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Ann Thorac Surg 2006;82:989-995
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Adaptation of the Right Ventricle to an Increased Afterload in the Chronically Volume Overloaded Heart

^a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
^b Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary
^c Department of Cardiology, University of Heidelberg, Heidelberg, Germany
^d Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany

Accepted for publication April 13, 2006.

^_* Address correspondence to Dr Szabó, Department of Cardiac Surgery, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. (Email: dzsi{at}hotmail.com).

Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Increased right ventricular afterload is a common problem after correction of various heart diseases with chronic volume overload. We determined the effects of an acute increase of right ventricular afterload in normal and chronically volume overloaded hearts.

METHODS: In 6 dogs, volume overload was induced by chronic arteriovenous shunts for 3 months. Six sham-operated animals served as controls. After closing the shunts, right ventricular systolic and end-diastolic pressure as well as end-diastolic volume were measured by conductance catheter. In addition, pressure–volume loops were recorded. Myocardial contractility was described by the slope of the end-systolic pressure–volume relationship. Afterload was increased to right ventricular systolic pressure to 35 mm Hg and to 50 mm Hg by pulmonary banding.

RESULTS: Chronic volume overload resulted in a significant increase of right ventricular systolic pressure (34 ± 2 versus 25 ± 2 mm Hg, p < 0.05), end-diastolic pressure (10.4 ± 1.7 versus 6.8 ± 0.4 mm Hg, p < 0.05), and end-diastolic volume (39 ± 2 versus 33 ± 3 mL, p < 0.05). Baseline contractility (1.47 ± 0.24 versus 1.53 ± 0.32 mm Hg/mL) did not differ. While afterload increase to 35 and 50 mm Hg led to stepwise increase in contractility (2.73 ± 0.30 mm Hg/mL and 4.15 ± 0.30 mm Hg/mL, p < 0.05 versus baseline, respectively) at unchanged end-diastolic pressure and volume in controls, it showed only a slight increase (2.11 ± 0.38 mm Hg/mL and 2.99 ± 0.29 mm Hg/mL, p < 0.05 versus sham) with concomitant increase in end-diastolic pressure (12.4 ± 2.2 mm Hg/mL and 16.3 ± 1.9 mm Hg, p < 0.05) and volume (42 ± 4 mL and 48 ± 8 mL, p < 0.05) in the chronically volume overloaded group.

CONCLUSIONS: Chronic volume overload per se does not impair right ventricular contractility. However, the inotropic adaptation (homeometric autoregulation) to an increased afterload is limited, which is partly compensated by the Frank-Starling mechanism (heterometric autoregulation).

	Introduction

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Until recently, right ventricular failure was a relatively neglected medical condition. The right ventricle was considered as a moderately passive conduit between the systemic and pulmonary circulations. This belief was supported by studies showing that complete destruction of the right ventricular free wall in dogs had no detectable impairment on overall cardiac performance [1]. However, precipitating factors for right ventricular failure are common in the clinical praxis of cardiothoracic surgery and intensive care medicine. These include increased pulmonary resistance, such as after cardiac transplantation, acute respiratory distress syndrome, the presence of left ventricular assist device, positive pressure mechanical ventilation, and sepsis. There is also a higher incidence of right ventricular failure than is generally recognized.

In general, right ventricular failure has a similar incidence to left-sided heart failure, with each affecting about 1 in 20 of the population [2]. In particular, cardiocirculatory dysfunction associated with cardiopulmonary bypass and cardiac arrest is often caused by depressed right ventricular function [3]. This situation is aggravated by a transient pulmonary hypertension occurring frequently after cardiopulmonary bypass as a result of endothelial injury [4], decreased nitric oxide [5], or increased thromboxane [6] synthesis. The phenomenon of acute elevation of right ventricular afterload—as a main cause of early morbidity and mortality—in the setting of cardiac transplantation has been studied extensively [7–9]. These studies showed that the adaptation mechanisms of right ventricle to an increased afterload might be exhausted under certain pathophysiologic conditions. We described previously [8] that right ventricle may adapt to an increased afterload by two different ways: by the increase of myocardial contractility (homeometric autoregulation or Anrepp effect) and by increase of preload (heterometric autoregulation or Frank-Starling mechanism) [8]. While these observations were made in the primarily healthy right ventricle, no data exist about the adaptive mechanisms of right ventricle in the failing heart.

