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Regression of ventricular hypertrophy abolishes cardiocyte vulnerability to acute hypoxia.

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THE ANATOMICAL RECORD 226:198-206 (1990)
Regression of Ventricular Hypertrophy Abolishes
Cardiocyte Vulnerability to Acute Hypoxia
Department of Anatomy and The Cardiovascular Center, The University of Iowa,
Iowa City, Iowa 52242
Left ventricular hypertrophy (LVH) secondary to a pressure overload commonly leads to perfusion abnormalities that may limit oxygen delivery to
the myocardium and, therefore, result in cardiocyte intracellular damage. We
initiated this study to test the hypothesis that the increased vulnerability of the
hypertrophied left ventricle to acute hypoxia is minimized when LVH regresses
and maximal coronary flow returns to normal. Six-month-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were divided into
control or one of two antihypertensive treatment groups. A 3-month treatment
consisted of captopril (75-100 mg/kg) or hydralazine (80-160 mg/L) with hydrochlorothiazide (500 mg/L) added to each therapy. At the conclusion of the treatment period, the rats were administered a 7% 02-93% Nz gas mixture for 20
minutes to induce acute hypoxic stress during which time hemodynamics, blood
gases, and pH were monitored. The heart was then rapidly fixed by vascular
perfusion and prepared for electron microscopy. Captopril and hydralazine were
equally effective in lowering arterial pressure in both strains, but only captopril
was efficacious in reducing heart mass. Hypoxia-induced changes in hemodynamics, blood gases, and pH were similar in all of the groups; POz was decreased by
about 70%. The electron micrographs revealed that the hypertrophied left ventricle consistently showed morphologic evidence of hypoxic damage (as indicated by
T-tubular swelling, intracellular edema, and mitochondrial alterations); in contrast hypoxia had little effect on the non-hypertrophied ventricle. Captopril treatment resulted in a disappearance of the lability to hypoxic damage while hydralazine caused a small reduction in the frequency of hypoxic damage. In conclusion,
reversal of hypertension alone had little effect on cardiocyte vulnerability to acute
hypoxia, but reversal of hypertension in conjunction with regression of LVH prevented the intracellular damage characteristic of hypoxia. Thus, LVH and its
associated maximal perfusion decrement, rather than hypertension per se, underlie cardiocyte vulnerability to hypoxic stress.
An increase in minimal coronary vascular resistance (MCVR) (Bache and Vrobel, 1979; Tomanek et
al., 1985) and a decrease in capillary density (Henquell e t al., 1977; Tomanek e t al., 1979) are associated
with left ventricular hypertrophy (LVH) secondary to
a pressure overload. Additionally, perfusion abnormalities have been shown to be more pronounced in the
endomyocardium than in the epimyocardium (Breisch
et al., 1986; Bache et al., 1981). Since myocardial
oxygen extraction is near maximum, coronary blood
flow must increase to match any increase in myocardial oxygen consumption. Also a n elevated MCVR and
a decreased capillary density would limit the ability of
the coronary circulation to increase blood flow and
would limit oxygen diffusion; thus, it seems likely that
the hypertrophied myocardium would be more vulnerable to hypoxia. Indeed, studies have shown that
performance in the hypertrophied left ventricle is
altered when exposed to hypoxia, compared to the
non-hypertrophied ventricle (Lore11 et al., 19861, and
that the hypertrophied ventricle, particularly the
endomyocardium, is more vulnerable to hypoxic cell
damage (Wangler e t al., 1980).
We recently demonstrated that the decrement in
maximal coronary perfusion, characteristic of pressure-overload hypertrophy, returns to normal in spontaneously hypertensive rats (SHR) following anti-hypertensive treatment which produces regression of
cardiac hypertrophy (Canby and Tomanek, 1988).
Based on this finding we proposed the hypothesis that
the increased vulnerability of the cardiocyte to acute
hypoxia is minimized or abolished with regression of
LVH and the normalization of maximal coronary flow.
