Disparate Effects of Early Pressure Overload Hypertrophy on Velocity-Dependent and Force-Dependent Indices of Ventricular Performance in the Conscious Baboon
Background The effects of early pressure overload on left ventricular (LV) chamber mechanics in the primate heart are poorly understood.
Methods and Results To test the hypothesis that early LV pressure overload hypertrophy is associated with depression of velocity-dependent indices of LV systolic (LV dP/dt) and diastolic function (time constant of relaxation, tau) but unchanged systolic elastance (Ees), we studied six conscious baboons instrumented with LV micromanometers and LV dimension and wall thickness sonomicrometers. Loading conditions were altered by pharmacological angiotensin II generation both before and 12 weeks after producing renovascular hypertension (2 kidney, 1 clip). The LV systolic pressure (149±11 [SD] versus 114±5 mm Hg) and LV mass (125±25 versus 91±20 g) were greater 12 weeks after than before (both P<.05). Both Ees and Ees normalized for LV mass were similar before versus 12 weeks after (23.0±9.6 versus 22.3±9.8 mm Hg/mL and 26.5±14.5 versus 19.8±12.5 mm Hg/mL, respectively; both P=NS). At matched LV systolic and diastolic pressures, LV fractional shortening was similar (18.6±6.8% versus 21.6±4.9%), but the time constant of LV isovolumic relaxation was significantly longer (42.3±5.3 versus 31.4±7.0 ms, P<.05) and LV dP/dt and Vcf were significantly less (1891±352 versus 2342±284 mm Hg/s and 0.9±0.4 versus 1.1±0.3 circ/s, respectively; both P<.05) 12 weeks after than before.
Conclusions In conscious baboons with systemic arterial hypertension and early LV hypertrophy, there is depression of velocity-dependent indices of LV contraction and relaxation but unaltered force-dependent measures of contractility.
Concentric left ventricular (LV) hypertrophy is initially an adaptive process that develops in response to a sustained pressure overload, such as occurs with systemic arterial hypertension. Although increased LV chamber wall stress is normalized by the hypertrophic response, alterations in systolic and diastolic chamber and muscle properties ultimately ensue. Despite a considerable amount of investigation, the effects of sustained pressure overload on LV chamber mechanics remain controversial.1 2 3 4 5 6 7 8 9 10 11 12 Disparate results in experimental models of pressure overload hypertrophy may be a result of species differences, the nature, timing, and severity of the pressure overload, the particular chamber evaluated, and the methods of analysis. Clinical studies are limited because they are by necessity cross-sectional in nature, are associated with pressure overload stimuli of unknown duration, and are usually confounded by associated disease, medical therapy, and other genetic and environmental factors that may influence cardiac function. Accordingly, we performed a longitudinal study in chronically instrumented, conscious baboons with surgically induced renovascular hypertension to examine the effects of early pressure overload hypertrophy on LV systolic and diastolic functions.
We tested the hypothesis that early pressure overload hypertrophy is associated with reduced velocity-dependent indices of LV systolic and diastolic functions and unchanged (or increased) systolic chamber elastance and passive LV chamber stiffness. The conceptual framework for our hypothesis is derived from myocardial energetics and the sliding filament theory of contraction; specifically, myocardial contractility may be depressed when either the number of active myosin crossbridges and/or the maximal rate of crossbridge cycling is decreased.13 14 We have shown previously that long-term pressure overload hypertrophy is associated with reductions in myosin ATPase activity, maximal rates of energy liberation during crossbridge cycling, and velocity-dependent indices of contractility.11 15 16 In the present study, we demonstrate a dissociation between measures of force development and fiber velocity early in the development of pressure overload hypertrophy in the nonhuman primate.