As chronic volume overload (congenital shunt defects, atrioventricular valve incompetence, and so forth) is a common cause of right heart failure in patients referred to cardiac surgery and often associated with transient or chronic pulmonary hypertension, we investigated the adaptation potential of the right ventricle to an increased afterload in the chronically volume overloaded canine heart.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animals
Twelve mongrel dogs weighing 15 to 30 kg (21 ± 5 kg) were used in this experiment. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1996). In 6 animals, an arteriovenous shunt was created as described below. Six sham-operated animals served as controls.

General Management, Surgical Preparation
The dogs were premedicated with propionylpromazine and anesthetized with a bolus of pentobarbital (15 mg/kg initial bolus and then 0.5 mg · kg^-1 · h^-1 intravenously), paralyzed with pancuronium bromide (0.1 mg/kg as a bolus and then 0.2 mg · kg^-1 · h^-1 intravenously) and endotracheally intubated. The dogs were ventilated with a mixture of room air and oxygen (FiO₂ = 60%) at a frequency of 12 to 15 per minute and a tidal volume starting at 15 mL/kg per minute. The settings were adjusted by maintaining arterial partial carbondioxide pressure levels between 35 and 40 mm Hg. The femoral artery and the saphenous vein were cannulated for recording aortic pressure (AoP) and taking blood samples for the analysis of blood gases, electrolytes and pH. Basic intravenous volume substitution was carried out with Ringer's solution at a rate of 1 mL · min^-1 · kg^-1. If necessary, the rate of volume substitution was modified according to the continuously controlled input-output balance to maintain cardiac output at baseline levels. According to the values of potassium, bicarbonate, and base excess, substitution included administration of potassium chloride and sodium bicarbonate (8.4%). Neither catecholamines nor other hormonal or pressor substances were administered. Rectal temperature and standard peripheral electrocardiogram were monitored continuously.

Chronic volume overload was induced by bifemoral arteriovenous shunts. Under general anesthesia (as described above), 3-cm-long inguinal incisions were performed bilaterally. The femoral artery and vein were dissected, and 6- to 7-mm side-to-side anastomosis were created between the vessels, and shunt flow was measured. Thereafter, the wounds were closed and the animals were allowed to recover. The animals were kept on normal diet for 3 months.

After 3 months, the animals were anesthetized again. Left anterolateral thoracotomy was performed in the fourth intercostal space. After pericardiotomy and isolation of the great vessels, a perivascular ultrasonic flow probe was attached to the ascendent aorta. A combined 6F Millar pressure-conductance catheter (Millar Instruments, Houston, Texas) with 6-mm spacing was inserted into the left ventricle through the apex. A second 6F Millar pressure-conductance catheter with 5-mm spacing was inserted into the right ventricle through the pulmonary artery. Aortic pressure and right atrial pressure were monitored with 5F Millar catheter tip manometers. In the animals with chronic volume overload, shunt blood flow was measured and then the shunts were closed. The animals were subjected to a 1-hour equilibrium period before the hemodynamic assessments were continued.

To examine the adaptation potential of the right ventricle to an afterload increase, the pulmonary artery was constricted by tightening a snare around the pulmonary artery 3 to 4 cm distal to the right ventricular outflow tract. An increase in right ventricular systolic pressure to approximately 35 mm Hg and approximately 55 mm Hg was achieved by progressive constriction of the pulmonary artery. Measurements were taken 20 minutes after pulmonary banding at both levels in steady state. After the second pulmonary banding level, the snare was loosened and the dogs were allowed to return to baseline steady state. If necessary, volume substitution was applied to keep cardiac output at a constant level during this protocol.

At the end of the experiments, the animals were euthanized by an overdose of potassium, and the hearts were excised to measure left ventricular and right ventricular weights.

Data Acquisition and Analysis
Heart rate and aortic pressure were monitored continuously. Left and right ventricular systolic pressure, end-diastolic pressure, and cardiac output as the equivalent of aortic flow were monitored continuously. Stroke volume was calculated from the integrated flow signal and was used to calibrate the volume signal from the conductance catheter. Parallel conductance was estimated by rapid injection of 1 mL hypertonic saline into the pulmonary artery or vena cava superior, respectively.

