THE CLINICAL EPIDEMIOLOGY OF CARDIOVASCULAR DISEASES IN CHRONIC KIDNEY DISEASE

Cardiovascular Disease in Chronic Renal Failure:

Pathophysiologic Aspects
rard M. London
Ge
rogis, France
Department of Nephrology, F. H. Manhes Hospital Center, Fleury-Me

ABSTRACT
Cardiovascular complications are the leading cause of
mortality in patients with end-stage renal disease (ESRD).
The excess cardiovascular risk and mortality is already
demonstrable in early renal disease and in patients with
chronic renal failure (CRF), with the highest relative risk of
mortality in the youngest patients. The high risk for
cardiovascular disease (CVD) results from the additive eect
of multiple factors, including hemodynamic overload and
several metabolic and endocrine abnormalities more or less
specic to uremia. CVD includes disorders of the heart (left
ventricular hypertrophy [LVH], cardiomyopathy) and disorders of the vascular system (atherosclerosis, arteriosclerosis),
these two disorders being usually associated and interrelated.
LVH is the most frequent cardiac alteration in ESRD,
resulting from a combined pressure and volume overload.
LVH in general is an ominous prognostic sign and an

independent risk factor for arrhythmias, sudden death, heart

failure, and myocardial ischemia. Regression of LVH needs a
combined intervention to reduce hemodynamic overload and
is associated with improved prognosis and survival. Clinical
studies have shown that damage of large conduit arteries is a
major contributing factor for the high incidence of congestive
heart failure (CHF), LVH, ischemic heart disease (IHD),
sudden death, cerebrovascular accidents, and peripheral
artery diseases. Damage to large conduit arteries is principally related to highly calcied occlusive atherosclerotic
lesions and to stiening of large capacitive arteries. These
two complications are independent risk factors for survival,
and improvement of arterial stiness is associated with better
prognosis and survival. The present review summarizes the
most recent works dealing with the pathophysiology of CVD
and some aspects of the therapeutic approach.

Cardiovascular disease (CVD) is the leading cause of

death in patients with end-stage renal disease (ESRD)
(1). The excess cardiovascular risk and mortality is
already demonstrable in early renal disease and in
patients with chronic renal failure (CRF), with the
highest relative risk of mortality in the youngest
patients (26). The high risk for CVD results from
the additive eect of multiple factors, including
hemodynamic overload and several metabolic and
endocrine abnormalities more or less specic to uremia
(Fig. 1). CVD includes disorders of the cardiac structure and function (left ventricular hypertrophy [LVH],
cardiomyopathy) and disorders of the vascular system
(atherosclerosis, arteriosclerosis) (7). These two disorders are frequently associated and can exacerbate each
other. Cardiomyopathy of overload and ischemic heart
disease (IHD) are the two principal causes of heart
failure and the most frequent causes of cardiac death.
Cross-sectional studies have shown that LVH is the
most frequent cardiac (8,9) alteration in ESRD and is
an ominous prognostic sign (10). Arterial disease,

whether due to atherosclerosis or arteriosclerosis (or

both) is another complication responsible for high
morbidity and mortality (11,12).

Disorders of Cardiac Function

LVH: Pathogenesis
LVH is an adaptive response that follows an increase
in cardiac work caused by volume or pressure overload
(13). The work of the heart performed per ventricular
beat (stroke work) equals the product of LV pressure and
stroke volume, and is dened as the total LV pressurevolume loop area (Fig. 2). The stroke work can increase
due to an increase in stroke volume, an increase in
pressure, or both. Cardiac work (LV minute work) is the
product of stroke work and heart frequency. Myocardial
oxygen consumption and energy expenditure increase
with stroke work. This is directly related to changes in LV
wall stress during the cardiac cycle. According to
Laplaces law, the tensile stress (r) is directly proportional to intraventricular pressure (P) and radius (r) and
inversely proportional to ventricular wall thickness (h)
according to the formula: r Pr/2h. This law states that
wall tension at any given pressure increases with radius,
and vice versa. The consequence of pressure-volumetension relationships is an increase in wall thickness

rard M. London, MD,

Address correspondence to: Ge
Center Hospitalier F. H. Manhes, 8 Grande Rue, Fleury rogis 91712, France, or e-mail: glondon@club-internet.fr.
Me
Seminars in DialysisVol 16, No 2 (MarchApril) 2003
pp. 8594
85

86

London
Volume/flow
overload

Pressure overload

stimuli

overload
pressure volume

GH
T4

Load +
RAAS RAAS

Local Infammation
factors ischemia

gender

age
LV hypertrophy

RAAS
catecholamines

Cardiac
failure

inflammation

Apoptosis

Fig. 1. Pathogenesis of cardiac disease in chronic renal failure.

