Diastolic Dysfunction of the Left Ventricle in Patients with Hypertensive Disease: Mechanisms of Formation, Early Diagnosis, Pathogenetic Justification for the Application of β-Adrenoblockers

The dissertation is dedicated to a comprehensive study of diastolic dysfunction of the left ventricle in patients with hypertensive disease. The work reveals pathogenetic mechanisms of the formation of early stages of hypertensive heart disease, including impairments of segmental and global diastolic function detected using tissue Doppler echocardiography. The interrelationships of diastolic abnormalities with the features of the circadian blood pressure profile, the geometric model of the left ventricle, and metabolic changes — shifts in the fatty acid composition of plasma lipids and erythrocyte membranes, the state of the lipid peroxidation and antioxidant protection system, and the level of adenine nucleotides — are investigated. The pathogenetic influence of selective β1-adrenoblockers (metoprolol) on the identified mechanisms is justified, and criteria for the early diagnosis of diastolic dysfunction of the left ventricle are developed.

The analysis of etiological factors of heart failure conducted in recent years has revealed an important characteristic feature of the Russian Federation — in almost 80% of cases the cause of its development is hypertensive disease [3,21,94]. This is associated with the extremely high prevalence of arterial hypertension in our country (approximately 35 million people) and the low percentage of its effective treatment [21,78,110,125,140,285].

Twenty-six regions of Russia participated in the first epidemiological study dedicated to the study of chronic heart failure in Russia — EPOCH-HF — completed in 2002 [26,124,140,285]. What did our studies show in comparison with the European EURO Heart Survey conducted approximately at the same time?

1. The prevalence of clinically overt heart failure in the Russian population amounts to 5.5%, which is 8–10 times greater than in Europe. If one takes into account patients with asymptomatic diastolic dysfunction of the left ventricle, the figure may reach 11.7% of the population, or 16 million people.

2. The main diseases leading to heart failure are arterial hypertension, coronary artery disease, and diabetes mellitus. As already noted above, hypertensive disease is the leading cause of heart failure in Russia — it was present in 87.7% of patients among all patients with circulatory insufficiency who sought medical care. The mean blood pressure level among all decompensated patients in Russia was 152.7/91.5 mmHg compared with 133/78 mmHg in Europe.

According to epidemiological data, in 30–40% of patients the clinical picture of heart failure is due to impairment of diastolic properties of the left ventricular myocardium at normal values of the ejection fraction [3,19,93,94,197,198,200,201]. In this regard, diastolic dysfunction of the left ventricle, being the initial stage of development of hypertensive heart disease (Frochlich E., 1987), attracts close attention from researchers [108,116,256]. Given the fact that at present the physician's arsenal contains a large number of antihypertensive drugs capable of not only hypotensive but also protective action on target organs [96,172,205,206], the importance of early diagnosis of diastolic abnormalities in patients with hypertensive disease becomes evident.

The most informative method for the diagnosis of heart failure is Doppler echocardiography, which allows the detection of systolic and diastolic dysfunction of the left ventricle [6,45,54]. Tissue Doppler imaging — a new method of studying the myocardium, which makes it possible to detect diastolic disturbances at the earliest stages of their development, which are "invisible" to traditional echocardiography [20,115,138,147,257]. Segmental diastolic function of the left ventricle using tissue Doppler has been studied mainly in patients with various forms of coronary artery disease and in systolic heart failure [7,103,108,193,286]. Diastolic function of the left ventricle in patients with hypertensive disease using tissue Doppler has been studied to an extremely insufficient extent at present.

