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Original Article

Acute pulmonary hypertension causes depression of left ventricular contractility and relaxation

Amà, R.1,*; Leather, H. A.1,*; Segers, P.; Vandermeersch, E.*; Wouters, P. F.*

Author Information
European Journal of Anaesthesiology: October 2006 - Volume 23 - Issue 10 - p 824-831
doi: 10.1017/S0265021506000317



Acute pulmonary hypertension has profound effects on left ventricular (LV) function and systemic haemodynamics that can be largely attributed to ventricular interdependence. It is generally assumed that diastolic ventricular cross-talk is the most important mechanism in this setting: reduced forward flow over the pulmonary circulation (serial interaction) and direct compression of the LV cavity by a dilated right ventricle (RV) (parallel interaction) both result in decreased LV preload and, subsequently, of LV function via the Frank–Starling mechanism [1–3]. However, the assumption that diastolic interventricular interaction is the main cause of haemodynamic instability in pulmonary hypertension is most probably oversimplified, and offers few therapeutic perspectives. For example, volume loading has only limited or even harmful effects in the clinical condition of acute pulmonary embolism [4].

There is also evidence for the existence of systolic interaction between the ventricles. For example, ischaemic RV dilatation has been shown to reduce LV contractility [5]. Similarly, LV contractility has been reported to be reduced by an increase in RV afterload in the isolated canine heart [6]. In the opposite direction, it has been reported that an increase in LV afterload may reduce RV contractility [7]. However, although there is evidence that ventricular interaction may actually involve changes in fundamental muscle properties such as contraction and active relaxation (rather than simple modification of passive loading conditions), there is a lack of information concerning the effect of pulmonary hypertension on LV systolic function in vivo, using load-independent parameters.

Pulmonary hypertension induces complex changes in LV geometry and causes a non-uniform contraction pattern in the LV wall [8,9]. Since (non-)uniformity is a major determinant of ventricular contraction and relaxation [10,11], we hypothesized that acute pulmonary hypertension may indeed have a direct impact on LV systolic performance, independent of its effects on preload. The aim of the present study was to test this hypothesis by studying load-independent indices of contraction and relaxation in both ventricles in an experimental model of acute pharmacologically induced pulmonary hypertension.


This investigation was approved by the Ethics Committee of the Katholieke Universiteit Leuven. Ten pigs (weight 34 ± 6 kg) were included in this study. The instrumentation used has previously been described in detail [12]. Briefly, the animals were premedicated with ketamine hydrochloride 20 mg kg−1, piritramide 1 mg kg−1 and atropine 0.5 mg intramuscularly. Anesthesia was induced with intravenous sodium pentobarbital 12 mg kg−1 and piritramide 1 mg kg−1 and maintained with sodium pentobarbital 4 mg kg−1 h−1 and piritramide 1.5 mg kg−1 h−1. The lungs were mechanically ventilated with a mixture of oxygen and room air to maintain normocapnia and normoxia. Lactated Ringer's solution was administered at a rate of 8 mL kg−1 h−1.

A triple-lumen catheter was inserted in the right jugular vein. A fluid-filled catheter was advanced into the proximal aorta via the left carotid artery for monitoring of systemic arterial pressure. Via a midline sternotomy, a tourniquet was placed around the inferior vena cava for controlled alterations of preload. A 20-mm perivascular flow probe (Transonic Systems Inc., Ithaca, NY, USA) was placed around the main pulmonary artery. A micro-tipped pressure transducer (Millar Instruments, Houston, TX, USA) was advanced into the pulmonary artery via a small stab wound in the pulmonary outflow tract. Combined pressure transducer and conductance catheters (Millar Instruments and CDLeycom, Zoetermeer, The Netherlands) were inserted into the RV and LV through a stab wound in the pulmonary outflow tract, and via the right carotid artery respectively.

