Download Cardiovascular abnormalities in ageing and in uraemia-

Nephrol Dial Transplant (1998) 13 [Suppl 7]: 6–11
Nephrology
Dialysis
Transplantation
Cardiovascular abnormalities in ageing and in uraemia—only analogy
or shared pathomechanisms?
K. Amann and E. Ritz
Departments of Pathology and Internal Medicine, Ruperto Carola University Heidelberg, Germany
Abstract. The analogies between the effects of ageing
and of uraemia on the function and the structure of
central elastic arteries and of the heart are striking.
Qualitatively similar changes are seen in pulse contour,
pulse wave velocity, and impedance and also similar
structural abnormalities with wall thickening, diminished elastin, and increased collagen content. The
altered ‘Windkessel’ function of central arteries in age
and uraemia is one factor contributing to left ventricular hypertrophy.
Introduction
In view of the ageing of the general population, and
particularly the ageing of the dialysis population [1,2],
it is of considerable interest to examine to what extent
in the genesis of cardiovascular end-organ damage the
effects of uraemia per se interact with, or are amplified
by, the effects of ageing. We select one example which
in the past has been underinvestigated, but recently
has attracted much attention, i.e. the effect of ageing
and of uraemia on the function of, and interaction
between, the peripheral vasculature and the heart.
Derangements of this relationship are a hallmark of
ageing [3], but are also an important aspect of cardiovascular dysfunction in uraemia [4]. In the following,
we point out some similarities between the ageing
process and uraemia. Based on studies of others and
our own investigations [5], we try to provide arguments
for the hypothesis [4,6 ] that the effects of uraemia on
the vasculature and the heart can be envisaged partially
as the result of accelerated ageing, amplified by the
adverse effects of hypertension.
Historical notes
Although investigation of this issue with modern technology has only begun in recent years, it is worth
pointing out that the effects of uraemia and ageing on
Correspondence and offprint requests to: E. Ritz, Department of
Internal Medicine, University of Heidelberg, Bergheimer Straße 56a,
D-69115 Heidelberg, Germany.
characteristics of the pulse, pulse wave velocity and on
the heart had been studied decades ago. In 1872,
Mahomed [7] analysed the pulse contour in patients
with Bright’s disease and noted a characteristic late
systolic shoulder [8], an important observation because
this feature will by necessity raise cardiac afterload
and contribute to left ventricular (LV ) hypertrophy in
renal failure.
In a systematic study on the effect of ageing, Bürger
in Leipzig analysed the central vessels and heart [9].
He stated that ‘aging changes the chemical composition
of the aorta and causes wall thickening’. He further
stated that ‘the quantity of elastic elements decreases
and consequently the elasticity of the aorta decreases
in parallel. This alters the ‘Windkessel’ function,
i.e. the dampening on the pulse wave’. He implied
that as one grows older, one’s vessels become stiffer.
Concerning the impact of ageing on the heart, he noted
that ‘with progressive age, the work load of the heart
increases. The elastic as well as the peripheral resistances increase progressively. In parallel, increased longitude of central vessels adds to the work load of the
central motor. Thus, hypertrophy is truely the result
of increased cardiac work load’.
The effects of ageing and uraemia on pulse contour
and pulse wave velocity
The methodology to analyse pulse contour and pulse
velocity in humans in vivo has been described in detail
by O’Rourke [3]. Pulse analysis evaluates pulse amplitude as a function of time, i.e. analysis in the time
domain. Ageing is accompanied by characteristic
changes of the amplitude and the contour of the
pressure wave. Figure 1 paradigmatically illustrates the
transitions in amplitude and contour of the pressure
wave between the aortic arch and iliac artery of a
young as opposed to an elderly human subject [3]. It
is obvious that the blood pressure amplitude, i.e. pulse
pressure, rises progressively between the ascending
aorta and the femoral artery. The peak systolic blood
pressure is increased and this is the result of the
summation of the incident wave and the reflected wave.
An exaggerated systolic peak has been noted not only
© 1998 European Renal Association–European Dialysis and Transplant Association
Cardiovascular abnormalities in ageing and in uraemia
7
Fig. 2. Change of pulse wave velocity (alpha; on the ordinate) as a
function of age (on the abscissa) in different arteries, i.e. leg, aorta,
arm. From ref. 9.
Fig. 1. Change in amplitude and contour of the pressure wave
between the aortic arch and iliac artery of a young human subject
(below) and of an elderly patient (above). (Reprinted with permission
from O’Rourke, M.F., Arterial Function in Health and Disease.
