Fabrice Bauer, Jean-Paul Henry and Christian ThuillezGeneviève Derumeaux, Paul Mulder, Vincent Richard, Abdeslam Chagraoui, Catherine Nafeh,

Left Ventricular Hypertrophy in RatsTissue Doppler Imaging Differentiates Physiological From Pathological Pressure-Overload

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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.0000012943.91101.D7

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Tissue Doppler Imaging Differentiates Physiological FromPathological Pressure-Overload Left Ventricular

Hypertrophy in RatsGeneviève Derumeaux, MD, PhD; Paul Mulder, PhD; Vincent Richard, PhD;

Abdeslam Chagraoui, PhD; Catherine Nafeh, MD; Fabrice Bauer, MD;Jean-Paul Henry, BS; Christian Thuillez, MD, PhD

Background—The myocardial velocity gradient (MVG) is a recent index of regional myocardial function derived fromendocardial and epicardial velocities obtained by tissue Doppler imaging (TDI). This index might be useful fordiscriminating between physiological and pathological left ventricular hypertrophy (LVH) and for documenting theearly transition from compensated LVH to heart failure. We sought to compare MVG measured across the leftventricular posterior wall between normal rats and rats with physiological (exercise) and pathological (pressure-overload) LVH.

Methods and Results—Wistar rats were assigned to one of the following groups: sedentary, exercise (swimming), and2-month or 9-month abdominal aortic banding. Compared with sedentary rats, exercise and 2-month banding led tosimilar and significant LVH. After 2-month banding, conventional parameters of systolic function (left ventricularfractional shortening and dP/dtmax) were not affected. However, systolic and diastolic MVG were similar in exercise andsedentary rats but were significantly lower in rats with aortic banding. Aortic debanding after 2 months led to a fullrecovery of MVG, whereas MVG remained decreased when debanding was performed after 9 months.

Conclusions—Myocardial contraction and relaxation assessed by TDI were impaired in pressure-overload LVH but not inexercise LVH. Therefore, TDI is more sensitive than conventional echocardiography for assessing myocardialdysfunction in pressure-overload LVH and for predicting early recovery in myocardial function after loading conditionsnormalization. (Circulation. 2002;105:1602-1608.)

Key Words: hypertrophy � echocardiography � imaging

Concentric left ventricular hypertrophy (LVH) is initiallyan adaptive process that develops in response to a

sustained pressure-overload to normalize LV wall stress.1,2

Exercise training also leads to concentric LVH, described asathlete’s heart, as demonstrated both in humans and inanimals.3,4 In physiological LVH, the increase in ventricularmass is characterized by a normal organization of cardiacstructure and no collagen increase.5 In contrast, in patholog-ical LVH, structural changes and collagen accumulationaccompany myocyte hypertrophy and may progressively leadto systolic and diastolic myocardial dysfunction.5–7

At present, conventional echocardiography is not sensitiveenough to distinguish physiological from pathological LVH,to precisely assess systolic and diastolic functions in LVH,and to detect in its early stage the transition from compen-sated LVH to heart failure in pressure-overload LVH.8,9

Tissue Doppler imaging (TDI), an emergent ultrasoundtechnique, provides new indexes of myocardial function suchas the myocardial velocity gradient (MVG) measured be-

tween endocardial and epicardial myocardial velocities,10–13

which might accurately detect subtle changes in cardiaccontractility otherwise undetectable by conventionalechocardiography.

Therefore, we investigated whether TDI might help indifferentiating physiological from pathological LVH. For thispurpose, we used rat models of physiological (exercise) andpathological (aortic constriction) LVH and documented non-invasively the early transition from compensated LVH toheart failure in rats with pathological LVH.

MethodsAll experiments performed in this study conformed to the GuidingPrinciples in the Care and Use of Animals approved by the AmericanPhysiological Society.

AnimalsWe included 3 groups of 3-month-old Wistar rats (Charles River,Saint-Aubin-Les-Elbeuf, France): 6 sedentary rats and 6 exercisedrats. Physical training consisted of two 30-minute swimming periods

Received December 27, 2001; revision received January 25, 2002; accepted January 28, 2002.From INSERM E9920, Rouen University, Rouen, France.Correspondence to Geneviève Derumeaux, MD, PhD, INSERM E9920, Rouen University, 22 Boulevard Gambetta, 76000 Rouen, France. E-mail

Genevieve.Derumeaux@chu-rouen.fr© 2002 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000012943.91101.D7

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each day (in a 150-L water tank; water temperature, 28°C), 5 daysper week for 10 weeks. Swimming sessions were supervised to avoidfloating and/or clinging of individual animals.14

Fourteen rats were subjected to abdominal aortic banding betweenthe origin of the two renal arteries. All animals had an echocardio-graphic evaluation 2 months after aortic banding. After echocardio-graphic measurement, they were subdivided into two groups, sub-jected either to immediate debanding (n�8) or kept another 7 monthsbefore debanding (n�6). In both groups, rats were analyzed justbefore and then again at 5, 30, and 60 minutes and 24 hours afterdebanding by both conventional echocardiography and TDI.

