(Circulation. 1996;94:2923-2929.)
© 1996 American Heart Association, Inc.
Articles |
Equipotent Antihypertensive Agents Variously Affect Pulsatile Hemodynamics and Regression of Cardiac Hypertrophy in Spontaneously Hypertensive Rats
the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Gary F. Mitchell, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail gfmitchell@bics.bwh.harvard.edu.
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Abstract |
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Background Converting enzyme inhibitors are more effective than arteriolar vasodilators at regressing left ventricular hypertrophy in spontaneously hypertensive rats (SHR), possibly because of nonhemodynamic factors. However, the pulsatile component of hemodynamic load has not been evaluated in this model.
Methods and Results We measured pulsatile hemodynamics in 18-month-old male SHR after 6 months of therapy with either zofenopril (Z), hydralazine (H), or water (W). Hydralazine and zofenopril reduced mean arterial pressure comparably (W, 106±23 versus H, 81±12 versus Z, 84±18 mm Hg, P=.002) yet had a differential effect on the ratio of left ventricular weight to body weight (W, 3.9±0.5 versus H, 3.3±0.4 versus Z, 2.4±0.2 g/kg, P<.005). Hydralazine-treated SHR had increased characteristic impedance (P=.0011) and a persistently low ratio of the reflected-wave transit time to left ventricular ejection time (P<.001), which contributed to early and late systolic loading, respectively, of the left ventricle. Consequently, only zofenopril-treated SHR had a significant reduction in left ventricular systolic force-time integral (P=.02), a measure of total ventricular load. There were no differences in systolic stress-time integral, suggesting that mass was appropriate to load when all elements of steady-flow and pulsatile load were considered.
Conclusions A blunted reduction in total left ventricular load, due to increased pulsatile load in SHR treated with hydralazine, provided a hemodynamic basis for the differential regression of hypertrophy in this model of genetic hypertension.
Key Words: aorta • hypertrophy • hypertension • Fourier analysis • ventricles
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Introduction |
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The importance of hypertension as a risk factor for cardiovascular morbidity and mortality is well known.1 This adverse association is accentuated when LV hypertrophy is detected by electrocardiography2 or echocardiography.3 4 5 Although hypertension is the most common cause of LV hypertrophy, the relationship between blood pressure and LV mass is weak and regression of ventricular hypertrophy with differing pharmacological agents is variable. In experimentally induced hypertension, LV hypertrophy is proportionate to the elevation in blood pressure, and prompt regression is generally achieved if the inciting stimulus is removed. When that stimulus remains intact and hypertension is controlled with pharmacotherapy, reduction in LV mass to normal levels is less certain.6 This applies to genetic hypertension, in which the stimulus for blood pressure elevation is unknown and pharmacotherapy is required to return blood pressure to normotensive levels.
The dissociation between blood pressure reduction and regression of ventricular mass has prompted the investigation of potential nonhemodynamic modulators of ventricular mass, such as the sympathetic nervous system7 8 or the renin-angiotensin system.9 10 11 It is important to note, however, that conventional hemodynamic analyses that use mean values of blood pressure, cardiac output, and peripheral resistance variably underestimate total ventricular load. The pulsatile component, which represents the energy necessary to overcome the inertial, viscous, elastic, and reflective characteristics of the arterial system, may contribute substantially to total load in pathological states such as hypertension. Furthermore, it is the pulsatile load that defines the time-dependence of the interaction between the ventricle and vasculature during systole. Because of the dynamic nature of LV wall thickness and cavity dimension, stroke volume,12 end-diastolic volume,13 and the time course of pressure and flow development during systole are as important as the mean or peak levels of pressure and flow. Measurements of aortic input impedance, a frequency-dependent representation of vascular load, fully characterize both the steady-flow and pulsatile components of external LV load.14 15
Previous work in this laboratory demonstrated that the vasodilator hydralazine16 and the converting enzyme inhibitor captopril17 were successful at normalizing blood pressure in the SHR. Whereas the vasodilator attenuated ongoing hypertrophy, only the converting enzyme inhibitor was successful at regressing established LV hypertrophy. The purpose of this study was to use the measurement of aortic input impedance and pulse-wave velocity to more fully assess the hemodynamic effects of antihypertensive therapy in this animal model of hypertension to determine whether a differential effect on the pulsatile component of LV load could contribute to these disparate alterations in LV mass.