Data acquisition and analysis

Each conductance catheter was connected to a signal processing unit (Sigma 5 DF; CDLeycom, Zoetermeer, The Netherlands), in one of which the excitation frequency had been adjusted from 20 to 19 kHz in order to avoid cross-talk [13]. The theory of conductance volumetry has been described extensively previously [14]. Parallel conductance and blood resistivity were measured at regular intervals using the hypertonic saline method (injection of NaCl 10% 5 mL into the right atrium) and the CDLeycom resistivity meter respectively. The correction factor α was re-calculated for each measurement.

All parameters were digitized at 300 Hz and stored for off-line analysis with algorithms written in Matlab® (The Mathworks Inc., Gouda, The Netherlands). End-systole was calculated in an iterative fashion as described previously [15]. The time constant of ventricular relaxation τ was calculated from steady state data using the monoexponential zero asymptote method [16,17]. The end-diastolic pressure–volume relationship (EDPVR), obtained during inferior vena cava occlusion, was fitted by means of a Levenberg–Marquard algorithm in order to calculate the chamber stiffness constant β [18] according to the following formula: EDP = −y0 + A1 · eβ·EDV where y0 is the pressure asymptote and A1 is a constant. The load-dependency of relaxation was quantified by the slope of the τ-end-systolic pressure relationship, R. This was calculated by analysing τ and end-systolic pressure beat by beat during inferior caval vein occlusion. Contractility was quantified by the slope of the preload recruitable stroke work relationship and the slope and volume intercept (at 100 or 30 mmHg for the left and right ventricle respectively, V100 and V30) of the end-systolic pressure–volume relationship (ESPVR). Effective arterial elastance was calculated using steady state data as described previously [19].

Experimental protocol

After completion of instrumentation and achievement of haemodynamic steady state, baseline measurements were performed with the ventilation suspended at end-expiration. Data were acquired during steady state conditions and during a brief (5–10 s) occlusion of the inferior vena cava to obtain a range of pressure–volume loops.

An infusion of U46619 (9,11-dideoxy-9α,11α-methanoepoxy Prostaglandin F) (Cayman Chemical, Ann Arbor, Michigan, USA) dissolved in saline 0.9% at a concentration of 6.25 μg mL−1 was started at a rate of 0.02 μg kg−1 min−1 and titrated to achieve an increase of pulmonary vascular resistance of at least 100% (mean dose 0.08 μg kg−1 min−1). Preliminary experiments had indicated that more pronounced effects with higher doses of U46619 resulted in unstable haemodynamics and sudden death. Once a stable infusion rate had been achieved (between 30 and 60 min following the starting of the infusion), the U46619 was administered continuously for at least 30 min. Arterial blood gases were determined every 15 min during U46619 administration and the ventilation was adjusted to maintain blood gases within the range of the baseline values. After a haemodynamic steady state had been present for at least 15 min, all haemodynamic measurements were repeated. The experimental protocol was completed within 1.5–2 h.

Statistical analysis

Alterations in haemodynamic parameters induced by acute pulmonary hypertension were analysed using two-tailed paired t-tests. All analyses were performed using Excel® (Microsoft Corporation) software package. A P-value <0.05 was considered statistically significant. All data are expressed as mean ± SD.


U46619 infusion caused a 130% increase in pulmonary vascular resistance, accompanied by an increase in pulmonary artery pressure (Table 1). Pulmonary arterial elastance increased threefold. Heart rate, systemic vascular resistance and systemic arterial elastance increased. Cardiac output decreased, and systemic arterial pressures did not change.

Table 1
Table 1:
Systemic and pulmonary haemodynamic parameters (mean ± SD).

RV end-diastolic volume (EDV) and pressure increased significantly in response to the pulmonary vasoconstriction, while ejection fraction decreased. Pulmonary vasoconstriction caused a deterioration of RV active relaxation, as assessed with τ, and of RV diastolic stiffness, as assessed with the chamber stiffness constant b of the EDPVR (Table 2 and Fig. 1a). The load dependence of relaxation (assessed by the slope R of the τ-end-systolic pressure relationship) deteriorated (Fig. 2). The slope of the preload recruitable stroke work relationship and ESPVR did not change significantly, but there was a leftward shift of the ESPVR.

