Chamber Stiffness Research Articles

Impact of pericardial restraint on right atrial mechanics during acute right ventricular pressure load.

Optimization of right atrial (RA) mechanics is important for maintaining right ventricular (RV) filling and global cardiac output. However, the impact of pericardial restraint on RA function and the compensatory role of the right atrium to changes in RV afterload remain poorly characterized. In eight open-chest sheep, RA elastance (contractility) and chamber stiffness were measured (RA pressure-volume relations) at baseline and during partial pulmonary artery (PA) occlusion. Data were collected before and after pericardiotomy. With the pericardium intact and partial PA occlusion, RA elastance increased by 28% (P < 0.04), whereas RA stiffness tended to rise (P = 0.08). However, after pericardiotomy, there was a significant fall in both RA elastance (54%, P < 0.04) and stiffness (39%, P < 0.04), and subsequent PA occlusion failed to induce a change in elastance (P > 0.19) or stiffness (P > 0.84). After pericardiotomy, RA elastance and stiffness fell dramatically, and the compensatory response of the right atrium to elevated RV afterload was lost. The ability of the right atrium to respond to changes in RV hemodynamics is highly dependent on pericardial integrity.

Can left ventricular diastolic stiffness be measured noninvasively?

Background: A noninvasive estimation of left ventricular (LV) diastolic chamber stiffness (KLV) is still a challenge. Experimental data suggests that Klv can be obtained by using Doppler mitral flow deceleration time (DT) as the only variable: Klv = (70/[DT−20])2 mm Hg/mL. We assessed the accuracy of this noninvasive estimate of Klv by comparing it with invasive measurement of Klv in intact patients with a wide range of LV size and function under varying loading conditions. Methods: Twenty-five patients (age 54 ± 12 years) with ischemic heart disease (n = 19) or primary LV dysfunction (n = 6), with a wide range of DT (79-324 ms) and ejection fraction (8%-57%), underwent simultaneous assessment of LV pressure by micromanometer and volume by 2-dimensional (2D) echocardiogrpahy-guided Doppler mitral flow velocity (where volume = mitral flow velocity integral × annular area) calibrated to 2D echocardiography stroke volume. Invasive Klv [delta pressure (from minimum to end-diastolic)/delta volume (during the same time interval)] was obtained at baseline and in 23 patients after LV unloading by prostaglandin E1 (30-60 ng/kg/min) (n = 12), nitroglycerin (0.2 mg) (n = 9) or magnesium (1 g) (n = 2). Noninvasive Klv was estimated according to the above formula. Results: In this set of patients with normal mitral annular area (3.9 ± 1.1 cm2/m2), multivariate analysis showed that DT is inversely related to Klv (P <.001) but not to left atrial chamber stiffness, LV volume, relaxation time constant, mitral valve opening pressure, or area. The relation between noninvasively calculated and directly measured Klv was close to the line of identity under all conditions, (y = 0.93x + 0.05, r = 0.67, n = 48, P <.001), although with a wide standard error of the estimate (0.26 mm Hg/mL). Conclusion: We conclude that Klv can be calculated ± 0.5 mm Hg/mL from noninvasively measured DT in patients. (J Am Soc Echocardiogr 2002;15:935-43.)

A model of closed chest regional myocardial infarction in the rabbit: a clinically relevant in vivo assay system of post-infarction remodelling.