(cardiac hypertrophy or remodeling) which reduces the

tension that must be developed during systole by each
individual cardiomyocyte. Tensile stress is a major
mechanical signal for LV remodeling. An increase in
pressure or volume workload of the left ventricle is
frequently associated with an increased release of
neurotransmitters, hormones, and vasoactive substances
that have a direct or permissive eect on the growth of
cardiomyocyte and cardiac interstitium. Mechanical or
neurohumoral initiating signals activate eectors of
intracellular signals that lead to reexpression of a fetal
gene program and expression of proto-oncogenes
encoding growth factors and growth factors receptors
(1416).
LVH is both benecial and detrimental. By distributing tension among a greater number of sarcomeres,
LVH reduces the load of each individual muscle ber
and regulates cardiac eciency and oxygen consumption, increasing the working capacity of the left
ventricle. The benecial eect permits maintenance
of normal systolic function during the phase of
compensated adaptive hypertrophy. While the benecial eects of LVH dominate in the initial adaptation
to overload, the sustained overload leads progressively
to a maladaptive hypertrophic response characterized
by the dominance of deleterious eects and development of cardiomyopathy of overload and heart failure
(1618).

Area under the

curve represents
the stroke work

Ventricular pressure

remodeling

Myocyte hypertrophy

Fibrosis

Ca, P, Vit D, PTH

Atherosclerosis
ischemia

GH T4,
Oxidative
stress

local growth
factors / inhibitors

Ventricular volume
Fig. 2. LV volume-pressure relationship during the cardiac cycle.

Function and
stiffness

normal

abnormal

Fig. 3. Stimuli to myocardial remodeling and their impact on

stiness and function.

In the maladaptive phase of hypertrophy the overloaded active myocardial cells have an increased rate of
energy expenditure and an imbalance between energy
expenditure and production resulting in chronic energy
decit and myocyte death (17). Cell death in the
overloaded ventricle adds further to overload on surviving myocytes, creating a vicious cycle with progressive
cardiosclerosis and heart failure (17,18). The pathogenesis of chronic energy decit is complex, including
decreased coronary reserve and ischemia (19,20). These
alterations are partly related to structural abnormalities
of intramyocardial microvasculature with diminished
myocardial capillary density and thickening of intramyocardial arterioles, and increased stiness of the aorta
and major conduit arteries (21).
There is growing evidence that abnormal expression of
proto-oncogenes promotes and regulates cell proliferation and dierentiation of nonmyocytes, especially
cardiac broblasts. Activation and proliferation of these
cellular populations results in a rapid increase in collagen
synthesis and a disproportionate increase in extracellular
matrix (17,22). The increase in extracellular matrix and
collagen content maintains the mechanical eciency of
the contracting heart at the expense of impaired diastolic
lling. The increase in myocardial brosis is more
marked in pressure overload than in volume overload
and is favored by factors such as senescence, ischemia,
catecholamines, angiotensin II, aldosterone, and transforming and growth factors (23) (Fig. 3). Impairment of
diastolic function can also be caused by lusitropic
abnormalities, that is, delayed relaxation as a result of
slower reuptake of calcium by the sarcoplasmic reticulum (24,25). The prolongation of cytosolic calcium
transients increases the duration of the action potential.
Delayed postdepolarization contributes to arrhythmias,
which are further favored by conduction abnormalities
linked to the brosis and enlargement of hypertrophied
hearts (26) (Fig. 4).
Cardiac hypertrophy usually develops in a pattern
specic to the inciting mechanical stress (27) (Fig. 5).
Pressure overload results in parallel addition of new
sarcomeres with a disproportionate increase of ventricular wall thickness at normal chamber radius and an
increase in the ratio between wall thickness and left
ventricle radius (h/r > 0.45; concentric hypertrophy).
Volume overload results primarily in addition of
new sarcomeres in series, with secondary addition of
sarcomeres in parallel, resulting in an enlargement of the