The volume signal provided by the conductance catheter was registered continuously (Sigma F5; Leycom, Leiden, Netherlands) and computed by the Conduct PC software (Leycom). Left and right ventricular pressure–volume loops were constructed on-line. Vena cava occlusions were performed while ventilation was discontinued to obtain a series of loops for calculation of the slope and intercept of the left and right ventricular end-systolic pressure–volume relationships. In addition, preload recruitable stroke work was calculated. As only one Sigma F5 device was available, pressure–volume data of the left and right ventricle were measured serially [9–11].

All values were expressed as mean ± SEM. A paired t test was used to compare two means within groups. Individual means between the groups were compared by one-way analysis of variance and unpaired t test. A probability value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Immediate flow measurements showed 500 to 600 mL/min flow in each shunt. After 3 months, all shunts were open and flow rates did not change significantly. Pleural effusions and ascites developed in the chronically volume overloaded animals as clinical signs of heart failure. Left ventricular weight (127 ± 16 g versus 91 ± 17 g, p < 0.05) and right ventricular weight (61 ± 8 g versus 41 ± 11 g, p < 0.05) ventricular weights were significantly higher in comparison with controls. General hemodynamic variables and indices of left ventricular function are shown in Table 1. Chronic volume overload lead to an approximately 30% increase of cardiac output in comparison to controls (3.38 ± 0.40 versus 2.68 ± 0.43 L/min, p < 0.05) whereas mean arterial pressure did not differ significantly from the control group. After closing the shunts and 1 hour of equilibrium, cardiac output decreased significantly (2.23 ± 0.14 L/min, p < 0.05), and mean arterial pressure stabilized at baseline levels. At this point, no differences could be observed between the groups. Chronic volume overload led to rightward shift of the left ventricular end-systolic pressure–volume relationships and to a decrease of preload recruitable stroke work, indicating reduced contractility.

The increase of right ventricular afterload showed different adaptation patterns in the two groups (Figs 1 through 4). Cardiac output remained unchanged in both groups, while stroke work increased similarly (Fig 1). It should be noted that baseline stroke work was higher in the volume overloaded group owing to the higher right ventricular systolic pressure. Right ventricular contractile parameter showed a proportional stepwise increase in the control group, whereas it showed only slight tendency toward higher values without reaching the level of significance in the chronically volume overloaded group (Fig 2). In contrast, end-diastolic pressure and volume showed a slight increase in the control group but it increased significantly in the chronically volume overloaded group (Fig 3). The end-diastolic pressure–volume relationships did not differ between the groups, although the chronically volume overloaded animals operated in the higher volume range (Fig 4).

View larger version (20K): [in this window] [in a new window]   Fig 1. Right ventricular pump performance. Cardiac output and stroke work are plotted against right ventricular systolic pressure (RVSP). All values are given as mean ± SEM. *p < 0.05 volume overload (circles) versus control (boxes); p < 0.05 versus baseline.

View larger version (18K): [in this window] [in a new window]   Fig 2. Homeometric autoregulation. The slope of the right ventricular (RV) end-systolic pressure–volume relationships (Ees) and preload recruitable stroke work (PRSW) are plotted against right ventricular systolic pressure (RVSP). All values are given as mean ± SEM. *p< 0.05 volume overload (circles) versus control (boxes); p < 0.05 versus baseline.

View larger version (18K): [in this window] [in a new window]   Fig 3. Heterometric autoregulation. Right ventricular end-diastolic pressure (RVEDP) and volume (RVEDV) are plotted against right ventricular systolic pressure (RVSP). All values are given as mean ± SEM. *p < 0.05 volume overload (circles) versus control (boxes); p < 0.05 versus baseline.