Coronary artery ligation is the standard technique to induce regional myocardial infarction in small animal models. However, opening the chest and incising the pericardium independently influence post-MI remodelling. Our purpose was to develop and characterize a novel closed chest model of regional myocardial infarction (MI) in the rabbit of increased clinical relevance. Coronary angiography was performed percutaneously in New Zealand White Rabbits (NZW) using pre-formed catheters. A 0.36 mm thrombogenic coil was positioned in the circumflex artery to induce closed chest MI. Of rabbits undergoing coil deployment 40 % survived until day 100. Rabbits were classified as small MI (n = 5), moderate MI (n = 6) and large MI (n = 6) < 15 %, 15 - 30 %, > 30 % of LV myocardial volume respectively) or sham controls (n=11). Transthoracic echocardiographic images were obtained 0, 3, 5, 7, 14, 28, 60, 100 days post procedure. At day 100, LVEDP was measured before and after plasma substitute infusion. Hearts were subsequently excised and chamber stiffness (Kc) was derived from the passive pressure-volume relationship. Cardiac weight, dimensions and MI as a percentage of LV volume (MI%) were also recorded. Differences in percentage fractional shortening (%FS) were apparent from day 14. %FS was reduced in rabbits with large and moderate MI compared to controls (day 100, p < 0.005 and p < 0.05, respectively). LVEDP was increased in large and moderate MI compared to small MI and controls (26 mmHg +/- 6 and 21 mmHg +/- 5 vs. 9 mmHg +/- 1 and 7 mmHg +/- 3 p < 0.005); these differences were maintained during plasma substitute infusion. Kc in large MI was significantly less than moderate MI, small MI or control (all p < 0.05). Direct morphometric measurements distinguished between all groups.This study provides the first description of post-infarction remodelling after coronary artery occlusion where the pericardium remains intact in a small animal model. We believe it may provide a more physiologically and clinically relevant in vivo assay system of left ventricular dysfunction after myocardial infarction.

Propofol alters left atrial function evaluated with pressure-volume relations in vivo.

The effects of IV anesthetics on left atrial (LA) function in vivo are unknown. We tested the hypothesis that propofol alters LA mechanics evaluated with pressure-volume relations in barbiturate-anesthetized dogs (n = 9) instrumented for measurement of aortic, LA, and left ventricular (LV) pressures (micromanometers) and LA volume (epicardial orthogonal sonomicrometers). LA myocardial contractility (E(es)) and dynamic chamber stiffness were assessed with end-systolic and end-reservoir pressure-volume relations, respectively. Relaxation was determined from the slope of LA pressure decline after contraction corrected for peak LA pressure. LA stroke work and reservoir function were assessed by A and V loop area, respectively, from the steady-state pressure-volume diagram. LA-LV coupling was determined by the ratio of E(es) to LV elastance. Dogs received propofol (5, 10, 20, or 40 mg. kg(-1). h(-1)) in a random manner, and LA function was determined after a 15-min equilibration at each dose. Propofol decreased heart rate, mean arterial blood pressure, and the maximal rate of increase of LV pressure. Propofol caused dose-related reductions in E(es), dynamic chamber stiffness, and E(es)/LV elastance. An increase in V loop area and declines in LA stroke work, emptying fraction, and the active LA contribution to LV filling also occurred. Relaxation was unchanged. The results indicate that propofol depresses LA myocardial contractility, reduces dynamic chamber stiffness, maintains reservoir function, and impairs LA-LV coupling but does not alter LA relaxation in vivo. Propofol depresses contractile function of left atrial (LA) myocardium, impairs mechanical matching between the LA and the left ventricular (LV), and reduces the active LA contribution to LV filling in vivo. Compensatory decreases in chamber stiffness contribute to relative maintenance of LA reservoir function during the administration of propofol.

The effects of acute normovolemic hemodilution on left ventricular systolic and diastolic function in the absence or presence of beta-adrenergic blockade in dogs.

