© 1995 American Heart Association, Inc.
Articles |
Peripheral Vascular Alterations During Experimental Heart Failure in the Rat
Do They Exist?
From the Departments of Pathology (S.H., P.J.J.W.A., J.W.A., M.J.A.P.D.) and Pharmacology (P.J.A.L., J.F.M.S.), Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, Netherlands.
Correspondence to Dr M.J.A.P. Daemen, Department of Pathology, University of Limburg, PO Box 616, 6200 MD, Maastricht, Netherlands.
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Abstract |
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Abstract Structural changes of the peripheral vascular component as seen during hypertension and atherosclerosis have been suggested during heart failure but have never been reported. Therefore, we studied possible structural alterations in the peripheral vasculature in an experimental model of heart failure, induced by ligation of the left coronary artery in rats. Large conduit and resistance-type arteries were excised at 1, 3, 5, and 12 weeks after myocardial infarct induction (MI) or sham surgery. Vessel dimensions (medial cross-sectional area [CSA], internal and external diameters, and media-to-lumen ratios) as well as medial collagen and elastin volume fractions were measured by computerized morphometry. The hydroxyproline assay was used to determine collagen and elastin content biochemically. In separate groups of animals, peripheral tissue flows were measured by using radioactive microspheres 5 and 12 weeks after MI. To evaluate the effects of the degree of heart failure, the animals of the 12-week group (n=10) were subdivided into groups of moderate (<45% infarct size) and large (>45% infarct size) infarction. At all time points, body weights of sham-operated and MI rats were comparable. Lung weights of infarcted animals were increased proportionally to infarct size. No major changes in vessel dimensions were seen at the earlier time points. Twelve weeks after coronary artery ligation, significantly smaller CSAs were observed in several large conduit arteries such as the thoracic aorta, carotid artery, and superior mesenteric artery. These changes coincided with reductions in both internal and external diameters. In contrast, internal and external diameters of mesenteric and pulmonary resistance arteries were increased after 12 weeks of coronary artery ligation. The medial CSAs of these resistance arteries showed a tendency to increase. Collagen and elastin volume fractions of the large conduit arteries were comparable in both sham-operated and MI animals during the entire experimental period. This latter observation was confirmed by the results of the hydroxyproline assay, which showed no differences in collagen and elastin content. In general, no major changes could be observed in the absolute blood flow to peripheral tissues measured in resting conditions at 5 and 12 weeks after coronary artery ligation. The data indicate that MI induces diverse adaptive changes in the vascular system. Medial CSAs and internal and external diameters of large conduit arteries of MI-operated animals are smaller 12 weeks after infarction. These parameters show a tendency to increase in resistance-type arteries.
Key Words: heart failure • myocardial infarction • rat • vascular structure • extracellular matrix
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Introduction |
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Changes in the structure of the vascular wall have received ample attention in hypertension research. Increases in wall thickness have been reported both in large conduit arteries and resistance arterioles (reviewed in References 1 and 21 2 ). This increase in wall thickness is the result of hypertrophy (in large vessels) or hyperplasia (in small vessels) as well as changes in ECM content. Both the absolute collagen and elastin contents increase3 without a change in relative volume fractions, indicating little change in the composition of the vascular wall.4 Structural changes of the vessel wall are also seen in other cardiovascular diseases such as atherosclerosis5 and restenosis after balloon angioplasty.6 The magnitude and role of possible structural changes in another cardiovascular disease, heart failure, are unknown.
Functional peripheral vascular alterations have been reported both in patients and in animal models for heart failure and consist of an increased resistance due to excessive vasoconstriction.7 8 Maximal vasodilator capacity of various peripheral vascular beds is decreased,9 10 probably caused by increased vascular stiffness, due to increased arterial sodium content.11 The distensibility of the aorta is also markedly reduced in patients with coronary artery disease.12 These functional vascular changes are thought to be partly related to the observed reduction in blood flow to peripheral tissues in rest and during exercise.13 14
Analogous to what is seen during hypertension, structural remodeling has been suggested as a possible mechanism for the above-described changes in vascular resistance and distensibility during heart failure (reviewed in References 15 and 1615 16 ). However, there are to our knowledge no studies documenting such structural changes. Also, data on the time course of possible structural changes in the vasculature during heart failure are lacking.
