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European Journal of Heart Failure 2003 5(6):741-749; doi:10.1016/S1388-9842(03)00152-1
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© 2003 European Society of Cardiology

The effects of acute afterload change on systolic ventricular function in conscious dogs with normal vs. failing hearts{star}

Richard B. Thompsona, Ewout J. van den Bosb, David J. Espositoa, Clarence H. Owena and Donald D. Glowera,c,*

a Departments of Thoracic Surgery Box 3851, Duke University Medical Center Durham, NC 27710, USA
b Departments of Cardiology Box 3851, Duke University Medical Center Durham, NC 27710, USA
c Departments of Biomedical Engineering Box 3851, Duke University Medical Center Durham, NC 27710, USA

* Corresponding author. Tel.: +1-919-681-5789; fax: +1-919-681-8912. E-mail address: glowe001{at}mc.duke.edu


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: To date, no data exist on the linearity and, therefore, the usefulness of the preload recruitable stroke work (PRSW) and end-systolic pressure–volume (ESPVR) relationships during acute afterload changes in heart failure.

Aims: Our aim was, therefore, to characterize both relationships in a model of ventricular pacing induced heart failure at baseline and during acute changes in afterload.

Methods: Dynamic left ventricular volume and transmural pressure were measured in 10 conscious dogs using sonomicrometry and micromanometry under control conditions and during heart failure produced by 3 weeks of rapid right ventricular pacing. Afterload was varied from baseline with intravenous infusions of nitroprusside and phenylephrine. Left ventricular function was assessed using the PRSW and ESPVR relationships.

Results: Cardiac output demonstrated a linear inverse relationship with afterload in both normal and failing hearts (r2>0.5, P<0.001) with failure producing a parallel, downward shift of the afterload (x) vs. cardiac output (y) relationship (P<0.01). Yet, afterload variation did not affect PRSW or ESPVR relationships in either normal or failing hearts (r2<0.12, P>0.05).

Conclusion: Thus, the PRSW and ESPVR relationships are insensitive to acute afterload changes in both failing and normal hearts, and the failing left ventricle is no more afterload-sensitive than the normal heart.

Key Words: Ventricular function • Tachycardia • Pacing • Cardiomyopathy • Arterial resistance • Afterload

Received February 12, 2003; Revised April 28, 2003; Accepted July 17, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Congestive heart failure due to pacing-induced cardiomyopathy or other etiologies is generally accompanied by alterations of both preload and afterload in the left ventricle [1–4]. Thus, valid assessment of left ventricular function in the setting of congestive heart failure ideally requires a measure of ventricular function insensitive to loading conditions. The end-systolic pressure–volume relationship (ESPVR) [5] and the stroke work vs. end-diastolic volume preload recruitable stroke work or PRSW relationship [6] have been shown to be insensitive to acute variation in preload or afterload in normal hearts [6–8]. Both relationships are mainly linear and describe the intrinsic contractile reserve of the left ventricle. Unfortunately, no data exist to demonstrate the sensitivity of either relationship to acute changes in afterload in the failing heart.

In addition, it has been speculated and reported that the failing heart is more sensitive to afterload changes than is the normal heart [1,9,10]. This exaggerated load sensitivity of the failing heart is thought to result from the failing heart functioning as a pressure source that is sensitive to afterload, while hypertrophied and non-failing hearts function as load-insensitive flow sources [10]. This afterload sensitivity has been proposed as a mechanism by which afterload reduction benefits the failing heart [9–11]. Further, afterload reduction has been shown to improve the outcome of patients with congestive heart failure [12]. However, although these data suggest that afterload indeed affects cardiac performance in the failing heart, few data exist to demonstrate whether the failing heart does have an impaired intrinsic contractile reserve and responds to changes in afterload in an inherently different manner from normal hearts.

A study was undertaken to examine the effects of acute afterload changes on ESPVR and PRSW relationships in normal and failing hearts. The study was designed to establish the applicability of these relationships as measures of ventricular function in the failing heart and to test the hypothesis that afterload sensitivity also affects the intrinsic contractile reserve of the failing hearts as opposed to normal hearts. We used a canine model of rapid ventricular pacing, a well recognized model of dilated cardiomyopathy [13,14].


