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MINISTRY OF EDUCATION MINISTRY OF DEFENCE MILITARY MEDICAL ACADEMY DOAN THINH TRUONG RESEARCH ON THE RELATIONSHIP BETWEEN PLASMA NT-PROBNP CONCENTRATION AND HEART RATE VARIABILITY, ARRHYTHMIA IN PATIENTS WITH CHRONIC ISCHEMIC HEART DISEASE WITH HEART FAILURE Major : Internal Medicine Code : 9720107 SUMMARY OF THE THESIS HA NOI – 2021 This thesis accomplished at: Medical Military University Supervisor: Prof Ph D Nguyen Oanh Oanh Reviewer 1: Prof Ph D Nguyen Thi Bach Yen Reviewer 2: Prof Ph D Pham Dang Khoa Reviewer 3: Prof Ph D Luong Cong Thuc Thesis will be defended at Sientific of Medical Military University Hold at on .may The thesis can be found at: National Library Military medical academy library INTRODUCTION Background The lack of blood supply to the heart muscle in chronic ischemic heart disease (CIHD) resulting in functional decline in a part of the left ventricular myocardium, impaired left ventricular relaxation, increased stiffness, decreased diastolic filling, hypertrophy and fibrosis of the myocardium, along with the process of myocardial restructuring are the causes leading to electrical changes of the myocardial organization, giving rise to arrhythmias and heart failure Myocardial ischemia causes increased myocardial cell stretch, resulting in left ventricular systolic and/or diastolic dysfunction, which is an important contributor to plasma NT-proBNP release In Vietnam, there have been many studies on the characteristics of arrhythmia and heart rate variability (HRV) in patients with CIHD, but there have not been many studies on the relationship between NT-proBNP levels and arrhythmias, HRV and characteristics of heart failure in these subjects Therefore, we conducted a study on the topic "Research on the relationship between plasma NT-proBNP concentration and HRV, arrhythmia in heart failure (HF) patients with CIHD" with two objectives: To investigate the changes in plasma NT-proBNP concentrations and characteristics of arrhythmias, HRV in HF patients with CIHD before and after days of inpatient treatment To explore the relationship between NT-proBNP concentration and some clinical and laboratory characteristics, HRV and arrhythmia in HF patients with CIHD The rationale of the thesis HRV and arrhythmia are common cardiovascular events and cause many serious consequences Does the presence of arrhythmias and HRV depend on NT-proBNP levels? Many previous studies showed the correlation between HRV, arrhythmia and NT-proBNP concentration However, these studies were performed in patients with myocardial infarction and unstable angina Thus, a question is raised whether there is a correlation between NT-proBNP concentration and HRV, arrhythmia in HF patients with CIHD or not? The studies on this topic are very scarce In Vietnam, there has been no study to fully evaluate the relationship between plasma NTproBNP level and HRV, arrhythmias in HF patients with CIHD Therefore, this research is to find a solution for the above-mentioned scientific and practical problem New contributions of the thesis Time domain HRV parameters (SDNN, RMSSD, SDNNI) and frequency domain HVR (LF, HF, LF/HF) among HF patients with CIHD showed this condition continued to increase, independent of baseline NT-proBNP (p < 0.05) Structure of the dissertation The thesis has 127 pages, including the following parts: Introduction (02 pages); Overview (30 pages); Research subjects and methods (24 pages); Results (31 pages); Discussion (36 pages); Conclusion (02 pages); Recommendations (01 page) The thesis has 57 tables, 06 charts, 05 pictures The thesis has 189 references, including 26 Vietnamese documents and 163 English documents CHAPTER 1: GENERAL OVERVIEW 1.1 Chronic ischemic heart disease and heart failure CIHD is a disease related to the relative stability of coronary atherosclerotic plaque, when there is no sudden rupture or after the acute phase or after intervention/surgery When the plaque progresses leading to significant luminal narrowing of the coronary arteries (usually more than 70% of the lumen diameter), symptoms can occur, most notably angina/dyspnea on exertion and these symptoms disappear at rest The mechanism of heart failure