Journal of Applied Physiology Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 103: 353-358, 2007. First published April 12, 2007; doi:10.1152/japplphysiol.01416.2006
8750-7587/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
103/1/353    most recent
01416.2006v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Renna, B. F.
Right arrow Articles by Libonati, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Renna, B. F.
Right arrow Articles by Libonati, J. R.

Relative systolic dysfunction in female spontaneously hypertensive rat myocardium

Brian F. Renna,1 Scott M. MacDonnell,2 Patricia O. Reger,1 Deborah L. Crabbe,2 Steven R. Houser,2,3 and Joseph R. Libonati1,2,3

1Department of Kinesiology, 2Cardiovascular Research Center, and 3Department of Physiology, Temple University, Philadelphia, Pennsylvania

Submitted 14 December 2006 ; accepted in final form 9 April 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Hypertension and exercise independently induce left ventricular (LV) remodeling and alter LV function. The purpose of this study was to determine systolic and diastolic LV pressure-volume relationships (LV-PV) in spontaneously hypertensive rats (SHR) with and without LV hypertrophy, and to determine whether 6 mo of exercise training modified the LV-PV in SHR. Four-month-old female SHR (n = 20), were assigned to a sedentary (SHR-SED) or treadmill-trained (SHR-TRD) group (~60% peak O2 consumption, 5 days/wk, 6 mo), while age-matched female Wistar-Kyoto rats (WKY; n = 13) served as normotensive controls. The LV-PV was determined using a Langendorff isolated heart preparation at 4 (no hypertrophy: WKY, n = 5; SHR, n = 5) and 10 mo of age (hypertrophy: WKY, n = 8; SHR-SED, n = 8; SHR-TRD, n = 7). At 4 mo, the LV-PV in SHR was similar to that observed in WKY controls. However, at 10 mo of age, a rightward shift in the LV-PV occurred in SHR. Exercise training did not alter the extent of the shift in the LV-PV relative to SHR-SED. Relative systolic function, i.e., relative systolic elastance, was ~50% lower in SHR than WKY at 10 mo of age (P < 0.05). Doppler-derived LV filling parameters [early wave (E), atrial wave (A), and the E/A ratio] were similar between groups. LV capacitance was increased in SHR at 10 mo (P < 0.05), whereas LV diastolic chamber stiffness was similar between groups at 10 mo. Hypertrophic remodeling at 10 mo of age in female SHR is manifest with relative systolic decompensation and normal LV diastolic function. Exercise training did not alter the LV-PV in SHR.

heart; left ventricle; exercise; heart failure; cardiovascular system

LEFT VENTRICULAR (LV) HYPERTROPHY associated with hypertension is characterized by the altered expression of cardiomyocyte contractile and noncontractile proteins, leading to myocardial hypertrophy and increased interstitial fibrosis (3). Hypertension-induced hypertrophy increases the risk for the development of heart failure (10), but controversy remains as to how hypertrophy impacts left ventricular (LV) performance before the development of overt heart failure (11). Cingolani et al.(11) recently reported that spontaneously hypertensive rats (SHR) with compensated hypertrophy presented with a profile of compromised LV diastolic function, i.e., delayed relaxation and augmented diastolic stiffness, with a concomitant improvement in LV systolic function. Given that diastolic dysfunction often precedes heart failure (4) and a number of studies have shown either increased, decreased, or unchanged systolic performance with hypertension-induced hypertrophy (2, 6, 8, 17), one aim of the present paper was to examine indexes of systolic and diastolic cardiac function specifically in the female SHR model, at age intervals in which hypertension-induced hypertrophy is either absent (4 mo of age) or present (10 mo of age). The rationale for the use of female animals in our study was based on clinical data that suggest that female patients are more apt to exhibit congestive heart failure with preserved LV systolic function and LV diastolic dysfunction, than are male patients (16). Our study was also intended to complement already existent in vivo and in vitro data from Cingolani et al. (11).

