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Lake Erie is the shallowest and most biologically productive system of the Great Lakes, surrounded by large urban, industrial, and agricultural areas. This combination prompted extensive efforts to promote best management practices (BMPs) to mitigate non-point source pollution in Lake Erie’s watershed. Recent technical and conceptual advancements caution that significant variability exists in the BMP efficiency to reduce the severity of runoff and nutrient concentrations due to differences in implementation, the dependence of operational performance on local soil and climatic conditions, storm events and seasonality, and declining performance over time owing to imperfect maintenance. Given the uncertainty surrounding the design and efficiency of BMPs in abating non-point source pollution, our primary objective is to review the critical strengths and potential weaknesses of nine agricultural BMPs promoted for use in the Lake Erie watershed. We examine the capacity of the current generation of watershed process-based models to recreate possible BMP-mediated changes in the water and nutrient cycles. After reviewing modelling strategies (dynamic, external forcing, and empirical) to recreate non-linear watershed responses and feedback loops to BMP efficiency, our study recommends adopting dynamic representations of the interplay among key mechanisms, like soil moisture, water table, nutrient availability, plant uptake, and subsequent growth. Notwithstanding the increased sophistication of complex mathematical models, their learning capacity is usually compromised by the coarse resolution of environmental data and limited empirical knowledge to accurately parameterize environmental properties and partially understood biogeochemical processes. Moreover, BMPs may differentially affect the provisions of an ecosystem (e.g., a BMP may amplify one ecosystem service while dampening another). In this context, we highlight the expression of the value of ecosystem services in monetary and non-monetary terms as a critical information piece when considering trade-offs among costly and diverse policy decisions. Our study also examines the degree to which different types of valuation methods, socioeconomic models, and data have been operationalized in Lake Erie. Consistent with the Integrated Watershed Management framework, we advocate the adoption of a rigorous mass-balance approach to assess the impact of BMPs on nutrient cycles, as well as the integration of the projected environmental improvements with terrestrial ecosystem services, beneficial use impairments, and aquatic ecosystem services. The proposed strategy has the potential to improve the decision-making process by identifying cost-effective management actions and balancing different goods and services provided by the agroecosystems at different time scales.

The recently developed synthetic oligonucleotides referred to as "click" nucleic acids (CNAs) are promising due to their relatively simple synthesis based on thiol-X reactions with numerous potential applications in biotechnology, biodetection, gene silencing, and drug delivery. Here, the cytocompatibility and cellular uptake of rhodamine tagged, PEGylated CNA copolymers (PEG-CNA-RHO) were evaluated. NIH 3T3 fibroblast cells treated for 1 h with 1, 10, or 100 μg/mL PEG-CNA-RHO maintained an average cell viability of 86%, which was not significantly different from the untreated control. Cellular uptake of PEG-CNA-RHO was detected within 30 s, and the amount internalized increased over the course of 1 h. Moreover, these copolymers were internalized within cells to a higher degree than controls consisting of either rhodamine tagged PEG or the rhodamine alone. Uptake was not affected by temperature (i.e., 4 or 37 °C), suggesting a passive uptake mechanism. Subcellular colocalization analysis failed to indicate significant correlations between the internalized PEG-CNA-RHO and the organelles examined (mitochondria, endoplasmic reticulum, endosomes and lysosomes). These results indicate that CNA copolymers are cytocompatible and are readily internalized by cells, supporting the idea that CNAs are a promising alternative to DNA in antisense therapy applications.

Evaluation of hydrological response to future climate change is essential for water quality risk assessment and adaptive management implementation within a watershed context. In this study, we present a modeling framework that integrates a hydrological model with projections of General Circulation Models (GCMs). Temperature and precipitation projections of six GCMs with two downscaling methods are used to force the Soil and Water Assessment Tool (SWAT) model in the Hamilton Harbour watershed in Ontario, Canada. A flow-based weighting strategy was developed to integrate the projections of multiple GCMs based on their ability to recreate empirical flow frequency distributions in multiple monitoring sites. Our study renders support to the ability of the weighted model ensemble to draw meaningful hydrological forecasts. Nonetheless, we also note that the ensemble strategy understates the frequency and magnitude of flow extremes, and therefore the domain that is collectively delineated by individual GCMs can still provide complementary planning information. Climate change is projected to trigger a distinct increase in air temperature and precipitation during the late winter-early spring period, which in turn will likely result in an earlier snowmelt and changes in the magnitude and timing of peak flow events. Analysis of the water cycle shows that the sensitivity of the individual hydrological components to climate change may vary along the urban-to-agriculture gradient. The projected declining soil–water content in agricultural catchments highlights the likelihood of more intensified drought conditions in the croplands. Evapotranspiration rates will likely increase across the entire watershed, whereas surface runoff could be reduced but less so in urbanized locations. Overall, our findings suggest that any future planning exercise to ameliorate the prevailing water quality conditions will only be insightful if we consider the interplay between climate change and urbanization processes in the area.

The increased use of Pharmaceuticals and Personal Care Products (PPCP’s) has led to an increase in many population health problems. In 1997, 15–50 % of women had developed breasts by the age of 8. Ten years prior to this, breast development by the age of 8 was uncommon. There are certain researchers who believe that this may be linked to the pharmaceuticals humans are consuming.Wastewater treatment plants are a significant gateway by which pharmaceuticals enter the water supply. Many pharmaceuticals find themselves in wastewater treatment plants, however the plants do not target these specific chemicals for treatment. As a result, they are released into the surrounding bodies of water, and accumulate in aquatic animals. When water treatment plants take water from the bodies of water and distribute it for human consumption, humans consume these chemicals.Many techniques for removing the pharmaceuticals have been tested, but there is still much uncertainty as to which are effective methods. The potential hazards associated with these chemicals are still uncertain, but the current evidence is indicating that it is very likely that these chemicals can be very hazardous.

