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Am J Physiol Heart Circ Physiol 287: H760-H766, 2004. First published March 18, 2004; doi:10.1152/ajpheart.00734.2003
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Saturated glucose uptake capacity and impaired fatty acid oxidation in hypertensive hearts before development of heart failure

Nozomu Fujii,1 Takashi Nozawa,1 Akihiko Igawa,1 Bun-ichi Kato,1 Norio Igarashi,1 Makoto Nonomura,1 Hidetsugu Asanoi,1 Shusaku Tazawa,2 Minoru Inoue,2 and Hiroshi Inoue1

1Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194; and 2Daiichi Radioisotope Laboratories, Chiba 289-1517, Japan

Submitted 10 November 2003 ; accepted in final form 27 February 2004


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using 131I- or 125I-labeled 9-methylpentadecanoic acid (131I- or 125I-9MPA), and [14C]deoxyglucose ([14C]DG), fatty acid {beta}-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaCl, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [14C]DG increased markedly with age in the DS rats, whereas 131I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of 125I-9MPA {beta}-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [14C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure.

cardiac; failure; deoxyglucose; methylpentadecanoic acid; {beta}-oxidation; insulin

MYOCARDIAL HYPERTROPHY due to pressure overload is initially an adaptive response to maintain normal wall stress. However, if pressure overload persists, myocardial hypertrophy may progress to heart failure. Although the adaptive mechanisms that lead to development of hypertrophy have been identified (4, 13), the mechanism involved in the transition from compensated hypertrophy to a decompensated failing heart remains poorly understood. Multiple cellular abnormalities contribute to the development of heart failure, and there is increasing evidence (10, 21) that alterations in metabolism may have a pathogenic role in the disorder. Many studies using glucose and fatty acid analogs have observed a switch from fatty acid to glucose as the main energy substrate in hypertrophied hearts, a change that results in more oxygen-efficient production of ATP (2, 12, 27). Despite this favorable change in energy metabolic pathways, the amount of ATP or high-energy phosphates in the myocardium is known to be reduced during cardiac hypertrophy (3, 28). Although this limited production of energy in hypertrophied myocardium has the potential to contribute to the development of heart failure, the pathogenic importance of these changes in the transition from compensated hypertrophy to heart failure has yet to be established.

The Dahl salt-sensitive (DS) rat is an animal model that develops systemic hypertension on increased intake of dietary sodium (6, 19). This animal model offers the advantage of providing a model for studying the progression from compensated hypertrophy to overt congestive heart failure in a relatively short period of time (11). We used this model to 1) determine the serial changes in myocardial uptake of fatty acids and glucose, 2) investigate myocardial fatty acid metabolism including {beta}-oxidation, and 3) determine the capacity of myocardial glucose uptake by insulin stimulation during the transition from compensated hypertrophy to decompensated heart failure.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental animals. The experimental procedures were in accordance with the guidelines for animal experimentation at Toyama Medical and Pharmaceutical University. A total of 172 male rats of the DS and Dahl salt-resistant (DR) strains were used in the study. The rats were fed a low-salt (0.3% NaCl) diet until 6 wk of age; thereafter, they were fed a high-salt (8% NaCl) diet for the remainder of the experimental period. The rats were divided into three groups. The first group was used for cardiac autoradiography to determine left ventricular (LV) accumulation and distribution of fatty acid and glucose analogs. The second group was used for measuring myocardial metabolic products of fatty acids as analyzed by thin-layer chromatography (TLC). The third group was used to determine insulin-stimulated glucose uptake via the euglycemic hyperinsulinemic glucose-clamp method. Data were collected on all groups at the ages of 6, 12, and 18 wk. Animals were fasted for 24 h before each metabolic study.

Assessment for cardiac function. In a previous hemodynamics study (16), we observed that DS rats developed compensated LV hypertrophy at 12 wk of age and subsequent heart failure at 18 wk. To confirm this transition, blood pressure measurement and cardiac echocardiography were carried out on 12- and 18-wk-old rats. Systolic blood pressure was measured using an indirect tail-cuff method (model BP-98A; Softron), whereas transthoracic echocardiography was performed using a 7.5-MHz transducer (model SSH140A; Toshiba) as described previously (9).

