Chronic Heart Failure in Women: Features of the Course and Pharmacotherapy

The dissertation is devoted to the study of etiological, clinical, and genetic features of chronic heart failure (CHF) in women, as well as a comparative evaluation of the efficacy of the main classes of drugs used in its therapy. The work is based on a clinical and statistical analysis of the course of CHF in multidisciplinary and narcological hospitals, an investigation of the structural and functional state of the left ventricle and clinical and hemodynamic characteristics in women with CHF, including those with a history of long-term alcohol abuse. The study performed a comparative investigation of the efficacy of ACE inhibitors (ramipril, enalapril, perindopril), beta-adrenoblockers (carvedilol, bisoprolol, nebivolol), and the calcium channel blocker amlodipine, and carried out a multivariate regression analysis of predictors of adverse outcomes, including brain natriuretic peptide levels and polymorphism of the estrogen receptor genes ESR1 and ESR2.

Despite the indisputable successes of modern cardiology, chronic heart failure (CHF) remains a syndrome associated with high morbidity and mortality. The prognosis of patients with this pathology is comparable to that of patients with malignant neoplasms (Bello N., 2004; Heart and Stroke Statistics, 2009).

In 2003, data were first published that convincingly demonstrated gender differences in the outcomes of cardiovascular pathology. Over the past 20 years, the level of cardiovascular morbidity among men has been declining, while it has been steadily increasing among women. In the United States, more than 500,000 women die annually from coronary heart disease. Despite the decline in cardiovascular mortality, the absolute number of women dying each year from coronary heart disease continues to increase (Peterson S., 2003). According to the Kaiser Permanente Study, the improvement in survival in cardiovascular pathology is more pronounced in men (Heart and Stroke Statistics, 2009).

The incidence of CHF is steadily increasing due to the aging of the general population. Data from various epidemiological studies indicate that the lifetime risk of developing CHF in women is 20% (Fox K., 1996; American Heart Association, 2003). The incidence of CHF increases with age: in men aged 70-79 years in Europe it is 13/1,000, and in women it is 9/1,000 (Lloyd-Jones D., 2001). At the age of 80-89 years, the incidence of CHF increases to 65.2/1,000 in men and 45.6/1,000 in women (Heart and Stroke Statistics, 2009).

CHF is the most common diagnosis at hospital discharge in patients over 65 years of age, and this syndrome is also the most common cause of rehospitalization (American Heart Association Review, 2003). The number of hospitalizations in the United States with a diagnosis of CHF during the period from 1979 to 1999 increased by 155%, and mortality from CHF during the same period increased by 145% (Heart and Stroke Statistics, 2009). At the same time, 3,390,000 physician visits for CHF are made annually, and the total cost of treatment is $37.2 million (Heart and Stroke Statistics, 2009).

According to the results of the domestic study EPOKHA-CHF, the diagnosis of CHF was established in 7.28% of all citizens of the Russian Federation, that is, 9.5 million people. At the same time, 2.1% of the population (2.7 million people) suffers from CHF of the most severe degree, that is, FC III-IV. The problem of CHF in Russia has a clear gender component - 72.5% of all patients with a confirmed diagnosis of CHF are women, with a mean age of 69.6 years (Fomin I.V., 2008).

Gender differences in the etiology of CHF lead to clinical features of the course of CHF in women, which must be taken into account in the development of individual therapeutic and preventive strategies.

Unfortunately, in most clinical studies of chronic heart failure, women constituted an insignificant part of the sample - from 15 to 32% (Heart and Stroke Statistics, 2009).

Thus, the results obtained in most clinical studies can be extended to women only after subgroup analysis, which has a large number of shortcomings and limitations.

A large amount of experimental and clinical evidence of gender differences in the adaptation of the cardiovascular system to stress and damage has been accumulated. According to the results of numerous studies, gender differences are most pronounced in the type of left ventricular dysfunction. Women develop diastolic dysfunction much more often than men, while the left ventricular ejection fraction remains unchanged (Krumholz H., 1999).

In addition, it is also necessary to take into account the older age of women with manifest CHF. As is known, with increasing age, the percentage of patients with preserved systolic function of the left ventricle increases (Fischer M., 2002; Redfield M., 2003). Thus, the prevalence of diastolic dysfunction of the left ventricle in women is associated both with the features of the response of the female heart to damaging factors and with gender-specific patterns of CHF distribution depending on age.

