The state of peripheral vascular reactivity in persons exposed to ionizing radiation in the long-term follow-up period

The dissertation is devoted to the evaluation of the state of peripheral vascular reactivity in persons subjected to ionizing radiation exposure, in the remote period of observation. The work was carried out on the basis of the State Research Center — Institute of Biophysics and belongs to the field of clinical radiation medicine. The study applies a comprehensive noninvasive ultrasound approach — duplex scanning with functional stress tests of myogenic and metabolic orientation, as well as a postocclusive reactive hyperemia test.

Comparison groups include patients with different doses of external uniform exposure (from 0.004 to 12 Gy), among them persons who have undergone acute radiation sickness, persons after total therapeutic irradiation, and those exposed at "low" doses, along with a control group without radiation contact. The study examines baseline blood flow parameters and the reactivity of the cerebral and limb arterial beds, including the intracranial portions of the brachiocephalic arteries and the distal portions of the radial and posterior tibial arteries.

In the majority of economically developed countries, cardiovascular pathology occupies a leading position among the causes of morbidity in the population and is the leading cause in the structure of mortality [76, 89, 108]. This problem is especially relevant for the Russian Federation, where, over the past years, due to a number of objective factors, the birth rate has been steadily declining and mortality has been rising, which leads to a regular "aging" of the nation. From 1990 to 1996 these negative tendencies acquired a particularly pronounced character. In the structure of mortality of the entire population of Russia, diseases of the circulatory system occupy the leading place (1998 — 748.5 cases per 100,000 people), neoplasms (1998 — 202.8 per 100,000), and injuries and poisonings (1998 — 185.3 per 100,000) [108].

Under the conditions of continued development of atomic power engineering and industry, the introduction of technologies that envisage the use of ionizing radiation sources in various spheres of activity, and the expansion of the contingents of workers and the population who, in one way or another, come into contact with radiation, the problem of studying the effects of radiation exposure on various organs and systems of the human organism remains relevant. The significance of the latter is not limited to theoretical and practical medical aspects, since the results of scientific research in this field constitute the basis for the legislative bills being developed that regulate the scope and types of social benefits granted to citizens [119, 207].

The greatest (and ever-increasing) contribution to anthropogenic exposure is made by the medical use of ionizing radiation (IR) [118, 207, 123]. Medical radiation sources include radiation diagnostics, radiation therapy, and interventional radiology. As a result of errors in the implementation of certain interventional procedures (such as radiological procedures for monitoring the dilation of coronary arteries, etc.) or radiation therapy for various oncological diseases, severe radiation injuries have repeatedly occurred [123].

The use of radioactive materials in industry, agriculture, and scientific research has been steadily expanding, which, as a consequence of errors in handling radiation sources, may cause substantial damage to the health of workers [207].

The question of the contribution of occupational exposure to the structure of disability and mortality among workers of the nuclear industry currently matters only in the case of emergency situations and the implementation of measures for the liquidation of their consequences [12, 40, 88, 119, 120]. In large-scale accidents, the population residing in the territories adjacent to the site of the disaster is also exposed to radiation, while the number of directly affected and involved persons varies considerably (from a few to hundreds of thousands of people) [207].

Over a relatively short (50-year) period of development of radiation medicine, a considerable amount of results of various investigations (clinical, biochemical, immunological, morphological) has been accumulated, demonstrating the presence of vascular changes in the acute and remote periods after external radiation exposure, mainly at doses leading to the development of deterministic effects [21, 22, 31, 38, 43, 44, 49, 74, 137, 150, 156, 157, 162, 166, 168, 170, 173, 176, 189, 195, 212, 229].

The most numerous are the works based on observations of patients who underwent radiation therapy. However, the data contained in publications devoted to the description of changes detected in large vessels are of a contradictory nature. Thus, a number of researchers [128, 154, 160, 197, 233] report the development of an early atherosclerotic process after radiation therapy in children, that is, in those cases where the usual for older ages risk factors for the development of atherosclerosis are absent. As a rule, changes were detected in the vessels that fell within the radiation field. The authors of these publications tend to consider such atherosclerotic changes as a consequence of direct radiation exposure. There are also data on earlier than in the population development of involutional changes in cerebral vessels in the remote period after acute and chronic external uniform exposure at doses of 3–4 Gy and more, 3–4 decades after radiation exposure [13, 90, 91, 106, 112, 114]. The proposition that irradiation is one of the factors inducing the development of atherosclerotic lesions is also supported by certain experimental data [172, 228].

