Skip Navigation

Cardiovascular Research 1997 35(2):206-216; doi:10.1016/S0008-6363(97)00118-1
© 1997 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Courtois, M.
Right arrow Articles by Ludbrook, P. A
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Courtois, M.
Right arrow Articles by Ludbrook, P. A
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1997, European Society of Cardiology

Postextrasystolic left ventricular isovolumic pressure decay is not monoexponential

Michael Courtois*, Benico Barzilai, Andrew F Hall and Philip A Ludbrook

Cardiovascular Division, Washington University School of Medicine, 660 S. Euclid, Box 8086, St. Louis MO 63110, USA

* Corresponding author. Tel.: +1 (314) 362-3794; fax: +1 (314) 362-9097; e-mail: mcourtoi@im.wustl.edu

Received 16 July 1996; accepted 15 April 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The relationship between the left ventricular (LV) relaxation time constant and early diastolic filling is not fully defined. This study provides additional evidence that LV isovolumic pressure fall in the normal intact heart in response to certain interventions is not adequately described by a model of monoexponential decay and that its relationship to filling is complex. Methods and results: To gain further insight into the relationship between LV relaxation and early rapid filling we measured LV isovolumic relaxation rate, peak early filling velocity (E), LV volumes, and transmitral pressures at baseline and in the first postextrasystolic beat after a short-coupled extrasystole in 9 anesthetized dogs. Postextrasystolic isovolumic relaxation rate was slowed as measured by 3 commonly used time constants, while E was increased 32%. LV contractility and peak pressure were also increased, while LV end-systolic volume was decreased. LV minimum pressure was deceased, while the early diastolic transmitral pressure gradient was increased. Although all relaxation time constants measured over the entire isovolumic relaxation phase indicated slowed relaxation, direct measurement of isovolumic relaxation time indicated no change in relaxation rate. Calculation of the time constants and direct measurement of isovolumic relaxation time during early isovolumic pressure decay indicated slowed postextrasystolic pressure decay rate compared with baseline, while calculation of time constants and direct measurement of isovolumic relaxation time during late isovolumic relaxation indicated augmented postextrasystolic pressure decay rate versus baseline. Conclusions: This non-exponential behavior of LV isovolumic pressure decay in postextrasystolic beats after short-coupled extrasystoles provides further evidence that the relationship that exists between ventricular relaxation and early filling is not simple. The results are interpreted in terms of current theoretical formulations that attribute control of myocardial relaxation to the interaction between inactivation-dependent and load-dependent mechanisms.

KEYWORDS Myocardial relaxation; Diastole; Cardiac mechanics; Postextrasystolic potentiation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The time course of myocardial relaxation, examined under various states of inotropy and loading, has been shown to be highly complex [1–3]. Brutsaert and Sys [4]have presented evidence obtained from isolated muscle indicating that in some situations the timing and subsequent rate of muscle relaxation can even vary in opposite directions. Furthermore, these authors have asserted that because both inactivation and loading conditions influence isovolumic pressure fall in the intact heart, during "... isovolumic pressure decline, the rate of part of this phase may be altered substantially even when the rate of the remaining part or peak rate is either unchanged or affected in an opposite sense" (p. 1292).

Several groups of investigators have presented evidence in the intact heart that subphases of the course of left ventricular (LV) pressure fall can be differentially altered by changes in loading, contractile state, non-uniform relaxation, and ischemia [5–8]. This evidence represents an important step toward understanding the manner in which multiple factors may interact to affect the time course of LV relaxation. Continued research in this area may lead eventually to a more complete delineation of certain subtle aspects of cardiac diastolic function and dysfunction, and help define the circumstances under which the assumption of monoexponential isovolumic pressure decay is inappropriate.

In this study we have further scrutinized the relationship between LV pressure fall and early rapid filling by examining the effects of postextrasystolic potentiation on indexes of relaxation and filling in the intact heart. Because postextrasystolic potentiation is a cardiac event that produces substantial changes in both the systolic function and loading conditions of the left ventricle, changes that are known to alter the time course of LV relaxation, examination of this phenomenon could provide additional insight into the relationship that exists between cardiac relaxation and filling. In this report we demonstrate that measurements obtained in the normal intact dog heart after induction of short-coupled extrasystoles provide additional strong evidence that the assumption of monoexponential LV isovolumic pressure fall in response to certain interventions can lead to erroneous conclusions regarding the relationship between LV relaxation and early rapid filling. The results are then interpreted with reference to current theoretical formulations that attribute control of myocardial relaxation to the interaction between mechanisms related to inactivation dependence, load dependence, and non-uniformity.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Nine mongrel dogs of either gender weighing 26–32 kg (28±0.8) were sedated with morphine (0.5 mg/kg s.c.) 30 min prior to induction of general anesthesia with sodium pentothal (12.5 mg/kg i.v.), and {alpha}-chloralose (80 mg/kg i.v.). Each dog was intubated and ventilated with room air with use of a Harvard respirator. The left common carotid artery, the right femoral artery, the right jugular vein, and the right and left femoral veins were isolated and a valved sheath (USCI; Hemaquet 8F) was placed in each. A bolus injection of heparin sodium (4000 USP units) was administered intravenously. A Swan-Ganz thermodilution catheter (Model 93A-131-7F; American Edwards Laboratories) was directed under fluoroscopy from the left femoral vein to the inferior vena cava. A micromanometer-angiographic catheter (Model 484A-8F, Millar Instruments) was directed from the right femoral artery to the aortic arch, and a second similar micromanometer catheter was directed from the left carotid artery into the LV apex with the transducer positioned as close as possible to the LV apex without inducing ectopy. A third micromanometer catheter was positioned in the left atrium by puncture of the interatrial septum using a Mullins transseptal catheter introducer set (8F, USCI) and a Brockenbrough needle (18 gauge, USCI) via the right femoral vein as described previously [9]. To induce premature ventricular contractions a bipolar pacing catheter (6F, USCI) was directed from the right jugular vein into the right ventricular apex, and extrasystolic contraction was induced with use of a programmed stimulator with electrical stimuli of twice diastolic threshold (<1 mA). Because the contractility of the postextrasystolic beat is maximal at short coupling intervals, the extrasystolic stimulus was delivered at an interval approximately 20 ms greater than refractory period.