The scientific methodology of mathematical models and their credibility to form the basis of public policy decisions have been frequently challenged. The development of novel methods for rigorously assessing the uncertainty underlying model predictions is one of the priorities of the modeling community. Striving for novel uncertainty analysis tools, we present the Bayesian calibration of process-based models as a methodological advancement that warrants consideration in ecosystem analysis and biogeochemical research. This modeling framework combines the advantageous features of both process-based and statistical approaches; that is, mechanistic understanding that remains within the bounds of data-based parameter estimation. The incorporation of mechanisms improves the confidence in predictions made for a variety of conditions, whereas the statistical methods provide an empirical basis for parameter value selection and allow for realistic estimates of predictive uncertainty. Other advantages of the Bayesian approach include the ability to sequentially update beliefs as new knowledge is available, the rigorous assessment of the expected consequences of different management actions, the optimization of the sampling design of monitoring programs, and the consistency with the scientific process of progressive learning and the policy practice of adaptive management. We illustrate some of the anticipated benefits from the Bayesian calibration framework, well suited for stakeholders and policy makers when making environmental management decisions, using the Hamilton Harbour and the Bay of Quinte—two eutrophic systems in Ontario, Canada—as case studies.

Objective: To evaluate the efficacy of a novel lipopolysaccharide (LPS) antagonist, E5531, in blocking LPS-induced cardiac responses including myocardial depression (as assessed by relatively load-independent echocardiographic indices of contractility) in a human model of experimental endotoxemia. Design: Randomized, prospective, placebo-controlled, double-blind trial. Setting: ICU procedure room. Participants: Thirty-two healthy, male volunteers. Interventions: Administration of LPS (4 ng/kg) and either a placebo or one of four sequential doses of E5531 (100 μg, 250 μg, 500 μg, or 1,000 μg) followed by volumetric echocardiography before and during 4-L saline solution infusion (3 L over 3 h, followed by 1 L over 2 h). Results: In addition to the generation of a hyperdynamic circulation throughout the study period, administration of LPS resulted in a biphasic contractility response. Ejection fraction (EF), rate-corrected mean velocity of circumferential fiber shortening (Vcfc), peak systolic BP (SBP)/end-systolic volume index (ESVI) ratio, and end-systolic pressure (Pes)/ESVI ratio increased at the 3-h post-LPS assessment, compared to a control group of subjects receiving only similar amounts of saline solution (minimum p Conclusions: Endotoxin generates significant myocardial depression when measured using highly load-independent indices of cardiac contractility. E5531 is a potent inhibitor of the early hyperdynamic cardiovascular and later myocardial depression response seen in experimental human endotoxemia.

Background: Digital recording of echocardiographic studies is on the clinical horizon. However, full digital capture of complete echocardiographic studies in traditional video format is impractical, given current storage capacity and network bandwidth. To overcome these constraints, we evaluated the diagnostic image quality of digital video by using MPEG (Motion Picture Experts Group) compression. Methods and Results: Fifty-eight complete, consecutive studies were recorded simultaneously with the use of MPEG-1 and sVHS videotape. Each matched MPEG and sVHS study pair was reviewed by two from a total of six readers, and findings were recorded with the use of a detailed, computerized reporting tool. Intrareader and interreader discrepancies were characterized as major or minor and analyzed in total and for specific subgroups of findings (left and right ventricular parameters, valvular insufficiency, and left ventricular regional wall motion). Intrareader discrepancies were reviewed by a consensus panel for agreement with either MPEG or sVHS findings. There was an exact concordance between MPEG and sVHS readings in 83% of findings. The majority of discrepancies were minor, with major discrepancies in only 2.7% of findings. There was no difference in the rate of consensus panel agreement with MPEG or sVHS for instances of intrareader discrepancy, either in total or for any subgroup of findings. Interreader discrepancy rates were nearly identical for both MPEG and sVHS. Conclusions: MPEG-1 digital video is equivalent to sVHS videotape for diagnostic echocardiography. MPEG increases the range of practical options for digital echocardiography and offers, for the first time, the advantages of digital recording in a familiar video format. (J Am Soc Echocardiogr 1998;11:819-25.)

We evaluated the accuracy of a new Doppler-based method using the mitral regurgitant velocity at the time of aortic valve opening for the noninvasive estimation of left ventricular end-diastolic pressure. Sixty unselected patients were studied immediately before routine catheterization. Invasive left ventricular end-diastolic pressure was obtained using a fluid-filled pig-tail catheter. Noninvasive estimation of left ventricular pressure at aortic valve opening was taken as systemic diastolic pressure using an automated cuff. Noninvasive left ventricular end-diastolic pressure was calculated as diastolic blood pressure - 4 × (mitral regurgitant velocity at aortic opening) 2 . Those making noninvasive determinations were blinded to catheterization results. An adequate mitral regurgitant Doppler recording was obtained in 24 patients (40%). In patients with a left ventricular end-diastolic pressure greater than 15 mm Hg the yield was 65%. Left ventricular end-diastolic pressures ranged from 4 mm Hg to 30 mm Hg. Bland and Altman analysis revealed no systematic bias and close agreement was found, with individual discrepancies not exceeding 5 mm Hg. (J Am Soc Echocardiogr 1998;11:126–31.)

