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Am J Physiol Heart Circ Physiol 287: H2762-H2767, 2004. First published August 19, 2004; doi:10.1152/ajpheart.00501.2004
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Chronic {beta}-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties

Mark Gibbs,* Demetri G. A. Veliotes,* Christopher Anamourlis, Danelle Badenhorst, Oleg Osadchii, Gavin R. Norton, and Angela J. Woodiwiss

Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 2193 Johannesburg, South Africa

Submitted 1 June 2004 ; accepted in final form 9 August 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 GRANTS
 REFERENCES
 
Chronic {beta}-adrenoreceptor ({beta}-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern {beta}-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg·kg–1·day–1 from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that {beta}-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.

cardiomyopathy; collagen; pump dysfunction; stiffness

CARDIAC DISEASE WITH pump dysfunction is often characterized by a rightward shift in cardiac chamber diastolic pressure-volume (P-V) relations and a subsequent increase in cavity volume during both diastole and systole (5). Increments in cavity volume are now considered to be an important independent determinant of pump dysfunction and mortality in cardiac disease. These effects are mediated by increments in wall stress (5, 15). A principal determinant of cavity volume increases in cardiac disease is neurohumoral activation (5) including stimulation of cardiac sympathetic nerves (10); this modification often accompanies progressive heart failure. In this regard, we have recently shown that chronic {beta}-adrenoreceptor ({beta}-AR) activation promotes the development of a rightward shift in left ventricular (LV) diastolic P-V relations and the development of cardiac pump dysfunction (2, 24). In the absence of intrinsic myocardial dysfunction, we have attributed the {beta}-AR-mediated alteration in pump function to a rightward shift in LV diastolic P-V relations (2). However, as previously reported (2, 24), the model of chronic {beta}-AR-mediated pump dysfunction is associated with a reduction in myocardial collagen cross-linking, which is a myocardial collagen change that is noted to occur in other forms of dilated cardiomyopathies (1, 8, 11, 19, 24). Importantly, diastolic P-V relations are well recognized as being determined by both changes in chamber geometry and size (chamber remodeling) as well as modifications in myocardial material properties (7). Moreover, reductions in the cross-linked properties of myocardial collagen are thought to be major determinants of cardiac chamber remodeling (1, 11, 19, 24) as well as myocardial material properties (9, 13, 14, 18). Intuitively, therefore, {beta}-AR-mediated rightward shifts in LV diastolic P-V relations could be the consequence of either chamber remodeling or modifications in myocardial material properties. We (2, 24) previously reported that chamber remodeling accounts for a portion of the {beta}-AR-mediated rightward shifts in LV diastolic P-V relations. However, what is not evident is whether rightward shifts in LV diastolic P-V relations are also the consequence of alterations in myocardial material properties and, if so, to what degree material property changes influence {beta}-AR-mediated increases in cavity volumes. In the present study, we sought to determine the relative contribution of adverse chamber remodeling vs. alterations in myocardial material properties toward rightward shifts in LV diastolic P-V relations mediated by chronic {beta}-AR-activation.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 APPENDIX
 GRANTS
 REFERENCES
 
The present study was approved by the Animal Ethics Screening Committee of the University of the Witwatersrand (approval numbers 99:01:2b, 2002:37:5, and 2002:39:5).

Groups, treatment regimen, and blood pressure. The rodent model studied was that induced by chronic administration of the {beta}-AR agonist isoproterenol (Iso) to spontaneously hypertensive rats (SHRs) with compensated LV hypertrophy (LVH) (2). Rats with compensated LVH were used in this study because rats without LVH are relatively insensitive to {beta}-adrenergic-induced changes in LV diastolic and systolic P-V relations (2). Twelve-month-old SHR and age-matched Wistar-Kyoto (WKY) control animals were randomized and subsequently studied over a time period (12–19 mo of age) before that when LV decompensation occurs in SHRs (21). SHRs were assigned to groups that received either no treatment for 7 mo or twice daily intraperitoneal injections of the {beta}-AR agonist Iso (Imuprel; Adcock Ingram; 0.02 mg·kg–1·injection–1 ~0.2 ml) for 7 mo. Twelve-month-old WKY rats were left untreated for 7 mo before data collection was performed. Iso was not given to WKY rats, because we have previously shown (2) that Iso has little effect on LV geometry and function in WKY control rats. In the present study, systolic blood pressure (SBP) was noninvasively assessed on three separate occasions in each group using a previously described tail-cuff technique (14).

