Comprehensive ultrasound assessment of the heart in persons exposed to radiation in various dose ranges

The dissertation is devoted to a comprehensive ultrasound assessment of the state of the heart in persons subjected to radiation exposure in different dose ranges and at different periods after exposure. The study covers participants in the liquidation of the consequences of the accident at the Chernobyl nuclear power plant, patients who survived acute radiation sickness, as well as patients with hemoblastoses who underwent total therapeutic irradiation as conditioning for bone marrow transplantation, and patients receiving local radiation therapy to the mediastinal region for oncological diseases. Using echocardiography with color Doppler mapping and spectral Doppler analysis, the frequency, character, and severity of structural and functional changes of the heart, their dose- and age-related dependence, and the dynamics of parameters during and in the late periods after irradiation are examined.

The work is aimed at clarifying the threshold radiation doses at which reliable echocardiographic differences from the control are detected, at evaluating the radioresistance of the heart, and at determining the place of echocardiography in the protocols of examination and follow-up of persons who have been in contact with ionizing radiation.

Cardiovascular diseases largely determine morbidity and mortality in the majority of economically developed countries [93,102,124]. Over the past several decades, for a number of reasons the Russian Federation has shown a steady decline in the birth rate and a rise in mortality. From 1990 to 1996 these negative trends became especially pronounced, with all three main components of the class of circulatory system diseases — ischemic heart disease, cerebrovascular disease, and other diseases of the circulatory system — participating in the deterioration of the situation and following the same pattern: mortality from them among men and women is rising in Russia and declining in the developed countries of the West [35,36,48]. Among men and women of working age, the leading causes of death are injuries and poisonings, followed by circulatory system diseases, followed by neoplasms [48]. In the structure of mortality of the entire population of Russia (per 100,000 people), the leading positions are occupied by circulatory system diseases (1998 — 748.5), neoplasms (1998 — 202.8), and injuries and poisonings (1998 — 185.3) [124].

An unfavorable ecological situation makes a significant contribution to population health: the anthropogenic load on the environment continues to grow and the quality of the air and water basins is deteriorating [35,36,124].

In connection with the development of nuclear power and the radiation incidents and emergency situations that have occurred, the question of the contribution of radioactive radiation to the increase in cardiovascular morbidity is becoming especially urgent. The occurrence of a large-scale radiation accident involving a large circle of persons dictates the need to resolve expert questions concerning the relationship of disease and (or) death to prior radiation exposure, which becomes considerably more complicated with the passage of years as the age of the affected persons increases, already burdened not only by constitutional factors but also by the development of involutional changes [23,24,37-39,112]. The development of clinical radiobiology and oncohematology requires a concrete assessment of the risk of radiation-induced cardiac pathology during radiation therapy and bone marrow transplantation with prior total therapeutic irradiation (TTI) (especially in elderly patients) [70-74,141,142,152,187,188].

All of the above determines the relevance of further in-depth investigation of the effects of ionizing radiation on cardiac structure and function.

Beginning in the 1940s, a large body of clinical, physiological, pathomorphological, and experimental data has been accumulated on the effects of radiation on various components of cardiac activity. These studies have mainly concerned emergency, therapeutic, or experimental (as a rule, in high doses) irradiation [23-25,42,45,98]. The results of the studies are contradictory [25,78,98,109]; this is because, although the heart has traditionally been regarded as a radioresistant organ, the powerful neurohumoral regulation of its activity means that exposure to various nonspecific factors leads to functional and, possibly, secondary structural changes in the tissues of the heart [7,8,13,15,20,26,39,66,90,164,169,173,179,193,198,220,224]. A number of works on the study of its state in various groups of persons occupationally exposed to sources of ionizing radiation and in participants in the liquidation of the consequences of the accident at the Chernobyl nuclear power plant have concluded that changes in cardiac structures and functions arise as a result of radiation exposure at low doses [101,107,116,117,121,122,123,133,139].

Earlier studies [25,44-47,53,78,105,109] mainly employed clinical and electrophysiological methods, which do not always yield adequate information on the state of the heart and have therefore created substantial difficulties in interpreting the results obtained.

The use of echocardiography, especially in combination with color Doppler mapping and spectral Doppler analysis, makes it possible to assess various structural and functional changes in the heart with a high degree of accuracy, as a rule even before the appearance of overt clinical manifestations and, in certain situations, in the absence of characteristic ECG changes [20,29,65,90,132,148,165,170,172,180,187,191]. This by no means implies that other methods are of little significance or are uninformative. However, among the existing imaging and functional methods, echocardiography rightly occupies the leading place.

AIMS AND OBJECTIVES OF THE STUDY

In view of the existence of contradictory data on the influence of irradiation on the structure and function of the heart, the aim of the present study was a clinical and echocardiographic assessment of the state of the heart in persons exposed to acute external (total and local — to the mediastinal region) ionizing radiation in different doses and at different follow-up periods.

