Vol.3, No.5, 263-270 (2011)
doi:10.4236/health.2011.35047
C
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Health
Impact of chemical elements on heart failure
progression in coronary heart disease patients
Karaskov Alexander, Kamenskaya Oksana*, Levicheva Elena, Loginova Irina, Okuneva Galina,
Cherniavsky Aleksander, Kliver Evgeni, Volkov Alexander
Federal State Institution Academician E.N.Meshalkin Novosibirsk State Research Institute of Circulation Pathology Rusmedtechnol-
ogy, Novosibirsk, Russian Federation; *Corresponding Author:
Received 31 January 2011; revised 20 April 2011; accepted 27 April 2011.
ABSTRACT
Background. The high prevalence, poor prog-
nosis of patients with coronary heart disease
with chronic heart failure determine the rele-
vance of the study pathophysiological and mo-
lecular mechanisms of this pathology. Re-
searches of the trace element metabolism in the
myocardium are scarce. With this in mind, an
attempt w as made to analyze the relationship of
macro and trace elements metabolism with the
functional state of the myocardium in coronary
heart disease patients against the background
of chronic heart failure progression. Methods
and Results. To study the content of the
chemical elements (S, K, Ca, Cr, Fe, Ni, Cu, Zn,
Se, Rb, Sr) in the myocardium of 43 patients
with coronary heart disease, use was made of
X-ray fluorescence with synchrotron radiation.
While doing autop sy, 43 samples of left ventricle
myocardiu m were taken off the car diac callosit y.
Myocardium samples were subjected to histo-
logical examination. Dynamics of macro and
trace elements content in the myocardium re-
flects the deve lopment of energy deficiency and
disorders of myocardial microcirculation with a
decrease of systolic myocardial function.
Structural/functional disorders in the myocar-
dium of the left ventricle of patients with coro-
nary heart disease that accompany the pro-
gression of chronic heart failure are associated
with profound changes of metabolic processes
in heart muscle. Conclusions. The structural/
functional changes accomp anyi ng chronic heart
failure progression are associated with wide
variations of metabolic processes in the myo-
cardium, which could be evaluated by the con-
tent of chemical elements in tissue.
Keywords: Heart Failure; Tissue; Myocardium
1. INTRODUCTION
Chronic heart failure (CHF) is a pathophysiological
syndrome caused by structural or functional cardiac dis-
orders that affect the ventricular function to pump and
eject the blood [1]. In spite of recent advances in medi-
cine, the prevalence of hospital admissions and lethal
outcomes in CHF patients remains high. Every year car-
diovascular diseases take 4.3 million human lives in
Europe and over 2 million cardiac patients annually die
in EU countries [2].
A coronary heart disease (CHD) is the primary cause
of CHF. At present a progression of cardiac insufficiency
is considered as the consequence of an imbalance in the
biochemical mechanisms system [3]. Direct damaging
actions of ischemia, hypertension or inflammation are
considered to be the main causes of such changes in
CHD patients.
Adequate metabolism is the main criterion of viability
of every cell in the organism. Therefore, any changes in
the concentration of chemical elements might serve as a
diagnostic marker of pathological changes in tissue.
A biochemical imbalance, which frequently accompa-
nies CHD, leads to progression of the left ventricular
dysfunction by speeding up myocardium remodeling
processes [4].
The contractility of the myocardium is maintained by
the appropriate electrolytic composition of cellular and
intercellular substances, as well as by enzymatic activity
of biochemical processes [5]. Metals are active enzyme
centers; therefore, determining the content of metals in
the myocardial tissue might shed some light on adequate
or inadequate metabolism of the heart.
However, the studies relating to the content of macro-
and microelements in the tissue of various organs (in-
cluding the myocardium) are largely conducted on ani-
mals. Humans are mainly involved when determining

K. Alexander et al. / Health 3 (2011) 263-270
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
264
the content of macro and trace elements in blood serum
in patients with different pathologies [6,7].
These studies are frequently incommensurable be-
cause the authors use different methods for measuring
the content of chemical elements and due to the fact that
blood being a common collector receives all products of
organism metabolism. Therefore, relating a particular
imbalance in the content of macro or trace elements in
blood to the pathology of a specific organ is a challenge.