To evaluate intrinsic myocardial contractility, additional rats(sedentary, 10; 2-month banding, 7; and 9-month banding, 5) weresubjected to ex vivo measurements of myocardial function.

EchocardiographyEchocardiography was performed in anesthetized animals (50 to 75mg/kg ketamine and 10 to 15 mg/kg xylazine IP) with the use of anATL5000 system. Wall thickness and LV dimensions were obtainedfrom a short-axis view at the level of the papillary muscles. LV masswas calculated by use of the following formula, assuming a sphericalLV geometry and validated in rats15: LV mass�1.04�[(LVd�PWd�AWd)3�LVd3], where 1.04 is the specific gravity of muscle,LVd is LV end-diastolic diameter, and PWd and AWd are end-dia-stolic posterior and anterior wall thicknesses. LV shortening wascalculated as (LVd�LVs)/LVd�100, where LVs is LV end-systolicdiameter.

To examine rat hearts characterized by a high heart rate and asmall size, we used a high-frequency transducer (8.5 MHz) andperformed TDI acquisition at 5 MHz. The spatial resolution alongthe ultrasonic beam was improved to 0.2 mm. The temporalresolution was adjusted at 5 ms. The autocorrelation method wasused to estimate the mean velocity between the sequentially receivedechoes. The velocity estimation error was �2% between the ana-lyzed pixel and the reference color bar.16,17 Measurement of myo-cardial velocities resulting from the LV radial contraction wasperformed on the short-axis view at the level of the papillarymuscles. Gray-scale receive gain was set to optimize the clarity ofthe endocardial and epicardial boundaries. Doppler receive gain wasadjusted to maintain optimal coloring of the myocardium. Dopplervelocity range (0.77 to 46.2 cm/s) was set as low as possible to avoidaliasing. The angle of interrogation of the M-mode beam wascarefully aligned to be perpendicular to LV walls. Freeze-frameimages were then downloaded to a magneto-optic disk and trans-ferred to an IBM-compatible computer for off-line analysis (HDILAB). Using this software, we manually traced by a multipointalgorithm subendocardial and subepicardial edges. The location ofthe subendocardial and subepicardial edges was visually definedafter color subtraction. The timing of the samples was similar to thetemporal resolution of TDI M-mode that was adjusted at 5 ms, andmyocardial velocity estimates were calculated automatically in eachpixel of the edge. MVG was defined as the difference betweenendocardial and epicardial velocities divided by wall thickness.Three beats were averaged for each of these measurements.

Hemodynamic MeasurementsIn all sedentary and exercise rats and in 2-month (n�6) and 9-month(n�6) aortic-banded rats, at the end of echocardiography, the right

carotid artery was cannulated with a micromanometer-tipped cathe-ter (SPR 407, Millar Instruments) and advanced into the aorta for therecording of peak systolic and diastolic arterial pressure. Thecatheter was then advanced into the LV for the recording of LVpressure and its maximal rate of rise (LVdP/dtmax) and decrease(LVdP/dtmin). All tracings were recorded on a physiological recorder(Windowgraph, Gould). At the end of the hemodynamic studies, ratswere euthanized and the heart was excised, weighed, and placed inBouin fixative solution.

Isolated Perfused HeartsAfter anesthesia, the heart was rapidly excised and placed in ice-cold(4°C) oxygenated (95% O2�5% CO2, pH�7.4) Krebs-Henseleitsolution. Within 30 seconds, the heart was transferred to a Langen-dorff perfusion apparatus and perfused at constant hydrostaticpressure (80 cm water). A balloon was inserted into the LV andconnected to a pressure transducer to record LV pressure andLVdP/dt minimum and maximum and heart rate. The balloon wasinflated with water, allowing a similar and constant LV distendingpressure of 10 mm Hg.