In order to record LV pressures referenced solely to atmospheric pressure rather than to an external fluid-filled transducer signal, which is highly dependent on the height of the external transducer relative to the height of the heart, the LV micromanometers were placed in a dry graduated cylinder that was immersed in a water bath warmed between 36 and 38°C, corresponding to the temperature of the animal. Because this position could be most easily standardized in each animal, the LV apical pressure signal was selected as the ‘standard’, and the left atrial high gain pressure signal was aligned with it during diastasis (Fig. 1). In the presence of rapid heart rates, alignment of pressures was accomplished during the long diastatic period occurring after premature ventricular contractions that produced a compensatory pause. At the conclusion of the experiment the position of the zero baseline of the LV apical transducer was confirmed by replacing the micromanometer in the graduated cylinder. In no case did the signal drift >1.0 mmHg from the original zero baseline.


Figure 1
View larger version (38K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Representative record of simultaneous left atrial, left ventricular, and aortic micromanometer pressure signals recorded in a representative dog at baseline and after a postextrasystolic beat. Scaling for high gain left atrial and left ventricular pressure signals in mmHg is on the left, scaling for low gain aortic pressure signal in mmHg is on the right. AOP = aortic pressure; ECG = electrocardiogram; LAP = left atrial pressure; LVP = left ventricular pressure; LVPmin = left ventricular minimum pressure; X1 = first crossover of LA and LV pressures (LAP at the moment of mitral valve opening). The increase in the early diastolic transmitral pressure gradient (X1–LVmin) from approximately 4.6 to 6.5 mmHg in the postextrasystolic beat is primarily the result of a drop in LV minimum pressure from –2.6 mmHg at baseline to –4.3 mmHg in postextrasystolic beat. This drop in LV minimum pressure occurred despite an increase in the index of isovolumic relaxation {tau}1/2 from 21.6 to 24.4 ms. LA pressure at mitral valve opening in the postextrasystolic beat (2.2 mmHg) is essentially unchanged from baseline (2.0 mmHg).

 
A low-gain pressure signal from the aortic micromanometer (100 mmHg = 10.0 cm), and the two high-gain pressure signals from the LA and LV catheters (20 mmHg = 15 cm) were transmitted to a photographic recorder (Honeywell Visicorder, model 1508B). The LV pressure signal was also transmitted to a multichannel high-fidelity magnetic tape system (Model 3968A, Hewlett-Packard), and to a heat-sensitive recorder attached to the ultrasound imaging system. This allowed for precise alignment of the high-gain transmitral pressures with the corresponding Doppler time–velocity profiles (Fig. 2). Transmitral Doppler recordings were made with a transesophageal two-dimensional phased-array echocardiographic 5-MHz transducer with pulsed Doppler capabilities (Model 77020A Ultrasound System, Hewlett-Packard). Pressure and Doppler recordings were made at a chart speed of 100 mm/s. The Doppler sample volume was placed at the level of the mitral annulus. The 4-chamber transesophageal view allows the echo beam to be aligned easily with mitral inflow so that Doppler insonation angle is minimized. Left ventriculograms were recorded at 30 frames/s in the left lateral projection following the acquisition of hemodynamic and transmitral flow velocity data; 22 ml of non-ionic contrast medium (Omnipaque 350; Winthrop) was injected by a power injector through the LV micromanometer-angiographic pigtail catheter at a rate of 12 cc/s. Induction of the short-coupled extrasystole was timed so that at least one baseline cardiac cycle was filmed in which the LV chamber was adequately opacified with contrast. Core body temperature was maintained with use of a circulating water (38°C) heating pad. In no case did the temperature drop below 36.0°C as measured by the Swan-Ganz catheter positioned in the inferior vena cava. Arterial blood gases were assessed periodically, and ventilator rate and volume adjusted accordingly.


Figure 2
View larger version (38K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Representative record of simultaneous micromanometer left ventricular pressure signal and transmitral Doppler time–velocity profile recorded from a transesophageal view at baseline and after a postextrasystolic beat. E = peak early diastolic rapid filling wave; ECG = electrocardiogram; LVP = left ventricular pressure. Peak early diastolic filling velocity was increased to 73 cm/s in the postextrasystolic beat from a baseline value of 62 cm/s. This increase in early diastolic filling velocity occurred despite an increase in the index of isovolumic relaxation {tau}1/2 from 21.3 to 24.2 ms.

 
2.1 Measurements derived from the high-gain LA and LV pressure signal recording, the transmitral time–velocity Doppler profile, and the LV cineangiogram
As shown in Fig. 1, high-gain LA and LV pressure signals were recorded simultaneously with the transmitral Doppler time–velocity profile. LA pressure at the moment of mitral valve opening (X1), and LV minimum early diastolic pressure (LVPmin) were measured in the normal sinus beat just prior to the normal sinus beat off which the short-coupled extrasystole was triggered, and in the first postextrasystolic beat. Peak early diastolic filling velocity (E) was measured from the Doppler time–velocity profiles recorded in these same beats (Fig. 2). LV end-systolic and end-diastolic volumes were calculated from the cineangiograms recorded just after completion of the simultaneously measured hemodynamic–flow velocity recordings. LV volumes were calculated using standard methods and formulas [10].

All hemodynamic and Doppler flow velocity measurements, and LV cineangiograms were recorded during a period of brief apnea with the animal in the supine position. Three to 5 simultaneous hemodynamic–flow velocity recordings during induction of short-coupled extrasystoles were obtained from each animal and the data were averaged.