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Methods |
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Study Animals
Experiments were performed on SHR and NWR obtained from colonies that were bred and maintained in our animal facility. Antihypertensive therapy was initiated in 12-month-old male rats and continued for 6 months. Rats were randomly assigned to receive either no therapy (SHR-W, n=16; NWR-W, n=8), tap water containing hydralazine (SHR-H, n=12; NWR-H, n=6), or rat chow containing the long-acting converting enzyme inhibitor zofenopril (SHR-Z, n=12; NWR-Z, n=11). The dose of hydralazine (80 mg/L) was previously shown to normalize blood pressure in SHR.16 The appropriate dose of zofenopril (0.07% by grams of zofenopril per gram rat chow), which produced a comparable reduction in mean arterial pressure, was established in a preliminary study. This optimal dose was then used for all zofenopril-treated animals in the present study. All studies were performed in accordance with the guidelines of the Harvard Medical Area Standing Committee on Animals.
Hemodynamic Preparation
The pressure transducers (model SPR-407, Millar Instruments Inc) and flowmeter (model SP2202, Statham Instruments) were prepared as previously described.18 Under ether anesthesia, a tracheotomy was performed, and the animal was connected to a rodent respirator. The right carotid and left femoral arteries were cannulated with 2F catheter-tip pressure transducers. The carotid catheter was advanced into the ascending aorta, and the femoral catheter was advanced 5 cm, which placed the tip in the abdominal aorta 
1 to 2 cm proximal to the aortic bifurcation. The right jugular vein was cannulated to allow for intravenous infusions. After midline thoracotomy, a flow probe was placed around the ascending aorta. The location of the tip of the proximal aortic pressure transducer was visually confirmed and adjusted to be 1 to 2 mm distal to the downstream edge of the electromagnetic flow probe to avoid interference with the flow measurements. In all subsequent calculations, compensation was made for this spatial separation between pressure and flow transducers through analysis of the ITR as previously described.18
Once animals were fully instrumented, four baseline recordings were taken over a period of 10 to 12 minutes, during which time the animals were hemodynamically stable, and the analyzed results were averaged. Subsequently, a graded infusion of the vasodilator sodium nitroprusside (0.5 to 30 µg/min) was administered to reduce mean arterial pressure into the low-normal range. After return of arterial pressure to baseline, a graded infusion of methoxamine (20 to 1600 µg·kg-1·min-1) was titrated to produce a rise in mean arterial pressure well into the hypertensive range. Steady-state recordings were made 1 minute after initiation of each new dosage level of nitroprusside and methoxamine.
At the completion of each hemodynamic study, after diastolic arrest of the heart with potassium chloride, LV pressure-volume relationships were determined with a double-lumen catheter as previously described.19 The heart was then excised and immersed in formalin for 24 hours. The right ventricular free wall was subsequently dissected from the LV, and both ventricles were blotted dry and weighed. LV mass was indexed to body weight. Because of the nonlinearity of the relationship between ventricular mass and body weight,20 LV weight was also indexed to tibial length. The distance between the proximal and distal pressure transducers, used in the calculation of pulse-wave velocity, was determined by measurement of the length of a segment of polyethylene tubing that was inserted into the proximal aorta at the level of the proximal transducer and advanced antegrade to the level of the distal pressure transducer.
Data Analysis
Details of the data acquisition and analysis have been presented elsewhere.18 For each experimental condition, the pressure and flow waveforms from five consecutive cardiac cycles were averaged in the time domain, with the first peak in the first derivative of pressure used as a fiducial point. These averaged pressure and flow waveforms were then subjected to frequency-domain analysis. The flow noise level was determined for each cardiac cycle by Fourier analysis of the middle third of the diastolic flow signal. Only harmonics with a flow modulus >1.5 times the flow noise level (greatest modulus in this portion of diastole) were included in subsequent calculations.21 In addition, only harmonics with a pressure modulus >0.1 mm Hg (approximately twice the resolution of the 12-bit A/D converter) were used.
