Arterial hypertension, structural and functional cardiac remodelling, lipid-releasing capacity of leukocytes, and evaluation of the effectiveness of antihypertensive therapy in patients with chronic obstructive pulmonary disease

The dissertation is devoted to the study of the features of the course of arterial hypertension and structural and functional cardiac remodelling in elderly and senile patients with chronic obstructive pulmonary disease (COPD), as well as to the evaluation of the lipid-releasing capacity of leukocytes as a possible factor of atherogenesis and systemic inflammation in combined cardiorespiratory pathology. The research is aimed at analysing the prevalence of arterial hypertension and carotid atherosclerosis in this category of patients, and at characterising morphometric changes in the myocardium and vascular wall depending on the stage of COPD and the concomitant pathology.

Special attention is paid to a comparative analysis of the state of the cardiovascular system in elderly and senile patients with COPD and chronic bronchitis without persistent bronchoobstructive syndrome. The practical part of the work is devoted to an evaluation of the effectiveness and tolerability of different groups of antihypertensive drugs (angiotensin II type 1 receptor antagonists, angiotensin-converting enzyme inhibitors, and slow calcium channel blockers) in combination with bronchodilator therapy, and of their influence on cardiac and carotid morphometric parameters, external respiratory function, and the lipid-releasing capacity of leukocytes.

Relevance. The problems of arterial hypertension (AH) and other diseases of the cardiovascular system (CVS) continue to be relevant for modern society in the scientific, practical, and socio-economic aspects. They are frequently combined with other diseases, including chronic obstructive pulmonary disease (COPD), especially in elderly and senile patients. It is known that population ageing is the most characteristic demographic phenomenon of the modern era [71]. Over the past 30 years, global ageing of the world's population has been observed. In Russia, an increase in the number of elderly people is also noted, their share in the overall population structure exceeding 20% [5]. The forecast for a continued rise in the share of elderly and senile persons, long-livers, and centenarians over the next 50 years is quite definite [157]. Obviously, this trend is associated with an increase in the diseases of this age group [71], which include CVS diseases and COPD.

In recent decades, cardiovascular diseases (CVDs) have occupied the first place in the structure of morbidity and mortality worldwide [48]. According to epidemiological studies, the prevalence of AH among the adult population ranges from 25 to 55% and increases with age [69]. According to data from a group of experts of the atherosclerosis section of the All-Russian Scientific Society of Cardiology (2005), more than 1 million people die annually in Russia from CVDs. The causes of death include both acute vascular events, cardiac rhythm and conduction disturbances, and chronic heart failure. CVS diseases are the most pressing problem of gerontology.

COPD is characterised by progressive respiratory and, subsequently, cardiopulmonary failure, and in combination with CVS diseases it leads to deterioration in the quality of life and shortening of the patient's life span. According to data from different authors, the prevalence of COPD ranges from 1 to 26% of the population, depending on the diagnostic criteria used by the authors [1, 21, 105, 120, 158]. According to WHO data, mortality from COPD is the 5th cause of all deaths from various internal diseases, and by 2020 it may occupy the 3rd place due to the increasing prevalence of the disease [1, 21, 33, 105, 112]. According to forecasts of the World Bank and the World Health Organization (WHO), by the magnitude of the economic and social damage caused by diseases, COPD will move from 12th place in 1990 to 5th place in 2020, taking a leading position among respiratory diseases [21].

According to the definition given by GOLD (2007), COPD is a disease characterised not only by progressive respiratory failure, but also by significant extrapulmonary manifestations capable of additionally aggravating the course of the disease in individual patients. The pulmonary component of COPD is characterised by not fully reversible limitation of airflow, which usually progresses and is associated with a pathological inflammatory response of the lungs to the action of inhaled pathogenic particles or gases. COPD is a disease that can be prevented and treated [21].

The disease is accompanied by damage to the cardiovascular system (a high prevalence of elevated systemic blood pressure, atherosclerosis, myocardial ischaemia, cardiac rhythm disturbances, and other clinical manifestations of CVS involvement in COPD) [2, 24, 33, 85, 105, 110], which leads to progressive cardiopulmonary failure [1, 30, 49, 79, 89, 110]. This aspect is particularly relevant in elderly and senile patients due to age-related changes in the cardiovascular and other body systems and the multi-organ nature of the lesions. Inflammatory mechanisms induced by hypoxia or by the influence of tobacco smoke components are often cited as the cause of cardiovascular pathology in COPD patients [32, 183, 200]. The inflammatory process in COPD is characterised by an increase in the number of neutrophils, macrophages, and T-lymphocytes. In this regard, it is necessary to continue studying various functions of these cells, including the lipid-releasing function of leukocytes (LRFL), as a factor influencing the state of the cardiovascular system [9, 25, 52, 59, 65, 93].