Unfortunately, there are very few studies on metabolism
of human organs (excluding biochemical studies) but
this problem attracts considerable attention of research-
ers. Of special interest is the investigation of metabolism
of the heart affected by a coronary disease, because the
morbidity of this pathology is rather high. With this in
mind, an attempt was made to analyze the relationship of
mineral metabolism with the functional state of the
myocardium in CHD patients against the background of
chronic heart failure progression.
2. METHODS
2.1. Patients
We studied 43 patients with CHD (66% males, 34%
females, mean age 61 ± 1.6 years). Coronary heart dis-
ease was diagnosed in the patients on the basis of medical
history, physical findings, electrocardiography, echocar-
diography and coronary angiography. In accordance with
New York Heart Association classification 24% of pa-
tients fell under functional class (FC) II, 62% – FC III
and 14% – FC IV. All CHD patients’ case history in-
cluded myocardial infarction of the LV with different
periods of duration, and all of them died at the hospital
as a result of heart failure progression.
2.2. Tissue Samples
Samples from heart muscle were obtained from 43
autopsies taken from CHD patients. 15 samples of LV
myocardium belonging to people who died as a result of
road accidents and who had no vascular pathologies
were used as a control group. The post-mortem time
from death to autopsy ranged from 12 to 24 h. Left ven-
tricle (LV) myocardium was taken off the cardiac callos-
ity.
Myocardium samples for histological examination
were excised from the anterior, posterior and apical parts
of LV, preserved in 10% formaline and embedded in
paraffin. 5 µm-thick slices were obtained by using Mi-
crom HM550 microtome and stained with haematoksy-
lin-eosin making use of van Gieson’s method, with the
elastic finished by combined application of orceine.
PAS-reaction and Gomori one-step trichrome stain were
also applied. Plain histology and morphometric studies
were done by means of a microscope-based set which
included a ZEISS optical microscope, an AxioCam MRc
digital videocamera and a Pentium-4 computer. Meas-
urements were performed by using an AxioVisio system
at 400x magnification, with the microscope calibrated on
a regular basis. The following morphological criteria
were chosen to be used in the study: muscle fiber di-
ameter, muscle tissue area, number of nuclei with the
calculation of their average and total area, as well as
nuclear-cytoplasmic index.
2.3. Chemical Element Analysis
The measurements were carried out at the experimen-
tal station of X-ray fluorescence elemental analysis
(Budker Institute of Nuclear Physics SB RAS, storage
ring VEPP-3). The masses of samples varied from 3 to 8
mg (wet tissue). The sample preparation was following:
specimens were drying on fluoroplastic films overnight
under the room temperature, samples were kept under
the weight to get more flat surface of the sample. The
coefficient of the loss of weight was from 1.7 to 2.0.
Thus, the mass of sample analyzed was from 1.5 to 4.7
mg (dry tissue). Than, the samples were placed between
two Mylar X-ray films (thickness of 2.5 µm) and
clamped by the Teflon rings. Elemental concentrations in
the samples of myocardium were calculated by the ex-
ternal standard method. Two certified reference materials
(CRM) were used: NIES #6 Mussel and NIST 1577 Bo-
vine Liver. Chemical elements (CE) detected: S, K, Ca,
Cr, Fe, Ni, Cu, Zn, Se, Rb, Sr. The content of CE was
measured at µg per 1 g of tissue.
2.4. Echocardiography Evaluation
Based on the life-time ECG data obtained 2 - 5 days
before the patient’s death, some structural/functional
parameters of the heart were measured and analyzed.
The end-diastolic dimension of the left ventricle (EDD
LV, cm), end-systolic and end-diastolic volumes of the
left ventricle (ESV and EDV LV, ml) and ejection frac-
tion of the left ventricle (EF LV, %) were determined.
Also calculated were myocardium mass (MM LV, g) and
relative thickness of the left ventricle wall (RTW LV, rel.
units). The ECG cardiometric data of healthy males of
the same age were used for comparison.
2.5. Statistical Analysis
Statistical analysis was performed using the STATIS-
TICA 6.1. The differences between the levels of the
chemical elements in the myocardium of CHD patients
with normal and low LV ejection fraction were tested by
Mann-Whitney U test. Correlations between the levels of

K. Alexander et al. / Health 3 (2011) 263-270
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
265265
the chemical elements were calculated using Spearman
rank correlation analysis. Value p < 0.05 was considered
statistically significant.