Six adult male baboons (Papio anubis) ages 6 to 7 years and weighing 20 to 28.5 kg were preinstrumented for physiological monitoring in the conscious state. After sedation with ketamine (10 mg/kg IM) and atropine (0.5 mg IV), the animals were intubated and anesthesia was maintained with 1.0% to 1.5% halothane. A Konigsburg micromanometer (P5-P7) and a polyvinyl catheter (OD, 0.095 mm; ID, 0.066 mm) were implanted in the LV apex, and miniaturized sonomicrometer pairs (Triton Technology) were placed in the endocardium across the LV anteroposterior minor axis (3 MHz, 6 mm) and transmurally at the mid LV free wall for measurement of wall thickness (5 MHz, 2.5 mm). A polyvinyl catheter (OD, 0.095 mm; ID, 0.066 mm) was implanted in the right atrial appendage for central venous access. Wires and tubes were tunneled subcutaneously into the interscapular area for later attachment to a tether system. After a minimum of 1 week, baseline hemodynamic studies were performed (vide infra). Wires were run from the tether cage into an adjoining room equipped with an eight-channel physiological recorder (Gould) and a microprocessor for analog-to-digital (A-D) conversion of pressure and dimension signals.
Pressure overload hypertrophy was produced by the creation of renovascular hypertension (1 clip, 2 kidney Goldblatt model) 1 to 6 weeks after the initial hemodynamic study.15 16 General anesthesia was induced with ketamine (10 mg/kg IM) and maintained with halothane (1.0% to 1.5%). Renal artery stenosis was accomplished using a flank incision; a Goldblatt clip was attached loosely to the renal artery adjacent to the aorta and was tightened until flow was reduced by 50% and stable reduced flow was documented for 15 minutes.
After each surgical procedure, postoperative pain was reduced by the use of Buprenet (0.01 mg/kg IM q 6 hours), and postoperative antibiotics (Monocid 25 mg/kg) were administered for 5 days to reduce the risk of infection.
Hemodynamic Data Acquisition and Analysis
The micromanometer and fluid-filled catheters were calibrated before implantation with a mercury manometer. Zero drift of the micromanometer was corrected by matching the LV end-diastolic pressure measured simultaneously through the LV catheter. The fluid-filled LV catheter was connected to a precalibrated Statham 23 dB transducer (housed in the connector box of the tether jacket) with zero pressure at the level of the mid right atrium. The transit time of ultrasound between the ultrasonic dimension crystals was measured with a multichannel sonomicrometer (Triton Technology, Inc) and converted to distance, assuming a constant velocity of sound in blood of 1.55 mm/ms.
LV dP/dt was obtained by electronic differentiation of the high-fidelity LV pressure signal. LV end diastole was defined as the time that peak positive LV dP/dt exceeded 400 mm Hg/s, and LV end systole was defined as the time of peak negative LV dP/dt. The time constant of LV relaxation was derived from the high-fidelity LV pressure tracing using the method of Weiss et al,17 which assumes a zero asymptote and has been shown to be directionally equivalent to other mathematical approaches for quantitation of isovolumic pressure decay.18
Analog signals for high-fidelity and fluid-filled LV pressures, LV short-axis and transmural dimensions, LV dP/dt, and the ECG were recorded on line on a Gould multichannel recorder and digitized through an A-D board (Dual Control Systems) interfaced to an IBM AT computer at 500 Hz and stored on floppy disk. Steady-state data were acquired over 10 seconds during spontaneous respiration and were averaged.
LV pressure-volume loops were generated off line by plotting instantaneous LV pressure and volume data every 2 ms from variably loaded steady-state beats produced by angiotensin (Ang) II generation (see “Experimental Protocol”). LV volume was calculated as volume=π/6 (D)3, where D is the instantaneous LV dimension. End systole was defined as the time of maximal systolic elastance (pressure/volume). Averaged end-systolic pressure-volume points from five steady-state runs, representing a wide range of LV pressures, were fitted by linear regression analysis; the resultant slope is the end-systolic elastance (Ees) and the volume-axis intercept is the extrapolated “unloaded” LV volume (Vo). To account for the effects of LV cavity dimension and wall thickness on elastance determinations, Ees was normalized by fitting pressure and (volume/LV mass) by linear regression, as suggested by Sagawa et al.19 To account for potential differences between total versus developed pressure before and after hypertensive modeling, the slope of the end-systolic developed pressure-volume relation was calculated, where developed end-systolic pressure equals LV end-systolic (total) pressure minus LV end-diastolic pressure.
The LV diastolic chamber stiffness constant, k, was determined by fitting steady-state LV end-diastolic pressure-volume coordinates derived from variably loaded beats to the exponential curve equation P=AekV (Delta Graph, Delta Point, Inc), where P is LV end-diastolic pressure, the constant A is the pressure intercept, e is the base of the natural logarithm, and V is the LV end-diastolic volume.