Aortic pressure and flow were converted to the first 10 harmonics of their respective Fourier series and corrected for the frequency-response characteristics of the measurement system. Aortic input resistance (the 0-Hz, or steady-flow, term of the impedance spectrum) was calculated by dividing mean pressure by mean flow. Aortic input impedance moduli, Zi, for the first through the 10th harmonic were obtained by dividing pressure modulus by flow modulus at each harmonic, i. Subtraction of the phase of flow from that of pressure at each harmonic gave the impedance phase, which was corrected for instrumentation and spatial delays.18 Characteristic impedance, Zc, was estimated by averaging values of Zi for all harmonics after and including the first impedance minimum through the 10th harmonic.18 Pulse-wave velocity, co, was calculated by dividing the distance between proximal and distal aortic pressure transducers by the foot-to-foot time delay between simultaneously recorded proximal and distal pressures. Stroke volume was calculated by dividing mean cardiac output by heart rate.
The RWTT (round-trip time required for the incident wave to travel to the "effective reflecting site" and back to the proximal aorta) was assessed by analysis of the derived ITR of the arterial system. The ITR was obtained by inverse transformation of the aortic input impedance spectrum after application of a Dolph-Chebyshev digital filter with side lobes set to 60 dB.18 22 23 The RWTT was the time from the primary (characteristic impedance) peak of the ITR to the peak of the distal reflection. LVET was measured from the aortic flow tracing. The relationship between the arrival of the reflected wave and completion of ventricular ejection was evaluated by dividing the RWTT by the LVET. This unitless index has an optimal value of 
1 if the reflected wave arrives in the root of the aorta in diastole. A value <1 indicates that the reflected wave overlaps end systole, imposing an additional pulsatile load on the ventricle.
The physiologically effective internal radius, r, of the proximal aorta was calculated from the water-hammer equation, Zc=co
/
r2, where co is pulse-wave velocity and is the density of blood, which was assumed constant at 1.06 g/cm3. Good agreement between pulse-wave velocity calculated from this equation and true phase velocity has been demonstrated, suggesting that this is a valid method of estimating aortic radius in vivo.24 Proximal aortic compliance was calculated from the Bramwell-Hill equation, co2=VdP/dV, where V is volume and P is pressure. Rearranging gives dV/dP=V/co2. Compliance per unit length, Cl, of the proximal aorta was calculated by dividing both sides of the equation by length to give Cl=r2/co2. Substituting the water-hammer equation into the numerator gave Cl=(co/Zc)/co2=1/(Zcxco). Total arterial compliance was calculated from the diastolic central aortic pressure decay.25
Total hemodynamic load on the LV was assessed by calculation of the LV systolic force-time integral. Instantaneous LV pressure was assumed equal to central aortic pressure. Instantaneous LV volume was determined by subtracting ejected volume (the integral of the aortic flow tracing from the beginning of systole to the time in question) from end-diastolic volume. To ensure a finite LV volume at each point during systole, a robust estimate of end-diastolic volume was obtained as follows. The LV volume at 10 mm Hg was determined from pressure-volume data. Baseline stroke volume was divided by the volume at 10 mm Hg for each animal to obtain an approximation of individual ejection fraction. Mean ejection fraction under basal conditions was then obtained for each treatment group. A final, robust end-diastolic volume was obtained for each animal by dividing individual stroke volumes by the group mean ejection fraction. Instantaneous endocardial surface area was calculated from instantaneous LV volume by assuming a spherical geometry. Total force was calculated by multiplying pressure and endocardial surface area at each point in systole. The systolic force-time integral was calculated by integrating the systolic force waveform.
LV wall stress, S, was calculated at each point in systole from the force equilibrium equation. Thus, PxAc=SxAw, or S=(PxAc)/Aw, where P is pressure and Ac and Aw are the midplane cross-sectional areas of the LV cavity and wall, respectively.26 The implications of assuming spherical geometry have been presented in detail.26 The systolic stress-time integral was calculated by integrating the systolic stress waveform.
Statistical Analysis
The effects of therapy within a strain were assessed by one-way ANOVA with Scheffe subtesting of individual means when a significant main effect was demonstrated. Repeated-measures ANCOVA was used to assess the main effect of therapy on pressure-dependent variables across the wide range of mean arterial pressures produced by vasodilatation and vasoconstriction within each animal. All values are presented as the mean±SD, except as noted in the figures.
