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Cardiovascular Research 1999 43(1):86-95; doi:10.1016/S0008-6363(99)00054-1
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Right ventricular systolic function and ventricular interaction during acute embolisation of the left anterior descending coronary artery in sheep

Anastazia Jerzewski, Paul Steendijk, Peter M.T. Pattynama, Boudewijn P.J. Leeuwenburgh, Albert de Roos and Jan Baan*

Leiden University Medical Centre, Department of Cardiology, Leiden, The Netherlands

* Corresponding author. Tel.: +31-71-526-2944/526-2020; fax: +31-71-522-6567 baan{at}cardio.azl.nl

Received 5 August 1998; accepted 21 December 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
Objective: Regional LV ischemia involving the septum affects LV systolic function and geometry. We investigated the effects of these changes on RV function and geometry. Methods: In six closed-chest sheep end-systolic pressure-volume relationships (ESPVRs) were constructed from ventricular volumes, measured with magnetic resonance imaging (MRI) and matching intraventricular pressures, before and after selective embolisation of the left anterior descending coronary artery (LAD). The extent of myocardial ischemia was assessed post-mortem by coronary perfusion with Evans-Blue. Alterations in septal geometry were studied by measuring the curvature, segmental length and thickness of the septum in two midventricular (short-axis) MRI slices before and during ischemia. From these data, changes in LV and RV free wall segmental lengths were calculated. Results: Selective embolisation of the LAD resulted in left ventricular ischemia (15±2.1% of the total LV) with 23% of the septum involved. Stroke volume did not change significantly, while LV systolic pressure decreased by 24 mmHg (p<0.05). Although RV systolic function decreased to a significantly lesser extent than LV function (p<0.01), systolic function of both ventricles diminished significantly as indicated by substantial rightward shifts of the ESPVRs: 121% for LV and 41% for RV (both p<0.01). At mid-ventricular level and end-systole, the septum showed significant increases in its radius of curvature and segmental length (both p<0.05), and a significant wall thinning (p<0.01). Calculated end-systolic lengths of LV and RV free walls also increased, by 57 and 14% respectively. Conclusions: LAD embolisation not only results in a significantly diminished LV systolic function but also causes RV systolic function to decline significantly. Regional dysfunction by necessity entails global dysfunction as well. Analysis of ventricular geometry reveals that both the septum and the RV free wall increase their length, which plays an important role in the pathophysiology of diminished RV systolic function concomitant with reduced LV function.

KEYWORDS Contractile function; Ischemia; Coronary disease; Ventricular function; Hemodynamics


   1 Introduction
Top
 Abstract
 1 Introduction
2 Materials and methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
In some patients with left ventricular (LV) dysfunction due to myocardial ischemia in the LV wall, right ventricular dysfunction coexists [1–4]. The RV dysfunction may lead to RV failure as frequently seen in the cardiac postoperative period. This suggests that an interaction may exist between the ischemic left and the normal right ventricle.

The function of each ventricle is known to influence the performance of the other. Ventricular interaction can occur via three mechanisms: (1) the two ventricles are arranged in series, (2) both ventricles are enclosed within the pericardium, and (3) the ventricles are connected via the interventricular septum. The phenomenon of septal shift (movement of the interventricular septum) is well known and plays a central role in the process of ventricular interdependence. The position of the septum between the ventricles can be influenced by both diastolic and systolic events and septal function may affect the performance of either ventricle [5,6]. More important even is that adequate systolic performance of the RV is governed largely by a well functioning septum and much less by the function of the RV free wall [5,7].

The present study is aimed at obtaining more insight in the factors and mechanisms that play a role in RV systolic function when part of the anteroseptal region of the heart is made ischemic.