Estimation of LV Wall StressLV meridional systolic wall stress was estimated as 0.334�LVpressure�LVs/PWs [1�(PWs/LVs)], in which LV pressure is LVsystolic pressure, LVs is systolic left ventricular diameter, and PWsis systolic posterior wall thickness.18

Cardiac MorphometryMorphometric analyses were performed as previously described.19

The LV was cut perpendicular to the apex-to-base axis into 3 slicesof equal thickness, then dehydrated and embedded in paraffin. Fromthese sections, 3-�m-thick histological slices were obtained andstained with Sirius red for the determination of cardiac collagendensity. The volume of the collagen fraction was calculated from500-fold-enlarged images, as the sum of the surface of all connectivetissue areas divided by the total surface of the image. Perivascularcollagen was excluded from this measurement.

StatisticsAll values are presented as mean�SEM. Differences between theyoung, exercised, and aortic-banded rats, as well as the effect ofaortic debanding, were determined by means of ANOVA. A value ofP�0.05 was considered statistically significant.

ResultsHemodynamic MeasurementsAs expected (Table 1), aortic systolic and diastolic bloodpressures were significantly higher in banded than in seden-tary and exercised rats, whereas LVdP/dtmin was significantlylower (P�0.01). LVdP/dtmax significantly decreased only in9-month banded rats. Aortic systolic and diastolic pressures,LVdP/dtmax, and LVdP/dtmin were similar in sedentary andexercised rats.

TABLE 1. Hemodynamic Measurements

Sedentary Exercise 2-Month Banding 9-Month Banding

Heart rate, bpm 393�12 323�9 360�11* 373�15

SBP, mm Hg 156�7 155�7 249�13* 208�19*

DBP, mm Hg 122�3 117�4 147�3* 153�5*

LVdP/dtmax, mm Hg/s 9667�865 10 917�820 10 000�447 5583�947*

LVdP/dtmin, mm Hg/s �10 458�726 �13 000�347 �4667�543* �4125�836*

SBP indicates systolic blood pressure; DBP, diastolic blood pressure.*P�0.01 vs sedentary.

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Isolated Heart StudiesAfter 2-month banding, LVdP/dtmax and LVdP/dtmin were notaltered compared with sedentary (4060�124 versus4633�93 mm Hg/s and 2490�136 versus 2801�83 mm Hg/s, P�NS). In contrast, after 9-month banding, LVdP/dtmax andLVdP/dtmin were significantly decreased compared with bothsedentary and 2-month banded rats (2143�558 and1324�450 mm Hg/s, respectively, P�0.01).

Echocardiographic and Histological MeasurementsExercised and 2-month banded groups demonstrated similarconcentric LVH compared with sedentary (P�0.01, Table 2),characterized by increased wall thickness with normal LV

cavity dimensions (Figure 1). LV weight compared withsedentary (0.9�0.1 g) significantly increased in exercise(1.48�0.06 g) and in banded groups (1.58�0.29 g). LVsystolic function assessed by LV fractional shortening wasconsidered normal and was similar in the different groups.LV systolic wall stress was significantly higher in banded ratscompared with the other groups (P�0.01).

Aortic-banded rats had a significantly higher LV collagendensity (3.1�0.1%) after 2-month banding compared withsedentary (2�0.1%) and exercised rats (2.4�0.3%) (P�0.01)(Figure 1). After 9-month banding, LV collagen densitysignificantly increased (5.1�0.1%, P�0.05 versus 2-monthbanding). Moreover, the increase in collagen was mostly

