Eur J Cardiothorac Surg 2009;35:229-234. doi:10.1016/j.ejcts.2008.09.010
Copyright © 2009, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Progressive right ventricular failure is not explained by myocardial ischemia in a pig model of right ventricular pressure overload
Jan D. Schmittoa,*,
Hilmar Doergea,
Heiner Postb,
Marlon Coulibalya,
Christian Sellina,
Aron F. Popova,
Samuel Sossallaa,
Friedrich A. Schoendubea
a Department of Thoracic-, Cardiac- and Vascular Surgery, Universitätsmedizin Goettingen, Georg-August-Universität Goettingen, Germany
b Department of Cardiology, University of Graz, Austria
Received 5 March 2008;
received in revised form 1 September 2008;
accepted 8 September 2008.
* Corresponding author. Address: Department of Thoracic-, Cardiac- and Vascular Surgery, University Hospital of Goettingen, Robert-Koch Straße 40, 37099 Goettingen, Germany. Tel.: +49 551 39 6001; fax: +49 551 39 6002. (Email: schmitto{at}med.uni-goettingen.de).
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Abstract
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Background: Current concepts of acute pulmonary embolism suggest that right ventricular (RV) dilatation and failure are the consequence of pressure overload-induced RV hypoperfusion and ischemia. Methods: Sixteen human-sized hybrid pigs were instrumented for the measurement of RV and aortic pressure, aortic and right coronary artery blood flow (RCA BF), RV oxygen consumption (RV MVO2) and RV free wall segment length. The pulmonary artery was constricted (PAC) to increase RV peak pressure acutely 2.5-fold (from 27 ± 2 to 64 ± 3 mmHg, n
= 9), and the constriction was maintained for 6 h. Results: At 10 min after PAC, a RV work index (RVWI, RV pressure-segment length loops) was increased 2.3-fold, indicating an initial RV adaptation to increased afterload. At 1 h, 3 h and 6 h after PAC, however, RVWI decreased progressively towards control levels, while RCA BF and RV MVO2 continued to increase. The arterial-coronary venous pH difference did not increase throughout the protocol. Arterial troponin T concentration increased from 0.08 ± 0.03 to 0.80 ± 0.20 ng/ml at 6 h after PAC. None of the parameters changed in control animals (n
= 7). Conclusion: We conclude that in our model RV failure during PAC develops in spite of increased coronary blood flow and MVO2. Thus, mechanisms different from ischemia may contribute to progressive RV failure after pulmonary embolism.
Abbreviations: AOPmean
= mean aortic pressure • BG = banding group • CG = control group • CVP = central venous pressure • HR = heart rate • LV = left ventricle • n.a. = not assessed • PAC = constricted pulmonary artery • pH art = arterial pH • pH ven = RV coronary venous pH • RCA BF = right coronary artery blood flow • RV = right ventricle • RV dP/dt
max
= maximum first derivative of RV pressure • RV dP/dt
min
= minimum first derivative of RV pressure • RV edP = end-diastolic RV pressure • RV MVO2
= right ventricular oxygen consumption • RV pP = RV peak pressure • RVWI = RV work index • SLed = end-diastolic RV segment length • SLes = end-systolic RV segment length • 
SL = percent segment shortening • Trop T = serum troponin T concentration
Key Words: Right ventricular function • Pressure overload • Ischemia • Pulmonary embolism
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1. Introduction
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Pulmonary embolism is followed by a high mortality when the sudden increase in right ventricular (RV) afterload leads to RV failure [7,13]. Such acute cor pulmonale is predicted by RV dilatation or increases of troponin T and natriuretic peptide levels [7,14,16] and requires immediate removal of the thrombus by either thrombolytic therapy or surgical intervention [1,3,17].