Acute normovolemic hemodilution (ANH) increases cardiac output because of a reduction in blood viscosity and enhancement of left ventricular (LV) contractility. The status of LV function, especially LV diastolic function during ANH, remains controversial. We therefore examined LV systolic and diastolic function during ANH. Sixteen dogs were anesthetized with isoflurane in the absence (Group 1) and presence (Group 2) of beta-adrenergic blockade (propranolol 1 mg/kg). LV contractility was quantified by the slope (M(w)) of the stroke work and end-diastolic volume relation. Diastolic function was evaluated with the time constant of LV relaxation (T), chamber stiffness constant (K(c)), peak LV diastolic filling rate during early filling (peak E) and atrial contraction (peak A), and ratio of peak E to peak A (E/A). Normovolemic exchange of blood (50 mL/kg) for 6% hydroxyethyl starch (ANH50) significantly increased M(w) in Group 1 but not in Group 2. In both groups, ANH50 significantly decreased T. ANH50 significantly increased peak E in both groups and peak A in Group 1, and it did not change the E/A ratio or K(c) in either group. ANH causes positive inotropic effects and enhances diastolic function without beta-blockade. Even after beta-adrenergic blockade, ANH improves diastolic function through the reduction of LV ejection impedance. Acute normovolemic hemodilution enhances LV (left ventricular) diastolic function by alterations in the LV loading condition produced by hemodilution, which mainly contributes to a compensatory increase in cardiac output.

Myocardial infarction scar plication in the rat: cardiac mechanics in an animal model for surgical procedures

Backgund. The immediate effects of surgical reduction of left ventricle cavity on cardiac mechanics have not been well defined. Methods. Cardiac mechanics were analyzed before and after myocardial infarction scar plication in 11 isolated infarcted rat hearts. Results. Despite a decrease in myocardial stiffness, an increase in chamber stiffness was noted after myocardial infarction scar plication. Systolic function was favored in more than one way. For the same diastolic pressures, maximal developed pressures were higher after myocardial infarction scar plication, and the slope of the systolic pressure-volume relationship was steeper afterwards as compared with before; this means that Frank-Starling recruitment is accentuated in smaller cavities. In addition, the developed net forces needed to generate these pressures were clearly lower afterward than before, indicating reduced ventricular afterload. Conclusions. The study results show that diastolic function is harmed and systolic function is favored by myocardial infarction scar plication. We suggest that preoperative evaluation of the degree of diastolic dysfunction and impairment of the Frank-Starling mechanism may help to identify patients who may have a poor postoperative outcome due to diastolic or systolic dysfunction.

Indexes of diastolic RV function: load dependence and changes after chronic RV pressure overload in lambs

Diastolic function is a major determinant of ventricular performance, especially when loading conditions are altered. We evaluated biventricular diastolic function in lambs and studied possible load dependence of diastolic parameters [minimum first derivative of pressure vs. time (dP/dt(min)) and time constant of isovolumic relaxation (tau)] in normal (n = 5) and chronic right ventricular (RV) pressure-overloaded (n = 5) hearts by using an adjustable band on the pulmonary artery (PAB). Pressure-volume relations were measured during preload reduction to obtain the end-diastolic pressure-volume relationship (EDPVR). In normal lambs, absolute dP/dt(min) and tau were lower in the RV than in the left ventricle whereas the chamber stiffness constant (b) was roughly the same. After PAB, RV tau and dP/dt(min) were significantly higher compared with control. The RV EDPVR indicated impaired diastolic function. During acute pressure reduction, both dP/dt(min) and tau showed a relationship with end-systolic pressure. These relationships could explain the increased dP/dt(min) but not the increased tau-value after banding. Therefore, the increased tau after banding reflects intrinsic myocardial changes. We conclude that after chronic RV pressure overload, RV early relaxation is prolonged and diastolic stiffness is increased, both indicative of impaired diastolic function.

Myocardial fibrosis determines left ventricular chamber stiffness in hypertensive patients. Effects of treatment with losartan

Myocardial fibrosis determines left ventricular chamber stiffness in hypertensive patients. Effects of treatment with losartan

Change in Diastolic Left Ventricular Filling After One Year of Antihypertensive Treatment