The use of magnetic resonance imaging (MRI) enabled us to study LV and RV volumes (along with intraventricular pressures) simultaneously, thus obtaining the end-systolic pressure-volume relationships (ESPVR) of both ventricles. The ESPVR is a relatively load independent measure of myocardial contractility and approaches linearity for both the LV [8,9] and the RV [10–12]. The ESPVR was obtained before and after embolisation of the left anterior descending coronary artery in an experimental sheep model. To approximate the clinical situation the heart was studied in situ, with closed chest and intact pericardium. Furthermore, MRI allowed us to study the geometry of the septum and its behavior after inducing ischemia, as a possibly important mechanism through which reduced systolic function of the LV might affect the systolic function of the RV. Studies of in vivo ESPVR during LV regional ischemia are limited [13,14] and simultaneous assessment of LV and RV ESPVR during ischemia has not been performed previously, except in a preliminary report [15].


   2 Materials and methods
Top
 Abstract
 1 Introduction
 2 Materials and methods
3 Results
 4 Discussion
 Acknowledgments
 References
 
Six sheep, weighing 25–29 kg (mean 27 kg), were used in this study. Originally eight experiments were performed, but two animals died post-ischemia due to arrhythmias. The study had been approved by the animal research committee of the Leiden University Medical Centre. The investigations conform with the Guide for the care and use of laboratory animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The experiments were performed under general anesthesia, brought about by intramuscular xylazin (1.0 mg·kg–1), subcutaneous atropine sulfate (0.5 mg·kg–1), intravenous ketamin (5–25 mg·kg–1·h –1) and atracurium (0.25 mg·kg–1). The sheep were intubated and artificially ventilated. Monitoring was done by means of capnography and arterial blood gas samples, physical signs and ventricular pressures which were displayed on-line.

Before the imaging studies, 7F and/or 8F sheaths were surgically inserted into the left carotid artery, both jugular veins and the femoral artery. Under fluoroscopic control, two MR-compatible 5F high fidelity micromanometer-tip catheters (model SPC-350MR, Millar Instruments, Houston, TX) were positioned in the LV and the RV, via the carotid artery and a jugular vein respectively. The manometer-tip catheters were calibrated before and after each experiment. The use of these catheters during MR imaging to obtain PV-loops of the LV has been described previously by Dell’Italia et al. [16] and later also in our institution [17,18]. Through the other jugular vein a MR compatible pacing catheter was introduced into the right atrium. This pacing catheter has been developed in our institution in co-operation with a catheter manufacturer (Cordis Europe NV, Roden, The Netherlands) [19]. Because of their special construction, the MR compatible catheters produce only minor imaging artifacts that do not interfere with image analysis. We paced the heart in an asynchronous mode. This was done to ensure good MR image quality because of a steady heart rate. The sheath in the femoral artery was used for introduction of a 4F multipurpose catheter for embolisation of the left anterior descending coronary artery. After completion of the surgical preparation, a 30-min period was allowed for the sheep to reach hemodynamic stability. We term the embolised condition also as ischemia. Following the 30-min period of stabilization the animal had to be repositioned in the scanner and scout images had to be performed before the actual functional scans could be performed. On average this took about 15 min.

In each animal we constructed PV-loops at different loading conditions before and after left ventricular ischemia. First we imaged the heart in the control state. To change the loading condition we administered an intravenous volume-load of 350 ml gelofusine® followed by a continuous gelofusine® drip and constructed a second PV-loop. On average this took about 20 min. Using the two PV-loops obtained before and after volume loading the ESPVR at the basal state was constructed. It has been shown that the ESPVR can be approximated by a straight line for both the left [8,9] and the right ventricle [10–12]. In the statistical analysis of the data, however, we applied a method that did not rely on the actual slope and position of the individual ESPVRs (see section ‘Statistical analysis’).