Significant sex differences have also been identified with respect to the pharmacotherapy of CHF. Differences are observed both in the effectiveness of certain groups as a whole (ACE inhibitors, angiotensin II receptor antagonists) and significant intra-group differences (beta-adrenoblockers, calcium antagonists) (Davis M., 1998; Shekelle P., 2003; Leibson C., 2006). In 2009, the calcium antagonist amlodipine was included in the recommendations of the American Heart Association/American College of Cardiology for patients with preserved LV systolic function and signs of CHF (AHA/ACC Heart Failure Guidelines, 2009).

There is evidence that differences in clinical outcomes of cardiovascular events in women are due to genetic polymorphism in the estrogen receptor gene ESR1, estradiol levels, and follicle-stimulating hormone levels.

Thus, the study of these factors as possible predictors of clinical outcome in the pharmacotherapy of women with CHF appears to be a highly relevant task.

Aim of the Study

To identify etiological, clinical, and genetic predictors of prognosis and pharmacotherapy efficacy in women with chronic heart failure.

Objectives of the Study

1. To conduct a clinical and statistical analysis of the features of CHF in women.

2. To determine the structural and functional state of the left ventricle and the clinical and hemodynamic features of the course of CHF in women.

3. To evaluate the effect of different classes of drugs (ACE inhibitors, beta-adrenoblockers, calcium channel blockers) on the clinical symptoms of CHF in women.

4. To determine the factors influencing differences in clinical outcomes in women suffering from chronic heart failure.

5. To determine the features of the course and pharmacotherapy of CHF in women with a history of long-term alcohol abuse.

6. To determine the relationship between genetic polymorphism of the estrogen receptor genes ESR1 and ESR2 and clinical outcomes of CHF in women.

7. To conduct a comprehensive analysis of prognostic factors in women with CHF.

Scientific Novelty.

Clinical and statistical analysis demonstrated the presence of gender differences in etiological causes, features of the clinical course, duration, and prognosis of CHF.

The fact of preservation of systolic function of the left ventricle in the majority of women with CHF has been established, and clinical and demographic predictors of reduced LV systolic function in women with CHF have been identified. Data on the high significance of eccentric left ventricular hypertrophy without cavity dilatation in women with CHF have been obtained.

For the first time, a comparative study of different classes of drugs was conducted in female patients with CHF and unchanged left ventricular ejection fraction.

In different categories of female patients, the features of CHF have been characterized, and approaches to pharmacotherapy with conflicting efficacy have been studied (the addition of amlodipine to standard treatment in postmenopausal women; the use of the beta-adrenoblockers carvedilol, bisoprolol, or nebivolol in systolic chronic heart failure, ramipril or enalapril in postmenopausal women with preserved left ventricular ejection fraction, carvedilol or perindopril in women with alcoholism).

It has been shown that in the treatment of CHF in women with a history of alcohol abuse, the leading role is assigned to the need to correct the pathological craving syndrome; the advantages of the alpha- and beta-adrenoblocker carvedilol over the ACE inhibitor perindopril have been demonstrated.

The fact of additional clinical benefits of the calcium antagonist amlodipine in women with a non-ischemic genesis of CHF and preserved estrogen status has been noted. Data have been obtained on a close relationship between estradiol levels and the dynamics of changes in quality of life during amlodipine therapy.

An association of high levels of brain natriuretic peptide with a more severe course of the disease and an unfavorable prognosis in women with CHF has been demonstrated.

Data have been obtained on the features of the differentiated prescription of beta-adrenoblockers in women with CHF based on baseline clinical and demographic characteristics. The unequal efficacy of different ACE inhibitors in women has been noted.

The relationship between the ESR1 PvuII genetic polymorphism and the risk of CHF progression in women has been established. The presence of the tt genotype increases the probability of an adverse clinical outcome in women with CHF and has no clinical significance in men.

Practical Significance of the Results.

The data obtained make it possible to identify among women with CHF a group at high risk of adverse cardiovascular events in the short and long term of the disease. Thus, assessment of BNP levels allows determining the severity of CHF, the risk of an adverse clinical outcome, as well as monitoring the effectiveness of the ongoing therapy with cardiovascular drugs. The study of the genetic polymorphism of the ESR1 gene makes it possible to determine the probability of complications of CHF or its progression.