Background — It is well established that hypertensive patients with left ventricular (LV) hypertrophy have impaired diastolic filling. However, the impact of antihypertensive treatment and LV mass reduction on LV diastolic filling remains unclear. Methods and Results — Echocardiograms were recorded in 728 hypertensive patients with ECG-verified LV hypertrophy (Cornell voltage-duration or Sokolow-Lyon) at baseline and after 1 year of blinded treatment with either losartan or atenolol-based regimen. Systolic and diastolic blood pressures (BP) were reduced on average 23/11 mm Hg; isovolumic relaxation time and E/A ratio became more normal, and LV inflow deceleration time prolonged (all P &lt;0.001). Directionally opposite changes in isovolumic relaxation time (IVRT) and deceleration time indicate improvement in active LV relaxation and passive chamber stiffness during early diastole. Prevalences of normal LV filling increased, abnormal relaxation and pseudonormalization decreased, and restrictive filling pattern remained unchanged ( P &lt;0.05). Patients with reduction in LV mass had smaller left atrial diameter, shortened IVRT, increased E/A ratio, and prolonged LV inflow deceleration time (all P &lt;0.001). Patients without LV mass reduction had no change in diastolic filling parameters ( P =NS). IVRT shortening was independently associated with reduction in LV mass. Increase in E/A ratio was independently associated with reduction in diastolic BP, and increase in the deceleration time was independently associated with reduced end-systolic relative wall thickness. Conclusions — Antihypertensive therapy resulting in LV mass or relative wall thickness regression is associated with significant improvement of diastolic filling parameters related to active relaxation and passive chamber stiffness compared with patients without regression, independent of BP reduction; however, abnormalities of diastolic LV filling remain common.

Heart failure in pressure overload hypertrophy: The relative roles of ventricularremodeling and myocardial dysfunction

ObjectivesWe sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BackgroundThe mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. MethodsTwenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. ResultsThe LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure–diameter relationship and ex vivo from the pressure–volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress–midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress–strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. ConclusionsThe two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.

Remodeling of the left atrium in pacing-induced atrial cardiomyopathy.

Rapid atrial pacing produces atrial systolic and diastolic failure characterized by absent atrial booster pump function, increased atrial chamber stiffness, enhanced atrial conduit function, and atrial enlargement. However, the processes underlying these abnormalities are poorly understood. Therefore, we examined left atrial myocardium from dogs with rapid pacing-induced atrial failure (400 bpm for 6 weeks) and from control dogs. Western blotting was used to determine the levels of proteins involved in calcium homeostasis (SERCA 2A, phospholamban, Na+-Ca2+ exchanger). Matrix metalloproteinase (MMP) activity was measured using gelatin and casein zymography, and levels of tissue inhibitor of metalloproteinase-4 (TIMP-4) and the TIMP-4 complexed with MMPs were measured with Western blot analysis. There were no differences in SERCA 2A or Na+-Ca2+ exchanger protein levels, but phospholamban level was significantly decreased in atrial samples from rapidly paced dogs (51.2 +/- 7.8 vs. 77.0 +/- 10.0, p < 0.01). The activity of MMP-9 was selectively and significantly increased by approximately 50%, and the level of complexed TIMP-4 protein was significantly decreased by approximately 50% in samples from dogs with atrial failure. Thus, rapid pacing-induced atrial failure is associated with differential changes in MMP activity, an unchanged number of calcium pumps, and compensatory changes in the level of phospholamban.

Echocardiographic characterization of fundamental mechanisms of abnormal diastolic filling in diabetic rats with a parameterized diastolic filling formalism

Abnormalities of diastolic function (DF) precede systolic dysfunction in diabetic cardiomyopathy. Transmitral Doppler flow analysis is the primary method for noninvasively assessing DF. We used model-based Doppler E-wave analysis to evaluate diastolic function differences between normal and diabetic rat hearts. Control rats and those with diabetes underwent echocardiography with analysis by traditional Doppler indexes and by the parameterized diastolic filling (PDF) formalism, generating 3 parameters, x0, c, and k, that uniquely characterize each E-wave. Significant intergroup differences in the E/A ratios (P <.01), isovolumic relaxation times (P <.01), and the modeling parameter c (P <.05) were found. There were no significant differences in shortening fraction, deceleration time, myocardial collagen content, or the parameters x0 and k between diabetic and control rats. These results indicate that differences in diastolic function may be noninvasively quantified and that diabetic hearts may exhibit defects in uncoupling of the contractile apparatus without concomitant increases in chamber stiffness. (J Am Soc Echocardiogr 2001;14:1166-72.)