Objectives. This study sought to assess the accuracy of Doppler echocardiographic techniques for the determination of right heart catheterization hemodynamic variables in patients with advanced heart failure and in potential heart transplant recipients. Background. Doppler echocardiographic techniques permit the noninvasive acquisition of hemodynamic variables traditionally used for the assessment of patients with advanced heart failure and potential heart transplant candidates. However, the accuracy of these techniques has not been sufficiently well documented for clinical application in individual patients. Methods. Echocardiographic data required for estimation of mean right atrial, pulmonary artery and mean left atrial pressures and cardiac output were obtained. Right heart catheterization was performed immediately after Doppler echocardiographic data were acquired, before any intervention that might have altered the subject’s hemodynamic status. Results. A complete Doppler echocardiographic hemodynamic data set was acquired in 21 (84%) of 25 subjects. For all variables, invasive and noninvasive hemodynamic values were highly correlated (p Conclusions. Doppler echocardiographic estimates of hemodynamic variables in patients with advanced heart failure are accurate and reproducible. This noninvasive methodology may assist with monitoring and optimization of medical therapy in patients with advanced heart failure and may obviate the need for routine right heart catheterization in potential heart transplant candidates.

BACKGROUND The Poiseuillian model of the arterial system currently applied in clinical physiology does not explain how arterial pressure is maintained during diastole after cessation of pulsatile aortic inflow. Arterial pressure-flow relations can be more accurately described by models that incorporate arterial viscoelastic properties such as arterial compliance. Continuous pressure and flow measurements are needed to evaluate these properties. Since the techniques used to date to acquire such data have been invasive, physiological models of the circulation that incorporate these properties have not been widely applied in the clinical setting. The purpose of this study was (1) to validate noninvasive methods for continuous measurement of central arterial pressure and flow and (2) to determine normal reference values for arterial compliance using physiological models of the circulation applied to the noninvasively acquired pressure and flow data. METHODS AND RESULTS Simultaneously acquired invasive and noninvasive aortic pressures (30 patients), flows (8 patients), and arterial mechanical properties (8 patients) were compared. Pressure was measured by high-fidelity catheter aortic micromanometer (invasive) and calibrated subclavian pulse tracing (noninvasive). Aortic inflow was determined from thermodilution-calibrated electromagnetic flow velocity data (invasive) and echo-Doppler data (noninvasive). Arterial compliance was determined for two- and three-element windkessel models of the circulation using the area method and an iterative procedure, respectively. Once validated, the noninvasive methodology was used to determine normal compliance values for a reference population of 70 subjects (age range, 20 to 81 years) with normal 24-hour ambulatory blood pressures and without Doppler-echocardiographic evidence for structural heart disease. The limits of agreement between invasive and noninvasive pressure data, compared at 10% intervals during ejection and nonejection, were narrow over a wide range of pressures, with no significant differences between methods. Invasive and noninvasive instantaneous aortic inflow values differed slightly but significantly at the start of ejection (P < .05), but during the latter 90% of ejection, values for the two methods were similar, with narrow limits of agreement. Total vascular resistance and arterial compliance values derived from invasive and noninvasive data were similar. Arterial compliance values for the normal population using the two-element model (C2E) ranged from 0.74 to 2.44 cm3/mm Hg (mean, 1.57 +/- 0.38 cm3/mm Hg), with a beat-to-beat variability of 5.2 +/- 3.9%. C2E decreased with increasing age (r = -.73, P < .001) and tended to be higher in men (1.67 +/- 0.41 cm3/mm Hg) than in women (1.51 +/- 0.35 cm3/mm Hg, P = .07). Compliance values for the three-element model (C3E) were predictably smaller than for the two-element model (mean, 1.23 +/- 0.30; range, 0.59 to 2.16 cm3/mm Hg, P < .001 versus C2E) but correlated with C2E values (r = .81, P < .001) and were also inversely related to age (r = -.56, P < .001). Ridge regression and principal component analyses both showed the compliance value to be a composite function whose variation could be best predicted by consideration of simultaneous values for five major hemodynamic determinants: heart rate, mean flow, mean aortic pressure, minimal diastolic pressure, and end-systolic pressure. Multivariate analysis revealed age and sex to be independent predictors of compliance (P < .01 for both). There were no differences in compliance between black and white subjects. CONCLUSIONS Noninvasive methods can be used to acquire the hemodynamic data necessary for clinical application of physiological models of the circulation that incorporate arterial viscoelastic properties such as arterial compliance. The strong inverse linear relation between model-based compliance estimates and age mandates incorporation of this demographic parameter in

Cardiovascular consequences of correction of the anemia of renal failure with erythropoietin. The purpose of this study was to define the physiologic responses of the heart and peripheral circulation to chronic anemia using noninvasive measurements while eliminating confounding biochemical, pharmacologic and physiologic variables. Stable chronic hemodialysis patients were studied at the University Hospital based chronic dialysis unit and echocardiography laboratory before and after therapy with human recombinant erythropoietin (rHuEPO). Subjects included maintenance hemodialysis patients free of left ventricular regional wall motion abnormalities discernible by echocardiography, rhythm disturbance, significant valvular or ischemic heart disease. Two-dimensional echocardiograms and simultaneous targeted M-mode echocardiograms, phonocardiograms and externally acquired subclavian artery pulse tracings were used to measure whole blood viscosity, arterial blood gases and ionized calcium, complete blood count, electrolytes, creatinine, blood urea nitrogen (BUN), and inorganic phosphate. All measurements were made immediately post-dialysis before and after therapy with rHuEPO. The interval between pre- and post-rHuEPO studies was 8.3 ± 2.3 months. We found that post-dialysis hematocrit rose from 24.7 ± 0.9 to 36.4 ± 0.9%, hemoglobin from 83 ± 3 to 121 ± 3 g/liter and whole blood viscosity from 2.87 ± 0.11 to 3.71 ± 0.18 centipoise (all, P < 0.001 after therapy with rHuEPO). The remaining biochemical measurements did not change. Heart rate fell from 83 ± 3 to 77 ± 3 beats/min (P = 0.013). Left ventricular preload and afterload were not statistically different before and after rHuEPO. Total vascular resistance rose from 1313 ± 84 to 1568 ± 129 dynes · sec · cm-5, P = 0.029. Cardiac output and cardiac index fell by 12 and 15% (P = 0.024 and 0.030), respectively. Left ventricular contractility assessed using load and heart rate independent indices fell after therapy with rHuEPO (P = 0.003) in the nine patients in whom it was measured. In conclusion, correction of the anemia of chronic renal failure in maintenance hemodialysis patients with rHuEPO reduces measurements of global left ventricular systolic function by decreasing the heart rate and contractile state without significantly altering chamber loading conditions. The net effect is a decrease in the hyperdynamic circulatory state that typically characterizes chronic anemia.