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Results |
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By design, hydralazine and zofenopril were equally effective at reducing mean arterial pressure in SHR compared with age-matched controls (Table 1
). Hydralazine attenuated the ongoing hypertrophy that occurred in SHRs between 12 and 18 months, whereas zofenopril regressed the LV weight–to–body weight ratio toward normotensive levels (Table 2). This change was attributable to a reduction in LV mass, since body weight was not different. End-diastolic volume, stroke volume, heart rate, and mean cardiac output were not affected by therapy in SHR (Table 1). In NWR, reductions in mean arterial pressure and LV weight–to–body weight ratio were seen with zofenopril (Table 2), whereas neither parameter decreased significantly in NWR-H. Stroke volume and mean flow were both increased in NWR-H (Table 1).
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Characteristic impedance was increased in SHR-H (Table 3), and this difference persisted across a wide range of mean arterial pressures (Fig 1). In contrast, the important first modulus of impedance, which corresponds to the dominant harmonic in the flow spectrum, was reduced in SHR-Z (Fig 2 and Table 3). Neither therapy had a significant effect on characteristic impedance in NWR (Table 3). Both antihypertensive agents were effective at reducing pulse-wave velocity in SHR (Table 3) because of both a lower operating pressure and a change in the relationship between pulse-wave velocity and mean pressure (Fig 1). Arrival of the reflected wave relative to end systole (RWTT/LVET) was premature (<1) in SHR-W, and this abnormality was ameliorated by therapy with zofenopril but not hydralazine (Table 3).
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) compared with SHR-W (
) and SHR-Z (
) was shown to be independent of mean arterial pressure. Values are mean±SEM.
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i, impedance phase. Values are mean±SD.
The disparate combination of an increased characteristic impedance and decreased pulse-wave velocity in SHR-H implied a reduction in the internal radius of the proximal conduit vessels (Table 3
), which persisted over a wide range of mean arterial pressures (Fig 1). Compliance per unit length of the proximal aorta was significantly improved only in SHR treated with zofenopril (SHR-W, 3.5±1.1; SHR-H, 3.1±0.5; and SHR-Z, 4.9±1.4x10-7 cm4/dyne, P<.0005). This parameter remained unchanged with therapy in NWR (NWR-W, 5.3±0.9; NWR-H, 5.1±0.2; and NWR-Z, 5.8±1.5x10-7xcm4/dyne, P=NS). Neither treatment had an effect on total arterial compliance in SHR (SHR-W, 3.6±0.6; SHR-H, 3.7±0.7; and SHR-Z, 3.7±0.5x10-6xcm5/dyne, P=NS), but this parameter increased considerably with either therapy in NWR (NWR-W, 3.4±0.6; NWR-H, 4.9±0.7; and NWR-Z, 4.7±0.9x10-6xcm5/dyne, P<.002).
The implications of the foregoing changes in pulsatile load were evident in the ventricular force calculations. The force-time integral was significantly reduced in SHR-Z, whereas SHR-H had a value that was quantitatively intermediate to that of SHR-W and SHR-Z (Fig 3). The systolic wall stress–time integral, however, was no different (SHR-W, 4.2±1.1; SHR-H, 4.2±1.7; and SHR-Z, 4.2±1.6x103 dyne·cm-2·s-1, P=NS), suggesting that the differential LV mass was appropriate to the total hemodynamic load imposed on the LV in each group.
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P<.05 SHR-Z vs SHR-H. |
Discussion |
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We have shown that when the vasodilator hydralazine and the converting enzyme inhibitor zofenopril were given to SHR in doses that equally reduced the steady-flow load on the LV, hydralazine paradoxically increased the pulsatile load on the heart. The reactive (characteristic impedance and proximal aortic compliance) and reflective components of pulsatile load were higher in SHR-H compared with SHR-Z. The higher pulsatile load in SHR-H resulted in a blunting of the reduction in the LV systolic force-time integral, which may have accounted for the diminished regression of LV hypertrophy. Analysis of the systolic stress-time integral confirmed that LV mass was appropriate to the differential total load seen in treated and untreated SHR.