Echocardiography. A week before rats were killed and ~24 h after the preceding dose of Iso, echocardiography was performed using a 7.5-MHz transducer and a Hewlett-Packard Sonos 2000 sector scanner as previously outlined (4, 15, 24). The LV internal dimension and wall thickness were measured according to the American Society for Echocardiography's leading-edge method (17). Measurements were made from three consecutive beats, and endocardial and midwall fractional shortening (FSend and FSmid, respectively) values were determined as previously described (4, 15). LV FSend and FSmid values were used as indexes of chamber and myocardial functions, respectively (4, 15).

Ex vivo studies. LV remodeling as well as load-independent measures of systolic and diastolic chamber and myocardial functions were determined ex vivo under controlled conditions as previously outlined (1, 2, 15, 24) (see APPENDIX for a summary of equations used). Briefly, rats were anesthetized with ketamine and xylazine (1, 2, 15, 24) ~24 h after the last dose of Iso, hearts were immediately excised and mounted on an isolated, perfused heart preparation, and LV developed pressures and LV end-diastolic pressure (LVEDP) were determined over a range of filling volumes (1, 2, 15, 24). Hearts were perfused retrogradely at a constant flow (12 ml·min–1·g–1 of wet heart wt) with physiological saline solution at 37°C gassed with 95% O2-5% CO2 and were paced at 360 beats/min with platinum electrodes attached to the right atrium and the apex of the heart. LV pressures were determined at as many multiple small increments in volume as were practically possible by use of a water-filled, balloon-tipped catheter. LV pressures were determined at incremental volumes in the absence of an inotropic stimulus and then after exposure of the heart to 10–7 M Iso, which was added to the perfusate to assess adrenergic inotropic reserve. LVEDP-volume relations were constructed to assess LV diastolic function. LV remodeling was evaluated by comparing LV volumes (LVV) obtained at an LVEDP of 0 mmHg (LV V0; Refs. 1, 2, 15, and 24) as well as by assessing the LVED wall thickness-to-radius ratio (h/r) at incremental filling pressures and subsequently calculating the LVED h/r intercept at 0 mmHg. LVED h and r were calculated from previously described formulae (22, 23). Myocardial material properties were assessed from diastolic stress-strain relations (1) whereby myocardial stiffness was determined from the slope of the diastolic stress-strain relation (myocardial k). Load-independent measures of intrinsic systolic myocardial function were assessed by constructing LV developed stress-strain relations and comparing the slope of the relation (En, intrinsic myocardial elastance) (2, 15). Both LV developed and diastolic stress and strain values were calculated using previously described equations (22).

Myocardial collagen. Samples of LV tissue were weighed and stored at –70°C before tissue analysis was performed. Myocardial hydroxyproline concentration ([HPRO]) values were determined after acid (HCl) hydrolysis (13, 20). Myocardial collagen was also extracted and digested (12, 14) with cyanogen bromide (CNBr). A portion of the CNBr-digested collagen sample was subjected to acid hydrolysis and [HPRO] determination. The amounts of non-cross-linked (soluble) and cross-linked (insoluble) collagen in the myocardium were determined from the solubility of myocardial collagen to CNBr digestion (14). Myocardial type I-to-type III collagen ratios and type I and type III collagen concentrations were determined from the remaining portion of the CNBr-digested samples using polyacrylamide gel electrophoresis (14).

Pathological scores. Before storing tissue for biochemical assessment, we obtained a longitudinal slice of the left ventricle from the apex to the base through the LV free wall from all rats for histology. LV tissue was stored, prepared, and sectioned as previously described (2, 21, 24) and was stained with Van Gieson stain. The degree of myocyte necrosis was determined from each slice (21), where grade 0 indicates no histological evidence of fibrosis; grade 1, patchy fibrosis in one to five areas (<20% of the field); grade 2, patchy fibrosis in >20% of the field; grade 3, diffuse, contiguous subendocardial fibrosis in <50% of the field; grade 4, diffuse, contiguous subendocardial fibrosis in >50% of the field; grade 5, transmural fibrosis in <50% of the field; and grade 6, transmural fibrosis in >50% of the field.