Current pathophysiological concepts suggest that RV dilatation and failure evolve from a RV oxygen supply/demand imbalance secondary to a decrease in cardiac output, coronary perfusion pressure and coronary blood flow while RV wall tension and oxygen demand are increased [7]. The RV would thus become ischemic and finally develop overt failure. In this context, the release of troponin T during pulmonary embolism is interpreted as a marker of ischemic RV cell death [16]. Indeed, experimental studies in dogs applying pulmonary artery constriction (PAC) [2]; or pulmonary blood clot infusion [11] have demonstrated that upon a sufficient increase in pulmonary resistance, RV function will deteriorate within minutes, along with a drop of high-energy phosphates. When in these studies right coronary artery perfusion pressure and blood flow were increased by mechanical perfusion [2] or norepinephrine [11], RV function and high-energy phosphates recovered promptly. On the other hand, a series of studies by the group of Greyson and Schwartz in pigs has demonstrated that below a critical threshold, the RV can maintain substantially elevated pressures (approximately 60 mmHg) for 1 h without a decrease of RV blood flow, coronary venous pH or a shift of lactate consumption to lactate production [8,9,24]. Of note, as has been extensively studied in the left ventricle, any level of myocardial ischemia is immediately followed by a proportionate decrease or even loss of contractile function [6,23]. In contrast, RV function in patients suffering from pulmonary embolism frequently decompensates only several hours after the initial event, rendering ischemia unlikely as the main cause of RV failure in these cases [7].
We have previously demonstrated that dysfunctional RV myocardium due to pressure overload shows ultrastructural signs of focal adrenergic overstimulation rather than ischemia [21]. In the present study, we thus aimed to characterize RV function and metabolism after pulmonary artery constriction sustained for 6 h. The degree of pulmonary stenosis was such that the RV would initially be able to compensate for the acute increase in afterload.
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2. Methods
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The experimental protocols employed in this study were approved by the bioethical committee of the district of Braunschweig, Germany, and they conform to the guiding principles for the care and use of laboratory animals published by the US National Institutes of Health.
2.1 Experimental preparation
Sixteen human-sized hybrid pigs of either sex (62.2 ± 5.1 kg) were sedated with intramuscular ketamine (10 mg/kg), atropine (0.03 mg/kg) and azaperone (4 mg/kg), anesthetized with intravenous ketamine (7–9 mg/kg h) and pentobarbital (6–9 mg/kg h) and ventilated with room air with a respirator (Dräger Ventilog 2, Dräger, Lübeck, Germany). Bolus injections of pancuronium (4 mg/h) were used for muscular relaxation. An ECG was recorded from needle electrodes. Fluid filled catheters were inserted into the right internal carotid artery and jugular vein for the measurement of aortic and central venous pressures. An inflatable Fogarty balloon catheter (8/22 F, Edwards Life Sciences, Irvine, USA) was positioned in the descending aorta via the right femoral artery to compensate for a decrease in aortic pressure during the protocol. The chest was opened by median sternotomy, the thymus removed and the pericardium was opened. A Millar tip catheter (5 F) was inserted transmurally into the right ventricle, and flow probes (Transonic type) were placed around the ascending aorta (type 20A) and the proximal right coronary artery (type 3S). A right ventricular free wall epicardial vein was cannulated, and a pair of piezoelectric crystals (Hugo Sachs Elektronik, March-Hugstetten, Germany) was implanted in the free right ventricular wall for sonomicrometry. The pericardium was left open after instrumentation to avoid displacement of the catheters and crystals. To perform stable PAC, an adjustable mechanic occluder was placed around the proximal pulmonary artery. The occluder consisted of the following.
2.2 Hemodynamic recordings, blood gas analysis and troponin T measurement
Analog signals were stored digitally on a personal computer via an analog–digital interface at a sampling rate of 400 Hz and processed by commercial software (HSE Hämodyn, Hugo Sachs Elektronik). Parameters stored were ECG, aortic pressure, central venous pressure, aortic blood flow, right coronary artery blood flow, right ventricular pressure and right ventricular segment length. End-diastole was derived from the R-wave of the ECG, and end-systole was defined as the time point of peak negative right ventricular dP/dt
[20]. Percent segment shortening was calculated as the ratio of end-diastolic minus end-systolic segment length and end-diastolic segment length. An index of regional external right ventricular work was determined by calculating the area of the right ventricular segment length-pressure loop during one cardiac cycle. Arterial and coronary venous blood gases and pH were determined in a blood gas analyzer (ABL 610, Radiometer, Copenhagen, DK), and the respective difference was calculated as a parameter of ischemia-induced acidosis [5]. Right ventricular oxygen consumption was estimated from the difference between arterial and right ventricular venous oxygen contents multiplied by right coronary artery blood flow. Troponin T concentration in arterial blood samples was determined by a commercial electro-chemical luminescence immunoassay (ECLIA, Roche Diagnostics, Mannheim, Germany).