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PATHOPHYSIOLOGIC ASPECTS OF CVD IN CRF

Fibrosis
Cellular disarray

Chambers
stiffness

Asynchrony

Reentry

Capillary density
Arrhythmia

Coronary reserve

Diastolic
pressure

Abnormal Ca ++ flux
(Ca++ overload ;
transmembrane
potentials)

h
Left atrial
hypertrophy
dilatation
(atrial arrhythmias)

Fig. 4. Adverse eects associated with LVH.

h/r < 0.45

Normal

ventricular chamber with increased wall thickness

just sucient to counterbalance the increased radius
(h/r < 0.45; eccentric hypertrophy) (Fig. 6).
Hemodynamic factors also determine the development of physiologic hypertrophy. The development of
cardiac hypertrophy is a physiologic process in such
conditions as growth and maturation of children,
pregnancy, and intense physical exercise. Cardiac hypertrophy is the primary method by which the myocardial
mass increases during the normal growth from infancy to
adulthood in response to a steady increase in blood
volume, cardiac output, and metabolic demand. Normal
cardiac growth thus is a form of volume overload and is
characterized by a proportional increase in left ventricle
radius and wall thickness (h/r < 0.45). The term
physiologic hypertrophy refers also to increased LV
mass after long-term conditioning in highly trained
athletes. Athletes engaged in isotonic exercise (longdistance runners, swimmers) have more eccentric LVH,
while those engaged in isometric exercise (wrestling,
weightlifting) have more concentric hypertrophy. In
physiologic conditions the hypertrophy is reversible, the
ratio between cardiomyocytes and interstitium is normal,
and it is not associated with deleterious functional
alterations such as diastolic dysfunction. The development and characteristics of cardiac hypertrophy are
inuenced by several other factors such as age, gender,
race, and coexistent or related diseases (28).
LVH in CRF and ESRD Patients
The prevalence of LV alterations, including LVH, is
high among CRF and ESRD patients in all age groups,
Primary stimulus
Volume
Volume overload
overload

Pressure
Pressure overload
overload

Increased diastolic pressure

Increased systolic pressure

Increased diastolic stress

Relaxation

Ischemia

+ Increased systolic stress

Series addition
of new sarcomeres

Parallel addition
of new myofibrils

Chamber enlargement

Wall thickening

Eccentric hypertrophy
hypertrophy

Concentric
Concentric hypertrophy
hypertrophy

Fig. 5. Hypothesis relating wall stress and patterns of hypertrophy.

r = radius

h/r < 0.45

h/r > 0.45

Eccentric LVH
h = wall thickness

Concentric LVH

h/r = relative wall thickness

Fig. 6. Geometric characteristics of LVH.

including children (38). The prevalence of LVH is

already increased in early renal disease and progresses
with a decrease in renal function (3). In patients with
early renal disease and LVH, 65% had eccentric
hypertrophy (29). On starting dialysis, 75% of adults
have LVH, with concentric hypertrophy in 42% of
patients and left ventricle enlargement (eccentric hypertrophy) in 44% of patients (including those with left
ventricle dilation and systolic dysfunction) (9). At the
beginning of dialysis therapy, 69% of pediatric patients
had LVH, with a similar proportion of concentric (31%)
and eccentric (38%) hypertrophy (5).
The classication of LVH into eccentric and concentric types is sometimes dicult in patients on dialysis
because of the absence of steady-state conditions,
associated with cyclic variations in extracellular uid
volume and humoral balance (30,31). The internal
dimensions of the left ventricle are inuenced by volume
status, and contraction of blood volume during hemodialysis sessions decreases the left ventricle diameter and
induces acute changes in relative wall thickness
(increasing wall:lumen ratio).
One of the consequences of the inuence of volume
status on left ventricle diameter is an overestimation of
LV mass by echocardiography relative to magnetic
resonance imaging (MRI) (32). As a result of the
weight of the left ventricle diameter in the formula
used for calculation of LV mass, an increase in the
internal diameter of the left ventricle that is frequently
observed in ESRD patients tends to overestimate the LV
mass, while a decrease in left ventricle diameter tends to
overestimate the regression of LVH.
LVH is an independent factor associated with poor
survival in dialysis patients (10). The prognostic impact
of LV mass depends in part on the indexation used to
take into account the body dimensions. Zoccali et al. (33)
have shown that indexing to body height provides more
powerful prediction of mortality and cardiovascular
outcome than indexing to body surface area (BSA).
Moreover, body height is not inuenced by body weight
ultraltration-associated variations in BSA.
The increase in LV mass in ESRD patients results
from a mild enlargement of LV end-diastolic diameter
and/or an increase in LV wall thickness, and combines
the features of eccentric and concentric hypertrophy