As a rule, a person aged 60 years and older suffers from 3-4 or more diseases, and with increasing age both the number of diseases and the number of medications required for their treatment increase [45, 121, 155]. For the treatment of arterial hypertension (AH) and chronic heart failure (CHF), as well as for the treatment of pulmonary hypertension and CLS in COPD patients, antihypertensive agents are used in combined therapy. This necessitates a comparative study of the effectiveness of various antihypertensive drugs, an assessment of their tolerability, and their influence on the course of respiratory disease. There are insufficient data on the effect of ARB II type 1 drugs on the state of the cardiovascular system in COPD.

The factors listed indicate the relevance of continuing to study the mutual influence of cardiovascular system diseases and COPD in order to clarify the mechanisms of formation of complications that threaten the life of elderly and senile patients and to optimise their treatment.

Aim of the work: to study the features of the course of arterial hypertension, morphofunctional changes in the cardiovascular system, and certain mechanisms of cardiovascular disease formation in elderly and senile patients with chronic obstructive pulmonary disease, as well as to evaluate the effectiveness of combined therapy including antihypertensive drugs.

Objectives

1. To study the frequency and features of the course of arterial hypertension and its interrelation with external respiratory function in elderly and senile COPD patients.

2. To investigate cardiac morphometric parameters (according to echocardiography data) in elderly and senile COPD patients, including in combination with arterial hypertension syndrome and carotid atherosclerosis.

3. To evaluate the frequency and features of atherosclerotic lesions of the carotid arteries in elderly and senile COPD patients by duplex scanning.

4. To investigate the lipid-releasing capacity of leukocytes in elderly and senile COPD patients of varying severity who have arterial hypertension and/or atherosclerotic lesions of the carotid arteries.

5. To study cardiac morphometric parameters (according to echocardiography data), features of atherosclerotic lesions of the carotid arteries, and the lipid-releasing capacity of leukocytes, as well as to evaluate external respiratory function in elderly and senile patients with chronic bronchitis.

6. To evaluate the effectiveness of antihypertensive drugs (angiotensin II type 1 receptor antagonists, angiotensin-converting enzyme inhibitors, slow calcium channel blockers) in combination with bronchodilator drugs and their influence on the dynamics of cardiac and carotid artery morphometric parameters, lipid-releasing capacity of leukocytes, and indicators of external respiratory function in elderly and senile COPD patients.

Scientific novelty. A study of the prevalence of AH and carotid atherosclerosis in elderly and senile COPD patients has been carried out. For the first time, an analysis of morphometric changes in the heart and carotid arteries in elderly and senile COPD patients has been performed depending on the stage of the disease, the presence of AH, and the severity of carotid atherosclerosis.

It has been established that the high frequency of atherosclerotic lesions of the carotid arteries in elderly and senile COPD patients (90%) does not depend on AH; an increase in the severity of atherosclerotic lesions of the carotid arteries has been noted in patients with an extremely severe course of the disease (stage IV). For the first time, LRFL has been evaluated and its increase in elderly and senile COPD patients has been established; it has been established that the degree of impaired functional activity of neutrophils does not depend on the COPD stage and the presence of AH.

An interrelation has been revealed between an increase in LRFL above the value of 0.150 mmol/l and the severity of the course of carotid atherosclerosis.

For the first time, a comparative characterisation of echocardiography data, duplex scanning of the carotid arteries, and LRFL in elderly and senile patients with COPD and chronic bronchitis without persistent bronchoobstructive syndrome has been carried out. It has been revealed that identical morphometric changes in the myocardium and manifestations of carotid atherosclerosis are observed in elderly and senile patients with COPD and chronic bronchitis.