3. RESULTS AND DISCUSSION
With CHF progressing, the myocardium undergoes
structural/functional changes known as myocardial re-
modeling. This process includes myocardium hypertro-
phy, its dysfunction and death of cardiomyocytes, as
well as alteration of the cardiac extracellular matrix,
often referred to as myocardial fibrosis [8]. A systolic
dysfunction evaluated primarily by LV EF is at present
regarded as an independent predictor of CHF patients’
diagnosis [9].
Undoubtedly, CHF progression is accompanied by
both the systolic and diastolic dysfunction, with the di-
astole being an earlier and more vulnerable target and
preceding the impairment of the systolic function. How-
ever, choosing the systolic rather than diastolic function
of LV as a predictor of CHF prognosis is associated with
the problem of early diagnostics of the diastolic dys-
function, since it is practically insidious [10,11].
Our ECG data show that as CHF progresses, by the
example of a decreased EF, increased end volumes of LV,
both systolic and diastolic ones, as well as a thinned
myocardium of LV are observed (Figure 1).
An ischemic damage of myocardium followed by the
development of a large-sized area of cicatrical tissue in
the LV wall turning into aneurismal thinning of LV
stimulates compensatory hypertrophy of myocardium
both in the percicatrical area and in the entire muscle on
a whole. With the coronary flow compromised, which is
typical of CHD, hypertrophic cardiomyocytes start los-
ing their hyperplastic intracellular structures (myofibrils,
mitochondria) and get mummified, while some part of
them is undergoing necrodystrophic and apoptotic
changes. The morphological pattern of cardiac insuffi-
ciency is characterized by the presence of areas of dead
cardiomyocytes, structural abnormalities of viable car-
diomyocytes and fibrosis progression [8,12].
Our evaluation of morphometric properties indicated
that an average diameter of myocardial muscle fibers of
LV in CHD patients (9.8 ± 2.2 µm) was nearly the same
as that of healthy ones (9.2 ± 1.8, p > 0.05). At the same
time the histogram of muscle fiber number distribution
depending on their diameter demonstrated a decrease in
the average-diameter fibers in CHD patients and an in-
crease in extreme values (atrophic and hypertrophic fi-
bers) as compared to the norm (Figure 2). Such a wide
variability of fibers in thickness in CHD patients indi-
cates that the compensatory hypertrophy stage starts
wearing off and changing to a decompensation stage
with muscle fiber atrophy.
Figure 1. Structural/functional parameters of LV as cardiac
insufficiency progresses in CHD patients.
Figure 2. Relationship between quantity of muscle fibers and
their diameter in LV in CHD patients and control group.
The analysis of the relationship between the number
of cardiomyocyte nuclei and their area in LV myocar-
dium revealed that in CHD patients the histogram of
nuclei area distribution was shifted towards smaller
structures. This evidences an earlier process of nuclear
material depletion as compared with other intracellular
structures, i.e. an atrophic and apoptotic focus of myo-
cardial parenchymal structures depression in addition to
their dysmetabolic necrosis in the case of ischemia.

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Histological symptoms of myocardial ischemia also
include microcirculatory disorders manifesting them-
selves as non-uniform blood filling of myocardium cap-
illaries, microhemorrhages. Nickel presents a vasoactive
endogenic agent which might play an important role in
this pathogenesis. This CE is assigned mainly a toxic
effect on tissues [13]. However, our data are at variance
with the categoricity of this point of view. In our study,
as cardiac insufficiency progressed, the content of Ni
decreased from 0.93 µg/g of tissue, with average value
of EF equal to 63.5%, to 0.35 µg/g of tissue, with aver-
age EF equal to 31.2%. In our earlier study we demon-
strated that Ni deficit reduced the possibility of angio-
genesis in the conditions of compensatory hypertrophy
development, which manifested itself as a low number
of intramyocardial arteries [14]. A statistically signifi-
cant direct correlation relationship has been found to
exist between a relative thickness of the LV wall and Ni
content (r = 0.76; p < 0.01), which also demonstrates a
considerable contribution of Ni to the development of
the microcirculatory bed of LV myocardium. Nickel
deficit has little effect on protein metabolism, however,
it induces noticeable shifts in carbohydrate and lipid
metabolism, thus suggesting that Ni influences energy
exchange in the myocardium [15].