The advent of Doppler echocardiography has enabled the noninvasive detection of diastolic mitral regurgitation (MR). 1,2 The description of the hemodynamic prerequisites for the occurrence of this finding remain ill defined. Previous studies combining M-mode echocardiography and intracardiac pressure recordings have demonstrated that atrial systole can induce a temporary reversal of the diastolic atrioventricular pressure gradient leading to a late diastolic apposition of the mitral valve leaflets or pandiastolic mitral valve “locking.” 3 This study examines whether this atrially induced atrioventricular pressure gradient reversal is also responsible for the physiologic mechanism governing diastolic MR.

Objectives. This study was designed to noninvasively assess the direct action of calcium channel blockers on left ventricular contractility in humans and to establish a framework for determining the importance of reflex sympathetic responses to any pharmacologic intervention. Background. Assessment of left ventricular contractility in patients taking calcium channel blockers by using traditional indexes of systolic performance is difficult because of the afterload-reducing and reflex sympathetic effects of the drugs. Methods. Fifteen hypertensive patients (mean blood pressure 127 ± 15 mm Hg) were studied with Doppler echocardiography and calibrated subclavian pulse tracings while receiving placebo and 1 week after randomization to treatment with oral nifedipine (20 mg three times daily; n = 7) or nicardipine (30 mg three times daily; n = 8). Left ventricular circumferential end-systolic wall stress versus rate-corrected velocity of shortening (Vcfc) relations were generated over a range of loads using nitroprusside. Data were acquired before and during esmolol infusion, thereby allowing assessment of hemodynamic responses with the sympathetic nervous system functionally intact as well as ablated. The adequacy of sympathetic blockade was confirmed with isoproterenol challenges. In each case, left ventricular contractile state was measured relative to placebo and esmolol data as ΔVcfcat a common end-systolic wall stress. Increased and decreased contractility were defined as ΔVcfc> 0 and ΔVcfc Results. Nifedipne and nicardipine equally decreased blood pressure and end-systolic wall stress and increased left ventricular percent fractional shortening and stroke volume. Neither drug alone consistently altered ventricular contractility compared with placebo. Ablation of reflex sympathetic tone with esmolol unmasked a negative intropic effect for nifedipine (p = 0.03 vs. esmolol alone) but not nicardipine (p = 0.68 vs. esmolol alone). The difference between the contractility effects of nifedipine plus esmolol versus those of nicardipine plus esmolol approached statistical significance (p = 0.07). Conclusions. Totally noninvasive techniques showed a differential effect on left ventricular contractility between nifedipine and nicardipine when alterations in afterload and reflex sympathetic responses were eliminated as confounding variables. This diagnostic approach, based on the use of pharmacologic probes, should have wide applicability for assessing the direct inotropic effect of any agent, even in the presence of complex primary and secondary physiologic modes of action.

Cardiovascular physiological studies in anesthetized animals may be confounded by the hemodynamic actions of the anesthetic agents themselves. To identify an anesthetic regimen that does not significantly influence cardiovascular physiology, the hemodynamic responses of 28 dogs were studied. Animals were equally divided among groups with 1) no anesthesia (i.e., trained conscious preparation), 2) pentobarbital sodium, 3) fentanyl citrate, and 4) a combination of morphine sulfate and alpha-chloralose. Anesthesia was maintained for 3 h. Data were acquired with the use of ultrasound imaging of the heart in conjunction with invasive pressure measurements. Left ventricular ejection phase indexes and end-systolic force-velocity relations were used to evaluate the effects of each anesthetic agent on overall systolic performance and myocardial contractility. Compared with the conscious animals, pentobarbital profoundly depressed systolic performance (P less than 0.05 vs. control) because of a reduction in myocardial contractility (P less than 0.01) and an increase in left ventricular afterload (end-systolic wall stress, P less than 0.05). Fentanyl increased myocardial contractility (P less than 0.05) but also tended to increase afterload with the net result that overall systolic performance remained unchanged. Morphine-chloralose did not affect overall ventricular systolic performance or its individual determinants. Pentobarbital and fentanyl also caused progressive time-dependent deteriorations in all parameters of systolic function during prolonged anesthesia. In contrast, cardiac function was stable for greater than or equal to 3 h after induction of morphine-chloralose anesthesia. The hemodynamic profile of dogs anesthetized with morphine-chloralose most closely resembled that of the conscious animals. Morphine-chloralose is recommended when prolonged anesthesia is required for studies of cardiovascular physiology.

Whether parathyroid hormone (PTH) has a clinically important effect on myocardial performance is unclear. Previous investigations of cardiac function before and after parathyroidectomy have failed to control for ionized calcium, other biochemical parameters, or heart rate and cardiovascular loading conditions. We performed load- and rate-independent measurements of myocardial contractility in seven stable hemodialysis patients before and after surgical parathyroidectomy under identical conditions of blood ionized calcium (Ca2+), electrolytes, pH, PO2, and hematocrit. Mid-molecule PTH decreased from 44 +/- 8 to 2 +/- 1 ng/mL. Aortic systolic and diastolic pressures, left ventricular chamber dimensions, end systolic wall stress, left ventricular contractility at a common level of afterload, and contractile reserve evaluated with dobutamine were similar before and after parathyroidectomy. Thus, PTH appears not to have a direct effect on myocardial contractile state in dialysis patients.