Captopril treatment was selected because our previous
experience showed that maximal coronary perfusion is
normalized in conjunction with the drug’s ability to
regress LVH. We also subjected a second group of rats
to hydralazine treatment, because this agent normal-
Received October 5, 1988; accepted May 16, 1989.
izes blood pressure without regression of LVH. Thus,
the two treatment protocols enabled us to separate the
anti-hypertensive effects of a n agent from the effects of
a reduction in LV mass.
General Experimental Design
We assigned male spontaneously hypertensive
(SHR) and normotensive Wistar-Kyoto (WKY) rats, obtained from Taconic Farms (Germantown, NY), to control (WKY and SHR), captopril-treated (C-WKY and
C-SHR), and hydralazine-treated (H-WKY and HSHR) groups. Captopril (75 mg/kg) or hydralazine (80
mg/L) were dissolved in the rats’ drinking water. Based
on the average body weight and water consumption of
the treated WKY and SHR groups, 540-730 mg of captopril was dissolved in 1 liter of drinking water. Hydrochlorothiazide (500 mg/L), a diuretic, was also
added in order to potentiate the antihypertensive effect
of each of the treatment protocols. A 3-month treatment was initiated to coincide with the time that hypertension and LVH were well established (6 months of
age) in order to focus on their reversibility. In order to
maintain arterial systolic pressure below 140 mmHg,
we increased the drug dosage of captopril to 100 mg/kg
at week 2, while hydralazine was increased to 120 and
160 mg/L at weeks 4 and 8, respectively. Arterial systolic pressure measurements (tail-cuff method) were
determined weekly in the four treated groups and at
the beginning and end of the experimental period in
the two control groups.
Forty-eight hours prior to hypoxic exposure the drug
water was replaced with tap water in order to eliminate the acute hemodynamic effects of the drugs during
the time of the study. Each animal was given atropine
(1.2 mg, i.p.1 and anesthetized with a mixture of ten
parts ketamine (100 mg/ml) to one part acepromazine
(10 mg/ml). The dosage was 0.10 m1/100 g of body
weight. Following anesthesia, the left femoral and
right common carotid arteries were cannulated with
PE-10 tubing telescoped into PE-50 tubing. Subsequently, the right common carotid catheter was introduced into the left ventricle. The catheters were filled
with heparinized saline (70 U/ml) and connected to a n
Ailtech M520 pressure transducer, and heart rate as
well a s arterial and ventricular pressures were recorded on a Gilson five-channel recorder.
Administration of Acute Hypoxia
Following measurement of arterial and ventricular
pressures, and heart rate, a tracheotomy was performed and the animal was artificially ventilated with
a Harvard small animal respirator. Respiration was
maintained at 30 strokes per minute and at a tidal
volume adjusted for body weight (5 ml for a 300-400 g
rat). Following a 5-minute stabilization period, after
performing a midsternal thoracotomy, arterial and
ventricular pressures and heart rate were recorded and
a 0.3 ml blood sample was withdrawn from the femoral
artery for measurement of blood gases, pH (Radiometer
BMS 3Mk2 pH/blood gas analyzer), and hematocrit.
This blood sample was immediately replaced with a n
equal volume of strain-matched donor blood. Subsequently, the ventilator was switched to a 7% 02-93%
N2 gas mixture. The animal was administered this gas
mixture for 20 minutes in order to produce a n acute
hypoxic environment. Pressures and heart rate were
then recorded and another blood sample was withdrawn for measurement of blood gases, pH, and hematocrit.
Electron Microscopy
At the conclusion of the 20-minute hypoxic period,
heparin (5,000 U) was injected into the inferior vena
cava. The heart was arrested in diastole with procaine
and removed, and the aorta was attached to a 20-gauge
animal feeding needle (Harvard) for perfuse-fixation. A
ligature was placed around the aorta so that the ball of
the needle was just above the coronary ostia. Next, the
right atrium was cut to provide a n outflow channel and
the coronary vasculature was perfused with 20 ml of
Locke’s solution (which also contained 5,000 U of heparin and 0.5 ml of procaine) a t 37°C via the feeding
needle, and then with 100 ml of a modified Karnovsky’s solution (Tomanek et al., 1979, 1981).
Subsequently, the organ was blotted dry and total
heart weight and left ventricular weight (including the
septum) were obtained. The septum was dissected out
and the left ventricle was placed in fresh fixative for a n
additional 20-24 hours, and then specimens were dissected from epimyocardium and endomyocardium.