Data analysis. Regression analysis was used to determine the lines of best fit for the cardiac function and other relations. Differences in LV weight, internal dimensions, and relative wall thickness and indexes of LV performance, myocardial collagen biochemical analyses, and myocardial fibrosis between groups were assessed by a one-factor ANOVA followed by Tukey's post hoc test. All values in the text are represented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 APPENDIX
 GRANTS
 REFERENCES
 
Blood pressure and heart weight. SHRs had markedly greater SBP compared with WKY control animals (i.e., at 19 mo of age: SHR untreated, 182 ± 8 mmHg; WKY, 136 ± 6 mmHg; P < 0.001). Iso failed to significantly modify SBP (SBP for SHRs at 19 mo of age given Iso, 178 ± 4 mmHg). An increase in LV weight was noted in SHRs compared with WKY control animals (Table 1). Daily administration of Iso tended to augment the increase in LV weight noted in SHRs (Table 1).


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  		Table 1. Effects of chronic Iso administration on LV weight, dimensions, and performance as assessed in vivo in SHRs

 
LV dimensions assessed in vivo. As assessed using echocardiography, SHRs at 19 mo of age had similar LVED internal diameter (LVEDD) measurements compared with WKY control animals (Table 1). However, SHRs that received Iso from 12 to 19 mo of age (Table 1) had increases in both LVEDD and LV end-systolic internal diameter (LVESD) measurements compared with WKY control animals and untreated SHRs (Table 1).

LV diastolic P-V relations. Untreated SHRs at 19 mo of age had similar LVV-LVEDP relations and LV V0 values compared with WKY control animals (Fig. 1). However, Iso administered to SHRs for 7 mo resulted in a rightward shift in the LVV-LVEDP relation with an increase in LV V0 (Fig. 1).



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  		Fig. 1. Effects of chronic administration of isoproterenol (Iso) on left ventricular (LV) volume-LV end-diastolic pressure (LVV-LVEDP) relations (A) and LVV at an LVEDP of 0 mmHg (LV V0; B) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto control animals (WKY). See Table 1 for sample sizes. *P < 0.01 vs. other groups.

 
LV diastolic relative wall thickness. Consistent with concentric LV hypertrophy, untreated SHRs at 19 mo of age had increased LVED h/r (relative wall thickness) values compared with age-matched WKY control animals (Fig. 2). However, chronic Iso administration to SHRs resulted in relative wall thinning with marked decreases in LVED h/r noted over a range of LVEDP values (Fig. 2) despite additional increases in LV weight (Table 1).



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  		Fig. 2. Effects of chronic Iso administration on LVEDP-relative wall thickness (h/r, LVED wall thickness-to-radius ratio) relations (A) and the LVED h/r intercept at 0 mmHg (B) in SHRs. *P < 0.01 vs. other groups.

 
Myocardial diastolic stiffness. SHRs at 19 mo of age had a marked leftward shift in LV diastolic midwall stress-strain relations and an increase in the slope (myocardial k) of these relations compared with WKY rats (Fig. 3). Chronic Iso administration to SHRs failed to modify either LV diastolic midwall stress-strain relations or myocardial k values (Fig. 3).



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  		Fig. 3. Effects of chronic Iso administration on LVED midwall stress-strain relations (A) and the slope (k) of the linearized midwall stress-strain relation (myocardial stiffness; B) in SHRs. *P < 0.01 vs. other groups.

 
Systolic function. As assessed both in vivo (Table 1, LV FSend) and ex vivo (Fig. 4B), chamber systolic function (pump function) was largely maintained in untreated SHRs at 19 mo of age. However, chronic Iso administration to SHRs promoted a decrease in chamber systolic function as assessed both in vivo and ex vivo.



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  		Fig. 4. Effects of chronic Iso administration on LV developed pressure (LVdev pressure)-LVV relations (A) and the mean slope of the relations (B), which represents systolic chamber function (E) in SHRs. *P < 0.01 vs. other groups.

 
Myocardial systolic function assessed in vivo (LV FSmid) was maintained in both SHRs and in SHRs that received Iso compared with WKY control animals (Table 1). Similarly, as assessed ex vivo, intrinsic myocardial systolic function (En in the presence or absence of an adrenergic stimulus) was unchanged in SHRs at 19 mo of age regardless of whether Iso had been administered chronically (Fig. 5 includes data obtained in the absence of an adrenergic stimulus).