It is well documented that exercise training favorably impacts the entire cardiovascular system and improves systolic and diastolic cardiac performance in human and experimental animal models (31). In normotensive animals, peak O2 consumption is well correlated to diastolic function (1, 5, 12, 20, 21, 25, 30, 40, 41), with training reported to decrease LV diastolic stiffness (43, 44) and induce a rightward shift in the pressure-volume relationship (23, 24, 26). Training has also been shown to enhance survival in rodent models of cardiomyopathy (19) and heart failure (14, 22). Thus we hypothesized that if LV diastolic dysfunction exists in the pressure-overloaded SHR myocardium, training would mitigate its severity. Few studies have specifically examined how cardiac performance is impacted when exercise training is superimposed on SHR, with no study to our knowledge specifically examining cardiac mechanics (28, 35, 36). Thus the second aim of the present study was to establish whether the intervention of exercise training altered the LV mechanical phenotype, i.e., the Frank-Starling relationship, in female SHR.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental paradigm.   Thirty-three, 4 mo-old, female Wistar-Kyoto rats (WKY; n = 13) and SHR (n = 20) were obtained from Charles River Laboratories (St.-Constant, Quebec, Canada). At 4 mo of age, 10 animals were killed (WKY; n = 5 and SHR; n = 5) to establish ex vivo LV performance when hypertension, but not compensated hypertrophy, is evident in SHR. The remaining 8 WKY served as the normotensive controls, while the remaining 15 SHR were further randomly subdivided into SHR sedentary (SHR-SED; n = 8) or SHR exercise-trained (SHR-TRD; n = 7) groups. As previously described (36), exercise training consisted of progressive low-intensity endurance training at speeds of 20–25 m/min, 0% grade, 60 min, 5 days/wk for 24 wk. All rats were housed three per cage, maintained on a 12:12-h light-dark cycle, and fed ad libitum (18% protein diet, Harlan Teklad Global Diets, Madison, WI). Blood pressures and heart rates were collected at 4 and 10 mo of age using a tail-cuff apparatus (model XBP 1000, Kent Scientific, Torrington, CT). Animals were acclimated to the tail cuff apparatus two times before blood pressure determination. At 10 mo of age, WKY and SHR animals underwent echocardiographic assessment of LV performance and on a separate day were killed for ex vivo LV functional studies. All animals received humane care in compliance with Temple University Institutional Animal Care and Use Committee and the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).

Echocardiography.   Rats were studied using echocardiography as previously described (28, 36). Values were determined by averaging the measurements of three consecutive cardiac cycles. In accordance with the American Society of Echocardiography conventions, M-mode imaging of the parasternal short-axis view allowed for measurement of LV end-diastolic and end-systolic internal dimensions (LVEDD and LVESD, respectively) and anterior and posterior wall thicknesses. Pulsed wave Doppler was used to assess the early (E wave) and atrial (A wave) components of the LV diastolic filling period.

Langendorff experiments.   To characterize the effects of exercise on LV mechanical function, LV pressure-volume relationships were determined in isolated, isovolumic, buffer-perfused hearts. Rats were anesthetized with sodium pentobarbital (60 mg/kg ip) and heparinized (500 U iv). A thoracotomy was performed, and the heart was excised and retrogradely perfused in a Langendorff mode as previously described (28, 35, 36). During equilibration, all hearts were loaded with an initial balloon volume yielding an LV end-diastolic pressure (LVEDP) of 10 mmHg. LV systolic pressure (LVSP), LVEDP, and coronary perfusion pressure (CPP) were continuously recorded by means of a data acquisition system (Powerlab/8SP, ADI Instruments, Colorado Springs, CO). LV developed pressure was calculated by subtracting LVEDP from the LVSP. Hearts were paced throughout the protocol at 5 Hz (Grass Instruments, Quincy, MA) and immersed in a water-jacketed organ chamber at 37°C.

LV pressure-volume relationship.   Following ~20 min of equilibration, the LV pressure-volume relationship was established over a wide range of LV filling volumes. Using a Hamilton syringe containing isotonic saline, LV balloon volume was increased in 5- to 10-µl increments until an LVEDP of ~30 mmHg was achieved. To compare the LV pressure-volume relationship between groups, LV volumes were determined from each pressure-volume curve at 5 mmHg intervals (26, 33). The LVSP-volume relationship (LVSP/V) and the LVEDP-volume relationship (LVEDP/V) were curve fit using a best-fit analysis with the linear slope of the LVSP/V, indicating the systolic elastance (Es). The slope of the LVEDP/V relationship was used to reflect the LV diastolic chamber stiffness. LV capacitance (V25) was measured as the LV volume that elicited an LVEDP of 25 mmHg (7).

