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1 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; 2 The Water and Salt Research Center, Department of Physiology, Faculty of Medicine, University of Aarhus, 8000 Aarhus C, Denmark; 3 Department of Clinical Pathology, McDonald Research Laboratories, The iCAPTURE Center, St Paul's Hospital, Vancouver, British Columbia, Canada V62 1Y6; 4 Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262; and 5 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypertrophic cardiac myopathy
(HCM) is the leading cause of mortality in young athletes.
Abnormalities in small intramural coronary arteries have been observed
at autopsy in such subjects. The walls of these intramural vessels,
especially in the ventricular septum, are thickened, and the lumen
frequently appears narrowed. Whether these morphological
characteristics have functional correlates is unknown. We studied
coronary myogenic tone in a transgenic mouse model of HCM that has
mutations in the cardiac 
-myosin heavy chain gene. This transgenic
mouse has a cardiac phenotype that resembles that occurring in humans.
We examined the possible vascular contributions to the pathology of
HCM. Septal arteries from 3- and 11-mo-old wild-type (WT) and
transgenic (TG) mice were studied on a pressure myograph. The myogenic
response to increased intravascular pressure in older animals was
significantly reduced [maximal constriction: 32 ± 4% (TG) and
46 ± 4% (WT), P < 0.05]. After inhibition of
endothelin receptors with bosentan, both WT and TG mice had similar
increases in myogenic constriction. The sensitivity to exogenous
endothelin was significantly reduced in TG mice, suggesting that the
reduced myogenic constriction in HCM was due to reduced receptor
sensitivity. In conclusion, we show for the first time that
1) myogenic tone in the coronary septal artery of the mouse
is regulated by a basal release of endothelin, and 2)
pressure-induced myogenic activation is attenuated in HCM, possibly
consequent to a reduction in endothelin responsiveness. The associated
reduction in coronary vasodilatory reserve may increase susceptibility
to ischemia and arrhythmias.
sudden cardiac death; acetylcholine; endothelin; myogenic tone
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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HYPERTROPHIC CARDIAC MYOPATHY (HCM),
first described in 1958, is the most frequent cause of sudden cardiac
death in young athletes, with an estimated incidence of 1:200,000
athletes (1, 11, 12). Estimates of HCM can be as high as
5% of young athletes based on data from tertiary referral centers
(15). It is usual for sudden cardiac death to be the first
sign of undiagnosed HCM. Significant myocyte hypertrophy, myofibrillar
disarray, increased interstitial collagen, intramyocardial vessel
thickening, and arrhythmias characterize HCM (3).
Abnormalities in small intramural coronary arteries (external diameter
1,500 µm) are frequently (incidence of 80%) found at autopsy in
subjects with HCM. The walls of these intramural vessels, often found
in the ventricular septum, are thickened by smooth muscle cells and
matrix, and their lumens frequently appear narrowed (14,
19). Several genetic mutations cause HCM, with the most common
gene responsible for human HCM being the 
-myosin heavy chain (MHC),
accounting for 35-50% of HCM cases (22).
A murine model of human HCM containing an arginine-to-glutamine
missense mutation at amino acid position 403 R403Q in -MHC and a
deletion in the actin-binding domain is phenotypically identical to the
human disease. In rodents, virtually all of the MHC protein is of the
-isoform. These animals develop myocardial and myocellular hypertrophy by 4 mo of age and in males progress to end-stage disease
by 10-12 mo of age. In addition, these animals express increased
levels of atrial natriuretic factor and -skeletal actin, several
markers of cellular hypertrophy. Perhaps most relevant to the current
study is the decrease in coronary flow per milligram of cardiac tissue
noted on Langendorff perfusion when mutant mice are compared with
10-mo-old wild-type controls (17). In the clinical heart
failure population, there is evidence of abnormal vascular function in
both endothelium-dependent and acetycholine-stimulated vasodilatation
(5) as well as from endothelin-related vasoconstriction (9). In this animal model, it is unclear whether the
coronary flow changes are intrinsic to the vascular system or
secondary to the myocellular disease.
