Differential laws of left ventricular isovolumic pressure fall

An attempt has been made to test for a reliable method of characterizing the isovolumic left ventricular pressure fall in isolated ejecting hearts by one or two time constants, tau. Alternative nonlinear regression models (three- and four-parametric exponential, logistic, and power function), based upon the common differential law dp(t)/dt = - [p(t)-P ]/ tau(t) are compared in isolated ejecting rat, guinea pig, and ferret hearts. Intraventricular pressure fall data are taken from an isovolumic standard interval and from a subinterval of the latter, determined data-dependently by a statistical procedure. Extending the three-parametric exponential fitting function to four-parametric models reduces regression errors by about 20-30%. No remarkable advantage of a particular four-parametric model over the other was revealed. Enhanced relaxation, induced by isoprenaline, is more sensitively indicated by the asymptotic logistic time constant than by the usual exponential. If early and late parts of the isovolumic pressure fall are discarded by selecting a subinterval of the isovolumic phase, tau remains fairly constant in that central pressure fall region. Physiological considerations point to the logistic model as an advantageous method to cover lusitropic changes by an early and a late tau. Alternatively, identifying a central isovolumic relaxation interval facilitates the calculation of a single ("central") tau; there is no statistical justification in this case to extend the three-parametric exponential further to reduce regression errors.     

Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo

The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective ET(B) receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 +/- 0.11 to 1.48 +/- 0.23 and preload recruitable stroke work value of 68.7 +/- 4.7 to 83.4 +/- 7.2) that appear to be mediated through ET(A) receptors, whereas impairment in left ventricular isovolumic relaxation (tau = 41.5 +/- 1.4 to 58.1 +/- 5.0 and t(1/2) = 23.0 +/- 0.7 to 30.9 +/- 2.6, where tau is the time constant for pressure decay and t(1/2) is the half-time for pressure decay) was ET(B) receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation (tau from 43.3 +/- 1.8 to 54.4 +/- 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from ET(A) and ET(B) receptor activation, respectively.     

Assessment of the time constant of relaxation: insights from simulations and hemodynamic measurements

The objective of this study was to use high-fidelity animal data and numerical simulations to gain more insight into the reliability of the estimated relaxation constant derived from left ventricular pressure decays, assuming a monoexponential model with either a fixed zero or free moving pressure asymptote. Comparison of the experimental data with the results of the simulations demonstrated a trade off between the fixed zero and the free moving asymptote approach. The latter method more closely fits the pressure curves and has the advantage of producing an extra coefficient with potential diagnostic information. On the other hand, this method suffers from larger standard errors on the estimated coefficients. The method with fixed zero asymptote produces values of the time constant of isovolumetric relaxation (tau) within a narrow confidence interval. However, if the pressure curve is actually decaying to a nonzero pressure asymptote, this method results in an inferior fit of the pressure curve and a biased estimation of tau.     

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.     

Half-logistic time constant: a more reliable lusitropic index than monoexponential time constant regardless of temperature in canine left ventricle

Temperature changes influence cardiac diastolic function. The monoexponential time constant (tauE), which is a conventional lusitropic index of the rate of left ventricular (LV) pressure fall, increases with cooling and decreases with warming. We have proposed that a half-logistic time constant (tauL) is a better lusitropic index than tauE at normothermia. In the present study, we investigated whether tauL can remain a superior measure as temperature varies. The isovolumic relaxation LV pressure curves from the minimum of the first time derivative of LV pressure (dP/dtmin) to the LV end-diastolic pressure were analyzed at 30, 33, 36, 38, and 40 degrees C in excised, cross-circulated canine hearts. tauL and tauE were evaluated by curve-fitting using the least squares method and applying the half-logistic equation, P(t) = PA/[1 + exp(t/tauL)] + PB, and the monoexponential equation, P(t) = P0exp(-t/tauE) + Pinfinity. Both tauL and tauE increased significantly with decreasing temperature and decreased with increasing temperature. The half-logistic correlation coefficient (r) values were significantly higher than the monoexponential r values at the 5 above-mentioned temperatures. This implies that the superiority of the goodness of the half-logistic fit is not temperature dependent. The half-logistic model characterizes the amplitude and time course of LV pressure fall more reliably than the monoexponential model. Hence, we concluded that tauL is a more useful lusitropic index regardless of temperature.     

Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 Uncovers Distinct Functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness

G protein-coupled receptor kinase-2 and -3 (GRK2 and GRK3) in cardiac myocytes catalyze phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain. Although GRK2 has been extensively investigated, the function of cardiac GRK3 remains unknown. Thus, in this study cardiac function of GRK3 was investigated in transgenic (Tg) mice with cardiac-restricted expression of a competitive inhibitor of GRK3, i.e. the carboxyl-terminal plasma membrane targeting domain of GRK3 (GRK3ct). Cardiac myocytes from Tg-GRK3ct mice displayed significantly enhanced agonist-stimulated alpha(1)-adrenergic receptor-mediated activation of ERK1/2 versus cardiac myocytes from nontransgenic littermate control (NLC) mice consistent with inhibition of GRK3. Tg-GRK3ct mice did not display alterations of cardiac mass or left ventricular dimensions compared with NLC mice. Tail-cuff plethysmography of 3- and 9-month-old mice revealed elevated systolic blood pressure in Tg-GRK3ct mice versus control mice (3-month-old mice, 136.8 +/- 3.6 versus 118.3 +/- 4.7 mm Hg, p < 0.001), an observation confirmed by radiotelemetric recording of blood pressure of conscious, unrestrained mice. Simultaneous recording of left ventricular pressure and volume in vivo by miniaturized conductance micromanometry revealed increased systolic performance with significantly higher stroke volume and stroke work in Tg-GRK3ct mice than in NLC mice. This phenotype was corroborated in electrically paced ex vivo perfused working hearts. However, analysis of left ventricular function ex vivo as a function of increasing filling pressure disclosed significantly reduced (dP/dt)(min) and prolonged time constant of relaxation (tau) in Tg-GRK3ct hearts at elevated supraphysiological filling pressure compared with control hearts. Thus, inhibition of GRK3 apparently reduces tolerance to elevation of preload. In conclusion, inhibition of cardiac GRK3 causes hypertension because of hyperkinetic myocardium and increased cardiac output relying at least partially on cardiac myocyte alpha(1)-adrenergic receptor hyper-responsiveness. The reduced tolerance to elevation of preload may cause impaired ability to withstand pathophysiological mechanisms of heart failure.     

Isovolumic pressure-to-early rapid filling decay rate relation: model-based derivation and validation via simultaneous catheterization echocardiography.

Transmitral Doppler echocardiography is the preferred method of noninvasive diastolic function assessment. Correlations between catheterization-based measures of isovolumic relaxation (IVR) and transmitral, early rapid filling (Doppler E-wave)-derived parameters have been observed, but no model-based, causal explanation has been offered. IVR has also been characterized in terms of its duration as IVR time (IVRT) and by tau, the time-constant of IVR, by approximating the terminal left ventricular IVR pressure contour as Pt= Pinfinity + P(o)e(-t/tau), where Pt is the continuity of pressure, Pinfinity and Po are constants, t is time, and tau is the time constant of IVR. To characterize the relation between IVR and early rapid filling more fully, simultaneous (micromanometric) left ventricular pressure and transmitral Doppler E-wave data from 25 subjects undergoing elective cardiac catheterization and having normal physiology were analyzed. The time constant tau was determined from the dP/dt vs. P (phase) plane and, simultaneous Doppler E-waves provided global indexes of chamber viscosity/relaxation (c), chamber stiffness (k), and load (xo). We hypothesize that temporal continuity of pressure decay at mitral valve opening and physiological constraints permit the algebraic derivation of linear relations relating 1/tau to both peak atrioventricular pressure gradient (kxo) and E-wave-derived viscosity/relaxation (c) but does not support a similar, causal (linear) relation between deceleration time and tau or IVRT. Both predicted linear relations were observed: kxo to 1/tau (r = 0.71) and viscosity/relaxation to 1/tau (r = 0.71). Similarly, as anticipated, only a weak linear correlation between deceleration time and IVRT or tau was observed (r = 0.41). The observed in vivo relationship provides insight into the isovolumic mechanism of relaxation and the changing-volume mechanism of early rapid filling via a link of the respective relaxation properties.     