An important aspect of the pathogenesis of hypertensive heart disease is the study of metabolic changes that can lead to the development of myocardial insufficiency both against the background of left ventricular hypertrophy and without it [97,99,111,119,123,152,308]. In this regard, the study of energetic and substrate metabolism of the myocardium becomes relevant. Early changes in the fatty acid composition of blood lipids and disruption of fatty acid utilization processes by the myocardium have been identified in such diseases as unstable angina, myocardial infarction, and hypertensive disease [16,46,111,112]. The role of shifts in the fatty acid composition of membranes and plasma lipids has been considered mainly in the context of the pathogenesis of arterial hypertension itself, rather than its complications [361]. However, there is virtually no information in the literature on the involvement of disturbances in the macroergic phosphate system, changes in the fatty acid composition of erythrocyte membranes, and their correlation with structural-functional parameters of the left ventricle in patients with hypertensive disease.

A great role in the disruption of myocardial metabolism is played by the activation of lipid peroxidation (LPO) processes, leading to the depletion and subsequent suppression of antioxidant protection and, as a consequence, the development of oxidative stress [15,30,80,82,107,126,145,160]. The significance of LPO process activation in the pathogenesis of heart failure in patients with overt symptoms of congestive heart failure due to systolic dysfunction of the left ventricle, developing against the background of various forms of coronary artery disease or dilated cardiomyopathy, has been established [46,107]. However, the role of LPO processes in the pathogenesis of diastolic dysfunction of the left ventricle in patients with hypertensive disease has been insufficiently studied [82].

Among antihypertensive agents, a special place belongs to selective β1-adrenoblockers, since, in addition to the hypotensive effect, they are fundamental drugs in the treatment of chronic heart failure [14,24,61,92,96,149,163]. At the same time, the literature data on the influence of β1-adrenoblockers on parameters of energetic myocardial metabolism, the fatty acid composition of blood lipids and erythrocyte membranes, and segmental diastolic function of the left ventricle in patients with hypertensive disease are isolated and not free of contradictions.

In this regard, it becomes relevant to conduct a research that would allow a comprehensive examination of the pathogenesis of the formation of early stages of hypertensive heart disease, determined using tissue Doppler with consideration of the features of circadian blood pressure fluctuations and the geometry of the left ventricle, as well as the interrelationship of diastolic abnormalities of the left ventricle with lipid peroxidation processes, shifts in the fatty acid composition of plasma lipids and erythrocyte membranes, parameters of macroergic phosphates, and the study of the possibility of pathogenetic influence of β1-adrenoblockers on the identified mechanisms.

Objective of the research:

To reveal pathogenetic mechanisms of diastolic dysfunction of the left ventricle in patients with hypertensive disease based on the study of cardiohemodynamic and metabolic changes, to develop criteria for its early diagnosis, and to justify the application of β1-adrenoblockers in this category of patients.

Tasks of the research:

1. To investigate global and segmental diastolic function of the left ventricle in patients with hypertensive disease depending on the severity of arterial hypertension, variability of the circadian blood pressure profile, and the geometric model of architecture using tissue Doppler echocardiography.

2. To investigate features of the fatty acid composition of blood lipids and erythrocyte membranes in patients with hypertensive disease.

3. To study patterns of changes in the parameters of the "LPO-antioxidant" system in patients with hypertensive disease and determine their significance in the pathogenesis of diastolic dysfunction of the left ventricle.

4. To evaluate the dynamics of adenine nucleotide content in erythrocytes of patients with hypertensive disease depending on diastolic properties of the left ventricle.

5. To identify the nature of correlation interrelationships between the studied biochemical parameters, features of the circadian blood pressure profile, and parameters of diastolic function of the left ventricle.

6. To determine the significance of the studied cardiohemodynamic and metabolic parameters in the pathogenesis of diastolic dysfunction of the left ventricle in patients with hypertensive disease.

7. To develop cardiohemodynamic and metabolic criteria for the early diagnosis of diastolic dysfunction of the left ventricle.

8. To study the influence of β1-adrenoblockers on circadian blood pressure profile parameters, parameters of the fatty acid composition of blood lipids, and adenine nucleotides in patients with hypertensive disease with diastolic dysfunction of the left ventricle.