The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy

Stress-induced mitogen-activated protein kinase (MAP) p38 is activated in various forms of heart failure, yet its effects on the intact heart remain to be established. Targeted activation of p38 MAP kinase in ventricular myocytes was achieved in vivo by using a gene-switch transgenic strategy with activated mutants of upstream kinases MKK3bE and MKK6bE. Transgene expression resulted in significant induction of p38 kinase activity and premature death at 7-9 weeks. Both groups of transgenic hearts exhibited marked interstitial fibrosis and expression of fetal marker genes characteristic of cardiac failure, but no significant hypertrophy at the organ level. Echocardiographic and pressure-volume analyses revealed a similar extent of systolic contractile depression and restrictive diastolic abnormalities related to markedly increased passive chamber stiffness. However, MKK3bE-expressing hearts had increased end-systolic chamber volumes and a thinned ventricular wall, associated with heterogeneous myocyte atrophy, whereas MKK6bE hearts had reduced end-diastolic ventricular cavity size, a modest increase in myocyte size, and no significant myocyte atrophy. These data provide in vivo evidence for a negative inotropic and restrictive diastolic effect from p38 MAP kinase activation in ventricular myocytes and reveal specific roles of p38 pathway in the development of ventricular end-systolic remodeling.

Left ventricular diastolic filling response to stationary bicycle exercise during pregnancy and the postpartum period

Objective: The purpose of this study was to determine the effects of pregnancy and of maximal exercise on left ventricular diastolic filling response. Study Design: Transmitral pulsed Doppler echocardiography was obtained in 10 healthy women during each trimester of pregnancy and at 12 weeks after delivery. Doppler studies were performed at rest and at each exercise workload. The P-R interval, the early and atrial peak flow velocities, the mitral early deceleration time, and the isovolumetric relaxation time were analyzed. Data are expressed as the mean and standard deviation of the mean. Values obtained during the last trimester of pregnancy were used as the pregnant value; values at the 12 weeks after delivery were used as the nonpregnant value. Paired t -test, analysis of variance, and mixed models were used to determine significance with a probability value of <.05. Results: Pregnancy significantly increased the early and atrial peak flow velocities. Pregnancy decreased the P-R interval, the early deceleration time, and the isovolumetric relaxation time. Exercise significantly decreased these diastolic functions; but pregnancy, in any of the 3 trimesters, did not significantly affect this response. Conclusion: Pregnancy increased left ventricular diastolic camber stiffness at rest and shifted left ventricular diastolic filling during exercise from predominantly early to atrial filling. This finding suggests that there is an increase in left ventricular chamber stiffness during maximal upright bicycle exercise in pregnancy. (Am J Obstet Gynecol 2001;185:822-7.)

Desflurane, sevoflurane, and isoflurane affect left atrial active and passive mechanical properties and impair left atrial-left ventricular coupling in vivo: analysis using pressure-volume relations.

