Sándor J. Kovács

Transmitral pressure-flow velocity relation. Importance of regional pressure gradients in the left ventricle during diastole.

Effects of regional diastolic pressure differences within the left ventricle on the measured transmitral pressure-flow relation were determined by simultaneous micromanometric left atrial (LAP) and left ventricular pressure (LVP) measurements, and Doppler echocardiograms in 11 anesthetized, closed-chest dogs. Intraventricular pressure recordings at sites that were 2, 4, and 6 cm from the apex were obtained. Profound differences between these sites were noted in the transmitral pressure relation during early (preatrial) diastolic filling. In measurements from apex to base, minimum LVP increased (1.6 +/- 0.7 to 3.1 +/- 0.8 mm Hg, mean +/- SD); the time interval between the first crossover of transmitral pressures and minimum LVP increased (31 +/- 3 to 50 +/- 17 msec); the slope of the rapid-filling LVP wave decreased (74 +/- 13 to 26 +/- 5 mm Hg/sec); the maximum forward (i.e., LAP greater than LVP) transmitral pressure gradient decreased (3.6 +/- 1.3 to 2.1 +/- 0.7 mm Hg); the time interval between the first and second points of transmitral pressure crossover increased (71 +/- 9 to 96 +/- 13 msec); and the area of reversed (i.e., LVP greater than LAP) gradient between the second and third points of transmitral pressure crossover decreased (101 +/- 41 to 40 +/- 33 mm Hg.msec). During atrial contraction, significant regional ventricular apex-to-base gradients were also noted. The slope of the LV A wave decreased (26 +/- 10 to 16 +/- 4 mm Hg/sec); LV end-diastolic pressure decreased (8.1 +/- 2.0 to 7.4 +/- 2.0 mm Hg), and the upstroke of the LV A wave near the base was recorded earlier than near the apex. All differences were significant at the 0.05 level. Simultaneous transmitral Doppler velocity profiles and transmitral pressures were measured at the 4-cm intraventricular site. The average interval between the first and second points of pressure crossover and between the onset of early rapid filling and maximum E-wave velocity were statistically similar (81 +/- 13 vs. 85 +/- 12 msec; NS); and the average area of the forward transmitral pressure gradient associated with acceleration of early flow was significantly greater than the area of reversed gradient associated with deceleration of early flow (133 +/- 36 vs. 80 +/- 46 msec.mm Hg; p less than 0.025).(ABSTRACT TRUNCATED AT 400 WORDS)

Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia.

A consistent pattern of intraventricular regional pressure gradients exists under physiological conditions during the rapid filling phase of diastole in the normal dog left ventricle. We hypothesized that this pressure gradient pattern is caused, in part, by early diastolic recoil of the left ventricular walls in conjunction with release of elastic potential energy stored during systole, generating suction and thus contributing to diastolic filling. If so, any condition that interferes with normal regional systolic function might be expected to modify the pattern of the normal early diastolic intraventricular pressure gradients. Accordingly, the present study was designed to determine whether acutely induced regional systolic left ventricular mechanical dysfunction is accompanied by changes in the pattern of the early diastolic intraventricular pressure gradients. Acute myocardial ischemia was induced by balloon occlusion of the left anterior descending coronary artery (LAD) in nine anesthetized closed-chest dogs. The maximum early diastolic intraventricular pressure gradient (MIVP) was measured between the mid-left ventricle and apex with a dual-sensor micromanometer (3-cm spacing between the sensors) before and 20 minutes after LAD occlusion. Ejection fraction (EF) and number of dyskinetic chords (DChords) were measured from left ventricular contrast ventriculograms. Twenty minutes after LAD occlusion, the nine dogs evidenced significant changes in EF (56 +/- 10% to 37 +/- 8%), DChords (0 +/- 0 to 17 +/- 16 chords), left ventricular minimum pressure (-1.7 +/- 0.5 to 0.0 +/- 1.5 mm Hg), left ventricular end-diastolic pressure (4.2 +/- 1.2 to 5.9 +/- 2.2 mm Hg), and heart rate (90 +/- 17 to 103 +/- 18 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)

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. Kovács 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 Newtons 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.

Low-Sodium DASH Diet Improves Diastolic Function and Ventricular–Arterial Coupling in Hypertensive Heart Failure With Preserved Ejection Fraction

Background—Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular–arterial coupling in hypertensive HFPEF. Methods and Results—Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular–arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre–post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155±35 to 138±30 and 130±16 to 123±18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116±18 to 111±16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3±5.3 to 22.7±8.1 g/s; P=0.03; k=252±115 to 170±37 g/s2; P=0.03), Ea decreased (2.0±0.4 to 1.7±0.4 mm Hg/mL; P=0.007), and ventricular–arterial coupling improved (Ees:Ea=1.5±0.3 to 1.7±0.4; P=0.04). Conclusions—In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular–arterial coupling. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640.