As noted, the majority of human HCM is due to familial autosomal
dominant transmission of mutations in sarcomeric proteins (22,
23). There is a smaller population of de novo mututions that
cannot be traced via family history. Over 100 mutations in more than 10 genes encoding sarcomeric proteins have been identified in patients
with HCM. Approximately two-thirds of these mutations occur in -MHC,
accounting for the most prominent fraction of the affected population
(10). One of these mutations is R403Q. In patients, this
mutation is associated with the histopathological changes noted above
as well as with premature sudden death.
The vascular contribution to ventricular pathophysiology in HCM is unknown. To this end, we investigated the myogenic properties of the small septal coronary arteries in wild-type and mutant MHC mice to determine whether the genetic defect in the cardiac sarcomeres and associated myocardial thickening could be accompanied by functional consequences in vascular smooth muscle cells and the endothelium.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
The transgenic (TG) mouse model of familial HCM used in this study has been described previously. In short, these TG mice express a mutant-MHC with the expression driven by a rat -MHC promoter.
The transgene coding region contains two mutations: a point mutation
(R403Q) and a deletion of 59 amino acids in the actin-binding site of
the -MHC bridged by an addition of 9 nonmyosin amino acids. The
mutant -MHC protein constitutes up to 10-12% of the total
myosin in the TG mice (20, 21). Polymerase chain reaction-amplified tail DNA was used to genotype the heterozygous TG
mice and their non-TG wild-type littermates in this study. The animals
were maintained under specific pathogen-free conditions with food and
water ad libidum. The Institutional Animal Use and Care Committee of
the University of Colorado (Boulder, CO) and University of British
Columbia (Vancouver, British Columbia, Canada) approved all animal protocols.
Male mice that were genotyped as either wild-type or TG were used. To examine the evolution of potential vascular dysfunction in hypertrophic cardiomyopathy, coronary septal arteries were examined at two time points, the first when the mice were between 10 and 16 wk old (referred to as 3 mo old), and the second when the mice were between 46 and 50 wk old (referred to as 11 mo old).
Vessel Isolation and Cannulation
Each mouse was anesthetized with pentobarbital sodium (Somnotol; 30 mg/kg ip) and heparin sodium (Hepalean; 500 U/kg ip). The animals were euthanized, and the heart was removed. The beating heart was placed in physiological salt solution (PSS) at 4°C. The right ventricular cavity was exposed, and the coronary septal artery was carefully dissected and transferred to an arteriograph filled with oxygenated PSS. The arteriograph contained two cannulas (tip diameter 40 ± 5 µm), both filled with oxygenated PSS. The distal cannula was occluded so that experiments were made under conditions of no flow. The proximal cannula was connected to a pressure servosystem (Living Systems; Burlington, VT). The artery was first mounted on the proximal cannula and tied with a single strand of braided 4-0 silk suture (diameter: 15 µm) and carefully emptied of residual blood. The free end of the vessel was then mounted and tied to a distal closed-off cannula. Vessels were checked for leaks, and only vessels without leaks were used for further experiments. After the septal coronary arteries were dissected, the hearts were weighed, and the apex was cut and frozen in OCT compound, whereas the rest of the heart was preserved in formalin for further histopathology.The PSS in the vessel chamber was recirculated continuously at a flow rate of 20-30 ml/min. The PSS was stored in an external reservoir where it was bubbled with a gas mixture containing 95% O2-5% CO2. The PSS was circulated via a double-jacketed heating coil placed in line from the external reservoir allowing the temperature in the chamber to be maintained at 36.5 ± 0.5°C. The pH in the arteriograph was 7.4 ± 0.05.
After the artery was mounted, the myograph was placed on the stage of an inverted microscope, and the vessel was observed through a videocamera attached to the microscope. Inner diameter and wall thickness were obtained by using a Video Dimension Analyzer (Living Systems). All data were saved cumulatively on a computer. The inner diameter and the wall thickness were measured at a pressure of 10 mmHg after the vessel had acclimatized at 37°C for 15 min.
Pressure-Diameter Responses and Dilator Responses
To obtain a pressure-diameter curve, the intraluminal pressure was increased in 10-mmHg increments, and a 5-min period allowed each vessel to reach a new steady-state diameter. In the 3-mo-old mice, the pressure was increased until a maximum pressure of 120 mmHg; in the 11-mo-old mice, the maximum pressure was only 80 mmHg. After the pressure-diameter curve was obtained, the pressure was maintained at 80 mmHg and each vessel rested for 30 min. During this time, the vessel diameter spontaneously reduced and was maintained at a new value representing pressure-induced vasoconstriction. Cumulative concentration-response curves to 10
9-105 M ACh and
108-105 M sodium nitroprusside (SNP)
were made by addition of these agents to the external reservoir and by
allowing 5-min periods between successive additions.