Following acquisition of the control state data the animal was returned to the operating room. In order to forestall arrhythmias a 100 mg bolus of lidocain was given intravenously followed by a continuous intravenous infusion of 3 mg/min. Under fluoroscopic control, using a contrast agent (Telebrix®), the multipurpose catheter was selectively inserted in the left anterior descending coronary artery. Ischemia was brought about by embolising the territory perfused by this artery through infusion of approximately 0.15 ml polyvinylalcohol particles (Ivalon®, 0.1 g/4ml NaCl 0.9%), which means approximately 13 000–14 000 particles, with a diameter of 150–300 µm suspended in physiological saline. This method is similar to that employed by Myhre et al. [20] to create LV ischemia. A 30 min period was allowed for obtaining hemodynamic stability.

Subsequently, the same procedure in the MR scanner as described before was repeated (repositioning and scout imaging; 15 min) approximately 30 min after embolisation, subsequently imaging the control state and altered loading condition (about 20 min). Thus, two ESPVRs were obtained at basal state and two at ischemic state for each of the ventricles.

2.1 MR imaging
Echo-planar imaging (EPI) MR imaging was performed at 1.5 T (Gyroscan NT15: Philips Medical Systems, Best, The Netherlands) with segmented k-space acquisition (EPI factor of 3) and a 30° flip angle. EPI MR imaging is a fast imaging technique allowing the acquisition of a full functional study of the entire heart in less than 4 min, in multiple interruptions of ventilation. Echo time was 13 ms and repetition time was equal to the duration of the cardiac cycle. MR imaging data were obtained with a 256x256 acquisition matrix and 350 mm field of view. The pacing pulse from the pulse-generator triggered the MR imaging data acquisition. Synchronicity of the pace-pulse and the actual heartbeats was verified during the experiments using an oscilloscope on which the pace-pulse and ventricular pressure waves from both ventricles were displayed. Scout images in the sagittal, coronal and transverse planes identified the long axis of the heart. Eight to nine 8 mm-thick contiguous short-axis images encompassed both ventricles. Acquisition of each section was done during a 20 s interruption of ventilation, whereby each section was imaged separately to achieve a temporal resolution of 22 ms, resulting in a sampling frequency of approximately 23 time frames per cardiac cycle, depending on the heart rate (132±3 BPM) (mean±SEM).

The infusion pumps, respirator, capnograph, pulse-generator and pressure-amplifiers were positioned inside the MR room. The personal computer used for recording pressure-data and the pace-pulses was placed outside the room. A special transit-lid was used to pass the electrical connections from the MR room to the personal computer, in order to avoid radiofrequency pulses entering the room through these wires.

2.2 Pathology
After excision, the hearts were taken to the laboratory preserved in a solution of buffered NaCl 0.9%. The hearts were perfused (100 mmHg) with HEPES buffer, pH 7.4 and further with Evans Blue® [21]. Using this method, normal myocardium was stained blue whereas the ischemic areas remained unstained. After the perfusion all intracardiac cavities were filled with AGAR® and the heart was placed in a cold room (4°C) overnight. The next day the hearts were cut in slices of 1 cm thickness in the short-axis plane, and stained with nitroblue tetrazolium (NBT®) (Sigma) [22]. With this method a distinction between ischemic areas and necrotic areas could be made.

2.3 Data analysis
The MR images were analyzed using dedicated software (MASS® Analysis Tool) which has been developed in our institute [23]. The MR images were displayed individually and in a movie-loop mode. On all time frames, endocardial borders of both ventricles were outlined manually. Measurements were performed using standardized window width and window level settings. The enclosed LV and RV surface areas were measured by the computer, multiplied by section thickness and summed according to Simpson’s rule to provide LV and RV chamber volumes. The ventricular pressures, sampled at a frequency of 200 Hz during MR imaging, were matched in time with the ventricular volume data to acquire LV and RV points in the PV plane. PV-loops were constructed by connecting these data points as described previously [17]. ESPVRs were then constructed by connecting the end-systolic PV points if they were clearly evident as the upper left corner of the PV loops. If not, the ESPVR was constructed as the line tangential to the two loops, which is often the case for the RV [12,24]. The resulting tangential points were defined as end-systolic P and V points used in the statistical analysis of our data. Stroke volumes were defined as the maximal ventricular volume minus the minimal volume.