The Role of Left Atrial Function in Diastolic Heart Failure

New heart failure affects 500 000 Americans yearly. Nearly 50% of these patients have a normal left ventricular ejection fraction (LVEF) or so-called diastolic heart failure (DHF). New onset symptomatic DHF is a lethal disease with a 5-year mortality that approaches 50%.1 Echo-Doppler techniques use LV filling patterns and tissue Doppler imaging of the mitral annulus to help identify and classify the degree of LV diastolic dysfunction, but work best in symptomatic patients with advanced disease.2 Therefore, the diagnosis of early diastolic dysfunction, when asymptomatic and most treatable, remains problematic. A detailed causality-based, mechanistic understanding of what causes DHF, and how to most easily detect it, remains one of the most important unsolved problems in cardiovascular physiology and clinical cardiology.3 Article see p 10 Segmental LV deformation analysis for calculating contractile parameters such as strain and strain rate is now possible using noninvasive echo-Doppler techniques.2 It has been reported that LA systolic and diastolic function can also be assessed using these Doppler strain techniques.4–6 Although LA enlargement increases with the severity of diastolic dysfunction,7 the ability of LA volume measurements to discriminate asymptomatic LV diastolic dysfunction from early DHF heart failure has not been possible. However, the concept that an alteration in LA function or stiffness may indicate this change is appealing. To that end in this issue Kurt et al8 seek to advance our knowledge of additional clinical, anatomic and physiological correlates of DHF, with a particular focus on LA “diastolic function” and LA stiffness. They report clinical and echo-Doppler data on 64 subjects undergoing right heart catheterization with simultaneous echocardiography, and a control group of 27 control subjects. The 64 subjects included 25 with systolic heart failure (LVEF<50%), 20 with DHF and normal LVEF and 19 with LV hypertrophy from hypertension, …

Prognostic value of diastolic filling parameters derived using a novel image processing technique in patients ≥70 years of age with congestive heart failure

Conventional echocardiographic characterization of diastolic function requires manual analysis of Doppler E-and A-wave amplitudes, deceleration times, isovolumic relaxation times, and pulmonary venous flow patterns. Mathematic modeling of the suction pump activity of the heart permits characterization of diastolic function through model-based image processing, which relies solely on transmitral Doppler images. This automated method uniquely specifies the entire E-wave contour using 3 parameters (x(o), k, and c) that determine E-wave amplitude, width, and rate of decay. Moreover, the index beta = c2 - 4k, reflecting the balance between chamber viscosity and stiffness/recoil, represents a novel parameter for characterizing diastolic function. We analyzed Doppler E waves from 39 patients (mean age 79 years, 61% women, mean ejection fraction 47%) using the model-based image processing technique. A value of beta <-900 was selected as indicative of severe diastolic dysfunction. Of 17 subjects with beta <-900, 8 (47%) were no longer alive at 1 year. Of 22 subjects with beta >-900, all were alive (p = 0.001). The index beta, dichotomized at <-900, had a predictive accuracy of 0.769 (30 of 39), a negative predictive value of 1.0 (22 of 22 alive), and a positive predictive value of 0.471 (8 of 17 deceased) for 1-year vital status. Of 14 subjects with deceleration time < or =160 ms, 5 (36%) were deceased at 1 year, whereas for deceleration time >160 ms, 22 of 25 patients were alive (p = NS). Of 16 subjects with ejection fraction <45%, 6 (38%) were deceased at 1 year. Of 23 subjects with ejection fraction >45%, 21 were alive at 1 year (p = 0.074). On multivariate analysis, beta dichotomized at -900 was the strongest independent predictor of 1-year mortality. We conclude that evaluation of diastolic function using model-based image processing provides valuable prognostic information in elderly patients with heart failure.

Can Transmitral Doppler E-Waves Differentiate Hypertensive Hearts From Normal?

Physiological models of transmitral flow predict E-wave contour alteration in response to variation of model parameters (stiffness, relaxation, mass) reflecting the physiology of hypertension. Accordingly, analysis of only the E-wave (rather than the E-to-A ratio) should be able to differentiate between hypertensive subjects and control subjects. Conventional versus model-based image processing methods have never been compared in their ability to differentiate E-waves of hypertensive subjects with respect to age-matched control subjects. Digitally acquired transmitral Doppler flow images were analyzed by an automated model-based image processing method. Model-derived indexes were compared with conventional E-wave indexes in 22 subjects: 11 with hypertension and echocardiographically verified ventricular hypertrophy and 11 age-matched nonhypertensive control subjects. Conventional E-wave indexes included peak E, E, and acceleration and deceleration times. Model-based image processing-derived indexes included acceleration and deceleration times, potential energy index, and damping and kinematic constants. Intergroup comparison yielded lower probability values for model-based compared with conventional indexes. In the subjects studied, Doppler E-wave images analyzed by this automated method (which eliminates the need for hand-digitizing contours or the manual placement of cursors) demonstrate diastolic function alteration secondary to hypertension made discernible by model-based indexes. The method uses the entire E-wave contour, quantitatively differentiates between hypertensive subjects and control subjects, and has potential for automated noninvasive diastolic function evaluation in large patient populations, such as hypertension and other transmitral flow velocity-altering pathophysiological states.