In this study we determined possible structural vascular alterations in experimental heart failure in the rat produced by coronary artery ligation. At specified times, several large conduit and resistance arteries were excised, and vessel dimensions (including medial CSAs, IDs and EDs, and media-to-lumen ratios) and collagen and elastin volume fractions were measured by histological staining methods and computerized morphometry. The hydroxyproline assay was used to determine the collagen and elastin content biochemically. This study provides evidence for structural alterations of the peripheral vasculature in an experimental model of heart failure, which were, however, present only at the later time points examined and showed a heterogenous pattern. While the medial mass and IDs and EDs of several large conduit vessels decreased, these parameters showed at least a tendency to increase in two resistance-type arteries. There were no major quantitative changes in the ECM within the experimental time span.
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Methods |
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Animals
Male Wistar rats (290 to 320 g, Winkelmann, Borchen, Germany) were housed under standard conditions and fed standard rat chow (RMH-TM, Hope Farms) and water ad libitum. The experiments were performed in accordance with local institutional guidelines.
Coronary Artery Ligation
MI was induced by ligation of the LAD according to the method of
Fishbein et al17 as described in detail
previously.18 After intraperitoneal
induction of anesthesia with sodium pentobarbital (60
mg/kg), positive pressure respiration was started through an
endotracheal tube. The thorax was opened in the fourth left intercostal
space, and the LAD was occluded near the origin of the
pulmonary artery by a 6-0 silk ligature. The thorax was closed
in layers. In the sham procedure a superficial suture was placed in the
epicardium of the left ventricle, near the LAD.
Experimental Protocol 1: Structural Changes in the Vascular Wall
After Coronary Artery Ligation
MI was induced at 1 week (n=7), 3 weeks (n=8), 5 weeks (n=7),
and 12 weeks (n=10) before euthanitization. At all time intervals,
sham-operated animals served as controls [1 week (n=6), 3 weeks (n=7),
5 weeks (n=7), and 12 weeks (n=9)].
Tissue Processing
The animals were euthanitized in ether anesthesia.
The heart was arrested in diastole, by injecting 1 to 2 mL
CdCl2 (0.1 mol/L) into the inferior caval vein.
The animals were perfused with PBS followed by perfusion with 5%
phosphate-buffered formalin (10 minutes each) at a pressure of 100
mm Hg, via a catheter in the right carotid artery. To ensure maximal
vasodilation, nitroprusside (50 mg/mL, Sigma Chemical Co) was added to
both perfusion solutions.
Vessel segments (2 to 3 mm) were obtained using anatomic landmarks. A vessel segment of the thoracic aorta was sampled between the first and second intercostal artery, the left carotid artery was sampled 0.5 cm cranial from the aortic arch, the abdominal aorta from the right iliolumbar artery to the bifurcation, the superior mesenteric artery from its origin at the aorta to its first branching point, the right renal artery from the suprarenal artery to its bifurcation at the hilus of the kidney, and the right iliac artery from its origin at the bifurcation of the abdominal aorta to its bifurcation of the femoral arteries. Three mesenteric resistance arteries draining the jejunum were excised. Also, the right lung was excised to study the pulmonary resistance arteries.
After excision of the heart and removal of the atria, the ventricles were blotted dry and weighed. For determination of the wet-dry weight ratio, the apex was removed and weighed separately. Apex dry weight was determined after freeze drying. The percentage of water in the heart (apex) was calculated as 100 · (wet wt-dry wt)/wet wt. Lungs were also excised and weighed. All tissues were fixed overnight in 10% phosphate-buffered formalin. Fixed tissues were processed and embedded in paraplast via routine histological procedures.
Morphometric Measurements
For elastin, rehydrated 4-µm sections were incubated for 30
minutes in Lawson's solution (Klinipath), differentiated in 70%
alcohol, dehydrated, and mounted with Entellan. For collagen,
rehydrated 4-µm sections were incubated for 5 minutes with 0.2%
(wt/vol) aqueous phosphomolybdic acid19 and then incubated
for 90 minutes with 0.1% sirius red F3BA (C.I. 35780, Polysciences) in
saturated aqueous picric acid, washed for 2 minutes with 0.01 N HCl,
dehydrated, and mounted with Entellan (Merck). Volume fractions of
collagen and elastin of the media of the large conduit arteries were
evaluated with a computerized morphometric system (Quantimet 570,
Leica). Approximately six fields of the medial area (defined as the
area between the internal and external elastica laminae) of two to
three cross sections of each vessel were analyzed at x400, and
the percentage of total tissue surface occupied by collagen or elastin
was calculated. Intraobserver and interobserver variations of this
method are less than 5% for the large conduit arteries (data not
shown). The analyses were performed in a blinded fashion by
three experienced investigators. Lawson-stained sections were also used
to measure the medial CSAs of the media, the IDs and EDs, and
media-to-lumen ratios (defined as the ratio of medial area and lumen
area times 100%). Infarct size was determined on AZAN-stained sections
(4 µm) of the heart using the same morphometric system. Infarct size
was expressed in percent of left ventricular
circumference.17 Animals with an infarct size less than
20% were excluded from the studies, as previous
hemodynamic measurements in our laboratory (data not
shown) indicated that these animals showed no signs of cardiac
failure.