Radiopharmaceuticals. Myocardial fatty acid and glucose metabolism rates were assessed using 131I- or 125I-labeled 15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid (131I- or 125I-9MPA; ref. 25) and [14C]deoxyglucose ([14C]DG), respectively. The 131I- or 125I-9MPA (Daiichi Radioisotope Laboratory; Tokyo) had a radiochemical purity of >98% and specific activity of 30–70 GBq/mmol; the purity of [14C]DG (Moravek) was >97% and specific activity was 60 mCi/mmol.

Dual-tracer autoradiography. In the study using dual-tracer autoradiography, the animals were injected with 5 µCi iv of [14C]DG; 40 min later, they were injected with 75 µCi iv of 131I-9MPA. The hearts were removed 5 min after the second injection and washed in cold saline. The specimens were frozen in isopentane, cooled in dry ice, embedded in methylcellulose, and cut into serial 20-µm-thick transverse sections. The first autoradiographic exposure on an imaging plate (BAS-UR; Fuji Film) was carried out for 8 h to reveal 131I-9MPA distribution. The second exposure for the [14C]DG image was initiated 75 days later (subsequent to the decay of 131I-9MPA activity) and required 30 days for an adequate image to be obtained. At the doses of 131I-9MPA and [14C]DG used in the study, cross-talk between the two tracers was <1%. This finding indicates that cross-talk between 131I and 14C would have been negligible.

To evaluate myocardial uptake levels and distributions of 131I-9MPA and [14C]DG, the autoradiographic images were analyzed using a computer-assisted imaging-processing system (model BAS3000; Fuji Film) as described previously (16). The region of interest in the images was the entire LV wall at the level of the papillary muscles; the myocardial uptake levels of 131I-9MPA and [14C]DG were calculated as the percentage of the administered dose per gram of heart (%kg dose/g) relative to 131I- and 14C-labeled graded standards.

Analysis of 125I-9MPA metabolites. Lipid extraction from myocardial tissue was performed according to a modification of the method of Folch et al. (8), and the metabolic products of 125I-9MPA were determined by TLC. While the animals were under pentobarbital sodium anesthesia, a 100 µCi iv dose of 125I-9MPA was administered. Hearts were removed rapidly and rinsed in cold saline, and the LV tissues were cut into small slices, homogenized, and extracted twice with a 2:1 dilution (vol/vol) of chloroform-methanol. After centrifugation for 10 min, the resulting organic, aqueous, and solid phases were separated. The radioactivity levels of the 125I-9MPA metabolites in the organic phase were assayed by TLC on aluminum sheets (RP-18F; Merck) in conjunction with standard lipid preparations (Daiichi Radioisotope Laboratory). The 125I-9MPA metabolites on the aluminum sheets were then exposed on the imaging plate for 2 wk and quantified with a bioimaging analyzer (model BAS3000). Two major metabolites of 125I-9MPA were detected on the exposed images. These were 3-methylnonanoic acid (3MNA), because the intermediate metabolite formed after three cycles of {beta}-oxidation from 125I-9MPA, and p-iodophenyl acetic acid (PIPA), which is the final product of 125I-9MPA. The sum of the 125I-9MPA metabolites was defined as the total amounts of PIPA, 3MNA, and the other intermediate metabolites formed by {beta}-oxidation.

Euglycemic insulin clamp. The euglycemic hyperinsulinemic glucose-clamp method was used to determine insulin-stimulated glucose uptake. A polyethylene-50 catheter was introduced into the femoral vein, and a continuous intravenous infusion of insulin was started at a rate of 18 mU·kg–1·min–1. Plasma glucose values were measured every 10 min using a HemoCue glucose analyzer (Ängelholm). A 20% glucose solution was then infused, and the rate was adjusted to maintain the plasma glucose concentration at the basal level identified before insulin infusion began. At 75 min after the start of insulin infusion, 5 µCi iv of [14C]DG was injected; 45 min later, the heart was removed rapidly and washed in cold saline. The myocardial [14C]DG uptake values were estimated by quantitative autoradiography.

