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Am J Physiol Heart Circ Physiol 287: H767-H772, 2004. First published April 1, 2004; doi:10.1152/ajpheart.00047.2004
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Cardiac structural and functional responses to salt loading in SHR

Jwari Ahn, Jasmina Varagic, Michel Slama, Dinko Susic, and Edward D. Frohlich

Hypertension Research Laboratory, Research Division, Ochsner Clinic Foundation, New Orleans, Louisiana 70121

Submitted 21 January 2004 ; accepted in final form 26 March 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (VE/VA), and slower propagation velocity of E wave (VP). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased VE/VP, an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.

sodium excess; ventricular systolic and diastolic function; echocardiography; spontaneously hypertensive rats

HYPERTENSION AND LEFT VENTRICULAR (LV) hypertrophy (LVH) are major risk factors accounting for cardiovascular morbidity and mortality (15). Increased deposition of fibrillar collagen within the hypertrophied LV may contribute to cardiac functional deterioration and, consequently, to the increased risk associated with LVH. Dietary salt excess exacerbates elevated arterial pressure (32) and further increased LV mass in patients with essential hypertension (11) as well as in experimental hypertension (6, 16, 20). More recently, the profibrotic effect of salt has been documented in spontaneously hypertensive rats (SHR) (38); however, little information has detailed the effects of dietary salt excess on ventricular function in either patients or experimental animals already at increased cardiovascular risk (22). Moreover, young normotensive rats on high dietary salt intake have been shown to be more susceptible to develop cardiac hypertrophy than older rats (39). Whether this same age effect of sodium sensitivity can be applied to SHR is not known. We hypothesized that salt excess adversely affects LV function in SHR by promoting LV collagen deposition and that it is more deleterious in younger than older animals. Thus, in this study, we compared the LV structural and functional responses to long-term salt loading in two different age groups of adult SHR utilizing techniques of transthoracic echocardiography (TTE) (9, 24, 28, 29) to determine whether the increased salt sensitivity that occurs in younger normotensive rats also applies to SHR and whether salt-induced changes in cardiac function relate to LV collagen content.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Male SHR were purchased from Harlan Laboratories (Indianapolis, IN) and were maintained thereafter in a temperature- and humidity-controlled room with a 12:12-h light-dark cycle. All rats were handled in accordance with National Institute of Health Guidelines, and our Institutional Animal Care and Use Committee approved the protocol in advance. Before the study was initiated, all rats were screened using echocardiography to exclude comorbid congenital cardiac abnormalities (30). The SHR were randomized so that 30 8-wk-old and 10 20-wk-old SHR were given an 8% NaCl diet (Harlan TEKLAD; Madison, WI) over the ensuing 8 wk. Because echocardiographic examination of the older rats after 8 wk on the high dietary salt intake did not reveal any significant functional changes, we maintained these rats on that diet until 52 wk of age (duration 32 wk). This group will be referred to as old salt-loaded SHR. The rats that were examined at 16 wk of age are referred to as young salt-loaded SHR. Age-matched control SHR (13 young and 10 old rats) were given a standard rat chow. All rats were permitted free access to chow and tap water. None of the old salt-loaded SHR and age-matched controls died during the study; however, 4 of the 30 (13.3%) young salt-loaded SHR died during salt loading. Therefore, 26 rats were studied in the young salt-loaded SHR group; among them, 8 rats developed signs of congestive heart failure (CHF).

TTE examinations were conducted on anesthetized rats at the end of salt loading as previously described (28, 29). To avoid excessive effects of anesthesia on cardiac function, this examination was conducted with only pentobarbital anesthesia (50 mg/kg ip; heart rate ~300 beats/min). However, at that heart rate, fusion of early (VE) and late filling waves (VA) were determined, and, therefore, xylazine (2 mg/kg ip) was added. With this combination, heart rate decreased to ~215 beats/min, thereby permitting measurement of clearly separated filling waves. The doses of these agents were reduced considerably in those rats with clinical evidence of CHF, which was manifested by labored respiration and decreased physical activity.