The ESPVRs of the LV and RV were characterized by their slopes and volume intercepts. These were computed using multiple linear regression (see section Statistical analysis). We quantified the extent of the rightward shift of the volume intercepts of the ESPVRs and the changes in their slopes during regional left ventricular ischemia. Differences between LV and RV in this respect were documented.

The photographs of the stained postmortem hearts were analyzed using the Cavalieri method, a highly accurate estimator of the volume V of an object, commonly used in stereology [25]. A grid of 0.2x0.17 mm was used. With this method the percentage of ischemic LV free wall and septum could be established.

2.4 Septal geometry
In order to assess septal behavior at end-systole we analyzed the end-systolic MR images of two mid-ventricular slices before and during LV ischemia, with and without volume loading, using only the septal part of the endocardial contours-points of both ventricles (Fig. 1). Selection of the slices was based on those showing the papillary muscles most clearly. Its midwall radius of curvature (Cs), its midwall segmental length (Ls) and its thickness (Ts) defined the geometry of the septum at the level of these slices. All measurements were performed before and after volume loading and also before and during ischemia. The radii of curvature on both borders of the septum of each slice were assessed first (Fig. 1) and the mean midwall radius of curvature of the septum was calculated as the mean between the above two curvatures. Secondly, Ls, defined as the length of the midwall curve part of the ventricle between the attachments of the RV to the LV, was measured from the MR images. Next we determined the mean wall thickness of the septum, Ts, in both slices in each animal by measuring the perpendicular distance between the LV and RV endocardial borders at 10–15 sites and subsequently averaging the data. The data on the two slices were averaged, thus giving a more robust picture of septal geometry at mid ventricular level.


Figure 1
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  		Fig. 1 Analysis of determining radii of curvature of the septum performed on MRI mid ventricular slices before and during LAD embolisation (see text for details).

 
All measurements were performed at both loading conditions as well as before and during ischemia. The septal geometry thus acquired is obviously dependent on the volume loading conditions. This problem is similar to the one in which slopes and volume intercepts of the ESPVR are calculated: like ESV, septal geometry is dependent on pressure (i.e. loading condition), on animal variability and, presumably, on absence or presence of embolisation. Thus, by multiple linear regression the average values were computed as well as the changes in these variables as a consequence of ischemia.

2.5 Calculated shape and free wall segment length of both ventricles
In order to obtain an impression of the average shape of the mid-ventricular cross sections of LV and RV and how these shapes change after embolisation we used an approach similar to the one employed by King et al. [6] to quantify changes in cross section in children with RV hypertension. These authors converted the actual cross section of the LV into a circle with effective radius in order to compute a normalized curvature of the septum. We went one step further and calculated the segmental shapes using the measured Cs, Ls and Ts values of the septum as well as the LV and RV cross sectional areas (ALV and ARV) at the slices used for septum geometry. In this process, we considered both the LV and the RV as consisting of two circle sectors, one of which is defined by the septal geometry and the other by a computed radius and subtended angle, the values of which follow from equalizing the concomitant cross sectional area with the average values for ALV and ARV (see Fig. 2). The mathematical equations for this process were solved numerically by computer. Having found the values for these radii and subtended angles, the endocardial segmental lengths of the LV and the RV free wall (as well as changes in them after ischemia) could be calculated.


Figure 2
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  		Fig. 2 Mid-ventricular, short-axis model (drawn to scale), to illustrate the changes in septal geometry as well as calculated free wall segments of LV and RV before (left) and after embolisation (right) (see text for details); length A–B=Cs (septal midwall radius of curvature) curve B–C–D=Ls (midwall segmental length of the septum) angle A–B–D=angle subtended by the septum attachments. Wall thickness of RV is fictitious.