Diastolic ventricular-vascular stiffness and relaxation relation: elucidation of coupling via pressure phase plane-derived indexes

Because systole and diastole are coupled and systolic ventricular-vascular coupling has been characterized, we hypothesize that diastolic ventricular-vascular coupling (DVVC) exists and can be characterized in terms of relaxation and stiffness. To characterize and elucidate DVVC mechanisms, we introduce time derivative of pressure (dP/dt) vs. time-varying pressure [P(t)] (pressure phase plane, PPP)-derived analogs of ventricular and vascular "stiffness" and relaxation parameters. Although volume change (dV) = 0 during isovolumic periods, and time-varying left ventricular (LV) stiffness, typically expressed as change in pressure per unit change in volume (dP/dV), is undefined, our formulation allows determination of a PPP-derived stiffness analog during isovolumic contraction and relaxation. Similarly, an aortic stiffness analog is also derivable from the PPP. LV relaxation was characterized via tau, the time constant of isovolumic relaxation, and vascular (aortic pressure decay) relaxation was characterized in terms of its equivalent (windkessel) exponential decay time constant kappa. The results show that PPP-derived systolic and diastolic ventricular and vascular stiffness are strongly coupled [K(Ao)(+)=1.71(K(LV)(+)) +154, r=0.86; K(Ao)(-)=0.677(K(LV)(-))-5.53, r=0.86]. In support of the DVVC hypothesis, a strong linear correlation between relaxation (rate of pressure decay) indexes kappa and tau (kappa = 9.89tau - 90.3, r = 0.81) was also observed. The correlations observed underscore the role of long-term, steady-state DVVC as a diastolic function determinant. Awareness of the PPP-derived DVVC parameters provides insight into mechanisms and facilitates quantification of arterial stiffening and associated increase in diastolic chamber stiffness. The PPP method provides a tool for quantitative assessment and determination of the functional coupling of the vasculature to diastolic function.     

Effects of acute changes in load and inotropic state on the exponential rate of fiber shortening and other indices of myocardial contractility in the anesthetized intact dog

The effects of an acute increase in preload, afterload, and inotropic state on several indices of left ventricular contractility were studied in 20 anesthetized intact dogs. The behaviour of the exponential rate of fiber shortening (ERFS), a newly described index, which is based on the instantaneous fiber length--time relationship through ejection, was compared with other classical ejection and isovolumic indices of left ventricular contractility. Acute volume overload by dextran 40 infusion produced a significant increase in preload as reflected by a 103% (p less than 0.01) increase in left ventricular end-diastolic pressure and a 121% (p less than 0.001) increase in end-diastolic circumferential wall stress. There was also a smaller but significant increase (p less than 0.05) of heart rate (30%) and of peak systolic circumferential wall stress (24%). None of the left ventricular contractility indices showed any significant change. Acute pressure overload, produced mechanically by an aortic balloon, increased the afterload significantly as reflected by a 33% (p less than 0.05) rise of end-systolic circumferential wall stress and a 43% (p less than 0.001) increase in systemic resistance. Stroke volume decreased significantly by 23% (p less than 0.05). All ejection indices, including ERFS, were significantly diminished by 30-37%; all isovolumic indices showed no significant changes. Positive inotropic intervention was induced by dopamine infusion, which caused a significant 28% (p less than 0.05) increase in cardiac output. End-diastolic and end-systolic circumferential wall stress were significantly diminished. All indices of left ventricular contractility increased significantly and ERFS showed the quantitatively greatest change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac effects of endothelin receptor antagonism in endotoxemic pigs

Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), power(max)/end-diastolic volume (PWR(max)/EDV) and dP/dt(max)/end-diastolic volume (dP/dt(max)/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWR(max)/EDV, and dP/dt(max)/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function.     

Dissociation between myocardial relaxation and diastolic stiffness in the stunned heart: its prevention by ischemic preconditioning

The effects of myocardial stunning and ischemic preconditioning on left-ventricular developed pressure and end-diastolic pressure (diastolic stiffness) as well as on coronary-perfusion pressure were examined in isolated isovolumic rabbit hearts. The isovolumic relaxation was evaluated, and the time constant of pressure decay during the isovolumic period was calculated. Our experimental protocol comprised: 1) myocardial stunning-global ischemia (15 min) followed by reperfusion (30 min); 2) myocardial stunning-global ischemia (20 min) followed by reperfusion (30 min); and 3) ischemic preconditioning — a single cycle of brief global ischemia and reperfusion (5 min each), before a second ischemic period, of 20-min duration. There was no effect upon systolic and diastolic parameters when 15 and 20 minutes of ischemia were evaluated. In both stunned groups the left ventricular developed pressure first recovered to near control values, but then stabilized at only 60% of the control values. Whereas the isovolumic relaxation time constant was increased after 5 min of reperfusion, and return to control values at late reperfusion, the end diastolic pressure remained elevated during the entire period. Values of dP/dV calculated at common pressure levels, were used as a second index of diastolic stiffness. They were increased after stunning, as also was the coronary perfusion pressure. When the heart was preconditioned with a single episode of ischemia, the systolic and diastolic alterations were completely abolished. We thus concluded that diastolic abnormalities incurred by myocardial stunning consist in both an increase in diastolic stiffness and an early impairment of isovolumic relaxation. The increase in stiffness cannot result from incomplete relaxation since these two parameters become temporally dissociated during the reperfusion period.     

Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart

Although the involvement of serotonin in exacerbating vascular abnormalities in ischemic heart disease has been established, its role in mediating changes in cardiac function due to ischemia reperfusion (IR) is poorly understood. The aim of this study was to investigate the effect of a serotonin blocker, sarpogrelate (5-HT2A antagonist), in preventing cardiac injury due to IR. Isolated rat hearts were subjected to 30 min of global ischemia followed by 1 h of reperfusion. Sarpogrelate (50 nM-0.9 microM) was infused 10 min before ischemia as well as during the reperfusion period. The IR-induced changes in left ventricular developed pressure, left ventricular end diastolic pressure, rate of pressure development, and rate of pressure decay were attenuated (P < 0.05) with sarpogrelate treatment. Sarpogrelate also decreased the ultrastructural damage and improved the high energy phosphate level in the IR hearts (P < 0.05). This study provides evidence for the attenuation of IR-induced cardiac injury by 5-HT2A receptor blockade and supports the view that serotonin may contribute to the deleterious effects of IR in the heart.     

Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function

Besides the core structure conserved in all troponin I isoforms, cardiac troponin I (cTnI) has an N-terminal extension that contains phosphorylation sites for protein kinase A under beta-adrenergic regulation. A restricted cleavage of this N-terminal regulatory domain occurs in normal cardiac muscle and is up-regulated during hemodynamic adaptation (Z.-B. Yu, L.-F. Zhang, and J.-P. Jin (2001) J. Biol. Chem. 276, 15753-15760). In the present study, we developed transgenic mice overexpressing the N-terminal truncated cTnI (cTnI-ND) in the heart to examine its biochemical and physiological significance. Ca(2+)-activated actomyosin ATPase activity showed that cTnI-ND myofibrils had lower affinity for Ca(2+) than controls, similar to the effect of isoproterenol treatment. In vivo and isolated working heart experiments revealed that cTnI-ND hearts had a significantly faster rate of relaxation and lower left ventricular end diastolic pressure compared with controls. The higher baseline relaxation rate of cTnI-ND hearts was at a level similar to that of wild type mouse hearts under beta-adrenergic stimulation. The decrease in cardiac output due to lowered preload was significantly smaller for cTnI-ND hearts compared with controls. These findings indicate that removal of the N-terminal extension of cTnI via restricted proteolysis enhances cardiac function by increasing the rate of myocardial relaxation and lowering left ventricular end diastolic pressure to facilitate ventricular filling, thus resulting in better utilization of the Frank-Starling mechanism.     

Dexamethasone blocks sepsis-induced protection of the heart from ischemia reperfusion injury

Previous investigations have shown that sepsis, while causing cardiac dysfunction, can protect the heart from ischemia-reperfusion injury. Sepsis-induced protection may be due to nitric oxide produced by an inducible form of nitric oxide synthase generated in response to cytokines released during sepsis. The glucocorticoid dexamethasone has been shown to inhibit the synthesis of the inducible form of nitric oxide synthase (iNOS). The goals of this study were to determine if dexamethasone would prevent sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In this experiment, rats were made septic by injecting Escherichia coli into the dorsal subcutaneous space. Control rats were injected with sterile saline. At the time of surgery, some of the control and septic animals were injected intraperitoneally with dexamethasone (3 mg/kg). The next day, 24-26 hr after injection of the first dose of E. coli, animals were anesthetized, and hearts were removed and studied in the isovolumic beating-heart preparation. Left ventricular end diastolic pressure was set to 5 mmHg, and left ventricular pressure was measured continuously throughout the protocol. Left ventricular developed pressure (LVDP) was used as an index of LV function. After stabilization, hearts were made globally ischemic for 35 min and then reperfused for 25 min. As has been shown previously, sepsis depressed LVDP but also protected the heart from further depression of LVDP by ischemia and reperfusion. Dexamethasone prevented both sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In addition plasma nitrite/nitrate levels were not different from control levels in the dexamethasone-treated septic rats whereas levels were elevated in the septic animals. The dexamethasone mediated abrogation of sepsis-induced cardiac dysfunction and protection during ischemia-reperfusion injury may be due to suppression of nitric oxide production.     

