Download Editorial Review Abnormalities of the coronary circulation

703
ClinicalScicncc (1991)81, 703-713
Editorial Review
Abnormalities of the coronary circulation associated with
left ventricular hypertrophy
D. J. O’GORMAN AND D. J. SHEFUDAN
Department of Academic Cardiology, St Mary’s Hospital Medical School, London
INTRODUCTION
Echocardiographic left ventricular hypertrophy is a
common clinical finding. Its prevalence increases with
age, rising to 23.7% in males over the age of 5 9 years and
to 33% in females of the same age [l].The electrocardiogram is a less sensitive index of left ventricular hypertrophy [2, 31, but it is an ominous prognostic sign, being
associated with a sixfold increase in cardiac mortality and
a threefold increase in the risk of cardiac failure [2]. The
presence of repolarization changes further increases the
risk of cardiac failure [4].
Hypertension, the most frequent cause of left ventricular hypertrophy, is associated with an increased risk of
coronary atheroma [5], yet left ventricular hypertrophy
defined by echocardiography is the most powerful independent predictor of mortality in multivariate analysis [6],
more powerful even than the presence of coronary
stenoses or impaired left ventricular function [6]. The risk
of cardiac failure from electrocardiographic left ventricular hypertrophy is greater than that from angina pectoris
and similar to that from a previous myocardial infarction
,I ] . The hypertrophied heart may show repolarization
changes, suggesting ischaemia, when it is stressed by an
exercise test [S] or even at rest [2] in the absence of
coronary stenoses. Perfusion defects in hypertrophied
hearts also may be detected during exercise with thallium
imaging, despite the epicardial vessels being normal [9].
Angina-like pain may occur in association with left
ventricular hypertrophy secondary to aortic valve disease
[ 10- 121, hypertrophic cardiomyopathy [ 131 and hypertension [14], in the absence of angiographic coronary
disease. Areas of subendocardial infarction and fibrosis
have been detected in hypertrophied hearts, even in the
presence of normal coronary arteries [ 15-18]. SubendoCorrespondence: Dr D. J. OGorman, Department of
Academic Cardiology, St Mary’s Hospital Medical School,
Praed Street, London W2 INY.
cardial ischaemia is believed to be due to hypoperfusion
rather than to occlusive coronary disease.
Together with the increased likelihood of ischaemia
seen in clinical studies of left ventricular hypertrophy,
experimental studies have shown that the hypertrophied
ventricle is more vulnerable to ischaemia. After ischaemia
and reperfusion, the return of myocardial function was
impaired in the hypertrophied heart [ 191. Twenty minutes
of hypoxic stress was sufficient to induce evidence of subendocardial ischaemia, as assessed by electron microscopy, in the hypertrophied left ventricle, at which time
there was little effect on the non-hypertrophied ventricle
POI.
When coronary occlusion occurs in the hypertrophied
heart, the resulting infarct tends to be larger than in the
non-hypertrophied heart [21]. Mortality is also increased,
even when the size of the occluded vascular bed is not
increased [22]. In clinical studies, sudden cardiac death is
markedly increased in patients with hypertension and left
ventricular hypertrophy; hypertension doubles the risk of
myocardial infarction and also doubles the proportion of
infarcts that are silent [23].
This tendency to ischaemia may contribute to the progression from left ventricular hypertrophy to left ventricular failure. When the hypertrophied left ventricle is
stressed, by pacing [24, 251, exercise [26] or infusion of
isoprenaline [25], evidence of left ventricular diastolic
dysfunction appears, in contrast to normal hearts. The
ventricular dilatation that accompanies the onset of
ventricular failure in the hypertrophied ventricle increases
myocardial demand, leading to an increased risk of
ischaemia and further deterioration in function [ 151.
When the perfusion pressure is decreased, left ventricular
systolic function becomes impaired at a higher pressure in
the hypertrophied heart [27]. This may occur clinically
when the blood pressure is reduced rapidly in patients
with hypertension, or it may occur because of the development of coronary occlusive disease, thereby lower-
704
D. J. O’Gorman and D. J. Sheridan
ing the distal coronary pressure. Thus impaired coronary
blood flow may lead to acute or chronic episodes of heart
failure in the hypertensive heart. Patients with hypertension and left ventricular hypertrophy present with
more frequent and more complex ventricular ectopy [28,
291, even when control subjects were matched for the
severity of hypertension. In addition, ventricular tachycardia was more frequent when repolarization changes
accompanied voltage criteria of left ventricular hypertrophy [29]. There was no evidence that diuretic therapy
was associated with an increased risk of ectopy.
Left ventricular hypertrophy is a major independent
risk factor for cardiac events. Evidence of ischaemia has
been documented in hypertrophied hearts in the absence
of epicardial stenoses and the hypertrophied heart is
more vulnerable to ischaemia. Episodes of ischaemia may
give rise to the complications associated with left
ventricular hypertrophy, progression to left ventricular
failure and ventricular arrhythmias.
AETIOLOGY OF LEkT VENTRICULAR HYPERTROPHY
Myocardial oxygen requirements are related to left ventricular generated pressure, heart rate, peak systolic wall
stress and contractility [30]. Peak systolic wall stress is
more closely correlated with myocardial oxygen consumption than other measures of left ventricular function
[311, including cardiac index, isovolumic contractility
indices and systolic pressure. According to the Laplace
equation wall stress is defined as:
systolic wall stress = ( p x r)/2d
where p is the left ventricular pressure, r is the radius of
the left ventricle and d is the left ventricular wall thickness. This value represents a mean value for the full thickness of the ventricular wall; stress is underestimated for
the subendocardium and overestimated for the subepicardium [32]. Thus myocardial oxygen requirements
can be reduced for a given pressure either by an increase
in wall thickness or a decrease in left ventricular volume.
The Laplace equation predicts that peak systolic wall
stress is inversely related to the left ventricular mass/
volume ratio. This relation has been confirmed in clinical
studies [32]. The relationship between systolic blood
pressure, left ventricular mass/volume ratio and systolic
wall stress may be used to describe the appropriateness of
hypertrophy [32]. Appropriate hypertrophy is associated
with a greater preservation of coronary reserve and
ventricular function [32].
Left ventricular hypertrophy occurs as a compensatory
adaptation when the heart is subjected to an increased
load. Increased pressure or a volume load increase the
wall stress, which may be reduced by the development of
hypertrophy [33]. Meerson [34] has described the development of compensatory hypertrophy in three stages.
In the first stage, The Stage of Hyperfunction, an
increased load leads to an increase in the intensity of
function and the activation of protein synthesis. The
development of hypertrophy reduces the intensity of
function per unit mass, leading to the second stage, The
Stage of Compensated Hypertrophy, when function and
oxygen requirements are normalized. Eventually the heart
progresses to the third stage, The Stage of Gradual
Exhaustion, when there is a reduction in protein synthesis
resulting in a failure to renew contractile proteins and
energy-producing structures. Ventricular function is
reduced further and cardiac insufficiency supervenes.
Although hypertrophy is initially beneficial, the
increased mass requires a greater coronary blood flow to
maintain normal function. When demand is increased by
tachycardia [24] or by a sudden increase in sympathetic
stimulation [25], the maximal coronary flow may be insufficient to meet myocardial demands leading to a
transient impairment of function or permanent ischaemic
damage to the myocardium.
The development of hypertrophy is a compensatory
response in order to reduce myocardial oxygen demand
per g of tissue and preserve myocardial function. The
increase in mass, however, increases the total metabolic
demand of the heart.
CORONARY HAEMODYNAMICS
Myocardial oxygen extraction is almost maximal and does
not increase until optimal vasodilatation has occurred
[30].An increase in demand is matched by an increase in
coronary flow. The coronary circulation differs from
other organs as systolic compression of intramyocardial
vessels limits coronary flow for the most part to diastole.
The transmitted left ventricular pressure, and hence
wall stress, increases from the subendocardial to the subepicardial layers of the myocardium [35]. As the basal
oxygen requirements are greater in the subendocardium,
the subendocardial/subepicardialratio of coronary flow is
greater than unity [36, 371. The vessels supplying the subendocardium are exposed to greater external eompression because of the greater effect of the generated intracavitary pressure in the subendocardium and also because
they have had to pass through the entire width of the
myocardium. Thus the subendocardium is at increased
risk of ischaemia because of increased demand and
impaired perfusion.