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animal preparation
Ten adult mongrel dogs (18–22 kg) were pre-medicated with intramuscular injection of ferrous gluconate, 37 mg and penicillin G, 500 000 units and intravenous infusion of cefazolin, 500 mg. They were anesthetized with intravenous administration of pentobarbital sodium, 25 mg/kg and fentanyl citrate, 20 mg/kg. After endotracheal intubation, each dog was mechanically ventilated with a volume respirator, and a thoracotomy was performed through the left fifth intercostal space under sterile conditions. Silicone rubber pneumatic occluders were positioned around both venae cavae, and paired orthogonal ultrasonic dimension transducers were positioned across the base-apex (major) and antero–posterior (minor) axes of the left-ventricular epicardium [15]. Two epicardial pacing electrodes were attached to the right ventricle approximately 1 cm apart. A heparinized Silastic (Dow, Corning, NY) tube was positioned in the left atrial appendage, and 2 similar tubes with multiple side holes were positioned in the pleural space adjacent to the left ventricular epicardium to allow future passage of micromanometers for measurement of true transmural left ventricular pressure. The pericardium was left widely open, the equipment exteriorized through a Teflon and Silastic skin button placed dorsal to the thoracotomy site, and the incision closed in multiple layers.

2.2. Data acquisition
Six to 20 days after instrumentation, each animal was studied for the first time in the conscious state following light sedation with subcutaneous morphine sulfate, 7.5 mg to obtain data under control conditions. The measurements were repeated in each dog after 3 weeks of rapid ventricular pacing to obtain data under heart failure conditions.

Two-dimensional echocardiographic images of the left ventricle were obtained from the right chest wall with a 5 MHz short focus transducer coupled to a phased-array ultrasonograph (Model 77020, Hewlett-Packard, Andover, MA). Short axis images of the left ventricle at mid-papillary level and long axis images through the mitral valve were obtained [16]. The base-apex and antero–posterior dimension transducers were coupled to a sonomicrometer (James W. Davis Associates, Durham, NC). Micromanometers (Model PC350, Millar Instruments, Houston, TX) were inserted into the left ventricle and the pleural space through the left atrial and pleural introducers. Analog data were passed through a 50 Hz low-pass filter, digitized in real time at 200 Hz by an analog-to-digital converter, and stored on digital magnetic tape. All data were recorded.

2.3. Experimental protocol
Pacing of the right ventricle (RV) at 240 beats per minute (BPM) was accomplished by using atrioventricular sequential pacemakers (Sequicor III, Model 2336R, Pacesetter Systems Inc., Sylmar, CA) programmed for a rate of 120 BPM with a 250 ms A–V interval. The atrial and ventricular leads were connected to one right ventricular wire while the pacemaker ground was attached to another right ventricular wire, to achieve right ventricular pacing at 240 BPM. Each animal received oral trimethoprim, 80 mg and sulfamethoxasol, 400 mg daily for infection prophylaxis and enteric-coated aspirin, 325 mg daily to prevent formation of ventricular thrombi.

The investigation conformed 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 1985).

All 10 animals were studied both under control conditions and in heart failure induced by 3 weeks of rapid RV pacing. Before each study, the dogs were weighed, examined for any physical signs of heart failure (edema, cyanosis, pleural effusion), and studied with two-dimensional echocardiography. During each study, pharmacological attenuation of autonomic reflexes was accomplished by intravenous infusion of propranolol, 1–2 mg/kg, which was repeated as necessary before starting the experimental protocol to maintain the change in spontaneous heart rate at less than 10% during vena cava occlusion. All data were recorded during transient ventricular pacing at 150 BPM after equilibration for 30 min. Data were obtained at baseline afterload under control conditions as well as during heart failure. Multiple data points were acquired at multiple stages of venae cavae occlusion. Phenylephrine (0–1.6 µg kg–1 min–1, average control dose 0.3 mg, average failure dose 1.6 mg) and nitroprusside (0–30 µg kg–1 min–1, average control dose 0.6 mg, average failure dose 4.0 mg) were infused intravenously in random order to vary systolic left ventricular pressure from 90–160 mmHg. Between drug infusions, sufficient time was allowed to permit return to baseline conditions.

At the conclusion of each final study, the animals were euthanized, an autopsy was performed, and the position of the transducers was confirmed. Left ventricular wall volume was measured by saline displacement after excising the atria, right ventricular free wall, aortic and mitral valves, chordae tendineae and papillary muscles.

