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J Am Coll Cardiol, 2000; 35:222-229
© 2000 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDIES

Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure

Takayuki Mishima, MDa, Mitsuhiro Tanimura, MDa, George Suzuki, MDa, Anastassia Todor, MDa, Victor G. Sharov, MD, PhDa, Sidney Goldstein, MD, FACCa and Hani N. Sabbah, PhD, FACCa

a Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA

Manuscript received April 22, 1999; revised manuscript received August 6, 1999, accepted October 5, 1999.

Reprint requests and correspondence: Dr. Hani N. Sabbah, Director, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202
HSABBAH1{at}hfhs.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF.

BACKGROUND

Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF).

METHODS

Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7).

RESULTS

In untreated dogs, EF decreased from 35 ± 1% before initiating therapy to 29 ± 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 ± 3 vs. 84 ± 8 ml, p = 0.08; ESV: 46 ± 2 vs. 60 ± 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 ± 2% before initiating therapy to 39 ± 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 ± 3 vs. 71 ± 4 ml, p = 0.05; ESV: 48 ± 2 vs. 43 ± 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis.

CONCLUSIONS

In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF.

Abbreviations and Acronyms
  EDV = end-diastolic volume
  EF = ejection fraction
  ESV = end-systolic volume
  ET = endothelin
  ETA = endothelin-1 type A receptor
  ETB = endothelin-1 type B receptor
  ET-1 = endothelin-1
  HF = heart failure
  LV = left ventricular

Endothelin (ET) is a vascular endothelial cell–derived vasoconstrictor peptide that functions as a circulating hormone as well as a paracrine factor in regulating vascular tone (1–3). Endothelin-1 (ET-1), one of three isoforms of endothelin (4), has been demonstrated to play an active role in the pathophysiology of heart failure (HF). The observation that ET-1 is elevated in HF and that ET-1 receptor antagonists can decrease both systemic and pulmonary pressures in patients and animal models of HF provides further support for its functional importance (5–8). In addition to its vasoconstrictor effects (4,9,10), ET-1 has been shown to augment the inotropic function of the heart (11–14). Endogenous ET-1 has also been shown to play a role in stimulating cardiomyocyte hypertrophy (15–17), to promote collagen turnover in cardiac fibroblasts (18) and to induce both myocardial ischemia and edema (19). All of these pathophysiologic effects suggest that ET-1 may potentially play a key role in the progression of left ventricular (LV) dysfunction and chamber remodeling that are characteristic features of HF.

The extent of plasma elevation of ET-1 in patients with HF has been shown to correlate with the magnitude of alterations in cardiac hemodynamic variables and New York Heart Association functional class (5). Plasma ET concentration has also been shown to be strongly related to mortality after acute myocardial infarction (14). With these associations in mind, and in view of endothelin’s well-known potent vasoconstrictor properties, ET-1 receptor antagonists have been suggested to have potential therapeutic benefit in HF by decreasing systemic vascular resistance (20–27), a hallmark of HF. The development of bosentan (28), a mixed endothelin-1 type A (ETA) and type B (ETB) receptor antagonist, provided an opportunity to study the effects of ET-1 blockade in chronic HF. In earlier studies, intravenous administration of bosentan was shown to decrease systemic vascular resistance and increase cardiac output both in patients with congestive HF (29,30) and in a canine model of chronic HF (22). The present study was designed to determine the effect of early, long-term therapy with bosentan on the progression of LV dysfunction and chamber remodeling in dogs with moderate HF induced by multiple, sequential intracoronary embolization of microspheres.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Animal model.   The canine model of chronic HF used in the present study was previously described in detail (31). In this experimental preparation, chronic LV dysfunction is induced by multiple, sequential intracoronary embolizations with polystyrene Latex microspheres (70 to 102 µm in diameter), which results in loss of viable myocardium as seen in myocardial infarction. The model manifests many of the sequelae of HF seen in humans, including marked and sustained depression of LV systolic and diastolic function, reduced cardiac output, increased LV filling pressures, increasing systemic vascular resistance, enhanced activity of the sympathetic nervous system and increased plasma concentration of ET-1 (22,31). In the present study, 14 healthy mongrel dogs, weighing between 18 and 31 kg, underwent serial coronary microembolizations to induce HF. Embolizations were performed one to three weeks apart and were discontinued when the LV ejection fraction (EF), determined angiographically, was between 30% and 40%. Microembolizations were performed during cardiac catheterization under general anesthesia and with sterile conditions. The anesthesia regimen used in the present study consisted of a combination of intravenous injection of oxymorphone (0.22 mg/kg body weight), diazepam (0.17 mg/kg) and sodium pentobarbital (150 to 250 mg to effect). This anesthesia regimen was previously shown to have no effect on global LV function (32). Each dog underwent an average of eight coronary microembolization procedures. Embolizations were performed one to three weeks apart and were discontinued when LVEF was between 30% and 40%.