Both longitudinal and cross sections were obtained.
These tissue samples were placed in a 0.1 M sodium
cacodylate buffer with 3% sucrose for approximately 24
hours, post-fixed in 1% osmium tetroxide for 2 hours,
washed with 0.1 M sodium cacodylate buffer, dehydrated through a graded series of ethanol and propylene oxide, and embedded in Spurr’s plastic.
Thin sections were cut both perpendicular and parallel to the long axis of myocytes with a diamond knife
on a Reichert ultratome. The sections were then
mounted on copper grids and stained with uranyl acetate and lead citrate solutions, and subsequently
viewed with a Hitachi 7000 electron microscope. Evaluation of hypoxic damage was done systematically by
scanning all cells in the field. In the rare case that
capillaries were not clear, indicating inadequate perfusion, the specimen was excluded. We evaluated 3045 cell profiles, cut in cross section, and tabulated the
morphological changes characteristic of hypoxia. Thin
sections cut parallel to the long axis of cardiocytes were
also photographed and used to evaluate sarcomere
changes and dilatations of the intercalated discs.
Statistical Methods
Data regarding most variables were analyzed by
analysis of variance and the Bonferroni multiple comparison procedure. Ultrastructural alterations resulting from acute hypoxia were analyzed with a Fisher’s
Exact Test for Frequencies. A P 5 0.05 was selected to
denote statistical significance for all comparisons. The
values presented in this paper are group means
Arterial Systolic Pressure, and Body and Heart Mass
Prior to antihypertensive therapy, arterial systolic
pressure (tail-cuff) in SHR was approximately 55%
higher than in WKY (Fig. 1). At this time all SHR had
systolic pressures greater than 180 mmHg and were,
2 2.8
3 2.6
& 2.4
= P+
0 WKY Control ( n = l l )
0 WKY Captopril Treated (n=9)
WKY Hydralame Treated ( n = l i )
SHR Control (n=l1)
SHR Caplopril Treated (n=10)
SHR Hydralame Treated (n=11)
Week of Treatment
Fig. 1. The effect of captopril and hydralazine treatment on arterial
systolic pressure (tail-cuff method in conscious rats) during the first
10 weeks of treatment. *, P <0.0001 vs. SHR;t, P <0.0001 vs. respective control group.
therefore, unequivocally hypertensive. Ten weeks of
anithypertensive treatment lowered arterial systolic
pressure in the C-WKY and H-WKY by 21% and 14%,
respectively. In SHR, captopril lowered pressure by
40% while hydralazine reduced pressure by 34%.These
reductions in arterial systolic pressure are significant
in both rat strains ( P < 0.0001).
Figure 2 illustrates the left ventricular weightlbody
weight (LVW/BW) ratios. SHR have significantly
greater LVWIBW ratio values than WKY (P < 0.0001).
Captopril treatment in SHR and WKY was associated
with LVWIBW ratios that were 22% and 14% lower
compared to their respective controls. While hydralazine did not alter the ratio in WKY, i t did result in a 6%
decrease in the ratio of SHR. However, H-SHR still had
a ratio that was markedly greater than C-SHR and the
control WKY.
The data provided in Table 1indicated that captopril
treatment was associated with significantly lower values for BW, heart weight (HW), and LVW in both r a t
strains, and that hydralazine treatment resulted in
lower values for BW, HW, and LVW in SHR, but not in
Arterial systolic pressure, measured directly via a
femoral catheter, in closed-chest, anesthetized SHR
was 78% greater than WKY (Table 1).C-SHR and H-
a C a p t o p r i l Treated D H y d r a l a z i n e Treated
Fig. 2. The effect of captopril and hydralazine treatment on left
ventricular weight (LVWIibody weight (BW) ratio.
SHR had arterial systolic pressures that were 26% and
12% lower than SHR. Arterial systolic pressures in CWKY and H-WKY are not significantly different from
Table 2 lists the various hernodynamic indices before
and after hypoxia in anesthetized, open-chest rats.