Coronary autoregulation matches coronary flow to
local metabolic needs, despite wide variations in perfusing
pressure [38, 391. When the perfusing pressure is
decreased within the autoregulatory range, the coronary
vasculature can maintain a constant coronary flow by
vasodilatation. Below the lower limit of autoregulation
coronary perfusion decreases markedly with a fall in
perfusing pressure [40](Fig. 1).
The minimal coronary resistance reflects the maximal
effective cross-sectional area of the coronary resistance
vessels. When expressed per g of tissue, it reflects the
relative vascularity and susceptibility to ischaemia. The
relationship between basal (autoregulated) flow and
maximal flow is illustrated in Fig. 1.The coronary reserve
is defined as the difference between basal and maximal
flow and this depends on the perfusing pressure. In
hypertension the coronary reserve may not be reduced,
Coronary flow and left ventricular hypertrophy
705
7140
-CO
.z2
v
s
,
/
120
'g
100
80
100
80
/
v
I;
0'
0
20
40
60
80
100
120
140
160
Inflow pressure (mmHg)
Fig. 1. Relationship between coronary inflow pressure
and coronary flow under conditions of autoregulation
(----) and maximal vasodilatation (-).
The minimal
coronary resistance is calculated as the inverse of the
slope of the pressure flow regression line during maximal
vasodilatation. The coronary reserve is defined as the
difference between the autoregulated flow and the
maximally dilated flow, at the same inflow pressure. It can
be seen that the coronary reserve is dependent on
perfusion pressure.
despite an increased minimal coronary resistance,
because of the increased perfusing pressure [41, 421 (Fig.
2).
The coronary circulation differs from the circulation in
other organs as perfusion occurs mainly in diastole.
Within the myocardium there are transmural gradients in
demand and supply. Under basal conditions coronary
flow is autoregulated. The resulting coronary reserve is
pressure-dependent.
CORONARY RESERVE AND HYPERTROPHY
Impaired coronary reserve has been documented in
association with left ventricular hypertrophy in many
clinical situations, despite normal epicardial coronary
arteries at angiography. Patients with hypertensive left
ventricular hypertrophy demonstrated a 34% reduction
in coronary reserve in response to dipyridamole-induced
vasodilatation [43]. In a similar study the minimal
coronary resistance was increased by 102% in hypertensive patients with left ventricular hypertrophy, anginalike chest pain and normal coronary arteriograms [ 141,
suggesting that angina may occur in those patients with a
greater degree of impairment of coronary perfusion.
These patients may show perfusion defects on thallium
scintigraphy [9] and on positron emission tomography
[441.
Coronary atheroma is commonly associated with
hypertension [5] and leads to a reduced perfusion
pressure distal to the coronary stenoses. Thus the
coronary reserve may be reduced independently of the
effect of left ventricular hypertrophy. The perfusion
pressure may therefore fall below the autoregulatory
range when the stenoses are sufficiently severe. Thus the
hypertensive ventricle is doubly at risk of ischaemia, being
more prone to coronary stenoses and less able to tolerate
low perfusion pressures.
8
0'
0
20
40
60
80
100
120
140
160
Inflow pressure (mmHg)
Fig. 2. Coronary reserve in hypertensive heart disease.
The Figure shows how coronary reserve may be normal
despite an increased minimal coronary resistance secondary to hypertrophy, induced by hypertension. In this
example, long-standing hypertension has induced hypertrophy, which has normalized wall stress and hence basal
coronary flow per g of tissue. The minimal coronary
resistance per g is increased by hypertrophy. However,
the increased perfusion pressure has compensated for the
increased minimal coronary resistance so that the reserve
in the hypertrophied heart (R-105) is equal to that in the
normal heart (R-90). -, Normal maximal dilatation;
-,
basal flow; ----, maximal dilatation with left
ventricular hypertrophy.
Patients with left ventricular hypertrophy secondary to
aortic stenosis have a normal coronary flow at rest [11,
33, 451, yet 50% of these patients developed lactate
production during the stress of atrial pacing [33], suggesting an impaired coronary reserve. Coronary reserve was
impaired only in those patients with severe left ventricular
hypertrophy (mass> 200 g), whereas it remained normal
when hypertrophy was less severe [11].In patients with
severe symptomatic aortic stenosis and normal coronary
arteriograms, coronary reserve, assessed in response to
transient coronary occlusion, was markedly impaired in
the vessels supplying the hypertrophied left ventricle [lo].
Coronary reserve is reduced in patients with left
ventricular hypertrophy secondary to aortic regurgitation
[12]. In patients with aortic regurgitation and angina, despite normal coronary arteriograms, reserve is markedly
reduced [46].
Coronary flow also may be impaired in supravalvular
aortic stenosis because of coronary ostial obstruction.
The impaired coronary reserve associated with supravalvular aortic stenosis was not improved immediately
after surgical repair when the possibility of ostial
occlusion had been eliminated [47], suggesting that left
ventricular hypertrophy is the prime determinant of the
decreased coronary reserve.
Minimal coronary resistance is increased in hypertrophic cardiomyopathy. The degree of impairment is
related to the left ventricular mass [48]. The vasodilator
response is more impaired in a subgroup with impaired
exercise tolerance, suggesting that ischaemia may lead to
impaired left ventricular function.
Abnormalities of coronary perfusion are present in
animal models of left ventricular hypertrophy, although
706
D. J. O’Gorman and D. J. Sheridan
the impairment of flow reserve is usually considerably less
than in clinical studies. Hypertrophy has been induced in
rats [41, 42, 49-52], dogs [27, 53-57], pigs [58] and
guinea pigs [ 591 by various methods: spontaneous hypertension [42,49], renal hypertension [27, 52, 53, 571, aortic banding [50, 54, 55, 591, aortic valve stenosis [56],
mineralocorticoid-induced volume overload [411, heartblock-induced volume overload [60] and reactive hypertrophy post-myocardial infarction [511.
In animal models of left ventricular hypertrophy it is
possible to look at transmural variation in coronary flow.
Left ventricular hypertrophy may lead to an abnormal
distribution of flow across the ventricular wall, resulting in
some areas having a higher risk of ischaemia. When dogs
with left ventricular hypertrophy were subjected to pacing
tachycardia (200 beats/min), flow per g of tissue increased
equally in the hypertrophied and control groups, but there
was a decrease in the endocardial/epicardial ratio in the
hypertrophied group [53].At a higher pacing rate (250
beats/min) subendocardial flow reserve, as determined by
adenosine-induced vasodilatation, was exhausted, whereas
some subepicardial reserve remained [37]. Similar
findings of redistribution of flow away from the subendocardium have been documented when demand is
increased [56,61].This redistribution of flow may explain
the presence of lactate production when coronary flow is
increasing [33]. More recent studies have shown that this
redistribution of flow is associated with subendocardial
dysfunction [24, 261. In the failing hypertrophied heart,
the resting subendocardial demand may be sufficient to
exhaust its reserve, leading to periodic episodes of endocardial ischaemia, which in turn result in an exacerbation
of the left ventricular failure [ 151.
Coronary reserve is impaired in left ventricular hypertrophy secondary to hypertension, aortic valve disease
and hypertrophic cardiomyopathy. Coexistent coronary
disease further impairs reserve. Animal models have been
developed in which to determine the mechanisms of the
impaired reserve and to investigate the transmural
variation in flow and demand.
Mechanisms of impaired coronary reserve
Basal flow per g of tissue is usually normal with left
ventricular hypertrophy. An increase in basal coronary
flow, due to the increased metabolic demand of increased
pressure or volume work, reduces the coronary reserve in
the absence of any change in coronary vascularity. Acute
administration of thyroxine can increase basal flow
causing a marked reduction in coronary reserve [62](Fig.
3). A reduced coronary reserve in patients with left
ventricular hypertrophy secondary to aortic regurgitation
was due to an increased basal flow rate, with no increase in
minimal coronary resistance [46]. If resting demand is
increased together with a reduced minimal coronary
resistance, then the heart is especially vulnerable to
ischaemic episodes [ 5 5 ] .
The hypothesis that the maximal cross-sectional area of
the coronary resistance vessels does not increase commensurate with the increase in ventricular mass is
-
140
120
.r 100
E
2 80
60
C
2
40
2
20
e
Rcrcrve oflcr T.