Characteristic impedance is a particularly important determinant of ventricular load because of the unfavorable, near-diastolic ventricular geometry in early systole when peak flow occurs. In normal hearts, peak stress occurs early in ventricular ejection and then falls in mid and late systole, despite an increasing intracavitary pressure, because of the decrease in chamber diameter and increase in wall thickness.27 Characteristic impedance dictates the change in pressure for a given change in flow in the critical early systolic period. Therefore, an increase in characteristic impedance will directly impact early systolic pressure and peak ventricular force and wall stress and their integrals, possibly in excess of any change in mean or peak systolic pressure. Ventricular hypertrophy in response to this elevated hemodynamic load serves to normalize LV wall stress.27 These changes may go unrecognized if only mean or systolic pressure is considered, since the early (primary) pressure peak generally does not determine the systolic pressure maximum, especially in humans.28
Changes in the timing of the reflected wave can likewise adversely affect LV load independent of any change in steady-flow load. Premature return of the reflected wave during systole increases the late systolic load on the LV without affecting mean arterial pressure. When the peak of the reflected wave is centered at the dicrotic notch, end-systolic pressure can be substantially increased relative to mean or diastolic pressure, truncating stroke volume.29 This could result in a higher heart rate at a higher average ventricular volume and wall stress and thus a lower cardiac efficiency at the same mean pressure and cardiac output.
There are several lines of evidence that suggest that changes in pulsatile load alone can result in an increase in LV mass. Numerous studies have related LV mass to various measures of pulsatile load, including proximal aortic elastance,30 pulse-wave velocity,31 characteristic impedance of the aorta,32 33 pulse pressure,34 and brachial arterial compliance.35 Experimental36 and therapeutic37 aortic bypass procedures that result in an increase in the stiffness of the aorta have been shown to increase ventricular mass independently of a change in steady-flow workload. An important relationship between pulsatile load and ventricular mass independent of blood pressure was recently demonstrated by use of an analysis of the carotid pressure waveform.14 Premature return of the reflected wave with late systolic pressure augmentation was associated with an increased LV mass even after control for body size, age, sex, and blood pressure. The conduit vessels are known to stiffen with increasing age, and this process is accelerated in hypertension.38 39 40 41 This progressive increase in pulsatile load may help to explain the ongoing ventricular hypertrophy and eventual decompensation with hypertension.42
The discordant changes in characteristic impedance and pulse-wave velocity in SHR-H underscore the impact of vessel geometry on the functional characteristics of the aorta. These measures of pulsatile load depend differently on wall stiffness and vessel diameter and may change divergently in certain conditions. When the water-hammer and Moens-Korteweg (co2=Eh/2r) equations are combined, it can be seen that Zc has a stronger dependence on radius than does pulse-wave velocity: Zc=co/r2=[(Eh/2r)½]/r2=(Eh/22r5)½, where r is the internal radius of the aorta, co is pulse-wave velocity, E is Young's modulus, h is arterial wall thickness, and is the density of blood. Aortic compliance per unit length, Cl, has an even stronger dependence on radius: Cl=r2/co2=r2/(Eh/2r)=2r3/Eh. Thus, whereas pulse-wave velocity is dependent on the (inverse) square root of radius, characteristic impedance and compliance are dependent on radius raised to powers of -2.5 and 3.0, respectively, making these variables much more sensitive to changes in aortic radius. As a result, using any one of these parameters as an indicator of pulsatile load without evaluating the others can be misleading.
The basis for the reduction in effective aortic diameter in the hypertensive rats treated with hydralazine is most likely multifactorial and requires further study, including histological correlation. Since mean arterial pressures were equivalent in SHR-H and SHR-Z, the difference in diameter was not a passive one, as confirmed in Fig 1. These agents are known to have a differential effect on the structural components of the arterial wall. Aging in untreated SHR results in progressive thickening of the aortic media due to smooth muscle cell hypertrophy and deposition of collagen in the extracellular matrix.38 Excess collagen in the conduit vessel wall is reduced to normal by converting enzyme inhibitors but not by antihypertensive doses of hydralazine, even though both normalize myocyte hypertrophy.43 44 This excess collagen may lead to remodeling of the vessel wall to a smaller diameter.