Study protocol.   Two weeks after the last coronary microembolization, all dogs underwent a prerandomization left and right heart catheterization (pretreatment). The two-week period was allowed to ensure that all infarctions produced by the last microembolization session were completely healed. One day after the cardiac catheterization, dogs were randomized to three months of oral monotherapy with bosentan (30 mg/kg twice daily, n = 7) or no treatment at all (control arm, n = 7). No other drugs were used in any of the study arms during the three months of follow-up. After a final hemodynamic and angiographic study performed at the end of three months of therapy (post-treatment), the dogs were killed, and the heart was removed for histologic examination. The study was approved by the Henry Ford Hospital’s Care of Experimental Animals Committee and conformed to the "Position of the American Heart Association on Research Animal Use," adopted by the Association in November 1984, and to the guiding principles of the American Physiological Society.

Hemodynamic and angiographic measurements.   In all study dogs, hemodynamic and angiographic measurements were obtained during left and right heart catheterizations. Aortic and LV pressures were measured with catheter-tipped micromanometers (Millar Instruments, Houston, Texas). Left ventricular peak rate of change in pressure during isovolumic contraction (peak rate of rise in LV pressure [+dP/dt]) and isovolumic relaxation (peak –dP/dt), as well as LV end-diastolic pressure, were measured from the phasic LV pressure waveform. Cardiac output was measured in duplicate using the thermodilution method by means of a Swan-Ganz catheter. Cardiac index was calculated as the ratio of cardiac output to body surface area. Systemic vascular resistance was calculated as the difference between mean aortic pressure and mean right atrial pressure x 80/cardiac output (32). Left ventriculograms were obtained during each cardiac catheterization procedure after completion of the hemodynamic measurements with the dog placed on its right side. Ventriculograms were recorded on 35-mm cine film at 30 frames/s during the injection of 20 ml of contrast material (Reno-M-60, Squibb, Princeton, New Jersey). Correction for image magnification was made using a radiopaque calibrated scale placed at the level of the left ventricle. Left ventricular end-systolic volume (ESV) and end-diastolic volume (EDV) were calculated from angiographic silhouettes using the area–length method (33). Ejection fraction was calculated as ([EDV – ESV]/EDV) x 100. Extrasystolic and postextrasystolic beats were excluded from all angiographic analyses. Venous blood samples were obtained from conscious dogs one day before the cardiac catheterization for evaluation of plasma concentration of norepinephrine. To minimize possible variations, blood samples were always obtained between 8:00 and 10:00 AM. Plasma norepinephrine concentration was measured using aluminum oxide absorption by high performance liquid chromatography.

