Impact of chemical elements on heart failure progression in coronary heart disease patients

doi:10.4236/health.2011.35047

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Vol.3, No.5, 263-270 (2011)

doi:10.4236/health.2011.35047

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: [email protected]

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

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

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.

K. Alexander et al. / Health 3 (2011) 263-270

266

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

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

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

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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