-type burns (LVP: 78 +/- 5 mmHg; +dP/dt: 1,889 +/- 160 mmHg/s; -dP/dt: 1,480 +/- 154 mmHg/s). The use of a pharmacological approach to inhibit iNOS (aminoguanidine, given ip) in additional wild-type shams and burns confirmed the iNOS KO data. Whereas the absence of iNOS attenuated burn-mediated cardiac contractile dysfunction, these experiments did not determine the contribution of cardiac-derived NO versus NO generated by immune cells. However, our data indicate a role for NO in cardiac dysfunction after major trauma.

Development of an acute burn model in adult mice for studies of cardiac function and cardiomyocyte cellular function.

The increasing availability of mice with gene supplementation (transgenic), site-specific inactivation mutations (gene "knock-outs"), or site-specific genetic modification mutations (gene "knock-ins") has spurred interest in the development of murine trauma models. In this study, C57 BL/6 mice (28 g) were given a cutaneous burn over 40% total body surface area by applying brass probes (1 x 2 x 0.003 cm) heated to 100 degrees C in boiling water to the animals side and back for 5 s. Shams received anesthesia alone and not burn. Mice were killed 24 h post-burn to determine presence of partial-thickness or full-thickness burn injury, cardiac contractile function (Langendorff perfusion, n = 7 or 8 mice/group) or to examine cardiac myocyte cytokine secretion in isolated cardiomyocytes (collagenase perfusion, n = 4 or 5 mice/group). All mice were killed 24 h post-burn for subsequent cardiac or cardiomyocyte studies. Our studies confirm that this murine model of burn trauma produced mixed partial- or full-thickness burn injury, whereas there was no necrosis or inflammation in sham burn mice. Baseline hematocrits were similar in all mice (44+/-1) but decreased after burn trauma (37+/-1), likely because of the volume of fluid resuscitation and hemodilution. Burn trauma impaired cardiac contraction and relaxation as indicated by the lower left ventricular pressure (LVP) measured in burn (56+/-4) compared to that measured in shams (84+/-1 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dt max, 1393+/-10 vs. 2000+/-41 mmHg/s, P < 0.002), and reduced LVP fall (-dP/dt max, 1023 - 40 vs. 1550+/-50, P < 0.001). These differences occurred despite similar coronary perfusion pressures and heart rates in both sham and burn mice. Ventricular function curves were shifted downward in the burn mice in the direction of contractile failure; in addition, hearts from burn mice had reduced LVP and +dP/dt responses to increases in coronary flow rate, increases in perfusate Ca2+, and to isoproterenol challenge (P < 0.05). Burn trauma promoted cardiac myocyte secretion of tumor necrosis factor (TNFalpha) (175+/-6 pg/mL) compared to that measured in shams (72+/-9 pg/mL, P < 0.05); burn trauma also increased cardiac myocyte secretion of interleukin 1beta (IL-1beta) (sham: 2+/-0.5; burn: 22+/-1 pg/mL, P < 0.05) and IL-6 (sham: 70+/-6; burn: 148+/-16 pg/mL, P < 0.05). Anti-TNFalpha strategies prevented burn-mediated cardiac contractile deficits. Burn trauma altered Ca2+ homeostasis in murine cardiomyocytes (Fura-2 AM loading). [Ca2+]i in myocytes from burns (185+/-4 nM) was higher than values measured in myocytes from shams (86+/-nM, P < 0.05). These data confirm that the murine burn model provides a reasonable approach to study the molecular and cell biology of inflammation in organ dysfunction after burn trauma.

In Vitro Model for Cardiac Function under Xenon Anesthesia

ProfessorProfessor: Departments of Anesthesiology and Physiology: Medical College of WisconsinPostdoctoral Research FellowAssistant ProfessorPostdoctoral Research Fellow: Department of Anesthesiology: Medical College of Wisconsin: Milwaukee, WisconsinProfessor and ChairmanDepartment of AnesthesiologyUniversity of UlmUlm, Germanyzbosnjak@mcw.eduIn Reply:—We appreciate the interest expressed by Drs. Schroth, Reyle-Hanh, and Rossaint with regard to our recent article. First, using a Marquette Gas Analyzer (Model 1100; Marquette Gas Analysis Corp., St. Louis, MO), we verified that the oxygen and nitrogen fractions were approximately 20 and 40%, respectively, and 20 and 0%, respectively, to give estimated xenon fractions of 40 and 80%, respectively, in the gas reservoir bags. In addition, effective xenon concentrations in solutions were verified by placing the samples and xenon standards into sealed 1-ml vials and conducting a head-space analysis using the H-P 5989 MS-ENGINE Mass Spectrometer (Hewlett-Packard, Palo Alto, CA).The second concern was that the hearts might become hypoxic with 20% oxygenated perfusate solution, despite the presence of approximately 2.8 g hemoglobin/100 ml perfusate. Most Langendorff preparations that are not perfused with crystalloid solutions are perfused with washed erythrocytes obtained from other species. As the authors pointed out, the venous oxygen tension and p H do not suggest hypoxia. Oxygen consumption of Langendorff hearts is approximately 50–70% of in vivo hearts, and lactate is not produced with carbogen equilibrated in crystalloid perfusate. This is caused in part by the lack of kinetic (stroke) work and decreased potential (isometric) work. Nevertheless, in our erythrocyte-perfused hearts, we conducted a control experiment suggested by the authors; that is, erythrocyte perfusion of hearts with 95% and 5% CO2before switching to the reservoirs containing 20% O2. The change from 95% to 20% O2produced no appreciable change in left ventricular pressure, and so we doubt that the hearts became hypoxic. However, we believe that the use of erythrocyte solution might result in a lower left ventricular pressure because of buffering of the calcium in the solution. A small increase in viscosity may also contribute to somewhat lower left ventricular pressure.