Soleus citrate synthase activity.   Immediately following the death of 10-mo-old animals, the right soleus was dissected from each hindlimb, frozen in liquid nitrogen, and stored at –80°C until analysis. In brief, samples were homogenized on ice in a cell lysis reagent (Sigma) and centrifuged at 4°C for 15 min at 12,000 rpm. The supernatant was collected and a standardized concentration of protein was assayed for citrate synthase activity using a commercial reagent kit (Sigma) by methods previously described by Srere (38).

Data analysis and interpretation.   Hemodynamics, animal characteristics, citrate synthase activity, Doppler analysis, systolic elastance, and LV capacitance were compared with one-way ANOVA and least significant difference post hoc analysis. LV diastolic chamber stiffness was compared with ANOVA with normalized ranks and Bonferonni post hoc analysis. LV pressure-volume loops were compared with ANOVA for repeated measures followed by least significant difference post hoc analysis. All analyses were performed using SPSS version 12.0 (SPSS, Chicago, IL). Statistical significance was set at an alpha level of P < 0.05. All data are reported as means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hemodynamic parameters.   Table 1 illustrates the systolic blood pressure (SBP), heart rate, and rate pressure product (RPP) in WKY and SHR at 4 and 10 mo of age. As expected, SBP was significantly lower in WKY compared with SHR at 4 mo (P < 0.01). SBP in WKY was similar at 4 and 10 mo of age. SBP increased in both groups of SHR from 4 to 10 mo (P < 0.001). At 10 mo of age, the SBP of WKY was lower than both groups of SHR (P < 0.001). Both heart rate and RPP were also lower in WKY vs. SHR at 4 mo (P < 0.01) and 10 mo of age (P < 0.001). At 10 mo of age, SBP, heart rate, and RPP were similar between SHR-TRD and SHR-SED.


View this table:
[in this window]
[in a new window]

  		Table 1. Hemodynamics at 4 and 10 mo of age

 
Animal characteristics.   The physical characteristics of all groups are presented in Table 2. Before death, body weight in WKY was significantly greater than SHR at 4 mo (P < 0.05) and significantly greater than both SHR groups at 10 mo of age (P < 0.001). Heart weight was greater in WKY vs. SHR at 4 mo. However, heart weight-to-body weight ratio was similar between WKY and SHR at 4 mo. Heart weight and heart weight-to-body weight ratio were lower in WKY compared with both SHR groups at 10 mo of age (P < 0.001). Heart weight and heart weight-to-body weight ratio also increased from 4 to 10 mo in both groups of SHR (P < 0.05) but not WKY. In fact, heart weight-to-body weight ratio was reduced in WKY from 4 to 10 mo (P < 0.001). At 10 mo of age, the physical characteristics of SHR-SED and SHR-TRD were similar. Soleus citrate synthase activity at 10 mo of age is also reported in Table 2. Citrate synthase activity was increased in SHR-TRD compared with both WKY and SHR-SED (P < 0.01 and P < 0.05, respectively).


View this table:
[in this window]
[in a new window]

  		Table 2. Animal characteristics at 4 and 10 mo of age

 
Echocardiography.   Echocardiographic indexes at 10 mo of age are reported in Table 3. Anterior wall thickness during diastole was greater in SHR-TRD than WKY or SHR-SED (P < 0.05). LV internal dimensions, peak E, A, E/A ratio, and LV fractional shortening between WKY and SHR at 10 mo of age were not statistically different between groups.


View this table:
[in this window]
[in a new window]