caused by ischemic heart disease is simply summarized below, including the following main phenomena: - Myocardial infarction/re-myocardial infarction: Cardiac muscle cell death and fibrosis, scarring => remodeling and activation of homeostatic factors - Anemia: Decreased function of one region of the left ventricular myocardium; left ventricular relaxation disorder, increased stiffness decreased diastolic filling 1.2 Arrhythmias and heart rate variability 1.2.1 Cardiac arrhythmias in CIHD and heart failure Cardiac arrhythmias is usually caused by disorders of impulse formation and/or impulse conduction These disturbances appear due to a single or combined mechanism, sometimes the arrhythmia can be initiated by one mechanism but perpetuated by others The disturbance of impulse formation is a disorder of the heart's natural pacemaker (sinus node) that causes a slow or fast heart rate, or due to the pacemaker activity The mechanism of cardiac arrhythmia are generally divided into major categories: - Automaticity: Enhanced normal automaticity, Triggered activity automaticity, Abnormal - Reentrant arrhythmias: Cardiac arrhythmias due to impulse conduction disturbance are often associated with a reentrant loop mechanism 1.2.2 Heart rate variability in chronic ischemic heart disease Analysis of HRV by conventional time and frequency domain methods has offered a novel approach for studying the abnormalities in cardiovascular neural regulation in ischemic heart disease HRV has been shown to be altered among patients with ischemic heart disease as compared with their age-matched controls without evidence of ischemic heart disease There were also obvious differences in various measures of HRV between patients with uncomplicated coronary artery disease and those with coronary artery disease complicated with myocardial infarction Reduced HRV predict an increased risk of death and cardiovascular events in patients with ischemic heart disease In particular, recent studies have shown that analysis methods of HRV predict the mortality and the onset of life-threatening arrhythmias in post-myocardial infarction patients These findings support the notion that HRV analysis methods give valuable clinical information among patients with ischemic heart disease patients with ischemic heart disease 1.3 Research on the association between NT-proBNP and chronic ischemic heart disease, heart failure, arrhythmia and Heart rate variability Rosenberg M.A et al (2014) “N-pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) is an independent predictor of ventricular arrhythmias in patients receiving primary prevention ICD” In a multivariate analysis on 161 patients with NTproBNP levels and 403 patients with BNP levels at the time of ICD implantation The results showed that elevated NT-proBNP and BNP concentrations were independently associated with risk of ventricular tachyarrhythmias, which significantly exceeds the risk for total mortality Solbiati M (2014): “The usefulness of N -terminal pro - B-type natriuretic peptide increase as a marker of cardiac arrhythmias in patients with syncope” The results showed that increase in the 6hour NTproBNP concentration can predict arrhythmic syncope Patton K.K et al (2013) “NT-pro BNP is a remarkably strong predictor of atrial fibrillation (AF) event in the Multiethnic Study of Atherosclerosis: the effects of age, sex and ethnicity" The study involved 5.518 subjects with a median follow-up of 7.6 years The results show that NT-proBNP is a robust predictor of incident atrial fibrillation; its prognostic value is more significant in younger patients and women compared with older patients and men NTproBNP was as strongly predictive in black patients, Hispanics, and Asian/Chinese as in white patients despite a lower incidence of arrhythmia Many studies have demonstrated that NT-proBNP is increased in patients with atrial fibrillation Pivatelli et al (2012) studied on 77 patients undergoing coronary angiography, the patients were divided into groups: the group with coronary artery disease and the group without coronary artery disease, HRV was recorded in 40 minutes The first 1000 RR intervals were selected for analysis, HRV parameters including SDNN, rMSSD, pNN50, HF