Trial of pulmonary artery banding: a diagnostic criterion for 'one-stage' arterial switch in simple transposition of the great arteries beyond the neonatal period.

Arterial switch operation (ASO) is the procedure of choice for the repair of simple d-transposition of the great arteries (TGA) during the neonatal period. Beyond this time such correction is performed in two stages. The first step incorporates banding of the pulmonary artery with or without a Blalock-Taussig shunt to train the left ventricle (LV). The second step consists of the ASO. To find out whether candidates for a two-stage procedure would tolerate a one-stage correction, a trial of pulmonary artery banding was performed. Between February 1986 and December 1995, 224 patients less than 3 months of age with TGA, intact ventricular septum or a small restrictive ventricular septal defect, had an ASO. Seven patients were 4 weeks of age or older (28-70 days). Two of these had a pulmonary artery to systemic pressure ratio higher than 0.6 and underwent primary ASO without complications. The remaining five patients had low left ventricular pressure with a pulmonary to systemic pressure ratio of 0.2-0.5; echocardiography showed a banana-shaped LV with left ventricular wall thickness as low as 3 mm. They underwent a trial of pulmonary artery banding to systemic pressure for 15-30 min. As this increase in workload was tolerated well with an anticipated decrease of oxygen saturation but without hemodynamic disturbances anticipated, the ASO was performed immediately. Postoperative course was uneventful in all five patients, although catecholamine dependence was prolonged and three patients received enoximone. There were no severe complications. Echocardiography showed an increase in posterior wall thickness from 3 to 6 mm after 19 days in one infant. Some of the children, assigned for a 'two-stage' ASO may tolerate a primary anatomic repair up to an age of at least three months. This subgroup can be selected by a trial of pulmonary artery banding.

Relation between left ventricular shape and Doppler filling parameters in patients with left ventricular dysfunction secondary to coronary artery disease

Left ventricular (LV) shape is an independent predictor of exercise capacity in patients with systolic LV dysfunction. Recent studies suggest that end-systolic LV shape is related to the generation of restoring forces during contraction that facilitate filling at lower LV pressure during subsequent diastole. To test the hypothesis that preservation of a more elliptical LV shape would be associated with a distribution of diastolic inflow characterized by increased early relative-to-late filling, 32 outpatients with coronary artery disease and ejection fraction <40% underwent quantitative 2-dimensional and Doppler echocardiography. LV volumes, ejection fraction, and eccentricity index were measured as were standard Doppler indexes of LV filling. Simple and multiple linear regression models were used to examine relations between LV shape and Doppler measurements. LV eccentricity at end-systole correlated strongly with the Doppler atrial filling fraction (r = −0.670; p < 0.001) and the ratio of early-to-late flow velocity integrals (r = 0.648; p < 0.001). No other 2-dimensional echocardiographic variable was significantly correlated with any other Doppler index of LV filling. Thus, LV shape at end-systole appears to be an important determinant of diastolic filling patterns. In patients with systolic LV dysfunction, preservation of a more elliptical chamber is associated with a diastolic inflow pattern characterized by increased early relative-to-late diastolic filling.

Delayed Hypertonic Saline Dextran Administration after Burn Injury

Experimental studies in our laboratory showed that hypertonic saline dextran (HSD; 7.5 NaCl in 6% dextran 70) given as a small bolus (4 mL/kg) immediately after burn injury in guinea pigs improved cardiac contractile performance and reduced the total fluids requirements. Although these data confirm the cardioprotective effects of HSD given immediately postburn, prehospital and early inhospital management of severely burned patients consists of aggressive crystalloid fluid resuscitation to correct intravascular volume deficits. The question arose as to whether delaying HSD for several hours after initiating crystalloid resuscitation would provide cardioprotection. Third-degree scald burns comprising 45 +/- 1% of the total body surface area (burn groups, n = 40) or 0% for controls (group 1, n = 12) were produced; in groups 2 to 5, lactated Ringer's (LR) resuscitation was initiated immediately postburn according to the Parkland formula, 4 mL/kg/% burn. In group 2, (n = 12), LR was continued for 24 hours. HSD was administered as an i.v. bolus at either 1 hour (group 3, n = 10), 4 hours (group 4, n = 9), or 8 hours postburn (group 5, n = 9); immediately after HSD administration, LR was continued (1 mL/kg/% burn) until 24 hours postburn. Compared to sham burn controls, hearts from burned animals treated with LR alone had significant cardiac dysfunction, as indicated by a lower left ventricular pressure and +/- dP/dt. Compared with hearts from LR-treated animals, hearts from burned animals treated with HSD 1 hour (HSD-1) and 4 hours (HSD-4) after burn injury had significantly higher LVP and +/- dP/dt. Ventricular function curves calculated for HSD-1 and HSD-4 groups were comparable to those calculated for hearts from sham burns. Delaying HSD administration until 8 hours after burn provided little cardioprotection. Our data indicate that HSD effectively maintains cardiac function and reduces overall total fluid requirements if administered within 4 hours after burn injury.