  		Table 3. Echocardiographic indexes at 10 mo of age

 
Langendorff Isolated Heart Performance.   Figure 1 illustrates the LVSP/V and LVEDP/V in WKY, SHR-SED, and SHR-TRD at 4 and 10 mo of age. At 4 mo of age both the LVSP/V and LVEDP/V were similar in WKY and SHR. From 4 to 10 mo of age the LVSP/V and LVEDP/V were also similar in WKY. However, in SHR at 10 mo of age, there was a rightward shift in the LVSP/V and LVEDP/V relationships relative to SHR at 4 mo, the magnitude of which was similar between SHR-SED and SHR-TRD. The rightward shift in the LV pressure-volume relationship at 10 mo of age did not, however, deleteriously alter absolute peak LV developed pressure between groups (WKY, 197 ± 5 mmHg; SHR-SED, 191 ± 11 mmHg; SHR-TRD, 186 ± 13 mmHg; P = not significant), nor did it alter the slope of the absolute LVSP/V relationship, i.e., Es, between groups (Fig. 1). However, with hypertension-induced hypertrophy at 10 mo of age, peak LV developed pressure normalized to heart weight was decreased in both groups of SHR compared with WKY (WKY, 184 ± 5 mmHg/g; SHR-SED, 149 ± 10 mmHg/g; SHR-TRD, 143 ± 12 mmHg/g; P < 0.05). Similarly, as Fig. 2 illustrates, the relative slope of the LVSP/V, i.e., Es/heart weight relationship, was blunted in SHR-SED hearts at 10 mo of age compared with WKY hearts at 10 mo of age (P < 0.05). The Es/heart weight relationship was not different in WKY from 4 to 10 mo, but declined in SHR hearts from 4 to 10 mo of age. As Table 4 illustrates, LV capacitance (i.e., V25) at 4 mo of age, was similar between WKY and SHR (P = not significant). V25 did not significantly change from 4 to 10 mo of age in WKY. However, V25 at 10 mo of age was significantly greater in both SHR groups relative to SHR at 4 mo of age (P < 0.05). The V25 was also increased in SHR-TRD compared with WKY at 10 mo (P < 0.01). LV diastolic chamber stiffness was similar between WKY and both groups of SHR at both 4 and 10 mo of age mo of age (Table 4). We also examined LVEDP/V relationship normalized to heart weight (Figure 3). As Fig. 3 illustrates, when normalizing the LVEDP/V relationship to heart weight, the rightward shift in the LVEDP/V was mitigated in SHR. We also evaluated the CPP at an LVEDP of 10 mmHg as a marker of coronary resistance. At 4 mo of age, the CPP was greater in SHR relative to WKY (WKY: 100 ± 11 mmHg vs SHR: 139 ± 17 mmHg; P < 0.05) and tended to remain elevated level in SHR through 10 mo of age (WKY: 104 ± 5 mmHg, SHR-SED: 123 ± 10 mmHg, SHR-TRD: 134 ± 15 mmHg; P = not significant).


Figure 1
View larger version (18K):
[in this window]
[in a new window]

  		Fig. 1. Left ventricular (LV) systolic and LV end-diastolic pressure-volume relationships for each group at 4 and 10 mo of age (age in mo indicated in center of pressure-volume loop). There was a rightward shift in the LV pressure-volume relationship in SHR not evident in Wistar-Kyoto (WKY) at 10 mo of age. Systolic elastance (Es) was well maintained in WKY from 4 to 10 mo of age and tended to be lower in spontaneously hypertensive rats (SHR) at 10 mo of age. Values are means ± SE. SHR-SED, SHR sedentary rats; SHR-TRD, SHR trained rats.

 

Figure 2
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 2. Relative Es [Es/heart weight (HW)] at 4 and 10 mo of age. Although Es/HW was not different between groups at 4 mo of age, it was significantly reduced in SHR-SED at 10 mo of age compared with WKY at 10 mo of age. Both groups of SHR had a lower Es/HW at 10 mo of age relative to WKY and SHR at 4 mo of age. Values are mean ± SE. *P < 0.05 vs. WKY at 10 mo.

 

View this table:
[in this window]
[in a new window]

  		Table 4. Diastolic indexes

 

Figure 3
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 3. LV end-diastolic pressure-volume relationship normalized to HW was similar between WKY, SHR-SED, and SHR-TRD at 10 mo of age. Values are means ± SE.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our results indicate that before the development of pressure induced-hypertrophy in SHR, i.e., 4 mo of age, the LVSP/V and LVEDP/V relationships were similar to that observed in WKY controls. However, concomitant with pressure-induced stress at 10 mo of age, a rightward shift in the LV pressure volume relationship was observed in SHR. Six months of exercise training in SHR did not mitigate hypertension nor the magnitude of the shift in the LV pressure volume relationship relative to SHR-SED animals. Absolute LV systolic function was well maintained in WKY from 4 to 10 mo of age. However, at 10 mo of age, systolic function in both SHR-SED and SHR-TRD showed signs of deterioration such that the absolute and relative systolic elastances were 30–50% lower, respectively, in SHR compared with WKY. Echocardiography-derived LV diastolic filling parameters, i.e., E, A, and E/A ratio were similar among groups at 10 mo of age. LV capacitance was increased in SHR from 4 to 10 mo of age, consistent with pressure-induced ventricular remodeling, whereas LV diastolic chamber stiffness was similar between groups. Thus pressure-induced hypertrophic remodeling at 10 mo of age in the female SHR model is manifest with mild absolute and relative systolic decompensation with normal LV diastolic function.

