Left Ventricular Function Curves Research Articles

Pulmonary Transit Time Derived from First-Pass Perfusion Cardiac MR Imaging: A Potential New Marker for Cardiac Involvement and Prognosis in Light-Chain Amyloidosis.

First-pass perfusion cardiac MR imaging could reflect pulmonary hemodynamics. However, the clinical value of pulmonary transit time (PTT) derived from first-pass perfusion MRI in light-chain (AL) amyloidosis requires further evaluation. To assess the clinical and prognostic value of PTT in patients with AL amyloidosis. Prospective observational study. 226 biopsy-proven systemic AL amyloidosis patients (age 58.62 ± 10.10 years, 135 males) and 43 healthy controls (age 42 ± 16.2 years, 20 males). SSFP cine and phase sensitive inversion recovery late gadolinium enhancement (LGE) sequences, and multislice first-pass myocardial perfusion imaging with a saturation recovery turbo fast low-angle shot (SR-TurboFLASH) pulse sequence at 3.0T. PTT was measured as the time interval between the peaks of right and left ventricular cavity arterial input function curves on first-pass perfusion MR images. Independent-sample t test, Mann-Whitney U test, Chi-square test, Fisher's exact test, analysis of variance, or Kruskal-Wallis test, as appropriate; univariable and multivariable Cox proportional hazards models and Kaplan-Meier curves, area under receiver operating characteristic curve were used to determine statistical significance. PTT could differentiate AL amyloidosis patients with (N = 188) and without (N = 38) cardiac involvement (area under the curve [AUC] = 0.839). During a median follow-up of 35 months, 160 patients (70.8%) demonstrated all-cause mortality. After adjustments for clinical (Hazard ratio [HR] 1.061, confidence interval [CI]: 1.021-1.102), biochemical (HR 1.055, CI: 1.014-1.097), cardiac MRI-derived (HR 1.077, CI: 1.034-1.123), and therapeutic (HR 1.063, CI: 1.024-1.103) factors, PTT predicted mortality independently in patients with AL amyloidosis. Finally, PTT could identify worse outcomes in patients demonstrating New York Heart Association class III, Mayo 2004 stage III, and transmural LGE pattern. PTT may serve as a new imaging predictor of cardiac involvement and prognosis in AL amyloidosis. 2 TECHNICAL EFFICACY: Stage 2.

Comparison of the prognostic value of stress and rest pulmonary transit time estimation using myocardial perfusion CMR

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Clinical Research Training Fellowship Background Pulmonary transit time (PTT) is a quantitative biomarker of cardiopulmonary status. Rest PTT was previously shown to predict outcomes in specific disease models, but clinical adoption is hindered but challenges in data acquisition. Whether evaluation of PTT during stress encodes incremental prognostic information has not been previously investigated as scale. Objectives To compare the prognostic value of stress and rest PTT derived from a fully automated, in-line method of estimation using perfusion CMR, in a large patient cohort. Methods A retrospective two-center study of patients referred clinically for adenosine stress myocardial perfusion assessment using CMR. Analysis of right and left ventricular cavity arterial input function curves from first pass perfusion was performed automatically, allowing the in-line estimation of both rest and stress PTT. Association with major adverse cardiovascular events (MACE) was evaluated. MACE was defined as a composite outcome of myocardial infarction, stroke, heart failure admission and ventricular tachycardia or appropriate ICD treatment (including ICD shock and/or anti-tachycardia pacing). Results 985 patients (67% male, median age 62 years (IQR 52,71)) were included, with median left ventricular ejection fraction (LVEF) of 62% (IQR 54-69). Median stress PTT was shorter than rest PTT 6.2 (IQR 5.1, 7.7) seconds versus 7.7 (IQR, 6.4, 9.2) seconds. Stress and rest PTT were highly correlated (r = 0.69; p < 0.001). Stress PTT also correlated with LVEF (r=-0.37), stress MBF (r=-0.31), LVEDVi (r = 0.24), LA area index (r = 0.32) (p < 0.001 for all). Over a median follow-up period of 28.6 (IQR, 22.6 35,7) months, MACE occurred in 61 (6.2%) patients. After adjusting for prognostic factors, both rest and stress PTT, independently predicted MACE, but not all-cause mortality. For every 1xSD (2.39s) increase in rest PTT the adjusted hazard ratio (HR) for MACE was 1.43 (95% CI 1.10-1.85, p = 0.007). The hazard ratio for one standard deviation (2.64s) increase in stress PTT was 1.34 (95% CI 1.048-1.723; p = 0.020) after adjusting for age, LVEF, hypertension, diabetes, sex and presence of LGE Conclusions In this 2-center study of 985 patients, we deploy a fully automated method of PTT estimation using perfusion mapping with CMR and show that both stress and rest PTT are independently associated with adverse cardiovascular outcomes. In this patient cohort, there is no clear incremental prognostic value of stress PTT, over its evaluation during rest. Figure 1. Stress and Rest Pulmonary Transit Time estimation using myocardial perfusion CMR Figure 2. Event-free survival curves for major adverse cardiovascular events (Heart failure hospitalization, myocardial infarction, stroke and ventricular tachycardia/ICD treatment) according to mean rest PTT (8.05seconds) and mean stress PTT (6.7seconds). Log-rank for both p < 0.05