Statistics. Data are expressed as means ± SD. Comparison of variables was performed using two-way ANOVA with time (week) and group (DS vs. DR) as the main effects. Where appropriate, Bonferroni's test for multiple comparisons was used to determine the significance of changes within the same group over time and between groups at each time point. A value of P < 0.05 was considered statistically significant.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Blood pressure in the DS rats increased markedly at 12 wk and remained elevated until 18 wk. In contrast, there was only a small increase in blood pressure in the DR rats. Heart weight was greater in DS rats than in DR rats at both 12 and 18 wk (Table 1), whereas LV end-diastolic and end-systolic dimensions were increased in 18-wk-old DS rats compared with DR rats of similar age. Although the percentages of fractional shortening were similar in both DS and DR rats at 12 wk, a significant decrease occurred by week 18 only in the DS rats. During the period of 16–18 wk, the DS rats displayed labored respiration, decreased activity, and a progressive deterioration in their general condition.


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  		Table 1. Heart weight and hemodynamic and echocardiographic data

 
Plasma glucose and insulin concentrations did not change significantly with age in either DS or DR rats (Table 2). Plasma triglyceride levels were greater in the DS rats compared with DR rats at both 12 and 18 wk, whereas nonesterified fatty acid concentrations decreased significantly with age only in the DS rats.


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  		Table 2. Plasma concentrations of glucose, insulin, and fatty acids

 
Uptake of 131I-9MPA and [14C]DG. Examples of autoradiography with 131I-9MPA and [14C]DG are shown in Figs. 1 and 2. In DS rats, myocardial 131I-9MPA uptake values were significantly greater at 12 than at 6 wk (1.30 ± 0.17 vs. 0.84 ± 0.07 %kg dose/g; Fig. 3A). This increase was attenuated at 18 wk (1.01 ± 0.11 %kg dose/g). In contrast, myocardial [14C]DG uptake in the DS rats markedly increased with age (0.27 ± 0.02, 0.59 ± 0.16, and 0.66 ± 0.17 %kg dose/g at 6, 12, and 18 wk, respectively; Fig. 3B), whereas in the DR rats, neither 131I-9MPA nor [14C]DG uptake varied significantly with age. As shown in Fig. 3C, the uptake ratio of [14C]DG to 131I-9MPA relative to each value at 6 wk increased markedly with age in the DS rats but decreased in the DR rats.



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  		Fig. 1. Representative examples of myocardial uptake of 15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid (131I-9MPA) obtained by dual-tracer autoradiography. Accumulation of 131I-9MPA was relatively homogeneous at all stages in both Dahl salt-sensitive (DS) and salt-resistant (DR) rats. Uptake of 131I-9MPA in DS rats increased at 12 wk but the increase was attenuated at 18 wk.

 


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  		Fig. 2. Representative examples of myocardial [14C]deoxyglucose ([14C]DG) uptake. Along with increasing age, [14C]DG uptake increased progressively and markedly in DS rats but decreased in DR rats at 18 wk.

 


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  		Fig. 3. Myocardial uptake values of 131I-9MPA (A) and [14C]DG (B). Uptake ratio of [14C]DG to 131I-9MPA (C) is normalized to each value at 6 wk. Solid bars, DS rats (n = 6 at 6 and 12 wk; n = 5 at 18 wk); open bars, DR rats (n = 6 at each week). Data in A and B are means ± SD. *P < 0.05; **P < 0.01 vs. age-matched DR rats; {dagger}P < 0.05; {ddagger}P < 0.01 vs. 6-wk-old rats in each group; #P < 0.05 vs. 12-wk-old DS rats.