The development of concentric hypertrophy has long been theorized to occur as an adaptational process necessary to normalize wall stress in the pressure-overloaded heart (37). However, recent reports have questioned whether pressure-induced hypertrophy is in fact a necessary compensation (15). Given that there appears to be both adaptive and maladaptive features of pressure-induced hypertrophy, we examined cardiac mechanics at ages in SHR in which hypertrophy was either absent or present. The SHR model is well established in this regard, with the recapitulation of a fetal cardiac phenotype and cardiomyocyte hypertrophy occurring relatively early on in the pathophysiological cascade, followed by the development of subsequent fibrosis later in the disease (3). These changes are hypothesized to lead to increased diastolic stiffness (11) and serve as the substrate for the development of overt heart failure (4).

In the present study, the directional rightward shift in the LV pressure-volume relationship and the increased ventricular capacitance in SHR, are consistent with the slight but statistically insignificant increase in LVEDD in 10-mo-old SHR hearts relative to age-matched WKY controls. Pfeffer et al. (32) showed nearly 3 decades ago that LV chamber dimensions were increased in SHR hearts relative to WKY up to 52 wk of age. Concomitant with increased LV remodeling in SHR hearts, Pfeffer et al. also reported a steady decline in in vivo peak pumping ability in SHR hearts up to 52 wk of age, an effect that became severely exacerbated by 90 wk of age. The rightward shift in the pressure-volume relationship in the present study did not impact LV diastolic chamber stiffness or the LV Doppler filling profile. Instead, perhaps the most interesting feature of our study is that while absolute systolic function was generally preserved in 10-mo-old SHR hearts, relative systolic function was impaired. In other words, our data in the SHR model can be interpreted in two very different ways: no LV systolic dysfunction as indexed by absolute markers, or relative systolic decompensation as indexed by the mismatch between heart mass and LV systolic pressure development. This is an important issue given the lack of consensus as to how hypertension impacts cardiac mechanics before the development of overt heart failure (11, 13, 18, 32). For instance, Kokubo et al. (18) showed echocardiographic evidence of both systolic and diastolic dysfunction in young (2–3 mo old), male SHR, whereas Cingolani et al. (11) reported that SHR hearts exhibited "hypersystolic" performance accompanied by delayed relaxation and increased diastolic stiffness relative to age matched, 10-mo-old WKY.

Clearly, differences in experimental models and paradigms may account for such discrepant findings. In the present study, we analyzed the Frank-Starling relationship in female SHR hearts by utilizing an isovolumic, Langendorff preparation. This model allowed us to precisely control coronary perfusion, preload, heart rate, and temperature while negating the confounding influences of pericardial restraint, the pulmonary and systemic circulation, ventilatory oscillations, and neural, humoral and paracrine influences on cardiac function. Studies primarily utilizing in vivo methodologies are less likely to account for all of these extraneous variables. Moreover, variations in ex vivo experimental paradigms are also important to consider. For example, Cingolani et al. (11) obtained in vivo pressure-volume loops by a direct volume loading method, i.e., via intravenously infusing 0.9% NaCl and measuring subsequent cardiac performance, whereas they measured ex vivo LV pressure-volume relationships in KCl-arrested hearts. Although the KCl-arrested heart methodology is valuable for establishing passive LV diastolic properties, it negates important regulators of LV lusitropic performance, particularly Ca2+ balance, ATP turnover, and turgor (1).

Given that exercise training in normal myocardium improves LV diastolic function (1, 5, 12, 20, 21, 25, 30, 40, 41), reduces LV stiffness (43, 44), and causes a rightward shift in the LV pressure-volume relationship (23, 24, 26), we hypothesized that exercise training superimposed on pressure overload in SHR would reduce LV diastolic chamber stiffness and improve the Frank-Starling systolic response. This hypothesis was based on our laboratory's recent findings showing that training in SHR reduced pacing-induced LV diastolic stiffness (28), improved beta-adrenergic signaling (28), and increased myocardial tolerance to acidosis (36). Clinically, this is an important question, because an increase in LV diastolic stiffness is a significant component of cardiovascular disease (1), particularly in women (16).