Chrome has a great impact on energy processes, since
its main biological role in a human organism is con-
nected with the regulation of carbohydrate and lipid me-
tabolism, as well as with maintenance of tolerance to
glucose [16,17]. Chrome is also important for normal
metabolism of fats and its shortage would undoubtedly
result in excess weight, obesity. Chrome is regarded as
an activator of a number of enzymes [18]. Chrome con-
centration decreases when a patient is under stress (pro-
tein starvation, physical load, hypoxia, etc.) because of
its increased discharge with urine. Perhaps, hypoxic
stress, when cardiac insufficiency progresses, is a trigger
for Cr deficit build-up in the myocardium, which further
contributes to disruption of energy processes in CHD
patients’ myocardium (Figure 3).
Cardiac insufficiency progression is accompanied by
the development of myocardial fibrosis, which originates
not only in the areas of old myocardial infarction but in
the non-involved zones as well. As LV contractility re-
duces, an increase in S concentration is observed in its
myocardium, which might be associated with the in-
crease in the content of connective tissue, because the
latter is known to consist of mainly sulphide-bearing
amino acids (Figure 4).
The same dynamics is typical for Fe content, the con-
centration of which increases, as the ejection fraction
reduces. A statistically significant correlation of a mod-
erately pronounced nature (r = 0.43: p < 0.01) can be
Figure 3. Dynamics of Cr content as cardiac insufficiency
progresses in CHD patients.
observed between the contents of S and Fe, which bears
witness to uniformity of processes related to the imbal-
ance of these elements. Diffuse propagation of connec-
tive tissue strengthens myocardium stiffness, which is a
contributory factor not only for systolic but also diastolic
dysfunction of LV [19].
Thus, an increase in S and Fe content demonstrates an
aggravation of rigid processes in LV myocardium, as
cardiac insufficiency progresses. Indeed, the morpho-
logical picture of a “rigid” myocardium with a low EF as
compared to the myocardium with a normal EF has its
own features. According to our data in chronic CHD
patients there appear signs of dystrophia, necrobiosis and
necrosis in different parts of the myocardium. In the area
of necrotic loci there develop small scars, stromal col-
lapse, coarsening of argyrophilic skeleton, with a scar
elaborated without apparent cellular proliferation. In the
cases of death as a result of incremental chronic cardio-
vascular insufficiency, myotomes in the state of contac-
tures are few and far between, while partial disintegra-
tion of myofibrils predominates. Alongside with fresh
necroses of myocytes, numerous cellular infiltrates con-
sisting of macrophages and fibroblasts can be observed
in the myocardium. This “patchy” picture of myocar-
dium composed of muscle fibers with a different degree
of dystrophy and necrobiosis, with dead myotomes re-
placed by connective tissue, testifies that the myocar-
dium is subject to continuous and repeated injuries, with
the connective tissue volume increasing in a gradual
manner.
As the connective tissue increases, the muscle fibers
gradually elongate, myocardium contractility reduces, LV
cavity dilates and its walls get thinned (see Figure 1).
Insufficiency of Cu contributes to Fe accumulation in
the tissue because it is impossible to borrow it from the
tissue depot [20]. Indeed, as cardiac insufficiency pro-
gresses, Cu content in LV myocardium drops considerably

K. Alexander et al. / Health 3 (2011) 263-270
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267267
(Figure 5). Copper deficit is a defective synthesis of
collagen. Faulty synthesis of collagen and elastin in par-
ticular manifests itself as profuse internal hemorrhage
caused by the formation of aneurisms in large arteries. A
failure of those compounds that are responsible for tissue
bridging is considered to be the main biochemical defect
typical for this pathology, therefore Cu deficit leads to
degeneration and fibrosis of the myocardium.
Openly accessible at
Many researchers suggest that cardiac insufficiency
development is associated with interrelations between
Cu and Zn [21-23]. A decrease in Cu concentration is
more expressed as compared with that of Zn, and as our
data demonstrate, with LV myocardium contractility
lowered, the Zn/Cu proportion is increased nearly by 1.5
times at the expense of a decrease in Cu concentration.
Antagonism between Cu and Zn might play an important
role in pathological processes; it stimulates a shift in
metabolism of fat acids and synthesis of prostaglandins
[24].
Wide variations are also observed at the level of
membrane processes. The content of K decreases, as
cardiac insufficiency progresses, and this tendency un-
doubtedly influences membrane permeability. As this
takes place, Ca is accumulated in the tissue, thus affect-
ing myocardium contractility (Figure 6). Calcium and
potassium metabolic imbalance followed by elongation
of the action potential and the associated increase in dis-
persion of the repolarization process brings about dis-
turbances of conductivity and rhythm.