Churchill Livingstone: Edinburgh, 1982.)
in the elderly [10–13], but also in the uraemic individual [4,14–16 ]. Figure 1 also illustrates that while in
the young individual pulse amplitude and contour are
markedly different between central and peripheral
arteries, this is no longer the case in the elderly. Such
a discrepancy of pressure profile between peripheral
and central arteries has implications for the definition
of hypertension and for the change of cardiac work
load with age. In young individuals, systolic blood
pressure in the brachial artery, as assessed by sphygmomanometric measurement after Korotkow, is higher
than the pressure in the ascending aorta. As age
advances, the difference progressively dissipates. It is
obvious that the age-dependent increase in pressure in
the ascending aorta (and, in parallel, of the left ventricular work load ) is greater than the increase in brachial
artery pressure. In other words, the increase in the
blood pressure load to the heart in the elderly is
underestimated based on blood pressure measurements
in the brachial artery. In view of the similarities in the
biomechanical properties of the central arteries, it is
sound to assume that in patients with renal failure the
increase is also underestimated. Increasing pulse wave
velocity in the elderly has been known for decades [9]
(see Figure 2), and this finding recently has been
substantiated by modern technology [3]. It is of note
that a similar increase in pulse wave velocity is found
in uraemia [14,15,17]. This observation raises the issue
of whether similar changes in central arterial tissue
composition and texture are present in the two
conditions.
The effect of ageing and uraemia on impedance
A type of pulse analysis which is complementary to
the analysis in the time domain (see above) is analysis
in the frequency domain. For this purpose, the arterial
pressure wave is considered as a mean value with
fluctuations around this mean. Using Fourier analysis,
one can express such fluctuations, as in a musical wave,
in terms of component harmonics. The harmonics
analysis permits calculation of the impedance, i.e. the
relationship between pressure and flow at the input of
the vascular bed. A modulus (i.e. ratio of pressure
amplitude and flow amplitude) and phase (i.e. delay
between pressure and flow as a function of frequency)
can be calculated. In the elderly, the ascending aortic
flow harmonics are unchanged, while the modulus of
aortic impedance is increased. This has important
consequences. While under normal circumstances,
effective coupling exists between the LV and the systemic circulation, such coupling is progressively lost in
the elderly. In the younger individual, the relationship
between vascular impedance in the ascending aorta
and the frequency content of the LV ejection is such
that maximal pulsatile flow from the heart generates
minimal pressure fluctuation. As a consequence, minimal energy is lost in pressure and flow pulsations. The
Table 1. Mechanisms altering vessel wall properties
Physical
Chemical
Autacoids/hormones
cyclical stretch/fatigue
advanced glycation end-products (AGES)
oxidative stress
renin
endothelin
PTH
8
K. Amann et al.
Table 2. Aortic cell hypertrophy and hyperplasia and deranged wall
matrix composition in subtotally nephrectomized rats
Systolic BP
(mmHg)
Volume of aortic
MC (m3)
Elastic fibres (%)
Collagen fibres (%)
Sham operated
(n=8)
Subtotal nephrectomy
(n=8)
117±9
119±9
85.5±14.8
97.7±5.8a
63.9±3.9
31.9±4.0
52.3±2.5a
41.4±2.3a
aTaken from ref. 5.
unfavourable relationship in the elderly, i.e. unchanged
flow into a stiffer tube, causes higher energy loss,
increased pulsatile cardiac work and predisposition to
LV hypertrophy [3]. It is again of note that recent
studies documented uncoupling between the LV and
the systemic circulation in renal failure, in striking
analogy to the changes seen in ageing [16 ].
Structural abnormalities of the central arteries in
uraemia
Early work of Bürger [9] documented a decrease in
elastin and an increase in collagen content in human
central arteries. This finding has been confirmed using
modern technologies [18]. It appears that the effect of
ageing is accelerated by hypertension, at least in experimental studies [19].
The change in viscoelastic properties of the vessel
wall with age is presumably explained by physical and
chemical factors ( Table 1). In engineering, it is well
known that cyclic stress causes fatigue fractures. At a
heart rate of 60 cycles per minute, 2.4 billion cycles
will have occurred during a life span of 75 years. The
half-life of vessel wall structural components, particularly of elastin, is in the range of decades. It is therefore
no surprise that as age advances, one notes thinning,
fraying and fractures of the elastic lamellae in the wall
of central arteries. This is accompanied by accumulation of glycosaminoglycans and collagen fibres. As a
consequence, arteries dilate, lengthen and stiffen.
Because of microfractures of individual elastic fibres,
stress is transferred to the less extensible collagen
fibres. Since according to Laplace’s law, wall tension
in the dilated artery increases, it must be counterbalanced by less structural elements. Consequently,
pulsatile stress per unit thickness of fibre increases with
age. Against this background, we were interested in the
changes that occur in renal failure. In the model of the
subtotally nephrectomized male Sprague–Dawley rat,
studied after uraemia of 8 weeks duration, the structural features in the aorta were quantitated by micromorphometric methods [5]. As indicated in Table 2,
vascular smooth muscle hyperplasia was documented
by increased cell number. Uraemia caused a marked
decrease in elastic fibre content and a substantial
Fig. 3. Sham-operated control animal. Normal ultrastructure of the aorta with regular distribution of elastic fibres and regularly sandwiched
vascular smooth muscle cells. Ultrathin sections, magnification: 1510 500.