Similar to our laboratory's previous reports, in the present study, exercise training did not reduce systolic blood pressure in SHR (28, 35, 36). Although exercise training increased LV anterior wall thickness relative to SHR-SED, LV remodeling appeared somewhat similar between SHR-SED and SHR-TRD. SHR-SED and SHR-TRD were similar in heart weight, the magnitude in the shift of the LV pressure-volume relationship, and ventricular capacitance. Moreover, training did not impact fractional shortening or the Doppler-derived LV diastolic filling profile. Although training is beneficial to the female SHR myocardium in many ways (28, 36), training did not alter LV diastolic chamber stiffness nor systolic elastance in our Langendorff studies. These data differ from previous reports from our laboratory using nonhypertensive (23, 26) and postinfarcted models (24), in which LV diastolic pressure-volume relationships were shifted rightward with training.

The SHR model was chosen for our research model because it well represents the clinical course of untreated hypertension in humans. We chose to study these animals at 10 mo of age because cardiac function is well maintained and fibrosis is minimal (13, 32). However, there are several design considerations that may affect the interpretability of the current study. First, our conclusions are limited to the Langendorff isovolumic model. Clearly, other experimental paradigms may provide alternative data. Second, we did not measure the Doppler profile in 4-mo-old animals, thus limiting our understanding of the in vivo time effect. Third, we acknowledge that the inclusion of a normotensive exercise group would have expanded our understanding of the exercise-induced adaptation. However, this was not the direct purpose of the present study as we instead focused our efforts toward understanding how exercise training impacts the hypertensive myocardium. Fourth, we acknowledge that in some instances LV diastolic chamber stiffness may be reflected by expressing the LV stress-strain relationship. However, this method has limitations, because whole hearts have a three-dimensional stress-strain relationship that is not easily independently quantified in the Langendorff model (7). Lastly, our data are sex specific. Clearly there are significant sex differences in the SHR model which may impact the interpretability of this study. For example, female SHR have been reported to have greater sympathetic tone (9), decreased parasympathetic tone (9), increased resting heart rates (9), and similar (9) or decreased (29) blood pressure relative to male, age-matched controls. Female SHR have also been reported to have greater heart-to-body weight ratios compared with their male counterparts even at similar levels of systemic blood pressure (42). The impact of estrogen appears to be critical in this response, because neutering has been shown to diminish relative hypertrophy in females, whereas estrogen replacement concomitant with neutering brought heart-to-body weight ratio back closer to intact values (42). Our study is also limited in that we did not control for estrus cycle status in our animals. Sex-specific differences in the renin-angiotensin and endothelin systems (34), oxidation status (39), and Ca2+ signaling (27) are also important considerations.

Significance.