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Pressure overload

AV fistula

Hypertension

Na+/H20 retention

Arteriosclerosis

Chronic anemia

Aortic stenosis

increased stroke
volume
increased heart rate
Fig. 7. Causes of changes in left ventricle structure and function.

(8,9). The LV mass increase in ESRD patients is

associated with increased concentration of many
humoral factors (cardiac natriuretic peptides, troponin,
homocysteine, asymmetric dimethylarginine [ADMA],
endothelin, etc.) whose signicance, that is, markers of
hypertrophy and function or factors of the hypertrophic process, remain to be determined (3438).
LVH in ESRD patients is due principally to a chronic
increase in stroke work and LV minute work resulting
from an association of volume and pressure overload
(7,8) (Fig. 7).
Volume Overload in ESRD
Left ventricular end-diastolic diameter is increased in
ESRD patients (8,9). The changes are moderate, the
values usually lying around the normal upper limits, but
true dilatation can be observed in 3238% of patients
(8,9). The ventricular enlargement is associated with an
increased stroke and cardiac index, and is most likely
attributable to chronic volume/ow overload associated
with three principal factors: sodium and water retention,
arteriovenous shunts, and anemia (79).
Sodium and Water Retention. Overhydration
contributes to the pathogenesis of LVH in ESRD by its
effects on blood pressure control and by induction of
volume overload. The internal dimensions of the left
ventricle, stroke volume, and end-diastolic pressure are
directly related to circulating blood volume (30). Body
uid volume contraction during dialysis sessions induces
a decrease in left ventricle diameter and cardiac output,
and there is a direct correlation between interdialytic
body weight changes and LV mass, as well as stroke
volume (31). LV mass is correlated with the concentration of atrial natriuretic peptides, which are inuenced by
extracellular uid volume (36). Regression of left ventricle dimensions and LVH in hemodialysis patients can
be achieved by ultraltration and reduced salt intake
(39). A similar reduction in LVH associated with better
blood pressure control, a decrease in extracellular uid
volume, and volume uctuation was demonstrated in
patients on daily dialysis (40).

increase in left ventricle diameter and LV mass which is

signicantly associated with AV stula ow (8). Acute
compression of AV shunts induces an immediate
decrease in stroke volume and heart rate (Branham
Nicaladonis sign). Long-term effects of high-ow AV
shunts can adversely affect cardiac function. Cardiomegaly with high-output cardiac insufciency occurs as a
complication of high-ow AV shunts (41). The creation
of an AV shunt for hemodialysis access is responsible in
part for left ventricle dilation and a high-output state (8).
However, symptomatic cardiac failure due to AV shunts
alone is uncommon and occurs more frequently in
patients with underlying cardiac disease.
Anemia. Anemia (Fig. 8) is associated with functional alterations that develop to maintain optimal
oxygen delivery to tissues and organs. Maintenance of
adequate organ oxygenation is achieved both by
nonhemodynamic and hemodynamic adaptations. Nonhemodynamic adaptations include a lower afnity of
hemoglobin for oxygen and increased oxygen extraction
and AV difference. Hemodynamic adaptation occurs
when nonhemodynamic factors are insufcient to compensate for a decrease in hemoglobin concentration. This
occurs at different levels according to age, physical
activity, and gender, and is almost always observed when
the hemoglobin concentration declines to less than
100120 g/L. The most typical hemodynamic change
observed is increased cardiac output due to high stroke
volume and increased heart rate (42). Several mechanisms are responsible: reduction in arterial resistance due
to arteriolar dilation and decreased blood viscosity,
increased preload due to increased venous return, and
increased left ventricle contractility attributed to sympathetic activity and noncatecholamine inotropic factors
(7,43).
The prospective multicenter Canadian cohort study of
CRF has identied a decrease in hemoglobin level and an
increase in systolic blood pressure as the principal
predictors of LVH and its progression (29). The odds
ratio for progression of LVH is 1.32 for each 0.5 g/dl of
hemoglobin decrease. Similar observations were made in
ESRD patients. After adjusting for age, diabetes,
ischemic heart disease (IHD), blood pressure, and serum
albumin levels, each 10 g/L decrease in hemoglobin level
was independently associated with left ventricle dilation
(odds ratio 1.46) (44). Finally, a recent publication
demonstrated a similar relationship between CRF and
250