2.2 Isovolumic relaxation index calculation
In this study 3 commonly used indexes of the rate of LV isovolumic pressure fall were employed to assess myocardial relaxation over a matched pressure range extracted from the entire isovolumic relaxation phases of normal sinus beats at baseline and in the first postextrasystolic beat after short-coupled extrasystoles. These 3 indexes are T, {tau}, and {tau}1/2 (Fig. 3). In addition, the indices {tau} and {tau}1/2 were both used to assess relaxation at baseline and after postextrasystolic contraction over matched early and late isovolumic pressure decay segments (Fig. 3). Because no strong basis currently exists for demarcating subphases of isovolumic relaxation, any division would necessarily be arbitrary. Visual comparison of individual baseline and postextrasystolic isovolumic pressure decay raw data curves from the 9 dogs indicated to us that postextrasystolic isovolumic pressure decay generally lagged behind baseline relaxation for approximately the first two thirds of pressure decay. After that point postextrasystolic pressure decay rate appeared to surpass that of the baseline beat (Fig. 4). On the basis of this observation we chose to apply the indexes of isovolumic relaxation to the first two-thirds and last one-third of matched pressure decay separately. Temporally, this division split the isovolumic pressure decay phases of these 9 animals roughly in half (30±4 versus 34±4 ms). Interestingly, the point of division of the isovolumic relaxation interval that we used in this study corresponds generally to that employed by other investigators [8]. Finally, direct measures of isovolumic relaxation time (IVRT) were obtained for the matched pressure intervals obtained from the entire isovolumic relaxation phases, and for the matched early and late isovolumic pressure decay subphases (Fig. 3).


Figure 3
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Four indexes were calculated for the entirety of the matched isovolumic relaxation pressure decay intervals for both the baseline and postextrasystolic beats: TIVRT, T, {tau}, and {tau}1/2. Three indexes were calculated for the first two-thirds of the matched isovolumic relaxation pressure decay intervals for the baseline and postextrasystolic beats: EIVRT, {tau}1, {tau}11/2. Three indexes were calculated for the last one-third of the matched isovolumic relaxation pressure decay intervals for the baseline and postextrasystolic beats: LIVRT, {tau}2, {tau}21/2. EIVRT = early isovolumic relaxation time; LIVRT = late isovolumic relaxation time; TIVRT = total isovolumic relaxation time; T, {tau}, {tau}1/2 = time constants of isovolumic relaxation computed by various methods (see text).

 

Figure 4
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Plot of matched isovolumic pressure from baseline and postextrasystolic beats from a representative animal. Close visual examination of the matched raw data curves of the 9 animals indicated that postextrasystolic isovolumic pressure decay generally lagged behind that of baseline relaxation for approximately the first two-thirds of the pressure interval. After that, postextrasystolic pressure decay rate appeared to surpass that of the baseline beat. On the basis of this empirical observation we chose to apply separately the indexes of isovolumic relaxation to the first two-thirds and last one-third of the matched pressure intervals.

 
The index {tau}, as first proposed by Weiss et al. [11], is based on the assumption that left ventricular pressure during the isovolumic relaxation period can be accurately represented by a monoexponential function that decays to a zero asymptote:


Formula 1

(1)
where P(t)= left ventricular pressure at time t, a = left ventricular pressure at t = 0, b = the variable defining the rate of pressure decay, and e = the base of the natural logarithm. These authors defined the time constant {tau}=–1/b, which quantifies the time needed for the pressure at t = 0 (a) to decay to 1/e of its value. Thus, for LV pressure at t = 0 of 70 mmHg and b = 0.015, {tau} represents the time needed for LV pressure to fall from 70 to 25.75 mmHg (70x(1/2.718)).

The second algorithm used in this study to index isovolumic pressure fall is based on the model of exponential decay with a variable asymptote originally proposed by Thompson et al. [12]:


Formula 2

(2)
where P(t)= left ventricular pressure at time t, a = left ventricular pressure at t = 0 with respect to the variable asymptote, c = the value of the asymptote at t = infinity, b = the variable defining the rate of pressure decay, and e = the base of the natural logarithm. These authors defined the time constant T = –1/b, which quantifies the time needed for the pressure at t = 0 to decay to a value 1/e of the pressure range between left ventricular pressure at t = 0 and the asymptote, above the asymptotic value. For LV pressure at t = 0 of 70 mmHg, b = 0.015, and c = –15 mmHg, T represents the time needed for LV pressure to fall from 70 to 16.27 mmHg ((85x(1/2.718))–15). Thus, for a given set of data, when c is negative, the value of T will generally exceed that of {tau}.

The third isovolumic relaxation index, {tau}1/2, is one proposed by Mirsky [13], also based on Eq. (2), where {tau}1/2 is defined as the time required for the pressure at t = 0 to decline by 50%. This index has the advantage of being based on a model which provides statistically superior fits to the observed data, its calculation is not tied to the pressure asymptote, and it has the added advantage of yielding a value that, except in rare cases, occurs within the isovolumic relaxation period. For LV pressure at t = 0 of 70 mmHg, b = 0.015, and c = –15 mmHg, {tau}1/2 is determined by solving the equation for the time required for LV pressure to fall from 70 to 35 mmHg (70x0.5). Thus, for a given data set, the value of {tau}1/2 will be less than that of {tau}.