Pulsus paradoxus is associated with many clinical conditions and is defined as a greater than 10 mm Hg end-inspiratory decrease in systolic blood pressure. Kussmaul's original definition of pulsus paradoxus is presented, along with an explanation of his choice of the term "pulsus paradoxus." A case of pulsus paradoxus is graphically described using simultaneous two-dimensional targeted M-mode, Doppler echocardiographic, and high-fidelity pressure recordings.

Increased systemic vascular resistance and contracted blood volume are characteristic findings in preeclampsia. These alterations in cardiovascular hemodynamics can adversely affect ejection phase indices of left ventricular performance making it difficult to separate abnormalities resulting from changes in load from those caused by depressed myocardial contractility. To address this issue the contractility-sensitive, load-independent relationship between left ventricular end-systolic wall stress and rate-corrected velocity of fiber shortening was assessed in 10 nulliparous patients with preeclampsia. Comparisons were made with data obtained from 10 age-matched normotensive women with uncomplicated pregnancies (control subjects). Studies were performed by means of two-dimensionally targeted M-mode echocardiography and calibrated carotid pulse tracings during early labor, 1 day after delivery, and 4 weeks after delivery. During early labor and 1 day after delivery, patients with preeclampsia had elevated blood pressure and increased total systemic resistance. These parameters returned to normal by 4 weeks after delivery. Before delivery and 24 hours after delivery, the patients with preeclampsia had lower overall left ventricular performance (as measured by cardiac output and rate-corrected velocity of fiber shortening) and higher left ventricular afterload (as measured by left ventricular end-systolic wall stress) when compared with control subjects. These differences were no longer present 4 weeks after delivery. Despite the time-related intergroup differences in hemodynamics, left ventricular contractility was similar between normotensive and preeclamptic subjects at all stages of the study. Thus when load is eliminated as a confounding variable, the decrements in overall left ventricular performance measured in patients with preeclampsia reflect a mechanically appropriate response to increased afterload rather than an abnormality in the ventricular contractile state.

Assessment of the pulsatile mechanical behavior of the coupled left ventricle and the peripheral arterial circulation requires accurate estimation of instantaneous aortic flow. Before the availability of Doppler technologies, this could only be achieved by invasive techniques. The purpose of this study was to assess the accuracy of Doppler-based measurement of instantaneous aortic blood flow and waveform morphology throughout ventricular ejection when compared with an established invasive method. Accordingly, data from electromagnetic flow and continuous-wave aortic Doppler recordings were simultaneously acquired and compared in five monkeys over a wide range of flows generated by intravenous infusions of the beta-adrenoceptor agonist dobutamine and the alpha-receptor agonist methoxamine. Instantaneous aortic pressure was measured using a high-fidelity micromanometer-tipped catheter placed in the ascending aorta. Excellent correlations were noted for stroke volume, cardiac output, left ventricular ejection time, maximal flow velocity, and maximal rate of change of flow velocity (dQ/dtmax). When compared with electromagnetic flows, continuous-wave aortic Doppler had significantly lower times to maximal flow velocity and dQ/dtmax. Frequency domain analysis indicated that both the magnitude and phase were within +/- 6% up to the third harmonic. Instantaneous comparison disclosed that during early systole (up to 10% of ejection) Doppler was higher than electromagnetic flow rate by 11 +/- 19% (p less than 0.05). At 20-30% of systolic ejection, electromagnetic flow rates were slightly higher than Doppler (5 +/- 4% at 20% of ejection, p less than 0.001 and 2 +/- 3% at 30% of ejection, p less than 0.05). From 40% of ejection to the end of systole, flow rates using both techniques were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac ultrasound imaging can be used in conjunction with calibrated external pulse recordings to provide detailed information regarding cardiovascular hemodynamics. This review establishes a physiological framework for the echo-Doppler assessment of cardiac mechanics, left ventricular energetics, and ventriculo-systemic vascular coupling in patients with dilated cardiomyopathy. The section on cardiac mechanics concerns the evaluation of overall cardiac performance and its individual determinants. Particular emphasis is placed upon the use of noninvasive methodology to identify the relative contributions of altered loading conditions and intrinsic myocardial contractility to cardiac performance. The noninvasive evaluation of left ventricular energetics is based oh the physiological premise that myocardial oxygen consumption is a function of three major determinants, i.e., heart rate, contractility, and the integral of left ventricular systolic load (or wall stress). Following a brief discussion of the vascular properties that determine the relationship between pressure and flow in the systemic circulation, noninvasive methods for determination of systemic vascular resistance and arterial compliance are described. At the end of each section, practical clinical applications of these techniques to the evaluation and management of patients with dilated cardiomyopathy are presented. (ECHOCARDIOGRAPHY, Volume 8, March 1991)