While the present paper summarizes predominantly negative findings with respect to the impact of exercise training, perhaps the most important aspect of our paper is the finding that female SHR show signs of LV systolic deterioration somewhat early in the pathophysiological cascade of hypertension. These data might put into question whether pressure-induced hypertrophy is truly "compensatory" in nature.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by a Beginning Grant in Aide from the American Heart Association (to J. R. Libonati).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. R. Libonati, Dept. of Kinesiology, 122 Pearson Hall, 1800 North Broad St., Philadelphia, PA 19122 (e-mail: jlibonat{at}temple.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Apstein CS, Libonati JR, Varma N, Eberli FR. Exercise, diastolic function, dysfunction. In: Exercise, and Heart Failure, edited by Balady G and Pina J. Armonk, NY: Futura, 1997, p. 39–83.
  2. Averill DB, Ferrario CM, Tarazi RC, Sen S, Bajbus R. Cardiac performance in rats with renal hypertension. Circ Res 38: 280–288, 1976.[Abstract/Free Full Text]
  3. Bing OH, Brooks WW, Robinson KG, Slawsky MT, Hayes JA, Litwin SE, Sen S, Conrad CH. The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure. J Mol Cell Cardiol 27: 383–396, 1995.[Web of Science][Medline]
  4. Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med 117: 502–510, 1992.[CrossRef][Web of Science][Medline]
  5. Brandao MUP, Wajngarten M, Rondon E, Giorgi MCP, Hironaka F, Negrao CE. Left ventricular function during dynamic exercise in untrained and moderately trained subjects. J Appl Physiol 75: 1989–1995, 1993.[Abstract/Free Full Text]
  6. Brower GL, Janicki JS. Contribution of ventricular remodeling to pathogenesis of heart failure in rats. Am J Physiol Heart Circ Physiol 280: H674–H683, 2001.[Abstract/Free Full Text]
  7. Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 289: H501–H512, 2005.[Abstract/Free Full Text]
  8. Capasso JM, Palackal T, Olivetti G, Anversa P. Left ventricular failure induced by long-term hypertension in rats. Circ Res 66: 1400–1412, 1990.[Abstract/Free Full Text]
  9. Chandler MP, DiCarlo SE. Acute exercise and gender alter cardiac autonomic tonus differently in hypertensive and normotensive rats. Am J Physiol Regul Integr Comp Physiol 274: R510–R516, 1998.[Abstract/Free Full Text]
  10. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289: 2560–2572, 2003.[Abstract/Free Full Text]
  11. Cingolani OH, Yang XP, Cavasin MA, Carretero OA. Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats. Hypertension 41: 249–254, 2003.[Abstract/Free Full Text]
  12. Colan SD, Sanders SP, MacPherson D, Borow KM. Left ventricular diastolic function in elite athletes with physiologic cardiac hypertrophy. Am J Cardiol 6: 545–549, 1985.
  13. Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 39: 89–105, 1998.[Free Full Text]
  14. Emter CA, McCune SA, Sparagna GC, Radin MJ, Moore RL. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. Am J Physiol Heart Circ Physiol 289: H2030–H2038, 2005.[Abstract/Free Full Text]
  15. Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation 10: 2863–2869, 2000.
  16. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 43: 317–327, 2004.[Abstract/Free Full Text]
  17. Kobayashi T, Hamada M, Okayama H, Shigematsu Y, Sumimoto T, Hiwada K. Contractile properties of left ventricular myocytes isolated from spontaneously hypertensive rats: effect of angiotensin II. J Hypertens 13: 1803–1807, 1995.[Web of Science][Medline]
  18. Kokubo M, Uemura A, Matsubara T, Murohara T. Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hupertens Res 28: 601–609, 2005.[CrossRef]
  19. Konhilas JP, Watson PA, Maass A, Boucek DM, Horn T, Stauffer BL, Luckey SW, Rosenberg P, Leinwand LA. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res 98: 540–548, 2006.[Abstract/Free Full Text]
  20. Levine BD, Lane LD, Buckey JC, Friedman DB, Blomqvist CG. Left ventricular pressure-volume and Frank-Starling relations in endurance athletes; implications for orthostatic tolerance and exercise performance. Circulation 84: 1016–1023, 1991.[Abstract/Free Full Text]
  21. Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton JR. Endurance exercise training augments diastolic filling at rest, and during exercise in healthy young, and older men. Circulation 88: 116–126, 1993.[Abstract/Free Full Text]
  22. Libonati JR, Gaughan JP. Low-intensity exercise training improves survival in Dahl salt hypertension. Med Sci Sports Exerc 38: 856–858, 2006.
  23. Libonati JR, Kendrick ZV, Houser SR. Sprint training improves postischemic, left ventricular diastolic performance. J Appl Physiol 99: 2121–2127, 2005.[Abstract/Free Full Text]