Relationship of the Third Heart Sound to Transmitral Flow Velocity Deceleration

BACKGROUND The third heart sound (S3) occurs shortly after the early (E-wave) peak of the transmitral diastolic Doppler velocity profile (DVP). It is thought to be due to cardiohemic vibrations powered by rapid deceleration of transmitral blood flow. Although the presence, timing, and clinical correlates of the S3 have been extensively characterized, derivation and validation of a causal, mathematical relation between transmitral flow velocity and the S3 are lacking. METHODS AND RESULTS To characterize the kinematics and physiological mechanisms of S3 production, we modeled the cardiohemic system as a forced, damped, nonlinear harmonic oscillator. The forcing term used a closed-form mathematical expression for the deceleration portion of the DVP. We tested the hypothesis that our models predictions for amplitude, timing, and frequency of S3 accurately predict the transthoracic phonocardiogram, using the simultaneously recorded transmitral Doppler E wave as input, in three subject groups: those with audible pathological S3, those with audible physiological S3, and those with inaudible S3. CONCLUSIONS We found excellent agreement between model prediction and the observed data for all three subject groups. We conclude that, in the presence of a normal mitral valve, the kinematics of filling requires that all hearts have oscillations of the cardiohemic system during E-wave deceleration. However, the oscillations may not have high enough amplitude or frequency to be heard as an S3 unless there is sufficiently rapid fluid deceleration (of the Doppler E-wave contour) with sufficient cardiohemic coupling.

Physical determinants of left ventricular isovolumic pressure decline: model prediction with in vivo validation

The rapid decline in pressure during isovolumic relaxation (IVR) is traditionally fit algebraically via two empiric indexes: tau, the time constant of IVR, or tau(L), a logistic time constant. Although these indexes are used for in vivo diastolic function characterization of the same physiological process, their characterization of IVR in the pressure phase plane is strikingly different, and no smooth and continuous transformation between them exists. To avoid the parametric discontinuity between tau and tau(L) and more fully characterize isovolumic relaxation in mechanistic terms, we modeled ventricular IVR kinematically, employing a traditional, lumped relaxation (resistive) and a novel elastic parameter. The model predicts IVR pressure as a function of time as the solution of d(2)P/dt(2) + (1/micro)dP/dt + E(k)P = 0, where micro (ms) is a relaxation rate (resistance) similar to tau or tau(L) and E(k) (1/s(2)) is an elastic (stiffness) parameter (per unit mass). Validation involved analysis of 310 beats (10 consecutive beats for 31 subjects). This model fit the IVR data as well as or better than tau or tau(L) in all cases (average root mean squared error for dP/dt vs. t: 29 mmHg/s for model and 35 and 65 mmHg/s for tau and tau(L), respectively). The solution naturally encompasses tau and tau(L) as parametric limits, and good correlation between tau and 1/microE(k) (tau = 1.15/microE(k) - 11.85; r(2) = 0.96) indicates that isovolumic pressure decline is determined jointly by elastic (E(k)) and resistive (1/mu) parameters. We conclude that pressure decline during IVR is incompletely characterized by resistance (i.e., tau and tau(L)) alone but is determined jointly by elastic (E(k)) and resistive (1/micro) mechanisms.

The Diastatic Pressure-Volume Relationship Is Not the Same as the End-Diastolic Pressure-Volume Relationship

The end-diastolic pressure-volume (P-V) relationship (EDPVR) is routinely used to determine the passive left ventricular (LV) stiffness, although the diastatic P-V relationship (D-PVR) has also been measured. Based on the physiological difference between diastasis (the LV and atrium are relaxed and static) and end diastole (LV volume increased by atrial systole and the atrium is contracted), we hypothesized that, although both D-PVR and EDPVR include LV chamber stiffness information, they are two different, distinguishable P-V relations. Cardiac catheterization determined LV pressures, and conductance volumes in 31 subjects were analyzed. Physiological, beat-to-beat variation of the diastatic and end-diastolic P-V points were fit by linear and exponential functions to generate the D-PVR and EDPVR. The extrapolated exponential D-PVR underestimated LVEDP in 82% of the heart beats (P < 0.001). The extrapolated EDPVR overestimated pressure at diastasis in 84% of the heart beats (P < 0.001). If each subjects diastatic and end-diastolic P-V data were combined to form a continuous data set to be fit by one exponential relation, the goodness of fit was always worse than if the diastatic and end-diastolic data were grouped separately and fit by two distinct exponential relations. Diastatic chamber stiffness was less than EDPVR stiffness (defined by the slope of P-V relation) for all 31 subjects (0.16 +/- 0.11 vs. 0.24 +/- 0.15 mmHg/ml, P < 0.001). We conclude that the D-PVR and EDPVR are distinguishable. Because it is not coupled to a contracted atrium, the D-PVR conveys passive LV stiffness better than the EDPVR. Additional studies that fully elucidate the physiology and biology of diastasis in health and disease are in progress.