Fig. 3. The Figure shows how an increased basal
metabolic demand, in this case induced by administration
of thyroxine (TJ, can reduce coronary reserve despite
having no effect on minimal coronary resistance. -,
Maximal vasodilatation; -, basal flow; - - - -, flow
after administration of T4.
supported by the finding that the minimal coronary resistance of the whole ventricle is unchanged in many models
of hypertrophy [41, 46, 52, 53, 56, 57, 591, despite a
reduction in minimal coronary resistance per g of tissue.
Morphological studies [57, 581 have shown a reduced
arteriolar density in hypertrophied hearts. A decrease in
the cardiac concentration of cyclic GMP kinase, an index
of vascularization, in the hypertrophied heart secondary
to hypertension [63] suggests that there is a failure of vascular proliferation.
Some studies suggest that proliferation of the coronary
vasculaturc may lag behind the development of
myocardial hypertrophy [49, 641. Spontaneously hypertensive rats had an increased minimal coronary resistance
when studied at 3 and 7 months, but by 15 months
minimal coronary resistance was normal [49]. A similar
study in dogs with renal hypertension found an impaired
vasodilator ability at 6 weeks that had returned to normal
at 7 months. No improvement in coronary rcserve with
increasing duration of hypertrophy has been found in
other models [65,66].
The finding of an impaired coronary reserve with
hypertension in the absence of left ventricular hypertrophy suggests that the high coronary perfusion pressure
may lead to structural change in the coronary resistance
vessels [67]. Medial hypertrophy of the coronary
arterioles has been detected in the hypertrophied heart of
the rat [68-701. This hypertrophy of the media does not
necessarily encroach on the lumen [68]. The right
ventricle is not significantly hypertrophied in animal
models of systemic hypertension, but is exposed to a high
perfusion pressure. Coronary reserve is decreased in the
right ventricle of the hypertensive rat [49, 711. In other
species, e.g. dog [57, 641, cat [72], pig [58] and man [14],
hypertension-induced changes have not been detected.
However, the conditions which lead to hypertensioninduced vascular changes in other organs do not prevail in
the hypertensive heart. The coronary vessels are not
exposed to an unduly high pressure, as most of the
coronary perfusion occurs in diastole. In other organs the
high perfusion pressure induces prolonged vasoconstric-
Coronary flow and left ventricular hypertrophy
tion so that flow is reduced to match metabolic needs. But
in the heart, metabolic demand is increased by the
increased blood pressure and there is less tendency to
coronary vasoconstriction.
The coronary vessels are not exposed to a high
perfusion pressure in valvular aortic stenosis. In this
situation coronary reserve is impaired [lo, 561. Coronary
reserve in the right ventricle is also impaired with right
ventricular hypertrophy when the perfusion pressure is
normal [73]. Thus vascular changes secondary to high perfusion pressures cannot explain the reduced coronary
reserve seen in these models of hypertrophy.
Extravascular compression may impair coronary perfusion. Coronary reserve was impaired in dogs with renal
hypertension only while hypertension was present. When
the blood pressure was normalized and before hypertrophy had regressed, the coronary reserve was not
impaired [53]. As most of the coronary perfusion occurs
during diastole, an elevated end-diastolic pressure
associated with left ventricular hypertrophy may reduce
maximal coronary flow, particularly to the subendocardium [74, 751. In addition, delayed ventricular relaxation induced by hypothermia or reperfusion, after
regional myocardial ischaemia, has also been shown to
decrease early diastolic coronary blood flow [76].
Altered systolic forces also may impair perfusion,
especially when the left ventricular intracavitary pressure
is greater than the coronary perfusion pressure [77]. The
magnitude of the reduction in coronary reserve with
aortic stenosis without left ventricular hypertrophy is
similar to that seen with a 60% lesion supplying a nonhypertrophied ventricle [78], illustrating the effects of
extravascular compression and the increased metabolic
demand of a higher left ventricular systolic pressure. In
hypertrophic cardiomyopathy with outflow tract obstruction, pacing to 130 beats/min causes left ventricular
systolic and diastolic pressures to rise, leading to an actual
increase in coronary vascular resistance despite biochemical evidence of ischaemia [ 131. This implies that
increased ’ extravascular forces are overcoming the
metabolic vasodilatation.
Impaired coronary reserve may result from an
abnormal regulation of coronary flow or from an
abnormal vasodilator response. The autoregulatory range
for the hypertrophied heart is shifted to the right [27,79],
making the ventricle more vulnerable to ischaemia at low
perfusion pressures. Over the physiological range,
increases in metabolic demand are accompanied by an
increase in coronary flow without an increased oxygen
extraction and a normally increased release of adenosine
in the hypertrophied heart [SO]. The supply of energy, as
assessed by nuclear magnetic resonance spectroscopy,
does not differ between the hypertrophied and normal
hearts [ 191. These findings suggest that metabolic regulation is intact, although it may only be effective at higher
perfusion pressures.
Intravenous infusion of ergonovine induced a coronary
constrictor response in some hypertensive patients
without left ventricular hypertrophy or coronary atherosclerosis. There was no change in the coronary resistance
707
of the control group [67], suggesting that the coronary
vessels in hypertension may have an increased sensitivity
to circulating vasoconstrictors.
A small increase in plasma viscosity has been detected
in patients with hypertension [81]. This also may contribute to a decreased maximal coronary flow [82,83].
Morphological studies have shown a reduced capillary
density in hypertrophy [84, 851, predominantly in the
subendocardium [57, 58, 86, 871. Thus there is an
increased diffusion distance for oxygen to enter the
myocytes, leading to a further impairment of oxygen
supply.
Coronary reserve depends on the basal coronary flow
and the minimal coronary resistance. Minimal coronary
resistance may be increased by many mechanisms: failure
(or delayed) proliferation of coronary vessels, medial
hypertrophy, extravascular compression, abnormal
vasodilator responses, altered regulation and changes in
viscosity of the blood. Delivery of oxygen to the tissues is
further impaired by an increased diffusion distance.
Factors affecting coronary reserve with left ventricular
hypertrophy
Hypertrophy may occur in response to many stimuli.
The coronary response depends on the stimulus and
coronary reserve is not reduced with all types of hypertrophy.
Acute administration of thyroxine reduced the
coronary reserve by increasing basal coronary flow [62].
Chronic therapy, however, induces hypertrophy in
which the coronary reserve is maintained [88] and the
minimal coronary resistance is decreased. The myocardial concentration of cyclic GMP kinase is normal in
thyroxine-induced left ventricular hypertrophy [63],
suggesting that vascular proliferation has paralleled the
increase in myocardial mass. Similarly hypertrophy
induced by exercise training is not associated with
impaired reserve [89]. Exercise thus promotes vascular
growth in the normal heart.
Hypertrophy induced by volume overload has a variable
effect on coronary haemodynamics. In clinical studies,
volume overload secondary to valvular regurgitation [ 12,
461 and right ventricular volume overload secondary to an
atrial septa1 defect [73] are associated with a reduced
coronary reserve. Increased basal demand may explain
the impaired coronary reserve, rather than an impaired
minimal coronary resistance. Hypertrophy secondary to
anaemia [90], aortocaval fistula [91] or complete heart
block [60]is associated with a preserved coronary reserve
and evidence of vascular proliferation [90]. Anaemia will,
however, decrease the minimal coronary resistance,
independently of any effect of volume overload on the
vasculature, by virtue of diminished viscosity [82,831.
Coronary reserve is reduced in the reactive myocardial
hypertrophy that occurs after a myocardial infarction [5 11.
The age of onset of hypertrophy also may play a role in
the adaptation of the coronary circulation. Proliferation of
the coronary vasculature occurs during the period of
normal body growth. However, left ventricular hyper-
D. J. O’Gorman and D. J. Sheridan
708
trophy induced during this period manifests a similarly
impaired minimal coronary resistance to that in the adult
[92]. Induction of hypertrophy in immature animals [37,
931 leads to a greater degree of hypertrophy and a greater
impairment of coronary reserve than when hypertrophy is
induced in mature animals [53,54].
The duration of hypertrophy is important in some
models. Coronary reserve appears to be most impaired
during the stage of development of hypertrophy and may
normalize when hypertrophy has stabilized [49, 64, 941.
Other studies have found no improvement in coronary
reserve with time [65, 951 and this is likely to be true in
patients with hypertension as they are likely to have had
long-standing hypertension before their investigation [32].