2.3 Calculation of matched isovolumic pressure intervals
The analog LV pressure data recorded on the FM tape system were transferred off-line into a computer (Macintosh IIvx, Apple Computer, Inc.) and digitized at a 1 ms sampling rate. A waveform analysis program determined peak LV pressure, and peak positive (+dP/dt) and negative (–dP/dt) rate of change of LV pressure, and LV end-diastolic pressure. LV isovolumic relaxation was assessed with use of the least-squares method using pressure points digitized every 1 ms. Initially, all 3 indices (T, {tau}, and {tau}1/2) were applied to matched isovolumic relaxation pressure intervals in the normal sinus beat just prior to the normal sinus beat off which the short-coupled extrasystole was triggered, and in the isovolumic relaxation period of the first postextrasystolic beat (Fig. 3). The matched isovolumic relaxation pressure decay intervals were determined as follows: first, the pressure limits of the isovolumic phases were calculated for the baseline and postextrasystolic beats as beginning at peak –dP/dt, and ending at LV end-diastolic pressure (LVEDP). Previous studies in our laboratory [14], as well as the present study, indicate no significant difference between LVEDP and X1 in normal dogs. Once the pressure limits for the isovolumic relaxation phases of the baseline and postextrasystolic beats were established, they were compared and their common interval was determined. For example, as shown in Fig. 3, if in the baseline beat peak –dP/dt occurred at 86 mmHg and LVEDP was 5 mmHg, and in the postextrasystolic beat –dP/dt occurred at 93 mmHg and LVEDP was also 5 mmHg, the common isovolumic pressure interval analyzed for the two beats was from 86 to 5 mmHg. Early and late isovolumic relaxation subphases were then determined from this common interval. Early relaxation phase was defined as the first two-thirds of the common interval (86 to 32 mmHg in the above example), late relaxation phase as the last one-third of the interval (32 to 5 mmHg in the example).

2.4 Isovolumic relaxation time
Isovolumic relaxation time (IVRT) was computed directly in the baseline and postextrasystolic beats as the time in milliseconds needed for isovolumic pressure to decay over the total range of the matched isovolumic pressure decay interval (TIVRT), and over the truncated ranges of the early (EIVRT) and late (LIVRT) relaxation subphases (Fig. 2).

Significant differences between the baseline and postextrasystolic data were set at the P<0.05 level using the Student's t-test for paired data.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Heart rate and coupling interval
Baseline heart rate for the 9 dogs was 78±13 beats/min. Coupling intervals for the extrasystoles were short (207±28 ms). At these short coupling intervals 6 of the 9 animals evidenced interpolated extrasystolic contractions without compensatory pauses. The only notable hemodynamic differences in postextrasystolic beats following interpolated extrasystoles versus beats following extrasystoles that produced a compensatory pause were that beats following interpolated extrasystoles had slightly reduced LV end-diastolic pressures (–0.6±0.5 mmHg for the group, n = 6; P<0.04), while beats following a compensatory pause had slightly increased LV end-diastolic pressures (+1.9±0.5 mmHg for the group, n = 3; P<0.02) prior to contraction. Additionally, whereas LV contraction following an interpolated extrasystole ejected against an afterload as estimated by aortic end-diastolic pressure that was nearly identical to baseline (–1±3 mmHg for the group, n = 6; NS), the normal sinus LV contraction immediately following the compensatory pause ejected against a moderately reduced aortic end-diastolic pressure (–14±2 mmHg for the group, n = 3; P<0.01). Changes in LV end-diastolic pressure have been shown to contribute minimally to the postextrasystolic potentiation effect of the left ventricle [15, 16], while the observed moderate reduction in afterload would be expected to affect only slightly the end-systolic volume to which the LV would contract following the compensatory pause [14](in fact end-systolic volumes in the beats following a compensatory pause were not reduced compared with those following an interpolated extrasystole). Because no other differences in transmitral hemodynamics or filling, or ventricular volume or relaxation were noted between the two types of postextrasystolic ventricular responses, the 9 animals are considered as a single group.

3.2 Postextrasystolic changes in LV peak and minimum pressures, maximum positive and negative rate of pressure change, end-diastolic pressure, ventricular volumes, left atrial pressure at mitral opening, transmitral pressure gradient, LV peak early filling velocity (Table 1)
In the first normal sinus postextrasystolic beat after a short-coupled extrasystole, significant increases were noted for the group of 9 dogs in LVPmax (8%), peak+dP/dt (80%), X1 (increase of 0.5 mmHg), the transmitral pressure gradient as estimated by subtracting LVPmin from X1 (increase of 1.6 mmHg), and E (32%). In this same beat, for the group, significant decreases were noted in LVPmin (decrease of 1.3 mmHg), and in left ventricular ESV (–27%). No significant differences were noted in peak –dP/dt, LVEDP, or EDV. Representative examples of these changes are illustrated in Figs. 1 and 2Go.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline and postextrasystolic hemodynamic data for 9 dogs

 
3.3 Indexes of the rate of isovolumic pressure fall calculated over the entire matched isovolumic relaxation pressure intervals (Table 2)
All 3 indexes of isovolumic relaxation (T, {tau}, {tau}1/2) were calculated over the entire matched isovolumic relaxation periods in the baseline and postextrasystolic beats (Fig. 3): measured by each method relaxation rate decreased significantly. Relaxation rate as indexed by T decreased by –37% in the postextrasystolic beat. This index was included for completeness, but we have previously shown that because its calculation is strongly influenced by shifts in the variable asymptote [17], as occur in postextrasystolic beats, this index is not applicable to the present data set and will not be considered further in this report. Changes in {tau} and {tau}1/2 also indicated significant decreases in relaxation rate over the entire matched isovolumic relaxation periods: –4% and –10%, respectively. In contrast, direct measurement of the total isovolumic relaxation time for the matched baseline and postextrasystolic pressure intervals indicated no significant change (2% statistically non-significant increase in relaxation rate as measured by TIVRT).


View this table:
[in this window]
[in a new window]

  		Table 2 Baseline and postextrasystolic isovolumic pressure decay data for 9 dogs calculated over the entire matched isovolumic relaxation periods, over the first two-thirds of the matched periods, and over the last one-third of the matched periods

 
3.4 Indexes of the rate of isovolumic pressure decay calculated over the first two-thirds of matched isovolumic relaxation pressure decay (Table 2)
{tau} ({tau}1) and {tau}1/2 ({tau}11/2) calculated over the first two-thirds of matched pressure decay both indicated a significant decrease in relaxation rate in the postextrasystolic beat: –11% and –14%, respectively. Direct measurement of the isovolumic relaxation times for the matched baseline and postextrasystolic pressure decay data during this subphase also showed a significant decrease in relaxation rate (–8%).