significantly decreased in patients with coronary artery disease CHAPTER 2: SUBJECTS AND METHODS 2.1 Subjects 136 HF patients were diagnosed with CIHD who were treated at the Cardiology Department, Military Hospital 103 and the Internal Medicine Department, Hanoi Heart Hospital, from April 2015 to January 2021 2.1.1 Selection criteria Patients were diagnosed with CIHD and heart failure, according to “European Society of Cardiology 2013” and “Diagnosis and treatment of heart failure according to ESC 2012” 2.1.2 Exclusion criteria - Acute coronary syndrome, acute heart failure, organic valvular disease, cardiomyopathy (dilated cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, alcoholic heart disease, peripartum cardiomyopathy), congenital heart disease - Severe acute systemic diseases, impaired liver and kidney function Patients and families did not agree to participate in the study, the medical records not have enough data for research 2.2 Methods 2.2.1 Research design: Prospective, descriptive, cross-sectional study with comparison pre- and post-treatment 2.2.2 Research parameters 2.2.2.1 Research on clinical features - Age, gender, risk factors of the research group - Anthropometric indicators: height, weight, BMI - Characteristics of chest pain, symptoms and signs failure of heart - Grading and stages of heart failure 2.2.2.2 Paraclinical tests - Blood count test, blood biochemistry: NT-proBNP, Glucose, Total cholesterol, Triglyceride, HDL-C, LDL-C, Urea, Creatinin, GOT, GPT, CK, CKMB before and after treatment - Record 12-lead electrocardiogram, echocardiogram - Contrast coronary angiogram to determine the location and extent of damage - Record Holter electrocardiogram before and after treatment Average heart rate, fastest heart rate, slowest heart rate Supraventricular arrhythmias, number and incidence of premature ventricular complexes (PVCs) Ventricular arrhythmias, number and rate of premature ventricular complexes (PVCs), nature of ventricular arrhythmias according to Lown's classification + Time-varying indices (unit: milliseconds): characterizes the tone of parasympathetic nerve system activity SDNN: Standard deviation of all normal R-R intervals over the entire 24-hour Holter electrocardiogram Decreased when SDNN < 50ms, reflecting the loss of circadian rhythm, reducing the impact of the CNS on heart rate rMSSD: Square root of the mean square of the difference between the 24-hour Holter normal R-R intervals This value reflects the function of parasympathetic nervous system Decreased when rMSSD < 15ms SDNNi: Mean value of standard deviation of all normal R-R intervals over all 5-minute segments of the 24-hour Holter ECG Decrease when SDNNi < 30ms 10 + Frequency spectrum analysis indicators (unit: ms2) TP: Total magnitude of HRV over the frequency spectrum, from 0-0.4 Hz LF: Low frequency region (0.04-0.15Hz), when increasing LF often increases sympathetic nerve activity HF: High frequency region (0.15-0.40Hz), when increasing HF often increases the activity of parasympathetic nerves LF/HF ratio: assesses the balance of sympathetic and parasympathetic nervous system activity 2.3 Data processing Information collected from research medical records will be processed according to medical statistical algorithms based on the software EPI DATA and SPSS 21.0 for Windows CHAPTER 3: RESULTS Through a study on 136 patients diagnosed with CIHD accompanied with heart failure who were treated at Cardiology Department A2, Military Hospital 103 and Internal Medicine Department, Hanoi Heart Hospital, from April 2015 to January 2021, we have obtained the following results: Table 3.4 Clinical features on admission (n = 136) X ± SD or n (%) Characteristics Chest pain, n (%) 118 (86.8) Drizzle (%) 19 (3.7) Enlarged liver, n (%) (3.7) Rale in the lungs, n (%) Heart rate, ( X ± SD) 25 (18.4) 88.4 ± 25.2 14 p < 0.001 < 0.058 (Correlation ) Table 3.31 Relationship between NT-proBNP concentration and EF level NT- proBNP after NT-proBNP before EF(%) treatment (n = 136) treatment (n = p 136) ( X ± SD) ( X ± SD) < 50% 3102.93 ± 5056.35 1234.54 ± 3091.46 0.05 13 26 5.8 5.8 1.94- < 36 37 0.9 17.63 0.46- 0.05 2 1.95 18 16.62 > 0.05 Table 3.43 The relationship between the reduced HRV