The effect of hypertrophy on coronary reserve
depends on the nature of the stimulus to hypertrophy, the
species, the age at onset and the duration of the stimulus.
IMPLICATIONS
THERAPY
FOR
ANTI-HYPERTENSIVE
Anti-hypertensive therapy has been successful in reducing mortality from stroke and renal failure, but the reduction in cardiovascular mortality has been disappointing
[96, 971. The relatively small effect may be due to the
adverse effect of anti-hypertensive therapy on blood lipid
levels or the provocation of arrhythmias by hypokalaemia.
In the Framingham study the incidence of sudden death
was correlated with anti-hypertensive therapy [98].Alternatively, anti-hypertensive strategies based solely on the
values of diastolic and systolic blood pressures, that d o
not address the phenomenon of impaired coronary
reserve, may contribute to the disappointing results.
The goal of anti-hypertensive therapy
There is some controversy over the optimal perfusion
pressure for the hypertensive heart. A meta-analysis of
observational studies showed a direct relationship
between the risk of coronary heart disease and diastolic
blood pressure, with no lower threshold [99]. Yet when
therapeutic studies in hypertensive patients were analysed
in this fashion, a J-shaped relationship between cardiac
events and diastolic blood pressure was demonstrated.
There appears to be a beneficial therapeutic threshold at
the level of 85 mmHg [ 1001. This threshold may be more
pronounced for patients with pre-existing ischaemic heart
disease [ 1011. These apparently conflicting results can be
reconciled by the concept of impaired coronary reserve in
hypertensive hearts. Thus in therapeutic studies the
benefits of reducing the perfusion pressure, and thus the
atherogenic potential, may be outweighed by the adverse
effect on maximal coronary flow in the hypertensive heart.
In normotensive hearts, the lower incidence of coronary
obstructive disease and the absence of hypertrophy yields
a greater coronary reserve. Thus a continued decrease in
risk may be seen with further reduction of diastolic blood
pressure.
Further evidence that an impairment of coronary
reserve may play a role in the onset of ischaemic events
was provided in a study when diastolic blood pressure
was reduced rapidly with nifedipine and nitroprusside to
between 85 and 90 mmHg in hypertensive patients.
Abnormal repolarization changes were seen in seven of
14 patients with left ventricular hypertrophy and in none
of 28 patients with a normal cardiac mass [102].
Overaggressive therapy may lead to episodic hypoperfusion and may increase the potential for progression to
heart failure and the risk of myocardial infarction.
Twenty-one per cent of patients with borderline hypertension (diastolic blood pressures of 90-104 mmHg)
measured at a clinic have ambulatory pressures within the
normal range [ 1031; these patients are particularly at risk
of myocardial hypoperfusion if they are put on antihypertensive medication. Nocturnal hypotension is
common in treated hypertensive patients, despite satisfactory clinic blood pressures. During sleep, mean hourly
diastolic blood pressures of 50 mmHg or less were
recorded in 11 of 34 treated patients compared with only
two of 34 before treatment [104].
Effects of anti-hypertensive therapy on coronary reserve
Reduction of the coronary perfusion pressure in isolation will reduce coronary reserve (Fig. 1).The overall
effect of anti-hypertensive therapy on coronary reserve
depends on the interaction between the reduction in
perfusion pressure, the reduction in metabolic demand
and the minimal coronary resistance. Total metabolic
demand may be reduced by the decreased systolic
pressure and a reduction in myocardial mass. Improving
the minimal coronary resistance requires modification of
vascular and extravascular factors. Tolerance of myocardial ischaemia also may be improved by anti-hypertensive therapy.
Reversal of left ventricular hypertrophy
Reversal of left ventricular hypertrophy can be
achieved with P-adrenoceptor blockers [ 105-108],aadrenoceptor blockers [ 1091, methyldopa [ 110-1 121,
clonidine [ 110, 1131, calcium-channel blockers (calcium
antagonists) [ 114-1 161 and angiotensin-converting
enzyme inhibitors [117-1191. Monotherapy with diuretics
has little effect on left ventricular hypertrophy [120, 1211.
Arteriolar vasodilators may increase the degree of hypertrophy [110, 1221. The degree of regression of left
ventricular hypertrophy is independent of the level of
blood pressure control [123].
The effect of reversal of hypertrophy on coronary
reserve has not been defined in hypertensive patients. But
in a study of patients with left ventricular hypertrophy
induced by aortic stenosis, regression of hypertrophy
after successful aortic valve replacement was associated
with an improved coronary reserve. This improvement in
reserve was due to a reduced basal flow consequent on a
reduced metabolic demand [ 1241. Animal models of
hypertrophy have also shown an improvement in
coronary reserve with regression of hypertrophy [50,125,
1261, although this is not universal [127].
Coronary flow and left ventricular hypertrophy
There is some concern that regression of hypertrophy
may be associated with an increased collagen concentration, leading to an increased vulnerability to arrhythmias
and impaired left ventricular function [128]. A sudden
increase in blood pressure may precipitate heart failure in
the heart that is now unprotected by hypertrophy. Experimental evidence, however, suggests that reversal of hypertrophy may be beneficial in reversing the abnormalities of
systolic function [105,116, 129,1301 and susceptibility to
arrhythmias [ 1211. Left ventricular diastolic dysfunction
has been reversed by anti-hypertensive therapy with a padrenoceptor blocker [ 1313 and a calcium antagonist
[ 1321, although this effect was independent of reversal of
hypertrophy. This may represent a direct effect on diastolic relaxation. One study demonstrated reversal of left
ventricular hypertrophy with an angiotensin-converting
enzyme inhibitor, but found no improvement in indices of
diastolic function [ 1171. Angiotensin-converting enzyme
inhibition can reduce cardiac mass and also reduce the
total amount of collagen [133,134].
Coronary vascular remodelling
The peripheral vascular changes induced by hypertension have been partially reversed by anti-hypertensive
therapy [135]. Drugs that have a coronary vasodilator
effect may reduce the chronically increased coronary
vasomotor tone. A reduction in the media/lumen ratio
and an improved coronary reserve have been induced by
therapy with hydralazine [69, 1361, isradipine [136] and
cilazapril [ 1371 in experimental animals. A potential disadvantage of coronary vasodilators is their ability to
induce a transmural steal syndrome by diverting flow
away from the subendocardium. Inappropriate vasodilatation in subepicardial regions may drain an excessive
proportion of the total coronary flow.
Extravascular compression
Decreasing the heart rate allows an increased time for
diastolic perfusion of the myocardium. Improving
diastolic relaxation enables an increased early diastolic
coronary blood flow [76].
Vulnerability to ischaemia
Calcium antagonists have been shown to improve
ventricular function after periods of ischaemia, both in the
normal [76, 1381 and the hypertrophied [139] heart, thus
providing cardioprotection. T h e extent of ischaemic
damage induced by hypoxic perfusion was reduced in
spontaneously hypertensive rats when the blood pressure
was reduced by hydralazine. There was a much greater
reduction in ischaemic damage when captopril reversed
left ventricular hypertrophy as well as reducing the blood
pressure [20].
Role of exercise
Exercise induces left ventricular hypertrophy that is
associated with a normal coronary reserve. However,
exercise training could neither prevent the development
709
of impaired coronary reserve I1401 nor reverse the
physiological or morphological changes [87] in the hypertensive heart.
Other factors
Other factors may be important in the selection of an
anti-hypertensive agent. The gradual onset of the antihypertensive effect of /?-adrenoceptor blockers is useful
in avoiding a sudden drop in myocardial perfusion and
allowing a concurrent reduction in mass and pressure
[141].The anti-arrhythmic effect of calcium antagonists
and p-adrenoceptor blockers also may be beneficial in
reducing cardiac mortality. There is some evidence that
calcium antagonists may prevent the development of
atherosclerotic lesions independently of changes in blood
lipid levels o r blood pressure [142].
Abnormalities of coronary perfusion may account for
the disappointing results of anti-hypertensive therapy.
The aim of therapy should be the gradual attainment of
the optimal perfusion pressure, which appears to be
approximately 85 mmHg. Anti-hypertensive therapy may
improve coronary reserve by various mechanisms, in
particular reversal of left ventricular hypertrophy,
remodelling of the coronary vasculature and reducing
extravascular compression.