2.3 Experimental protocol
The animals were anticoagulated with a bolus injection of 10,000 IE heparin followed by 5000 IE/h. Arterial blood gases were monitored frequently, and 50 ml of sodium bicarbonate (8.4%) were given when the arterial pH dropped below 7.3. Sodium chloride solution (0.9%) was infused with a rate of 500 ml/h. After baseline measurements, the pulmonary artery constrictor was adjusted to acutely increase peak right ventricular pressure approximately 2.5-fold (banding group, BG, n
= 9) [21]. The amount of mechanic PAC was not altered thereafter. Since six of nine animals in BG developed transient arrhythmias after PAC, the first measurement was performed not before 10 min after PAC and at 1 h, 3 h and 6 h after PAC thereafter. In BG, the Fogarty balloon catheter was inflated stepwise when mean aortic pressure decreased by more than 10 mmHg below baseline to keep coronary perfusion pressure constant. No PAC was applied in the control group (CG, n
= 7).
2.4 Data analysis and statistics
Hemodynamic measurements were taken and averaged during a 10 s period corresponding to two respiratory cycles. All data reported are mean ± SD. To consider changes in spontaneous beating rate, the RV work index was also multiplied by heart rate. Statistical analysis was performed by a two-way ANOVA for repeated measurements (RM) followed by Tukey's post hoc tests when overall effects were detected (Sigma Stat 2.03, Urbana, IL, USA).
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3. Results
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3.1 Systemic hemodynamics and regional right ventricular function
Heart rate increased during PAC (Table 1
). Aortic flow decreased by 21% at 10 min and by 40% at 6 h after PAC. At 10 min after PAC, RV peak pressure was increased but decreased significantly throughout the protocol. Central venous pressure increased slightly, while RV end-diastolic pressure did not change significantly. Mean aortic pressure was prevented from significant changes during PAC by aortic balloon inflation but was lower in BG than in CG at 6 h after PAC. Inflation of the aortic balloon catheter was not started before 1 h after PAC.
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Table 1 Systemic hemodynamics in pigs at baseline and after pulmonary constriction compared to sham-treated animals.
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RV end-diastolic segment length increased by approximately 6% and 11% at 10 min and 6 h after PAC (Table 2
and Fig. 1
), while RV segment shortening decreased progressively after PAC, respectively. The RV free wall external work index increased two-fold at 10 min after PAC but then decreased progressively below baseline values at later time points. This biphasic response of the work index remained apparent also when the increase in heart rate was considered (Fig. 2
). None of the parameters changed in CG except from a slight decrease of aortic flow at 6 h (–13%).
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Table 2 Regional myocardial function and metabolism in pigs at baseline and after pulmonary constriction compared to sham-treated animals.
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Fig. 1. Representative right ventricular pressure-segment length loops after pulmonary artery constriction (PAC). Increased end-diastolic segment lengths indicate progressive RV dilatation, while an increase of the loop area at 10 min is not maintained at 1 h and 6 h.
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Fig. 2. RV work index multiplied by heart rate. The work index increases 2.3-fold after PAC in BG but decreases towards baseline values at later time points. CG: control group; BG: banding group. Values are mean ± SEM; two-way ANOVA RM + Tukey's post-hoc test. *p
< 0.05 vs baseline; #p
< 0.05 vs 10 min; &
p
< 0.05 vs 1 h; 
p
< 0.05 vs CG.
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3.2 Right coronary artery blood flow, RV oxygen consumption and pH
Right coronary artery blood flow continued to increase after PAC but remained constant in CG (Table 2). Similarly, RV oxygen consumption increased progressively after PAC, while it did not change in CG (Fig. 3
). Arterial and coronary venous pH decreased at 3 h and 6 h after PAC in BG, whereas the respective difference did not change throughout the protocol (Fig. 4
).