Experimental Protocol 2: Biochemical Changes in the ECM of the
Vascular Wall 12 Weeks After Coronary Artery
Ligation
In a second group of 12-week MI (n=7) and sham-operated (n=9)
animals, total collagen and elastin concentrations were determined
biochemically using the hydroxyproline assay.20 Animals
were euthanitized in ether anesthesia. Large segments of
conduit vessels were excised, again using anatomic landmarks. A segment
of the thoracic aorta was sampled from the first to the eighth
intercostal artery. Both carotid arteries were taken from their origin
at the aortic arch to the bifurcation in the internal and external
carotid branches. A 2-cm segment of the superior mesenteric artery was
taken from its origin at the aorta. Both renal arteries were excised
from their origin at the aorta to the bifurcation at the kidney.
Finally, a 2-cm segment of the abdominal aorta was taken out.
The vessels were washed free of blood and cleared of adhering tissues. The medial layer of the thoracic aorta, the abdominal aorta, and both carotid arteries were carefully separated from the adventitial layer with fine forceps; the renal arteries and the mesenteric artery were analyzed intact. Vessel segments of 2 to 3 animals were pooled for subsequent analyses.
Pooled vessels were lyophilized and weighed, 1.0 mL/4 mg dry wt of hot 0.01 mol/L phosphate buffer containing 1.0% SDS was added, and the mixture was boiled for 15 minutes, followed by overnight extraction at 20°C in the same buffer. The SDS extract was dialyzed against distilled water and lyophilized. Separation of elastin and collagen exploits the fact that elastin contains no methionine residues and thus resists digestion by CNBr.21 The residue after SDS extraction was digested with cyanogen bromide (CNBr, 50 mg/mL in 70% formic acid) at 20°C for 24 hours. The CNBr extract, which contains collagen and other solubilized proteins, was lyophilized. Insoluble residues remaining after CNBr extraction of the tissues were taken as elastin, lyophilized, and weighed.
The amount of tissue elastin and collagen were measured by quantification of the amount of hydroxyproline in the CNBr residue (elastin) and the SDS extracts and CNBr extracts (total collagen).20 All separate lyophilized fractions were hydrolyzed in 200 µL 6 mol/L HCl for 16 hours at 105°C. The samples were dried under vacuum and reconstituted in 200 µL double distilled water. Five to 100 µL of each sample was taken, and the volume was adjusted to 100 µL with distilled water. Subsequently, 300 µL of acetate-citrate-isopropanol buffer and 100 µL oxidant solution (84.5 mg chloramine T/mL) was added and incubated during 5 minutes at 25°C. Finally, 1.3 mL 3.5 mol/L p-dimethylaminobenzaldehyde in 72% perchloric acid was added and incubated during 30 minutes at 65°C. The oxidation of hydroxyproline results in the formation of a pyrrole, which reacts with p-dimethylaminobenzaldehyde to form a colored compound. Absorbance was measured at 558 nm (Ultrospec III, Pharmacia Biotech). Calculation was performed using a calibration curve. Results are expressed as micrograms hydroxyproline/milligram dry wt for both elastin and collagen fractions. Finally, DNA concentrations in these segments were determined with the Hoechst assay.
Experimental Protocol 3: Regional Blood Flow Measurements 5 and 12
Weeks After Coronary Artery Ligation
In a third group consisting of 5- and 12-week MI (n=11 and n=11,
respectively) or sham-operated animals (n=9 and n=7, respectively),
radioactive microspheres (Sn113, 15±5 µm
in diameter, Du Pont–NEN Products) were used to measure regional
blood flow according to the reference sample technique, adapted for use
in the rat.22 Microspheres were suspended in
saline, 0.01% Tween 80, and thoroughly mixed and agitated by
sonification before each injection to prevent clumping.