CONCLUSIONS
The hypertrophied heart is at increased risk of ischaemic
events. The importance of the various mechanisms underlying the impaired perfusion needs to be determined in
the hypertensive hypertrophied heart in man. Anti-hypertensive therapy can then be tailored to modifying these
factors. T h e ultimate success of an anti-hypertensive
strategy would be to improve cardiac risk to the extent
predicted by epidemiological studies.
REFERENCES
1. Savage, D.D., Garrison, R.J., Kannel, W.B. et al. The
spectrum of left ventricuIar hypertrophy in a general population sample: the Framingham study. Circulation 1987;
75, (Suppl.I), 26.
2. Kannel, W.B. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am. J. Med.
1983;75.4-1 1.
3. Dreslinski, G.R. Identification of left ventricular hypertrophy: chest roentography, echocardiography, and
electrocardiography. Am. J. Med. 1983: 75,47-50.
4. Kannel, W.B. Common electrocardiographic markers for
subsequent clinical coronary events. Circulation 1987; 75,
11-25-7.
5. Kannel, W.B. Role of blood pressure in cardiovascular
morbidity and mortality. Prog. Cardiovasc. Dis. 1974; 17,
5- 17.
6. Cooper, R.S., Simmons, B.E., Castaner, A., Santhanam, V.,
Ghali, J. & Mar, M. Left ventricular hypertrophy is
associated with worse survival independent of ventricular
function and number of coronary arteries severely
narrowed. Am. J. Cardiol. 1990; 65,441-5.
7. Gordon, T. & Kannel, W.B. Premature mortality from
coronary heart disease. The Framingham study. J. Am.
Med.Assoc. 1971;215, 1617-25.
D. J. O'Gorman and D. J. Sheridan
710
8. Wrobewski, E.M., Pearl, F.J., Hammer, W.J. et al. Falsepositive stress test due to undetected left ventricular
hypertrophy.Am. J. Epidemiol. 1982; 115,412-17.
9. Houghton, J.L., Frank, M.J., Carr, A.A., Von Dohlen, T.W.
& Prisant, L.M. Relations among impaired coronary flow
reserve, left ventricular hypertrophy and thallium
perfusion defects in hypertensive patients without obstructive coronary artery disease. J. Am. Coll. Cardiol. 1990;
15,43-51.
10. Marcus, M.L., Doty, D.B., Hiratzka, L.F., Wright, C.B. &
Eastman, C.L. A mechanism for angina pectoris in patients
with aortic stenosis and normal coronary arteries. N. Engl.
J. Med. 1982; 307, 1362-7.
11. Pichard, A.D., Gorlin, R., Smith, H., Ambrose, J. & Meller,
J. Coronary flow studies in patients with left ventricular
hypertrophy of the hypertensive type. Evidence for an
impaired coronary vascular reserve. Am. J . Cardiol. 1981;
47,547-53.
12. Pichard, A.D., Smith, H., Holt, J. et al. Coronary vascular
reserve in left ventricular hypertrophy secondary to
chronic aortic regurgitation. Am. J. Cardiol. 1983; 51,
3 15-20.
13. Cannon, R.O., 111, Schenke, W.H., Maron, B.J. et al.
Differences in coronary flow and myocardial metabolism
at rest and during pacing between patients with obstructive
and patients with nonobstructive hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 1987; 10,53-62.
14. Opherk, D., Mall, G., Zebe, H. et al. Reduction of coronary
reserve: a mechanism for angina pectoris in patients with
arterial hypertension and normal coronary arteries. Circulation 1984; 69, 1-7.
15. Hittinger, L., Shannon, R.P., Bishop, S.P., Gclpi, R.J. &
Vatner, S.F. Subendomyocardial exhaustion of blood flow
reserve and increased fibrosis in conscious dogs with heart
failure. Circ. Res. 1989; 65, 971-80.
16. Capasso, J.M., Palackal, T., Olivetti, G. & Anvcrsa, P. Left
ventricular failure induced by long-term hypertension in
rats. Circ. Res. 1990; 66, 1400-12.
17. Tomanek, R.J., Wangler, R.D. & Bauer, C.A. Prevention of
coronary vasodilator reserve decrement associated with
long-term hypertension in spontaneously hypertensive
rats. Hypcrtcnsion 1985; 7,533-40.
18. Siri, EM., Nordin, C., Factor, M.. Sonncnblick, E. 6:
Aronson, R. Compensatory hypertrophy and failure in
gradual prcssurc-overloaded guinea pig heart. Am. J.
Physiol. 1989; 257, H 10 16-24.
19. Buser, P.T., Wagner, S., Wu, S.T. et al. Verapamil preserves
myocardial performance and energy metabolism in left
ventricular hypertrophy following ischemia and repcrfusion. Phosphorus 3 1 magnetic resonance spectroscopy
study. Circulation 1989; 80, 1837-45.
20. Canby, C.A. & Tomanek, R.J. Regression of ventricular
hypertrophy abolishes cardiocyte vulnerability to acute
hypoxia. Anat. Rec. 1990; 226, 198-206.
21. Mueller, T.M., Tomanek, R.J., Kerber, R.E. & Marcus,
M.L. Myocardial infarction in dogs with chronic hypertension and left ventricular hvt~ertroohv.Am. J. Phvsiol.
1980; 8, H37 1-5.
22. Kovanagi, S.. Eastham. C. & Marcus. M.L. Effect of
chronic-hypertension and left ventricular hypertrophy on
the incidence of sudden cardiac death after coronary
artery occlusion in conscious dogs. Circulation 1982; 65,
1192.
23. Kanncl, W.B., Dannenberg, A.L. & Abbott, R.D. Unrecognised myocardial infarction and hypertension: the
Framingham study. Am. Heart J. 1985; 109,581-5.
24. Nakano, K., Corin, W.J., Spaan, J.F., Jr., Biederman,
R.W.W., Denslow, S. & Carabello, B.A. Abnormal subendocardial blood flow in pressure overload hypertrophy
is associated with pacing-induced subendocardial dysfunction. Circ. Res. 1989; 675, 1555-64.
25. Vatner, S.F., Shannon, R. 6: Hittinger, L. Reduced subendocardial coronary reserve. A potential mechanism for
,.
.,
26.
27.
28.
29.
30.
31.
32.
3 3.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
impaired diastolic function in the hypertrophied and
failing heart. Circulation 1990; 81 (Suppl. H I ) , 111-8- 14.
Hittinger, L., Shannon, R.P., Kohin, S., Manders, W.T.,
Kelly, P. & Vatner, S.F. Exercise-induced subendocardial
dysfunction in dogs with left ventricular hypertrophy. Circ.
Res. 1990; 66,329-43.
Jeremy, R.W., Fletcher, P.J. & Thompson, J. Coronary
pressure-flow relations in hypertensive left ventricular
hypertrophy. Comparison of intact autoregulation with
physiological and pharmacological vasodilation in the dog.
Circ. Res. 1989; 65,224-36.
Messerli, F.H., Ventura, H.O., Elizardi, D.J., Dunn, F.G. &
Frohlich, E.D. Hypertension and sudden death. Increased
ventricular ectopic activity in left ventricular hypertrophy
Am. J. Med. 1984; 77,18-22.
McLenachan, J.M., Henderson, E., Morris, K.I. 6( Dargie,
H.J. Ventricular arrhythmias in patients with hypertensive
left ventricular hypertrophy. N. Engl. J. Med. 1989; 317,
787-92.
Weber, K.T. & Janicki, J.S. The mctabolic demand and
oxygen supply of the heart: physiological and clinical considerations. Am. J. Cardiol. 1979; 44, 722-9.
Strauer, B.E. The coronary circulation in hypertensive
heart disease. Hypcrtcnsion 1984; 6 (Suppl. Ill), 11174-80.
Strauer, B.E. Myocardial oxygen consumption in chronic
heart disease: role of wall stress, hypertrophy and coronary
reserve. Am. J. Cardiol. 1979; 44,730-40.
Trenouth, R.S., Phelps, N.C. & Neill, W.A. Determinants
of left ventricular hypertrophy and oxygen supply in
chronic aortic valve disease. Circulation 1976; 53,
644-50.
Meerson, F.Z. The myocardium in hyperfunction, hypertrophy and heart failure. Circ. Res. 1969; 25,11-1-8.