 
2.6 Statistical analysis
To determine the ESPVR slopes and volume intercepts two points are not sufficient for linear regression, but specifically because we had this limited data set we performed a more sophisticated statistical analysis based on a multiple linear regression model which provides a fit on all pooled data.

The effects of embolisation on the ESPVR were analyzed using the following multiple linear regression model: (Table 1)

Formula


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  		Table 1 Volume intercepts (a) and inverse slopes (b) pre- and post embolisation for both ventriclesa,b,cGoGo

 
The analysis was applied separately for the LV and the RV. For each animal, PESMEAN was calculated as the mean end-systolic pressure for the four conditions (i.e., the basal condition and volume load before and after embolisation). The coefficients a describe the intercept of the relation between VES and PES, which represents end-systolic volume at PESMEAN (83±18 mmHg for the LV, 26.8±1.8 mmHg for the RV). The bs describe the slope of this relation, which represents the inverse of end-systolic elastance (1/EES). The dummy variables ANIMi code the animals (effects coding), the dummy variable EMBO codes the embolisation (EMBO=0 before embolisation, EMBO=1 after embolisation). Consequently, the aO gives the mean VES (at PESMEAN) before embolisation, the coefficients aAi decribe the interanimal variability of VES, and aE quantifies the effect of the embolisation on VES. The interaction term ({Sigma} aA.Ei.ANIMi.EMBO) decribes the interanimal variability of the embolisation effect. The interpretation of the bs is the same, but applies to the slope of the VES–PES relation (note that no interaction term was included for the slope because the embolisation effect turned out to be not significant for the slope). The interanimal variability was calculated as the standard deviation of the corresponding animal coefficient [26].

The effects of loading and embolisation on end-systolic pressures for both ventricles and on stroke volume were also tested by using a similar multiple linear regression model

Formula

In this model the effect of the volume load is quantified by aL and the effect of the embolisation by aE. A similar analysis as for the end-systolic volumes was also applied for the radius of curvature, length and thickness of the septum. However, rather than using Pes as independent variable, the dependence of Cs, Ls and Ts on transmural pressure (calculated as PESLV–PESRV) was determined in the regression model.


   3 Results
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
4 Discussion
 Acknowledgments
 References
 
The MR based ventricular volume calculations could be performed in all experimental situations in six animals. In a previous study using this animal model the inter- and intra-observer variability of ventricular volumes were measured and showed good reproducibility [18], with intra- and interobserver variability being 3.72±2.29% (mean±SD) and 6.98±5.86%, respectively. Examples of PV-loops and resulting ESPVRs before and after ischemia are shown in Fig. 3a for the LV and in Fig. 3b for the RV, respectively. Mean pressure-volume loops as well as ESPVRs computed from all data (averaging basal and volume load loops) are represented in Fig. 4a for the LV and in Fig. 4b for the RV.


Figure 3
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  		Fig. 3 Example of pressure-volume loops of respectively the left (a) and right ventricle (b) before and during embolisation, without and with volume loading. End-systolic pressure-volume relationships before and during embolisation, both show a clear shift to the right during embolisation, but the changes in their slopes are not typical for the average behavior (see text). bas pre=pre-embolisation without volume loading vol pre=pre-embolisation with volume loading bas post=post-embolisation without volume loading vol post=post-embolisation with volume loading.

 

Figure 4
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  		Fig. 4 Schematic representation of pressure-volume loops (PV loops) in the LV (a) and RV (b) before and after embolisation. Each end-systolic PV point represents the average ES pressure and volume before and after volume loading. The other three points of the loop are derived from (idealized) isovolumic relaxation and contraction, taking into account measured average stroke volume. ESPVRs are shown with actual average slopes and intercepts with standard deviations in both of these parameters identical to those in Fig. 5. These data summarize on the average parallel rightward shifts of both ventricular ESPVRs and the decrease in LV systolic pressure after embolisation. Also, note that SV decreases only slightly.