Table 2
Table 2:
RV function and mechanical performance (mean ± SD).
Figure 1.
Figure 1.:
Ventricular contractility in baseline and pulmonary hypertension. Representative example of the pressure–volume loops (main windows) and preload recruitable stroke work (small windows) during caval occlusion in baseline and pulmonary hypertension. Panel A: right ventricle. Panel B: left ventricle. RV: right ventricle; LV: left ventricle; EDV: end-diastolic volume; RVP: right ventricular pressure; LVP: left ventricular pressure; PRSW: preload-recruitable stroke work; EDPVR: end-diastolic pressure–volume relationship.
Figure 2.
Figure 2.:
Load-dependency of relaxation in baseline and pulmonary hypertension. Representative beat-by-beat regression of τ vs. end-systolic pressure relationships (slope of which is R) in baseline and pulmonary hypertension in both left (Panel A) and right (Panel B) ventricles. LV: left ventricle; RV: right ventricle; τ: time constant of isovolumic relaxation; ESP: end-systolic pressure.

Pulmonary vasoconstriction caused a decrease in LV EDV, without a change in EDP. Ejection fraction decreased. As in the RV, both τ and the stiffness constant β of the EDPVR increased (Table 3 and Fig. 1b). The load dependence of relaxation deteriorated (Fig. 2). Most importantly, the slope of the preload recruitable stroke work relationship decreased by 22% and there was a rightward shift of the ESPVR (Fig. 1b). Regression analysis showed a relationship between the decrease in LV preload-recruitable stroke work (PRSW) and the increase in RV peak pressure (Fig. 3).

Table 3
Table 3:
LV function and mechanical performances (mean ± SD).
Figure 3.
Figure 3.:
Scatterplot of change in LV preload recruitable stroke work vs. increase in RV peak pressure from baseline to pulmonary hypertension. LV PRSW: left ventricular preload recruitable stroke work; peak RVP: right ventricular peak pressure. The line is the second order polynomial regression line.


The main finding of the present study is that pulmonary hypertension depresses LV contractile properties and active relaxation. This provides additional evidence for the existence of a negative systolic ventricular interaction in pulmonary hypertension.

There are several mechanisms that may explain the observed systolic interaction. Intuitively, one could expect the reduction in LV preload (i.e. one consequence of the well-known diastolic ventricular interaction) to result in a reduction in LV pump performance via the Frank–Starling relationship. However, the contractile indices that we used, the ESPVR and the preload recruitable stroke work relationship in particular, are relatively load-independent (Fig. 1b) [20–22] and inherently account for effects of filling on ventricular performance. This suggests that the reduction in LV performance that we observed is not only caused by altered LV diastolic filling, but also by a decrease in LV contractility. We speculate that acute pulmonary hypertension causes abnormal instantaneous transseptal pressure gradients, disturbed ventricular geometry [8] and a dyssynchronic contraction pattern during ejection [9], resulting in a reduction in LV contractility. It has indeed previously been demonstrated that, during acute pulmonary hypertension, diastolic and systolic septal bulging occurs [23].

Our findings are compatible with a number of previous studies that provide evidence for the existence of systolic interaction between left and right ventricle in circumstances such as RV ischaemia [5], LV ischaemia [24] and increased LV afterload [7]. In the specific setting of acute pulmonary hypertension, there is still controversy. In two previous articles, where LV contractility was assessed in neonatal lambs during lavage-induced respiratory distress syndrome, no change in LV contractility was observed [25,26]. However, the physiological setting of these two studies cannot be directly compared with the present study since the model involved neonatal animals with major disturbances in arterial blood gas parameters. In another study, Feneley and co-workers described that partial pulmonary artery occlusion did not reduce steady-state LV stroke work at a given LV EDV [27]. This finding does not necessarily contradict our observations because in this setting a possible change in slope of the preload recruitable stroke work relationship could be masked by a change in its intercept. In agreement with our observations, systolic ventricular interaction causing a reduction in LV contractility has been described in an isolated canine heart model [6]. Additionally, several in vivo studies have reported a reduction in LV performance [8,28–30] during acute pulmonary hypertension. To our knowledge, no previous in vivo study has described a reduction in LV contractility during acute pulmonary hypertension using load-independent parameters.

