[Heart rate variability in chronic obstructive pulmonary disease].

Background and purpose: Cardiopulmonary disorders coexist and contribute to the morbidity and mortality of Chronic Obstructive Pulmonary Disease (COPD). There is also a significant contribution of COPD to heart disease. Hypoxemia and respiratory acidosis have been implicated as a major cause of cardiac arrhythmias in patients with COPD through an increase in catecholamines, fluid retention and peripheral edema (electropathy hypothesis). Alternatively, arrhythmias may be the result of autonomic neuropathy. We investigated the relationship between COPD and cardiac arrhythmias and particularly the impact of COPD on heart rate variability (HRV). Patients and methods: We studied a total of 68 consenting consecutive patients (30 women and 38 men (M = 67.37 years, SD 10.24 years) that met strict inclusion criteria, regarding cardiac or vascular disease, diabetes or medications. Pulmonary function tests, 12-lead ECG and blood gases were performed on all patients. Two different ECG parameters were calculated: Dispersion of QT interval (QTd) and coefficient of variation of the RR interval (CVRR). Analysis was through regression (single or multiple) and cross-correlation methods. Results: Examination of the cross-correlation of PaO2, PaCO2, pH and HCO3 with QTd and CVRR showed that CVRR correlated best with PaO2 We, therefore, reject the electropathy hypothesis (i.e., that arrhythmia is a result of hypoxia, hypercapnia, or acid-base balance disorders) and conclude that hypoxemia is the likely mechanism of sudden cardiac death in COPD. Correspondence to: Golidakis Diamantis, MD, PhD, Department of Physiology, Faculty of Medicine, University of Ioannina, Greece, E-mail: [email protected] Received: August 02, 2017; Accepted: August 23, 2017; Published: August 26, 2017 Introduction Chronic Obstructive Pulmonary Disease (COPD) is a chronic, permanent and irreversible lung disease characterized by airway obstruction. In fact, it represents two concomitant diseases: chronic bronchitis (which is characterized by excessive mucus production) and mucosal edema. The coexistence of these two disease entities result in bronchoconstriction, coughing, sputum production, frequent respiratory infections and pulmonary emphysema. Emphysema destroys the walls of alveoli, reduces the ratio between the gas-exchange surface and the volume of air contained in the alveoli and results in inadequate oxygen uptake. COPD is accompanied by comorbidities. Among them are low intensity diffuse inflammation, cardiovascular disease, metabolic disorders, cachexia and psychological disorders. Of interest are the cardiovascular comorbidities, especially the incidence of COPD in disturbances involving the RR interval of the ECG. The importance of focusing on the impact of COPD on cardiovascular disease is demonstrated in Table 1 which summarizes the relationship between COPD and its co-morbidities. COPD is emerging as one of the biggest health problems of the 21st century as it is the fourth cause of death and morbidity in the United States [1], where it is predicted that it will become the third cause of morbidity mortality by 2020 [2] while 24 billion dollars are spent every year, on medicines and COPD related hospitalizations, in the US alone. The prevalence of COPD worldwide is estimated at around 10% of adults over the age of 40 [3] with country-to-country fluctuations impacting significantly on the healthcare costs of the disease which is significantly high [4] and causing significant burdens on the quality of life of patients [5]. It is characteristic that more than half of COPD sufferers are unaware of it, as the disease is under-diagnosed [6]. The main cause of COPD (80-90%) is smoking [6,7] while biomass burning, car exhaust, dust and volatile chemical emissions are also recognized causative factors. COPD is a comorbidity of importance for cardiology as supraventricular and abdominal arrhythmias, and conduction disorders are very often encountered in COPD. Despite its obvious significance, however, this phenomenon has not merited attention, and treatment has been symptomatic at best. The basis for the COPD related treatment of arrhythmias is based on the perception that arrhythmias are the result of local deviations from normal myocardiocyte function due to hypoxemia, hypercapnia and associated acid-base disturbances. However, given that the