r = 0.386
P <0.0001

200

150

100

50

Arteriovenous (AV) Shunts. AV shunts lower

peripheral resistance, with blood pressure maintained
through elevation of cardiac output via increased heart
rate and stroke volume (7). These changes induce an

Left ventricular mass (g/m2)

Volume overload

Left ventricular end-diastolic

volume (mL/m2)

88

400

r = 0.460
P <0.0001
300

200

100

0
0

5
Hb (mmol/L)

10

5
Hb (mmol/L)

10

Fig. 8. Correlation between hemoglobin levels, LV diastolic

volume, and LV mass.

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PATHOPHYSIOLOGIC ASPECTS OF CVD IN CRF

hemoglobin level in posttransplant patients, as well as a

signicant relationship between hemoglobin level and
LV mass (45).
Several studies in CRF and ESRD have shown that
partial or complete correction of anemia with erythropoietin decreases the cardiac output and heart rate, and
induces a partial regression of the LVH, principally in
relation with decreased left ventricular end-diastolic
diameter, while the eects on wall thickness are less
evident (4649). The eects of anemia correction on left
ventricle dimensions were challenged by Foley et al. (50),
who showed that normalization of hemoglobin in
hemodialyzed patients with asymptomatic cardiomyopathy prevented the development of further left ventricle
dilation with a limited eect on LV mass as such. The
latter result may be partly related to type II error or
insucient duration of follow-up.

200

Left
ventricular
mass
(g/m2)

r = 0.52
p < 0.001

100

500

1000

1500

2000

Aortic pulse wave velocity (cm/sec)

Fig. 9. Correlation between aortic stiness (pulse wave velocity)
and LV mass in ESRD patients.

Pressure Overload in ESRD:

Role of Arteriosclerosis

160.0

113.3
LVmass

In a prospective study of CRF, Levin et al. (29) showed

that increased systolic blood pressure is an independent
predictor of LVH and left ventricle growth (odds ratio of
1.11 for each 5 mmHg increase). In ESRD patients, LVH
is closely related to systolic or pulse pressure (5153).
Pulse pressure is an independent cardiovascular risk
factor in the general population (54,55). Recent epidemiologic studies have shown that pulse pressure is associated with a risk of death in patients undergoing
hemodialysis (56,57). Systolic pressure and pulse pressure are simplied markers of pressure load and result
from the interaction between cardiac factors (stroke
volume, ejection velocity) and the opposition to LV
ejection. The arterial factors opposing LV ejection
include peripheral resistance, stiness of the aorta and
large central arteries, and the intensity and timing of
wave reections (the fourth factor opposing LV ejection
is the inertial forces due to the mass of blood in the aorta
and left ventricle) (58,59). Peripheral resistance and mean
and diastolic blood pressure are frequently increased in
early renal disease and CRF. With the progression of
anemia, a decrease in blood viscosity, and the creation of
AV shunts, the peripheral resistances are most frequently
normal or lower in uncomplicated ESRD and the
principal pressure factors opposing ventricular ejection are arterial stiness and early return of wave
reections (5153,59,60). Increased arterial stiness of
elastic-type arteries is associated with reduced creatinine
clearance in subjects with mild to moderate impairment
of renal function (61) and in patients with CRF (62).
Arterial stiness and early wave reections are the
principal determinants of systolic and pulse pressures in
ESRD patients and are associated with LVH (60) and its
progression over time (63) (Figs. 9 and 10). Recent
prospective studies have demonstrated that aortic
stiness and early wave reections are independent
predictors of all-cause and cardiovascular mortality in
ESRD patients (11,12,64,65) and in the general population (66,67) (Fig. 11). In experimental studies of patients
with ESRD, arterial function alterations are associated with arterial remodeling including dilatation and