The differentiated choice of a beta-adrenoblocker makes it possible to optimize therapy, decrease the frequency of complications, and improve the course of CHF in women.

Determining estrogen status provides the opportunity for a more differentiated use of the calcium antagonist amlodipine, which makes it possible to reduce the severity of CHF symptoms and improve the quality of life in women with non-ischemic genesis of CHF.

In female patients with CHF and a history of alcohol abuse, the use of the alpha/beta-blocker carvedilol makes it possible to significantly improve the clinical course of the disease, reduce the risk of CHF progression, and improve clinical outcomes.

Key Statements Defended

1. There are significant differences in the etiology and clinical outcomes of CHF in men and women. For women, the most significant cause of the development of CHF is arterial hypertension; the median survival in women after the diagnosis of CHF is longer than in men.

2. Determining the polymorphism of estrogen receptor genes, as well as the baseline level of brain natriuretic peptide (BNP) and the levels of female sex hormones, can be used to assess the prognosis of adverse cardiovascular events in women with CHF, as well as to evaluate the effectiveness of therapy.

3. The course and prognosis of CHF in women are influenced by early therapy with amlodipine and beta-adrenoblockers. Significant differences in the effect of ACE inhibitors on the clinical course of CHF in women are observed.

4. Antihypertensive therapy with the calcium channel blocker amlodipine leads to an improvement in the course of CHF and a favorable change in the quality of life in women with a non-ischemic nature of this disease. Determining estrogen status makes it possible to use this drug in a more differentiated manner.

5. The development of alcoholic cardiomyopathy in women is associated with a more severe clinical picture, rapid disease progression, and an unfavorable prognosis. The use of the alpha-beta-adrenoblocker carvedilol in a comprehensive treatment regimen makes it possible to improve the clinical picture of CHF in women with alcoholic cardiomyopathy.

6. The greatest improvement in the quality of life in women with CHF is observed against the background of the use of calcium channel antagonists and beta-adrenoblockers. The use of ACE inhibitors has a lesser effect on this indicator.

Implementation. The materials of the dissertation have been used since 2005 in the treatment of patients with CHF in the therapeutic and cardiological departments of City Clinical Hospital No. 68 in Moscow, the Scientific and Practical Center for Narcology of the Moscow Department of Health, and in the educational process of the Department of Emergency Medical Care of MSMSU.

Approval of the work was carried out at a joint meeting of the Departments of Emergency Medical Care of FPDO, Clinical Functional Diagnostics of FPDO, Internal Diseases of the Faculty of Dentistry of MSMSU, the Department of Cardiology and General Therapy of the Federal State Institution "Educational and Scientific Medical Center of the Administration of the President of the Russian Federation," the Laboratory of Clinical Cardiology of the Federal State Institution "Scientific Research Institute of Physical and Chemical Medicine of Roszdrav," and City Clinical Hospital No. 68 in Moscow on March 27, 2009. The materials of the dissertation were presented at the Annual Conferences of the Society of Specialists in Heart Failure (December 13-14, 2001, Moscow; December 5-7, 2007, Moscow), the XI Specialized Exhibition "Pharmacy-2004" (October 26-30, Moscow), the 4th International Conference "Biological Basis of Individual Sensitivity to Psychoactive Substances" (March 13-16, 2006, Moscow), the Heart Failure Congress of the European Society of Cardiology (June 9-12, 2007, Hamburg, Germany), and the Russian National Congress of Cardiology "From Clinical Examination to High Technologies" (October 10-12, 2006, Moscow).

Publications on the Topic of the Dissertation. Forty-one printed works have been published on the topic of the dissertation, including 26 works in publications recommended by the VAK of the Ministry of Education and Science of Russia. Based on the materials of the dissertation, a textbook for the system of postgraduate professional education of physicians "Chronic Heart Failure (Issues of Diagnosis and Treatment)" (2006) was published, approved by the Educational and Methodological Association for Medical and Pharmaceutical Education of Universities of Russia with the assignment of the UMO seal. The materials are presented in the chapters of the book "Some Unresolved Issues of Chronic Heart Failure" (2007).