Histologic and morphometric assessments.   At the end of three months of therapy and immediately after the final hemodynamic and angiographic evaluation, each dog’s chest was opened through a left thoracotomy, the pericardium was opened and the heart was rapidly removed and placed in ice-cold cardioplegia solution. From each heart, a transverse slice, ~3 mm thick, was obtained from the LV at the mid-ventricular level. Transmural tissue blocks were obtained from the free wall segment of the slice, mounted on cork using Tissue-Tek embedding medium (Miles Inc., Mishawaka, Indiana) and rapidly frozen in isopentane precooled in liquid nitrogen and stored at –70°C until used. Cryostat sections, ~8 µm thick, were prepared from each block and stained with fluorescein-labeled peanut agglutinin (Vector Laboratories Inc., Burlingame, California) after pretreatment with 3.3 U/ml neuroaminidase type V (Sigma Chemical Co., St. Louis, Missouri) to delineate the myocyte border and the interstitial space, including capillaries as previously described (34). Sections were double-stained with rhodamine-labeled Griffonia simplicifolia lectin I to identify capillaries. Ten radially oriented microscopic fields, magnification x 100 (objective 40 and ocular 2.5), were selected at random from each section and photographed using 35-mm color film. Fields containing scar tissue (infarcts) were excluded. Images were projected with a photo magnifier, and the cross-sectional area of each myocyte was measured using computer-based planimetry. An average myocyte cross-sectional area was calculated for each dog using data obtained from all fields. The total surface area occupied by interstitial space and the total surface area occupied by capillaries were measured from each randomly selected field using computer-based video densitometry (JAVA, Jandel Scientific, Corte Madera, California). The volume fraction of interstitial collagen (interstitial fibrosis) was calculated as the percent total surface area occupied by interstitial space, minus the percent total area occupied by capillaries (34). An average volume fraction of interstitial fibrosis was calculated for each dog using data obtained from all fields. For comparison purposes, measurements of myocyte cross-sectional area and volume fraction of interstitial fibrosis were made using identical techniques in LV tissue sections obtained from seven normal dogs.

Data analysis.   To ensure that all study measures were similar at baseline, before any embolizations, and at the time of randomization before initiation of therapy, comparisons were made between the two study groups. For these comparisons, a t statistic for two means was used, and a p value ≤0.05 was considered significant. Intragroup comparisons between pretreatment and post-treatment measures were made using the Student paired t test, with p < 0.05 considered significant. To assess the treatment effect, the change in each measure from pretreatment to post-treatment was calculated for each of the two study arms. To determine whether significant differences in change were present between the two groups, a t statistic for two means was used, with p ≤ 0.05 considered significant. Repeated measures analysis of variance was also used to test for time by treatment interaction. All data are reported as the mean value ± SEM.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
At baseline, all dogs entered into the study had hemodynamic data and angiographic findings that were within the normal limits for mongrel dogs in our laboratory. Baseline data for both study groups are shown in Table 1. There were no significant differences in any of the variables between dogs that were subsequently randomized to no treatment and dogs randomized to active treatment with bosentan. Furthermore, there were no significant differences in any the study variables measured just before randomization between the two study groups. These data are shown in Tables 2 and 3.


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  		Table 1 Baseline Hemodynamic, Angiographic and Plasma Norepinephrine Measurements

 

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  		Table 2 Hemodynamic, Angiographic and Plasma Norepinephrine Measurements Obtained Before Randomization and After Three Months of Follow-Up

 

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  		Table 3 Hemodynamic, Angiographic and Plasma Norepinephrine Measurements Obtained Before Initiating Therapy and After Three Months of Therapy

 
Progression of LV dysfunction in untreated dogs.   The pretreatment and post-treatment hemodynamic, angiographic and neurohumoral measures are shown in Table 2. As expected, EF decreased significantly during the three-month follow-up period (Table 2, Fig. 1). This was accompanied by an increase in both ESV and EDV, although the increase in EDV did not reach statistical significance (Fig. 2). Lack of therapy was also associated with a decrease of peak +dP/dt, a decrease in cardiac index and an increase in plasma norepinephrine concentration. Systemic vascular resistance tended to increase, and LV end-diastolic pressure remained unchanged (Table 2).



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  		Figure 2 Left, Bar graph depicting the mean (±SEM) LV end-diastolic volume (EDV) in untreated control dogs (CON) and in dogs treated with bosentan (BOS). Right, Bar graph depicting the mean (±SEM) LV end-systolic volume (ESV) in untreated control dogs and in dogs treated with bosentan. Solid bars indicate values obtained before initiating treatment and hatched bars to values obtained after three months of follow-up or active therapy. Probability values are based on intragroup pretreatment to post-treatment comparisons.