150

r=0.33; p<0.001
66.7

20.0
-40.0

-6.7

26.7

60.0

Wave Reflection-Augmentation index

Left ventricular mass (g/m2.7)

Fig. 10. Wave reection versus LV mass.

intima-media hypertrophy of large elastic arteries

(6872). These arterial changes resemble those that occur
with aging, such as arteriosclerosis, which is primarily
medial and characterized by diuse dilation and stiening of the major arteries.
Intima-media thickening and arterial stiening in
ESRD patients are associated with many factors
including nonspecic factors such as age, gender,
smoking, blood pressure, and diabetes, as well as alterations more specic to ESRD, such as ow overload,
1
Einc <1 kPa x 103
0.75

Einc >1 kPa x 103

0.5

0.25

0
0

7.5

15

22.5

30

Duration of follow-up (months)

(2 = 10.41; P = 0.0013)

Fig. 11. Probability of survival in the study population according

to the level of Einc.

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increased endothelin-1, hyperphosphatemia, parathormone activity, increased ADMA concentrations, microinammation, and alterations in blood lipids (34,6975).
Arterial stiening in ESRD patients is due to an
abnormal increase in incremental elastic modulus (Einc),
characteristic of the intrinsic properties of the biomaterials of arterial walls (76). In ESRD, these alterations are
associated with the presence of arterial calcications and
increased calcium deposits in the arterial media (77,78).
A recent study in hemodialysis patients has shown that
an increase in Einc and a high degree of arterial
calcication are independent prognostic factors for allcause and cardiovascular survival (79) (Fig. 11). In the
majority of uremic patients, arterial remodeling is
accompanied by a high prevalence of highly calcied
atherosclerotic plaques (80).
As for left ventricle alterations, in ESRD patients,
arterial remodeling is also associated with hemodynamic changes, principally tensile stress and shear stress
(8186). According to Laplaces law, tensile stress (r) is
directly proportional to arterial transmural pressure
(P) and radius (r), and inversely proportional to artery
wall thickness (h) according to the formula r Pr/h. In
response to increased blood pressure or arterial radius,
tensile stress is maintained within the physiologic range
by thickening of the vessel wall. Blood ow alterations
result in changes in shear stressthe dragging frictional
force created by blood ow. Shear stress is the product of
shear rate times blood viscosity. Thus shear stress (s) is
directly proportional to blood ow (Q) and blood
viscosity (g) and inversely proportional to the radius (r)
of the vessel according to the formula s Qg/r3 (Fig. 12).
Changes in shear and tensile stresses are interrelated
because any modication of arterial radius caused by an
alteration in shear stress induces changes in tensile stress
(unless the pressure varies in the opposite direction).
The characteristics of arterial remodeling depend on
the nature of the hemodynamic stimuli applied to the
vessel (81). Chronic augmentation of arterial blood ow
induces proportional increases in the vessel lumen,
whereas decreasing ow reduces arterial inner diameter
(Fig. 13). An example of ow-mediated remodeling
associates arterial dilation and sustained high blood ow
after the creation of an AV stula (87). In ESRD,
increased arterial diameter of large elastic-type arteries is
associated with ow overload and a chronic increase in
blood ow velocity (69) (Fig. 14). The left ventricle and
arterial system are a coupled functional unit inuenced

flow Q

Flow/volume
load

Pressure load

atherosclerosis

Fig. 13. The spectrum of vascular remodeling.

by the same hemodynamic factors responsible for

parallel and similar alterations of the heart and vessels
(69,88). The importance of arterial stiness as a determinant of LVH was recently demonstrated in an
interventional study demonstrating that alterations of
aortic stiness were the principal factor responsible for
longitudinal changes in LV mass (89). While concentric
LVH and increased left ventricle wall thickness are more
characteristic of pressure overload, it can also be
inuenced by nonhemodynamic factors, especially catecholamines and sympathetic activity (90,91). High
sympathetic activity is also associated with sleep apnea
and nocturnal hypoxemia, which are frequently observed
in ESRD and are associated with cardiovascular complications in dialysis patients (92).
Interstitial brosis is a prominent nding in uremic
heart disease, and clinical studies have shown that the
extent of myocardial brosis in ESRD patients is more
marked than in diabetic patients or essential hypertensive
patients with similar LV mass (93,94). Myocardial brosis contributes to the development of inadequate LVH
and the development of high-stress cardiomyopathy as
observed in ESRD patients with hyperparathyroidism
(in association with the facilitating action of parathyroid
hormone on broblast activity) (95,96). Myocardial
brosis is marked in pressure overload accompanied by
activation of the renin-angiotensin-aldosterone system,
and it has been shown that, in patients with ESRD, the
importance of LVH is associated with plasma renin
activity (97) and aldosterone concentration (98). The
r = 0.50
P <0.0001

Diameter (mm)

90

h
4

circumferential wall stress

=PxR
h

fluid shear stress

=4Q
R 3

Fig. 12. Mechanical stresses in the blood vessel.