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Fig. 3. RV oxygen consumption continues to increase after PAC in spite of progressive RV free wall dysfunction. CG: control group; BG: banding group.
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Fig. 4. The difference between arterial pH and RV coronary venous pH (pH) remains unchanged in BG and CG throughout the protocol, rendering it unlikely that the RV suffered from ischemia during the protocol. CG: control group; BG: banding group.
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3.3 Troponin T
Arterial plasma troponin T concentration increased significantly at 6 h after PAC, but remained constant in control animals (Table 2).
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4. Discussion
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The prognosis of patients suffering from acute pulmonary embolism critically depends on whether RV function will remain sufficient to ensure an adequate cardiac output in spite of elevated pulmonary resistance. Importantly, clinical observations demonstrate that RV failure may not only occur immediately after pulmonary embolism, but also several hours thereafter under conditions of intensive care monitoring and anticoagulatory treatment [7]. Experimental studies indicate that above a critical threshold of pulmonary obstruction, RV failure will occur within minutes as a consequence of RV hypoperfusion [2,11], while at slightly lower levels of pressure load, RV perfusion and function can remain constantly elevated for 1 h [8,9,24]. However, whether such successful RV adaptation can extend to clinically more relevant periods >1 h has not yet been tested experimentally. We thus designed the present study to apply an increase of RV afterload that could be met by RV function at an early time point (10 min) after pulmonary artery constriction and followed the time course of RV function and metabolism for a further 6 h.
In the present study, there was a pronounced increase of RV pressure and RV work index at 10 min after pulmonary constriction, while RCA blood flow and RV MVO2 were elevated and the arterial-coronary venous pH difference remained constant. It was previously illustrated that in the left ventricle, myocardial ischemia reduced myocardial function [6,23] and coronary venous pH [23] within minutes, even at a mild level of ischemia that would allow for myocardial hibernation and not induce myocardial infarction [5,22]. Therefore, the RV most likely had adapted to the increased afterload with no sign of ischemia at 10 min after pulmonary artery constriction in the present study. However, a decrease of aortic flow and percent RV segment shortening and an increased RV diastolic segment length already indicated some degree of RV dysfunction. At 1 h after the onset of pressure overload, RV pressure and RV work index had decreased to some extent, together with further end-diastolic segment length dilatation and decrease of segment shortening and aortic flow. In contrast, RCA blood flow and RV MVO2 remained increased, while a slight change of the arterial-coronary venous pH was not significant versus baseline and not different from control animals at this time point. Thus, while RV functional parameters tended to decrease, metabolic measurements did not present a correlate of hypoperfusion. Interestingly, the changes of RV peak pressure, segment dimensions, aortic flow and MVO2 at 1 h after pulmonary constriction in the present study were close to the findings of Greyson and Schwartz at the same time point in a similar pig model [8,9,24]. These authors did not observe a decrease of lactate extraction or a drop of coronary venous pH, but demonstrated a mild drop of high-energy phosphates by 31P nuclear magnetic resonance spectroscopy [24]. However, in contrast to the study of Vlahakes et al. measuring a massive fall in RV creatine phosphate after severe pulmonary constriction, increasing RV blood flow by aortic constriction in the study of Schwartz et al. did not have an impact on RV pressure or increase high-energy phosphates [24]. They did therefore not interpret slightly lowered high-energy phosphates as an indicator of insufficient RV perfusion. In the present study, further decreases of RV peak pressure, RV work index, segment shortening and aortic flow indicated progressive and severe RV dysfunction at 3 h and 6 h after onset of pressure load. In contrast, with coronary perfusion pressure kept constant by inflation of the aortic balloon catheter, there was a further increase of RCA blood flow and RV MVO2, while the arterial-coronary venous pH difference remains constant, respectively. Thus, even though an approximately 40% reduction of aortic flow indicated severe cardiac failure, metabolic parameters did still not point to RV ischemia as the underlying cause of aggravating RV failure in our model.