9. To evaluate the influence of monotherapy with the selective β1-adrenoblocker metoprolol on segmental and global diastolic function of the left ventricle in patients with hypertensive disease using tissue Doppler echocardiography.

10. Taking into account the obtained data, to pathogenetically justify the application of β1-adrenoblockers in the treatment of diastolic dysfunction of the left ventricle in patients with hypertensive disease.

Scientific novelty.

For the first time in patients with hypertensive disease, a comprehensive study of metabolic and cardiohemodynamic parameters was conducted, their significance in the pathogenesis of diastolic dysfunction of the left ventricle was determined, and the application of β1-adrenoblockers in this category of patients was justified.

It has been shown that in 17.2% of patients with hypertensive disease with normal myocardial mass and unimpaired geometry of the left ventricle, in the absence of echocardiographic signs of global diastolic dysfunction, tissue Doppler echocardiography revealed impairment of diastolic properties of the myocardium in the form of "hidden" segmental diastolic dysfunction.

The application of tissue Doppler makes it possible to differentiate pseudonormal and normal types of diastolic filling of the left ventricle in patients with hypertensive disease.

For the first time, using tissue Doppler echocardiography, the nature of the interrelationship between the structure of diastolic filling and the geometric model of the left ventricle in patients with hypertensive disease was established, revealing their close interrelationship, whereby the impairment of diastolic filling of the left ventricle depends not only on the increase in myocardial mass but also on the characteristics of its cavity — that is, the model of architecture. It was established that diastolic dysfunction of the left ventricle develops most frequently in patients with hypertensive disease with concentric hypertrophy of the left ventricle. In all patients with hypertensive disease who had a pathological blood pressure profile without signs of nocturnal reduction (non-dippers), segmental diastolic disturbances of the left ventricle were identified.

For the first time, it was established that shifts in the fatty acid composition of plasma lipids and erythrocyte membranes in patients with hypertensive disease are pathogenetically interrelated with parameters of diastolic filling of the left ventricle. It has been shown that, along with an increase in the relative content of saturated and monounsaturated fatty acids and a decrease in the amount of polyunsaturated acids, there are multidirectional shifts in the pools of saturated and unsaturated acids. Thus, in the pool of saturated acids, the content of myristic and palmitic acids is elevated, whereas the relative amount of stearate is, on the contrary, reduced; in the pool of polyunsaturated acids, an increase in the content of dihomo-γ-linolenic and arachidonic acids is noted, while the content of linoleic and α-linolenic acids is significantly reduced compared with healthy individuals. Systolic function parameters of the left ventricle in patients with hypertensive disease are practically not interrelated with the content of fatty acid fractions.

For the first time, an interrelationship was identified between parameters of 24-hour blood pressure monitoring and the content of various fatty acids in plasma lipid lipids, and it was shown that the main parameters of 24-hour monitoring characterizing the severity of arterial hypertension and blood pressure variability are in negative correlation with the total content of unsaturated fatty acids, relative content of linoleate (correlation coefficients from -0.30 to -0.72, p<0.05). With the level of palmitate, arachidonate, γ-linolenate, dihomo-γ-linolenate, and total content of saturated fatty acids, the majority of 24-hour monitoring parameters correlate positively (correlation coefficients from 0.31 to 0.72, p<0.05).

For the first time, the content of adenine nucleotides in erythrocytes of patients with hypertensive disease was studied, and a decrease in ATP level was demonstrated with a simultaneous increase in the concentration of ADP and AMP in the presence of echocardiographic signs of diastolic dysfunction of the left ventricle. In this category of patients, a syndrome of impaired fatty acid utilization by the myocardium was also identified, which is accompanied by an increase in the NEFA/ATP coefficient characterizing the severity of heart failure.