For the first time, the high effectiveness and safety of antihypertensive drugs (ARBs, ACE inhibitors, CCBs) as part of combined therapy for CLS and AH in elderly and senile COPD patients has been established. It has been proven that the use of ARBs and ACE inhibitors does not affect ERF indicators, reduces LRFL, exerts a preventive effect on cardiac morphometric parameters, and improves the state of the arterial wall.

Practical significance. The results of the study revealed a high frequency of cardiovascular system lesions (AH and carotid atherosclerosis) in elderly and senile COPD patients, which indicates the need for their prevention (elimination of risk factors, adequate treatment of COPD), active diagnosis of CLS, AH, and carotid atherosclerosis (echocardiography, duplex scanning of the carotid arteries, LRFL) in COPD patients, and the prescription of antihypertensive drugs in the presence of AH, carotid atherosclerosis, or CLS.

The work has shown that the study of ERF, echocardiography, duplex scanning of the main (carotid) arteries, and LRFL should be used at the stage of rehabilitation of COPD patients.

The results of the study make it possible to develop new approaches to the treatment of COPD complicated by CLS and to the combination of COPD with cardiovascular pathology in elderly and senile patients, optimising treatment tactics through the use of complex programmes (antihypertensive drugs from the groups of ARBs, ACE inhibitors, CCBs, and bronchodilators), taking into account their tolerability, contraindications, and side effects.

Impairment of neutrophil function is a central link in the inflammatory lesion of the bronchi in COPD patients. The dissertation continues the investigation of a new neutrophil function — LRFL — and the influence on it of certain groups of antihypertensive drugs.

The application in clinical practice of a new method of examination (the LRFL study) in COPD and chronic bronchitis patients makes it possible to assess the activity of the systemic inflammatory process, to predict an unfavourable course of the disease, and to increase the effectiveness of the therapy administered.

Statements put forward for defence

1. The course of COPD in elderly and senile patients is associated with a high prevalence of arterial hypertension (80%) and atherosclerosis, including that of the carotid arteries (90%). They undergo structural and functional remodelling of the myocardium and vascular wall (myocardial remodelling with a predominance of eccentric left ventricular hypertrophy, an increase in intima-media thickness, and the formation of atherosclerotic plaques).

2. An increase in the lipid-releasing capacity of leukocytes in elderly and senile COPD patients is associated with the onset and progression of atherosclerosis. Thus, in carotid atherosclerosis, a significant increase in LRFL (more than 0.150 mmol/l) is observed in 60% of cases. This indicator should be considered an important prognostic criterion of an unfavourable course of atherosclerosis.

3. The inclusion in the complex therapy of ARBs, ACE inhibitors, and CCBs in the presence of AH and CLS in elderly and senile COPD patients, along with a good antihypertensive and general clinical effect, exerts a positive influence on the state of the vascular wall, does not worsen ERF and cardiac morphometric characteristics. ARBs and ACE inhibitors reliably reduce LRFL.

Implementation into practice. The results of the study have been implemented in the practical work of the therapeutic department of the State Healthcare Institution "Perm Regional Hospital for War Veterans", the pulmonology department of the State Healthcare Institution "Order of the Badge of Honour" Perm Regional Clinical Hospital, and the educational process at the Department of Hospital Therapy No. 1 of the Faculty of General Medicine and the Department of Internal Diseases of the Paediatric and Stomatological Faculties of the SEI HPE "PSMA named after Academician E.A. Wagner of the Russian Health Ministry".

Personal contribution of the author. The author independently performed the clinical examination, defined the inclusion and exclusion criteria during the recruitment of clinical material, monitored patients dynamically, performed repeated examinations according to the study design, created the computer database, carried out the statistical processing of the data, and analysed the results obtained.

Approval of the work and publications. The work was approved at a joint meeting of the Scientific Coordination Council for Cardiology and the Departments of Hospital Therapy No. 1 and Hospital Therapy No. 2 of the FPE of the SEI HPE "PSMA named after Academician E.A. Wagner of the Russian Health Ministry" on 11.06.2009.

On the topic of the dissertation, 7 scientific works have been published, including 3 articles in a peer-reviewed publication recommended by the Higher Attestation Commission.

Structure and scope of the work. The dissertation consists of an introduction, 6 chapters, conclusions, and a list of references. The material is presented on 174 pages of typewritten text and includes 69 tables, 4 figures (30 pages), and 4 clinical examples. The list of references contains 205 sources (115 domestic and 90 foreign).