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  		Fig. 5. Effects of chronic Iso administration on LV developed stress-LV strain relations (A) and the mean slope of the relations, which represents systolic myocardial function (En; B) in SHRs. There are no differences between groups.

 
Myocyte necrosis. Myocardial necrosis as determined from a pathological score was noted to occur in untreated SHRs compared with WKY control animals (Table 2). Iso administration tended to additionally increase the degree of myocardial fibrosis in SHRs, but this failed to achieve statistical significance (Table 2).


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  		Table 2. Effects of chronic Iso administration on myocyte necrosis and myocardial collagen characteristics of left ventricle in SHRs

 
Myocardial collagen. An increase in myocardial [HPRO] and a decrease in the percent of myocardial [HPRO] solubility occurred in untreated SHRs. As a consequence of myocardial solubility changes in untreated SHRs, only insoluble (cross-linked) myocardial collagen concentrations contributed to the increase in total [HPRO] (Table 2). Iso administered to SHRs resulted in an additional increment in myocardial [HPRO] but also increased the percent solubility of myocardial collagen (Table 2). Consequently, changes in soluble (noncross-linked) but not insoluble myocardial collagen concentrations occurred in response to Iso administered to SHRs (Table 2).

As compared with WKY control animals, SHRs at 19 mo of age had no change in the ratio of type I to type III myocardial collagen (Table 2). Moreover, Iso failed to modify type I-to-type III myocardial collagen ratios in SHRs. Consequently, both types I and III myocardial collagen concentrations were increased in SHRs, and Iso resulted in additional increments in both subtypes (Table 2).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
APPENDIX
 GRANTS
 REFERENCES
 
The main findings of the present study are as follows. Consistent with data obtained in younger SHRs (2), chronic administration of a {beta}-AR agonist to older SHRs promoted an increase in LV cavity dimensions in association with a rightward shift in LV diastolic P-V relations. As intrinsic myocardial systolic function was preserved, a reduction in pump function was noted to occur subsequent to chronic {beta}-AR agonist administration and was attributed to an increase in LV cavity dimensions. With respect to the mechanism of the altered diastolic P-V relation, although chronic {beta}-AR agonist administration to SHRs resulted in the accumulation of myocardial collagen with a relatively low tensile strength (non-cross-linked myocardial collagen concentrations), this collagen change failed to modify diastolic myocardial material properties (myocardial stiffness). The {beta}-AR agonist-induced rightward shift in the LV diastolic P-V relations was therefore attributed to adverse chamber remodeling as confirmed by increases in the volume intercept of the LV diastolic P-V relation and reductions in LV relative wall thickness.

The present data are largely consistent with data published after the use of an LV assist device (LVAD) in patients with dilated cardiomyopathy (3). Whereas patients with dilated cardiomyopathy have a rightward shift in the LV diastolic P-V relation, implantation of an LVAD produces a marked leftward shift in LV diastolic P-V relations to control values; this alteration is attributed to reverse remodeling and not to alterations in myocardial material properties (3). LVAD-induced reverse remodeling suggests that the rightward shift in LV diastolic P-V relations noted to occur in dilated cardiomyopathy could be attributed to alterations in remodeling rather than to passive myocardial properties. Importantly, however, reverse remodeling after LVAD use does not modify the markedly reduced wall thickness-to-radius ratio that is noted in patients with dilated cardiomyopathy (3). It is therefore questionable whether reductions in cavity size after the use of an LVAD truly represent the "reverse" of the mechanisms involved in producing the initial increments in cavity size that are noted to occur during the development of a dilated cardiomyopathy. Nevertheless, data obtained in the present study provide additional evidence to indicate that the evolution of increases in cavity volume in cardiac disease involve adverse remodeling and not modifications in myocardial material properties. The model of increased cavity volumes studied by us is particularly relevant, as it is well recognized that chronic {beta}-AR activation occurs in chronic heart failure and contributes to increases in cavity volumes and that {beta}-AR blocking agents reduce cardiac cavity volumes in chronic heart failure (5, 16).