Alterations in aortic smooth muscle tone can also affect the radius of the aorta and may account for some of the differences between treatment groups. Hydralazine is known to cause reflex sympathetic activation,45 and the latter has been shown to increase characteristic impedance in dogs.46 Acute administration of hydralazine reduces both blood pressure and conduit vessel diameter, whereas nitrates, calcium channel blockers, and converting enzyme inhibitors reduce pressure yet increase conduit vessel diameter.47 Favorable concordant effects of the AT1 angiotensin II receptor antagonist losartan on peripheral resistance and characteristic impedance have been demonstrated in the SHR.48 Furthermore, an increase in characteristic impedance has been found after administration of hydralazine to patients with congestive heart failure.49 In addition to these acute effects of the drugs, abnormal baseline endothelial function in SHR is returned toward normal with converting enzyme inhibition. Aortic rings from rats treated with converting enzyme inhibitors, even in "nonhemodynamic" doses, but not hydralazine, become less reactive to phenylephrine50 and serotonin51 and more reactive to acetylcholine,50 51 such that resting aortic tone may be modified even in the absence of a change in the neurohumoral milieu. It is possible, then, that the increased characteristic impedance seen in our SHR-H was due to combined changes in aortic structure and physiology. The result was an augmentation of pulsatile load that contributed to the maintenance of ventricular hypertrophy despite the reduction in mean arterial pressure. Although our study was performed in aging SHR, the inability of hydralazine to produce complete regression of hypertrophy in SHR has been observed in younger animals as well.43 45 52 Further study will be required to determine whether this differential effect of hydralazine in younger animals is also related to differences in pulsatile load.
An alternative explanation for the failure of hydralazine to regress hypertrophy in the SHR is that volume overload was substituted for pressure overload, leading to a transition from concentric to eccentric hypertrophy with no net effect on LV mass. Such a volume-overloaded state with eccentric LV hypertrophy has clearly been associated with guanethidine and minoxidil therapy in hypertensive rats and with hydralazine in normotensive rats. However, there is no change in LV volume or filling pressure in SHR-H, suggesting that eccentric hypertrophy does not play an important role in the sustained LV mass in these animals.52 53 Our postmortem volumes measured at a common pressure of 10 mm Hg confirm that end-diastolic volumes were not increased in the SHR-H, making eccentric hypertrophy an unlikely explanation for the difference in LV mass.
The additive negative prognostic implications of hypertension and LV hypertrophy have focused attention on this end-organ complication. Use of LV mass to further stratify risk and target antihypertensive therapy has been proposed,3 4 5 under the as yet unproven assumption that the return of LV mass to normal will concurrently reduce the excess risk associated with this pathological condition. To effectively treat, or preferably prevent, this cardiac complication of high blood pressure, it is important to better understand the relationship between hemodynamics and ventricular mass so that the stimulus to ventricular growth, rather than the end point of ventricular hypertrophy, can be assessed and therapeutic measures more successfully applied. Measurements of aortic input impedance and pulse-wave velocity and calculation of the impulse response function of the arterial system provide the tools necessary to fully describe the external load placed on the ejecting ventricle. Using this approach in the SHR, we have shown that pulsatile load may play an important role in the maintenance of ventricular hypertrophy during antihypertensive therapy despite a favorable reduction in mean blood pressure. We have shown that LV mass paralleled the hemodynamic load when all aspects of load were considered. As a result, ventricular wall stress was the same in the treatment groups. We found no evidence for a nonhemodynamic effect of hydralazine or zofenopril therapy on LV mass in the aging SHR.
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Acknowledgments |
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During this study, Dr Mitchell was a recipient of a Clinical Investigator Development Award (K08-HL-02775) from the National Institutes of Health, National Heart, Lung, and Blood Institute. Dr Janice Pfeffer was a recipient of a grant-in-aid from Bristol-Meyers Squibb, Princeton, NJ.
Received May 2, 1996; revision received June 19, 1996; accepted July 8, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Kannel WB, Castelli WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure: the Framingham Study. N Engl J Med. 1972;287:781-787.
2. Kannel WB. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med. 1983;75:4-11.
3. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561-1566.[Abstract]
4. Casale PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH. Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med. 1986;105:173-178.
5. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991;114:345-352.
6. Pfeffer MA, Pfeffer JM. Pharmacologic regression of cardiac hypertrophy in experimental hypertension. J Cardiovasc Pharmacol. 1984;6:S865-S869.
7. Devereux RB. Hypertensive cardiac hypertrophy: pathophysiologic and clinical characteristics. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1989:359-377.
8. Sen S, Tarazi RC, Bumpus FM. Cardiac hypertrophy and antihypertensive therapy. Cardiovasc Res. 1977;11:427-433.[Medline] [Order article via Infotrieve]
9.