After an initial concentration-response curve to ACh, tissues from the
11-mo-old mice were incubated with 106 M of the
dual-endothelin receptor (ETA/ETB) antagonist
bosentan for 60 min. A second pressure-diameter curve was obtained,
starting at a pressure of 10 mmHg and increasing by 10-mmHg increments until a maximum pressure of 80 mmHg was reached. Also, here the vessel
was given a 5-min resting period between each increment, allowing the
vessel to reach a new steady-state diameter. At the end of each
experiment, tissues were exposed to calcium-free PSS to obtain the
maximal passive diameter of each artery.
Constrictor Responses
Cumulative concentration-response curves to KCl (8-114 mM) or endothelin-1 (1011-108 M) were also
obtained. These data were obtained from vessel segments set at 30 mmHg,
a pressure below the threshold for myogenic activation. Thus
constrictor responses were made in the absence of resting tone.
Cumulative concentration-response curves were made to these agents,
with additions made at 5-min intervals to allow for new equilibriums.
At the end of each experiment, tissues were exposed to calcium-free PSS
to obtain the maximal passive diameter of each artery.
Morphometric Analysis of Hypertrophic Hearts
Hearts from TG and wild-type mice were harvested, formalin fixed, and paraffin embedded. With the use of the software Image Pro Plus, ventricular transverse sections of TG and wild-type hearts stained with Masson's trichrome were used to visualize fibrosis. A color segmentation file was created that recognized light blue staining, and this was used to determine the fibrous area (mm2) in the myocardium. The total area of light blue staining was quantified and divided by the total cross-sectional area of the heart to obtain the percent area of fibrous tissue.Expression of Results
Vessel constriction in the pressure-diameter curves was expressed as 100% × [(DCa free
DPSS)/DCa
free], where D is the intraluminal diameter in
Ca2+-free PSS or standard PSS. Vessel dilation was
expressed as 100% × (Dconcn of
drug/ DCa free).
Vessel constriction for the agonist stimulation was expressed as
100% × (DPSS Dconcn of
drug)/(DPSS Dhighest drug concn). The effect of bosentan on
the myogenic tone was expressed as percent constriction at 80 mmHg
minus percent constriction at 80 mmHg with bosentan.
Statistics
All results are expressed as means ± SE, and the statistical analysis was made by unpaired Student's t-test. P < 0.05 was considered significant. All statistical analysis was made with GraphPad Prism 3.02 (GraphPad Software).Solutions and Chemicals
The composition of the standard PSS was (in mM) 120 NaCl, 4.7 KCl, 1.18 KH2PO4, 0.57 MgSO4 · 7H2O, 24.9 NaHCO3, 1.6 CaCl2, and 11.1 glucose. Ca2+-free solution was PSS with no CaCl2 containing 2.0 mM EGTA. In a K+-rich solution, Na+ was substituted by an equimolar concentration of K+ to make a 60 mM K+ solution. ACh chloride, SNP, and endothelin-1 were all obtained from Sigma Chemical (St. Louis, MO). Bosentan was a gift from Actelion Pharmaceuticals (Allschwil, Switzerland).| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Morphological Measurements
Heart and body weight.
Male TG mice at 3 mo of age showed an increase in the heart weight
(Fig. 1), resulting in an increase in
heart weight-to-body weight ratio (P < 0.05, Fig. 1).
Although there was no significant difference in absolute heart weight
of the TG and wild-type mice at the age of 11 mo, they too showed an
increased heart weight-to-body weight ratio (P < 0.05, Fig. 1).
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Arterial thickness.
Coronary septal artery wall thickness and internal diameters were
obtained from 3- and 11-mo-old mice while the arteries were mounted in
the mygoraph at a pressure of 10 mmHg. As shown in Table
1, there were no significant differences
in wall thickness or internal diameter as a function of age or genetic
background (P > 0.05).
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Fibrosis of myocardium.