However, such assumptions are disputed by many researchers [38, 61, 68, 142, 193, 201]. Thus, F. Mettler and A. Upton [189] emphasize that the heart and large vessels are sufficiently highly radioresistant. Similar conclusions are contained in the publications of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) [43].

Data concerning damage to medium- and small-caliber vessels are not so numerous. For the most part, these are experimental data from histological, biochemical, and morphological investigations [5, 6, 21, 30, 165–167, 212]. The changes revealed in this case occur under the influence of rather high radiation doses (from 30 to 100 Gy).

The results of pathomorphological investigations of persons who died at various times from acute radiation sickness are of great value, but their number is also small. After the accident at the Chernobyl Nuclear Power Plant (ChNPP) on April 26, 1986, the results of investigations concerning the state of health of a huge cohort of liquidators of the consequences of this, one of the largest in the history of mankind, technogenic radiation accident have been published. Data are also known from the observation of professionals who were subjected to significant exposure during the start-up period of the first nuclear enterprise of the country [45].

Some researchers [80, 85, 86, 87, 93, 97, 99, 120, 164, 227] assert that noticeable (clinically and paraclinically detectable) functional and organic changes can be detected after human exposure at doses that do not lead to the development of deterministic effects; at the same time, in a number of cases, the presence of a direct relationship between the latter and the exposure that took place is established on the basis of comparison with the dose value with a narrow step (10–25 cSv).

Thus, the multitude of persons coming into contact with radiation sources and the prevalence among them (as in the population as a whole) of cardiovascular diseases, in the absence of unified views on the character of changes on the part of the vascular system after exposure at various doses, determine the relevance of the present study.

In the 1950s–1970s in the USSR, the most widespread and accessible paraclinical methods for the detection of small-vessel lesions were rheovasography (RVG) and rheoencephalography (REG) [41, 124]. With the use of these methods, numerous scientific investigations have been carried out, including in the field of radiation medicine [19, 29, 110, 111, 112, 114]. Subsequently, in connection with the introduction of radiation diagnostic methods with incomparably higher information content of the latter, RVG ceased to be used for the verification of vascular lesions. The highest information content is possessed by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) with the use of various radiopharmaceuticals (133Xe, 123I, 99mTc) and the application of stress tests [16, 68, 199]. However, both methods are expensive and involve additional irradiation of patients.

Ultrasound investigations have been applied in clinical practice for more than 40 years, but only over the past two decades technologies have been widely introduced thanks to which the resolving power of the method and the quality of visualization have risen to a fundamentally new level. As a result, the accuracy and information content of ultrasound, primarily duplex scanning (DS), has approached, in terms of information content and specificity for a number of organs and systems, that of X-ray computed tomography (RCT), and, in the aspect of studying the state of vessels, that of X-ray contrast angiography, which remains to this day the "gold standard" in angiology. Using modern diagnostic equipment with an adequate set of technologies, it is possible to detect the earliest hemodynamic disturbances, while noninvasiveness, relative cheapness, high accuracy, and information content make the method most preferable both for the assessment of structural–functional and hemodynamic disturbances of the vascular system and for observing the dynamics of the development of the main pathological processes in it. The use of functional stress tests makes it possible not only to determine the fact of the presence of hemodynamic disturbances in the microcirculation system, but also to evaluate the degree of their severity, and in a number of cases their prognostic significance.

The aim of the present investigation was a comprehensive evaluation, by means of duplex scanning with the use of functional stress tests, of the state of the peripheral arterial bed in persons subjected to external uniform exposure at various doses, in the remote period of observation.

To achieve this aim, the following tasks were set:

1) to investigate by means of duplex scanning the intracranial portions of the brachiocephalic arteries (middle and posterior cerebral arteries) with the use of functional stress tests of myogenic and metabolic orientation;

2) to investigate the state of the peripheral vascular bed by means of duplex scanning (distal portions of the radial and posterior tibial arteries) with the use of functional stress tests with graded physical load and a postocclusive reactive hyperemia test;

3) to evaluate the presence and severity (degree of expression) of disturbances of vascular reactivity in persons subjected to external exposure at various doses, in the remote period of observation, and their relationship to the level of doses;

4) to compare, on the basis of clinical data and the results of ultrasound investigation, the state of reactivity in persons subjected to external exposure at various doses (in the remote period of observation) and in persons who had no contact with ionizing radiation.