Fractional shortening of the LV minor axis was calculated as 100×(EDD−ESD)/EDD, where EDD is LV end-diastolic dimension and ESD is LV end-systolic dimension. The mean velocity of LV circumferential fiber shortening (Vcf) was calculated as LV fractional shortening divided by LV ejection time; LV ejection time was defined as the time from peak positive to negative dP/dt. Fractional LV wall thickening was calculated as
where ESWTh is LV end-systolic wall thickness and EDWTh is LV end-diastolic wall thickness. In the four baboons with wall thickness signals adequate for analysis, fractional shortening and Vcf were also calculated using a midwall method (as opposed to the conventional endocardial-based measurement).20 For purposes of comparison, midwall and endocardial measurements were each computed as the difference between before and after clipping values and were expressed as a percent of the preclipped value.
Circumferential stress (ςc) was calculated at end diastole and end systole as
where P is LV pressure, D is LV dimension, and h is LV wall thickness.21
Hemodynamic studies were performed before and 12 weeks after hypertensive modeling, with the animal resting quietly in an individual tether cage. Animals were allowed to acclimate to the tether system for at least 2 days. After baseline hemodynamic data were acquired, loading conditions were altered by administration of an Ang II precursor [Pro11 DAla12] Ang I. This Ang I analogue is converted by human heart chymase (but not angiotensin-converting enzyme) to Ang II. Human heart chymaselike activity and immunoactivity have been demonstrated in baboon hearts (Hussain et al, unpublished data), and we have shown previously that incremental doses of [Pro11 DAla12] Ang I causes systemic vasoconstriction mediated by Ang II.22 Intravenous [Pro11 DAla12] Ang I was administered sequentially as a 0.1-mg bolus, an hour-long infusion of 5 mg (in 75 mL 5% dextrose in water), and as a 3-mg bolus to provide a wide range of LV pressures and volumes. The specific nonpeptide Ang II antagonist losartin (Merck Sharp & Dohme) was administered subsequently as a 1-mg/kg bolus in order to lower systemic arterial pressure and provide an additional pressure-volume coordinate.
The animals used in this study were maintained in accordance with the “Guide for the Care and Use of Laboratory Animals.” The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Cincinnati.
Serial noninvasive studies of LV mass were used as a basis for timing the hemodynamic studies in hypertensive animals. Baboons were sedated with ketamine (10 mg/kg) and placed in a partial left lateral decubitus position for the echocardiographic studies. Two-dimensional targeted M-mode echocardiograms were obtained using a Hewlett Packard 7750C ultrasonograph. A 5.0-MHz transducer was placed in the third or fourth left intercostal space, and images of the left ventricle were obtained at a level just below the mitral valve chordae. Data were recorded on half-inch VHS videotape and on strip chart tape recordings at a paper speed of 100 mm/s.
M-mode echocardiographic measurements were made by an observer blinded to the status of the animal. Measurements of LV cavity and septal and posterior wall thicknesses at end diastole and end systole were made by hand from strip chart recordings using the convention adopted by the American Society of Echocardiography.23 LV mass was calculated using the formula described by Devereaux et al.24 Interobserver variability for echo measurements of LV mass was 10±6%.
Data are expressed as mean±SD. Paired hemodynamic and dimensional data were compared with Student’s t tests (two tailed). End-systolic pressure-volume and natural log end-diastolic pressure-volume data were fit by linear regression analysis (statview 4.0, Abacus Concepts). A P value of <.05 was considered significant.
Effects of Renal Artery Clipping
The mean weight of the six baboons was 23.1±3.1 kg before and 23.3±1.7 kg 12 weeks after renal artery clipping. Renal artery clipping resulted in significant increases in LV systolic and diastolic pressures (149±11 versus 114±5 mm Hg and 21.5±3.8 versus 10.4±3.0 mm Hg, respectively) and end-diastolic and systolic dimensions (33.1±8.0 versus 29.1±6.9 mm and 27.5±8.1 versus 22.6±6.6 mm, respectively) and significant decreases in LV fractional shortening (18.6±6.8% versus 24.5±5.4%) and the mean velocity of circumferential shortening (0.9±0.4 versus 1.3±0.4 circ/s). Heart rate was unchanged.