TABLE 2. Echocardiographic Measurements

Sedentary Exercise 2-Month Banding 9-Month Banding

AWd, mm 1.7�0.1 2.5�0.1* 2.6�0.1* 2.7�0.9*

PWd, mm 1.7�0.2 2.2�0.1* 2.5�0.1* 2.6�0.7*

LVd, mm 5.8�0.5 7.1�0.3 6.3�0.4 8.5�1.2*

LVs, mm 3.0�0.1 4.0�0.4 3.5�0.4 4.5�0.9*

LV FS % 46�8 44�5 45�3 45�7

LVM, g 0.6�0.1 1.3�0.1* 1.3�0.1* 1.9�0.3*

LVSWS, kdyne/cm2 26.5�2.2 27.4�2.9 53.0�5.5* 45�9.2*

Systolic velocities, cm/s

Endocardium 5.2�0.3 4.8�0.3 3.5�0.2* 2.8�0.6*

Epicardium 2.4�0.3 2.6�0.2 2.9�0.2 1.6�0.2*

SMVG, s�1 2.8�0.1 2.2�0.1 0.4�0.1* 0.7�0.2*

Early diastolic velocities, cm/s

Endocardium �6.1�0.5 �4.1�0.4 �2.9�0.4* �2.7�0.5*

Epicardium �3.5�0.4 �2.5�0.2 �2.4�0.6 �2.1�0.9

Atrial contraction velocities, cm/s

Endocardium �2.8�0.5 �3�0.4 �4.5�0.5* �4.8�0.3*

Epicardium �1.9�0.2 �2�0.2 �3.6�0.4 �3.9�0.4

EMVG/AMVG 1.4�0.2 2.3�0.1 0.7�0.1* 0.8�0.1*

LV FS indicates left ventricular fractional shortening; LVM, left ventricular mass; and LVSWS, leftventricular systolic wall stress.

*P�0.05 vs sedentary.

Figure 1. M-mode (left), TDI M-mode (mid-dle), and LV collagen density (right) in the 3groups. Note decrease in myocardial velocityin the banded group associated withincreased collagen density.

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localized in endomyocardial area after 2-month banding butwas homogeneous throughout the myocardial wall after9-month banding (Figure 2).

Tissue Doppler ImagingAs shown in Table 2, after 2-month banding, the systolicmyocardial velocity gradient (SMVG) was significantlylower in the banded group than in sedentary and exercisedanimals (P�0.001). This lower SMVG was related to lowerendocardial velocities in the banded group, whereas epicar-dial velocities were similar in the 3 groups.

In early diastole (E), myocardial velocity gradient (EMVG)was also significantly lower in banded rats than in the othergroups (P�0.001). During atrial contraction (A), endocardialvelocities were significantly higher in banded rats than inyoung and exercised rats. This resulted in diastolic abnormal-ities in the banded group, as shown by the EMVG/AMVG

ratio, which was significantly lower than in the other groups.Despite similar LV mass, SMVG and EMVG could clearlydifferentiate the exercise group from the 2-month bandedgroup, that is, physiological from pathological LVH (Figure3). An SMVG cutoff value of 1 s�1 clearly separated rats fromthe banded group from the others. Thus, despite normalconventional indexes of systolic function (LV fractionalshortening and LVdP/dtmax), TDI revealed abnormal systolicparameters in banded rats. Furthermore, the linear relationbetween SMVG and systolic wall stress suggests that in-creased wall stress contributed to the abnormal systolic datain the 2-month banded rats (Figure 4). Finally, the linearrelation between EMVG/AMVG and LVdP/dtmin shows thatTDI could accurately and noninvasively detect early diastolicdysfunction (Figure 5). Despite similar SMVG values, veloc-ities in both endocardial and epicardial layers were lower 9months than 2 months after banding (P�0.05) (Figure 6).

Figure 2. M-mode and LV collagen den-sity in 2-month (left) and 9-month (right)banded rats. Note predominant increasein collagen density within endocardiumafter 2-month banding as opposed tohomogeneous increase throughout themyocardium after 9-month banding.

Figure 3. Left, Relation between SMVG (s�1) and LV mass. Right, Relation between EMVG (s�1) and LV mass. Despite similar LV mass,exercise and banded groups could be clearly distinguished by SMVG and EMVG, which were significantly lower in banded rats.

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Effects of Aortic DebandingWhen aortic debanding was performed early (2 months afterbanding), it resulted in significant and rapid increases inSMVG, EMVG, and AMVG that returned to normal valueswithin 5 minutes after debanding and remained unchangedthereafter, despite persistent LVH. Conversely, when aorticdebanding was performed 9 months after banding, SMVG,EMVG, and AMVG did not recover normal values afterdebanding and remained severely depressed (Figure 6).

DiscussionThe main findings in this study are that (1) TDI providessensitive indexes to differentiate physiological (ie, exercisedgroup) from pathological (ie, aortic banding group) LVH, (2)in pressure-overload LVH, TDI could reveal early systolicand diastolic myocardial abnormalities despite normal usualindexes of systolic function, and (3) based on the respectivedecrease in endocardial only, or both epicardial and endocar-dial velocities, TDI could predict early recovery in regionalmyocardial function after normalization of afterload.