 
Effects of monotherapy with bosentan.   The pretreatment and post-treatment hemodynamic, angiographic and neurohumoral measures are shown in Table 3. In dogs treated with bosentan, heart rate and mean aortic pressure were unchanged between pretreatment and post-treatment (Table 3). Left ventricular EF tended to increase but did not reach statistical significance, whereas both ESV and EDV decreased significantly (Fig. 1 and 2, Tables 2 and 3). Three months of treatment with bosentan maintained peak +dP/dt and significantly increased peak –dP/dt. Cardiac index increased significantly, and systemic vascular resistance decreased significantly (Table 3). Left ventricular end-diastolic pressure and circulating levels of plasma norepinephrine tended to decrease but did not reach statistical difference (Table 3).



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  		Figure 1 Bar graph depicting the mean (±SEM) LVEF in untreated control dogs and in dogs treated with bosentan. Solid bars indicate values obtained before initiating treatment (pretreatment); hatched bars indicate values obtained after three months of follow-up or active therapy (post-treatment). Probability values are based on intragroup pretreatment to post-treatment comparisons.

 
Comparisons of treatment effect.   In the post-treatment analysis, the two treatment arms were compared. The changes in hemodynamic, angiographic and neurohumoral measures between untreated control dogs and dogs treated with bosentan are shown in Table 4. Compared with no treatment, bosentan significantly increased the LVEF and significantly reduced ESV and EDV (Fig. 3). With bosentan, cardiac index, peak +dP/dt and peak –dP/dt increased significantly, and systemic vascular resistance and plasma norepinephrine concentration decreased significantly as compared with no treatment. Left ventricular end-diastolic pressure tended to be lower and heart rate and mean arterial pressure were unchanged with bosentan as compared with no treatment (Table 4). The p values for repeated measures interaction are shown in Table 4.


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  		Table 4 The Change Between Pretreatment and Post-treatment Hemodynamic, Angiographic and Plasma Norepinephrine Levels in Control Dogs and Bosentan-Treated Dogs

 


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  		Figure 3 Bar graph depicting the mean (±SEM) value of the intragroup change ({Delta}) from pretreatment to post-treatment of LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) in untreated control dogs (solid bars) and in dogs treated with bosentan (hatched bars). Probability values are based on comparisons of change between control and bosentan (treatment effect).

 
Histomorphometric findings are shown in Table 5. Cardiac myocyte cross-sectional area and volume fraction of interstitial fibrosis were both significantly higher in untreated dogs with HF than in normal dogs. Treatment with bosentan modified these processes. Average cardiomyocyte cross-sectional area was significantly smaller in dogs treated with bosentan than in untreated control dogs. Similarly, volume fraction of interstitial fibrosis was significantly lower in dogs treated with bosentan than in control dogs (Table 5).


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  		Table 5 Histomorphometric Findings

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study demonstrates that long-term oral therapy with a mixed ETA and ETB receptor antagonist prevents progressive LV dysfunction and attenuates progressive LV chamber remodeling in this dog model of moderate HF. The results of the study clearly show that bosentan improves LV systolic function and substantially alters the course of LV remodeling. The beneficial effects of bosentan on LV remodeling are shown by attenuation of 1) progressive LV chamber dilation; 2) cardiomyocyte hypertrophy as evidenced by reduced myocyte cross-sectional area; and 3) reduced reactive interstitial fibrosis as evidenced by less accumulation of collagen in the cardiac interstitium. Modulation of the remodeling process by bosentan was accompanied by an increase in cardiac index and a decrease in systemic vascular resistance in the absence of changes in systemic blood pressure and in the chronotropic state—features that have been deemed desirable in the treatment of chronic HF in humans.