View larger version (11K): [in this window] [in a new window]   Fig 4. Diastolic function. Steady state end-diastolic pressure (RVEDP)–volume (RVEDV) coordinates are plotted at baseline and each level of pulmonary banding. Dotted line indicates the estimated end-diastolic pressure–volume relationship. It should be noted that all end-diastolic coordinates could be fitted on the same end-diastolic pressure–volume relationship indicating the neither acute afterload elevation and nor chronic volume overload substantially changed diastolic function (see more explanation in text). All values are given as mean ± SEM. *p < 0.05 volume overload (circles) versus control (boxes).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

Although right ventricular function after chronic volume overload have not been studied yet, numerous experimental and clinical investigations characterized the behavior of the normal right heart under different loading conditions. Several investigators have previously studied the hemodynamic response to a comparable acute increase in pulmonary arterial pressure or right ventricular systolic pressure [12–18]. The results of these studies are partially controversial. In few of these studies, a different degree of right ventricular failure developed. Some of the differences in hemodynamic response to similar increases in right ventricular afterload may in part be due to an unphysiologically elevated baseline sympathetic tone [16, 17]. That might have reduced the adaptation reserve to a further increase in sympathetic tone necessary to compensate for a progressive pulmonary artery constriction [19]. Additionally, a relative hypovolumic state might have also influenced the development of right ventricular failure [16].

In the control group of our study (animals with sham operation without volume overload), the increase of right ventricular afterload resulted in no impairment of right ventricular function but an increase in pump performance, which is in concert with other experimental and clinical studies [12, 13, 19, 20]. The analysis of the pressure–volume relationships showed a higher contractile performance and a complex adaptation process. The compensatory mechanisms maintaining right ventricular performance during increased afterload are homeometric autoregulation with augmentation of contractility and the Frank-Starling mechanism (heterometric autoregulation) through increased myocardial stretch. The existence of the so-called homeometric autoregulation in the right heart was a matter of debate previously. Now, we described this autoregulatory mechanism in the right heart using pressure–length relationships [10] and confirmed in a canine orthotopic heart transplantation model [11] applying conductance catheter-derived pressure–volume analysis. Meanwhile, the importance of right ventricular homeometric autoregulation was demonstrated in other settings of pulmonary constriction [21], respiratory distress syndrome [22], and endotoxin shock [23]. In a recent study, Wanthy and colleagues [24] demonstrated that acute elevation of pulmonary resistance leads to an increase of right ventricular contractility regardless how pulmonary pressure has been increased (hypoxia versus distal embolisation versus pulmonary banding) and which species was used (goat versus pig versus dog).

There was no evidence of any deterioration in right ventricular pump performance in the chronically volume overloaded animals: stroke work increased in the similar way as in the control group, and cardiac output remained stable. However, the increase in stroke work, which was comparable to the control group, was associated with a greater rise in end-diastolic pressure and volume, which indicates the utilization of the Frank-Starling mechanism as a primary form of adaptation to increased afterload. There are many possible explanations for the decreased ability of the right ventricle to adapt by inotropic mechanisms. The right ventricle is anatomically adapted for the generation of low pressure perfusion. It comprises two anatomically and functionally different cavities, termed the sinus and the cone. Right ventricular contraction occurs in three phases: contraction of the papillary muscles, then movement of the right ventricular free wall toward the interventricular septum, and, finally, contraction of the left ventricle causes a "wringing," which further empties the right ventricle. The net effect of this "peristaltic" contraction pattern is that the ejection into the pulmonary circulation is sustained and peak pressure is prolonged [25]. Chronic volume overload leads to an enlargement of the right ventricle and thereby changes functional anatomy. In these ventricles, the peristaltic contraction is lost, causing an accelerated increase in pulmonary artery pressure and flow [25]. The altered ejection and contraction pattern may limit the inotropic adaptation potential of the right ventricle after chronic volume overload.

Alterations of cellular calcium handling and contractile proteins may also contribute to the changes of inotropic response [26, 27]. Several sarcolemmal proteins have been shown to be involved in the stretch-induced increase in the intracellular calcium transient, for example, stretch-activated calcium channels [28] and the Na⁺/H⁺ as well as the Na⁺/Ca²⁺ exchanger. Stretching may also modulate the sarcoplasmatic reticulum calcium release through Pi(3) kinase-dependent phosphorylation of AKT-kinase stimulation of the endothelial nitric oxide–synthetase [29]. Thus, increasing muscle length may result in mechanisms increasing the sarcolemmal calcium influx, but may not support the sarcoplasmatic reticulum calcium uptake. In the chronically volume overloaded, the Anrep effect was almost absent. This finding is in concert with a novel study by Brixius and associates [30], in which decreased homeometric autoregulation was associated with alterations of calcium homeostasis in muscle stripes isolated from terminally failing human hearts. They proposed that both altered calcium sensitivity of the myofibrils and altered calcium supply to the myofibrils are responsible for these changes.