The following objectives were set to attain this aim:

1) To assess the presence and severity (degree of expression) of cardiac pathology in persons exposed to acute external irradiation in different dose ranges in the acute and late periods, and their relationship with the level of dose load.

2) On the basis of clinical data and the results of echocardiographic examination, to compare the state of the heart in persons exposed to external irradiation in different doses (in the late period) and in persons of the same age groups who had no contact with ionizing radiation.

3) To study the dynamics of structural and functional changes of the heart during TTI (within the myeloablative conditioning regimen before bone marrow transplantation or transplantation of peripheral blood stem cells) and in the late period, as well as during and in the late period after radiation therapy to the mediastinal region.

Scientific novelty. — For the first time, with the use of echocardiography with color Doppler mapping and spectral Doppler analysis, an assessment has been made of cardiac function and structure in patients exposed to brief external radiation in different doses — from low doses (up to 100 cGy, without the development of bone marrow syndrome) to damaging doses (from 100 to 1000 cGy, with the development of acute radiation sickness) — at different periods after exposure, as well as in patients exposed to high doses of fractionated irradiation: total therapeutic and local irradiation to the mediastinal region at different periods after exposure. — The dose- and age-related dependence of the frequency, character, and severity of clinical and echocardiographic cardiac changes in patients exposed to “low” doses has been investigated. — A dynamic ultrasound study of the heart has been performed during TTI and during radiation therapy to the mediastinal region.

Theoretical significance. By the chosen evaluation criteria, an approximate threshold dose value (4 Gy) has been shown, below which no reliable echocardiographic differences from an adequate control are detected. In the dose range from 1 to 12 Gy, the genesis of these changes is mixed and the manifestations are subclinical. The results of some earlier studies indicating radioresistance of the heart have been confirmed [39,91,98,142,143,182,197,206].

Practical significance.

1. The results of the study demonstrate the absence of any cardiac sequelae after exposure to “low” doses, which does not allow the detected echocardiographic changes (myocardial hypertrophy, impairment of left ventricular diastolic function) to be attributed to ionizing radiation. These changes correspond to those in patients of the control group suffering from similar cardiovascular diseases.

2. Reliable changes in cardiac diastolic function (of mixed nature), detected in patients exposed to irradiation in the dose range from 1 to 12 Gy and having a subclinical character, require further observation to determine their contribution to the dynamics of general somatic cardiovascular pathology. For this category of patients, annual echocardiography with color Doppler mapping and spectral analysis is indicated.

3. The data obtained also make it possible not to impose strict limitations on the state of the heart when deciding on TTI, since the changes detected are mainly functional and subclinical, which is consistent with the data of other authors. In particular, valvular pathology without significant hemodynamic disturbances is not a contraindication to TTI.

4. Echocardiography with color Doppler mapping and spectral analysis should be included in the protocol of examination of patients exposed to irradiation in different dose ranges in order to detect nonspecific signs of the sequelae of high-dose exposure.

Implementation in practice. Echocardiography with color Doppler mapping and spectral analysis is widely used at the clinic of the State Research Center — Institute of Biophysics and at Clinical Hospital No. 6 of the FUMBP at the Ministry of Health of the Russian Federation in the examination of patients with cardiac pathology, including persons exposed to ionizing radiation in different doses, in the preparation and conduct of TTI with polychemotherapy, and in radiation therapy to the mediastinal region. The published results confirm data on the high radioresistance of the heart [70-75].

Statements to be defended:

1) Structural and functional changes of the heart in ULPA personnel at the Chernobyl nuclear power plant suffering from cardiovascular pathology in general do not differ from those in patients of the control group who had no contact with ionizing radiation.

2) In patients irradiated in the dose range from 100 to 1000 cGy, echocardiographic changes are detected that reliably differ from the control.

3) With total therapeutic irradiation at a dose of 12 Gy (in 6 fractions) in combination with high-dose chemotherapy with cardiotoxic drugs, a decrease in global contractility and in left ventricular diastolic function has been observed. Recovery of the altered left ventricular diastolic function occurs in some cases over several years, while global contractility returns to its initial level by the time of hematopoietic recovery.

4) In persons subjected to local irradiation of the mediastinal region and the heart at total doses of 20–100 Gy during radiation therapy, a progressive impairment of left ventricular diastolic function is observed, which apparently reflects radiation damage to the microvasculature of the heart. In the late period, increased echogenicity of the valves is detected, with possible development of transvalvular hemodynamic disturbances, impairment of left ventricular diastolic function, pericardial involvement with the appearance of transudate in its cavity, adhesions or constriction, and in some cases disturbances of coronary blood supply with the development of local myocardial hypokinesia. The above changes may be regarded as manifestations of radiation cardiopathy with the development of fibrotic changes of the valvular apparatus, pericardium, stroma, and microvasculature of the heart.