Prognostic Value of Pulmonary Transit Time and Pulmonary Blood Volume Estimation Using Myocardial Perfusion CMR

ObjectivesThe purpose of this study was to explore the prognostic significance of PTT and PBVi using an automated, inline method of estimation using CMR. BackgroundPulmonary transit time (PTT) and pulmonary blood volume index (PBVi) (the product of PTT and cardiac index), are quantitative biomarkers of cardiopulmonary status. The development of cardiovascular magnetic resonance (CMR) quantitative perfusion mapping permits their automated derivation, facilitating clinical adoption. MethodsIn this retrospective 2-center study of patients referred for clinical myocardial perfusion assessment using CMR, analysis of right and left ventricular cavity arterial input function curves from first pass perfusion was performed automatically (incorporating artificial intelligence techniques), allowing estimation of PTT and subsequent derivation of PBVi. Association with major adverse cardiovascular events (MACE) and all-cause mortality were evaluated using Cox proportional hazard models, after adjusting for comorbidities and CMR parameters. ResultsA total of 985 patients (67% men, median age 62 years [interquartile range (IQR): 52 to 71 years]) were included, with median left ventricular ejection fraction (LVEF) of 62% (IQR: 54% to 69%). PTT increased with age, male sex, atrial fibrillation, and left atrial area, and reduced with LVEF, heart rate, diabetes, and hypertension (model r2 = 0.57). Over a median follow-up period of 28.6 months (IQR: 22.6 to 35.7 months), MACE occurred in 61 (6.2%) patients. After adjusting for prognostic factors, both PTT and PBVi independently predicted MACE, but not all-cause mortality. There was no association between cardiac index and MACE. For every 1 × SD (2.39-s) increase in PTT, the adjusted hazard ratio for MACE was 1.43 (95% confidence interval [CI]: 1.10 to 1.85; p = 0.007). The adjusted hazard ratio for 1 × SD (118 ml/m2) increase in PBVi was 1.42 (95% CI: 1.13 to 1.78; p = 0.002). ConclusionsPulmonary transit time (and its derived parameter pulmonary blood volume index), measured automatically without user interaction as part of CMR perfusion mapping, independently predicted adverse cardiovascular outcomes. These biomarkers may offer additional insights into cardiopulmonary function beyond conventional predictors including ejection fraction.

Hemodynamic effects of molsidomine on weight sustaining isometric exercise in patients with ischemic heart disease.

Hemodynamic effects of 2 mg of sublingual molsidomine were evaluated in 11 patients with ischemic heart disease using a weight-sustaining isometric exercise (WSIE) that we developed. Left ventricular end diastolic pressure (LVEDP), mean pulmonary pressure, mean systemic arterial pressure (mAP), cardiac index and stroke work index increased significantly during WSIE before and after molsidomine. Although WSIE resulted in a similar rise of mAP before and after molsidomine, the increment value of LVEDP during WSIE was significantly lower after molsidomine. The recovery time to the resting state of all parameters was shorter and the left ventricular function curves showed a leftward deviation with molsidomine. In conclusion, the results suggest that molsidomine will produce a preload reduction and improve the left ventricular function during WSIE in patients with ischemic heart disease.