2.4. Data analysis
Left ventricular transmural pressure (P) was calculated as the difference between left ventricular and pleural pressures. The first time derivative of left ventricular transmural pressure (dP/dt) was computed from the digital pressure waveform as a running five-point polyorthogonal transformation. The cardiac cycle was defined automatically using dP/dt. Diastole was defined as beginning 15 ms after the first zero crossing of dP/dt after peak negative dP/dt and ending 20 ms prior to the beginning of the systolic upstroke of LV transmural pressure. Beginning and end ejection were placed at peak positive and peak negative dP/dt, respectively [6]. Beat point definitions were checked visually on all data with a videographics display system.

Left-ventricular cavitary volume (V) was calculated from the base–apex (a) and antero–posterior (b) dimensions by modeling the left ventricle as a prolate ellipsoid and subtracting ventricular wall volume (Vwall)


Formula 1

(1)

Stroke work (SW) was calculated as the integral of left-ventricular transmural pressure (P) and cavitary volume over each cardiac cycle


Formula 2

(2)

Linear regression analysis was performed on data from individual vena caval occlusions, including data from beginning vena caval occlusion to steady-state maximal vena caval occlusion. By linear regression analyses, data were fitted to the formulae


Formula 3

(3)


Formula 4

(4)

Eq. (3), termed the preload recruitable stroke work (PRSW) relationship because it quantified the amount of stroke work which may be recruited by change in preload [6], related SW to end-diastolic volume (Ved) with slope (Mw) and x-intercept (Vw). Eq. (4) was the end-systolic pressure–volume relationship between end-systolic pressure (Pes) and volume (Ves) defined by Sagawa [5] using slope (Ees) and x-intercept (Vd).

To quantify the degree to which left ventricular afterload was varied, systolic arterial resistance (Rsa) or the arterial resistance encountered by the left ventricle during systole was calculated as the approximation


Formula 5

(5)
where Pme (mmHg) was left ventricular mean ejection pressure, SV (ml) was left ventricular stroke volume or the difference between left ventricular end-diastolic and end-systolic volumes, and 80 was a factor to convert Rsa to units of dyn s cm–5. Tej was left ventricular ejection time (s) and was found to be 0.158 s under control conditions and 0.172 s under failure conditions without significant effect of nitroprusside or phenylephrine infusion.

Echocardiographic data were analyzed to document any changes in left ventricular wall volume (Vwall) calculated as the product of short axis myocardial cross-sectional area and epicardial long axis length [16].

2.5. Statistical analysis
Following calculation of all dynamic and static beat to beat variables, all the statistical analysis was performed using customized programs developed with a statistical software package (SAS Institute, Cary, NC). With the exception of echocardiographic data, all steady state data are reported as mean values over 10–20 consecutive cardiac cycles. For each variable, one way analysis of variance was utilized to compare failure to control and to compare nitroprusside and phenylephrine data to baseline observations. Slopes, intercepts and correlation coefficients were derived from least squares regression analysis. The effects of physiological variables on relationship slopes and intercepts were examined using multivariate analysis of variance. Unless otherwise stated, all the data were presented as mean±standard deviation.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
At autopsy, the positions of the hardware were intact in all 10 animals. Analysis of echocardiographic data revealed that left ventricular wall volume did not change significantly from control to failure (111±26 ml vs. 94±16 ml, P=NS). Furthermore, differences between failure wall volume by echocardiography and wall volume from post-mortem saline displacement (83±7 ml) were insignificant. Therefore, post-mortem saline displacement wall volumes were used in all the subsequent analyses.

By 3 weeks of rapid ventricular pacing at 240 BPM, all animals developed symptomatic congestive heart failure with tachypnea and mild anorexia. Cyanosis, ascites and pleural effusions were noted in some animals. All animals demonstrated left ventricular dilation by echocardiography. Increased left ventricular dimensions and decreased left ventricular pressure, cardiac output and stroke work were evident (Table 1). Under control conditions and during failure, nitroprusside and phenylephrine, each significantly varied left ventricular mean ejection pressure at an average of 40 mmHg (Table 1).


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  		Table 1 Effects of interventions on hemodynamics

 
Of note, large doses of phenylephrine under failure conditions (1.6 mg vs. 0.3 mg under control conditions) were not able to increase mean ejection pressure back to control baseline levels (Table 1). Under control conditions, infusion of nitroprusside decreased stroke work and end-diastolic volume, but did not significantly affect cardiac output. Conversely, infusion of phenylephrine decreased cardiac output, but had no effect on stroke work or end-diastolic volume. During heart failure, infusion of nitroprusside decreased end-diastolic volume and increased cardiac output, but nitroprusside did not affect stroke work. Infusion of phenylephrine did not significantly alter end-diastolic volume, stroke work or cardiac output during failure (Table 1).

