Download Left ventricular hypertrophy: why does it happen?

Nephrol Dial Transplant (2003) 18 [Suppl 8]: viii2–viii6
DOI: 10.1093/ndt/gfg1083
Left ventricular hypertrophy: why does it happen?
Gerard M. London
Department of Nephrology and Dialysis, Manhes Hospital, Fleury Mérogis, France
Abstract
Patients with end-stage renal disease (ESRD) have
much higher rates of cardiovascular disease than the
healthy population. Left ventricular hypertrophy
(LVH), in particular, is common in this patient
group. The impact of a decline in haemoglobin
concentration on left ventricular mass index has been
well documented. Partial correction of anaemia with
recombinant human erythropoietin (epoetin) treatment has been recognized as a significant step forward
in decreasing left ventricular mass and improving
cardiovascular morbidity and mortality. However,
LVH and cardiac failure in patients with ESRD
comprise a complex condition, which is influenced
by a number of factors in addition to anaemia. This
article examines some of the pathophysiological
aspects of LVH in patients with ESRD.
Keywords: anaemia; chronic renal failure; end-stage
renal disease; epoetin; left ventricular hypertrophy;
pathophysiology
Introduction
Cardiovascular disease is the leading cause of death in
patients with end-stage renal disease (ESRD). The
prevalence of coronary artery disease is 40% in these
patients, which is much higher than in the general
population (Table 1) [1]. Cardiovascular mortality in
haemodialysis (HD) and peritoneal dialysis patients has
been estimated to be 9% per year. The most common
cardiac anomaly in ESRD is left ventricular hypertrophy (LVH), which has been observed in 75% of
patients at the start of dialysis [1]. The prevalence of
LVH is related to the degree of renal insufficiency [2].
LVH is an ominous prognostic sign that may result in
Correspondence and offprint requests to: G. M. London, MD,
Department of Nephrology and Dialysis, Manhes Hospital,
Fleury-Mérogis, 8 grande rue, F-91712, France. Email: glondon@
club-internet.fr
systolic and/or diastolic dysfunction and is an independent risk factor for arrhythmias, sudden death, heart
failure and myocardial ischaemia [3,4].
Pathogenesis of cardiac disease in
chronic renal failure
LVH and cardiac failure are adaptive responses to
increased cardiac work, which is the product of left
ventricular pressure and stroke volume. Combined
volume and pressure overload is the primary cause
of LVH in patients with ESRD. This is exacerbated
by a number of other factors including gender, age,
renin–angiotensin–aldosterone system (RAAS) activity,
level of oxidative stress, etc.
There is a close relationship between changes in the
stroke work index and left ventricular mass in patients
with ESRD [5]. Stroke work is related to the changes
in ventricular volume (stroke volume) and the changes
in mean systolic pressure in the left ventricle. These
factors are the principal determinants of left ventricular
mass.
Increased left ventricular mass is frequently seen
in individuals such as highly trained athletes (longdistance runners, cyclists), during pregnancy and physiologically also with growth from infancy to adulthood.
In these cases, it is a normal compensatory physiological mechanism and is reversible. The rise in the
number of sarcomeres and the increase in wall thickness
increase the working capacity of the left ventricle, while
keeping parietal tensile stress stable and thus sparing
energy. This allows the heart to maintain normal
systolic function during the phase of compensated
(adaptive) hypertrophy.
LVH that is accompanied by the serious complication of fibrosis, however, leads to abnormal function
and stiffness. Fibrosis is observed when volume or pressure overload is associated with non-haemodynamic
factors such as the RAAS, local inflammation and
ischaemia. Sustained overload leads progressively to
maladaptive hypertrophy, which is characterized by the
development of cardiomyopathy of overload and heart
failure.
ß 2003 European Renal Association–European Dialysis and Transplant Association
Left ventricular hypertrophy: why does it happen?
viii3
In the maladaptive phase, energy expenditure by the
overloaded myocardial cells exceeds energy production,
resulting in a chronic energy deficit and myocyte death.