 
In all animals there was a significant shift to the right of the ESPVR for both LV and RV after the ischemia, consistent with diminished systolic function. The volume intercept shifts were calculated (using MLR) for each ventricle separately at a mean ESP of the four pressure-volume loops before and during ischemia (Table 1). The volume intercept (Fig. 5a) of the LV ESPVR in the control state was 15.46±1.63 [ml] (mean±SD), increasing to 34.16±3.57 [ml] after the ischemia. The volume intercept of the RV ESPVR increased from 10.41±0.10 [ml] in the control situation to 14.67±0.18 [ml] after the ischemia. Thus, the mean rightward shift of the LV ESPVR was 18.70±3.18 [ml] p<0.01; that of the RV ESPVR was 4.26±0.14 [ml] p<0.01. The rightward shift of the LV ESPVR was significantly larger than that of the RV ESPVR, p<0.01.


Figure 5
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  		Fig. 5 (a) Shift of the volume intercept of the end-systolic pressure-volume relationship±error (note that these errors do not include interanimal variability, see Table 1) of both ventricles following LAD embolisation. Both are statistically significant. Furthermore, there is a significantly larger rightward shift for the LV than for the RV. (b) Slopes (Ees) of the end-systolic pressure-volume relationship of both ventricles following LAD embolisation. Neither of the changes in them are statistically significant. (c) End-systolic septal geometry following LAD embolisation. The midwall septal radius of curvature (Cs), midwall segmental length of the septum (Ls) both increase significantly, and average wall thickness (Ts) of the septum decreases significantly.

 
The slope (Fig. 5b) of the LV ESPVR (Ees) in the control state was 3.93±1.24 [kPa/ml] and after the ischemia 3.98±1.68 [kPa/ml]. For the RV ESPVR, the slope was 2.02±0.11 [kPa/ml] in the control state and 2.01±0.11 [kPa/ml] after the ischemia. The changes in slopes before and after the ischemia were not significant, p=0.97 and p=0.54, for the LV and RV respectively.

Note that these errors do not include the interanimal variability (see Table 1).

The end-systolic pressures (ESP) of both ventricles decreased, though failing statistical significance for the RV. LV ESP dropped from 95.11±12.92 to 70.82±9.58 mmHg (mean±SEM) p<0.05, RV ESP dropped from 28.19±2.63 to 25.37±1.44 mmHg, p>0.09. Stroke volume did not decrease significantly following embolisation, on average from 23.91±1.88 to 22.39±1.87 ml, p>0.08. Transmural end-systolic pressure decreased significantly following embolisation, from 66.92±11.74 to 45.45±9.32 mmHg, p<0.05.

The end-systolic septal midwall radius of curvature (Cs) increased significantly, from 23.51±0.85 mm to 26.12±1.38 mm or 11%, p<0.01. The end-systolic midwall segmental length of the septum (Ls) also increased significantly from 28.88±1.21 mm to 32.34±1.55 mm, or 12%, p<0.05. The average end-systolic wall thickness (Ts) of the septum decreased from 11.45±0.35 mm to 9.97±0.58 mm, or 13%, p<0.01 (Fig. 5c). The end-systolic cross-sectional area (Fig. 2) of the LV increased from 386±40.7 mm2 to 854±89.2 mm2 (p<0.01), while for the RV it increased from 232±2.3 mm2 to 326±4.0 mm2 (P<0.01). Based on these measurements the free wall segment length (inner boundary) of the LV increased from 48.5 to 76.1 mm or 56.9%, while RV free wall segment length increased from 47.5 to 54.3 mm or 14.3%.