Respiratory variations in the arterial pressure during mechanical ventilation reflect volume status and fluid responsiveness.

Optimal fluid management is one of the main challenges in the care of the critically ill. However, the physiological parameters that are commonly monitored and used to guide fluid management are often inadequate and even misleading. From 1987 to 1989 we published four experimental studies which described a method for predicting the response of the cardiac output to fluid administration during mechanical ventilation. The method is based on the analysis of the variations in the arterial pressure in response to a mechanical breath, which serves as a repetitive hemodynamic challenge. Our studies showed that the systolic pressure variation and its components are able to reflect even small changes in the circulating blood volume. Moreover, these dynamic parameters provide information about the slope of the left ventricular function curve, and therefore predict the response to fluid administration better than static preload parameters. Many new dynamic parameters have been introduced since then, including the pulse pressure (PPV) and stroke volume (SVV) variations, and various echocardiographic and other parameters. Though seemingly different, all these parameters are based on measuring the response to a predefined preload-modifying maneuver. The clinical usefulness of these 'dynamic' parameters is limited by many confounding factors, the recognition of which is absolutely necessary for their proper use. With more than 20 years of hindsight we believe that our early studies helped pave the way for the recognition that fluid administration should ideally be preceded by the assessment of "fluid responsiveness". The introduction of dynamic parameters into clinical practice can therefore be viewed as a significant step towards a more rational approach to fluid management.

Cardiac function and tolerance to ischemia–reperfusion injury in chronic kidney disease

Cardiac dysfunction is an independent risk factor of ischemic heart disease and mortality in chronic kidney disease (CKD) patients, yet the relationship between impaired cardiac function and tolerance to ischemia-reperfusion (IR) injury in experimental CKD remains unclear. Cardiac function was assessed in 5/6 ablation-infarction (AI) and sham male Sprague-Dawley rats at 20 weeks of age, 8 weeks post-surgery using an isolated working heart system. This included measures taken during manipulation of preload and afterload to produce left ventricular (LV) function curves as well as during reperfusion following a 15-min ischemic bout. In addition, LV tissue was used for biochemical tissue analysis. Cardiac function was impaired in AI animals during preload and afterload manipulations. Cardiac functional impairments persisted post-ischemia in the AI animals, and 36% of AI animals did not recover sufficiently to achieve aortic overflow following ischemia (versus 0% of sham animals). However, for those animals able to withstand the ischemic perturbation, no difference was observed in percent recovery of post-ischemic cardiac function between groups. Urinary NOx (nitrite + nitrate) excretion was lower in AI animals and accompanied by reduced LV endothelial nitric oxide synthase and NOx. LV antioxidants superoxide dismutase-1 and -2 were reduced in AI animals, whereas glutathione peroxidase-1/2 as well as NADPH-oxidase-4 and H(2)O(2) were increased in these animals. Impaired cardiac function appears to predispose AI rats to poor outcomes following short-duration ischemic insult. These findings could be, in part, mediated by increased oxidative stress via nitric oxide-dependent and -independent mechanisms.

Bench-to-bedside review: Functional hemodynamics during surgery - should it be used for all high-risk cases?

The administration of a fluid bolus is done frequently in the perioperative period to increase the cardiac output. Yet fluid loading fails to increase the cardiac output in more than 50% of critically ill and surgical patients. The assessment of fluid responsiveness (the slope of the left ventricular function curve) prior to fluid administration may thus not only help in detecting patients in need of fluids but may also prevent unnecessary and harmful fluid overload. Unfortunately, commonly used hemodynamic parameters, including the cardiac output itself, are poor predictors of fluid responsiveness, which is best assessed by functional hemodynamic parameters. These dynamic parameters reflect the response of cardiac output to a preload-modifying maneuver (for example, a mechanical breath or passive leg-raising), thus providing information about fluid responsiveness without the actual administration of fluids. All dynamic parameters, which include the respiratory variations in systolic blood pressure, pulse pressure, stroke volume and plethysmographic waveform, have been repeatedly shown to be superior to commonly used static preload parameters in predicting the response to fluid loading. Within their respective limitations, functional hemodynamic parameters should be used to guide fluid therapy as part of or independently of goal-directed therapy strategies in the perioperative period.