 
TLC of 125I-9MPA. An example of TLC analysis of 125I-9MPA is shown in Fig. 4. The 125I-9MPA that is transported into the cytosol is metabolized by {beta}-oxidation in mitochondria or stored in the triglyceride pool. At 18 wk, the accumulation of 125I-9MPA metabolites processed by {beta}-oxidation (i.e., the sum of PIPA, 3MNA, and intermediate metabolites) was lower in DS rats than in DR rats. The ratio of 125I-9MPA metabolites to total 125I-9MPA uptake is summarized in Fig. 5. In the DS rats, this ratio was significantly lower at 12 and 18 wk (36.1 ± 8.8 and 34.1 ± 7.8%, respectively) compared with values at 6 wk (45.1 ± 3.2%). No age-related change in this ratio was observed in the DR rats.



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  		Fig. 4. Representative examples of thin-layer chromatography of 125I-9MPA in 18-wk-old DS and DR rats (DS-18w and DR-18w, respectively). Bottom spots indicate 125I-9MPA in triglyceride pool. Sums of radioactivity from the intermediate metabolites above 125I-9MPA to p-iodophenyl acetic acid (PIPA) are defined as metabolites processed by {beta}-oxidation. 3MNA, 3-methylnonanoic acid.

 


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  		Fig. 5. Ratio of 125I-9MPA metabolites processed by {beta}-oxidation to the total uptake. Total uptake is the sum of 125I-9MPA metabolites with {beta}-oxidation and 125I-9MPA before {beta}-oxidation. Solid bars, DS rats (n = 5 at each week); open bars, DR rats (n = 7 at 6 and 18 wk; n = 6 at 12 wk). Data are means ± SD. {dagger}P < 0.05 vs. 6-wk-old rats in each group.

 
[14C]DG uptake during insulin clamp. Plasma glucose concentrations before and during insulin infusion were similar in the two strains of rats at all ages. The insulin-clamp procedure resulted in a >20-fold increase in plasma insulin concentration with no differences in levels between DS and DR rats at any age. Insulin-stimulated [14C]DG uptake values were similar between DS and DR rats at all times except in 18-wk-old DR rats, which had a significantly lower uptake value compared with 6-wk-old animals (Fig. 6A). The amount of [14C]DG uptake more than doubled during insulin infusion in both DS and DR rats at 6 wk, and this increase was sustained until 18 wk of age in DR rats; however, it was markedly attenuated in DS rats at both 12 and 18 wk (Fig. 6B).



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  		Fig. 6. Myocardial [14C]DG uptake during insulin clamp (A) and the increased rate of myocardial [14C]DG uptake during insulin clamp from basal [14C]DG uptake before insulin administration (B). Solid bars, DS rats (n = 7, 6, and 8 at 6, 12, and 18 wk, respectively); open bars, DR rats (n = 7, 5, and 10 at 6, 12, and 18 wk, respectively). Data in A are means ± SD. {dagger}P < 0.05 vs. 6-wk-old rats in each group.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The major findings of the present study are as follows. First, the uptake of myocardial energy substrate in DS rats shifted from fatty acids to glucose during the development of hypertrophy and heart failure. This shift was associated with an increase in myocardial fatty acid uptake at the stage of hypertrophy, but the increase was attenuated in heart failure. Our data indicated that the shift in substrate uptake in hypertrophied and failing hearts was due to a considerably greater proportional increase in [14C]DG uptake. Second, myocardial hypertrophy was associated with a reduction in the ratio of 125I-9MPA metabolites formed by {beta}-oxidation to total 125I-9MPA uptake. This change occurred before the development of heart failure, which suggests an impairment in either {beta}-oxidation or fatty acid transport from the cytosol to mitochondria. Third, glucose uptake was maximally stimulated under basal conditions in the hypertrophied heart, and administration of insulin did not further increase this uptake. It is possible that these changes in fatty acid and glucose metabolism in the hypertrophied heart are involved in the transition from compensated hypertrophy to heart failure.