Cell proliferation and differentiation of non-myocytes,
especially cardiac fibroblasts, is thought to be abnormal
in chronic energy deficit. There is a rapid increase in
collagen synthesis and a disproportionate increase in
the extracellular matrix. These responses allow the
mechanical efficiency of the contraction of the heart
to be maintained, at the expense of impaired diastolic
filling.
Patterns of hypertrophy
The relationship between pressure and volume overload influences the type of subsequent LVH (Figure 1).
If the primary stimulus is volume overload, there is an
Table 1. Approximate prevalence of cardiovascular disease by
target population
General population
Chronic renal failure
Haemodialysis
Peritoneal dialysis
Renal transplant recipients
CAD
(%) clinical
LVH
(%) echo
5–12
N/A
40
40
15
20
25–50
75
75
50
CAD, coronary artery disease; LVH, left ventricular hypertrophy.
increase in diastolic pressure and stress, which initially
causes the addition of new sarcomeres in series,
followed by new sarcomeres in parallel. LVH termed
eccentric hypertrophy develops with an increased wall
thickness that is just sufficient to counterbalance the
increased radius. In these patients, the relative wall
thickness (wall thickness [h]/ventricle radius [r]) is
<0.45 as is also seen in those patients with healthy
ventricles.
If the primary stimulus is pressure overload, then
LVH is related to systolic or pulse pressure (see
Figure 1). Arterial stiffness determines the pulse pressure amplitude and the propagative properties of the
arterial system, which in turn determine the speed of
the pressure wave and the timing of the wave reflected
from peripheral sites. Pressure overload results in the
parallel addition of new sarcomeres, with a disproportionate increase in ventricular wall thickness at normal
chamber radius. This is termed concentric hypertrophy
as the left ventricle does not change its internal
dimensions. In these patients, the relative wall thickness
is >0.45 as the ventricle does not increase in radius
despite an increase in wall thickness.
Haemodynamic overload and cardiac hypertrophy
in ESRD
The relationship between volume overload and pressure overload in patients with ESRD is complex.
Volume overload in patients receiving HD is associated
Fig. 1. Hypothesis relating wall stress and patterns of hypertrophy. Adapted, with permission from Excerpta Medica Inc., from Grossman [6].
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with the presence of an arteriovenous fistula, which
may result in an increase of up to 25% in cardiac
output. In addition, the presence of intermittent
sodium and water retention and associated chronic
anaemia is responsible for increased stroke volume
and increased heart rate. Anaemia is already present in
the majority of patients initiating HD and is probably
the most important factor in explaining why 75% of
these patients have LVH. Pressure overload is associated with hypertension, principally in pre-dialysis
patients, with arteriosclerosis that is related in part to
calcification, and to aortic stenosis.
The impact of decreasing left ventricular mass
Early work published by Silberberg et al. showed that
LVH is associated with poor outcome in patients
with ESRD [7]. This study showed that LVH is an
important, independent determinant of survival in
these patients. It also suggested that if left ventricular
mass could be decreased in these patients, it might result
in improved survival rates. Anaemia, hypertension
and the presence of an arteriovenous fistula were all
considered to be important contributors to LVH in
ESRD. Anaemia was suggested as being of primary
importance because this can be treated effectively with
recombinant human erythropoietin (epoetin).
Another, more recent observational study in 150
patients with 5 years of follow-up showed that those
patients who responded to treatment for anaemia
and high blood pressure that resulted in a decrease in
ventricular mass had statistically significant improved
survival rates, compared with non-responders
(Figure 2) [8]. LVH was present in 90% of these
patients with ESRD receiving HD and partial LVH
regression had a favourable and independent effect on
G. M. London
their survival. The study demonstrated that attenuation
of haemodynamic overload reduced LVH and that a
reduction of LVH was a favourable prognostic marker,
which predicted a lower risk for subsequent non-fatal
cardiovascular morbid events. One of the reasons why
LVH is an independent risk factor for mortality in
patients with ESRD is that it decreases the coronary
reserve as more blood is required for perfusion.