3.5 Indexes of the rate of isovolumic pressure fall calculated over the last one-third of matched isovolumic relaxation pressure decay (Table 2)
{tau} ({tau}2) and {tau}1/2 ({tau}21/2) calculated over the last one-third of the matched pressure decay intervals both indicated a significant increase in relaxation rate in the postextrasystolic beat: both +9%. Direct measurement of the isovolumic relaxation times for the matched baseline and postextrasystolic pressure decay data during this subphase also showed a significant increase in relaxation rate (+10%).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
Our study provides additional clear evidence that the course of isovolumic pressure fall is not always adequately described by a simple exponential and that the relationship between relaxation and early rapid filling can be complex. Numerous investigators have examined the relationship between relaxation, as assessed by the LV isovolumic relaxation pressure decay time constant, and early diastolic filling. The current view is that LV relaxation is but one of several factors which interact to generate the early diastolic transmitral pressure gradient. It is this instantaneous atrial-ventricular pressure difference that determines flow at any given moment across the mitral valve [18]. On the atrial side of the mitral valve, the motive force for LV filling manifests itself as left atrial pressure (LAP) at the moment of mitral valve opening, then by the rate at which LAP falls as the atrium empties. Thus, left atrial and pulmonary vein loading, and left atrial and pulmonary vein compliance are primary determinants of LV early diastolic filling [18, 19]. On the ventricular side of the mitral valve, the motive force for early diastolic filling is governed by the rate and degree of LV pressure decline, which is determined by the rate and extent of myocardial relaxation, the passive viscoelastic properties of the myocardium, and LV end-systolic volume [20, 21]. In addition, factors relating to right-heart encroachment and output, and pericardial constraint [22]may modify the determinants of early diastolic function. It is these sources of energy above and below the mitral valve, and these sources of impingement, input, and constraint that are thought to interact to produce the characteristic early diastolic filling profiles documented for both normal and abnormal left ventricles [23].

Thus, it is not surprising that changes in the rate of pressure fall, as measured by the time constant of LV relaxation, may vary in similar or in opposite direction to changes in the rate of early rapid filling. All 4 possible permutations between the value of the time constant and early diastolic filling have been demonstrated: (1) positive inotropic stimulation can decrease the time constant without changing LA pressure, resulting in a net increase in the transmitral pressure gradient and an increase in early diastolic filling rate [24]; (2) augmentation of volume load can increase the time constant and increase LA pressure, resulting in a net increase in the transmitral pressure gradient and an increase in early diastolic filling rate [25, 26], as can alterations associated with congestive heart failure [27]; (3) augmentation of afterload can increase the time constant and increase LA pressure, resulting in a net decrease in the transmitral pressure gradient and a decrease in early diastolic filling rate [25, 28]; (4) afterload reduction and venous pooling can decrease the time constant and decrease LA pressure, resulting in a net decrease in the transmitral pressure gradient and a decrease in early rapid filling rate [29].

The present investigation further documents the complex relationship between LV early diastolic filling and LV isovolumic pressure decay. Our study again presents evidence that the time constant of isovolumic relaxation and early diastolic filling can be affected in opposite directions. Significantly increased levels of postextrasystolic peak early diastolic filling were found to be associated with a decrease in overall LV relaxation rate as measured by 3 standard indexes of isovolumic relaxation. This increase in peak early filling occurred without a physiologically commensurate increase in LA pressure. Closer scrutiny of the course of isovolumic relaxation pressure decay in these animals revealed that whereas the early portion of postextrasystolic isovolumic pressure decay was slowed versus control beats, the late portion of isovolumic pressure decay was augmented versus control. This resulted in a ‘bow shaped’ postextrasystolic isovolumic pressure decay time course with an overall isovolumic pressure decay time that was not different from the baseline beat. Thus, in the case of postextrasystolic potentiated beats following short-coupled extrasystoles, standard monoexponential time constants provide an incomplete picture of the process of LV relaxation. As shown in Fig. 5, curve fitting the postextrasystolic relaxation pressure data with standard techniques results in values for the time constant that are predominately weighted by the early phase of isovolumic pressure decay.


Figure 5
View larger version (15K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Plot of matched isovolumic pressure from baseline and postextrasystolic beats from a representative animal. Curve fitting the postextrasystolic relaxation pressure data with standard techniques yields index values that tend to reflect relaxation in the early phase of isovolumic relaxation, even when direct measurement of isovolumic relaxation time yields values that indicate an opposite trend. In the example shown here, the time constant {tau}1/2 indicates a decrease in relaxation rate over baseline in the postextrasystolic beat (21.3 to 24.2 ms), while total isovolumic relaxation time (TIVRT) indicates overall relaxation rate has increased in the postextrasystolic beat (62 to 60 ms).

 
In addition, the consistently increased rate of LV pressure decline during the late portion of isovolumic relaxation was noted to extend into the early rapid filling phase as evidenced by the significant overall decrease in LV minimum pressure for the group. This decrease in LV minimum pressure was primarily responsible for the increase in the early diastolic pressure gradient, which caused the increase in peak early diastolic filling. It is interesting to note that Yellin and colleagues [30], using end-systolic volume clamping in normal dogs, found that inclusion of pressure decay data beyond the isovolumic relaxation phase also resulted in a curve that was concave with respect to the plot origin.