15

30

45

LV outflow velocity integral (cm/beat)

CCA = common carotid artery

Fig. 14. Correlation between LV outow velocity and CCA

diameter in ESRD patients.

PATHOPHYSIOLOGIC ASPECTS OF CVD IN CRF

possible role played by the renin-angiotensin-aldosterone

system in pathogenesis of myocardial alterations in
hemodialyzed patients was also demonstrated by the
blood pressure-independent eect of angiotensin converting enzyme (ACE) inhibitors on regression of LVH.
In a randomized, blinded study, it has been shown that
for a comparable antihypertensive eect the ACE
inhibitor perindopril, but not the calcium channel
blocker nitrendipine, signicantly decreased LV mass
(99). Finally, several humoral factors with autocrine/
paracrine function can participate in the hypertrophic
process (34,36,37).
LV Functional Alterations in ESRD Patients
The inuence of loading conditions and humoral
changes on systolic and diastolic function complicates
the assessment of left ventricle function. This is particularly true in dialysis patients because of changing
volume status and variation in humoral parameters
(ionized calcium and its inotropic eect, sympathetic
stimulation, etc.) during a dialysis session (100105).
Decreased systolic function and congestive heart failure
(CHF) are frequently observed in ESRD patients who
suer from preexisting cardiac disease or in patients with
sustained or marked hemodynamic overload (9).
In ESRD patients it may not be easy to distinguish
CHF due to an intrinsic impairment of myocardial
function from circulatory congestion due to pure volume
overload. Moreover, signs of pulmonary congestion and
acute pulmonary edema may be observed in patients with
normal systolic function and may be related to diastolic
impairment. Besides the use of echocardiography and
radionuclide techniques to analyze ventricular function,
the concentrations of atrial natriuretic peptides (associated more with volume congestion) and brain natriuretic
peptides (associated with ventricular dysfunction) can
help in establishing a diagnosis of intrinsic CHF (38).
Decreased myocardial contractility may result from
overload cardiomyopathy and has a poorer prognosis
than LVH or dilation with normal systolic function
(106108). In ESRD patients without cardiac antecedents, the indices of systolic function are usually normal or
even increased (8). Systolic function is maintained at
normal levels or increased by several mechanisms
including increased lling pressure of the left ventricle
(Starlings mechanisms), increased sympathetic activity,
and the presence of one or more substances which, by
inhibition of the sodium pump, increase the force of
myocyte contraction (ouabain-like eect). These substances impair the recovery of cardiac myocyte calcium
concentration which impairs myocyte relaxation and
diastolic lling (109). Diastolic lling is frequently altered
in dialysis patients (7,8,110). The increased left ventricle
stiness is characterized by a marked eect of LV volume
changes on LV lling pressure. A small increase in LV
volume can thus cause pulmonary congestion, while
volume depletion can induce a decrease in lling
pressure, systemic hypotension, and hemodynamic
instability (111).
LVH and LV dilation are independent risk factors for
mortality in uremic patients (10,107,112). In the absence