TDI is a relatively new modality, developed primarily toevaluate the direction and magnitude of myocardial motion.Myocardial velocities have been shown to be closely relatedto sonomicrometry measurements, a reference method forevaluation of myocardial function.16,20 Since TDI has beenmainly evaluated in the setting of experimental and clinicalischemic cardiomyopathy, TDI has recently been shown to bevery sensitive in the detection of hypertrophic cardiomyopa-thy in a transgenic rabbit model, irrespective of the presenceor absence of LVH.21 Previous studies have also shown theability of TDI to distinguish hypertrophic cardiomyopathyfrom athlete’s heart in humans.22,23

The most important finding in this study is that we couldaccurately distinguish physiological from pressure-overloadLVH by color M-mode TDI. Despite similar levels of LVmass, SMVG and EMVG/AMVG were significantly lower inthe aortic-banded group than in exercised rats, whereas theconventional parameters of systolic function including LVfractional shortening and LVdP/dtmax were normal and similarin the 3 groups. At this very early stage of pressure overload(2 months), this finding is particularly interesting because theearly state of concentric LVH is classically described as“compensated.” It has been a matter of controversy whetherthe myocardium preserves normal systolic function inpressure-overload hypertrophy. Such a controversy results inpart from the fact that most whole-heart studies incorporateendocardial measurements (eg, LV fractional shortening andejection fraction) that reflect LV chamber function, whereasmany in vitro studies use myocyte function. In fact, studiesthat use midwall circumferential stress-shortening relations toassess myocardial function in pressure-overload LVH dem-onstrate that myocardial contractile function is depresseddespite the presence of a normal LV fractional shortening.23–26

Our data suggest that SMVG might be an accurate markerof early systolic dysfunction in response to elevated LVafterload, as suggested by the negative linear relation withsystolic wall stress observed at 2 months. At this time ofbanding, EMVG/AMVG ratio was also significantly lowerthan in the other groups. This alteration in diastolic functionwas correlated with LVdP/dtmin and could be explained bothby LVH and by the moderate increase in ventricular collagencontent.27–29

It is noticeable that SMVG had similar values in sedentaryand exercised rats. However, in clinical studies, systolic anddiastolic MVG failed to distinguish normal patients andpatients with LVH secondary to systemic hypertension.21

This discrepancy between clinical and experimental studiesmay be explained by the fact that MVG is influenced byaging.12

There are various possible causes for the decrease in MVGin the rats with pathological LVH. Indeed, this decrease mayreflect (1) early systolic and diastolic myocardial abnormal-ities that could not be detected by conventional echo methods,(2) structural alterations of the cardiac interstitium withincreased content of myocardial collagen matrix, which hasbeen demonstrated to be a major determinant of myocardialdiastolic stiffness in hypertensive heart disease,30 whereas nosign of myocardial dysfunction has been reported in forms ofLVH in which myocardial fibrosis is absent, for example,

Figure 4. Correlation between LV systolic wall stress andSMVG. This correlation suggests that increased afterload con-tributes to early systolic dysfunction in rats after 2 months ofpressure overload.

Figure 5. Correlation between LVdP/dtmin and ratio of EMVG/AMVG. This relation suggests that TDI may help to identify earlydiastolic dysfunction in rats after 2 months of pressure overload.

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athlete’s heart,31,32 (3) a decrease in myocardial �-adrenoceptordensity,33 and (4) an increase in afterload.33

Although all these parameters probably influence myocar-dial velocity decrease in LVH, their impact varies with thetime course of the disease, as demonstrated by the differencebetween early (2 months) or late (9 months) debanding. Earlydebanding leads to an immediate recovery of normal velocityand MVG, suggesting the main influence of afterload in-crease on the observed myocardial dysfunction. This hypoth-esis is supported by the fact that at that stage, both LVdP/dtmax

and LVdP/dtmin in isolated hearts (ie, at identical loadingconditions) are similar to control sedentary values. Further-more, the fact that the increase in collagen content is limitedto the endocardial layer probably cannot by itself causemyocardial dysfunction unless accompanied by an increasedafterload (as in the case of 2-month banding).

In contrast to debanding after 2 months, late (9-month)debanding does not improve velocities and MVG. At thatstage of pressure-overload LVH, collagen content is mark-edly increased throughout the myocardial wall. Moreover, thestudies in isolated hearts confirm the existence of severealterations in intrinsic myocardial contractility. This probablyexplains the absence of recovery in myocardial function after9-month banding.

ConclusionsDespite similar increase in LV mass in exercise and bandedrats, TDI revealed early systolic and diastolic dysfunctiononly in pressure-overload LVH despite normal indexes ofsystolic function. Therefore, TDI is an accurate method todifferentiate physiological from pathological (ie, pressureoverload) hypertrophy and to predict early recovery in re-gional myocardial function after normalization of the loadingconditions.

AcknowledgmentsWe thank Françoise Lallemand for excellent technical expertise inhistology.

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