4.1 Multi-factor control of myocardial relaxation
Although at present we cannot account precisely for the underlying physiology responsible for the complex alterations in the form of isovolumic pressure decay noted in this study following short-coupled extrasystoles, our results may best be understood by employing the conceptual framework of load- and inactivation-dependent processes developed by Brutsaert and colleagues [1, 4, 31]. The significant increase in contractility evoked by short-coupled extrasystoles in the first postextrasystolic beat may induce alterations in the determinants of relaxation in the intact heart by increasing systolic load as evidenced by the increase in LV peak pressure over baseline. Increased early systolic pressure loads have been associated with slowed isovolumic relaxation [32], whereas increased contractility and systolic shortening have been shown to produce increased rates of relaxation [24, 33]. In addition, the increase in contractility produces significant reductions in end-systolic volume [16]which constitutes a major source of ventricular restoring forces [33, 34]. Brutsaert and Sys have cited evidence that configurational deformation at end-systole represents an important determinant of isovolumic relaxation [35–38]. Such an increase in restoring forces might be expected to produce an increase in the rate of isovolumic relaxation, especially during the late portion of the isovolumic relaxation phase when the effects of inactivation are declining and the effects of elastic recoil loading would tend to predominate [4]. Transient calcium overload of the contractile elements during postextrasystolic potentiation may also contribute to alterations in relaxation rate by modifying inactivation processes. Such modifications of the inactivation process might include mechanisms related to crossbridge detachment such as thin-filament regulation by troponin, shortening inactivation, and non-uniformity [39–42]. Clearly, further experiments are needed to determine conclusively the mechanism(s) responsible for the apparent differential modification of subphases of the isovolumic relaxation period found in our study. Nevertheless, our results do appear consistent with the notion of multi-factor control of relaxation in the intact heart. Thus, it seems reasonable to contemplate the possibility that, as has been previously hypothesized [4], certain mixes of factors that determine relaxation may be expected to produce time courses of isovolumic relaxation that deviate significantly from the predominately monoexponential course usually found in the normal left ventricle under basal conditions [30].

4.2 Postextrasystolic early diastolic filling
To our knowledge, this is the first report to examine in detail the effects of short-coupled extrasystoles on the dynamics of postextrasystolic early rapid filling in the intact heart. In our study, using normal anesthetized dogs, such short-coupled extrasystoles were associated with large increases in LV contractility as measured by peak +dP/dt, with significant increases in peak early diastolic rapid filling velocity. Three other studies have, however, examined the effects of moderate to long extrasystolic coupling intervals on postextrasystolic early filling in differing groups of patients. Carrol et al. [43]studied postextrasystolic rapid filling in patients with coronary artery disease and atypical chest pain. In these patients postextrasystolic contractility was only mildly elevated, and peak early rapid filling rate did not change. Paulus et al. [44]studied postextrasystolic early diastolic function using right ventricular electrical stimulation or spontaneous ventricular extrasystoles in normal patients, patients with aortic stenosis (AS), and patients with hypertrophic cardiomyopathy (HCM). Postextrasystolic contractility was also only mildly to moderately elevated in the 3 groups. Significant decreases in postextrasystolic early diastolic rapid filling were noted in the AS and HCM groups. No filling data were reported for the normals. Stoddard et al. [45]examined LV postextrasystolic early rapid filling in patients with coronary artery disease, AS, and hypertension, relying on spontaneous long-coupled ventricular extrasystoles. Postextrasystolic potentiation was moderately elevated over baseline, while the overall increase in LV peak filling rate observed for the combined patients was not statistically significant. In a related study, Cooper et al. [46]measured maximal diastolic excursion velocity of the LV posterior wall in postextrasystolic beats in dogs using echocardiography. Their results indicated a significant inverse relationship between extrasystolic coupling and maximal diastolic excursion velocity of the LV posterior wall in postextrasystolic beats. Thus, it appears that very short coupling intervals may be needed to produce the significant increases in postextrasystolic early diastolic filling noted in our study.

4.3 The relationship between the time constant of relaxation and early rapid filling
Of the factors currently considered to be determinants of LV early diastolic function, the relationship between the relaxation pressure decay time constant and LV rapid filling is perhaps the least well understood [47]. Implicit in the consideration of the relationship between the relaxation time constant and early diastolic filling is the assumption that the time constant provides a valid reflection of the relaxation process. In this study, the disparity between the calculated standard time constants and the directly measured isovolumic relaxation time indicates that this assumption is not always valid. Even comprehensive mathematical models describing the dynamics of ventricular filling include in their formulations the relaxation time constant as an input variable [19, 21], a variable which may be insensitive to the occurrence of subtle subphase alterations due possibly to interactions between processes related to loading dependence, inactivation dependence, and non-uniformity. Thus, more sophisticated models for quantifying the time course of the isovolumic pressure decay phase may be needed to delineate more precisely certain aspects of early diastolic function.

In this study our method of dividing the isovolumic relaxation phase into early and late subphases, based on visual assessment, is purely arbitrary and merely descriptive. We are aware of only one other study which divided the isovolumic relaxation period into subphases. In that study Rousseau et al., also using visual inspection, found that impairment of isovolumic relaxation in patients with coronary artery disease was limited to the first 40 ms after peak –dP/dt compared to normal controls [8]. Although such arbitrary divisions of LV pressure decay are utilitarian, discovering the physiological laws which govern the precise form of the time course of myocardial relaxation remains an important part of the goal of understanding fully the process of cardiac diastolic function. Despite evidence such as ours that hints that certain subtle changes in the time course of isovolumic pressure decay may be related to interactions between mechanisms related to loading- and inactivation-dependence, no conclusive empirical links between such processes and the form of LV isovolumic pressure decline have been found.

