Features of the Cardiovascular System in Patients with Chronic Biliary-Dependent Pancreatitis

The dissertation is devoted to the investigation of the features of the cardiovascular system in patients with chronic biliary-dependent pancreatitis, a pancreatic disease pathogenetically linked to biliary tract pathology. The work addresses the clinical manifestations of the pancreato-cardiac syndrome, electrocardiographic, echocardiographic, and Doppler findings, systolic and diastolic left ventricular function, and microcirculatory disturbances in patients during exacerbation and remission, including in the setting of pancreatogenic myocardial dystrophy.

The study includes an assessment of the frequency and character of chronic and acute pancreatogenic myocardial dystrophy, an analysis of their association with markers of CP severity and exacerbation, cytokine status, and microcirculation. Particular attention is given to a comparative analysis of cardiovascular dynamics under different outpatient maintenance therapy regimens, including the combination of differentiated replacement polyenzyme therapy and trimetazidine. The aim of the work is to develop approaches to the diagnosis and correction of cardiac disturbances in patients with non-obstructive forms of chronic biliary-dependent pancreatitis.

RELEVANCE OF THE PROBLEM

Over the past 30 years, a global trend toward an increase in the incidence of acute and chronic pancreatitis (AP and CP) by more than two times has been observed [24, 53, 97, 178]. If in the 1980s the frequency of CP was 3.5–4.0 per 100,000 population per year [129, 164], in the last decade a steady increase in the frequency of pancreatic diseases (PD) has been recorded, affecting 8.2–10 people per 100,000 of the world population annually [49, 97, 124, 216]. The prevalence of CP in Europe is 25.0–26.4 cases per 100,000 population [49, 126, 129]. In Russia, a more intensive growth in CP incidence has been observed. The prevalence of CP in adults is 27.4–50 cases per 100,000 population [48, 124].

Accordingly, one may assume an increase in the frequency of clinical manifestations of the pancreato-cardiac syndrome, which requires the development of an assessment of its role in the prognosis of the underlying disease, diagnostic criteria, and treatment tactics. Under physiological conditions, the pancreas has a weak influence on cardiovascular function, although hormones produced by the normal pancreas (insulin, glucagon, somatostatin) affect myocardial contractility in pharmacological doses. In pancreatic diseases, disturbances in the cardiovascular system develop, substantially affecting the outcome of the disease [142].

Changes in the cardiovascular system in CP are determined by etiopathogenetic mechanisms associated with the development of this disease and include: manifestations of the abdominal-cardiac syndrome (cardialgia, dyspnea, headaches, cardiac rhythm disturbances), autonomic dysfunction, decrease in global systolic function of the heart, dilation of cardiac chambers, changes in cardiac output, arterial blood pressure (BP), total peripheral vascular resistance (TPVR), increased pressure in the pulmonary artery, disturbances of microcirculation, pulmonary and porto-hepatic blood flow. Moreover, a significant proportion of these changes are caused by such a manifestation of non-coronary myocardial diseases as pancreatogenic myocardial dystrophy [2, 3, 15, 18, 32, 35, 41, 70, 77, 80, 87, 106, 151, 160, 190, 197, 203, 219, 222, 223].

At the same time, despite a relatively large number of studies, the literature contains no clear indications regarding the possibility of investigating changes in the cardiovascular system as a criterion for assessing the stage, severity, and prognosis of CP. Data on the nature and mechanisms of these changes are highly contradictory, and there are no recommendations for the prevention and correction of these changes.

Traditional metabolic agents used for the treatment of non-coronary myocardial diseases require their combined administration. Taking a large number of medications is undesirable, due to the predicted decrease in compliance in most patients and its inappropriateness in such a severe digestive pathology as CP. Trimetazidine is a modern medicinal agent whose galenic form allows it to be taken twice a day. The available literature lacks data on the possibility of using the drug for the treatment of non-coronary diseases, in particular pancreatogenic myocardial dystrophy. However, there is a large body of experimental, clinical, and morphological evidence permitting the conclusion that the basis of myocardial dystrophy is hypoxia, in the development of which the leading role belongs to the disruption of the histohematic barrier of the myocardium — a complex system of interaction between the myocardial microcirculatory bed and cardiomyocytes [12, 15, 23, 32, 35, 40, 41, 71, 77, 87, 101]. Moreover, morphological data reveal changes in the myocardial microcirculatory bed close to those found in ischemic cardiomyopathy [21, 35, 82, 83, 185, 200]. Accordingly, one may assume a high effectiveness of trimetazidine in the treatment of myocardial dystrophy in CP, which requires clinical studies based on the principles of evidence-based medicine.