The TG mice showed a significant increase in myocardial fibrosis at 11 mo with 4.7 ± 0.4% compared with their wild-type littermates, who only showed 3.17 ± 0.2% fibrosis (P < 0.05, Fig. 2).
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Vascular Function in 3-Mo-Old Mice
Constriction.
MYOGENIC REACTIVITY. The myogenic response due to
increased transmural pressure was examined in coronary septal
resistance arteries. When the intraluminal pressure was increased,
arteries spontaneously developed tone in PSS. In coronary arteries
taken from 3-mo-old mice, the maximal vasoconstriction was 40.8 ± 3% in wild-type mice compared with 34.6 ± 6.7% in TG mice at an
intraluminal pressure of 80 mmHg (Fig.
3).
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11-108 M endothelin-1 were studied
in coronary septal arteries at 30 mmHg. There were no differences in
the endothelin-induced vasoconstriction, and no difference in
sensitivity was observed when wild-type and TG mice were compared
(Table 2 and Fig. 4).
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Dilation.
SODIUM NITROPRUSSIDE. Coronary septal arteries with
spontaneous myogenic tone (80 mmHg) dilated to
108-105 M of the nitric oxide donor
SNP. The response to SNP was similar in arteries from TG and wild-type
mice (Table 2).
9-105 M ACh and vasodilatation
recorded. There were no differences between TG and wild-type mice
(Table 2).
Vascular Function in 11-Mo-Old Mice
To determine whether age is an important factor in the pathophysiological state and development of hypertrophic cardiomyopathy, a series of experiments was performed on 11-mo-old animals.Constriction. MYOGENIC REACTIVITY. The myogenic response in 11-mo-old TG mice is impaired. The onset of myogenic tone occurs at similar transmural pressures in arteries from both wild-type and TG mice, but the TG mice are not able to develop as powerful a myogenic response as their wild-type littermates. The 11-mo-old TG mice reached a maximum constriction of only 32.3 ± 3.6% compared with 45.8 ± 4.0% in their wild-type littermates at a transmural pressure of 80 mmHg (P < 0.05, Fig. 3B). After incubation of the endothelin dual-receptor antagonist bosentan, the myogenic response in both wild-type mice and TG mice was substantially inhibited. The myogenic response was now 11.9 ± 1.7% in the wild-type mice and 11.3 ± 2.7% in the TG mice at a pressure of 80 mmHg (P > 0.05, Fig. 3B).
POTASSIUM . Exposing the coronary septal arteries to KCl (8-84 mM) resulted in a similar response at maximal concentration of KCl, but a slight difference was seen in pD2 (P < 0.05) when TG mice were compared with their wild-type littermates (Table 2). ENDOTHELIN . When arteries from the 11-mo-old mice were exposed to 1011-108 M endothelin-1, both
wild-type and TG mice showed constriction, but the TG mice showed an
impaired sensitivity to endothelin-1 with a pD2 = 8.8 ± 0.4 compared with a pD2 = 10.3 ± 0.3 in the wild-type littermates (P < 0.05) (Fig. 4).
Dilation.
SODIUM NITROPRUSSIDE. The maximum
dilation of the coronary septal arteries in the 11-mo-old mice to
108-105 M of the nitric oxide donor
SNP was similar in the TG mice compared with their wild-type
littermates, and there were no differences in pD2 either
(Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of the study was that in 11-mo-old mice the pressure-induced response of isolated coronary small arteries was reduced in the TG mice compared with the wild-type mice and that this difference in responsiveness disappeared after treatment with the dual-endothelin receptor antagonist bosentan. These observations suggest that an abnormality in the physiology of the vascular endothelin system is present in the TG mice. To address the background for this, we investigated the responsiveness to exogenously applied endothelin and found a reduced responsiveness to endothelin. These results provide strong evidence for the possibility that the reduced pressure-induced response is reflecting a dependence on this response on vascular endothelin production and that a reduction of this responsiveness to endothelin is involved in the reduced pressure-induced response in the TG mice. The dependence of the pressure-induced response on the vascular endothelin system (presumably release of endothelin from the artery wall) confirms our previous observations in CD-1 mice (8) and extends thereon to the C57/BL6 mice used in this study. Others (2, 4, 16) have also reported a role for endothelin in the myogenic response in a number of laboratory animals as well as in humans (7).