Instrumentation
Under ether anesthesia, polyethylene catheters were
placed into the left ventricle (through the right carotid artery, PE50)
and into the tail artery (PE10). The catheter for the left ventricle
catheter was connected to a pressure transducer (Honeywell
Microswitch). The pressure signal was fed into an AT-compatible
personal computer. Placement of the left ventricular
catheter was verified by the change in pressure waveform upon its
entrance into the ventricle. Both catheters were exteriorized in the
neck. After closure of all incisions, animals were given a minimum of 3
hours to recover from surgery.
Blood Flow Measurements
Sn113-labeled microspheres (total
number±200 000) were injected into the left ventricle in a 0.3-mL
volume over a 15-second period, followed by a 0.1-mL flush of 0.9%
NaCl over another 15-second period. Blood withdrawal was started 30
seconds before injection through the caudal arterial
catheter at a rate of 0.656 mL/min by a Harvard suction pump and
continued for 3 minutes after injection. Rats were killed by
pentobarbital injection into the left ventricle. Thereafter, organs and
tissues were excised (listed in Tables 5
and 6, the left ventricle
represents septum, viable free wall, and infarcted area). All
tissues were blotted, weighed, and counted in a two-channel gamma
scintillation counter. Absolute blood flow was calculated by the
reference sample method22 and expressed as millimeters x
minutes-1 x grams-1 tissue. Relative flow
was calculated as percentage of cardiac output.
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Statistics
Data are expressed as mean±SEM. The level of significance was
set at P<.05. For statistical analysis the
following tests were used: the Mann-Whitney test
(nonparametric) was used for individual comparison of the
group means at specific time points. One-way ANOVA was used to test for
effect in time per group.
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Results |
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Characteristics of the Experimental Groups
The characteristics of animals at the different time points are listed in Table 1
. Both MI rats and sham-operated
controls showed increases in body weight during the entire experimental
period. No differences were observed between the groups. The mean
infarct size for all MI animals was 38±2% (n=32) and comparable
between all MI groups. To evaluate the effects of the degree of heart
failure, animals of the 12-week group (n=10) were subdivided into
groups of moderate (30±2%, n=5) and large (49±4%, n=5)
infarction.
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Heart weights and ratios of heart weight to body weight increased 5 and
12 weeks after coronary artery ligation (Table 1
). There was no
evidence of edema in the heart, as the mass fraction of water was
comparable at all time points (data not shown). Lung weights of the
infarcted animals were increased compared with sham-operated controls
at all time points, suggesting that induction of MI resulted in a
substantial pulmonary edema, indicative of heart failure. Also,
the changes in heart and lung weight became more pronounced as infarct
size increased.
Vessel Dimensions
Larger Conduit Arteries (ID >600 µm)
Changes in vessel dimensions of the large conduit arteries became
evident as heart failure progressed. Only the data from the 12-week
time point are shown (Table 2). However, small changes
were observed at earlier time points. Five weeks after coronary
artery ligation, these changes consisted of significantly smaller
medial CSAs of the abdominal aorta (MI versus sham -9%,
P=.06), carotid artery (-25%, P=.08), and renal
artery (-13%, P<.05). Also, significantly smaller EDs of
the thoracic aorta (-5%, P=.07), mesenteric artery
(-25%, P<.05), and renal artery (-15%,
P=.06) were observed as well as smaller IDs of the
mesenteric artery (-13%, P=.06) and renal artery (-16%,
P=.09). Twelve weeks after coronary artery ligation,
significantly smaller medial CSAs of the thoracic aorta and superior
mesenteric artery were observed, as illustrated in Figs 1 and 2, accompanied by a reduction in IDs and
EDs (Table 2). Similar changes were seen in the renal artery, carotid
artery, and the abdominal aorta (Table 2). These changes coincided with
a reduction in the media-to-lumen ratio of the abdominal aorta, carotid
aorta, and the iliac artery (Table 2).
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Resistance Arteries (ID <300 µm)
Both IDs and EDs of the mesenteric and pulmonary
resistance arteries (Table 2, see also Fig 3) were
increased 12 weeks after coronary artery ligation, while the
media-to-lumen ratios decreased (Table 2). CSAs of these arteries
increased slightly, but this difference did not reach statistical
significance.