In the four baboons with wall thickness signals of sufficient quality for analysis, LV end-diastolic circumferential wall stress was increased significantly at 12 weeks (32.4±9.9 versus 13.5±6.8 g/cm2); in contrast, LV end-systolic wall stress was unchanged (238±124 versus 150±64 g/cm2).
The slopes of the pressure-volume relations at end systole (Ees) were unchanged after 12 weeks of renovascular hypertension (23.0±9.6 versus 22.3±9.8 mm Hg/mL, Fig 1⇓). Moreover, both Ees normalized for LV mass (26.5±14.5 versus 19.8±12.5 mm Hg/mL per 100 g, P=NS) and the slopes of the end-systolic developed pressure-volume relation (16.2±7.8 versus 18.6±11.7 mm Hg/mL, P=NS) were similar before versus after hypertensive modeling, respectively.
The LV diastolic chamber stiffness constant (k) tended to decrease with experimental hypertension, but the change was not statistically significant (0.35±0.32 versus 0.21±0.19 mL−1, P=NS, Fig 2⇓). At matched LV end-diastolic pressures (23 mm Hg), there was a borderline statistically significant increase in LV end-diastolic volume (18.3±12.1 versus 22.4±15.8 mL, P=.06).
Echocardiographic data averaged for the six animals are presented in Table 1⇓. LV end-diastolic and end-systolic dimensions increased, although the changes were not statistically significant. Interventricular septal (IVS) thickness and the sum of IVS and posterior wall thickness (h) increased significantly after hypertensive modeling. Consequently, echocardiographically determined LV mass increased significantly at 12 weeks compared with baseline values (91.2±18.9 versus 124.8±25.3 g, P<.01). LV geometry as assessed by the wall thickness/cavity dimension ratio (h/D) was unchanged.
Hemodynamic and Dimension Data at Matched LV Pressures
Representative hemodynamic recordings from a hypertensive baboon in response to infusion of the Ang II precursor [Pro11 DAla12] Ang I are shown in Fig 3⇓. To dissect the effects of increased hemodynamic loading from hypertrophy per se, data from steady-state afterloaded beats in normotensive (preclipped) baboons were compared with baseline data from hypertensive baboons (Table 2⇓). Both end-diastolic and end-systolic circumferential wall stresses were similar when matched beats from the afterloaded-normotensive and baseline-hypertensive states were used for the analysis. When beats were matched for LV systolic and diastolic pressures, peak +LV dP/dt and the mean velocity of circumferential shortening were significantly greater and the time constant of LV relaxation was significantly shorter before hypertrophy was produced than afterward; LV dimensions, fractional shortening, and wall thickening were unchanged.
The percent changes in both the LV shortening fraction and Vcf were similar when comparing endocardial versus midwall methods (12.7±12.2% versus 10.3±16.9% and 17.0±7.2% versus 15.5±11.2%, respectively; both P=NS by paired t tests). The midwall end-systolic wall thicknesses calculated by the midwall method20 and as one-half the end-systolic wall thickness were highly correlated (r=.99, slope=1.05, P<.0001).
Stress-Vcf and stress-shortening in each of the four baboons with wall thickness signals are shown in Fig 4A⇓ and 4B⇓, respectively. In these four baboons, there was a significant decrease in the slope of the stress-Vcf relation (8.6×10−4±4.0×10−4 versus 5.4×10−4±2.7×10−4 circ/g per cm4) but no change in the slope of the stress-shortening fraction (0.06±0.03% versus 0.7±0.04%/g per cm4). Although there is minimal overlap of data points before versus after renal artery clipping, these data are consistent with the LV fractional shortening and Vcf data at a matched level of end-systolic stress (Table 1⇑).