autonomic control of the heart is particularly important for its pacing, and that the sympathetic and parasympathetic inputs are not evenly distributed over the myocardium, it is also possible that the COPD related arrhythmias may be due to the “autonomic neuropathy” that characterizes COPD. Indeed, hypoxemia and respiratory acidosis have been implicated as major causes of cardiac arrhythmias in patients with COPD [8,9]. The putative causative mechanism is apparently the increase of catecholamines which occurs in hypercapnic COPD patients especially when hypercapnia and hypoxia are accompanied by fluid retention and peripheral edema [10]. As COPD cardiac output remains normal, under these circumstances, Diamantis G (2017) Heart rate variability in chronic obstructive pulmonary disease Volume 1(2): 2-5 Res Rev Insights, 2017 doi: 10.15761/RRI.1000111 while systemic vascular resistances remain low (due to the vasodilatory effect of hypercapnia), it is believed that the resulting drop in arterial pressure triggers neurohormonal mechanisms that result in water and electrolyte retention while they increase the concentration of norepinephrine in the blood. In addition, the (inhaled) β2-stimulants used in COPD treatment may potentially increase the heart rate and induce cardiac arrhythmias through non-selective β-stimulation [11,12]. Salbutamol, which is a drug of choice in the treatment of COPD, reduces the duration of the atrial cycle and the sinoatrial (SA) restoration time, increases the speed of atrioventricular conduction and decreases the duration of the refractory period of the myocardium and of the SA cells. It should be also mentioned that beta-agonists cause arrhythmias, such as atrial tachycardia, atrial fibrillation, syncope, heart failure, arrest and sudden death. It is noteworthy that administering a dose of inhaled β2-stimulant results in an increase in heart rate of 9 IU / min in cases of asthma, whereas the administration of prolonged β2-stimulatory activity (LABA), such as salmeterol or formoterol, atrial tachycardia but no increase in mean heart rate [13,14]. Patients and methods We recruited 68 consecutive patients (30 women and 38 men, with mean age of 67.37 years and standard deviation of 10.24 years. All patients were properly informed of the aims and methods of the study following the procedures of the Helsinki Declaration, and they all provided their informed consent. Our patients were selected after a rigorous application of exclusion criteria. We excluded patients with hypertension, heart failure, ischemic heart disease, valvular heart disease, supraventricular and ventricular heart rhythm disorders, atrial fibrillation or flutter, conduction disorders and, finally, diabetes mellitus. Patients on certain medications were also excluded. Thus, patients on medicines that prolong the QT interval such as antiarrhythmics (quinidine, disopyramide, procainamide, amiodarone, sotalol), certain antibiotics (macrolides, chloroquine, quinine), psychiatric medications (tricyclic antidepressants, phenothiazines, haloperidol) or cholinergic antagonists (cisapride), were excluded. Finally, patients treated with sympathomimetic drugs and/or aminophylline were excluded from the study unless they could discontinue their medication at least 48 hours prior to their examination for the present study. All patients underwent pulmonary function tests and ECG and simultaneous measurement of blood gases. ECG was recorded with patients in the supine position while they displayed a regular, relaxed breathing pattern. Patients were at rest before measurement. ECG recording length was 3 minutes, with each patient completing about 45 respiratory cycles during the recording. From the data collected, two different ECG parameters were calculated: The dispersion of the QT interval (QTd) which is associated with ventricular repolarization, [15] and the Coefficient of Variation of the RR interval (CVRR). The QTd is defined as the difference between the maximum and minimum QT interval in the 12-lead ECGs [16]. The QT interval was measured from the onset of QRS to the end of the T wave. Leads where the T-wave was level (absent) were excluded from the QTd calculation [17]. If U waves appeared in the EEG, then the QT interval was measured from the onset of the QRS to the lowest point of the curve between the T and the U waves [18]. The ECG at each lead was recorded for three consecutive cycles. For