SHR exhibited significantly greater values for arterial
systolic, arterial diastolic and mean pressure, and left
ventricular systolic pressure than did WKY. Captopril
treatment in SHR reduced the values for all of these
variables (P < 0.01). Captopril treatment in WKY and
hydralazine treatment in WKY and SHR did not sig-
Figs. 3-10. Transmission electron micrographs of left ventricular
Fig. 3. Cross section of cardiocyte from SHR not subjected to acute
hypoxia. Note the close packing of myofibrils, mitochondria, and tubular system. Transverse (T)-tubule is indicated by arrow. x 14,400.
Fig. 4. Cross section of cardiocyte from SHR following 20 minutes of
hypoxia. Note that T-tubules (arrows) are markedly dilated. In comparing to Figure 3, note that the magnification is less in Figure 4,
which underestimates the magnitude of the dilations. x 9,900,
Figs. 5 and 6. Longitudinal sections of cardiocytes from SHR following 20 minutes of hypoxia. These micrographs show the more severe,
but less common alterations. Edema is evidenced by the exaggerated
sarcoplasmic areas (Fig. 5).Translucence of mitochondrial matrix and
disruption of cristae (arrows) are evident in Figure 6. Figure 5,
x 10,200. Figure 6, x 13,600.
Figs. 3-6
Figs. 7-9.
TABLE 1. Body weight, heart weight, and arterial systolic pressure'
BW ( g )
HW (g)
LVW (g)
ASP (mmHg)
(n = 9)
495 t 11
1.515 f 0.045
1.084 t 0.032
116 t 5
(n = 7)
436 k 2
1.196 t 0.052**
0.820 f 0.036**
116 t 6
'BW = body weight, HW = heart weight, LVW
* P < 0.01 vs. WKY.
** P < 0.01 vs. respective control group.
(n= 11)
464 ? 10
1.476 f 041
1.046 t 0.029
125 t 4
( n = 11)
432 t 10*
1.671 f .041*
1.345 k 0.029*
207 t 4*
(n= 9)
376 t 11*
1.298 t 0.045**
0.918 t 0.032**
153 t 5**
(n = 11)
387 k 10**
1.471 f 0.041**
1.132 f 0.029**
182 f 4**
left ventricular weight, and ASP = arterial systolic pressure (direct measurement in femoral
TABLE 2. Hemodynamics prior to and following hypoxia'
Prior to hypoxia
After hypoxia
(n = 9)
(n= 11)
( n = 11)
100 f 6
73 4 5
82 f 6
104 t 7
345 f 12
91 f 7
68 t 6
76 f 6
90 t 8
328 t 14
101 t 6
79 f 5
86 + 5
102 t 6
12 t 1
350 f 11
151 k 6*
108 t 5*
122 f 5*
9 t 1
341 t 11
120 t 6**
90 f 5**
100 t 6**
120 f 7**
10 t 2
372 t 2
138 f 6
105 f 5
116 ? 5
137 t 6
356 t 11
66 t 4***
41 t 3***
49 f 3***
75 t 5***
322 17
61 k 4***
39 t 3***
46 + 4***
67 k 6***
305 f 19
60 t 4***
39 t 3***
46 f 4***
72 ? 4***
13 f 1
323 f 15
72 2 4***
41 f 3***
51 t 3***
74 4***
12 t 1
314 2 15
79 2 4
48 t 3***
58 f 3***
go f 5***
361 t 17
68 t 4***
39 t 3***
48 t 3***
72 t 4***
359 ? 15
(n = 9)
(n = 11)
'ASP and ADP = arterial systolic and diastolic pressure (mmHg), respectively; MAP = mean arterial pressure (mmHg); LVSP and LVEDP
= left ventricular systolic and end diastolic pressure (mmHg), respectively; HR = heart rate (beatdmin.). * P < 0.01 vs. WKY.