A strong linear correlation between left ventricular afterload and cardiac output was present Eq. (5) with increased afterload or systolic arterial resistance decreasing cardiac output under both control and failure conditions (P<0.001, Fig. 1). Note that the linear relationship between cardiac output and systolic arterial resistance did not differ between control and failure conditions in slope (P=0.09), but failure did significantly decrease the relationship y-intercept from 6.8+1.8 to 5.4±1.7 l/min (P<0.01), suggesting that failure produced a slight parallel downward shift of the CO–Rsa relationship (Fig. 1).


Figure 1
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  		Fig. 1 Linear regression between systolic arterial resistance and cardiac output under control conditions and during congestive heart failure for all 10 studies.

 
Failure shifted the stroke work vs. end-diastolic volume relationship downward and to the right with a decrease in baseline slope from 8.3±1.8 to 6.4±2.1 mJ/ml and increase in baseline x-intercept from 49±18 to 72±16 ml (Figs. 2 and 3). Afterload variation with either phenylephrine or nitroprusside did not affect the slope or x-intercept of the Frank–Starling relationship under control conditions or during failure (Fig. 3). Linear regression of afterload assessed by systolic arterial resistance (Eq. (5)) against slope or x-intercept demonstrated no significant relationship.


Figure 2
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  		Fig. 2 Relationship between left ventricular stroke work and end-diastolic volume in one typical study at baseline and during infusion of phenylephrine (Phenyl) or nitroprusside (Nitropr) under control conditions and during congestive heart failure.

 


Figure 3
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  		Fig. 3 Mean±S.D. for slope (Mw) and x-intercept (Vw) of stroke work vs. end-diastolic volume relationship at baseline and during infusion of nitroprusside (Nitropr) or phenylephrine (Phenyl) under control conditions and during congestive heart failure.

 
Failure shifted the ESPV relationships downward with baseline slope decreasing from 2.5±0.8 to 1.6±0.6 mmHg/ml, but without significant change in x-intercept (Figs. 4 and 5). No significant change in ESPVR was noted with afterload variation under control conditions or in failure. Linear regression of systolic arterial resistance against slope or x-intercept of ESPVR failed to detect a relationship (r2<0.12, P>0.05).


Figure 4
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  		Fig. 4 End-systolic relationships between left-ventricular pressure and volume in one typical study at baseline and during infusion of phenylephrine (Phenyl) or nitroprusside (Nitropr) under control conditions and during congestive heart failure.

 


Figure 5
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  		Fig. 5 Mean±S.D. for slope (Ees) and x-intercept (Vo) of the end-systolic pressure–volume relationship at baseline and during infusion of nitroprusside (Nitropr), or phenylephrine (Phenyl) under control conditions and during congestive heart failure.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
By definition, any measure of ventricular intrinsic contractility or contractile performance must be insensitive to changes in ventricular preload and afterload [17]. To be practical in studies of congestive heart failure, measures of contractile performance must also be insensitive to loading conditions because preload and afterload are affected both by congestive heart failure [1–4] and by treatment for heart failure [12,18,19]. The present study demonstrated that the preload recruitable stroke work and end-systolic pressure–volume relationships are indeed insensitive to afterload changes in both the normal and failing heart. Other more commonly used measures of cardiac function such as ejection fraction are load-sensitive in the normal heart [20].

As a treatment of congestive heart failure, afterload reduction has been shown to be useful but to have unclear effects on intrinsic cardiac function. Randomized trials in congestive heart failure patients have found that afterload reduction improved patient survival and improved patient symptoms [12]. Several investigators demonstrated that afterload reduction in patients with congestive heart failure resulted in a significant reduction of end-systolic volume after 1–2 years [18,21]. Shannon [22] showed that afterload reduction normalized impairments of diastolic relaxation and myocardial stiffness produced by pacing-induced heart failure. Ishizaka [23] found increased load sensitivity of left ventricular relaxation in failing vs. normal dog hearts. Using load-insensitive measures of cardiac performance (ESPVR and the dP/dtmax vs. end-diastolic volume relationship), Cheng [1] observed that angiotensin II depressed relaxation and contractile performance in failing but not normal hearts, yet the effects of angiotensin II appeared to be independent of any afterload change. Till date, investigators have not determined, however, whether afterload change alone affects load-insensitive measures of cardiac function in the failing vs. normal hearts. Furthermore, clinical observations of improved function in failing hearts treated with afterload reduction hinge on very load-sensitive measures of function such as stroke work, cardiac output, stroke volume and ejection fraction [11,24].