In hypertensive animals, an abnormality of the vascular endothelin physiology has also been suggested to play a role (18). In hypertension, though, the system may be responsible for an enhancement of the pressure-induced response (2, 4). This is in contrast to the reduced responsiveness we report in coronary arteries from HCM (also known as TG) mice.
It is also of substantial importance to appreciate that apart from the change in myogenic tone, which could be ascribed to a change in endothelin responsiveness, there were no other differences between the coronary arteries from 11-mo (and 3 mo)-old mice. The responses to potassium were identical indicating that depolarization-induced contractility is unaffected, supporting the interpretation that the reduced response to endothelin is not the result of a general reduction of the contractility of smooth muscle. Furthermore, the responses to ACh and to SNP were identical in the two groups indicating that the endothelium, nitric oxide, cGMP axes were not affected.
To assess the time course for the development of the abnormality in the
vascular endothelin system, 3-mo-old mice were also investigated. The
observation that the pressure-induced response was not impaired in
3-mo-old HCM mice indicates that the vascular expression of the disease
may not be completely manifest until later in adulthood when growth and
development have occurred. In this regard, it is of interest that,
whereas coronary blood flow (in
ml · min1 · g
heart wt1) was similar in 3-mo-old wild-type and HCM
mice, there was a nearly 50% reduction of resting coronary blood flow
in HCM mice at 10 mo of age (17), and these data strongly
implicate a late development of vascular changes in this model of HCM.
The pathophysiological consequence of a reduced pressure-induced response may be important if coronary autoregulation is impaired in HCM. In particular, if a fall in coronary perfusion pressure does not lead to an appropriate reduction of vascular tone, an ischemic response may more easily be elicited. Of interest in this context are the findings of Krams et al. (6), who found that coronary resistance values in HCM patients were lower under resting conditions but similar to control patients during reactive hyperemia. Although this finding may have many explanations, it is also consistent with reduced pressure-induced tone of the coronary arteries in these patients. The reduced pressure-induced response would also tend to increase capillary pressure for a given change in blood pressure, potentially leading to edema formation in the heart. An aberrant vasoregulation may thus lead to ischemia and in part be responsible for the observation that many patients with HCM have small vessel coronary disease (13, 14, 19). It should be appreciated, though, that the in vitro experiments reported here are made in the absence of flow and without the influence of neural and hormonal input. Whereas this has some advantages, it also calls for caution in interpretation in terms of patophysiological importance in vivo.
The main finding in this study, that there is an abnormality in the endothelin physiology of the coronary arteries, which has consequences for the pressure-induced response in this model of HCM, leads to a number of new questions. Two very important questions that need to be addressed are 1) which part of the excitation-contraction coupling for endothelin is abnormal and 2) which mechanisms are of importance for the change in the endothelin responsiveness between the age of 3 and 11 mo? Our observations of a reduced pressure-induced response, which is bosentan sensitive, and a reduced responsiveness to exogenous endothelin thus provide evidence for an important aspect of the pathophysiology of HCM and provides the background for further intensive investigation.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the insightful comments of Dr. Mansoor Husain (Division of Cardiology, Toronto General Hospital and The Faculty of Medicine, University of Toronto).
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FOOTNOTES |
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This work was made possible by operating grants from the Canadian Heart and Stroke Foundation of British Columbia and Yukon (to I. Laher and B. M. McManus), the Danish Heart Foundation (to C. Aalkjaer and H. H. Petersen) and National Institutes of Health (to L. Leinwald and B. Stauffer).
Address for reprint requests and other correspondence: I. Laher, Dept. of Pharmacology and Therapeutics, Faculty of Medicine, Univ. of British Columbia, Vancouver, BC Canada V6T 1Z3 (laher{at}interchange.ubc.ca).
This article belongs to a collection of papers accepted in response to the Editor's special call for papers entitled "Mechanisms of vascular myogenic tone."
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.
August 29, 2002;10.1152/ajpheart.00606.2002
Received 25 July 2002; accepted in final form 19 August 2002.
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TOP
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METHODS
RESULTS
DISCUSSION
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G. Osol and J. Brayden Prologue: vascular myogenic mechanisms Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2157 - H2159. [Full Text] [PDF]
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