4.4 Conclusion
Our study clearly demonstrates that an intervention can cause LV pressure decay to deviate significantly from a monoexponential course in the normal intact dog heart. In the case of postextrasystolic potentiated beats, we found that despite evidence of slowed relaxation during early isovolumic relaxation, early diastolic peak filling rate is significantly increased without a physiologically commensurate increase in LA pressure. The primary determinant of this increased filling rate is an augmented rate of late isovolumic pressure decline which extends into the rapid filling phase of diastole. This biphasic postextrasystolic relaxation response suggests that the relationship between the standard time constants of relaxation and filling, and the relationship between relaxation and filling may not always be concordant. By reliance on simple measures of LV pressure decay the complex effects on relaxation that may possibly result from the interplay of forces related to alterations in myocardial inactivation, load, and uniformity may be overlooked. Thus, more sophisticated methods of quantifying the time course of the isovolumic pressure decay phase may be needed to model more precisely cardiac early diastolic filling in both health and disease. More importantly, additional research is needed to elucidate the basic physiological mechanisms underlying such subtle aspects of the diastolic process.

Time for primary review 31 days.


   Acknowledgements
 
Supported in part by SCOR in Ischemic Heart Disease, Grant HL17646, National Institute of Health, Bethesda, MD.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. Goethals M.A, Housmans P.R, Brutsaert D.L. Loading determinants of relaxation in cat papillary muscle. Am J Physiol (1982) 242:H303–H309.[Web of Science][Medline]
  2. Zatko F.J, Martin P, Bahler R.C. Time course of systolic loading is an important determinant of ventricular relaxation. Am J Physiol (1987) 252:H461–H466.[Web of Science][Medline]
  3. Zile M.R, Gaasch W.H, Wiegner A.W, Robinson K.G, Bing O.H.L. Mechanical determinants of maximum isotonic lengthening rate in rat left ventricular myocardium. Circ Res (1987) 60:815–823.[Abstract/Free Full Text]
  4. Brutsaert D.L, Sys S.U. Relaxation and diastole of the heart. Physiol Rev (1989) 69:1228–1314.[Abstract/Free Full Text]
  5. Leite-Moreira A.F, Gillebert T.C. Nonuniform course of left ventricular pressure fall and its regulation by load and contractile state. Circulation (1994) 90:2481–2491.[Abstract/Free Full Text]
  6. Lew W.Y.W, Rasmussen C.M. Influence of nonuniformity on rate of left ventricular pressure fall in the dog. Am J Physiol (1989) 256:H222–H232.[Web of Science][Medline]
  7. Gaasch W.H, Blaustein A.S, Bing O.H.L. Asynchronous (segmental early) relaxation of the left ventricle. J Am Coll Cardiol (1985) 5:891–897.[Abstract]
  8. Rousseau M.F, Veriter C, Detry J.-M.R, Brasseur L, Pouleur H. Impaired early left ventricular relaxation in coronary artery disease: effects of intracoronary nifedipine. Circulation (1980) 62:764–772.[Abstract/Free Full Text]
  9. Courtois M, Kovács S.J Jr., Ludbrook P.A. The transmitral pressure–flow velocity relationship: The importance of regional pressure gradients in the left ventricle. Circulation (1988) 78:661–671.[Abstract/Free Full Text]
  10. Sandler H, Dodge HT. Angiographic methods for determination of left ventricular geometry and volume. In: Mirsky I, editor. Cardiac mechanics. New York: John Wiley, 1974:141–170.
  11. Weiss J.L, Frederiksen J.W, Weisfeldt M.L. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest (1976) 58:751–760.[Web of Science][Medline]
  12. Thompson D.S, Waldron C.B, Juul S.M, et al. Analysis of left ventricular pressure during isovolumic relaxation in coronary artery disease. Circulation (1982) 65:690–697.[Free Full Text]
  13. Mirsky I. Assessment of diastolic function: suggested methods and future considerations. Circulation (1984) 69:836–841.[Free Full Text]
  14. Courtois M, Mechem C.J, Barzilai B, Ludbrook P.A. Factors related to end-systolic volume are important determinants of peak early diastolic transmitral flow velocity. Circulation (1992) 85:1132–1138.[Abstract/Free Full Text]
  15. Edmands R.E, Greenspan K, Fisch C. The role of inotropic variation in ventricular function during atrial fibrillation. J Clin Invest (1970) 49:738–746.[Web of Science][Medline]
  16. Sung C.-S, Mathur V.S, Garcia E, De Castro C.M, Hall R.J. Is postextrasystolic potentiation dependent on Starling's law? Circulation (1982) 62:1032–1035.
  17. Courtois M, Ludbrook PA. Indexing left ventricular isovolumic relaxation pressure decay: variable asymptote shifts. In: Ingels NB, Daughters GT, Baan J, Covell JW, Reneman RS, Yin F C-P, editors. Systolic and diastolic function of the heart. Amsterdam: IOS Press, 1996:167–174.
  18. Yellin E, Nikolic S.D, Frater R.W.M. Left ventricular filling dynamics and diastolic function. Prog Cardiovasc Dis (1990) 33:247–271.
  19. Thomas J.D, Wilkins G.T, Choong C.Y.P, et al. Inaccuracy of mitral pressure half-time immediately after percutaneous mitral valvotomy. Dependence on transmitral gradient and left atrial and ventricular compliance. Circulation (1988) 78:980–993.[Abstract/Free Full Text]
  20. Thomas J.D, Weyman A.E. Echocardiographic Doppler evaluation of left ventricular diastolic function: physics and physiology. Circulation (1991) 84:977–985.[Free Full Text]
  21. Yellin E, Nikolic SD. Diastolic suction and the dynamics of left ventricular filling. In: Gaasch WH, Lewinter MM, editors. Left ventricular diastolic dysfunction and heart failure. Philadelphia: Lea & Febiger, 1994:89–102.