The first TTE examinations were made 10–30 min after the administration of pentobarbital anesthesia at a heart rate of ~300 beats/min using a commercially available echocardiographic system (Agilent Technologies Sonos 2000 with a 7.5-MHz transducer). The TTE probe was carefully placed to obtain the short and long axis as well as four- and five-chamber apical cardiac views (28, 29). From the short axis, an M-mode tracing of the LV was obtained, and measurements of LV end-diastolic diameter (LVDd), LV systolic diameter (LVSd), and posterior (PWd) and septum diastolic wall thicknesses (SWd) were made according to the American Society of Echocardiography guidelines (26). LV mass and relative wall thickness were calculated using standard formulas: LV mass = 1.04x[(LVDd + PWd + SWd)3 – LVDd3] and relative wall thickness = PWd + SWd/LVDd. Fractional shortening [FS = (LVEDD – LVSD)/LVEDD, where LVEDD is LV end-diastolic dimension and LVSD is LV systolic dimension] and rate-corrected mean velocity of circumferential fiber shortening (VCFc) provided indexes of systolic function (7). From the five-chamber apical view, aortic flow was recorded using pulsed Doppler with the smallest sample volume placed at the level of the aortic annulus, and velocity time integral (VTIAo) was measured. Aortic annulus diameter (DAoA) was measured during systole from the two-dimensional images. Stroke volume was calculated using the following formula: (DAoA)2 x 3.14 x (VTIAo)/4 . To obtain cardiac output, stroke volume was multiplied by heart rate, and the cardiac index was derived from cardiac output divided by body weight. Mitral flow was recorded at the tip of mitral valve from an apical view using Doppler. The velocity time integral of mitral flow (VTIE) was measured at this heart rate. Isovolumic relaxation time (36) was defined as the interval between the aortic closure click and the start of mitral flow measured from the mitral flow. On the same tracing, the time between the closure and opening of the aortic valve (DD) and between the opening and closure of mitral valve (MD) was measured. The myocardial index (MI) of combined systolic and diastolic function described by Tei et al. (4, 35) was calculated as follows: MI = (DD – MD)/ET, where ET is ejection time. From an apical view, flow propagation velocity (VP) was measured using color M-mode Doppler echocardiographic image (5). A good correlation between this index and the relaxation time constant as well as preload insensitivity of this index have been reported (18). The ratio of VE and VP (VE/VP), an index of LV filling pressure, was also calculated (13).

After all measurements at the 300 beats/min heart rate were obtained, xylazine (2 mg ip) was injected, and VE, VA, and VE/VA (1, 21) were determined. The deceleration time of E wave was measured as the interval between the peak of VE and the point where the steepest deceleration slope was extrapolated to the baseline (17). From the apical view, wall movement at the level of lateral mitral annulus was recorded using pulsed Doppler tissue imaging. The peak velocities of early (Em) and late diastolic waves (Am) were recorded, and Em/Am was calculated (23, 31). All measured and calculated indexes are presented as the average of three to five consecutive measurements.

Within 2 days of echocardiographic examination, a subgroup of 43 rats (9 rats in each group except for the CHF group, which contained 7 rats) was anesthetized with pentobarbital (50 mg/kg ip), and the femoral artery was cannulated with a polyethylene catheter (PE-50). This catheter was connected to a pressure transducer (P23 Db, Statham Instruments; Oxnard, CA), and arterial pressure was recorded on a multichannel physiograph (Sensor medics R612; Yorba Linda, CA). After the arterial pressure measurement, the rat was killed with pentobarbital overdose, the hearts and lungs were removed, and their weights were determined. After cardiac removal, the atria were dissected free from the ventricles and discarded, and the free wall of the right ventricle was separated carefully from the LV (the septum remaining with LV). As an estimate of ventricular collagen content, hydroxyproline concentration was determined in LV samples and expressed as milligrams per gram of dry weight, as previously described (33).

All data are reported as means ± SE. The differences between young groups were determined by one-way ANOVA, whereas comparison of the two old groups was made by Student unpaired t-test (2). A value of P < 0.05 was considered to be of statistical significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
During the course of the experiment, it became obvious that some young SHR (8/26), but none of the old SHR, receiving a high-salt diet developed clinical signs of CHF (labored respiration and decreased physical activity). Necropsy examination of these rats at the end of the experiment revealed increased lung mass and pleural effusions, and in some increased right ventricular mass and peritoneal effusions were demonstrated. Their echocardiographic findings confirmed previously made clinical diagnosis, underlining the necessity to analyze data from this subgroup separately. Thus, based on the clinical, echocardiographic, and pathological responses, young salt-loaded SHR were divided into two groups: young salt-loaded without CHF (n = 18) and young salt-loaded with CHF (n = 8).

The body mass of all salt-loaded SHR was significantly less than their control rats, particularly in those rats with CHF. Systolic pressure was higher in the young salt-loaded SHR without CHF and the old salt-loaded SHR compared with their respective controls; however, systolic pressure was lower in the rats with CHF (Table 1). Right ventricular and lung masses were increased in SHR with CHF compared with the age-matched control rats and salt-loaded SHR without CHF (Table 1). In response to increased salt intake, LV hydroxyproline concentration was increased in both young salt-loaded SHR groups, although it was significantly greater in those rats with CHF. The increased amount of collagen fibers was also evident on histological sections from LV of young SHR rats on a high-salt diet (Fig. 1). LV hydroxyproline concentration was also increased in the old salt-loaded SHR (Table 1).