At the end of the protocol, there was a significant increase of troponin T comparable to clinical findings in critical patients [15], which might reflect ischemic cardiomyocyte death. In a previous study, we performed ultrastructural analyses of RV samples taken before and after a similar protocol [21]. We found an increased sarcoplasmic volume fraction and cellular edema, but no signs of mitochondrial integrity disruption as would be typical for ischemic damage. Moreover, necrosis appeared in a single cell pattern close to nerve endings, as demonstrated previously with adrenergic overstimulation. Therefore, cardiomyocyte death as indicated by elevated troponin T may have resulted from elevated regional catecholamine levels due to severe cardiac failure and did not necessarily stem from myocardial ischemia.
Given that progressive RV dysfunction in the present study is not the consequence of RV ischemia, the question arises as to what other mechanisms may be responsible for RV failure. Greyson found that 1 h of RV pressure overload-induced RV dysfunction for at least 2 h after release of pulmonary artery obstruction without any change in blood flow versus control values; clearly demonstrating that acute RV pressure overload may compromise RV function apart from ischemia [9]. A pattern of progressive loss of cardiac function in spite of preserved blood flow, similar to the present study, has also been observed in experimental studies of myocardial function after cardioplegia [18] and coronary microembolization [4], the latter being essentially mediated by tumor necrosis factor alpha and inhibited by corticoid treatment [Circulation 2004 May 18;109(19):2337–42). Remarkably, myocardial stretch, as indicated by end-diastolic segment length increase in the present study, is also a trigger of myocardial tumor necrosis factor alpha production [12]. It remains to be assessed whether steroids could also protect RV function during pressure overload following, for example, pulmonary embolism. Furthermore, myocardial stretch activates p38 MAP kinase [26], which exerts a pronounced negative inotropic effect in isolated cardiomyocytes [19]. p38 MAP kinase inhibitors are currently being tested for several inflammatory diseases [J Dent Res 2007 September;86(9):800–11], and possibly, targeting stretch-activated or inflammatory signal transduction pathways will give way to further therapeutic approaches in acute RV pressure overload and subsequent RV dysfunction.
4.1 Limitations
The RCA perfusion territory in pigs does not only encompass the RV free wall (approximately 43%), but also the right atrium (14%) and posterior interventricular septum (43%) [10]. Changes in RCA blood flow may therefore not completely reflect blood flow in the RV free wall, where segment length dimensions and RV coronary venous data were obtained. Since the left ventricle in the present study was not subjected to pressure or volume load but rather the opposite, RCA blood flow measurement might have underestimated changes in RV free wall blood flow and RV MVO2. Nevertheless, the data reported in the present study at 1 h after pulmonary artery constriction were similar to changes in regional blood flow reported by Greyson et al. in a similar porcine model [8].
Pulmonary embolism initiates a multi-faceted release of vasoactive factors in the pulmonary vasculature that is not mimicked by pulmonary artery constriction [25]. However, with RV function as the final determinant of survival, we applied pulmonary artery constriction rather than, for instance, pulmonary blood clot infusion in order to induce a stable and reproducible degree of increased RV afterload.
Finally, the decrease of cardiac output measured as aortic flow does not necessarily only reflect decreased RV contractility, but can also be mediated by tricuspid insufficiency and paradoxical septum movement, which in addition impairs left ventricular filling [J Am Coll Cardiol 1987;10:1201–1206; Prog Cardiovasc Dis 1998 January–February;40(4):289–308]. Our model did not allow for measurement of tricuspid function and septal movement, but assessed RV function on a regional level in the RV free wall. However, an additional RV volume load by potential tricuspid insufficiency would be included in the regional segmental dimensions by an increased end-diastolic segment length. Paradox septal movement in turn may further compromise global cardiac function, but would not impact on regional RV free wall shortening and oxygen consumption.
In conclusion, our findings suggest that RV pressure overload can induce progressive RV dysfunction without metabolic signs of myocardial ischemia. Therefore, RV pressure and stretch themselves may be triggers of RV failure during pulmonary embolism.
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Abstract
1. Introduction