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ECM
Volume fractions of collagen and elastin (Table 3;
only 12-week time point is shown) measured by morphometric
analysis were comparable in both sham-operated and MI animals
in the large conduit arteries during the entire experimental period.
The hydroxyproline assay of these vessels confirmed this observation
for the large conduit arteries and the renal artery (Table 4). Also, medial DNA concentrations (expressed as
nanograms per milligram dry weight [Table 4] or as nanograms per
millimeter vessel; data not shown) were similar between groups.
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Regional Flow Measurements
Blood flow at rest was measured 5 and 12 weeks after
coronary artery ligation. Again, infarcted groups were divided
into moderate and large MIs. At 5 weeks, a small decrease in cardiac
output was observed (sham, 401±30
mL · min-1 · g-1 versus moderate MI,
303±42 mL · min-1 · g-1
[P=.09] and sham versus large MI, 307±35
mL · min-1 · g-1
[P=.07]). Twelve weeks after coronary artery
ligation, resting cardiac output did not differ between groups (sham,
330±38 mL · min-1 · g-1; moderate
MI, 308±38 mL · min-1 · g-1; large
MI, 341±44 mL · min-1 · g-1). In
general, no major changes could be observed in absolute or relative
peripheral flow (not shown) in the examined tissues at both
time points (5 weeks, Table 5; 12 weeks, Table 6). Gastrocnemius muscle flow was
slightly decreased in large MI 5 weeks after coronary ligation.
Also, after 12 weeks, flow to gastrointestinal tissues increased
slightly, but liver flow was decreased.
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Discussion |
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This study provides the first evidence for structural alterations of the peripheral vasculature in an experimental model of heart failure. Changes in vessel dimensions were, however, present only at the later time points examined. This might indicate that coronary artery ligation produced only mild heart failure. However, the lung weights of MI-operated animals were increased proportionally to infarct size at all time points, suggesting a substantial pulmonary edema, indicative of heart failure. Also, infarct sizes comparable with the ones presented in this study (38±2%) are known to induce a significant decrease in stroke volume and stroke work,18 a decrease in cardiac output after a volume overload,23 and elevated left ventricular end-diastolic pressures.24 25
In contrast to the decrease in diameters and CSAs in large conduit
arteries, IDs and EDs of resistance arteries (mesenteric and
pulmonary arteries) increased. Moreover, a tendency toward
increased medial CSA of the pulmonary arteries was noted in the
different MI groups (Fig 3). Schieffer et al26 reported a
similar increase in medial thickness of muscular resistance arteries 1
year after MI. In our study, media-to-lumen ratios of the resistance
arteries decreased, which is unexpected in view of the reported
increase in peripheral resistance, indicating resistance
artery vasoconstriction during heart failure.7 8 It should
be remembered that all arteries were excised using the vasodilator
nitroprusside. Thus, our data indicate that resistance arteries still
have the potential for maximal vasodilation in contrast to the large
conduit arteries and suggest that the observed vasoconstriction of
resistance arteries during heart failure has a functional rather than a
structural basis. An alternative possibility is that the
vasoconstriction is primarily regulated in vascular beds other than the
ones studied here. However, as the two resistance-type arteries
measured in this study showed the same phenomenon, this seems
unlikely.
CSAs and diameters of several large conduit arteries were shown to decrease. A similar reduction in vessel diameter also has been reported for the brachial artery of patients with moderate and severe heart failure.27 The reduction in diameter, together with a decrease in media-to-lumen ratio, suggest a reduction in maximal vasodilation and/or reduced distensibility, which is also seen in humans with heart failure.9 10 12 On a functional basis, this limited vasodilation could be beneficial, preventing hypotension during exercise.28 We did not observe major changes in the ECM content of the larger conduit arteries, suggesting that the possible decrease in distensibility is not related to changes in the amount of ECM. A vascular stiffening, caused by an increased arterial sodium content,11 has been suggested in literature, but changes in cross-linking capacities of the various ECM components also could play a role in the possible decrease in distensibility.12
There are several possibilities to explain the smaller CSAs of the
large conduit arteries. The first possibility is that the growth of the
animals in the infarct group was retarded compared with that of the
animals in the sham group. Medial mass of the large arteries in
sham-operated animals increased over the 12-week time period, whereas
medial mass of infarct animals did not show this apparently normal
growth pattern, as illustrated in Fig 2C for the mesenteric artery.