Reversal of oxidant-mediated biochemical injury and prompt functional recovery after prolonged single-dose crystalloid cardioplegic arrest in the infantile piglet heart by terminal warm-blood cardioplegia supplemented with phosphodiesterase III inhibitor

The benefit of terminal blood cardioplegia (TWBCP) is insufficient after prolonged ischemia associated with inevitable oxidant-mediated injury by this modality alone. We tested the effects of TWBCP supplemented with high-dose olprinone, which is a phosphodiesterase III inhibitor, a clinically available compound with the potential to reduce oxidant stress and calcium overload. We evaluated the effects with respect to avoiding oxidant-mediated myocardial reperfusion injury and prompt functional recovery after prolonged single-dose crystalloid cardioplegic arrest in a infantile piglet cardiopulmonary bypass (CPB) model. Fifteen piglets were subjected to 90 min of cardioplegic arrest on CPB, followed by 30 min of reperfusion. In group I, uncontrolled reperfusion was applied without receiving TWBCP; in group II, TWBCP was given; in group III, TWBCP was supplemented with olprinone (3 μg/ml). Myocardial performance was evaluated before and after CPB by a left ventricular (LV) function curve and pressure-volume loop analyses. Biochemical injury was determined by measurements of troponin-T and lipid peroxide (LPO) in coronary sinus blood. Group III showed significant LV performance recovery (group I, 26.5% ± 5.1%; group II, 42.9% ± 10.8%; group III, 81.9% ± 24.5%, P < 0.01 vs. groups I and II), associated with significant reduction of troponin-T and LPO at the reperfusion phase. No piglets in group III needed electrical cardioversion. We concluded that TWBCP with olprinone reduces myocardial reperfusion injury by reducing oxidant-mediated lipid peroxidation, and it accelerates prompt and persistent LV functional recovery with suppression of reperfusion arrhythmia.

Left Ventricular Performance and Dimensions in Patients with Severe Emphysema

Concomitant heart dysfunction during the course of chronic obstructive pulmonary disease is well recognized. The prevailing view is that mainly the right side of the heart is involved. We evaluated left ventricular (LV) function and dimensions in patients with severe emphysema. Patients with severe emphysema undergoing lung volume reduction surgery were studied after anesthesia induction (n = 10). Non-emphysematous patients scheduled for lobectomy served as controls (n = 10). LV dimensions were measured with patients in the supine position by transesophageal two-dimensional echocardiography and systemic hemodynamics by a pulmonary artery thermodilution catheter, before and during central blood volume expansion by passive leg elevation. Baseline cardiac index (-25%), stroke volume index (SVI, -32%) stroke work index (-34%) and LV end-diastolic area index (EDAI, -33%) were significantly (P < 0.001) lower in the emphysema group. Passive leg elevation increased SVI and LV area ejection fraction more in the emphysema group than in controls (P < 0.05). The DeltaSVI/Delta pulmonary capillary wedge pressure and the DeltaSVI/DeltaEDAI relationships were significantly (P < 0.05) higher in the emphysema group compared to controls (2.2 +/- 0.71 vs 0.6 +/- 0.2 mL/mm Hg x m2 and 5.8 +/- 0.89 vs 2.8 +/- 0.8 mL/cm2 x m2, respectively). Preload-recruitable stroke work (Deltastroke work index/DeltaEDAI), a load-independent index of systolic LV function, did not differ between the two groups. The LV in patients with severe emphysema is hypovolemic, and operates on a steeper portion of the LV function curve, while indices of systolic function are not significantly impaired compared to non-emphysematous controls.

Digitalis therapy for patients in clinical heart failure.

