Nephrol Dial Transplant (2002) 17: 332–335
Effects of excess calcium load on the cardiovascular system measured
with electron beam tomography in end-stage renal disease
Paolo Raggi
Cardiology and Non-Invasive Imaging, Tulane University, New Orleans, LA, USA
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients and current
research indicates that it might be linked to high serum
phosphorus levels and calcium–phosphorus product.
The severe osteopathy known to exist in end-stage
renal disease (ESRD) patients is often coupled with
an inability of bone to handle excess calcium loads.
This might predispose to overflow and deposition
of calcium and phosphate crystals in various soft
tissues and in particular the cardiovascular apparatus.
Atherosclerosis is a slow process that expands in the
context of the arterial intimal layer and it is for the
most part associated with extracellular calcification.
Electron beam tomography (EBT) is a radiological
technique utilized to non-invasively visualize this
silent marker of atherosclerosis: vascular calcification.
Several investigations conducted in non-ESRD
patients have conclusively demonstrated that coronary
calcification indicates a high risk for cardiac events. As
EBT allows precise estimates of the extent of vascular
and valvular calcification, it might become an important clinical tool in ESRD patients to assess the effect
of excess calcium and phosphate load in soft tissues,
estimate the cardiovascular risk of events and gauge
the effectiveness of therapy.
Keywords: calcification; calcium; cardiovascular disease; chronic renal failure; coronary artery disease;
phosphorus; EBCT; haemodialysis; phosphate binders
Atherosclerosis, cardiac calcifications and imaging
with electron beam tomography
Atherosclerotic lesions form in the context of the
intimal layer of the arterial wall and are composed of
Correspondence and offprint requests to: Paolo Raggi, MD, FACP,
FACC, Director of Preventive Cardiology and Non-Invasive
Imaging, Tulane University, 1430 Tulane Avenue, SL-48,
New Orleans, LA 70112, USA. Email: [email protected]
#
variable amounts of cholesterol debris, inflammatory,
smooth muscle and foam cells, fibrotic tissue, and
calcium according to their degree of development w1x.
Calcium accumulates steadily in the plaque and its
presence is verifiable via microscopic examination from
the very early stages of disease formation. It is not
until the more mature developmental phases of the
plaque, however, that this marker of atherosclerosis
can be identified non-invasively via external body
imaging. Calcification of atherosclerotic lesions is due
to a process of active deposition of calcium in the
atherosclerotic plaque that utilizes metabolic pathways
similar to those found in normal human bone w2,3x.
Indeed, several anabolic and catabolic bone enzymes
can be found in the plaque milieu w2x, and vascular cells
of different origin may develop osteoblastic and
osteoclastic phenotypes when exposed to appropriate
stimuli w3x. Of note, the nucleating factor for calcified
foci both in cardiac valves and atherosclerotic plaques
often consists of cholesterol crystals w4x. Therefore,
lipids may constitute a common link to several forms
of cardiovascular diseases that evolve into calcified
lesions. Patients undergoing haemodialysis are known
to suffer high cardiac morbidity and mortality and
frequently show extensive cardiovascular calcifications
w5,6x. As a result of treatment with large oral doses of
calcium-based phosphate binders and the utilization
of high concentrations of calcium salts in the dialysate,
these patients are often in positive calcium balance.
Further, several ESRD patients demonstrate adynamic
bone disease features with the inability to buffer
excess calcium w7,8x. Therefore, it could be argued
that the overflow of calcium due to excess mineral load
may predispose to the development of soft-tissue calcification. The composition of atherosclerotic plaques
does not qualitatively differ in patients undergoing
chronic dialysis and patients with coronary artery
disease without ESRD. However, Schwarz et al.
showed in pathological studies that the atherosclerotic
lesions found in the intimal layer of the arteries of
patients with ESRD, contain more extensive calcium
deposits than those of patients with and without
established coronary artery disease of similar age w9x.
They also found that although the thickness of the
2002 European Renal Association–European Dialysis and Transplant Association
Excess calcium load: measured with EBT in ESRD
media layer was increased, no calcification could be
detected in its context.
Electron beam tomography (EBT) is a high-speed
radiological technique, which enables the imaging
specialist to obtain accurate and detailed pictures of
cardiac valves, coronary arteries, and other cardiovascular and chest structures w10x. It employs a fourth
generation computed tomography (CT) device with
a design substantially different from that of spiral
CT technology. In fact, in the EBT design a fan of
X-ray is rotated around the stationary human body,
while in the conventional spiral CT’s a mechanical
pair—consisting of an X-ray source and detector—is
revolved around the human body while this is slowly
advanced through the CT gantry (Figure 1). The
attendant mechanical inertia slows the imaging
process with frequent blurring of the cardiac images.
EBT is highly sensitive for the detection of cardiovascular calcifications (Figure 2) and the calcium
scores calculated from the ensuing tomographic images
provide an accurate quantification of the extent of
calcium deposition w11–13x. As the calcified portion
of an atherosclerotic plaque represents only 15–20%
of the total plaque volume, calcium is considered a
333
marker of atherosclerosis and not the expression of the
entire disease.
Use of EBT imaging in clinical practice
The extent of coronary calcification measured by
means of the traditional calcium score shows a good
correlation with the total plaque burden found at
autopsy w14x, and there is a fair relationship between
calcium score and the probability of underlying
obstructive coronary disease w15x. Further, the negative
predictive value for coronary artery disease of a
negative EBT scan (CSs 0) is very high, as only 2–4%
of obstructive coronary artery lesions show no
calcification w16x. Conversely, the presence of coronary
calcification in asymptomatic individuals is a strong
predictor of cardiovascular morbidity and mortality.