The principal finding of this study is that velocity-dependent indices of LV systolic (Vcf, peak +LV dP/dt) and diastolic function (tau) are depressed in baboons with early LV pressure overload hypertrophy effected by systemic arterial hypertension. These alterations are associated with unchanged load-normalized indices of LV function (Ees and nEes) and diastolic chamber stiffness. Depressed rates of contraction and relaxation cannot be explained on the basis of altered load because differences in Vcf and tau in normotensive and hypertensive hypertrophied animals were present when animals were matched for LV systolic and diastolic pressures (in four animals, end-systolic circumferential stress) produced by Ang II generation. In contrast, the decreased LV fractional shortening in hypertensive animals reflected alterations in load, not contractile state, since there were no differences in fractional shortening between afterloaded-preclipped and hypertensive, postclipped animals. These data are consistent with both clinical12 and experimental studies9 10 11 of pressure overload hypertrophy. For example, a dissociation between peak force development and velocity of shortening was found in one study of isolated papillary muscles from rats subjected to gradual-onset hypertensive hypertrophy.9 In addition, the early cardiac mechanical changes observed in the present study are similar to those reported for long-term (4.6±0.1 years) pressure overload hypertrophy in the anesthetized baboon.11 25 However, other experimental studies have reported either unchanged or increased LV systolic function,1 2 3 4 5 and data from hypertensive patients are conflicting.6 8 In one study, both LV ejection fraction and Vcf were normal in patients with a moderate (40%) increase in LV mass and normalized wall stress.6 In another report,8 both the LV ejection fraction and Vcf were similar in normal control subjects and hypertensive patients with and without LV hypertrophy. These conflicting data may be explained by the variable and unknown duration and severity of hypertension and hypertrophy and the use of concomitant medications in clinical studies. In addition, although many patients with hypertension and LV hypertrophy may have both force-dependent and velocity-dependent indices of LV function that fall within the range of normal,6 8 the cross-sectional nature of these studies may fail to identify a change in these indices.
It should be emphasized that our findings apply to early pressure overload hypertrophy; by contrast, very soon after the imposition of a load, before LV hypertrophy appears, and late, when poorly characterized cellular and biochemical processes further alter the intrinsic contractile state of the left ventricle, both force-dependent and rate-dependent indices of systolic function may be coordinately altered. Few studies have examined ventricular performance early in the course of pressure overload. In one study, 24 hours after acute aortic stenosis was produced in dogs, LV systolic function increased, as measured by fractional shortening and a leftward shift of the end-systolic stress-diameter relation.2 In another study, LV wall shortening velocity increased, but the end-systolic pressure-dimension relation was unchanged after an average of 18 days of ascending aorta occlusion.1 Finally, velocity-dependent isovolumic and ejection phase indices of LV systolic function (LV dP/dt, Vcf, and LV dD/dt) were increased during the initial phases of perinephritic hypertension; however, LV function was not enhanced after ganglionic or β-adrenergic blockade.3 In that study, measurements were made 2 weeks after the initiation of hypertension, at a time when LV mass had increased approximately 20%.3 In contrast, after 14 weeks of hypertension, wall stress was normalized, and the augmented response owing to catecholamines was no longer evident.7 Thus, the duration of pressure overload is a critical determinant of LV systolic function in experimental hypertension.
There are several possible mechanisms responsible for the disparate effects of early pressure overload hypertrophy on velocity-dependent and velocity-independent parameters of LV performance. The differences may reflect the different subcellular bases for these parameters; altered catalytic hydrolysis of ATP by changes in myosin ATPase activity principally affect maximal rates of energy liberation during crossbridge cycling, as has been shown in long-term pressure overload.15 Thus, it is possible that a reduced rate of actin-myosin crossbridge cycling precedes a depression in either the number and/or strength of the crossbridges.
It is also possible that the differences we observed relate to methodological limitations. First, LV dP/dt was shown to be more sensitive to a change in inotropic state than Ees in both the isolated, supported heart26 and in vivo.27 Second, Zile et al28 suggested that systolic elastance determinations based on total pressure (that is, developed plus end-diastolic pressure) may fail to reflect LV contractile depression when LV diastolic pressures are elevated. However, the slopes of the end-systolic developed pressure-volume relation were similar before and after hypertensive modeling, making it unlikely that the increased LV end-diastolic pressure in hypertensive baboons masked an unrecognized decrease in contractile function. Third, endocardial-based measurements of shortening overestimated fiber velocities compared with midwall methods of measurement to a greater extent in patients with LV hypertrophy than in control subjects.20 However, the percent changes (from before to after hypertensive values) in both LV shortening fraction and Vcf were similar with endocardial and midwall methods. Taken together, these data suggest that disparity between velocity-dependent and force-dependent indices in early LV hypertrophy cannot be explained entirely by methodological differences.