Scientific novelty. For the first time, a comprehensive noninvasive investigation of the state of the peripheral vascular bed by the method of duplex scanning was carried out in persons exposed at various doses, with an evaluation of the degree of expression of changes depending on the value of the radiation dose in the remote period of observation.

Theoretical significance. The absence of significant changes in peripheral vascular reactivity in persons subjected to external uniform exposure at various doses, in the remote period of observation, has been shown.

Practical significance. Investigations of peripheral vascular reactivity have been introduced into the everyday clinical practice of the Clinic of the SRC — Institute of Biophysics and are used as objectifying methods in various vascular diseases, as well as for the early detection of the latter in persons subjected to the effects of ionizing radiation and in those who had no contact with ionizing radiation sources.

Statements put forward for defense.

1. In the remote period of observation, in patients who have undergone acute radiation sickness of varying severity (as a result of external exposure at doses from 1.16 to 8.6 Gy), subjected to total therapeutic irradiation (at a total dose of 12 Gy), and exposed at "low" doses (from 0.004 to 0.58 Gy), no changes are observed in the baseline blood flow parameters in various peripheral vascular beds, as well as in the level of peripheral vascular reactivity (on the basis of the tests used), which could be caused by the fact of the exposure that took place and the magnitude of its dose.

2. On the level of peripheral vascular reactivity of arteries (predominantly of small caliber) of the brain and limbs, determined with the use of various functional stress tests of myogenic and metabolic orientation, arterial hypertension exerts a predominant influence. No evidence of the influence of other factors (age, smoking, overweight, burdened heredity, atherosclerotic lesion of main arteries with a degree of lumen reduction of no more than 50% in diameter) has been obtained.

3. The absence of changes in peripheral vascular reactivity in patients subjected to external exposure at various doses (0.004–12 Gy), in the remote period, testifies to the preservation of the main vasomotor functions of the distal arterial bed and to the insignificance of the structural changes in various elements of the vascular wall that may occur after irradiation.

I. REVIEW OF THE LITERATURE

The main characteristics of radiation exposure that determine the type and severity of changes on the part of the vascular system, as well as of the organism as a whole, are the total magnitude of the radiation dose, as well as its spatial and temporal distribution [38, 39]. By the magnitude of the total dose, it is customary to distinguish "large" and "small" doses, which differ substantially in the biological effects they determine. Thus, "large" radiation doses cause the development of threshold (deterministic, non-stochastic) effects (acute and chronic radiation sickness, local radiation injuries), whereas "small" doses cause the occurrence of stochastic (or probabilistic) effects (diseases, syndromes) of polyfactorial origin [38]. Stochastic effects, unlike deterministic ones, may occur over a wider range of doses; however, the probability of their occurrence also increases with increasing radiation dose [104]. For single external exposure, doses of 0.5 Gy or less are considered "small" [189] (in accordance with the recommendations of the International Commission on Radiological Protection (ICRP)). "Large" doses necessary for the development of the pronounced clinical manifestations of acute radiation sickness (ARS) under short-term whole-body irradiation are considered to be 1 Gy or more; for the formation of the symptom complex of chronic radiation sickness (CRS) — more than 1 Gy per year and cumulatively reaching values exceeding 1.5–2.0 Gy over 1–2 years; the time frames for the development of CRS (1–2 years or 5–10 years) depend on the intensity (dose rate) of the radiation [36, 37, 38, 92].

To characterize the changes in hemodynamics under the action of ionizing radiation on the organism, it is expedient briefly to consider the morphological changes in vessels of various calibers and their dependence on the total magnitude and dose rate of the absorbed dose. This is necessary for further prediction of the potential influence of the changes revealed on hemodynamics, depending on the absorbed dose, under conditional extrapolation of experimental data to humans.

At present, detailed data are available on the character of the changes developing in various layers of the vascular wall in connection with radiation exposure that has taken place [1, 21, 22, 30, 31, 38, 43, 44, 49, 52, 56–58, 74, 80, 100, 110, 130, 137, 139, 142, 150, 156, 157, 161, 162, 165, 166, 168, 170, 172, 173, 176, 188, 189, 195, 205, 212, 213, 229]. The components of the vascular wall have differing radiosensitivity and, accordingly, the changes revealed will depend on the total magnitude and dose rate reaching certain threshold values. Among the layers of the vascular wall, the most radiosensitive is the intima and its cellular basis — the endothelium.