91

of therapeutic interventions, the left ventricle alterations,

principally left ventricle enlargement, tend to progress
over time in the majority of patients (8,113115). Several
studies have shown that treatment of hemodynamic
overload could stabilize (50) or partly reverse LV dilation
and hypertrophy (4649,89,99,116) and can decrease
arterial stiening (89,99,117,118). Improvement of
arterial stiening and even partial regression of LVH
and dilation had favorable and independent eects on
patients all-cause and cardiovascular survival (89,118).
This positive eect on survival was associated with the
preferential use of ACE inhibitors, whose use was
independently associated from their eect on cardiovascular alterations with improved survival (118).
Atherosclerosis and Alteration in Conduit
Function
While arteriosclerosis (arterial stiening) alters the
dampening function of arteries and is a major factor of
pressure overload, atheromatosis (atherosclerosis) alters
the conduit function of arteries (119). The role of
conduit function is to deliver, at all times, an adequate
supply of blood to peripheral tissues and organs in
accordance with their metabolic needs. Conduit-function eciency is the consequence of the width of the
arteries and the very low resistance of large arteries to
ow. The principal long-term alterations of conduit
function occur through narrowing or occlusion of
arteries with restriction of blood ow, resulting in
ischemia or infarction of downstream tissues (119).
Atherosclerosis is the principal cause of alterations in
conduit function. Atherosclerosis, characterized by the
presence of plaques, is primarily an intimal disease, focal
and patchy in its distribution, occurring preferentially in
medium-size conduit arteries, such as epicardial coronary arteries, femoral and iliac arteries, infrarenal aorta,
carotid bulb, and cerebral arteries, and usually sparing
muscular-type arteries in the arms, internal mammary,
and other arteries.
Mechanisms of atherogenesis are complex and include
smoking, lipid disturbances, thrombogenesis, production of vasoactive substances, growth factors, and
mediators of inammation. Tensile stress and shear
stress also inuence the natural history of atherosclerotic
lesions (120). Evidence that enhanced tensile stress is
relevant to the pathogenesis of atherosclerosis comes
from the following observations: atherosclerotic plaques
are conned primarily to systemic arteries where tensile
stress is high (121,122) and are absent from the venous
system; atherosclerosis develops in autogenous venous
bypass grafts, but can be prevented by applying rigid
external support to counteract the increased transmural
pressure in the graft (123); in aortic coarctation,
atherosclerosis is accelerated in arteries cephalad to the
coarctation (124), while it is decreased in arteries caudal
to the coarctation (122).
The role of shear stress is demonstrated by the
predilection of atherosclerosis for certain sites, such as
ostia, branching points, bifurcations, bending, or pronounced arterial tapering (120,125127). These sites are

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characterized by ow-pattern and shear-stress disturbances, for example, low-average shear stress or secondary and turbulent ows with variable shear stress over
the cardiac cycle (125,126). While it was initially thought
that atherogenesis was the consequence of injury evoked
by high shear stress (128), it was later demonstrated that
atherosclerosis is uncommon in sites with high shear
stress, such as at ow dividers on the inner aspects of
arteries downstream from ow dividers or on the outer
aspect of an arterial bend (127,129). In these locations,
the endothelial cells are aligned in the direction of ow,
thereby decreasing the eective resistance to friction and
autoregulating shear stress (130). The increase in shear
stress promotes the secretion and synthesis of nitric oxide
(131), prostacyclin (132), and antithrombotic and antigrowth factors that mediate atheroprotection (133), and
survival of endothelial cells, which then become more
adherent to the intima and less permeable to the entry of
lipoproteins and monocytes (134). At sites of low shear
stress or turbulent ows (characterized by ow reversal
and time-averaged shear stress approaching zero),
endothelial cells secrete prothrombotic and progrowth
factors, and trigger endothelial apoptosis (135). Moreover, blood is in contact with the endothelium for a
longer time, thereby prolonging particle residence time at
the blood and vessel wall interface, thus favoring
enhanced interaction between blood and atherogenic
factors, and facilitating the diusion of lipids or
macromolecules and migration of inammatory cells
across the endothelium (136,137).
The pathophysiologic mechanisms and clinical aspects
of atherosclerotic disease in ESRD patients are beyond
the scope of this article. The high incidence of atherosclerosis-related complications led Lindner et al. (138) to
hypothesize that atherogenesis is accelerated in chronic
hemodialysis patients. However, it remains a matter of
debate whether or not the atherogenesis of dialysis
patients is, indeed, accelerated and whether or not the
nature of atherosclerotic plaques is similar in hemodialysis patients and the general population. Ultrasonographic studies and electron beam tomography have
shown a much higher prevalence of calcied plaques and
calcium content in ESRD patients than in age-matched
controls (77,78,80,139,140). Aortic and coronary calcications are reliable predictors of cardiovascular events
and it has been reported that the extent of arterial
calcications is an independent cardiovascular risk
factor in ESRD patients and general populations
(79,140,141).
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