Staining with Evans Blue® of the postmortem hearts revealed ischemic areas of the LV with an average 15±2.1% of the total LV wall, with 23% of the septum involved. Staining with nitroblue tetrazolium (NBT®) revealed that none of the ischemic areas showed any necrosis.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
Acknowledgments
 References
 
In this study, left and right ESPVRs were determined simultaneously, as well as (systolic) septum geometry, before and after embolisation of the left anterior descending coronary artery. Although stroke volume was maintained after this intervention, it led to a substantial reduction of LV systolic performance, evidenced by a reduction in systolic pressure and a large shift (+121%) of the LV ESPVR, the slope of which was unchanged. Other investigators [13,14] have reported similar findings. Remarkably, the ESPVR of the RV also shifted significantly toward an increased volume intercept (by 41%), which, albeit much less than in the LV, indicates a reduced systolic function. Most likely, this behavior is caused in part by the involvement of the partially ischemic septum, in view of its important role in determining RV performance [5,7]. These rightward shifts of the ESPVRs were not accompanied by a significant decrease in stroke volume and, only in the LV, by a significantly reduced systolic pressure. Therefore, both ventricles maintained their ability to pump a sufficient amount of blood, but at the cost of increased volumes, thereby indicating reduced ejection fractions and greatly limited reserve capacity.

No gross changes in geometry of the septum were observed, but its systolic length, as well as its radius of curvature, increased significantly while its thickness decreased, all of them by more than 10%. Transmural (LV–RV) systolic pressure also decreased significantly.

These changes in septal geometry were accompanied by not only an increase in the septal to RV free wall dimension, but also by substantial increases in the free wall segments of both LV and RV. Whereas this finding would be expected for the partly ischemic LV free wall, it is not so easily explained for the RV free wall. The effects of changes in the LV pressure and/or volume on right ventricular dimensions have been studied previously in non-ischemic preparations in which it was possible to vary LV and RV pressures and/or volumes independently. Chow et al. [27] demonstrated that a large reduction in LV pressure and volume caused a substantial rightward shift in the relation between RV end-systolic pressure-and septal-free wall dimension, which implies a rightward shift of the RV ESPVR. Conversely, in an isolated heart preparation, Yamaguchi et al. found that increasing LV volume (and pressure) resulted in a slight but significant leftward shift of the RV ESPVR, with slightly increased slopes [28]. The latter authors suggest that a LV volume increase enhances septal segmental length as well as its radius of curvature, thereby pulling the RV free wall (with marginal increase in its dimensions) towards the septum, resulting in a thinner ‘moon-crescent’ of the RV cross section, and thus a decreased volume. In contrast, in our study the increases in LV volume were accompanied by increases in RV volume. The obvious difference is that in our study the LV volume increase was caused by ischemia, while it was not accompanied by an increase but rather by a decrease in systolic pressure. Moreover, because of the septal involvement of the ischemia, RV volume may have increased on the basis of segmental septum lengthening. Apparently, these effects ‘override’ the response in the normal heart of the RV to volume increase of the LV. However, our analysis indicates that the length of the RV free wall also increases, despite its presumably normal coronary blood supply. This phenomenon is probably similar to that observed for the non-ischemic areas of the LV wall in studies of LV ischemia by other investigators [29,30]: utilization of the Frank-Starling effect is thought to be the mechanism by which the non-ischemic segment compensates for the reduced function in the ischemic part. The employment of this mechanism is likely to play an important role in the intact circulation. When ischemia sets in, one of the very first phenomena to occur, is an increase in ventricular volume, which is caused by the (temporary) imbalance of constant filling volume and transiently diminished ejected volume. After a new balance is reached, however, stroke volume is more or less restored as required by homeostasis. Furthermore, the finding that RV free wall dimension increases more than septal dimension is undoubtedly related to the fact that the free wall, being much thinner, is more compliant than the septum. The subject of the influence of ischemia in the LV wall and/or the septum on global RV function has not been studied widely so far. Brooks et al. [31] found a decrease in dP/dtmax of the RV with infarction of the septum in pigs; this study did not include recording of dimensions or volume. Geiran et al. [32] studied changes in stroke volume and segmental lengths in the septum and free walls of the LV and RV during occlusion of the LAD coronary artery. They found a substantial increase in end-systolic segment length of the LV free wall and some increase in the septum, but, unlike us, no change in RV free wall segment length. In a previous study of the same preparation, the same investigators [33] had found that occlusion of the septal artery caused a large increase in septal segment length (also accompanied by a slight fall in SV), but, in addition, a reduction in the distance between septum and RV free wall, which indicates bulging of the septum towards the RV. Crottogini et al. [34] studied LV and RV anterior wall thickening in response to LAD coronary occlusion in conscious pigs. Whereas these investigators found substantial wall thinning as well as dyskinesis in the ischemic portion of the LV wall, they found little effects on a presumably ischemic portion of the RV anterior wall restricted to some dyskinesis and reduced systolic wall thickening. However, septal dynamics were not included in their study. Danchin et al. [35] studied RV function by means of a thermodilution catheter before, during, and after percutaneous transluminal angioplasty of the LAD (among other coronary occlusions) in patients with single vessel disease. Brief occlusion of the proximal segment of the LAD resulted in marked deterioration of RV performance, measured by cardiac index and ejection fraction, and a significant increase in RV end-systolic volume index.