The most commonly used preparation of digitalis is digoxin, which is obtained from the leaves of Digitalis lanata , a common flowering plant called “foxglove.” The words digitalis and digoxin in this article are used interchangeably. An exhaustive review published in 19961 cited a large number of references and had detailed data and descriptions of a large number of studies and all early trials. The present article summarizes those data but focuses on and emphasizes data collected since that time. These have been described in detail previously1 and are briefly summarized. ### Inotropic Effects The inotropic effects have been documented in the isolated papillary muscles and in the normal hearts of animals and humans. The inotropic action occurs in both ventricles and in both atria. In the normal heart and in those with coronary artery disease and normal left ventricular (LV) systolic function, with digitalis the LV function curve is moved upward and to the left.1 As a result, LV end-diastolic pressure and LV end-diastolic and end-systolic volumes are reduced, and there is an increase of LV ejection fraction (LVEF).1 ### Patients With Heart Failure In patients with heart failure (HF), digoxin slows the ventricular rate (1) in sinus rhythm because of an improvement in HF and withdrawal of sympathetic stimulation and (2) in atrial fibrillation by increasing parasympathetic tone. The combination of digoxin and carvedilol is superior to digoxin or carvedilol alone.2 ### Peripheral Vessels In normal subjects given intravenous ouabain, there is arterial and venous vasocontriction.3 The vasoconstriction is obviated by administering digoxin slowly over a period of 15 to 20 minutes1; moreover, the vasoconstriction lasts up to 30 minutes. The seminal study of Mason and Braunwald3 showed that in HF, the effects are different. Digitalis produces an increase of blood flow, a decrease of vascular resistance, venodilation, and a …

Modeling the Blood Pressure Response to a Ventricular Premature Complex with Special Reference to Heart Rate Turbulence

Ventricular premature beats have been used to characterize a risk factor for patients after myocardial infarction. This risk stratification has recently been improved by estimating the so-called heart rate turbulence, i.e., the acceleration and subsequent deceleration of the sinus beats following a ventricular premature beat. This response is triggered by oscillations in aortic blood pressure following a ventricular premature beat. In the following we report on a model to fit blood pressure oscillations due to ventricular premature beats in patients following myocardial infarction. The data on which this analysis is based were derived from 39 patients with varying degrees of left ventricular dysfunction following myocardial infarction. The recording included high-quality ECG and a noninvasive beat-to-beat recording of blood pressure from a finger artery. Records were chosen such that 5 to 30 ventricular premature beats occurred within a 30-min recording period. In a first step, we fed our data, i.e., a given series of coupling intervals, into two established cardiac models (Ten-Voorde and Mrovka et al.) and observed the blood pressure behavior. It turned out that both models were not able to reflect the full range of the observed blood pressure oscillations. For this reason we expanded the model of Mrovka et al. (Am J Physiol Regul Integr Comp Physiol 279: R1171–R1175, 2000), such that the desired pattern approximately appeared. This was achieved by introducing a more subtle left ventricular function curve and keeping track of the endsystolic volume in the left ventricle. After parameter fitting, a detailed picture of the hemodynamics appeared for each patient. It was found that left ventricular function and, in particular, post-extrasystolic potentiation was crucial for the prediction of the blood pressure response following a ventricular premature beat. Thus, in patients following myocardial infarction, not only impaired baroreceptor function but also altered left ventricular contraction behavior contributes to the phenomenon of heart rate turbulence.

Protective role of heat stress in burn trauma.

This study was designed to determine whether cutaneous burn injury up-regulated expression of myocardial heat shock protein (HSP)70 and to determine a potential cardioprotective role of inducible HSP70 (iHSP70) in postburn myocardial contractile function. Experimental study. Research laboratory. Adult Hartley guinea pigs. The first set of studies determined whether heat stress (increasing body temperature to 42 degrees C for 20 mins) in adult Hartley guinea pigs would increase expression of myocardial iHSP70. Our model of heat stress increased expression of inducible HSP in the myocardium (Western blot), and this response persisted 1, 2, 4, and 24 hrs after the initial heat stress. We then determined whether burn trauma over 40% total body surface area (TBSA) increased myocardial expression of iHSP70. Time-matched sham and burned guinea pigs were killed 1, 2, 4, 12, 18, or 24 hrs postburn, and hearts were used either to examine myocardial iHSP70 expression by Western blot or to determine myocardial contractile function (Langendorff). Burn trauma produced a two-fold increase in myocardial iHSP70 that was evident as early as 1 hr postburn and persisted 24 hrs postburn; increased iHSP70 expression occurred despite only a modest and transient increase in body temperature after burn trauma. We then determined whether heat shock stress before burn trauma provided a protective or detrimental effect on cardiac function. Body temperature was increased to 42 degrees C for 20 mins, animals were allowed to recover, and body temperature returned to baseline; burn trauma was then produced (40% TBSA) either 1, 2, 4, or 24 hrs after the initial heat stress. Myocardial contraction and relaxation deficits were evident after burn trauma alone; however, heat stress 1 hr before burn trauma improved left ventricular developed pressure and positive or negative maximum change in pressure in time and shifted left ventricular function curves upward and leftward from those calculated for burn in the absence of heat stress, indicating improved ventricular performance. Increasing the time between the initial heat stress and burn injury decreased the cardioprotective effects of heat stress. Thus, organ protection was evident only when the time period between the initial heat stress and the second insult was brief (1 hr). Our finding that the amount of myocardial iHSP70 remained constantly elevated after heat stress while the cardio-protective effect afforded by a prior heat stress declined with time suggested that the initial heat stress evoked several compensatory/adaptive mechanisms that may include modulation of autonomic nervous system responses, changes in metabolic function, modulation of pro/anti-inflammatory cytokine responses, and heat stress-related alterations in antioxidant capacity.

Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease.

The preceding article in this series1 reviewed evidence as to why age-associated changes in the central arterial system are risky with respect to vascular disease. In a similar vane, the focus of this article is on the potential link between age-associated changes in the heart and clinical cardiac disease outcomes. Left ventricular hypertrophy, heart failure, and atrial fibrillation increase dramatically with age (Figure 1). The prevalence of left ventricular hypertrophy (LVH) also increases with rising blood pressure and body mass index, a measure of obesity.2–4 Whether identified by electrocardiography or echocardiography, left ventricular hypertrophy has been shown to be associated with increased risk for coronary heart disease, sudden death, stroke, and overall cardiovascular disease.4,5 Figure 1. A, Prevalence of echocardiographic left ventricular hypertrophy (LVH) in women according to baseline age and systolic blood pressure. B, Prevalence of echocardiographic LVH in men according to baseline age and systolic blood pressure. Both A and B are reprinted from Levy D, Anderson KM, Savage DD, et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors: the Framingham Heart Study. Ann Intern Med . 1988;108:7–13. C, Prevalence of heart failure by age in Framingham Heart Study men (light bars) and women (dark bars). Reprinted from Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22:6A–13A. D, Prevalence of AF by age in subjects from the Framingham Heart Study. Reprinted from Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke . 1991;22:983–988. It has been increasingly appreciated that the development of heart failure with apparently preserved systolic function, as evidenced by a “normal” ejection fraction, occurs in about one-third to one-half of older patients with heart failure.6–9 In a …

Effects of surgery for postinfarction ventricular tachycardia on parameters of left ventricular function

Heart failure is the leading cause of death in patients after surgery for ventricular tachycardia. This study examines the effects of antiarrhythmic surgery on 4 parameters of left ventricular (LV) function. Global ejection fraction, segmental wall motion score, homogeneity of contraction, and diastolic function were measured in 32 patients by technetium-99m radionuclide ventriculography. Ejection fraction was measured from the left anterior oblique image. Wall motion score was assessed semiquantitatively for 11 LV segments from 3 projections. Homogeneity of contraction was expressed as the SD of the LV phase analysis curve during systole from the left anterior oblique image. Diastolic function was expressed in terms of peak and mean first time derivative of the action potential (dV/dt) of the LV function curve. Subgroup analyses were performed to distinguish the effects of aneurysmectomy, coronary artery bypass grafting, and changes in angiotensin converting enzyme inhibitor therapy. Mean systolic function improved after surgery (ejection fraction 22% vs 32%, p <0001; wall motion score 20 vs 13, p <0.0001; phase analysis 18 vs 12, p <0.03). Mean diastolic function also improved (peak dV/dt 0.83 ± 0.32 vs 1.49 ± 0.39, p = 0.006; mean dV/dt 0.41 ± 0.15 vs 0.76 ± 0.27, p = 0.006). Improvements were not confined to those who had aneurysmectomy or coronary bypass grafting and were not explained by changes in vasodilator therapy. Thus, antiarrhythmic surgery does not inherently damage LV function. Significant improvements were observed in most patients. Failure to improve indicated a poor longer term prognosis.

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation.