Energy intensity for Ca inactivation considerably ex-
ceeds energy demand for its delivery to myofilaments. A
decrease of Cr, as CHF develops (see Figure 2), is in-
dicative of energy imbalance in the myocardium, there-
fore, when an increase of intercellular concentration of
Ca is not balanced by increased activity of Na/Ca pump,
overload of Ca in the diastole might lead to a postdepo-
larization phenomenon, trigger activity and eventually to
the development of life-threatening ventricular arrhyth-
mias [25].
Of special interest are interrelations between the ele-
ments considered as chemical analogs that can replace
each other in biochemical reactions (Table 1).
Depending on the functional capabilities of LV myo-
cardium the relationships of these element concentra-
tions change by several times. As cardiac insufficiency
aggravates, there occurs a statistically significant reduc-
tion of K content, with Rb content remaining practically
the same, which allows for determining this process as
accumulation of Rb relative to K. It is necessary to note
that being a heavier chemical element Rb is a less desir-
able one for metabolism.
The relationship of Сa/Sr in the case of a decrease in
LV contractility results in a statistically significant in-
crease, almost by 2 times, primarily because of Ca ac-
cumulation, with Sr concentration staying invariable,
which can be described as Sr deficit relative to Ca.
Figure 4. Dynamics of Fe and S content as cardiac insufficiency progresses in CHD patients.

K. Alexander et al. / Health 3 (2011) 263-270
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268
Figure 5. Dynamics of Zn and Cu content as cardiac insufficiency progresses in CHD patients.
Figure 6. Dynamics of Ca and K content as cardiac insufficiency progresses in CHD patients.

K. Alexander et al. / Health 3 (2011) 263-270
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269269
Table 1. Relationships of some chemical elements in the myo-
cardium of CHD patients with normal and low contractility of
LV (M ± SD).
К/Rb Ca/Sr
Patients with Normal LV
Ejection Fraction (63.5±1.79%) 1859 ± 458.2 369 ± 69.6
Patients with Low LV Ejection
Fraction (31.2±1.53%) 919 ± 87.8* 701 ± 69.6*
Openly accessible at
The role of Se in human metabolism is evaluated
largely by its concentration in blood, which, as a rule,
decreases in the case of a disease. This tendency makes
many researchers regard Se deficit as an alarm signal in
the development of one or another pathogenesis [26-28].
Even in their first studies some authors attempted to as-
sess the impact of Se on dystrophic processes in muscle
tissue [29]. They have found out that Se concentration in
blood decreases, as myotic dystrophy develops. How-
ever, we have failed to find the works which would ex-
plain what is happening to Se concentration in humans
with a different functional state of muscle tissue.
Unfortunately, in our study we were also unable to
evaluate the contribution of Se to the development of
functional dysfunction of LV myocardium in the process
of CHF progression due to the absence of a clear rela-
tionship of this element content with EF (r = 0.23; p >
0.05). It can be only noted that no statistically significant
differences in Se content in the myocardium of CHD
patients and the control group have been revealed (0.78 ±
0.067 и 0.96 ± 0.056 µg/g of tissue respectively). In lit-
erature it is suggested that selenium is very much the
same as sulphur. At the same time in living organisms
these two elements behave in a completely different way.
Specifically, in animals Se compounds tend to regenerate,
while S compounds are subject to oxidation. Selenium is
capable of repairing disulfide links in proteins in SH
groups.
We have also found out that there exists a statistically
significant correlation relationship of Se content with
Mn (r = 0.34; p < 0.05) and with Zn (r = 0.44; p < 0.01),
as well as with Rb (r = – 0.45: p < 0.01) and Sr (r = 0.40;
p < 0.05), which may be explained by free radical oxida-
tion.
Thus, the structural/functional changes accompanying
CHF progression are associated with wide variations of
metabolic processes in the myocardium, which could be
evaluated by the content of chemical elements in tissue.
With clinical data on the severity of heart failure, we can
assume the status of metabolic processes in the myocar-
dium. Study results on the contents of chemical elements
in the myocardium during CHF progression is a funda-
mental basis for drug development and new approaches
in the therapy of heart failure. The results obtained
demonstrate that in order to understand the pathogenesis
of cardiac insufficiency progression, we need further
research in this direction.
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