Studies of the performance of the RV by pressure-volume loops, using load variations to obtain ESPVRs, have been undertaken by a limited number of investigators, most likely because of the difficulty of measuring RV volume simultaneously with pressure. Very few studies have been performed in which LV and RV P–V relations were obtained simultaneously [15,18,36], while only two studies are known to us in which RV PVR were compared before and after ischemia created in the LV wall: Bishop et al. [37] measured P–V loops by conductance catheter in patients undergoing PTCA in either the LAD or right coronary artery. Occlusion of the LAD led to a small reduction of RV systolic pressure and a small increase in end-systolic as well as end-diastolic volumes, resulting in a fall of stroke work. ESPVRs, however, were not acquired in this study. The same group of investigators, in a preliminary report [15], studied open-chest, open-pericardium, pigs before and after 50 min of mid-LAD occlusion, finding that this increased both LV and RV end-systolic volumes (though not as much as in our study), while end-systolic pressure of the RV remained the same, as we found.

Obviously, the effects on RV performance of ischemia in the septum and LV free wall, created by the LAD embolisation, observed in this acute study are merely an early indication of what may happen to RV systolic function on a long term basis. Thus, clinical implications of these findings may only be speculated upon with caution. The circumstance that the decrease in RV systolic performance is borne out in particular by an increase in end-systolic as well as end-diastolic volume (while SV and cardiac output are maintained) deserves attention: Apparently the RV, at least in this sheep model, is not able to compensate for the loss of contractile performance of the partly ischemic septum by enhancing the systolic shortening of its free wall. Rather, perhaps related to the distensible properties of this wall, the RV responds by stretching it to maintain SV. The resulting increase in volume might be an early hallmark of volume overload, eventually leading to RV remodeling and subsequent failure. Volume loading has been reported as a therapeutic measure [38,39], but inotropic support, e.g by dobutamine, appears more desirable than volume loading [40], as it has been shown to reduce RV volume, shifting the ESPVR to the left [12,18,41].

In summary, diminished systolic function of the RV is a clear consequence of ischemia of the LAD perfusion area. The ESPVR shifts are a result of regional dysfunction, however, regional dysfunction by necessity entails global dysfunction as well. Although systolic septal geometry did not change dramatically, the increase in RV free wall length seems to play an important role in the pathogenesis of RV diminished systolic function and must be secondarily related to the ischemia of the LV free wall and septum.

Time for primary review 26 days.


   Acknowledgments
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 Acknowledgments
References
 
This study was supported in part by the Netherlands Heart Foundation (grant number 94.081).


   References
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 

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