Haemodynamic changes induced by anaemia
The relationship between anaemia and left ventricular
mass is now well known. Anaemia is responsible for a
chronic increase in cardiac output and chronic volume
overload (Figure 3). One result of anaemia is the
decrease in erythrocyte mass and blood viscosity. This
in turn decreases peripheral resistance, which results in
increased venous return and cardiac output. Another
result is that oxygen delivery is reduced leading to
recruitment of vessels and angiogenesis in chronic
conditions with a resulting increase in heart rate and
cardiac output. In addition, it is hypothesized that the
presence of a low haemoglobin (Hb) concentration
results in a higher availability of endothelium-derived
relaxing factor (nitric oxide), which leads to vessel
dilatation and increased cardiac output.
The benefits of treating anaemia in ESRD patients
Treating anaemia improves the cardiac status of
patients with ESRD. A consistent finding in different
groups worldwide is that partial correction of Hb
concentration results in partial regression of LVH.
Treatment of pre-dialysis patients with epoetin partially
corrects anaemia and induces left ventricular mass
Fig. 2. Probability of cardiovascular survival in ESRD patients whose LV mass decreased (responders) and in those in whom it did not
change or increased (non-responders).
Left ventricular hypertrophy: why does it happen?
viii5
Fig. 3. Haemodynamic changes induced by anaemia.
index regression without improvements in blood
pressure control [9]. Improving anaemia also improves
cardiac status and function, even in patients with
congestive heart failure [10], although there are
many other factors that influence the growth of left
ventricular mass.
The importance of systolic pressure and
pulse wave velocity
Pressure overload is measured in terms of systolic or
diastolic blood pressure. Systolic pressure related
to arterial stiffening is much more important than
diastolic pressure in these patients and there is a
significant relationship between systolic blood pressure
and end-organ damage. Diastolic pressure is usually
normal in these patients with ESRD. Therefore, in the
presence of systolic hypertension and a stiff arterial
system, coronary perfusion is low and the load imposed
on the left ventricle is high.
Pulse pressure is an independent predictor of
mortality in the general population and is increased in
patients with ESRD in association with increased
arterial stiffness and a pronounced effect of arterial
wave reflections. Pulse pressure is determined by the
interaction of cardiac factors (stroke volume and
ejection time) and vascular factors (arterial stiffness
and arterial wave reflections).
Pulse wave velocity is perhaps a more accurate means
of measuring pressure overload than measuring systolic hypertension itself. There is a close relationship
between aortic pulse wave velocity and left ventricular
mass index [11]. High pulse wave velocity is associated
with increased aortic stiffness and increased LVH.
A recent study has shown that aortic stiffening, determined by measurement of aortic pulse wave velocity,
was an independent predictor of all-cause and
cardiovascular mortality in patients with ESRD [12].
Although treatment of anaemia has already been
shown to produce a partial regression of LVH, which
improves the mechanical properties of the aorta, microinflammation has also been shown to have a significant influence [7]. There is a significant independent
relationship between serum C-reactive protein level
and aortic stiffness in patients with ESRD [13]. In the
presence of micro-inflammation, there is resistance to
epoetin treatment and other antihypertensive drugs,
which illustrates the complexity of the mechanisms
of LVH.
A recent study has provided direct evidence that the
increased effect of arterial wave reflections, independent of arterial stiffness, blood pressure and other
cardiovascular risk factors, is a significant predictor
of all-cause mortality and cardiovascular mortality in
patients with ESRD [14]. This study showed that
cardiovascular mortality in patients with ESRD is
dependent on a number of factors including high
aortic pressure wave velocity, wave reflection, prior
cardiovascular disease and low diastolic blood pressure.
Conclusion
Anaemia is a significant factor affecting LVH in
patients with ESRD, and treatment of anaemia with
epoetin has been shown to induce a partial regression of
left ventricular mass. However, there are many other
factors, including micro-inflammation, which influence
this condition and require further study.
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