An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 degrees C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1+/-1.7 ml min-1, 83+/-5 mm Hg and 6283+/-552 mm Hg s-1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6+/-1.8 ml min-1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.

Protein kinase C inhibition improves ventricular function after thermal trauma.

To examine the effect of protein kinase C (PKC) inhibition on cardiac performance and intracellular Ca2+ homeostasis. Previous studies have shown that trauma impairs cardiac mechanical function, and recent studies suggest that PKC activation and subsequent perturbations in Ca2+ sequestration/release contribute to this cardiac dysfunction. In this study, anesthetized guinea pigs were given third-degree scald burns over 43 +/- 1% of the total body surface area and resuscitated with lactated Ringer's solution (LR) 4 mL/kg per percent of burn, Parkland formula. Animals with sham burns served as controls (n = 18). Burns were randomly divided into two groups: LR alone (N = 18) or LR + PKC inhibitor, calphostin C (0.1 mg/kg, intravenous bolus), given 30 minutes and 3, 6, and 21 hours after burn (n = 18). Cardiac function was assessed by Langendorff preparation 24 hours after burn in 8 to 12 animals per group. Intracellular calcium concentration ([Ca2+]i) was measured in cardiac myocytes (collagenase digestion) from additional animals in each experimental group (n = 5-9 per group) after Fura-2 AM loading of myocytes; fluorescence ratios were measured with a Hitachi spectrofluorometer. Cardiac dysfunction occurred 24 hours after burn in LR burns as indicated by lower left ventricular pressure and a reduced rate of left ventricular pressure rise and fall, +/-dP/dt (61 +/- 3 mm Hg, 1,109 +/- 44 mm Hg/s, and 880 +/- 40 mm Hg/s, respectively) compared with values measured in sham-burned animals (86 +/- 2 mm Hg, 1365 +/- 43 mm Hg/s, and 1183 +/- 30 mm Hg/s, respectively; p < 0.05). Ventricular function curves confirmed significant postburn contractile depression despite aggressive fluid resuscitation. Cardiac injury in burned animals was indicated by an increase in perfusate creatine kinase and lactate dehydrogenase, and Ca2+ dyshomeostasis was confirmed by increased myocyte [Ca2+]i (sham 151 +/- 6 vs. burn 307 +/- 20 nmol/L, p < 0.05). PKC inhibition improved all indices of cardiac performance, producing left ventricular pressure (82 +/- 3 mm Hg), +/-dP/dt (1,441 +/- 48 and 1,294 +/- 32 mm Hg/s), and left ventricular function curves that were comparable with those of sham-burned animals. In addition, [Ca2+]i in calphostin-treated burned animals (154 +/- 11 nmol/L) was identical to values in sham-burned animals. Our data suggest that PKC may serve as a final common pathway in signal transduction events mediating postburn cardiac dysfunction.

A cardiologist's perspective on evolving concepts in the management of congestive heart failure.

The conceptual framework for treatment of congestive heart failure has changed dramatically in the past 30 years. The 1950s and 1960s were characterized by manipulation of the left ventricular function curve by digitalis and diuretics. The 1970s focused on relief of symptoms by afterload reduction with vasodilators. Then stimulation of cardiac output with inotropes was shown to relieve symptoms, but patients died sooner. Now the focus is on the neurohumeral milieu and methods to counteract excess renin-angiotensin and sympathetic nervous system stimulation. Angiotensin-converting enzyme inhibitors are the drugs of choice because they also improve survival, but beta-blockers are becoming popular. The effect of molecular cardiology on practice guidelines for congestive heart failure is yet to be seen.