It was established that shifts in the energy metabolism of the myocardium in patients with hypertensive disease are pathogenetically interrelated with structural-functional changes of the left ventricle, with the strongest correlation found with parameters of diastolic filling of the left ventricle. Thus, the peak E velocity positively correlated with the total content of unsaturated fatty acids, the amount of pentadecenoic acid, and the ATP level in erythrocytes, and negatively — with the levels of NEFA and glycerol, total content of saturated acids, levels of other monounsaturated acids, and the concentration of AMP (r = -0.58 to 0.55). The peak atrial filling (A) velocity, on the contrary, positively correlated with the NEFA/glycerol coefficient, total content of saturated and levels of monounsaturated acids, the concentration of AMP, and negatively — with total content of unsaturated acids, the amount of pentadecenoic acid, and the ATP level (r = -0.61 to 0.60).

It was established that the level of diene conjugates, ketodienes, and conjugated trienes, TBC-positive products in the blood serum increased depending on the severity of arterial hypertension and the presence of diastolic dysfunction of the left ventricle, along with a decrease in catalase activity of erythrocytes, their peroxide resistance, and the total antioxidant activity of blood plasma.

For the first time, a favorable influence of the selective β1-adrenoblocker metoprolol on parameters of segmental diastolic function of the left ventricle and the circadian blood pressure profile, the fatty acid composition of blood lipids, and the macroergic phosphate system in patients with hypertensive disease was demonstrated. The indicated changes indicate the enhancement of fatty acid utilization processes by the myocardium in the background of metoprolol treatment.

Theoretical and practical significance of the work.

The obtained results make it possible to evaluate the contribution of metabolic changes to the development of diastolic dysfunction of the left ventricle in patients with hypertensive disease already at the stage of impaired cellular relaxation, established using tissue Doppler, as well as to pathogenetically justify the application of β1-adrenoblockers in this category of patients.

For the early diagnosis and timely treatment of diastolic disturbances of the left ventricle, the necessity of conducting a comprehensive examination of patients with hypertensive disease, including 24-hour blood pressure monitoring with determination of the type of circadian profile, echocardiography with evaluation of the geometric model of the left ventricle, tissue Doppler investigation, as well as the study of biochemical parameters with determination of the state of the "LPO-antioxidant" systems, adenine nucleotides, and the fatty acid status of plasma lipids and erythrocyte membranes, is indicated.

Given the insufficiency of diastolic function assessment by standard echocardiography methods, patients with hypertensive disease are indicated to undergo tissue Doppler echocardiography for the early diagnosis of segmental diastolic disturbances of the left ventricle.

An integral criterion (K) for the early instrumental diagnosis of diastolic dysfunction of the left ventricle in patients with hypertensive disease is proposed, based on the determination of the left atrial size (LA in cm), mean nocturnal blood pressure according to the circadian blood pressure profile (mmHg), body mass index (BMI): LA (cm) × mean NABP (mmHg) × BMI K = 10000

When its value exceeds 8 arbitrary units, one may indirectly judge about segmental disturbances of myocardial relaxation of the left ventricle, despite normal parameters of its global diastolic function.

In patients with hypertensive disease with instrumental signs of diastolic dysfunction of the left ventricle, significant shifts in the fatty acid composition of blood lipids and erythrocyte membranes and signs of a syndrome of impaired fatty acid utilization by the myocardium were identified. These changes in the fatty acid composition of blood lipids may serve as an additional criterion for the early diagnosis of the formation of hypertensive heart disease, which will allow timely conduct of treatment correction. A metabolic criterion for the early biochemical diagnosis of diastolic disturbances of the left ventricle in patients with hypertensive disease — the NEFA/ATP coefficient — is proposed.

When performing tissue Doppler echocardiography, in all patients with hypertensive disease who had a pathological blood pressure profile without signs of its nocturnal reduction (non-dippers), signs of segmental diastolic dysfunction of the left ventricle were identified. Taking into account the obtained data, it is precisely in this category of patients that the prescription of β1-adrenoblockers is most justified.