The fundamental cellular and biochemical mechanisms responsible for the altered mechanics we observed in hypertrophied myocardium are not completely understood. In smaller mammals (for example, rats and rabbits), pressure overload hypertrophy is associated with a transcriptionally regulated α to β myosin heavy chain isoform switch and concomitant decreases in myosin ATPase activity and velocity-dependent indices of LV function.29 In contrast, the left ventricles of larger mammals exhibit predominantly the β (slow) myosin heavy chain isoform29 ; changes in the electrophoretic pattern of LV myosin in response to pressure overload typical of smaller mammals are not observed.30 It is interesting that a novel β myosin subspecies (β2) associated with reduced myosin ATPase activity was recently demonstrated in hypertrophied baboon myocardium15 ; it is unknown, however, whether there are increased levels of β2 myosin heavy chain in human pressure overload hypertrophy. In unpublished data, we were unable to detect increased levels of β2 myosin heavy chain in explanted hearts from either dilated, ischemic, or hypertrophic cardiomyopathy; however, we have not had the opportunity to study patients with pressure overload hypertrophy. Alternatively, changes in the structure and regulation of myosin light chains,16 thin filaments, or calcium cycling proteins may selectively impair velocity-dependent indices of ventricular function.31 32 Regardless of the mechanism, our data clearly demonstrate depressed (load-corrected) velocity-dependent indices of contraction and relaxation in vivo in early pressure overload hypertrophy when force-dependent indices are unchanged.
Abnormalities of diastolic function, either alone or associated with systolic dysfunction, may be responsible for symptoms of congestive heart failure.33 In our study, modest LV hypertrophy was associated with impaired LV chamber relaxation, as reflected by a prolonged time constant of LV relaxation. Comparable changes were reported in conscious dogs with hypertension of similar duration.34 Slowed LV relaxation contributes to elevated diastolic pressures and impairs diastolic ventricular filling. Myocardial relaxation is influenced by the interaction of inactivation (an energy-dependent detachment of actin-myosin crossbridges), loading conditions, and temporal and spatial nonuniformity of load and inactivation.35 Abnormalities of cytosolic Ca2+ regulation related to reduced activity of the sarcoplasmic reticulum36 and alterations in the calcium sensitivity of the contractile apparatus37 are postulated as potential cellular mechanisms for impaired myocardial relaxation. Although our study does not address the potential role of nonuniformity, systolic loading is unlikely to be responsible for our findings because at matched LV pressures, tau was significantly longer in baboons with than in those without hypertrophy.
In addition to impaired myocardial relaxation, LV hypertrophy may be associated with increased LV diastolic chamber stiffness.38 LV chamber stiffness is influenced by intrinsic myocardial stiffness, chamber volume and mass, LV relaxation, and extrinsic factors such as pericardial restraint. In patients with hypertrophy due to aortic stenosis, the extent of myocardial fibrosis correlates closely with myocardial stiffness.38 In our study, the diastolic stiffness constant (k) was not significantly altered after 12 weeks of hypertension; in fact, there was a tendency toward decreased LV chamber stiffness (decreased k). These results are similar to those reported in a study of conscious dogs with perinephritic hypertension.34 In that study, LV diastolic function, as assessed by end-diastolic stress and myocardial stiffness, was similar at baseline and after production of stable (14 weeks) hypertension.34 By contrast, renovascular hypertension of several years’ duration is associated with LV remodeling and decreased end-diastolic chamber stiffness.11 Thus, our results may reflect the early stage of hypertrophy and further suggest that abnormalities of intrinsic myocardial relaxation may precede abnormalities of passive LV diastolic properties. It should be recognized that normal LV chamber stiffness does not preclude a concomitant increase in myocardial stiffness, since the chamber stiffness constant may change in a directionally opposite manner to intrinsic myocardial stiffness, depending on the volume/mass ratio.39 In this regard, the hypertrophic response we observed at this early stage of hypertension was not associated with a change in geometry, as indicated by an unchanged h/D ratio.