Dzau VJ, Safar MD. Large conduit arteries in hypertension: role of the vascular renin-angiotensin system. Circulation. 1988;77:947-954.
10. Devereux RB, Pickering TG, Cody RJ, Laragh JH. Relation of renin-angiotensin system activity to left ventricular hypertrophy and function in experimental and human hypertension. J Clin Hypertens. 1987;3:87-103.[Medline] [Order article via Infotrieve]
11.
Morgan HE, Baker KM. Cardiac hypertrophy: mechanical, neural, and endocrine dependence. Circulation. 1991;83:13-25.
12. Ganau A, Devereux RB, Roman MJ, De Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I, Laragh JH. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 1992;19:1550-1558.[Abstract]
13.
Ganau A, Devereux RB, Pickering TG, Roman MJ, Schnall PL, Santucci S, Spitzer MC, Laragh JH. Relation of left ventricular hemodynamic load and contractile performance to left ventricular mass in hypertension. Circulation. 1990;81:25-36.
14. Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol. 1993;22:1873-1880.[Abstract]
15. Milnor WR. Pulsatile blood flow. N Engl J Med. 1972;287:27-34.
16.
Pfeffer JM, Pfeffer MA, Fletcher PJ, Fishbein MC, Braunwald E. Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats. Am J Physiol. 1982;242:H776-H784.
17.
Pfeffer JM, Pfeffer MA, Mirsky I, Braunwald E. Regression of left ventricular hypertrophy and prevention of ventricular dysfunction by captopril in the spontaneously hypertensive rat. Proc Natl Acad Sci U S A. 1982;79:3310-3314.
18.
Mitchell GF, Pfeffer MA, Westerhof N, Pfeffer JM. Measurement of aortic input impedance in the rat. Am J Physiol. 1994;267:H1907-H1915.
19.
Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction: effects on systolic function. Circ Res. 1981;49:618-626.
20. De Simone G, Devereux RB, Camargo MJF, Volpe M, Wallerson DC, Atlas SA, Laragh JH. In vivo left ventricular anatomy in rats with two-kidney, one clip and one-kidney, one clip renovascular hypertension. J Hypertens. 1992;10:725-732.[Medline] [Order article via Infotrieve]
21.
Zuckerman BD, Yin FCP. Aortic impedance and compliance in hypertensive rats. Am J Physiol. 1989;257:H553-H562.
22. Laxminarayan S, Sipkema P, Westerhof N. Characterization of the arterial system in the time domain. IEEE Trans Biomed Eng. 1978;BME-25:177-184.
23. Sipkema P, Westerhof N, Randall OS. The arterial system characterized in the time domain. Cardiovasc Res. 1980;14:270-279.[Medline] [Order article via Infotrieve]
24. Newman DL, Sipkema P, Greenwald SE, Westerhof N. High frequency characteristics of the arterial system. J Biomech. 1986;19:817-824.[Medline] [Order article via Infotrieve]
25.
Liu Z, Brin KP, Yin FCP. Estimation of total arterial compliance: an improved method and evaluation of current methods. Am J Physiol. 1986;251:H588-H600.
26.
Mirsky I, Pfeffer JM, Pfeffer MA, Braunwald E. The contractile state as the major determinant in the evolution of left ventricular dysfunction in the spontaneously hypertensive rat. Circ Res. 1983;53:767-778.
27. Grossman W. Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med. 1980;69:576-584.[Medline] [Order article via Infotrieve]
28.
Kelly R, Hayward C, Avolio A, O'Rourke M. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80:1652-1659.
29.
Suga H, Kitabatake A, Sagawa K. End-systolic pressure determines stroke volume from fixed end-diastolic volume in the isolated canine left ventricle under a constant contractile state. Circ Res. 1979;44:238-249.
30. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study. J Am Coll Cardiol. 1989;13:399-405.[Abstract]
31. Girerd Z, Laurent S, Pannier B, Asmar R, Safar ME. Arterial distensibility and left ventricular hypertrophy in patients with sustained essential hypertension. Am Heart J. 1991;122:1210-1214.[Medline] [Order article via Infotrieve]
32. Merillon JP, Motte G, Masquet C, Azancot I, Guiomard A, Gourgon R. Relationship between physical properties of the arterial system and left ventricular performance in the course of aging and arterial hypertension. Eur Heart J. 1982;3:95-102.