Acute pulmonary hypertension also caused an impairment of LV relaxation as indicated by the prolongation of τ. Moreover, load-dependency of relaxation, quantified by the slope R of the relationship between τ and end-systolic pressure, deteriorated significantly compared to baseline conditions. R is generally accepted to be a load-independent measure of relaxation and has been suggested to reflect a fundamental systolic property of the myocardium [31–34]. Interestingly Brutsaert and Sys previously suggested that RV distortion would affect both LV contraction and relaxation [31]. Our findings are in agreement with this hypothesis. The effects of pulmonary hypertension on the passive filling phase of the left ventricle, as quantified by the EDPVR in the present study, are consistent with previous data [35]. We observed an increase of the stiffness constant β (i.e. an increase in the curvilinearity of the EDPVR), which demonstrates a deterioration of LV passive diastolic properties. This indicates that diastolic interaction is also important in open pericardium settings such as cardiac surgery.

In the RV, pulmonary hypertension had little effect on contractility. Although there was a leftward shift in the ESPVR, the slopes of the preload recruitable stroke work relationship and the ESPVR did not change significantly. This is consistent with a previous study where we observed no significant change in the slope of the RV preload recruitable stroke work relationship in dogs with U46619-induced pulmonary hypertension [19]. As in the left ventricle, changes in RV τ and R suggest a deterioration of active relaxation and its load-dependency during pulmonary hypertension. However, when interpreting a change in R, one must take into account the non-linearity of the τ-end-systolic pressure relationship. A change in operating pressures can cause the ventricle to shift on its ( J-shaped) τ-end-systolic pressure curve, causing a change in measured R without this signifying a change in the load dependence of relaxation [34,36,37]. In the present study, right ventricular end-systolic pressure increased significantly during pulmonary hypertension (in contrast to the left ventricle). We therefore cannot exclude that the change in R which we observed was due to a shift in operating pressures rather than a genuine increase in load-dependency of RV relaxation properties [36].

We observed a reduction in RV diastolic compliance (assessed with the chamber stiffness constant β, a load-independent method) in response to pulmonary hypertension. This study therefore provides evidence of a change in RV passive diastolic properties in response to pulmonary hypertension, even in the open pericardium setting.

The present findings have a number of potential clinical implications. Besides causal therapy and attempts to reduce pulmonary vascular resistance [38], supportive therapy is very important in the treatment of acute pulmonary hypertension at present. Particularly in the perioperative and intensive care settings, acute pulmonary hypertension still has a high-mortality rate [39,40]. The supportive therapy often focuses on compensating for the disturbed LV diastolic compliance by increasing diastolic filling. Volume loading is still routinely used in this context, despite ample evidence that this is not effective [4]. The present study provides preliminary evidence that more attention should be paid to supporting LV contractile function and relaxation. It would appear that positive ionotropic and lusitropic drugs might deserve a more prominent role in the treatment of acute pulmonary hypertension.

A limitation of the present study is the fact that we cannot exclude a direct cardiac depressant effect of U46619 on the LV. However, U46619 has been shown to have a positive inotropic effect on guinea pig left atrium [41,42] and our data also show a tendency toward an increase of RV contractility. At present no single experimental model is superior in mimicking the clinical syndrome of acute pulmonary hypertension.

We conclude that, in the present model, acute pulmonary hypertension decreases LV contractility and relaxation. This provides evidence for the presence of systolic ventricular interaction in the pathophysiology of acute pulmonary hypertension. Further studies are required in order to explore the relative importance of this phenomenon and the appropriateness of ionotropic and lusitropic therapy in the closed chest, closed pericardial setting.


The authors thank Kirsten Ver Eycken for her technical assistance. This study was supported by the Fund for Scientific Research, Flanders, Belgium (Grant K.A.N. to P.W. and a doctoral grant to H.A.L.) and the Research Fund K.U. Leuven.


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