Stiffness and relaxation components of the exponential and logistic time constants may be used to derive a load-independent index of isovolumic pressure decay

In current practice, empirical parameters such as the monoexponential time constant tau or the logistic model time constant tauL are used to quantitate isovolumic relaxation. Previous work indicates that tau and tauL are load dependent. A load-independent index of isovolumic pressure decline (LIIIVPD) does not exist. In this study, we derive and validate a LIIIVPD. Recently, we have derived and validated a kinematic model of isovolumic pressure decay (IVPD), where IVPD is accurately predicted by the solution to an equation of motion parameterized by stiffness (Ek), relaxation (tauc), and pressure asymptote (Pinfinity) parameters. In this study, we use this kinematic model to predict, derive, and validate the load-independent index MLIIIVPD. We predict that the plot of lumped recoil effects [Ek.(P*max-Pinfinity)] versus resistance effects [tauc.(dP/dtmin)], defined by a set of load-varying IVPD contours, where P*max is maximum pressure and dP/dtmin is the minimum first derivative of pressure, yields a linear relation with a constant (i.e., load independent) slope MLIIIVPD. To validate the load independence, we analyzed an average of 107 IVPD contours in 25 subjects (2,669 beats total) undergoing diagnostic catheterization. For the group as a whole, we found the Ek.(P*max-Pinfinity) versus tauc.(dP/dtmin) relation to be highly linear, with the average slope MLIIIVPD=1.107+/-0.044 and the average r2=0.993+/-0.006. For all subjects, MLIIIVPD was found to be linearly correlated to the subject averaged tau (r2=0.65), tauL(r2=0.50), and dP/dtmin (r2=0.63), as well as to ejection fraction (r2=0.52). We conclude that MLIIIVPD is a LIIIVPD because it is load independent and correlates with conventional IVPD parameters. Further validation of MLIIIVPD in selected pathophysiological settings is warranted.     

Effects of dihydroergotamine on hemodynamic molsidomine actions in anesthetized dogs

In pentobarbital-anesthetized mongrel dogs the intravenous actions of 0.50 mg/kg molsidomine on pulmonary artery and left ventricular (LV) end-diastolic pressures and internal heart dimensions (preload), left ventricular systolic and peripheral blood pressures, and total peripheral resistance (afterload), as well as on heart rate, dP/dt, stroke volume, and cardiac output (heart performance) were studied for 2 h. Hemodynamic molsidomine effects were influenced by increasing amounts of intravenously infused dihydroergotamine solution (DHE, 1-64 micrograms X kg-1 X min-1). Molsidomine decreased preload, stroke volume, and cardiac output for over 2 h but decreased ventricular and peripheral pressures for 45 min. Systemic vascular resistance showed a tendency to decrease while heart rate and LV dP/dtmax were not altered. DHE infusion reversed molsidomine effects on the preload and afterload of the heart. The diminished stroke volume was elevated so that cardiac output also increased. Total peripheral resistance increased while heart rate fell in a dose-dependent fashion. The LV dP/dtmax remained unchanged until the highest dose of 64 micrograms X kg-1 X min-1 DHE elevated the isovolumic myocardial contractility. These experiments indicate that DHE can reverse the intravenous molsidomine effects on hemodynamics. Most likely, this is mediated through peripheral vasoconstriction of venous capacitance vessels, thereby affecting molsidomine's action on postcapillary beds of the circulation.     

Differences in the reaction of rat and guinea pig hearts to ischemia and reperfusion

The response of rat and guinea-pig hearts to ischemia and reperfusion has been studied in identical conditions. Total 15-min ischemia of isolated rat hearts at 36 degrees C induced an almost 3-fold rise in isovolumic left ventricular diastolic pressure as well as a fall in the developed pressure and heart rate. Guinea-pig hearts, in the same conditions, exhibited a more steep fall in heart rate, with no rise in diastolic pressure. With constant heart rate produced by electrical stimulation at 4 Hz, the difference between two groups remained unchanged, while a more rapid fall in developed pressure in guinea-pig hearts coincided with a more profound fall in extracellular pH and almost a 2-fold rise in extracellular K+ activity. Rapid elimination of K+ and H+ at the early stages of reperfusion was followed by fibrillation in the majority of guinea-pig hearts, while no fibrillation was observed in rat hearts.     