The fundamental observation of this study—namely, that initiation of early treatment with an ET-1 antagonist prevents the progression of LV dysfunction and ameliorates LV chamber remodeling in dogs with moderate HF—is supported by observations made in other animal models (25,26,35,36) and in patients with HF (21,29,30,37). In rats with large myocardial infarcts induced by coronary artery ligation, eight-week treatment with bosentan improved stroke volume index and prevented, in part, the rightward shift of the pressure–volume curve as compared with rats given placebo (25). In a Dahl salt-sensitive rat model of LV hypertrophy and failure, long-term treatment with bosentan as compared with placebo significantly attenuated the decrease in LV fractional shortening and the increase LV systolic wall stress (35). In the same rat model, bosentan significantly improved survival (35). Improved survival was also observed in rats with HF secondary to myocardial infarction treated long-term with bosentan (23) or with the selective ETA receptor antagonist BQ-123 (25). In rabbits with pacing-induced HF, Spinale et al. (26) showed that concomitant three-week administration of a selective ETA receptor antagonist significantly attenuated the decline in LV fractional shortening and the increase in LV end-diastolic dimension as compared with untreated control animals. In patients with chronic HF and LVEF ≤30%, intravenous bosentan reduced pulmonary artery wedge pressure and systemic vascular resistance and increased cardiac index as compared with patients receiving placebo (21,29). Short-term administration of oral bosentan for two weeks in patients with severe HF being treated with diuretics, digoxin and angiotensin-converting enzyme inhibitors elicited significant improvement in systemic and pulmonary hemodynamic data, as evidenced by increased cardiac output and a reduction in both pulmonary artery wedge pressure and systemic vascular resistance (30).

In the present study, average cardiomyocyte cross-sectional area, a measure of cardiomyocyte hypertrophy, was significantly lower in dogs treated with bosentan than in untreated control dogs. This finding is consistent with studies in which ET has been shown to play a role in stimulating cardiomyocyte hypertrophy (15–17). Exposure of cultured rat neonatal cardiomyocytes to ET-1 for 6 h resulted in cardiomyocyte hypertrophy associated with increased expression of muscle-specific gene transcripts, including myosin light chain 2 and alpha-actin (15). Studies in cultured rat neonatal cardiomyocytes have also suggested that endogenous ET-1, locally generated and secreted by cardiomyocytes, may contribute to angiotensin II–induced cardiac hypertrophy, possibly through an autocrine/paracrine fashion (38). In this study, the angiotensin II–induced protein synthesis was blocked by the ETA receptor antagonist BQ-123. Endothelin-1 has also been implicated in the release of norepinephrine from adrenal chromaffin cells (39) and in having a direct involvement in norepinephrine-induced ventricular hypertrophy (40). In the present study, treatment with bosentan blunted the rise in plasma norepinephrine concentration observed in untreated dogs. Although the exact mechanism for this interaction is not known, the finding can explain, in part, the attenuation of cardiomyocyte hypertrophy seen in dogs treated with bosentan. Studies in rats with pressure overload hypertrophy induced by aortic banding also showed that blockade of endogenous ET-1 by BQ-123 prevented the increase in LV weight to body weight ratio and in the diameter of cardiomyocytes as compared with untreated rats (16). Similarly, in rats with HF secondary to myocardial infarction, long-term treatment with bosentan was shown to attenuate LV hypertrophy assessed echocardiographically (23). Not all studies in which ET-1 antagonists were in the setting of HF have reported an amelioration of cardiac hypertrophy (26,35,41). In rats surviving an acute myocardial infarction for 24 h, four-week treatment with the ETA receptor antagonist LU-135252 led to impaired scar healing, LV dilation and dysfunction (41). The authors concluded that these negative findings may have been due, in part, to the early use of ETA receptor antagonist after acute myocardial infarction (41). In rabbits with HF induced by rapid ventricular pacing, long-term treatment with an ETA receptor antagonist had no effect on cardiomyocyte remodeling in terms of length or cross-sectional area (26). Treatment with bosentan in Dahl salt-sensitive rats with pressure overload cardiac hypertrophy and failure also failed to alter the course of cardiac hypertrophy (35). The reasons for these differences are not clear and may be, in part, model- and species-dependent and perhaps due to differences in the effects derived from the use of ETA-selective as compared with mixed ET-1 antagonists. Nonetheless, additional studies may be needed to further examine the effects of ET blockade on cardiac hypertrophy in the setting of HF.