Transition from compensated hypertrophy to heart failure. Inoko et al. (11) observed that DS rats, when fed a high-salt diet from the age of 6 wk, developed congestive heart failure from LV hypertrophy with normal systolic function in a relatively short period. Our study confirmed these observations: echocardiography in the DS rats showed progressive deterioration with normal LV systolic function at 12 wk and dilation of left ventricles with reduced percentage of fractional shortening values at 18 wk. These findings are also consistent with our previous observation in DS rats (16).

Fatty acid metabolism. Previous studies using a fatty acid analog of [14C]{beta}-methylheptadecanoic acid showed that cardiac fatty acid uptake decreased with the development of hypertrophy in association with an energy substrate shift from fatty acids to glucose (12, 27). In our study, the amount of 131I-9MPA uptake was greater at 12 wk than at 6 wk of age in DS rats. Neely et al. (15) showed that an increase in cardiac work was accompanied with increased utilization of available fatty acids. In addition to increased workload in the hypertensive heart, DS rats on a high-salt diet would have enhanced adrenergic activity (23),which would result in increased fatty acid utilization.

With regard to analysis of 125I-9MPA metabolites, {alpha}-oxidation is required after three cycles of {beta}-oxidation of 125I-9MPA, because the compound has a methyl branch at the ninth carbon location of the fatty acid chain (25). Metabolic processing of fatty acid tracers with a methyl branch may be limited in the heart, whereas straight-chain fatty acids would be expected to be metabolized rapidly by {beta}-oxidation. However, a recent study by Yamamichi et al. (26) using the fatty acid tracer {beta}-methyl-p-iodophenylpentadecanoic acid showed that a considerable amount of the initial {alpha}-metabolites and subsequent metabolites of {beta}-oxidation were detectable in isolated rat heart preparations. We were also able to detect {beta}-oxidative products of 125I-9MPA, which allowed us to use this fatty acid analog to evaluate myocardial fatty acid metabolism in this study (25).

Our finding that 131I-9MPA uptake was increased in 12-wk-old DS rats implies that neither the function of fatty acid transporters to myocytes and fatty acid-binding proteins nor the ability of myocyte membranes to preserve fatty acids within the cytosol is impaired in hypertrophied hearts. We also demonstrated a decreased ratio of 125I-9MPA metabolites to total 125I-9MPA uptake at the hypertrophic stage in the DS rats, which indicates that a considerable amount of fatty acids accumulated within the myocytes as either fatty acyl-CoA and acylcarnitine or were stored in the triglyceride pool. This finding suggests that either the capacity of long-chain fatty acid transport from the cytosol to the mitochondria is reduced or the process of {beta}-oxidation is already impaired in hypertrophic hearts. Possible explanations for the reduced quantity of 125I-9MPA metabolites that occur in association with hypertrophy may be a decrease in myocardial carnitine content (1) or reduced activity of {beta}-oxidation enzymes (20). Our observation that 131I-9MPA uptake was increased or unchanged in 12- and 18- compared with 6-wk-old DS rats despite significantly lower levels of plasma nonesterified fatty acids suggests that myocardial extraction efficiency is enhanced in hypertrophied and failing hearts. On the basis of these findings, we suggest that impaired fatty acid metabolism associated with inappropriately elevated uptake in hypertrophied and failing hearts may lead to an imbalance between substrate uptake and utilization.

Glucose metabolism. Before insulin infusion, basal plasma glucose and insulin concentrations were similar in DS and DR rats at all ages. In the DS rats, both basal myocardial [14C]DG uptake and the [14C]DG/131I-9MPA uptake ratio increased markedly with age. It is important to note that these changes in myocardial substrate uptake do not necessarily imply a shift to glucose as the major energy substrate during the development of hypertensive heart failure, because an increase in glucose uptake does not necessarily result in increased ATP production. Considerable evidence exists showing that myocardial glucose uptake increases in pressure-overload hypertrophy (2, 12, 27) as a consequence of increased workload in the compensated heart and increased sympathetic activity (7) and possibly as a result of myocardial ischemia (7).