33. Levy BI, Babalis D, Lacolley P, Poitevin P, Safar ME. Cardiac hypertrophy and characteristic impedance in spontaneously hypertensive rats. J Hypertens. 1988;6:S110-S111.
34. Pannier B, Brunel P, El Aroussy W, Lacolley P, Safar ME. Pulse pressure and echocardiographic findings in essential hypertension. J Hypertens. 1989;7:127-132.[Medline] [Order article via Infotrieve]
35. Bouthier JD, De Luca N, Safar ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Heart J. 1985;109:1345-1352.[Medline] [Order article via Infotrieve]
36.
Morita S, Asou T, Juboyama I, Tokunaga K, Harasawa Y, Sunagawa K. Increased characteristic impedance causes left ventricular hypertrophy in dogs. Circulation. 1989;80:299. Abstract.
37. Maeta H, Hori M. Effect of a lack of aortic `windkessel' properties on the left ventricle. Jpn Circ J. 1985;49:232-237.[Medline] [Order article via Infotrieve]
38.
Wolinsky H. Long-term effects of hypertension on the rat aortic wall and their relation to concurrent aging changes. Circ Res. 1972;30:301-309.
39.
O'Rourke M. Arterial stiffness, systolic blood pressure, and logical treatment of hypertension. Hypertension. 1990;15:339-347.
40. Nichols WW, O'Rourke MF, Avolio AP, Yaginuma T, Murgo JP, Pepine CJ, Conti CR. Effects of age on ventricular-vascular coupling. Am J Cardiol. 1985;55:1179-1184.[Medline] [Order article via Infotrieve]
41.
Nichols WW, O'Rourke MF, Avolio AP, Yaginuma T, Pepine CJ, Conti CR. Ventricular/vascular interaction in patients with mild systemic hypertension and normal peripheral resistance. Circulation. 1986;74:455-462.
42. Westerhof N, O'Rourke MF. Haemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical therapy. J Hypertens. 1995;13:943-952.[Medline] [Order article via Infotrieve]
43.
Owens GK. Influence of blood pressure on development of aortic medial smooth muscle hypertrophy in spontaneously hypertensive rats. Hypertension. 1987;9:178-187.
44.
Albaladejo P, Bouaziz H, Duriez M, Gohlke P, Levy B, Safar ME, Benetos A. Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats. Hypertension. 1994;23:74-82.
45.
Tsoporis J, Leenen FH. Effects of arterial vasodilators on cardiac hypertrophy and sympathetic activity in rats. Hypertension. 1988;11:376-386.
46. Stone DN, Dujardin JL. Changes in smooth muscle tone influence characteristic impedance of the aorta. Am J Physiol. 1984;246:H1-H7.
47. Simon AC, Safar ME, Levenson JA, Bouthier JE, Benetos A. Action of vasodilation drugs on small and large arteries of hypertensive patients. J Cardiovasc Pharmacol. 1983;5:626-631.[Medline] [Order article via Infotrieve]
48. Cody RJ, Binkley PF, Haas GJ, Brown DM. Acute myocardial and vascular responses to specific angiotensin II antagonism in the spontaneously hypertensive rat. Am J Hypertens. 1995;8:500-508.[Medline] [Order article via Infotrieve]
49. Binkley PF, Van Fossen DB, Haas GJ, Cody RJ, Leier CV. Persistence of abnormal ventriculoarterial coupling and decreased conduit vessel compliance despite peripheral vasodilation with hydralazine and nitroglycerin in congestive heart failure. J Am Coll Cardiol. 1994;23:382A. Abstract.
50. Gohlke P, Lamberty V, Kuwer I, Bartenbach S, Schnell A, Unger T. Vascular remodeling in systemic hypertension. Am J Cardiol. 1993;71:2E-7E.[Medline] [Order article via Infotrieve]
51.
Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension. 1990;16:532-540.
52. Friberg P, Folkow B, Nordlander M. Cardiac dimensions in spontaneously hypertensive rats following different modes of blood pressure reduction by antihypertensive treatment. J Hypertens. 1986;4:85-92.[Medline] [Order article via Infotrieve]
53. Leenen FHH, Tsoporis J. Cardiac volume load as a determinant of the response of cardiac mass to antihypertensive therapy. Eur Heart J. 1990;11:100-106.
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