It is well recognized that accumulation of collagen occurs in the interstitium of the hypertrophied and failing heart, a process termed "reactive interstitial fibrosis" (42,43). This fibrous tissue response is thought to be responsible for abnormal LV stiffness and systolic and diastolic function (43) and has been implicated in the progression of HF (44). In the present study, we observed a salutary effect of bosentan on reactive interstitial fibrosis. Dogs treated with bosentan had a significantly lower volume fraction of interstitial collagen than untreated dogs. A reduction in cardiac interstitial fibrosis was also reported in rats with HF secondary to myocardial infarction after long-term treatment with bosentan (23). The mechanism by which ET-1 blockade elicits this beneficial effect is not known but may involve the cardiac fibroblast, an active participant in the remodeling process of several cardiac diseases (45,46). Functionally active ETA and ETB receptors have been reported to exist in fibroblasts (47). It is possible that the increased release of ET-1 in HF can activate these receptors, which, in turn, can promote synthesis and deposition of collagen by cardiac fibroblasts. Endothelin-1 has also been shown to affect collagen synthesis in cardiac fibroblasts and reduce collagenase activity (18).

The mechanisms by which ET-1 receptor blockade elicits its beneficial effects on LV function and remodeling in HF are not fully understood. Some benefit is derived from amelioration of cardiac hypertrophy and reactive interstitial fibrosis. Elevated levels of ET-1 in HF can lead to vasoconstriction and increased systemic vascular resistance. Receptor blockade can reverse this deleterious process with an attendant reduction in systemic vascular resistance. Although not measured in the present study, we have previously shown that plasma ET-1 level is elevated in this dog model of HF, with further increases after administration of bosentan, as expected (22). It is possible, however, that the improvement in LV systolic function in HF with the use of ET-1 antagonists may be independent of afterload reduction (35). Although ET-1 may elicit a positive inotropic effect in normal myocardium, it has been shown to elicit a negative inotropic effect in the presence of beta-adrenergic stimulation (48), a response consistent with the pathophysiology of the HF. In cardiomyocytes isolated from rabbits with pacing-induced HF treated with an ETA receptor antagonist, Spinale et al. (26) demonstrated improvement in indexes of contractile function, an observation consistent with the findings of the present study. Other reported effects of ET-1 may also lead to negative inotropic effects in HF. Endothelin-1 can elicit negative inotropic effects on the heart by reducing forskolin-induced increases of cyclic adenosine monophosphate (49) or by decreasing Ca2+ adenosine triphosphate messenger ribonucleic acid levels, or both (50). Endothelin-1 may also have a direct cytotoxic effect through degradation of phospholipids (51).

There are some limitations of the present study that warrant consideration. A single dose of bosentan was used on the basis of data generated in other mammalian species as well as patients with HF. A dose-ranging study in dogs with HF, and perhaps the use of both low- and high-dose bosentan study arms, would have facilitated interpretation of the efficacy of bosentan in this canine model of HF. Another possible limitation of the study is the difficulty in interpreting whether the benefits of bosentan on LV function and chamber remodeling were due to vasodilation alone or instead to a specific antagonism of endothelin. This issue could have been better resolved had the study contained another monotherapy arm in which a vasodilator was used that was less likely to impact LV performance and remodeling. In salt-sensitive hypertensive rats with HF, bosentan prevented the progression of LV dysfunction, whereas the alpha1-receptor antagonist doxazosin, a vasodilator, had no effect, even though both compounds reduced afterload by the same extent (35).

Conclusions.   The results of this study indicate that early, long-term monotherapy with bosentan prevents progressive LV dysfunction and attenuates progressive LV chamber remodeling in dogs with moderate HF. In addition to improving cardiac hemodynamic variables and preserving LV chamber size, treatment with bosentan also attenuated cardiomyocyte hypertrophy and reduced cardiac interstitial fibrosis. The study findings support the use of mixed ETA and ETB receptor antagonists as adjuncts to the long-term treatment of chronic HF.


   Footnotes
 
This study was supported in part by grant HL-49090 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and by F. Hoffman-La Roche, Ltd., Basel, Switzerland.


   References
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 Discussion
 References
 

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