Comparison of Doppler flow Tei-indexes with pulmonary artery thermodilution measurement of cardiac output in an experimental porcine model

The objective of our study was to compare Doppler echocardiography imaging with pulmonary artery thermodilution measurement during mechanical ventilation. Total 78 piglets (6 weeks old, average weight 24 kg, under general anesthesia) were divided into 4 groups under different cardiac loading conditions (at rest, with increased left ventricular afterload, with increased right ventricular preload, and with increased afterload of both heart ventricles). At 60 and 120 min the animals were examined by echocardiography and simultaneously pulmonary artery thermodilution was used to measure cardiac output. Tei-indexes data were compared with invasively monitored hemodynamic data and cardiac output values together with calculated vascular resistance indices. A total of 224 parallel measurements were obtained. Correlation was found between values of right Tei-index of myocardial performance and changes in right ventricular preload (p<0.05) and afterload (p<0.01). Significant correlation was also found between left index values and changes of left ventricular preload (p<0.001), afterload (p<0.001), stroke volume (p<0.01), and cardiac output (p<0.01). In conclusion, echocardiographic examination and determination of the global performance selectively for the right and left ventricle can be recommended as a suitable non-invasive supplement to the whole set of methods used for monitoring of circulation and cardiac performance.     

Stress–strain behavior of mitral valve leaflets in the beating ovine heart

Excised anterior mitral leaflets exhibit anisotropic, non-linear material behavior with pre-transitional stiffness ranging from 0.06 to 0.09 N/mm² and post-transitional stiffness from 2 to 9 N/mm². We used inverse finite element (FE) analysis to test, for the first time, whether the anterior mitral leaflet (AML), in vivo, exhibits similar non-linear behavior during isovolumic relaxation (IVR). Miniature radiopaque markers were sewn to the mitral annulus, AML, and papillary muscles in 8 sheep. Four-dimensional marker coordinates were obtained using biplane videofluoroscopic imaging during three consecutive cardiac cycles. A FE model of the AML was developed using marker coordinates at the end of isovolumic relaxation (when pressure difference across the valve is approximately zero), as the reference state. AML displacements were simulated during IVR using measured left ventricular and atrial pressures. AML elastic moduli in the radial and circumferential directions were obtained for each heartbeat by inverse FEA, minimizing the difference between simulated and measured displacements. Stress–strain curves for each beat were obtained from the FE model at incrementally increasing transmitral pressure intervals during IVR. Linear regression of 24 individual stress–strain curves (8 hearts, 3 beats each) yielded a mean (±SD) linear correlation coefficient (r²) of 0.994±0.003 for the circumferential direction and 0.995±0.003 for the radial direction. Thus, unlike isolated leaflets, the AML, in vivo, operates linearly over a physiologic range of pressures in the closed mitral valve.     

Effect of stimulation of sublobule IX-b of the cerebellar vermis on cardiac function

Activation of sublobule IX-b of the cerebellar vermis evokes hypotension, bradycardia and decrease of the phrenic nerve activity in the anesthetized animal. Cardiac performance during the isovolumic phases of systole and relaxation can be evaluated by dP/dtmax, Vpm, dP/dt/DP40 and tau, respectively. In the present study, we evaluated the changes on cardiac function evoked by the stimulation of sublobule IX-b. New Zealand white rabbits were anesthetized, paralyzed and artificially ventilated. A posterior craniotomy was made to reveal and stimulate the cerebellar uvula (4 s train; 50 Hz; 1 ms; 20 microA). The femoral artery and veins were cannulated and a Swan-Ganz catheter was advanced in the upper abdominal aorta to control afterload when inflating the balloon. The left ventricle was catheterized with a Millar catheter. Blood pressure, heart rate, left ventricular pressure were monitored. Results showed a significant decrease on sublobule IX-b stimulation of all the indices of systolic function and an increase of tau indicating a decrease in the speed of the relaxation. These data provide the first evidence of the influence of sublobule IX-b on cardiac function. They may contribute to the understanding of the origin the cardiovascular changes that were observed in two patients with vermian and paravermian hemorrhage.