The application of selective β1-adrenoblockers (metoprolol) favorably influences the parameters of diastolic filling of the left ventricle, as well as leads to the normalization of shifts in the adenine nucleotide system and fatty acids, which indicates the existence of a pathogenetic connection of the identified metabolic disturbances in the formation of diastolic dysfunction of the left ventricle in patients with hypertensive disease.

The obtained data allow the pathogenetic justification of the use of selective β1-adrenoblockers (metoprolol) in patients with hypertensive disease with identified diastolic disturbances.

Main provisions for defense:

1. Diastolic function of the left ventricle in patients with hypertensive disease has a clear connection with the features of the circadian blood pressure profile and the state of its architecture. Impairment of diastolic filling is most frequently registered with concentric hypertrophy of the left ventricle. In all patients from the non-dipper group and in 17.2% of patients with hypertensive disease with normal myocardial mass of the left ventricle and its unimpaired geometry, tissue Doppler echocardiography revealed segmental diastolic disturbances.

2. In patients with hypertensive disease with identified diastolic disturbances of the left ventricle, there are substantial changes in the fatty acid composition of lipids, the "LPO-antioxidant" system, and adenine nucleotides of the blood.

3. Between the main parameters of diastolic function of the left ventricle, the circadian blood pressure profile, and the studied biochemical parameters, multidirectional correlation interrelationships have been established, indicating a pathogenetic role of metabolic and hemodynamic disturbances in the formation of diastolic dysfunction of the left ventricle in patients with hypertensive disease.

4. When performing tissue Doppler echocardiography, it was established that monotherapy with a selective β1-adrenoblocker (metoprolol) in patients with hypertensive disease leads to a decrease in the number of left ventricular segments with diastolic disturbances.

5. In addition to the hypotensive effect, the application of β1-adrenoblockers (metoprolol) in patients with hypertensive disease with diastolic dysfunction of the left ventricle leads to the normalization of shifts in the fatty acid composition of lipids and adenine nucleotides of the blood, which testifies to the improvement of metabolic processes in the cardiac muscle.

Dissertation defense.

The results of the research were reported at the 9th Medical Japan-Russia International Symposium in 2001 (Kavazawa); the VIII Russian National Congress "Man and Medicine," Moscow, April 2–6, 2001; the Russian National Congress of Cardiologists (Moscow, 2001); the Russian National Congress of Cardiologists (St. Petersburg, October 8–11, 2002); the Scientific and Practical Conference with International Participation "Actual Problems of Cardiology" (Tyumen, November 21–22, 2002); the IV Russian Forum "Mother and Child" (Moscow, October 21–25, 2002); the Congress of the Association of Cardiologists of the CIS Countries (St. Petersburg, September 18–20, 2003); at the 10th Russia-Japan International Medical Symposium "Yakutia-2003" in 2003 (Yakutsk); the Russian National Congress of Cardiologists, Moscow, 2003; the All-Russian Scientific and Practical Conference dedicated to the 50th anniversary of the formation of the ChGMA (Chita, 2003); the 6th Russian Scientific Forum "Keys to Diagnosis and Treatment of Heart and Vascular Diseases"; the Russian National Congress of Cardiologists, Tomsk, 2004; the XII Russia-Japan International Medical Symposium (Krasnoyarsk, 2005).

Publications.

Fifty works have been published on the dissertation topic, including 10 articles in peer-reviewed journals recommended for publication by the VAK of Russia, and the monograph "Hypertensive Heart Disease: Mechanisms of Development, Diagnosis, Application of β-Adrenoblockers."

Structure and volume of the dissertation.

The dissertation is presented on 267 pages of typed text and consists of an introduction, seven chapters, conclusions, practical recommendations, and a reference list; illustrated with 44 tables, 7 schemes, and 9 figures. The reference list includes 150 domestic and 242 foreign sources.