  24. Libonati JR. Exercise and diastolic function after myocardial infarction. Med Sci Sports Exerc 35: 1471–1476, 2003.
  25. Libonati JR. Exercise and myocardial diastolic function. Med Sci Sports Exerc 31: 1741–1747, 1999.
  26. Libonati JR. Exercise training improves left ventricular isovolumic relaxation. Med Sci Sports Exerc 32: 1399–1405, 2000.
  27. Loukotova J, Kunes J, Zicha J. Gender-dependent difference in cell calcium handling in VSMC isolated from SHR: the effect of angiotensin II. J Hypertens 20: 2213–2219, 2002.[CrossRef][Web of Science][Medline]
  28. MacDonnell SM, Kubo H, Crabbe DL, Renna BF, Reger PO, Mohara J, Smithwick LA, Koch WJ, Houser SR, Libonati JR. Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension. Circulation 111: 3420–3428, 2005.[Abstract/Free Full Text]
  29. Maris ME, Melchert RB, Joseph J, Kennedy RH. Gender differences in blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats. Clin Exp Pharmacol Physiol 32: 35–39, 2005.[CrossRef][Web of Science][Medline]
  30. Matsuda M, Sugishita Y, Koseki S, Ito I, Akatsuka T, Takamatsu K. Effect of exercise on left ventricular diastolic filling in athletes and nonathletes. J Appl Physiol 55: 323–328, 1983.[Abstract/Free Full Text]
  31. Moore RL, Palmer BM. Exercise training and cellular adaptations of normal and diseased hearts. Exerc Sport Sci Rev 27: 285–315, 1999.[Medline]
  32. Pfeffer JM, Pfeffer MA, Fishbein MC, Frohlich ED. Cardiac function and morphology with aging in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 237: H461–H468, 1979.[Abstract/Free Full Text]
  33. Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E. Progressive ventricular remodeling in rat with myocardial infarction. Am J Physiol Heart Circ Physiol 260: H1406–H1414, 1991.[Abstract/Free Full Text]
  34. Radin MJ, Holycross BJ, Sharkey LC, Shiry L, McCune SA. Gender modulates activation of rennin-angiotensin and endothelin systems in hypertension and heart failure. J Appl Physiol 92: 935–940, 2002.[Abstract/Free Full Text]
  35. Reger PO, Barbe MF, Amin M, Renna BF, Hewston LA, MacDonnell SM, Houser SR, Libonati JR. Myocardial hypoperfusion/reperfusion tolerance with exercise training in hypertension. J Appl Physiol 100: 541–547, 2006.[Abstract/Free Full Text]
  36. Renna BF, Kubo H, MacDonnell SM, Crabbe DL, Reger PO, Houser SR, Libonati JR. Enhanced acidotic myocardial Ca2+ responsiveness with training in hypertension. Med Sci Sports Exerc 38: 847–855, 2006.
  37. Sandler H, Dodge HT. Left ventricular tension and stress in man. Circ Res 13: 91–104, 1963.[Abstract/Free Full Text]
  38. Srere PA. Citrate synthase. Methods Enzymol 13: 3–11, 1969.[CrossRef]
  39. Sullivan JC, Sasser JM, Pollock JS. Sexual dimorphism in oxidant status in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 292: R764–R768, 2007.[Abstract/Free Full Text]
  40. Takemoto KA, Bernstein L, Lopez JF, Marshak D, Rahimtoola SH, Chandraratna PAN. Abnormalities of diastolic filling of the left ventricle associated with aging are less pronounced in exercise-trained individuals. Am Heart J 124: 143–148, 1992.[CrossRef][Web of Science][Medline]
  41. Vanoverschelde JJ, Essamri B, Vanbutsele R, d'Hondt A, Cosyns JR, Detry JR, Melin JA. Contribution of left ventricular diastolic function to exercise capacity in normal subjects. J Appl Physiol 74: 2225–2233, 1993.[Abstract/Free Full Text]
  42. Wallen WJ, Cserti C, Belanger MP, Wittnich C. Gender-differences in myocardial adaptation to afterload in normotensive and hypertensive rats. Hypertension 36: 774–779, 2000.[Abstract/Free Full Text]
  43. Woodiwiss AJ, Norton GR. Exercise-induced cardiac hypertrophy is associated with an increased myocardial compliance. J Appl Physiol 78: 1303–1311, 1995.[Abstract/Free Full Text]
  44. Woodiwiss AJ, Kalk WJ, Norton GR. Habitual exercise attenuates myocardial stiffness in diabetes mellitus in rats. Am J Physiol Heart Circ Physiol 271: H2126–H2133, 1996.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J CARDIOVASC PHARMACOL THERHome page
H. Hwang, R. A. Kloner, M. T. Kleinman, and B. Z. Simkhovich
Direct and Acute Cardiotoxic Effects of Ultrafine Air Pollutants in Spontaneously Hypertensive Rats and Wistar--Kyoto Rats
Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 189 - 198.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
103/1/353    most recent
01416.2006v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Renna, B. F.
Right arrow Articles by Libonati, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Renna, B. F.
Right arrow Articles by Libonati, J. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.