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  		Table 1. Body, lung, LV and RV masses, systolic arterial pressure, and LV hydroxyproline concentration

 


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  		Fig. 1. Representative images showing interstitial collagen (blue staining) in rats on a control (A) and high-salt diet (B) (Masson's trichrome staining; magnification, x400).

 
Echocardiographic examination revealed that LVDd was increased significantly in the CHF group only, whereas SWd, PWd, and LV mass were increased in all salt-loaded groups, either young or old, compared with their respective controls (Table 2). The relative wall thickness was significantly greater in young salt-loaded group without CHF compared with control rats. The relative wall thickness in rats with CHF was greater as well, but it was less than in rats without CHF mirroring increased LV diameter. The echocardiographic findings of increased LV mass in both age groups on high dietary salt intake were confirmed on necropsy examination (Table 1). However, LV mass increased by 26% in young SHR without CHF, and LV mass increased even further (by 48%) in SHR with CHF. In contrast, LV mass in older rats increased by only 8% with salt loading. There was no difference in the systolic function indexes (FS and VCFc) between young salt-loaded SHR without CHF or old SHR and their respective controls; however, they were significantly reduced in rats with CHF.


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  		Table 2. M-mode measurements of LV geometry and systolic function

 
Aortic flow-derived indexes demonstrated lower stroke volume and cardiac output in young salt-loaded SHR without CHF but not in rats with CHF compared with their controls. Cardiac index was not changed in young salt-loaded SHR without CHF (Table 3).


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  		Table 3. Aortic flow-derived indexes

 
Diastolic indexes showed impaired LV relaxation in the young salt-loaded SHR without CHF manifested by decreased VTIE, VE, and VE/VA and increased MI, reflecting longer isovolumic relaxation time and shorter duration time of mitral flow (Tables 4 and 5). Similar changes were found in old salt-loaded SHR. In contrast, the rats with CHF demonstrated a restrictive pattern of mitral flow manifested as pseudonormalized VTIE, VE, and VE/VA and shorter deceleration time of the E wave (Fig. 2). Isovolumic relaxation time was longer in this group compared with control rats but was shorter than in young salt-loaded SHR without CHF. Indexes based on tissue Doppler and color M-mode VP were consistent with a specific diastolic filling pattern observed by Doppler mitral flow in each group (Fig. 2 and Tables 4 and 5). In young salt-loaded SHR without CHF, impaired relaxation was also manifested as slower VP and decreased Em, Am, and Em/Am compared with control rats. In old salt-loaded SHR, decreased Em but not Am and Em/Am was demonstrated. In young salt-loaded SHR with CHF, significantly decreased VP and higher VE/VP were demonstrated compared with controls (Fig. 2). Together with a restrictive filling pattern of this group, the increased VE/VP in these rats (consistent with increased lung weight) indicated increased LV stiffness.


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  		Table 4. Diastolic indexes at 300 beats/min

 

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  		Table 5. Diastolic indexs at 215 beats/min

 


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  		Fig. 2. Effects of salt excess on deceleration time of the mitral E wave (A); velocity of early mitral flow propagation into the left ventricle (VP; B); and VE/VP, an index of left ventricular filling pressure (C) in spontaneously hypertensive rats (SHR). CHF, congestive heart failure. *P < 0.05 vs. aged-matched controls. {dagger}P < 0.05 vs. the salt without CHF group.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, cardiac structural and functional responses to high dietary salt intake were examined at two different ages in adult SHR, a naturally occurring model for essential hypertension. Our data demonstrated that in the most of SHR (both young and old) dietary salt excess increased arterial pressure and promoted diastolic dysfunction associated with increased LV mass and hydroxyproline concentration. However, a subgroup of young salt-loaded SHR developed CHF with altered systolic as well as diastolic function associated with still greater myocardial fibrosis. Thus accumulation of ventricular collagen associated with excessive salt intake appears to be an important contributor to the LV filling abnormalities. Our study therefore demonstrated that salt sensitivity in SHR is manifested not only by increased arterial pressure, but, in addition, cardiac structure and function were even more adversely affected, especially in the young.