Ricin Depresses Cardiac Function in the Rabbit Heart

Ricin, a toxic glycoprotein from the castor bean, causes myocardial hemorrhage and a decrease in blood pressure. We studied the effects of ricin on myocardial function in the isolated rabbit heart. Rabbits were given 0.22 μg/kg of ricin iv and 48 hr later, the heart was isolated and retrogradely perfused through the aorta with Tyrode's solution. A latex balloon was inserted into the left ventricle and isovolumic left ventricular function curves were generated. Left ventricular developed pressure (LVDP), heart rate, coronary artery flow, left ventricular end diastolic pressure, myocardial oxygen consumption, oxygen extraction (a−vO2), and contractility (+dp/dt) were measured over a range of left ventricular volumes. Dose–response curves to isoproterenol (10−9–10−8m) and phenylephrine (10−9–10−6m) were also obtained. Compared to the control group, ricin pretreatment markedly decreased ventricular compliance (p< 0.01), diminished maximum left ventricular developed pressure (p< 0.05), and reduced maximal +dp/dt(p< 0.05). Myocardial oxygen consumption, heart rate, electrocardiographic PR, QRS, and QT intervals were not different in control and ricin treatment groups. Ricin did not significantly alter the inotropic or chronotropic responses to isoproterenol and phenylephrine. The results from the binding studies showed that ricin neither reduced β-adrenergic receptor numbers nor altered the dissociation constant. Thus, ricin reduced both systolic (LVDP and +dp/dt) and diastolic (compliance) left ventricular functions, perhaps due to increased vascular permeability, without altering responses to the α- and β-adrenoceptor agonists phenylephrine and isoproterenol.

Early hemodynamic course of septic shock.

To assess the relative contributions of changes in vascular tone and changes in cardiac function to hemodynamic recovery from septic shock. Case series, observational study. Multidisciplinary department of intensive care in an academic hospital. Sixty-seven patients with septic shock (prolonged hypotension, signs of tissue hypoperfusion, signs of sepsis, suspected source of infection, or documented bacteremia). In addition to the antibiotic therapy and the removal of the source of sepsis whenever possible, each patient received intravenous fluids and vasoactive agents (dopamine, norepinephrine, and dobutamine). Each patient was also treated with mechanical ventilation. Twenty-four (36%) patients survived their intensive care unit course. Hemodynamic measurements were obtained at baseline, after initial resuscitation (as soon as apparent hemodynamic stability was achieved), after 12 hrs, and after 24 hrs. There were no significant differences in hemodynamic or oxygen-derived variables at baseline between the survivors and the nonsurvivors. During the initial resuscitation period, only the survivors demonstrated a significant increase in mean arterial pressure (from 69 +/- 17 to 82 +/- 18 mm Hg; p < .02) and left ventricular stroke work index (from 25.2 +/- 11.0 to 35.5 +/- 19.4 g.m/m2; p < .05). The increases in cardiac index and systemic vascular resistance were greater in the survivors than in the non-survivors, but the differences did not reach statistical significance. Study of the left ventricular function curves indicated an improvement of left ventricular function in the survivors but not in the nonsurvivors. An early improvement in left ventricular function is a hallmark of the survivors from septic shock.

The role of toxic oxygen metabolites in a young model of thermal injury.

Production of oxygen-free radicals has been proposed as one pathophysiologic mechanism for postburn cardiac contractile dysfunction in adults. To examine this hypothesis in young subjects, we studied the cardiac effects of polyethylene glycol-superoxide dismutase (PEG-SOD) and PEG-catalase (PEG-CAT), each given as 20 U/g of body weight with fluid resuscitation (Parkland formula), after a third-degree burn constituting 33% of the total body surface area in young (6- to 7-day old) guinea pigs (group 3, n = 12). Fluid-treated burns without scavenger therapy (group 2, n = 15) and sham burn controls (group 1, n = 15) were included. Animals were killed 24 hours postburn, and hearts were studied in vitro (Langendorff). Compared with sham burn controls, fluid-treated burns (group 2) had significant cardiac dysfunction as indicated by a lower peak systolic left ventricular (LV) pressure (LVP: 67 +/- 2 vs. 57 +/- 4 mm Hg, p = 0.01, mean +/- SEM), maximal rate of LV pressure development (+dP/dt max: 1169 +/- 45 vs. 988 +/- 45 mm Hg/second, p = 0.01), and fall (-dP/dt max: 1109 +/- 45 vs. 919 +/- 49 mm Hg/second, p = 0.01). In addition, LV function curves calculated for group 2 were shifted downward and to the right of those calculated for sham burn controls in the direction of contractile depression, p = 0.01. PEG-SOD/PEG-CAT treatment in burns did not significantly improve LVP (60 +/- 5 mm Hg), but scavenger therapy improved +/-dP/dt max values (1112 +/- 74 and 988 +/- 98 mm Hg/second, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)