Baird, R.J., Goldbach, M.M. 6r dc la Rocha, A. Intramyocardial pressure. The pcrsistance of its transmural
gradient in the empty heart and its relationship to
myocardial oxygen consumption. J. Thorac. Cardiovasc.
Surg. 1972; 64,635-46.
Rembert, J.C., Kleinman, L.H. & Fedor, J.M. Myocardial
blood flow distribution in concentric L.V. hypertrophy. J.
Clin. Invest. 1978; 62,379-86.
Bache, R.J., Vrobel, T.R., Arentzen, C.E. & Ring, W.S.
Effect of maximal coronary vasodilation on transmural
myocardial perfusion during tachycardia in dogs with left
ventricular hypertrophy. Circ. Res. 1981; 49, 742-50.
Mosher, P., Ross, J., McFate, P.A. & Shaw, R.F. Control of
coronary blood flow by an autoregulatory mechanism.
Circ. Res. 1964; 14, 250.
Driscol, T.E., Moir, T.W. & Eckstein, R.W. Autoregulation
of coronary blood flow: effect of interarterial pressure
gradients. Circ. Res. 1964; 15, 103- 1 I .
Masher, P., Ross, J., Jr., McFatc, P.A. 61 Shaw, R.F. Control
of coronary blood flow by an autoregulatory mechanism.
Circ. Res. 1964; 14,250-9.
Yamamoto, J., Tsuchiya, M., Saito, M. & Ikeda, M. Cardiac
contractile and coronary flow reserves in deoxycorticosterone acetate-salt hypertensive rats. Hypertension
1985; 7,569-77.
Kobayashi, K., Tarazi, R.C., Lovenberg, W. & Rakusan, K.
Coronary blood flow in genetic cardiac hypertrophy. Am.
J. Cardiol. 1984; 53, 1360-4.
Strauer, B.E. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am. J. Cardiol.
1979;44,999-1006.
Goldstein, R.A. & Haynie, M. Limited myocardial perfusion reserve in patients with left ventricular hypertrophy.
J. Nuclear Med. 1990;. 31,255-8.
,
Bertrand, M.E., Lablanche, J.M., Tilmant, P.Y., Thieuleux,
F.P., Delforge, M.R. & Carre, A.G. Coronary sinus blood
flow at rest and during isometric exercise in patients with
aortic valve disease. Am. J. Cardiol. 1981; 47, 199-205.
Coronary flow and left ventricular hypertrophy
46. Nitenberg, A., Foult, J., Antony, I., Blanchet, F. & Rahali,
M. Coronary flow and resistance reserve in patients with
chronic aortic regurgitation, angina pectoris and normal
coronary arteries. J. Am. Coll. Cardiol. 1988; 11,478-86.
47. Doty, D.B., Eastham, C.L., Hiratzka, L.F., Wright, C.B. &
Marcus, M.L. Determination of coronary reserve in
patients with supravalvular aortic stenosis. Circulation
1982; 66 (SUPPI.I), 1-186.
48. Shimamatsu, M. & Toshima, H. Impaired coronary vasodilatory capacity after dipyridamole administration in
hypertrophic cardiomyopathy. Jpn. Heart J. 1987; 28,
387-401.
49. Wangler, R.D., Peters, K.G., Marcus, M.L. & Tomanek,
R.J. Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator
reserve. Circ. Res. 1982; 51, 10-18.
50. Isoyama, S., Ito, I., Kurcha, M. & Takishima, T. Complete
reversibility of physiological coronary vascular abnormalities in hypertrophied hearts produced by pressure
overload in the rat. J. Clin. Invest. 1989; 84,288-94.
51. Karam, R., Healy, B.P. & Wicker, P. Coronary reserve is
depressed in post myocardial infarction reactive cardiac
hypertrophy. Circulation 1990; 81,238-46.
52. Wicker, P., Tarazi, R.C. & Kobayashi, K. Coronary blood
flow during the development and regression of left
ventricular hypertrophy in renovascular hypertensive rats.
Am. J. Cardiol. 1983; 51, 1744-9.
53. Mueller, T.M., Marcus, M.L., Kerber, R.E., Young, J.A.,
Barnes, R.W. & Abboud, F.A. Effect of renal hypertension
and left ventricular hypertrophy on the coronary circulation in dogs. Circ. Res. 1978; 42,543-9.
54. OKeefe, D.D., Hoffman, J.I.E., Cheitlin, R., ONeill, M.J.,
Allard, J.R. & Shapkin, E. Coronary blood flow in experimental canine left ventricular hypertrophy. Circ. Res.
1978; 43,43-51.
55 Parrish, D.G., Steves Ring, W. & Bache, R.J. Myocardial
perfusion in compensated and failing hypertrophied left
ventricle. Am. J. Physiol. 1985,249, H534-9.
56. Alyono, D., Anderson, R.W., Parrish, D.G., Dai, X.Z. &
Bache, R.J. Alterations of myocardial blood flow
associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis. Circ. Res.
1986; 58,47-57.
57. Tomanek, R.J., Palmer, P.J., Peiffer, G.L., Schreiber, K.L.,
Eastham, C.L. & Marcus, M.L. Morphometry of canine
coronary arteries, arterioles, and capillaries during hypertension and left ventricular hypertrophy. Circ. Res. 1986;
58,38-46.
58. Breisch, E.A., White, F.C., Nimmo, L.E. & Bloor, C.M.
Cardiac vasculature and flow during pressure overload
hypertrophy. Am. J. Physiol. 1986; 251, H1031-7.
59. OGorman, D.J., Thomas, P., Turner, M.A. & Sheridan,
D.J. Investigation of impaired coronary vasodilator reserve
in the hypertrophied guinea pig heart. Eur. Heart J. 1992
(In press).
60. Gascho, J.A., Mueller, T.M., Eastham, C. & Marcus, M.L.
Effect of volume-overload hypertrophy on the coronary
circulation in awake dogs. Cardiovasc. Res. 1982; 16,
288-92.
61. Bache, R.J., Dai, X.-Z., Alyono, D., Vrobel, T.R. &
Homans, D.C. Myocardial blood flow during exercise in
dogs with left ventricular hypertrophy produced by aortic
banding and perinephritic hypertension. Circulation 1987;
76,835-42.
62. Talafih, K., Briden, K.L. & Weiss, H.R. Thyroxine-induced
hypertrophy of the rabbit heart. Effect on regional oxygen
extraction, flow, and oxygen consumption. Circ. Res. 1983;
52,272-9.
63. Ecker, T., Gobel, C., Hullin, R., Rettig, R., Seitz, G. &
Hofmann, F. Decreased cardiac concentration of cGMP
kinase in hypertensive animals. An index for cardiac
vascularization? Circ. Res. 1989; 65, 1361-9.
711
64. Tomanek, R.J., Schalk, K.A., Marcus, M.L. & Harrison,
D.G. Coronary angiogenesis during long-term hypertension and left ventricular hypertrophy in dogs. Circ. Res.
1989; 65,352-9.
65. Ito, N., Isoyama, S., Kuroha, M. & Takishima, T. Duration
of pressure overload alters regression of coronary circulation abnormalities. Am. J. Physiol. (Heart Circ. Physiol.)
1990; 258, H1753-60.
66. Marcus, M.L., Mueller, T.M. & Eastham, C.L. Effects of
short- and long-term ventricular hypertrophy on coronary
circulation. Am. J. Physiol. 1981; 241, H358-62.
67. Brush, J.E., Jr., Cannon, R.O., 111, Schenke, W.H. et al.
Ang.ina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N.
Engl. J. Med. 1988; 319, 1302-7.
68. Rakusan, K. & Wicker, P. Morphometry of the small
arteries and arterioles in the rat heart: effects of chronic
hypertension and exercise. Cardiovasc. Res. 1990; 24,
278-84.
69. Anderson, P.G., Bishop, S.P. & Digerness, S.B. Vascular
remodeling and improvement of coronary reserve after
hydralazine treatment in spontaneously hypertensive rats.
Circ. Res. 1989; 64, 1127-36.
70. Yamori, Y., Mori, C., Nishio, T. et al. Cardiac hypertrophy
in early hypertension. Am. J. Cardiol. 1979; 44,964-9.
71. Wicker, P. & Tarazi, R.C. Right ventricular coronary flow
in arterial hypertension. Am. Heart J. 1985; 110,845-50.