It is well known from clinical and experimental studies that dietary salt excess frequently elevates arterial pressure in both essential and experimental hypertension and promotes concentric LVH or remodeling (6, 11, 16, 20, 38). Furthermore, hypertensive LVH has been associated with impaired relaxation (1, 8, 9, 14, 21, 29), and some abnormalities (reduced E wave and E-to-A ratio) have been demonstrated in sodium-sensitive patients with essential hypertension but not in sodium-resistant patients (22). Nevertheless, the precise mechanisms by which excessive salt intake impairs relaxation remain to be elucidated. They may include cardiac myocyte alterations frequently found in hypertensive heart disease (37) but also enhanced myocardial collagen deposition. In the present study, increased LV hydroxyproline concentration in the salt-loaded young SHR without CHF as well as in the salt-loaded older rats were associated with impaired LV relaxation. Indeed, diffuse interstitial fibrosis may interfere with ventricular relaxation (3); it may also decrease myocardial perfusion because coronary flow occurs primarily during diastole and in that way enhances diastolic dysfunction. On the other hand, perivascular fibrosis may interfere with coronary vasodilation as well further diminishing myocardial perfusion (27). In our previous study, we showed that salt loading in young SHR increased coronary vascular resistance while decreasing blood supply to the heart (16), thereby providing support to the notion that ischemia might also contribute to observed abnormal LV filling. Our findings are in agreement with a recent morphological study where increased LV interstitial and perivascular collagen deposition was described in young SHR under the similar experimental condition (38). However, ventricular function was not examined in that study. Furthermore, exacerbation of hypertension may explain the observed excessive collagen accumulation in the LV of the salt-loaded SHR, although additional mechanisms may also be important. Dietary salt intake has been recently related to variety of local hormones and growth factors that promote collagen synthesis (10, 19, 20, 34, 38). Thus additional studies clearly are necessary to elucidate further the contribution of these nonhemodynamic factors in the development of myocardial fibrosis in response to dietary salt excess.

We also clearly identified a group of the young SHR on high dietary salt intake that developed CHF. These rats showed LV dilation along with increased wall thickness and impaired both systolic and diastolic function. Furthermore, significantly increased lung mass, LV filling pressure, and restrictive filling pattern were demonstrated as well, indicating stiff chamber. The greater hydroxyproline concentration in the SHR with CHF compared with the age-matched control rats suggests myocardial fibrosis as an important contributor to the increased LV chamber stiffness. At this point, we offer no explanation as to why a certain percentage of the young SHR developed CHF, whereas the others demonstrated isolated diastolic dysfunction after the same period on high dietary salt intake. Doi et al. (9) described that Dahl salt-sensitive rats placed on a high-salt diet from 7 wk of age developed isolated diastolic failure at ~19 wk of age. On the other hand, rats given excess salt from 8 wk of age developed systolic heart failure (around the 26th wk) (9). We used commercially available rats that are labeled with the same date of birth. Actually, they were born within 1 wk of each other, with actual final date labeled as the date of birth. Whether that small difference in age could result in different response to salt loading observed in the present study still needs to be examined.

Finally, it has been shown that young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats (39). Here, we extend this notion to the SHR. We found that dietary salt excess elicited the most severe alterations in structure and function in younger SHR, even after relatively short salt loading period. In addition, the food, and therefore salt intake, was similar in rats given a high-salt diet (young: 6.65 ± 0.46 g·day–1·100 g body wt–1 vs. old: 6.74 ± 0.45 g·day–1·100 g body wt–1). Sympathetic overactivity associated with high dietary salt intake in young SHR (20) may become less prominent with aging attenuating in that way sodium-related cardiac damages in older animals. Although it is not known whether these effects could be applied to humans, data from the present study underline a need for more information regarding detrimental effects of dietary salt, particularly at a young age.

A number of limitations could be identified in this study. In the absence of invasive measurement of LV function, the interpretation of the observed echocardiographic parameters should be made with caution because they could be influenced by heart rate, LV preload, and afterload as well as myocardial contractility. We attempted to overcome these limitations by analyzing as many functional indexes as possible at the same, more physiological heart rate (~300 beats/min). All measurements of the duration of Doppler flows and color M-mode VP were made at this heart rate. We also believe that using some parameters that have been shown to be less load sensitive, such as VP and tissue Doppler velocity (12, 18), would strengthen our conclusion. It is also worth noting that in our study echocardiographic assessment of systolic function was obtained in penthobarbiatal anaesthesia only to avoid possible cardiodepression induced by xylazine (25).

In conclusion, sodium sensitivity in SHR is manifested not only by further elevated arterial pressure but also by significant LV functional impairment that is most likely related to enhanced ventricular fibrosis. It also appears that SHR are more susceptible to cardiac damage when high dietary salt intake is introduced earlier in life. Some recent experimental and clinical evidence suggested dietary salt intake as an independent determinant of LV hypertrophy. Taken together with the results of the present study, this indicates a need for careful evaluation of the role of dietary salt in cardiovascular morbidity and mortality, particularly at a young age.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by an award from the American Heart Association, Southeast Affiliate (to J. Varagic).


   ACKNOWLEDGMENTS
 
The authors are deeply grateful to Dr. Gladden W. Willis for important contributions to this study by providing the histological evaluation of the hearts. Philips Medical System kindly provided the echocardiographic instrument used in this study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Varagic, Ochsner Clinic Foundation, 1516 Jefferson Highway, New Orleans, LA 70121 (E-mail: jvaragic{at}ochsner.org).

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.


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 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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