The effects of volatile anesthetics on left atrial function in vivo have not been described. The authors tested the hypothesis that desflurane, sevoflurane, and isoflurane alter left atrial mechanics evaluated with invasively derived pressure-volume relations. Barbiturate-anesthetized dogs (n = 24) were instrumented for measurement of aortic, left atrial, and left ventricular pressures (micromanometers) and left atrial volume (orthogonal sonomicrometers). Left atrial contractility and chamber stiffness were assessed with end-systolic and end-reservoir pressure-volume relations, respectively, obtained from differentially loaded diagrams. Relaxation was determined from the slope of left atrial pressure decline after contraction. Stroke work and reservoir function were assessed by A and V loop areas, respectively. Left atrial-left ventricular coupling was determined by the ratio of left atrial contractility and left ventricular elastance. Dogs received 0.6, 0.9, and 1.2 minimum alveolar concentration desflurane, sevoflurane, or isoflurane in a random manner, and left atrial function was determined after 20-min equilibration at each dose. Desflurane, sevoflurane, and isoflurane decreased heart rate, mean arterial pressure, and maximal rate of increase of left ventricular pressure and increased left atrial end-diastolic, end-systolic, and maximum volumes. All three anesthetics caused dose-related reductions in left atrial contractility, relaxation, chamber stiffness, and stroke work. Administration of 0.6 and 0.9 minimum alveolar concentration desflurane, sevoflurane, and isoflurane increased V loop area. All three anesthetics decreased the ratio of stroke work to total left atrial pressure-volume diagram area, increased the ratio of conduit to reservoir volume, and reduced left atrial contractility-left ventricular elastance to equivalent degrees. The results indicate that desflurane, sevoflurane, and isoflurane depress left atrial contractility, delay relaxation, reduce chamber stiffness, preserve reservoir and conduit function, and impair left atrial-left ventricular coupling in vivo.

Cardiomyoplasty for treatment of heart failure.

Cardiomyoplasty for treatment of heart failure.

Chamber properties from transmitral flow: prediction of average and passive left ventricular diastolic stiffness.

A chamber stiffness (K(LV))-transmitral flow (E-wave) deceleration time relation has been invasively validated in dogs with the use of average stiffness [(DeltaP/DeltaV)(avg)]. K(LV) is equivalent to k(E), the (E-wave) stiffness of the parameterized diastolic filling model. Prediction and validation of 1) (DeltaP/DeltaV)(avg) in terms of k(E), 2) early rapid-filling stiffness [(DeltaP/DeltaV)(E)] in terms of k(E), and 3) passive (postdiastasis) chamber stiffness [(DeltaP/DeltaV)(PD)] from A waves in terms of the stiffness parameter for the Doppler A wave (k(A)) have not been achieved. Simultaneous micromanometric left ventricular (LV) pressure (LVP) and transmitral flow from 131 subjects were analyzed. (DeltaP)(avg) and (DeltaV)(avg) utilized the minimum LVP-LV end-diastolic pressure interval. (DeltaP/DeltaV)(E) utilized DeltaP and DeltaV from minimum LVP to E-wave termination. (DeltaP/DeltaV)(PD) utilized atrial systolic DeltaP and DeltaV. E- and A-wave analysis generated k(E) and k(A). For all subjects, noninvasive-invasive relations yielded the following equations: k(E) = 1,401. (DeltaP/DeltaV)(avg) + 59.2 (r = 0.84) and k(E) = 229.0. (DeltaP/DeltaV)(E) + 112 (r = 0.80). For subjects with diastasis (n = 113), k(A) = 1,640. (DeltaP/DeltaV)(PD) - 8.40 (r = 0.89). As predicted, k(A) showed excellent correlation with (DeltaP/DeltaV)(PD); k(E) correlated highly with (DeltaP/DeltaV)(avg). In vivo validation of average, early, and passive chamber stiffness facilitates quantitative, noninvasive diastolic function assessment from transmitral flow.

Modelling cardiac fluid dynamics and diastolic function

Two complementary mathematical modelling approaches are covered. They contrast the degree of mathematical and computational sophistication that can be applied to cardiovascular physiology problems and they highlight the differences between a fluid dynamic versus kinematic (lumped parameter) approach. McQueen & Peskin model cardiovascular tissue as being incompressible, having essentially uniform mass density, and apply a modified form of the Navier–Stokes equations to the four chambered heart and great vessels. Using a supercomputer their solution provides fluid, wall and valve motion as a function of space and time. Their computed results are consistent with flow attributes observed in vivo via cardiac MRI. Kovacs focuses on the physiology of diastole. The suction pump attribute of the filling ventricle is modelled as a damped harmonic oscillator. The model predicts transmitral flow–velocity as a function of time. Using the contour of the clinical Doppler echocardiographic Eand A–wave as input, unique solution of Newton9s Law allows solution of the ‘inverse problem’ of diastole. The model quantifies diastolic function in terms of model parameters accounting for (lumped) chamber stiffness, chamber viscoelasticity and filling volume. The model permits derivation of novel (thermodynamic) indexes of diastolic function, facilitates non–invasive quantitation of diastolic function and can predict ‘new’ physiology from first principles.

Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate

OBJECTIVESThe goal of this study was to determine the subcellular mechanism(s) underlying increased left ventricular (LV) diastolic chamber stiffness (DCS) during angina (demand ischemia).BACKGROUNDIncreased DCS may result from increased diastolic myocyte calcium concentration and/or rigor. Therefore, we assessed the effects of direct alterations of both calcium-activated tension and high-energy phosphates on increased DCS.METHODSDemand ischemia was reproduced in isolated, isovolumic, red-cell perfused rabbit hearts by imposing low-flow ischemia and pacing tachycardia. This resulted in increased DCS. Interventions were performed after LV end-diastolic pressure had increased approximately 7 mm Hg. Initially, to determine the effects of altered calcium concentration or myofilament calcium responsiveness, hearts received either: 1) 5 or 14 mmol/L calcium chloride; 2) 8 mmol/L egtazic acid; 3) 5 mmol/L butane-dione-monoxime (BDM); or 4) 50 mmol/L ammonium chloride (NH4Cl). Then, to assess the contribution of decreased high-energy phosphate supply, hearts received 5) glucose (25 mmol/L) and insulin (400 μU/ml).RESULTS1) Calcium chloride, 5 and 14 mmol/L, increased LV systolic pressure by 42% and 70%, respectively (p < 0.001), indicating increased calcium-activated tension, but did not further increase DCS, implying intact diastolic calcium resequestration. 2) Egtazic acid reduced LV systolic pressure by 30% (p < 0.001), indicating reduced intracellular calcium, but failed to reduce increased DCS. 3) Butane-dione-monoxime and NH4Cl chloride affected contractile function (i.e., a calcium-driven force) but did not alter increased DCS. 4) Glucose and insulin, which increase high-energy phosphates during ischemia, reduced increased DCS by 50% (p < 0.001).CONCLUSIONSIncreased DCS during demand ischemia was insensitive to maneuvers altering intracellular calcium concentration or myofilament calcium-responsiveness, that is, evidence against an etiology of calcium-activated tension. In contrast, increased glycolytic substrate ameliorated increased DCS, supporting a primary mechanism of rigor-bond formation.

Determining optimal cardiac preload during resuscitation using measurements of ventricular compliance.

While the right ventricular end-diastolic volume index (RVEDVI) has been shown to be a better indicator of preload than cardiac filling pressures, optimal values during resuscitation from trauma are unknown. This study examines right ventricular stiffness as a guide to optimal values of RVEDVI. Prospective study of 19 critically injured patients monitored with a volumetric pulmonary artery catheter during resuscitation. Per resuscitation protocol, the target RVEDVI was > or = 120 mL/m2. Sequential fluid boluses of 500 to 1000 mL were administered to obtain at least four values of RVEDVI and right ventricular end-diastolic pressure (estimated by central venous pressure [CVP]). For each patient, nonlinear regression was used to construct the ventricular compliance curve based on the equation, CVP = aek(RVEDVI), where k is the coefficient of chamber stiffness. Overall, the derived compliance curves had excellent fit with the theoretical equation (mean R2, 0.95 +/- 0.04). Mean k was 0.043 +/- 0.012 (range, 0.029-0.067). For each patient, mean RVEDVI during resuscitation was significantly correlated with k (R2 = 0.75, p < 10-5) indicating that chamber stiffness, measured during initial fluid administration, may be used to determine RVEDVI during the ensuing resuscitation. In critically injured patients, bedside assessment of right ventricular compliance is possible and may help determine optimal values of RVEDVI during resuscitation.