Beside direct changes of the right ventricular muscle mass (both anatomical and subcellular level) indirect factors may also contribute to altered response to afterload elevation. The changes of coronary perfusion may also play a role in the impairment of contractile response to increased afterload in the failing heart. In contrast to the left ventricle, in the right heart, coronary perfusion pressure is decoupled from afterload: an elevation of afterload is not associated with an automatic increase of coronary perfusion pressure. Even if coronary autoregulation is probably satisfactory to cover energy demand associated with increased contractility in the normal hearts, it may be exhausted earlier in the chronically volume overloaded animals after right ventricular afterload increase, especially at higher elevations. There are only very few data available even under physiologic conditions that describe the effect of coronary perfusion pressure on right ventricular function, and the results are controversial. Unfortunately, we also do not have any evidence at this point.

Whether alterations in the phosphorylation status, mutations, or alterations in the expressions of contractile proteins influence contractile response also remain to be clarified [30].

At least, it should be stressed, that independently from the possible mechanisms leading to a decreased ability of inotropic adaptation after chronic volume overload, the functional reserve of the right ventricle still remains sufficient to compensate for increased right ventricular afterload by the Frank-Starling mechanism. Sibbald and colleagues [20] showed that under clinical conditions, the right ventricular pump function could be dissociated from right ventricular contractile function. In patients with depressed right ventricular contractility (right ventricular contusion) or severe pulmonary arterial hypertension, they achieved the maintenance of the right ventricle pump function by augmentation of right ventricular preload, thereby utilizing the Frank-Starling mechanism.

The changes of diastolic function was not in focus of this study; however, it should be noted that diastolic function was influenced neither by the acute increase of afterload nor by chronic volume overload. The former is in accordance with the study of Hon and coworkers [21], who observed unchanged end-diastolic pressure–volume relationships in a sheep model of pulmonary banding in normal hearts. It was rather surprising that diastolic function did not change in the chronically volume overloaded hearts. That partly contradicts previous studies [20, 30] in which also diastolic function occurs in failing hearts. Nevertheless, these data are from the terminally failing human myocardium, which is not directly comparable with our data. In the present model, only moderate heart failure develops, with opposite effects on the myocardium: chronic volume overload leads to a right ventricular hypertrophy, which leads to a leftward shift of the diastolic pressure volume relationships and to a right ventricular dilatation, which leads to rightward shift of the diastolic pressure–volume relationships. The net effect of these changes in the present model is unchanged diastolic pressure–volume relationships and thereby nominally unchanged diastolic function. This allows the volume overloaded hearts to compensate for the increased afterload by the heterometric autoregulation operating in the high-volume zone of the Frank-Starling relationship. It is likely, however, that at more severe degrees of heart failure the heterometric autoregulation probably also fails to compensate for acute afterload elevation.

Even if the present experimental model does not cover all causes of right ventricular failure, it has relevance to the clinical situation, especially in cardiac surgery. Disease states with chronic volume overload and perioperative elevation of right ventricular afterload are common both in congenital and adult cardiac surgery. The present findings stress that even if baseline right ventricular function seem satisfactory in the chronically volume overloaded hearts, the adaptation to an acute elevation of afterload by inotropic mechanisms may be impaired. Furthermore, under certain circumstances, the augmentation of preload may be useful for maintaining right ventricular pump performance by the Frank-Starling mechanism at increased afterloads.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The present study was supported by Grants "Forschungsschwerpunkt Transplantation," University of Heidelberg, and SFB414 of the German Research Foundation to Dr Szabó.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Gábor Szabó Ernst Weigang Siegfried Hagl Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Szabó, G. Articles by Hagl, S. Search for Related Content PubMed PubMed Citation Articles by Szabó, G. Articles by Hagl, S. Related Collections Cardiac - physiology Related Article