AIM OF THE STUDY

To investigate the features of cardiovascular disturbances in patients with non-obstructive forms of chronic biliary-dependent pancreatitis at different stages of the disease and the possibilities for their correction.

OBJECTIVES OF THE STUDY

1. To assess the character and differences in clinical manifestations of the pancreato-cardiac syndrome, ECG changes, cardiac rhythm disturbances, the state of central hemodynamics, systolic and diastolic function of the left ventricle (LV), and microcirculation in patients with chronic biliary-dependent pancreatitis during exacerbation, with and without myocardial dystrophy.

2. To assess the character and differences in clinical manifestations of the pancreato-cardiac syndrome, ECG changes, cardiac rhythm disturbances, the state of central hemodynamics, systolic and diastolic function of the LV, and microcirculation in patients with chronic biliary-dependent pancreatitis during remission, with chronic or acute myocardial dystrophy or in its absence.

3. To determine the frequency of chronic and acute myocardial dystrophy and its absence in patients with chronic biliary-dependent pancreatitis.

4. To analyze the association between the levels of markers of severity and exacerbation of chronic pancreatitis during exacerbation and remission and changes in clinical status, ECG, cardiac rhythm disturbances, central hemodynamics, systolic and diastolic function of the LV, and microcirculatory disturbances.

5. To perform a comparative analysis of changes in the cardiovascular system in patients with chronic myocardial dystrophy caused by chronic biliary-dependent pancreatitis during outpatient follow-up against the background of: the absence of maintenance therapy; differentiated polyenzyme therapy; and the combination of differentiated polyenzyme therapy and trimetazidine.

SCIENTIFIC NOVELTY

For the first time, an analysis was carried out of the dynamics of clinical manifestations of the pancreato-cardiac syndrome, ECG changes, cardiac rhythm disturbances, central hemodynamic changes, global systolic and diastolic function of the LV, and microcirculation during exacerbation, clinical-instrumental remission, and outpatient follow-up in patients with chronic non-obstructive biliary-dependent pancreatitis. For the first time, the features of clinical and electrocardiographic manifestations and hemodynamic changes characteristic of chronic and acute pancreatogenic myocardial dystrophy have been studied. For the first time, the frequency of chronic and acute myocardial dystrophy and its absence has been assessed in patients with chronic non-obstructive biliary-dependent pancreatitis. The relationship of the revealed changes with markers of severity and exacerbation of CP at different stages of chronic non-obstructive biliary-dependent pancreatitis has been studied. It has been proved that the degree of cardiovascular changes during exacerbation is determined by the severity of the abdominal pain syndrome, the intensity of inflammation, the degree of pancreatostasis, pancreatic hyperenzymemia, and disturbances of cytokine status; during remission — by disease duration, frequency of exacerbations, the degree of exocrine pancreatic insufficiency, and the malabsorption syndrome. It has been proved that microcirculatory disturbances are an important predictor of the development of myocardial dystrophy. For the first time, the role of high cytokine expression with a pronounced imbalance toward the pro-inflammatory component of the "cytokine network" in the development of cardiovascular changes in chronic biliary-dependent non-obstructive pancreatitis has been demonstrated. For the first time, the high effectiveness of outpatient combined administration of replacement polyenzyme therapy with Creon, dosed according to the degree of exocrine insufficiency, together with trimetazidine, has been demonstrated in patients with chronic pancreatogenic myocardial dystrophy.

PRACTICAL SIGNIFICANCE

Analysis of the clinical picture, ECG changes, echocardiographic and Doppler-echocardiographic findings, and buccal microscopy with quantitative assessment of microcirculation demonstrated that the course of chronic non-obstructive biliary-dependent pancreatitis is frequently complicated by the development of pancreatogenic myocardial dystrophy, which is chronic in 52.2% of cases, acute in 23.0% of cases, and absent in 24.8% of cases. Algorithms have been developed for the detection of acute and chronic pancreatogenic myocardial dystrophy and for the differential diagnosis between pancreatogenic myocardial dystrophy and ischemic heart disease. It has been proved that patients with a severe course of CP, marked abdominal pain syndrome, high levels of inflammatory markers, and altered cytokine expression may be regarded as having a risk factor for the development of pancreatogenic myocardial dystrophy. A maintenance therapy strategy for CP patients has been worked out using the differentiated administration of pancreatin microcapsules and trimetazidine.