** P < 0.01 vs. respective control.
***P < 0.001 vs. pre-hypoxic value.
TABLE 3. Arterial blood gases and pH prior to and following hypoxia
After hypoxia
(n = 7)
(n = 11)
115 t 6
37 + 2
7.36 f 0.02
123 f 7
36 t 2
7.33 + 0.02
101 f 5
38 _t 1
7.42 f 0.02
1.6 t 5
33 t 1
7.34 t 0.02
110 t 6
35 t 2
7.38 + 0.02
108 t 5
36 t 1
7.39 t 0.02
34 + 2*
30 ? 2 *
7.32 t 0.02
37 t 2*
29 k 2*
7.26 f 0.03*
32 t 1*
26 f 2*
7.36 t 0.02
37 f 1"
25 f 2"
7.27 t 0.02*
37 t 2*
23 t 2*
7.33 _t 0.02"
33 t 1*
28 f 2*
7.32 t 0.02*
to hypoxia
(n = 11)
(n = 9)
(n= 11)
(n = 9)
* P < 0.001vs. value prior to hypoxia.
Fig. 7. Cross section from WKY subjected to 20 minutes of hypoxia.
Note that the ultrastructural appearance is characteristic of myocardium from rats maintained under normoxic conditions. T-tubules (T)
are not dilated. x 14,400.
Fig. 8. An intercalated disc from a captopril-treated SHR subjected
to 20 minutes of hypoxia is seen in longitudinal section. There is no
evidence of dilated T-tubules or expansions of the non-specialized regions (between arrows) of the disc. x 32,000.
Figs. 9 and 10. Cross and longitudinal fields from hydralazine
treated SHR after 20 minutes of hypoxia. This pharmacological treatment did not minimize the hypoxic alterations characteristic of SHR.
Large dilatations in the region of intercalated discs are seen in Figure
9, while Figure 10 illustrates dilated T-tubules (T).Two type of dilatations are evident in Figure 9: the non-specialized regions of the dlsc
(NS) and adjacent T-tubules (T). Figure 9, ~ 2 9 , 0 0 0 ,Figure 10,
x 8,500.
nificantly alter these indices. Left ventricular end diastolic pressure and heart rate are not significantly
different for any of the comparisons. All of these indices, except for LV end diastolic pressure and heart rate,
were reduced by 20 minutes of hypoxia (P < 0.001).
Arterial Blood Gases and pH
While there are no significant intergroup differences
in arterial blood gases and pH (Table 3) it is evident
that the 7% Oz-93% N2 gas mixture markedly reduced
POz in all six groups (P < 0.001). Hypoxemia developed
in all groups as indicated by an approximate 70% reduction in P02. PCOz fell by 19-32%. Three possible
factors may explain the decrease in PCOz. First, the
TABLE 4. Percentage of rats exhibiting various characteristics of hypoxic damage'
T-tubule dilation only
Mitochondrial swelling
Mitochondrial disruption
A t least one of
the above
(n = 8 )
(n = 7)
(n = 9)
56$; l l t
(n = 8 )
(n = 8 )
37$; 25t
12$; 12t
123; 25t
12$; 25t
'Number of rats per group is indicated in parentheses. t , mild-moderate change; $, marked change. For each rat, 30-45 cell profiles were
evaluated. * Statistically significant difference (P5 0.05), between drug-treated group and its strain control, determined by Fisher's Exact Test
for Frequencies. All differences between SHR and WKY groups, except mitochondrial disruption, are statistically significant.
gas mixture did not contain COz. Second, i t is possible
that a lower Oz cellular utilization contributed to the
decreased PCOz. Finally, a decrease in bicarbonate
concentration may have occurred. In addition, hypoxia
lowered pH in the C-WKY, SHR, C-SHR, and H-SHR
(P < 0.001).
Hypoxia-Induced Tissue Damage
Figures 3-10 are representative micrographs obtained from the various groups subjected to acute hypoxia. The characteristics of hypoxic damage are summarized in Table 4. When SHR were subjected to
hypoxia they predictably exhibited dilated T-tubules
(Fig. 4). In four of the nine hearts from SHR cardiocytes
showed evidence of edema as demonstrated by large
sarcoplasmic areas (Fig. 5), dilatations of the intercalated disc, and mitochondrial alterations (Fig. 6). The
latter consisted of a decreased matrix density, swelling,
and disruption of cristae. In contrast, hypoxia caused
few and infrequent alterations in WKY (Fig. 7). While
most cells lacked any alteration, some occasionally displayed dilated T-tubules.