Given that ESPVR and PRSW relationships are load-insensitive in heart failure, the present study shows that there is no intrinsic effect of acute changes in afterload on diastolic dimensions (Vw) or inotropic state in the failing heart. In addition, the effect of afterload on load sensitive measures of ventricular function (i.e. cardiac output) are not different in normal and failing hearts except for a parallel downward shift in the cardiac output vs. the afterload relationship in failing hearts (Fig. 2). Therefore, differing responses to afterload reduction in respect to the intrinsic contractility in the normal and the failing heart cannot be the mechanism for clinical improvement with afterload reduction. The mechanism by which afterload reduction improves function in the failing heart is more likely to be correction of an abnormally high afterload to normal levels. Moreover, the altered diastolic properties observed in congestive heart failure are not due to altered loading conditions alone and must result from other factors such as the presence of creep in the myocardium of failing hearts [25].

The observations of this study are unlikely to be unique to the pacing-induced failure model because multiple studies have demonstrated similarities between pacing-induced failure in animals and dilated cardiomyopathy due to volume overload in humans [13,19]. Although sympathetic blockade was achieved with propranolol in the present study, parasympathetic reflexes were not blocked to prevent the spontaneous heart rate from exceeding that of the pacemaker at 150 BPM. Yet, because the main cardiac effect of parasympathetic reflexes is to vary heart rate, ventricular pacing at 150 BPM should have minimized any effects of parasympathetic reflexes. Calculation of left ventricular volume from two ventricular diameters assumed that interventions did not cause significant shift to the interventricular septum. Two-dimensional echocardiographic short axis images of the left ventricle confirmed that no such septal shifting occurred with failure and acute changes in left ventricular afterload do not produce septal shifting [26].

Although the calculated systolic arterial resistance can only approximate the measure of afterload, only relative changes in afterload were sought. Eq. (5) neglected right artrial pressure, but its affect should be negligible because the right atrial pressure in this model is smaller than 10 mmHg [25]. However, whether larger changes in afterload may have produced differing results, remains uncertain. Interestingly, increased doses of both nitroprusside and phenylephrine were required during heart failure to produce an afterload variation comparable to control conditions. It remains unclear whether this phenomenon was due to receptor saturation, down-regulation of peripheral {alpha}-receptors, or other alterations of the systematic vasculature in heart failure.

The current study is important in demonstrating for the first time that, contrary to previous speculation [9,10], the intrinsic contractile reserve of the failing heart responds to the acute changes to afterload in the same manner as normal hearts. Specifically, afterload reduction increased cardiac output without change in intrinsic contractile performance in both normal and failing hearts. No increased load sensitivity was observed for failing vs. normal hearts in this model over the physiological range of arterial pressure. Thus, one mechanism by which afterload reduction is beneficial in treating heart failure is to increase cardiac output by decreasing the pathologically increased systemic vascular resistance [27]. Whether afterload reduction with agents such as angiotensin converting enzyme inhibitors may benefit heart failure by mechanisms other than mechanical afterload reduction cannot be excluded. The current study is also important in establishing for the first time that the ESPVR and PRSW relationships are load insensitive in both normal and in failing hearts. Thus, ESPVR and PRSW should be especially applicable to studies of cardiac function in the setting of cardiac failure accompanied by altered loading conditions.

In the future, ESPVR and the PRSW relationship may prove useful in other studies where the inotropic state of failing hearts must be assessed and followed over time independent of loading conditions. Before this can be done in a clinical setting, however, future studies must establish the validity of the relationships, which are similar to ESPVR and PRSW yet can be derived from minimally invasive and clinically available measurements [28]. The fact that failure changed both the slope and the x-intercept of the PRSW relationship implies that examination of only the PRSW relationship slope could be inadequate to assess ventricular performance in the failing heart. This difficulty could be overcome using such parameters as SWedv or stroke work at a constant end-diastolic volume [29,30], which mimics Sarnoff's original concept of contractility as the ability of the heart to do work under specified loading conditions [17].


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} This work was supported by NIH grants HL46242 and HL17670. Back


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

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