72. Breisch, E.A., Houser, S.R., Carey, R.A. et al. Myocardial
blood flow and capillary density in chronic pressure overload of the feline left ventricle. Cardiovasc. Res. 1980; 14,
469-75.
73. Doty, D.B., Wright, C.B., Hiratzka, L.F. et al. Coronary
reserve in volume-induced right ventricular hypertrophy
from atrial septa1 defect. Am. J. Cardiol. 1984; 54,
1059-63.
74. Ellis, A.K. & Klocke, F.J. Effects of preload on the transmural distribution of perfusion and pressure-flow
relationships in the canine coronary vascular bed. Circ.
Res. 1979; 46,68-77.
75. Jeremy, R.W., Hughes, C.F. & Fletcher, P.J. Effects of left
ventricular diastolic pressure on the pressure-flow relation
of the coronary circulation during physiological vasodilatation. Cardiovasc. Res. 1986; 20,922-30.
76. Domalik-Wawrynski, L.J., Powell, W. M. J., Jr., Guerrero,
L. & Palacios, I. Effect of changes in ventricular relaxation
on early diastolic coronary blood flow in canine hearts.
Circ. Res. 1987; 61,747-56.
77. Sabbah, H.N. & Stein, P.D. Reduction of systolic coronary
blood flow in experimental left ventricular outflow tract
obstruction. Am. Heart J. 1988; 116,806-1 1.
78. Feldman, R.L., Nichols, W.W., Edgerton, J.R. et al.
Influence of aortic stenosis on the hemodynamic importance of coronary artery narrowing in dogs without left
ventricular hypertrophy. Am. J. Cardiol. 1983; 51,
865-71.
79. Harrison, D.G., Florentine, M.S., Brooks, L.A., Cooper,
S.M. & Marcus, M.L. The effect of hypertension and left
ventricular hypertrophy on the lower range of coronary
autoregulation. Circulation 1988; 77, 1108-15.
80. Ely, S.W., Sun, C.W., Knabb, R.M. et al. Adenosine and
metabolic regulation of coronary blood flow in dogs with
renal hypertension. Hypertension 1983; 5,943-50.
81. Letcher, R.L., Chien, S., Pickering, T.G., Sealey, J.E. &
Laragh, J.H. Direct relationship between blood pressure
and blood viscosity in normal and hypertensive subjects.
Am. J.Med. 1981; 70,1195-202.
82. Baer, R.W., Vlahakes, G.J., Uhlig, P.N. & Hoffman, J.I.E.
Maximum myocardial oxygen transport during anemia and
polycythemia in dogs. Am. J. Physiol. 1987; 252,
H1086-95.
83. Leschke, M., Vogt, M., Motz, W. & Strauer, B.E. Blood
rheology as a contributing factor in reduced coronary
712
D. J. OGorman and D. J. Sheridan
reserve in systemic hypertension, Am. J. Cardiol. 1990;
65,56-9G.
84. Anversa, P., Olivetti, G., Melissari, M. & Loud, A.V.
Morphometric study of myocardial hypertrophy induced
by abdominal aortic stenosis. Lab. Invest. 1979; 40, 341.
85. Tillmanns, H., Neumann, F.J., Parekh, N. et al. Microcirculation in the hypertrophic and ischaemia heart. Eur. J.
Clin. Pharmacol. 1990; 39, S9-12.
86. Michel, J.B., Ossondo, M., Barres, D. & Camilleri, J.P.
Effects of experimental myocardial hypertrophy on the
coronary microcirculation -of the rat.-Arch. 'Ma1 Coeur
Vaiss. 1984: 77, 1 172-5.
87. Tomanek, R.J.,'Gisolfi, C.V., Bauer, C.A. & Palmer, P.J.
Coronary vasodilator reserve, capillarity, and mitochondria in trained hypertensive rats. J. Appl. Physiol.
1988; 64,1179-85.
88. Chilian, W.M., Wangler, R.D., Peters, K.G. et al.
Thyroxine-induced left ventricular hypertrophy in the rat.
Anatomical and physiological evidence for angiogenesis.
Circ. Res. 1985; 5 7 , 5 9 1-8.
89. Cohen, M.V. Coronary vascular reserve in the greyhound
with left ventricular hypertrophy. Cardiovasc. Rcs. 1986;
20,182-94.
90. Scheel, K.W. & Williams, S.E. Hypertrophy and coronary
and collateral vascularity in dogs with severe chronic
anemia. Am. J. Physiol. 1985; 18, H1031-7.
91. Badke, F.R., White, F.C., LeWinter, M., Covell, J., Andres,
J. & Bloor, C. Effects of experimental volume-overload
hypertrophy on myocardial blood flow and cardiac
function.Am. J. Physiol. 1981; 241, H564-570.
92. Bache, R.J., Alyono, D., Sublett, E. & Dai, X.Z.
Mvocardial blood flow in left ventricular hvDertroDhv
developing in young adult dogs. Am. J. Physiol. 3b86; i S i ,
H949-56.
93. Enzig, S., Leonard, J.J., Tripp, M.R. et al. Changes in
regional myocardial blood flow and variable development
of hypertrophy after aortic banding in puppies.
Cardiovasc. Res. 198 1; I 5 , 7 1 1-1 9.
94. Peters, K.G., Wangler, R.D., Tomanek, R.J. & Marcus,
M.L. Effects of long-term cardiac hypertrophy on
coronary vasodilator reserve in SHR rats. Am. J. Cardiol.
1984; 54,1342-8.
95. Marcus, M.L., Mueller, T.M. & Eastham, C.L. Effects of
short- and long-term left ventricular hypertrophy on
coronary circulation. Am. J. Physiol. 1981; 10, 358-62.
96. Multiple risk factor intervention trial research group.
Multiple risk factor intervention trial. Risk factor changes
and mortality results. J. Am. Med. Assoc. 1982; 248,
1465-77.
97. Collins, R., Peto, R., MacMahon, S. et al. Blood pressure,
stroke, and coronary heart disease. Part 2. Short-term
reductions in blood pressure: overview of randomised
drug trials in their epidemiological context. Lancet 1990;
335,827-38.
98. Kannel, W.B., Cupples, L.A., DAgostino, R.B. & Stokes, J.,
111. Hypertension, antihypertensive treatment, and sudden
coronary death. The Framingham study. Hypertension
. 11-45-50.
1988; 11 ( S ~ p p lII),
99. McMahon, S., Peto, R., Cutler, J. et al. Blood pressure,
stroke, and coronary heart disease. Part 1. Prolonged
differences in blood pressure: prospective observational
studies corrected for the regression dilution bias. Lancet
1990; 335,765-74.
100. Farnett, L., Mulrow, C.D., Linn, W.D., Lucey, C.R. &
Tuley, M.R. The J-curve phenomenon and the treatment
of hypertension. Is there a point beyond which pressure
reduction is dangerous? J. Am. Med. Assoc. 1991; 265,
489-95.
101. Cruickshank, J.M., Thorp, J.M. & Zacharias, F.J. Benefits
and potential harm of lowering high blood pressure.
Lancet 1987; i, 581-3.
102. Pepi, M., Alimento, M., Maltagliati, A. & Guazzi, M.D.
Cardiac hypertrophy in hypertension. Repolarization
abnormalities elicited by rapid lowering of pressure.
Hypertension 1988; 11,84-91.
103. Pickering, T.G., James, G.D., Boddie, C., Harshfield, G.A.,
Blank, S. & Laragh, J.H. How common is white coat
hypertension? J. Am. Med. Assoc. 1988; 259,225-8.
104. Floras, J.S., Jones, J.V., Hassan, M.O. & Sleight, P.
Ambulatory blood pressure during once-daily randomised
double-blind administration of atenolol, metoprolol,
pindolol, and slow-release propranolol. Br. Med. J. 1982;
285,1387-92.
105. Hartford, M., Wendelhag, I., Berglund, G., Wallentin, I.,
Ljungman, S. & Wikstrand, J. Cardiovascular and renal
effects of long-term antihypertensive treatment. J. Am.
Med. Assoc. 1988; 259,2553-7.
106. Dunn, F.G., Ventura, H.O., Messerli, F.H., Kobrin, I. &
Frohlich, E.D. Time course of regression of left ventricular
hypertrophy in hypertensive patients treated with atenolol.
Circulation 1987; 76,254-8.