Most cells in captopril-treated SHR resembled those
of WKY; i.e., most showed no alterations; the only
change seen was mild-moderate dilations of T-tubules,
but this occurred in only 12% of the animals. Figure 8
demonstrates a normal intercalated disc which contrasts with those commonly observed in untreated
SHR. Thus, captopril treatment in SHR completely
abolished the structural alterations common to hypoxic
exposure. Hydralazine treatment in SHR, which did
not affect LVH, had little effect in reducing subcellular
damage. Dilatations in the region of intercalated discs
(Fig. 9) and expanded T-tubules (Fig. 10) persisted, and
the incidence of edema was also unaltered. Thirtyseven percent of the H-SHR group presented mitochondrial changes and cellular edema. As summarized in
Table 4, the hypoxic changes consistently observed in
SHR were prevented by captopril but not hydralazine
treatment. The latter treatment did cause a slight decrease in the severity of the edema and mitochondrial
alterations. By using the Fisher's Exact Test for Frequencies (Table 41, the conclusion is reached that captopril significantly lowered the incidences of all characteristic subcellular changes in SHR.
The major findings of this study are: 1)cardiocytes of
SHR are more vulnerable to acute hypoxic damage
than cells from WKY; and 2) lowering arterial pressure
and reversing LVH with captopril prevents the vulnerability to hypoxic damage in SHR.
Ischemia or hypoxia, if adequate, causes rather predictable ultrastructural changes. These alterations
may be irreversible; irreversibility is related to the
length of time the cell is deprived of Oz. In our study
the described alterations were reversible. Reversible
damage is morphologically characterized by a decrease
in glycogen (Jennings and Ganote, 19741, slightly swollen mitochondria, some margination of nuclear chromatin, intracellular edema (Hearse et al., 19751, swollen T-tubules, swollen sarcoplasmic reticulum, and
swollen intercalated disks (Denker et al., 1969; McCallister et al., 1979). Irreversible damage is identified by
dense intramitochondrial granules, almost complete
depletion of glycogen, disorganization of the sarcoplasmic reticulum, disruption of the sarcolemma, pronounced peripheral aggregation of nuclear chromatin,
and mitochondrial alterations, such as disruption of
the cristae and a decrease in matrix density (Jennings
et al., 1965; Jennings and Ganote, 1974). Studies have
been conducted to discern the time course of reversible
vs. irreversible damage (Schaper et al., 1979; Jennings
et al., 1965; Ganote et al., 1975; Edoute et al., 1983).
Dog hearts subjected to 15 minutes or less of ischemia
in vivo exhibited anatomical characteristics of reversible damage, while 30 minutes or more resulted in irreversible damage (Jennings et al., 1965). A study employing a n isolated, beating, rat heart working against
a n afterload of 100 mmHg reported signs of infrequent,
irreversible damage in the endomyocardium following
just 15 minutes of anoxic perfusion. The frequency of
this damage progressively increased after 20 and 25
minutes of anoxia (Edoute et al., 1983).
Although previous studies have examined the time
sequence of ultrastructural alterations in ischemic
myocardium, the effects of various magnitudes of ischemia on myocardial cellular structures were not studied until 1981 when four stages of flow reductions, expressed a s percent of control flow, i.e.: 75-80 (Stage 1);
50-74 (Stage 2); 25-49 (Stage 3); and 0-24 (Stage 41,
were examined in our laboratory (Tomanek et al.,
1981). These flow reductions were maintained for a
period of 12 hours. Stage 1 was characterized by normal cardiac structure except for rare instances of focal
mitochondrial disruption. Stage 2 was associated with
more pronounced changes in sarcoplasm and mitochondria. Mitochondria exhibited focal swelling and disrup-
tion in all cells and there was enhancement of the sarcoplasmic compartment in most cells. More severe
ischemia (Stage 3) resulted in severe swelling of mitochondria, amorphous densities in many of the mitochondria, glycogen loss, marked enhancement of the
sarcoplasm, Z-line irregularity, focal I-band disruption,
presence of contraction bands, and clumping and margination of chromatin in many nuclei. Stage 4 was associated with mitochondrial vesiculation and occasional destruction of cristae, vesiculation and marked
expansion of the sarcoplasm, decrease in the amount of
sarcoplasmic reticulum, disruption of myofibrils, loss of
Z-lines, presence of contraction bands, and clumping
and margination of chromatin in all nuclei.