Advantages of the Model
There are several unique features of the experimental model used in this study. First, we used a longitudinal experimental design that permits paired comparisons and detects important physiological changes using a relatively small number of experimental subjects. Second, the baboon is phylogenetically closely related to humans and shares many genetic and physiological characteristics. Third, myosin isoform switches in response to pressure overload hypertrophy are well described in the baboon.15 16 Fourth, animals were chronically instrumented and studied in the conscious, unsedated state using high-resolution, analytic methods to evaluate LV systolic and diastolic functions.
Our laboratory previously has characterized cardiac mechanics and arterial dynamics in this model.11 25 However, these studies were performed in closed chest anesthetized baboons after long-term (5 years) pressure overload hypertrophy. In the present study, we demonstrate the ability to study this unique model in the awake, preinstrumented state, without the confounding effects of anesthetic or autonomic reflexes, myocardial contractility, and neurohormonal profiles.
In contrast to clinical studies, we evaluated subjects with pressure overload of similar nature, duration, and severity. Although the baboons were all adults raised in a similar environment, the variability in the hypertrophic and hemodynamic responses we observed reinforces the importance of biological variability and the interaction between genetic and environmental factors in the development of hypertensive heart disease. The relevance of age at the onset of pressure overload hypertrophy was emphasized recently in a study that found that maturation decreases the capacity of myocardium to maintain normal function in developing pressure overload hypertrophy produced by aortic banding.40
Limitations of the Model
A potential criticism of our study is that a midwall analysis of LV function was not performed in the larger study. However, in the subset of animals with wall thickness sonomicrometers, the percent changes in Vcf and LV fractional shortening (before versus after renal artery clipping) were similar using midwall and endocardial methods. A related criticism is that use of end-systolic elastance in chronically diseased hearts is problematic. However, end-systolic elastance was similar in normal and hypertensive hearts when normalized for LV mass and when calculated using developed rather than total end-systolic pressure.
Although our studies were performed without β-adrenergic blockade, the inotropic state, inferred from end-systolic elastance determinations, was similar in baboons before and after development of hypertensive hypertrophy. In one study, an augmented response to catecholamines after 2 weeks of perinephritic hypertension was no longer evident at 14 weeks.7 In another study, β-adrenergic tone was unchanged from baseline in lambs with pressure overload hypertrophy (ascending aorta constriction for 5 weeks) and was not responsible for changes in contractility.40 Thus, it is unlikely that β-adrenergic tone significantly influenced our results.
Another potential problem is the use of a single LV dimension to represent LV volume. However, changes in ventricular geometry were minor; the modest hypertrophy we observed was unassociated with changes in the h/D ratio. In addition, although different LV minor axes were measured by echo and sonomicrometry, the results were qualitatively similar. Thus, it is unlikely that changes in LV geometry during the hypertrophic process substantially altered our results.
We compared pharmacologically afterloaded beats in normotensive animals with pressure-matched beats after hypertensive modeling. Although this permits comparison of hemodynamic data at matched loads, it is possible that differences exist between an acute and chronic afterload excess.
It is possible that with a larger sample size and greater statistical power that the small differences in end-systolic elastance between normal and hypertensive baboons and LV fractional shortening at matched load would achieve statistical significance. However, these differences are small compared with the changes in velocity-dependent indicies, which did achieve statistical significance despite the relatively small sample size.
In adult baboons, modest LV hypertrophy developed after 12 weeks of renovascular hypertension and was associated with depressed rates of LV pressure generation and relaxation and unchanged end-systolic elastance. The subcellular mechanisms responsible for these divergent effects on rate-dependent and force-dependent measures of contractility are a subject of ongoing investigation in our laboratory.
This work was supported in part by National Institutes of Health grant HL-33579, a Grant-in-Aid from the American Heart Association with funds contributed in part by the AHA Ohio Affiliate (93006860), and Merck Sharp and Dohme Research Laboratories. The authors would like to acknowledge the expert secretarial skills of Norma Burns and the technical assistance of Gary Flesher.
- Received July 21, 1994.
- Revision received September 6, 1994.
- Accepted September 28, 1994.
- Copyright © 1995 by American Heart Association
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