  22. Slinker B.K, Glantz S.A. End-systolic and end-diastolic ventricular interaction. Am J Physiol (1986) 251:H1062–H1075.[Medline]
  23. Shintani H, Glantz SA. The left ventricular diastolic pressure volume relation, relaxation, and filling. In: Gaasch WH, Lewinter MM, eds. Left ventricular diastolic dysfunction and heart failure. Philadelphia: Lea & Febiger, 1994:57–88.
  24. Cheng C.-P, Freeman G.L, Santamore W.P, Constantinescu M.S, Little W.C. Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res (1990) 66:814–823.[Abstract/Free Full Text]
  25. Ishida Y, Meisner J.S, Tsujioka K, et al. Left ventricular filling dynamics: Influence of left ventricular relaxation and left atrial pressure. Circulation (1986) 74:187–196.[Abstract/Free Full Text]
  26. Yamamoto K, Masuyama T, Tanouchi J, et al. Importance of left ventricular minimal pressure as a determinant of transmitral flow velocity pattern in the presence of left ventricular systolic dysfucntion. J Am Coll Cardiol (1993) 21:662–672.[Abstract]
  27. Ohno M, Cheng, C-P, Little WC. Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure. Circulation 1994;89;2241–2050.
  28. Courtois M, Mechem C.J, Barzilai B, Gutierrez F, Ludbrook P.A. Delineation of determinants of left ventricular early filling: saline versus blood. Circulation (1994) 90:2041–2050.[Abstract/Free Full Text]
  29. Choong C.Y, Hermann H.C, Weyman A.E, Fifer M.A. Preload dependence of Doppler-derived indexes of left ventricular diastolic function in humans. J Am Coll Cardiol (1987) 10:800–808.[Abstract]
  30. Yellin E.L, Hori M, Yoran C, Sonnenblick E.H, Gabbay S, Frater R.W.M. Left ventricular relaxation in the filling and nonfilling intact canine heart. Am J Physiol (1986) 250:H620–H629.[Web of Science][Medline]
  31. Brutsaert D.L, Housmans P.R, Goethals M.A. Dual control of relaxation. Its role in the ventricular function of the mammalian heart. Circ Res (1980) 47:637–652.[Free Full Text]
  32. Ariel Y, Gaasch W.H, Bogen D.K, McMahon T.A. Load-dependent relaxation with late systolic volume steps: servo-pump studies in the intact canine heart. Circulation (1987) 75:1287–1295.[Abstract/Free Full Text]
  33. Caillet D, Crozatier B. Role of myocardial restoring forces in the determination of early peak velocity of fibre lengthening in the conscious dog. Cardiovasc Res (1982) 16:107–112.[Abstract/Free Full Text]
  34. Nikolic S, Yellin E.L, Tamura K, et al. Passive properties of canine left ventricle: diastolic stiffness and restoring forces. Circ Res (1988) 62:1210–1222.[Abstract/Free Full Text]
  35. Cohn P.F, Liedtke A.J, Serur J, Sonnenblick E.H, Urschel C.W. Maximal rate of pressure fall (peak negative dP/dt) during ventricular relaxation. Cardiovasc Res (1972) 6:263–267.[Abstract/Free Full Text]
  36. Papapietro S.E, Coghlan H.C, Zissermann D, Russell R.O, Rackley C.E, Rogers W.J. Impaired maximal rate of left ventricular relaxation in patients with coronary artery disease and left ventricular dysfunction. Circulation (1979) 59:984–991.[Abstract/Free Full Text]
  37. Weisfeldt M.L, Scully H.E, Fredericksen J, et al. Hemodynamic determinants of maximum negitive dP/dt and the period of diastole. Am J Physiol (1974) 227:H613–H621.
  38. Mathey D, Bleifeld W, Franken G. Left ventricular relaxation and diastolic stiffness in experimental myocardial infarction. Cardiovasc Res (1974) 8:583–592.[Abstract/Free Full Text]
  39. Wang Y.-P, Fuchs F. Length, force, and Ca2+-troponin C affinity in cardiac and slow skeletal muscle. Am J Physiol (1994) 266:C1077–C1082.[Web of Science][Medline]
  40. Brady A.J. Mechanical properties of isolated cardiac myocytes. Physiol Rev (1991) 71:413–428.[Abstract/Free Full Text]
  41. Kentish A.D.G. Calcium concentration in the myoplasm of skinned ferret ventricular muscle following changes in muscle length. J Physiol (1988) 407:489–503.[Abstract/Free Full Text]
  42. ter Keurs HEDJ, Rijnsburger WH, van Heuningen, Nagelsmit MJ. Tension development and sarcomere length in rat cardiac trabeculae. Circ Res 1980;46:703–714.
  43. Carroll J.D, Widmer R, Hess O.M, Hirzel H.O, Krayenbuehl H.P. Left ventricular isovolumic pressure decay and diastolic mechanics after postextrasystolic potentiation and during exercise. Am J Cardiol (1983) 51:585–590.
  44. Paulus W.J, Sys S.U, Nellens P, Heyndrickx G.R, Andries E. Postextrasystolic potentiation worsens fast filling of the hypertrophied left ventricle in aortic stenosis and hypertrophic cardiomyopathy. Circulation (1988) 78:928–940.[Abstract/Free Full Text]
  45. Stoddard M.F, Pearson A.C, Kern M.J, Labovitz A.J. The effect of premature ventricular contraction on left ventricular relaxation, chamber stiffness, and filling in humans. Am Heart J (1989) 118:725–733.[CrossRef][Web of Science][Medline]
  46. Cooper M.W, Lutherer L.O, Lust R.M. Postextrasystolic potentiation and echocardiography: the effect of varying basic heart rate, extrasystolic coupling interval and postextrasystolic interval. Circulation (1982) 66:771–776.[Free Full Text]
  47. Reneman RS, Yellin EL, Little W, et al. Ventricular relaxation and diastolic filling. In: Ingels NB, Daughters GT, Baan J, Covell JW, Reneman RS, Yin FC-P, editors. Systolic and diastolic function of the heart. Amsterdam: IOS Press, 1996:101–117.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Courtois, M.
Right arrow Articles by Ludbrook, P. A
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Courtois, M.
Right arrow Articles by Ludbrook, P. A
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?