107. Corea, L., Bentivoglio, M. & Verdecchia, P. Echocardiographic left ventricular hypertrophy as related to arterial
pressure and plasma norepinephrine conccntration in
arterial hypertension reversal by atenolol treatment.
Hypertension 1983; 5,837-43.
108. Sau, F., Cherchi, A. & Seguro, C. Reversal of left ventricular hypertrophy after treatment of hypertension by
atenolol for one year. Clin. Sci. 1982; 6 3 (Suppl. 8),
367-9s.
109. Venkata, S.R., Gonzalez, D., Kulkarni, P. et al. Regression
of left ventricular hypertrophy in hypertension. Effects of
prazosin therapy. Am. J. Med. 1989; 86,66-9.
110. Pegram, B.L., Ishie, S. & Frohlich, E.D. Effect of methyldopa, clonidine, and hydralazine on cardiac mass and
hemodynamics in Wistar-Kyoto and spontaneously hypertensive rats. Cardiovasc. Res. 1982; 16,40-6.
111. Hori, M., Kitakaze, M., Tamai, J. et al. Alpha2
adrenoceptor stimulation can augment coronary vasodilation maximally induced by adenosine in dogs. Am. J.
Physiol. 1989; 257, H132-40.
112. Fouad, EM., Nakashima, Y., Tarazi, R.C. & Salccdo, E.E.
Reversal of left ventricular hypertrophy in hypertensive
patients treated by methyldopa. Am. J. Cardiol. 1982; 49,
795-801.
113. Timio, M., Venanzi, S., Gentili, S., Ronconi, M., Del Re, G.
& Del Vita, M. Reversal of left ventricular hypertrophy
after one-year treatment with clonidine: relationship
between echocardiographic findings, blood pressure, and
urinary catecholamines. J. Cardiovasc. Pharmacol. 1987;
10, S142-6.
114. Schmieder, R.R.E., Messerli, F.H., Garavaglia, G.E. &
Nunez, B.D. Cardiovascular effects of verapamil in
patients with essential hypertension. Circulation 1987; 75,
1030-6.
115. Grossman, E., Oren, S., Garavaglia, G.E., Messerli, F.H. &
Frohlich, E.D. Systemic and regional hemodynamic and
humoral effects of nitrendipine in essential hypertension.
Circulation 1988; 78, 1394-400.
116. Strauer, B.E., Mahmoud, M.A., Bayer, F. et al. Reversal of
left ventricular hypertrophy and improvement of cardiac
function in man by nifedipine. Eur. Heart J. 1984; 5 ,
53-60.
117. Shahi, M., Thorn, S., Poulter, N., Sever, P.S. & Foale, R.A.
Regression of hypertensive left ventricular hypertrophy
and left ventricular diastolic function. Lancet 1990; 336,
458-61.
118. Dunn, F.G., Oigman, W., Ventura, H.O., Messerli, F.H.,
Kobrin, I. & Frohlich, E.D. Enalapril improves systemic
and renal hemodynamics and allows regression of left
ventricular mass in essential hypertension. Am. J. Cardiol.
1984; 53,105-8.
119. Nakashima, Y., Fouad, EM. & Tarazi, R.C. Regression of
left ventricular hypertrophy from systemic hypertension by
enalapril. Am. J. Cardiol. 1984; 53, 1044-9.
Coronary flow and left ventricular hypertrophy
120. Ferrara, L.A., De S h o n e , G., Mancini, M. et al. Changes
in left ventricular mass during a double-blind study with
chlorthalidone and slow-release nifedipine. Eur. J. Clin.
Pharmacol. 1984; 27,525-8.
121. Messerli, F.H., Nunez, B.D., Nunez, M.M., Garavaglia,
G.E., Schmieder, R.E. & Ventura, H.O. Hypertension and
sudden death: disparate effects of calcium entry blocker
and diuretic therapy. Arch. Intern. Med. 1989; 149,
1263-7.
122. Connor, G., Wilburn, R.L. & Bennet, C.M. Double-blind
comparison of minoxidil and hydralazine in severe hypertension. Clin. Sci. 1976; 5 1 (Suppl. 3), 593-5s.
123. Liebson, P.R. Clinical studies of drug reversal of hypertensive left ventricular hypertrophy. Am. J. Hypertens.
1990;3,512-17.
124. Eberli, ER., Ritter, M., Schwitter, J. et al. Coronary reserve
in patients with aortic valve disease before and after
successful aortic valve replacement. Eur. Heart J. 1991;
12,127-38.
125. Sato, F., Isoyama, S. & Takishima, T. Normalization of
impaired coronary circulation in hypertrophied rat hearts.
Hypertension 1990; 16,26-34.
126. Canby, C.A. & Tomanek, R.J. Role of lowering arterial
pressure on maximal coronary flow with and without
;egression of cardiac hypertrophy. Am. J. Physiol. 1989;
257. H110-18.
127., Kobayashi, K. & Tarazi, R.C. Effect of nitrendipine on
coronary flow and ventricular hypertrophy in hypertension. Hypertension 1983; 5,45-5 1.
128. Frohlich, E.D. Cardiac hypertrophy in hypertension. N.
Engl. J. Med. 1987; 317,831-3.
129. Trimarco, B., De Luca, N., Ricciardelli, B. et al. Cardiac
function in systemic hypertension before and after reversal
of left ventricular hypertrophy. Am. J. Cardiol. 1988; 62,
745-50.
130. Phillips, R.A., Ardeljan, M., Goldman, M.E., Eison, H.B.
& Krakoff, L.R. Cardiac and hemodynamic adjustments to
rapid and sustained blood pressure reduction. Am. J.
Hypertens. 1989; 2, 196-9s.
I3 1. Trimarco, B., De Luca, N., Rosiello, G. et al. Improvement
of diastolic function after reversal of left ventricular
hypertrophy induced by long-term antihypertensive treatment with tertatolol. Am. J. Cardiol. 1989; 64,745-51.
713
132. Cody, R.J., Kubo, S.H., Covit, A.B., Muller, F.B., LopezOvojero, J. & Laragh, J.H. Exercise hemodynamics and
oxygen delivery in human hypertension. Response to
verapamil. Hypertension 1986; 8,3-10.
133. Sen, S., Tarazi, R.C. & Bumpus, EM. Effect of converting
enzyme inhibitor (SQ 14,225)on myocardial hypertrophy
in spontaneously hypertensive rats. Hypertension 1980; 2,
169-77.
134. Mukherjee, D. & Sen, S. Collagen phenotypes during
development and regression of myocardial hypertrophy in
spontaneously hypertensive rats. Circ. Res. 1990; 67,
1474-80.
135. Heagerty, A.M., Bund, S.J. & Aalkjaer, C. Effects of drug
treatment on human resistance arteriole morphology in
essential hypertension: direct evidence for structural
remodelling of resistance vessels. Lancet 1988; ii,
1209- 12.
136. Nielsen, H., Christensen, H.R.L., Christensen, K.L.,
Baandrup, U. & Lennard, T. Antitrophic properties of
antihypertensive drugs may depend solely on their blood
pressure-lowering capability. Am. J. Med. 1989; 86 (Suppl.
4A), 67-9.
137. Clozel, J., Kuhn, H. & Hefti, F. Effects of chronic ACE
inhibition on cardiac hypertrophy and coronary vascular
reserve in spontaneously hypertensive rats with developed
hypertension. J. Hypertens. 1989; 7,267-75.
138. Walsh, R.A. The effects of calcium entry blockade on
normal and ischemic ventricular diastolic function. Circulation 1989; 80 (Suppl. IV), IV-52-8.
139. Buser, P.T., Wagner, S., Wu, S.T. et al. Verapamil preserves
myocardial performance and energy metabolism in left
ventricular hypertrophy following ischemia and reperfusion. Phosphorus 3 1 magnetic resonance spectroscopy
study. Circulation 1989; 80, 1837-45.
140. Wicker, P., Abdul Samad, M., Rakusan, K. et al. Effects of
chronic exercise on the coronary circulation in conscious
rats with renovascular hypertension. Hypertension 1987;
10,74-81.
141. Floras, J.S. Antihypertensive treatment, myocardial infarction, and nocturnal myocardial ischaemia. Lancet 1988; ii,
994-6.
142. Henry. P.D. & Bentley, K.I. Suppression of atherogenesis
in cholesterol-fed rabbits treated with nifedipine. J. Clin.
Invest. 1981; 68, 1366-9.