Arad et al. reported on the cardiovascular outcomes
of a cohort of 1173 asymptomatic patients after an
average follow-up of 19 months from the initial EBT
screening w17x. The sensitivity, specificity, and negative
predictive value of a calcium score )160 for the
Fig. 1. Schematic representation of an EBT scanner. A fan of X-ray, generated during the impact of an electron beam against a series of
tungsten rings, is swept along an arch of 2108. The high imaging speed due to absence of mechanical inertia, typical of conventional helical
CTs, prevents image blurring.
334
P. Raggi
prediction of an event were 89, 82, and 99% respectively. The odds of suffering an event with a calcium
score )160, were 35.4 times that of patients without
calcium. Additionally, in this analysis the ability of
coronary calcification to predict an event was greater
than that of all traditional risk factors for coronary
artery disease. Similar results were reported in a more
recent study by Raggi et al. w18x. The authors showed
Fig. 2. Example of EBT image showing a moderate of calcium
deposited in the middle portion of the left anterior descending
coronary artery (arrow).
that not only the absolute calcium score, but also a
high score relative to the expected age and sex range
for the patient under investigation indicated a severe
risk of suffering a myocardial infarction and death in
the short term. These observations may be very relevant for the care of ESRD patients. In fact, cardiovascular disease represents the leading cause of
morbidity and mortality in these patients, accounting
for nearly half of all deaths. As EBT can be used to
assess the extent of cardiovascular calcification and
to estimate the associated risk of cardiovascular events,
it can be a very useful tool in the management of
ESRD patients. Braun et al. w5x first employed this
technology in a group of 49 patients undergoing
regular dialysis. They demonstrated extensive calcific
disease of both coronary arteries and cardiac valves
and an accelerated rate of progression of calcification
during a short follow-up period. Similarly, in an
ongoing experience with a large cohort of haemodialysis patients, Raggi et al. found extensive calcification of the aorta, coronary arteries, mitral, and aortic
valves w19x. In that study, )76% of the patients had
coronary calcium scores exceeding the 75th percentile
of age and sex matched controls, a level known to
indicate a high risk for cardiac events w18x. In observational studies conducted in ESRD patients, the
risk of suffering cardiovascular events has been related
to the presence of elevated serum phosphorus levels
and calcium–phosphate product w20x. Therefore, a
strict control of these factors appears to be of
utmost importance to limit soft-tissue calcification
and potentially reduce cardiovascular risk. Another
application of EBT that can potentially aid physicians
involved with the treatment of dialysis patients is serial
Calcium & Phosphorus
Smooth Muscle Cells
Calcium deposits
Macrophages/Foam Cells
+
Statins
-
HDL
+
LDLox
-
Renagel®
+
Statins
+
MCP apoptosis
+
-
LDLox
-
HDL
-
+
Renagel®
Fig. 3. Hypothetical mechanisms through which medical therapy might be able to slow progression of cardiovascular calcification. Oxidized
LDL is accumulated in the intima as atherosclerosis progresses. LDL is ingested by macrophages, which transform into foam cells. Heavily
laden macrophages eventually go through a process of programmed cell death (i.e. apoptosis) and release several mediators of inflammation
in the plaque milieu. Both statin therapy and Renagel1 lower oxidized LDL and raise HDL serum levels. The latter facilitate reverse transport
of cholesterol debris outside of the plaque and slows the inflammatory processes initiated by LDL-ox. Renagel1 couples an ability to lower
the serum calcium–phosphorus product with a strong beneficial activity on the lipid status.
Excess calcium load: measured with EBT in ESRD
assessments of the calcification status of cardiovascular
tissues. As reported above, Braun et al. showed that
valvular calcifications progress very rapidly in chronic
dialysis patients w5x. Callister et al. on the other hand,
demonstrated that in non-ESRD patients progression of coronary calcification could be substantially
reduced with the implementation of lipid-lowering
therapy w21x. Accordingly, a prospective and randomized study with sequential EBT imaging is currently
being conducted on haemodialysis patients treated
with either conventional doses of oral calcium-based
phosphate binders or Renagel1 w19x. This synthetic
polymer binds phosphate in the gut without exchanging calcium and helps to significantly reduce the
serum calcium–phosphorus product w22x. Further, in
long-term studies Renagel1 has been shown to reduce
LDL-cholesterol and increase HDL-cholesterol levels
to an extent similar to those of statins w22x. Therefore,
the hypothesis behind the current investigation is that
Renagel1 may slow the progression of cardiovascular
calcifications in ESRD patients due to its multiple
potentially beneficial mechanisms (Figure 3). It is
further hoped that in the future the slowing of cardiovascular calcification processes may translate into
reduction of cardiovascular events as it has already
been shown in asymptomatic individuals w23x.
In summary, ESRD patients are at high risk of
suffering serious cardiovascular events. The development of calcified atherosclerotic disease and the
frequent occurrence of events are secondary to the
high prevalence of risk factors for cardiovascular
disease w24x and, probably, to the mismanagement of
calcium and phosphorus balance w25,26x. EBT imaging
can be utilized to non-invasively detect and quantitate cardiovascular calcification providing relevant
prognostic information. Further, sequential EBT
imaging can be employed to assess the effectiveness
of medical therapy instituted to slow the progression
of disease.
Acknowledgements. Supported by an unrestricted grant from
Genzyme Corporation.
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