A number of studies have documented hemodynamic
and biochemical consequences of hypoxia. These include a decline in myocardial performance a s suggested
by a drop in dP/dt (Carey et al., 1976), and a decrease
in myocardial ATP and creatine phosphate (Edoute et
al., 1983; Schaper et al., 1979; Hearse et al., 1976).
Lore11 et al. (19861, using a n isolated, beating heart,
noted t h a t hypoxia alters diastolic properties of both
the hypertrophied and non-hypertrophied ventricles.
However, the changes are more pronounced in the hypertrophied left ventricle, which undergoes a greater
increase in end diastolic pressure and a greater upward
shift of the asymptote of left ventricular pressure decay. Thus, hypoxia seemed to be associated with a
greater loss of left ventricular diastolic distensibility
and a lesser extent of relaxation in hypertrophied
hearts than in non-hypertrophied controls. Although
hypoxia led to a depression of hemodynamics in our
study, we did not discern any differences between hypertrophied and non-hypertrophied left ventricles.
Nevertheless, a decrement in more sensitive measures
of ventricular performance and contractility may have
occurred in the hypertrophied hearts.
The effects of hypoxia on the cell structure of the
hypertrophied myocardium were previously studied in
our laboratory (Wangler et al., 1980). SHR and normotensive, non-hypertrophied controls (WKY) were
subjected to 15 minutes of 7% 0?93% Nz. This acute
hypoxic episode resulted in a n arterial POz of 43-55
mmHg. When the hypoxic cardiac tissue was examined
with the electron microscope, slight and infrequent mitochondrial and T-tubular swelling was observed in the
endomyocardium of WKY. However, SHR were associated with focal cellular edema, frequent T-tubular
swelling, and a decrease in mitochondrial matrix density. That SHR cardiocytes are more vulnerable to hypoxia than are WKY cardiocytes and that the damage
is morphologically characteristic of reversible damage
are in agreement with the present results, which are
based on a greater degree of hypoxia. Thus, i t is not
surprising that we observed characteristics of irreversible damage, albeit infrequent, in the hypertrophied
myocardium. This damage was characterized by decreased mitochrondrial matrix density and disruption
of mitochondrial cristae. We submit that increased vulnerability to hypoxia is most likely due to perfusion
abnormalities associated with LVH secondary to pressure overload, such as increased MCVR (O’Keefe et al.,
1978; Wangler et al., 1982) and decreased capillary
density (Tomanek et al., 1979; Rakusan et al., 1980;
Anversa et al., 1979). Since oxygen extraction in the
myocardium is near maximum the cardiocyte depends
on a n increase in blood flow to meet any increase in
oxygen requirement (Feigl, 1983). An elevated MCVR
would tend to limit the ability of the coronary circulation to deliver oxygenated blood to the cardiocytes during times of metabolic stress (e.g., hypoxia). Moreover,
decreased capillary density would be expected to result
in increased oxygen diffusion distance and a corresponding decrease in myocardial oxygen pressure.
Thus, elevated MCVR and reduced capillary density
could act in concert to hinder the ability of the coronary
circulation to deliver oxygen to the hypertrophied myocardium during physiological stress resulting in ischemic or hypoxic damage.
Based on the foregoing discussion i t is concluded that
myocardial hypertrophy in response to pressure overload renders the myocardium more vulnerable to hypoxia. Such vulnerability is characterized by ultrastructural alterations as well as biochemical and
physiological abnormalities. Our findings indicate that
cardiac hypertrophy (which is associated with a decrease in capillary density), rather than elevated blood
pressure, is the major contributor to this increased vulnerability.
We thank The Squibb Institute for Medical Research
for their generous supply of captopril.
This work was supported by National Heart, Lung,
and Blood Institute Grants HL 18629, HL 14388, and
HL 32295.
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vulnerability, regression, abolishes, hypertrophic, acute, hypoxia, ventricular, cardiocytes
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