The disease entity "diabetic cardiomyopathy" has been extensively described in young patients with diabetes in the absence of ischemic, hypertensive or valvular heart disease. The most convincing data have been a 30% to 40% incidence of decreased radionuclide angiographic left ventricular ejection fraction response to dynamic exercise. In the current study, the hypothesis was tested that this abnormal ejection fraction response was due to alterations in ventricular loading conditions or cardiac autonomic innervation (extrinsic factors), or both, rather than to abnormalities in intrinsic ventricular systolic fiber function (contractility). Twenty normotensive patients with diabetes (mean age 30 +/- 5 years, mean duration 15 +/- 6 years) and 20 age-matched normal subjects were studied. All patients with diabetes had a normal treadmill exercise tolerance test without evidence of myocardial ischemia. By radionuclide angiography, all normal subjects increased ejection fraction with exercise (62 +/- 4% to 69 +/- 6%; p less than 0.001). In contrast, 11 (55%) of 20 patients with diabetes maintained or increased ejection fraction with exercise (group 1; 62 +/- 4% to 69 +/- 6%; p less than 0.001) and 9 (45%) of 20 showed an exercise-induced decrease (group 2; 73 +/- 4% to 66 +/- 6%; p less than 0.001). No difference in the incidence of microangiopathy, as noted by funduscopic examination, was present between the diabetic groups. Despite the abnormal ejection fraction response to exercise in the group 2 patients with diabetes, all patients with diabetes had a normal response to afterload manipulation, normal baseline ventricular contractility as assessed by load- and heart rate-independent end-systolic indexes and normal contractile reserve as assessed with dobutamine challenge. Autonomic dysfunction did not explain the disparate results between the group 2 patients' radionuclide angiographic data and their load-independent tests of ventricular contractility and reserve. In addition, the high ejection fraction at rest in group 2 patients (73 +/- 4% versus 62 +/- 4% for normal subjects; p less than 0.001) was not related to the abnormal tests of autonomic function. Thus, when left ventricular systolic performance was assessed by load- and rate-independent indexes, there was no evidence for cardiomyopathy in young adult patients with diabetes who have normal blood pressure and no ischemic heart disease.

Clinical experience has shown that the antiarrhythmic effect of lidocaine on atrial arrhythmias, and specifically for the conversion of atrial fibrillation to normal sinus rhythm, is minimal. This study summarizes our experience in 30 dogs in which atrial fibrillation was initiated and sustained (≥15 minutes) under increased vagal tone achieved by either alpha-chloralose anesthesia (26 dogs) or pentobarbital sodium anesthesia combined with direct external electrical vagal stimulation (four dogs). Under increased vagal tone (regardless of the procedure), an intravenous bolus of lidocaine (2 to 3 mg/kg) was 100% effective (101 of 101 episodes) in pharmacologically converting atrial fibrillation to normal sinus rhythm. This was associated with marked slowing of intra-atrial electrical activity, as shown by fast Fourier analysis of intra-atrial electrograms. Over a period of 3 to 5 minutes, lidocaine progressively shifted the peak frequency content from 84±18 mV 2 /Hz in the 10 to 20 Hz frequency band during the pre-lidocaine phase to 110±34 mV 2 /Hz in the 0 to 10 Hz frequency band immediately prior to conversion to normal sinus rhythm. When atropine was administered or electrical vagal stimulation was discontinued, the conversion of atrial fibrillation to normal sinus rhythm followed a similar electrophysiologic pattern. When isoproterenol was infused, it was difficult to induce atrial fibrillation; when the arrhythmia was initiated, it could not be sustained even with concomitant electrical vagal stimulation. Thus in this model of parasympathetically sustained atrial fibrillation, lidocaine was 100% effective in converting atrial fibrillation to normal sinus rhythm. This previously undescribed drug effect suggests the possibility that the level of autonomic tone may have an important effect on the electrophysiologic efficacy of lidocaine in atrial arrhythmias.

The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis.The authors conducted a randomized, placebo-controlled, double-blind trial.The study was conducted in a procedure room of an intensive-care unit.The study comprised 24 healthy male volunteers.Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo.The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography.Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.

To evaluate the efficacy of a novel lipopolysaccharide (LPS) antagonist, E5531, in blocking LPS-induced cardiac responses including myocardial depression (as assessed by relatively load-independent echocardiographic indices of contractility) in a human model of experimental endotoxemia.Randomized, prospective, placebo-controlled, double-blind trial.ICU procedure room.Thirty-two healthy, male volunteers.Administration of LPS (4 ng/kg) and either a placebo or one of four sequential doses of E5531 (100 microg, 250 microg, 500 microg, or 1,000 microg) followed by volumetric echocardiography before and during 4-L saline solution infusion (3 L over 3 h, followed by 1 L over 2 h).In addition to the generation of a hyperdynamic circulation throughout the study period, administration of LPS resulted in a biphasic contractility response. Ejection fraction (EF), rate-corrected mean velocity of circumferential fiber shortening (Vcfc), peak systolic BP (SBP)/end-systolic volume index (ESVI) ratio, and end-systolic pressure (Pes)/ESVI ratio increased at the 3-h post-LPS assessment, compared to a control group of subjects receiving only similar amounts of saline solution (minimum p0.001). End-systolic myocardial wall stress (sigmaes)/ESVI ratio, one of the most load independent of the contractility indices, was unchanged. At 5 h after endotoxin, EF, Vcfc, SBP/ESVI, Pes/ESVI, and sigmaes/ESVI were all decreased (minimum p0.01), indicating myocardial depression. When present, early (3 h after LPS), apparent enhancement of myocardial contractility and later (5 h after LPS) myocardial depression were substantially blunted by administration of E5531 (minimum p0.025), typically in a concentration-dependent manner.Endotoxin generates significant myocardial depression when measured using highly load-independent indices of cardiac contractility. E5531 is a potent inhibitor of the early hyperdynamic cardiovascular and later myocardial depression response seen in experimental human endotoxemia.