MAIN STATEMENTS DEFENDED

1. The signs of pancreatogenic myocardial dystrophy against the background of CP exacerbation are: the presence of clinical manifestations of the pancreato-cardiac syndrome, primarily cardialgia; predominance of sympathicotonia; sinus tachycardia, changes in the terminal portion of the ventricular complex on ECG; polytopic extrasystoles, conduction disturbances along the branches of the His bundle, LV dilation, decrease in global systolic function of the LV, impaired LV diastolic function, hyperkinetic hemodynamic syndrome, a tendency toward an increase in mean pulmonary artery pressure (mPAP), and a decrease in specific peripheral vascular resistance (SPVR). In patients with CP exacerbation without myocardial dystrophy, clinical manifestations of the pancreato-cardiac syndrome are revealed, representing autonomic dysfunction with predominance of parasympathicotonia, a tendency toward sinus bradycardia, a decrease in ejection fraction (EF) within the normal variation range, and an increase in SPVR.

2. Against the background of clinical-instrumental remission of CP, patients with chronic pancreatogenic myocardial dystrophy exhibit persistence, although to a lesser degree, of pancreato-cardiac syndrome manifestations, changes in the terminal portion of the ventricular complex, rhythm and conduction disturbances, a tendency toward LV dilation, a decrease in EF, and LV diastolic dysfunction against a background of persistent LV myocardial hypertrophy. In patients with acute myocardial dystrophy and in those without it, clinical manifestations of the pancreato-cardiac syndrome persist, representing autonomic dysfunction, with hemodynamic parameters close to those in the control group (CG).

3. The course of chronic non-obstructive biliary-dependent pancreatitis is complicated by the development of chronic pancreatogenic myocardial dystrophy in 52.2% of cases; during CP exacerbation, acute pancreatogenic myocardial dystrophy develops in 23.0% of cases; in 24.8% of patients, myocardial dystrophy is not detected.

4. The development of acute and/or aggravation of chronic pancreatogenic myocardial dystrophy is determined by the severity of CP exacerbation. The maintenance of chronic pancreatogenic myocardial dystrophy is determined by the severity of the CP course.

5. In patients with chronic pancreatogenic myocardial dystrophy, the refusal of maintenance differentiated replacement polyenzyme therapy with pancreatin microcapsules in combination with trimetazidine leads to persistence or aggravation of myocardial dystrophy manifestations. The use of maintenance differentiated replacement polyenzyme therapy with pancreatin microcapsules alone promotes a certain reduction in myocardial dystrophy manifestations. High effectiveness in reducing the manifestations of chronic pancreatogenic myocardial dystrophy in outpatient settings has been noted with maintenance differentiated replacement polyenzyme therapy with pancreatin microcapsules in combination with trimetazidine.

IMPLEMENTATION INTO PRACTICE

The developed methods are applied for prognostic assessment and decision-making on treatment tactics in patients with CP complicated by pancreatogenic myocardial dystrophy in the cardiology, therapeutic, and gastroenterology departments of the Central Clinical Hospital No. 2 of JSC "Russian Railways" and in the therapeutic departments of Medical-Sanitary Unit No. 33, Moscow. The data are used in conducting classes with students and trainees of qualification and certification cycles at the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education "Moscow State University of Medicine and Dentistry" of the Federal Agency for Health Care and Social Development (Roszdrav).

APPROBATION OF THE WORK

The materials of the dissertation were presented as poster reports at the Eleventh Russian Gastroenterological Week (Moscow, 2005), at the Tenth Russian Conference "Hepatology Today" (Moscow, 2005), and at the Seventh International Slavonic-Baltic Scientific Forum "Saint Petersburg — Gastro-2005" (Saint Petersburg, 2005). The work was approved at a joint meeting of the Department of Propaedeutics of Internal Diseases and Gastroenterology and the Department of Hospital Therapy No. 1 of the State Educational Institution of Higher Professional Education Moscow State University of Medicine and Dentistry (Moscow, 28.10.2005).

PUBLICATIONS

On the topic of the dissertation, 8 printed works have been published.

STRUCTURE AND VOLUME OF THE DISSERTATION

The dissertation is presented on 187 pages of typewritten text and consists of an introduction, a literature review, a description of materials and methods, the results of original observations and their discussion, conclusions, and practical