There is sufficient evidence to indicate that the cross-linked properties of myocardial collagen determine myocardial material properties and that increased cross-linking produces collagen with a high tensile strength (9, 13, 14, 18). Therefore, the question arises as to why chronic {beta}-AR activation, which results in increased concentrations of myocardial collagen in the non-cross-linked form in either younger (2) or older SHRs (the present study), do not modify myocardial material properties. Insights into an answer to this question may be obtained from data obtained in even older SHRs (1). Importantly, in older SHRs at 21–22 mo of age, although a rightward shift in LV diastolic P-V relations is noted, myocardial stiffness is maintained at a considerably higher level than in normotensive control animals despite the accumulation of myocardial collagen in the non-cross-linked form (1). We previously attributed the increased myocardial stiffness in SHRs to an initial increase in myocardial collagen of the cross-linked form, which is a change that occurs well before the onset of heart failure and is maintained in older animals (1, 14). Similarly, in the present study, SHRs not receiving Iso had a marked increase in myocardial collagen of the cross-linked form, and this change was sustained in SHRs that received Iso. Hence, not surprisingly, myocardial stiffness was maintained in SHRs that received Iso, because the amplified quantity of cross-linked collagen that purportedly mediates an increased myocardial stiffness (1, 14) was preserved.

In the present study, alternative changes in the qualitative characteristics of myocardial collagen mediated by chronic {beta}-AR agonist administration could have offset the impact of an accumulation of myocardial collagen in the non-cross-linked form on myocardial stiffness. In this regard, myocardial collagen type I-to-type III ratios were previously suggested (12) to influence myocardial stiffness in SHRs. However, in the present study, chronic {beta}-AR agonist administration to SHRs produced an equivalent percentage increase in type I compared with type III collagen. Nevertheless, an increased concentration of the stiffer collagen phenotype, namely, type I collagen, could have been sufficient to counteract the accumulation of non-cross-linked collagen and hence maintain the elevated myocardial stiffness that characterizes SHRs.

It may be argued that {beta}-AR-mediated rightward shifts in LV diastolic P-V relations in hypertensive LVH could be beneficial, because heart failure in hypertension may be the outcome of a leftward shift in LV diastolic P-V relations following both concentric LV remodeling and a stiffer myocardium (6). However, as clearly demonstrated in the present study, pump function is reduced after chronic {beta}-AR activation, and this effect is attributed to adverse remodeling and not to intrinsic myocardial systolic dysfunction.

A potential limitation of the present study is that we did not assess myocardial stiffness in SHRs at various time intervals during the administration of the {beta}-AR agonist. It may be argued that myocardial stiffness changes are the early modifications that mediate rightward shifts in LV diastolic P-V relations after chronic {beta}-AR activation, and that these alterations ultimately translate into adverse geometric remodeling. However, there are no data to support this supposition. Furthermore, the myocardial collagen changes that could have mediated a reduced myocardial stiffness (increased myocardial collagen of the non-cross-linked form) after chronic {beta}-AR activation were clearly evident in the present study. Consequently, in the present study, it is reasonable to have expected to identify material property changes at the time that these were measured.

In conclusion, the present study indicates that despite inducing the accumulation of myocardial collagen with a low tensile strength (noncross-linked collagen), chronic {beta}-AR activation mediates rightward shifts in LV diastolic P-V relations with subsequent pump dysfunction through adverse chamber remodeling rather than through alterations in myocardial material properties. The impact of LV cavity dimensions on pump function in the present study underscores the need to identify those factors responsible for the adverse remodeling process.


   APPENDIX
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX
GRANTS
 REFERENCES
 

where LVED is left ventricular (LV) end-diastolic pressure, r is is radius, and LVEDV is LV end-diastolic volume.

where h is wall thickness.

where LVEDD is LV end-diastolic diameter.


where V0 is volume at 0 mmHg.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 GRANTS
REFERENCES
 
This research was supported by the University Research Council of the University of the Witwatersrand and the Medical Research Council of South Africa. A. J. Woodiwiss was the recipient of the Friedel Sellschop Research Award.


   ACKNOWLEDGMENTS
 
The authors are grateful to Adcock Ingram for the generous donation of Imuprel for this study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. J. Woodiwiss and G. R. Norton, Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Univ. of the Witwatersrand Medical School, 7 York Rd., Parktown, 2193 Johannesburg, South Africa (E-mail: woodiwissaj{at}physiology.wits.ac.za)

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.

* M. Gibbs and D. G. A. Veliotes contributed equally to this work. Back


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 GRANTS
 REFERENCES
 

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