Pulmonary artery occlusion pressure and central venous pressure have been considered to be reliable measures of left and right ventricular preload in patients requiring invasive hemodynamic monitoring. Studies in recent years have questioned the correlation between these estimates of ventricular filling pressures and ventricular end-diastolic volumes/cardiac performance variables in specific patient groups, but clinicians have continued to consider the relationship valid in the broader context. The objective of this study was to assess the relationship between pressure estimates of ventricular preload (pulmonary artery occlusion pressure, central venous pressure) and end-diastolic ventricular volumes/cardiac performance in healthy volunteers.Prospective, nonrandomized, nonblinded interventional study.Cardiac catheterization and echocardiography laboratories.Normal healthy volunteers (n = 12 group 1, n = 32 group 2).Pulmonary catheterization and radionuclide cineangiography (group 1) and volumetric echocardiography (group 2) during 3 L of normal saline infusion over 3 hrs.In group 1, the initial pulmonary artery occlusion pressure and central venous pressure did not correlate significantly with initial end-diastolic ventricular volume indexes or cardiac performance (cardiac index and stroke volume index). Changes in pulmonary artery occlusion pressure and central venous pressure following saline infusion also did not correlate with changes in end-diastolic ventricular volume indexes or cardiac performance. In contrast, initial end-diastolic ventricular volume indexes and changes in these ventricular volume indexes in response to 3 L of normal saline loading correlated well with initial stroke volume index and changes in stroke volume index, respectively. The relationship between left ventricular end-diastolic volume index and stroke volume index was confirmed in group 2 subjects using mathematically independent techniques to measure these variables. In addition, initial central venous pressure, right ventricular end-diastolic volume index, pulmonary artery occlusion pressure, and left ventricular end-diastolic volume index failed to correlate significantly with changes in cardiac performance in response to saline infusion in group 1 subjects.Normal healthy volunteers demonstrate a lack of correlation between initial central venous pressure/pulmonary artery occlusion pressure and both end-diastolic ventricular volume indexes and stroke volume index. Similar results are found with respect to changes in these variables following volume infusion. In contrast, initial end-diastolic ventricular volume indexes and changes in end-diastolic ventricular volume indexes in response to saline loading correlate strongly with initial and postsaline loading changes in cardiac performance as measured by stroke volume index. These data suggest that the lack of correlation of these variables in specific patient groups described in other studies represents a more universal phenomenon that includes normal subjects. Neither central venous pressure nor pulmonary artery occlusion pressure appears to be a useful predictor of ventricular preload with respect to optimizing cardiac performance.

Characterize the normal human cardiovascular response to large volume infusion of normal saline.Prospective, interventional trial.ICU procedure room.Healthy male volunteers ( n=32). INTERVENTIONS. Volumetric echocardiography during 4-L saline infusion (3 L over 3 h followed by 1 L over 2 h).Following 3-L saline infusion, stroke volume and cardiac output increased approximately 10% without a significant change in heart rate or blood pressure. A decrease in end-systolic volume contributed to the increase in stroke volume to an extent similar to that provided by the increase in end-diastolic volume. All contractility indices except end-systolic wall stress/end-systolic volume index were increased at 3 h post-initiation of saline infusion. Stroke volume but not cardiac output remained elevated at 5 h with persistence of ventricular volume responses; only ejection fraction was significantly elevated among the contractility indices. Afterload measures including total peripheral resistance and end-systolic wall stress were significantly decreased after 3-L infusion but were unchanged compared to baseline following infusion of an additional 1 L over 2 h. Modeled blood viscosity studies demonstrate that changes in apparent contractility after 3-L saline infusion can be explained solely by viscosity reduction associated with hypervolemic hemodilution.The initial increase in stroke volume associated with high volume saline infusion in normal volunteers is associated with increases of most load-dependent and ostensibly load-independent parameters of left ventricular contractility. This phenomenon is unlikely to represent a true increase in contractility and appears to be caused by reduced afterload as a consequence of decreased blood viscosity. This decrease in blood viscosity may complicate analysis of some previous in vivo studies examining the effect of volume loading on cardiac function using low-viscosity solutions.

In a clinical investigation, Kumar and coworkers reported the hemodynamic events that accompany plasma volume expansion over 3 hours in healthy adult volunteers, and found that increases in stroke volume (SV) may be related to increases in left ventricular (LV)/right ventricular (RV) end-diastolic volume, as they expected, but also to decreases in LV/RV end-systolic volume. The latter finding suggests increased contractility and/or decreased afterload, which do not fit with their perception that clinicians ascribe increases in SV to increases in end-diastolic volume based on Starling's work. Increased ejection fraction and decreased vascular resistances were also observed. The same authors recently reported novel data suggesting that reduced blood viscosity may account for the observed reduction in vascular resistances with saline volume expansion. However, the variances in preload and afterload, along with uncertainty in estimates of contractility, substantially limit their ability to define a primary mechanism to explain decreases in LV end-systolic volume. A focus on using ejection fraction to evaluate the integrated performance of the cardiovascular system is provided to broaden this analytic perspective. Sagawa and colleagues described an approach to estimate the relationship, under clinical conditions, between ventricular and arterial bed elastances (i.e. maximal ventricular systolic elastance [Emax] and maximal arterial systolic elastance [Ea]), reflecting ventricular–arterial coupling. I used the mean data provided in one of the reports from Kumar and coworkers to calculate that LV Emax decreased from 1.09 to 0.96 mmHg/ml with saline volume expansion, while Ea decreased from 1.1 to 0.97 mmHg/ml and the SV increased (i.e. the increase in mean SV was associated with a decrease in mean afterload while the mean contractility decreased). The results reported by Kumar and coworkers invite further studies in normal and critically ill patients during acute saline-induced plasma volume expansion and hemodilution. If reduced viscosity decreases afterload, then this raises the questions by what mechanism, and what is the balance of benefit and harm associated with reduced blood viscosity affecting oxygen delivery? Why the mean Emax might decrease must be evaluated with respect to benefit in reducing ventricular work or a negative inotropic effect of saline.

Presents a technique for automatically computing stroke volume from 2-D color flow echocardiographic cineloops of the left ventricular outflow tract (LVOT). By utilizing the anatomical and blood velocity information in the color flow image, the measurement technique eliminated many of the technical obstacles and assumptions in existing methods. This technique determines the blood flow vector, LVOT conduit border, and ejection period without human guidance, and the stroke volume is computed automatically. The resulting automated technique improves measurement accuracy and speed and only requires one data set (a color flow cineloop).