Body weights of MI animals, however, were comparable to sham-operated
controls, indicating that this growth retardation in MI animals is not
a general phenomenon but specific for the large conduit arteries of the
vascular system. The unchanged DNA concentration (Table 4) and elastin
and collagen contents (Tables 3 and 4) after 12 weeks of
coronary artery ligation in the media of these large conduit
arteries suggest alterations in the control of vessel wall mass in
infarcted animals, leading to the observed inhibition of growth of the
large conduit arteries.
A reduction in peripheral flow may explain the inhibition of vascular growth of large conduit arteries. A decrease in flow has been shown to reduce vessel diameters and medial CSA.29 30 During heart failure, a flow restriction has been mentioned as a possible cause for the abnormal skeletal muscle metabolism, but studies on measurements of peripheral flow changes during heart failure have yielded conflicting results. Most of these studies show decreased peripheral blood flow,7 13 14 25 31 32 but some show unchanged blood flow.33 34 35 36 In our study, no major changes in resting peripheral blood flow were observed, despite the decrease in cardiac output after 5 weeks of heart failure and a substantial ventricular damage of approximately 50% of the circumference of the left ventricle. It should be noted that blood flow measurements were taken at rest, and therefore possible flow changes during exercise, for example, cannot be excluded. Also, blood flow measurements were taken with a technique that could be sensitive to potential errors22 ; although this cannot be fully excluded, it seems unlikely that the observed vascular changes are induced by changes in flow.
The inhibition of vascular growth of the conduit arteries during experimentally induced heart failure is remarkable in view of the described elevated plasma levels of several potential stimulators of vessel wall growth during heart failure. Human heart failure is associated with an increase in the plasma levels of angiotensin II,37 catecholamines,38 39 and endothelin.40 41 Also, in the rat infarct model used in this study, plasma levels of angiotensin II, catecholamines, and endothelin are increased at least during the first phase of heart failure (P.M.H. Schiffers, unpublished data, 1994). This neurohumoral activation is considered to be important in cardiovascular adaptations during heart failure. For instance, angiotensin II is one of the regulators of cardiac remodeling and blood pressure after infarction.18 23 The peptide also promotes vascular smooth muscle cell growth42 43 and synthesis of various ECM components.44 45 Catecholamines and endothelin also have growth-promoting effects.46 47 The apparent paradox, ie, increased circulating levels of several potential stimulators of vessel wall growth without actual increases in vessel wall mass, may be explained by a concomitant increase in plasma levels of other factors that have growth-inhibitory effects, like atrial natriuretic peptide and nitric oxide, which are also elevated during heart failure.48 49 50 Both factors have antimitogenic effects in cultured vascular smooth muscle cells.51 52 53 In vivo, infusion of nonpressor doses of atrial natriuretic peptide decreases medial thickness in spontaneously hypertensive rats,54 while nitric oxide is thought to be important in inhibition of neointima formation by angiotensin-converting enzyme inhibitors in the rat balloon injury model.55 Elevations of both vasoconstrictor and vasodilating mediators during heart failure may serve functional hemodynamic purposes (eg, maintenance of the blood pressure) but may also have a diverse effect on the structure of the vascular system. One could hypothesize that during progressing heart failure a neurohumoral imbalance between counteracting systems becomes evident, with a dominating effect of potential inhibitors of vessel wall growth. This could result in the observed growth inhibition of the large arteries. Subsequent studies will be performed to substantiate this hypothesis. Furthermore, the existence of different smooth muscle phenotypes and/or genotypes may explain the observed different response of the conductance and resistance vascular system during heart failure.56
In summary, this study showed changes in the vessel dimensions of the larger peripheral conduit arteries during experimental heart failure. Moreover, changes became more pronounced as infarct size increased. IDs and EDs of larger arteries were reduced after 12 weeks, suggesting a reduction in maximal vasodilation and distensibility. Also, medial CSAs decreased, while no changes were observed in ECM components. In contrast, IDs and EDs of resistance arteries were increased. It is suggested that after MI both stimulatory and inhibitory neurohormonal mechanisms are activated that over time lead to regional diverse adaptive changes in the vascular system. This diverse adaptation of the vascular system could have consequences for cardiac function during experimental heart failure.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Dutch Heart Foundation and Medical Research NWO (902-18-291). The authors wish to thank Dr F. Prinzen for expert advice during blood flow measurements.
Received December 19, 1994; accepted June 27, 1995.
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