indexes over time and NT-proBNP level HRV NT-proBNP NT-proBNP before treatment after treatment (pg/ml) (pg/ml) SDNN < 50 ms (ms) 2480.37 ± (n = 40) 5546.48 ≥ 50 ms 987.00 ± 669.5 p< 1082.16 ± p< 0.05 2165.62 0.05 592.99 ± 16 (n = 96) 468.98 < 15ms 2370.48 RMSSD (n = 44) 5486.54 p< 2265.16 p< 900.87 ± 650.69 0.05 599.29 ± 0.05 (ms) ≥ 15 ms ± 1162.08 ± (n = 92) 489.68 < 30 ms 2468.45 SDNNi (n = 34) 5307.84 (ms) ≥ 30 ms 950.96 (n = 102) 600.78 ± 1265.61 ± 2162.8 p< ± 0.05 589.86 p< ± 0.05 499.92 Table 3.44 The relationship between NT-proBNP concentration and HRV over time before and after treatment NT-proBNP ≥ 767.8 NT-proBNP < 767.8 pg/ml pg/ml (n = 84) (n = 52) HRV Before After treatment treatment SDNN (ms) RMSSD (ms) SDNNi (ms) p# p* Before After treatment treatment 31.53 ± 63.24 ± < 42.13 ± 51.78 ± 26.55 31.26 0.05 20.03 31.83 13.83 ± 21.45 ± < 14.53 ± 17.78 ± 6.56 6.01 0.05 6.03 8.17 25.9 45.44 < 27.61 ± 36.41 ± ±17.03 ±18.43 0.05 15.21 14.24 *: comparison before and after treatment #: comparison after treatment between groups p* < 0.0 < 0.0 < 0.0 < 0.05 < 0.05 < 0.05 17 Table 3.45 Relationship between NT-proBNP concentration and HRV in frequency spectrum before and after treatment HRV NT-proBNP ≥ 767,8 pg/ml NT-proBNP < 767,8 pg/ml (n = 52) (n = 84) Before After Before After treatment treatment treatmen treatment 1438.61± 1923.56± < 1844.68± 1916.92± (ms ) 535.07 664.13 0.05 517.32 1060.6 HF 155.76 ± 483.53 ± < 311.31 ± 582.29 ± (ms ) 61.24 136.56 0.05 74.57 129.85 LF 362.11 ± 615.74 ± < 545.03 ± 733.68 ± 463.23 232.1 0.05 510.02 170.24 TP 2 (ms ) LF/HF 3.3 ± 0.71 2.43 ± 0.7 p* < 0.05 3.02 ± 0.54 2.31 ± 0.52 p* > p# > 0.05 0.05 < < 0.05 0.05 < < 0.05 0.05 < > 0.05 0.05 CHAPTER 4: DISCUSSION 4.1 Changes in plasma NT-proBNP levels with arrhythmia characteristics, HRV in HF patients with CIHD before and after days of treatment 4.1.1 Characteristics of arrhythmias in patients with CIHD Results (Table 3.18) showed that: before treatment, the rate of paroxysmal supraventricular tachycardia was 3.7%, atrial premature beat 47.1% and atrial fibrillation 14.0% After treatment, this rate was 3.7%; 36.8% and 13.2%, respectively, there was no difference as compared with pre-treatment In a study by Patton K.K, 5.518 subjects were followed over a median of 7.6 years, of whom 267 patients developed atrial fibrillation (AF) High NT-proBNP had a 23.7-fold increased risk of AF in younger patients (95%CI 11.1 to 18 50.6) compared with older patients NT- proBNP is a strong predictor of AF, which is more significant in younger patients and women than in older patients and men Tran Minh Tri in a study on, 43 patients with CIHD who were monitored using Holter ECG after myocardial infarction to explore the features of arrhythmias and myocardial ischemia showed the following results: supraventricular premature beats were found in 79.1%; AF in 25.6%; ventricular premature beats in 62.8%; atrioventricular block in 4.7% The number of PVCs substantially decreased compared to pretreatment (600.7 ± 1472.2 vs 1277.5 ± 4510.6, respectively) Ventricular tachycardia: There was no difference in the rate of ventricular tachycardia between post-treatment (2.2%) and pretreatment (3.7%) According to the Lown system for grading premature beats in premature ventricular contractions, the results (Table 3.18) showed that the rate of grade after treatment (50.7%) had no difference compared to pre-treatment (50.0%) Grade II, III, IV after treatment (4.4%, 1.5%, 6.6%, respectively) decreased significantly compared to pre-treatment (6.6%, 5.1%, 13.2%, respectively) Notably, no cases in this study displayed Grade V both pre- and post-treatment In a study by Tran Minh Tri, among 43 CIHD patients post-myocardial infarction, 37.2% of the cases witnessed premature ventricular complexes, which proves the effectiveness of treatment methods in reducing the rate of ventricular premature beat, especially in the cases of severe premature ventricular contraction 4.1.2 Characteristics of HRV in people with CIHD The results (Table 3.20) showed that the HRV indices including SDNN, RMSSD, SDNNi, TP, LF, HF/LF after treatment increased significantly as compared to pre-treatment (p
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