In order to measure left ventricular regional wall motion and wall thickening, one must accurately track regional movement of the epicardial and endocardial borders. Here, the authors describe a computer-assisted technique for tracking regional wall movement using "dynamic M-mode" images that combine the spatial continuity of 2-D cineloops with the temporal continuity of M-mode images. Measurements made using this technique are more accurate than those made from 2-D stop-frame images and have significantly lower interobserver differences than measurements made on either 2-D images or conventional M-mode hardcopy charts.

The authors investigated a method to identify regional myocardial abnormalities based on the temporal pattern of LV contraction. Nineteen stress echo studies were either normal (NML=9) or abnormal (ABN=10) by standard rest and stress images. Six radial, computer-generated synthetic M-modes (SMM) front a short axis cineloop were used to measure change in time to peak contraction during stress (/spl Delta/t) for each segment. Mean /spl Delta/t for all segments was -38/spl plusmn/15% for NML and -22/spl plusmn/27% for ABN studies (p

Myocardial ischemia is usually identified by echocardiography using qualitative analysis of regional left ventricular (LV) endocardial excursion. This is often hampered by sub-optimal endocardial visualization and lack of quantitative standards and measurement techniques Ischemia changes the temporal pattern of LV contraction, and a method for quantifying changes in this temporal sequence would have clinical applicability. The authors developed and tested a computer-assisted technique using Synthetic M-mode (SMM) to measure the temporal variations in regional LV contraction. Using a LV short axis image, 6 SMM images were created through a user-defined LV center. The time to peak (t) contraction in 6 LV segments was then measured using the R-wave as a timing reference point. In the authors' study of 15 closed chest dogs with induced regional ischemia, t was significantly prolonged only in those LV segments subtended by the occluded artery. Temporal SMM is a promising technique for defining temporal contraction patterns indicative of regional ischemia.

A small animal model of sepsis that reproduces the vasodilation, hypotension, increased cardiac output, and response to treatment seen in patients with septic shock would be useful for studies of pathophysiology and treatment, but no current models replicate all of these features. Mice were made septic by cecal ligation and puncture and resuscitated with fluids and antibiotics every 6 h. Blood pressure was measured in anesthetized mice with manometric catheters, and echocardiography was performed in these animals every 6 h. Survival in treated septic mice was improved compared with untreated mice (44% versus 0%, p < 0.01). In control mice, heart rate (HR, 420 +/- 31 beats/min), mean arterial pressure (Pa, 100 +/- 8 mm Hg), stroke volume (SV, 26 +/- 4 microl), and cardiac output (12.5 +/- 6.6 ml/min) were unchanged over 48 h. In septic mice Pa was significantly decreased (102 +/- 14 to 65 +/- 19 mm Hg, p < 0.02), starting at 12 h. HR and cardiac output increased significantly (HR, 407 +/- 70 to 524 +/- 76 beats/min, cardiac output, 11.6 +/- 2.0 to 17.1 +/- 1.5 ml/min, p < 0.01). SV (24 +/- 5 microl) remained constant. This fluid-resuscitated, antibiotic-treated model replicates the mortality, hypotension, and hyperdynamic state seen in clinical sepsis. Precise determination of serial hemodynamics in this model may be useful to elucidate pathophysiologic mechanisms and to evaluate new therapies for septic shock.

Digital format is rapidly emerging as a preferred method for displaying and retrieving echocardiographic studies. The qualitative diagnostic accuracy of Moving Pictures Experts Group (MPEG-1) compressed digital echocardiographic studies has been previously reported. The goals of the present study were to compare quantitative measurements derived from MPEG-1 recordings with the super-VHS (sVHS) videotape clinical standard. Six reviewers performed blinded measurements from still-frame images selected from 20 echocardiographic studies that were simultaneously acquired in sVHS and MPEG-1 formats. Measurements were obtainable in 1401 (95%) of 1486 MPEG-1 variables compared with 1356 (91%) of 1486 sVHS variables (P

BACKGROUND Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome. METHODS In a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 microg of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times. RESULTS In subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 microg, p < .05). Tumor necrosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531. CONCLUSIONS E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.

Current protocols for risk stratification of patients with acute chest pain syndromes rely on clinical parameters and are oriented toward identification of patients at high risk for adverse cardiac events; however, this paradigm for risk stratification does not adequately address the observation that adverse cardiac events are relatively uncommon in this population. In an era of cost containment, consideration also should be given to identification of patients at low risk for adverse cardiac events, who may be safely discharged without expensive inpatient hospitalization.The purpose of this study was to develop echocardiographic predictors that identify unstable angina patients at low risk for adverse cardiac events and that discriminate between low- and high-risk patients.The predictive accuracy of retrospectively determined echocardiographic predictors were compared in a population-based sample of 66 consecutive unstable angina patients undergoing echocardiography within 24 h of admission.Echocardiographic predictors of adverse events included wall motion score indexor = 0.2, ejection fractionor = 40%, and mitral regurgitation severity2. One or more echocardiographic predictors of adverse events were present in 32 patients (48%). A composite echocardiographic predictor of adverse events was specific, had a high positive predictive value for the identification of high-risk patients, and discriminated between unstable angina patients at high and low risk for adverse cardiac events.Echocardiographic predictors of adverse events are specific and discriminate between unstable angina patients at high and low risk for adverse cardiac events.

Clinical estimates of right atrial pressure from the jugular venous pulse were accurate when right atrial pressure was normal, but systematically underestimated elevated right atrial pressures. Because the increased distance from the mid-right atrium to the sternal angle is not accounted for, apparently normal right atrial pressure estimates by this technique do not reliably exclude elevated right atrial pressure in patients with congestive heart failure.

We describe the first reported patient with a persistent left superior vena cava that communicates directly with the left atrium as an isolated congenital defect. She developed mitral stenosis and physiologic conditions that favored left-to-right shunting--a modified Lutembacher's syndrome. Noninvasive cardiac imaging completely elucidated her cardiac anatomy and physiology.