In the DS rats, [14C]DG uptake under basal conditions increased with age, whereas the increase in myocardial [14C]DG uptake induced by insulin infusion became markedly inhibited in DS rats older than 12 wk. This attenuation of insulin-stimulated [14C]DG uptake may be a consequence of either impaired insulin-receptor signaling or reduced levels of glucose transporters (GLUT; Refs. 17, 18). Morisco et al. (14) demonstrated that hypertrophic hearts of spontaneously hypertensive rats had maximal activity levels of basal insulin signaling that could not be increased further by exposure to insulin. Similarly, a large fraction of the intracellular GLUT pool is translocated into sarcolemmal membranes in hypertrophic hearts, which results in insulin infusion being unable to further stimulate GLUT translocation (17). These findings in conjunction with evidence that the level of high-energy phosphate is reduced in hypertrophied myocardium (3, 28) indicate that a limited reserve of glucose uptake may contribute to the transition from compensated hypertrophy to heart failure.

Study limitations. When interpreting the results of the present study, some limitations should be taken into account. First, the insulin-clamp procedure was performed on animals under pentobarbital sodium anesthesia, which has been shown to affect glucose metabolism (5). However, because all of our metabolic studies were performed using pentobarbital, the effect of this anesthetic would be expected to be similar in all of the animals and therefore would have had a minimal effect on any observed difference between the two rat strains. Second, although we assessed the 125I-9MPA metabolites, we did not determine the amounts of substrates that are capable of producing ATP. We considered that a decrease in 125I-9MPA metabolites indicates impaired {beta}-oxidation, although it is possible that this decrease may occur as a result of increased substrate flux. In a preliminary study on rats, we found that etomoxir, an inhibitor of fatty acid oxidation, markedly decreased myocardial 125I-9MPA clearance and led to its accumulation and additionally decreased the ratio of 125I-9MPA metabolites. In the present study, the ratio of 125I-9MPA metabolites was decreased in 12- and 18-wk-old DS rats compared with 6-wk-old animals despite increased or unchanged total 131I-9MPA uptake values. This suggests that fatty acid oxidation was impaired in the older animals. Our study was also unable to identify the factors that cause accelerated glycolysis or increased myocardial glycogen synthesis or to determine whether these changes were related to increased [14C]DG uptake. Allard et al. (2) reported that although rates of palmitate oxidation were lower in hypertrophied hearts compared with controls, the glucose oxidation rate remained unchanged. We were unable to clarify the fate of glucose taken into myocytes; therefore, the marked attenuation of insulin-stimulated glucose uptake that we observed in hypertrophied and failing hearts does not necessarily imply that the capacity of glucose metabolism to generate ATP is impaired. Additional studies are required to better understand the mechanisms of the increase in glucose uptake that occurs under basal conditions and the attenuation of glucose uptake during insulin stimulation.

Clinical implications. Although the precise mechanisms of the transition from compensated hypertrophy to heart failure are yet to be elucidated fully, our findings of impaired fatty acid metabolism in association with the attenuation of insulin-stimulated glucose uptake in hypertrophied hearts support the hypothesis that changes in fatty acid and glucose metabolism contribute to decreased contractile function and, ultimately, heart failure. The effectiveness of {beta}-adrenergic blockers and angiotensin-converting enzyme inhibitors to improve ventricular function in patients with heart failure may be due in part to the action of these agents in decreasing energy demand. Other compounds that may also have beneficial effects in hypertrophied hearts include vanadyl sulfate, which improves tolerance of ischemia by stimulating membrane glucose transport (24), and propionyl-L-carnitine, which prevents myocardial mechanical alterations associated with pressure overload (1). There is evidence that administration of propionyl-L-carnitine increases both glucose and palmitate oxidation in hypertrophied hearts and improves the efficiency of translating ATP production into cardiac work (22). On this basis, a restoration of glucose and fatty acid metabolism may have potential as a new therapeutic treatment of the hypertensive heart and heart failure.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Takashi Nozawa, Second Dept. of Internal Medicine, Toyama Medical and Pharmaceutical Univ., 2630 Sugitani, Toyama 930-0194, Japan (E-mail: tnozawa{at}ms.toyama-mpu.ac.jp).

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
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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