Cardiovascular abnormalities in ageing and in uraemia
9
Fig. 4. Subtotally nephrectomized animal. Marked ultrastructural changes of the aorta with slight hypertrophy of vascular smooth muscle
cells with more irregular cell shape and slightly increased intracellular actin filaments. Elastic lamellae are much thinner than in control
animals, and the extracellular matrix is increased. In addition, there is focal distribution of collagen bundles in the interstitial space.
Ultrathin section, magnification: 1510 500.
increase in matrix (and collagen fibre) content of the
aortic wall. The reduction in the volume fraction of
elastin does not reflect adequately the potential
derangement in aortic wall properties, since at the
ultrastructural level instead of the regular bedding of
elastic fibres, a higgeldy piggeldy arrangement was
noted (Figures 3 and 4). It has been proposed that
altered vessel wall properties are related to increased
vessel wall calcium content.
In the above study, we did not see evidence of medial
calcification, as previously described by Ibels in
humans [20], but it is possible that the duration of
experimental uraemia was too short. It is of interest,
however, that in muscular and elastic arteries of the
subtotally nephrectomized rat, alterations were markedly less in parathyroidectomized uraemic animals,
suggesting a permissive effect of parathyroid hormone [21].
Apart from the physical factor of fatigue as a result
of cyclic stretch, our unpublished studies suggest that
in the aortic wall advanced glycation end-products
(AGEs) are present in high concentrations. They crosslink proteins, possibly also the lysine groups of elastin,
thus causing vascular stiffening.
It is of interest that according to recent experimental
work, oxygen radicals play a definite regulatory role
in vascular remodelling. However, pathologically high
concentrations, they may cause vascular damage.
Finally, we recently found increased mRNA for
renin in the cardiac interstitium [22] and in adventitial
tissue of the aorta and conversely, striking prevention
of morphological changes in the aortic wall by administration of angiotensin-converting enzyme (ACE) inhibitors [23]. This is illustrated in Figure 5. Furthermore,
similar prevention was noted with a specific and
non-specific endothelin receptor ( ET ) antagonist
A
( Figure 6). These observations argue for a role of the
renin–angiotensin system (RAS ) and endothelin systems respectively. The latter finding is in good agreement with recent observations that a relationship exists
between biomechanical vascular characteristics and
ET-1 levels [24].
Repercussions of abnormal biomechanics of central
arteries on the left ventricle
The pulse characteristics are markedly altered in a
(hypothetical ) uraemic subject compared with a
normal individual. In the uraemic individual, peak
systolic blood pressure is higher, increasing LV
afterload, augmenting LV wall stress and stroke work
index and thus contributing to concentric LV hypertrophy. At the same time, the decrease in diastolic
aortic pressure is accelerated in the non-compliant stiff
aorta of the uraemic patient. Since coronary perfusion
10
K. Amann et al.
Fig. 5. Effect of ACE inhibitors on aortic wall changes in experimental renal failure. Aortic wall thickness is markedly increased after
subtotal nephrectomy (SNX ). This increase can be completely prevented by the ACE inhibitor Trandolapril.
Fig. 6. Effect of specific and unspecific endothelin receptor antagonists on aortic wall changes in experimental renal failure. Aortic wall
thickening in subtotally nephrectomized rats (SNX ) can be partly prevented by the endothelin A receptor blocker BMS 182874 and the
unselective endothelin A/B receptor antagonist Ro 46-2005 independently of blood pressure reduction.
Cardiovascular abnormalities in ageing and in uraemia
occurs only during diastole, this will compromise coronary blood flow in the heart itself, the oxygen demand
of which is high because of increased stroke work. It
is therefore logical to postulate that altered biomechanical properties of central arteries are one factor which
contributes to the development of LV hypertrophy in
the ageing individual and in the uraemic individual.
Indeed, the LV mass index in uraemic patients is
strikingly correlated with age [25], consistent with the
hypothesis that there is interaction between the effect
of ageing and uraemia. On the other hand, while the
effect of uraemia is not pronounced in younger individuals [26 ], the effect of uraemia is relatively more
pronounced with age, raising the issue of whether the
effects of ageing and uraemia are additive or mediated
via the same pathways.
11
8.
9.
10.
11.
12.
13.
14.
15.
The concept of uraemia as accelerated ageing
It is obvious from the above that some analogies exist
between ageing and uraemia. The concept does have
limitations, however.
The vascular wall abnormalities in uraemic patients
are reversible, at least partially, after transplantation,
as shown by Barenbrock [27]. One would be delighted
if similar success could be achieved in reversing the
age-induced vascular changes. Second, biomechanical
vessel wall characteristics can be altered by medication,
for instance ACE inhibitors and calcium channel blockers, and this is also true for uraemic individuals [15,26 ].
The relative roles played by irreversible structural and
reversible functional abnormalities in the genesis of
uraemic changes remain unknown.
16.
17.
18.
19.
20.
21.
Acknowledgements. Parts of the underlying experimental studies were
supported by the DFG (Am 93/2-2) and an extramural grant from
Baxter Health Care Co., USA.
22.
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