each ECG cycle the corrected QT interval (QTc) was calculated based on the Bazett formula (i.e., QTc = QT/√RR). Finally, the QTd was calculated as the difference between the maximum and minimum QTc in the 12-lead pattern, in order to avoid errors from the pulse-topulse fluctuations between the leads [19]. The ECG parameter we measured was the instantaneous heart rate, i.e., the inverse of the duration of the RR intervals between two consecutive QRS complexes of physiological morphology and of SA origin. Thus, for each continuous ECG record, the duration of the RR interval between two normal QRS was measured. The simple time domain variables that were calculated include the mean “RR interval between two normal QRS” and the mean heart rate. Following the instructions of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) [20], all electrocardiographic recordings were conducted with patients in supine position and with regular and calm breathing while the patients were rested before the start of the measurement. Each electrocardiographic recording lasted 3 minutes, and each patient completed about 45 breathing cycles (inhalation exhalation). The ECG was continuously recorded, covering all inhalation and exhalation cycles during this time, and was therefore not stable with respect to the respiratory cycle, which ensured the normalization of the influence of the vagus nerve on the SA node, which takes place mainly during the exhalation phase and which, is usually week or absent during inhalation. Data were reviewed of the independence of the measured variables and checked for any correlations between the independent and dependent parameters. Subsequently, correlation matrices were created for each independent parameter and the remaining (dependent) parameters. Patients were then divided according to their respiratory fitness for each studied parameter in two groups: those of better and those of worse fitness and each group was analyzed for its response when FVC, FEV1, pH, PaO2, PaCO2, or CVRR were increased. Only statistically significant (p<0.05) relations were considered. The results were tabulated in five tables (Tables 2-4). Hole et al, 1996 Ebi-Kryston, 1988 Schunneman et al, 2000 Persson et al, 1986 Sample size 15411 17717 1195 1492 Duration of observation 15 years 10 years 28 years 12 years Mean age 15 10 29 12 Pulmonary function FEV1 73-113% FEV1<65% FEV1 80%-114% PEFR 123-545 l/min Main conclusion ↑ relative risk X 1.56 Chronic sputum production is connected with increased cardiovascular mortality which can be corrected by improvementη of FEV1 ↑ relative risk X 2.11 Inversely related to risk of death from Infarction Results adjusted for Age, smoking, serum cholesterol, BMI, social class Age, smoking, occupation, blood pressure (BP), BP medication, serum cholesterol, diabetes ECG Age, smoking, BP, BMI, education, ischemia Age, height, BMI, waist to hips ratio, chest skeletal problems, pulmonary disease, smoking, serum lipids, BP, diabetes, physical activity Table 1. Major studies of COPD and cardiovascular co-morbidities. Diamantis G (2017) Heart rate variability in chronic obstructive pulmonary disease Volume 1(2): 3-5 Res Rev Insights, 2017 doi: 10.15761/RRI.1000111 COPD patients with Worse respiratory system fitness COPD patients with Better respiratory system fitness Better respiratory system fitness for PaCO2 ↑ pH Better respiratory system fitness for FEV1 ↑ PaO2 Worse respiratory system fitness for pH ↑ PaO2 Better respiratory system fitness for FVC ↑ PaO2 Worse respiratory system fitness for pO2 ↑ pH Worse respiratory system fitness for pCO2 ↑ PaO2 Worse respiratory system fitness for FEV1 ↓ CVRR Better respiratory system fitness for CVRR ↓ CVRR Worse respiratory system fitness for FVC ↓ CVRR Better respiratory system fitness for pH ↓ CVRR Better respiratory system fitness for PaCO2 ↓ PaCO2 Worse respiratory system fitness for PaCO2 ↓ CVRR Worse respiratory system fitness for PaO2 ↓ CVRR Better respiratory system fitness for pO2 ↓ PaCO2 Worse respiratory system fitness for FEV1 ↓ PaCO2 Worse respiratory system fitness for CVRR ↓ PaCO2 Worse respiratory system fitness for FVC ↓ PaCO2 Table 2. Effect of FEV1 increase on different spirometry and ECG parameters of COPD patients. Worse respiratory system fitness for FVC ↓ PaCO2 Better respiratory system fitness for FVC ↓ PaCO2 Worse respiratory system fitness for FEV1 ↓ PaCO2 Better respiratory system fitness for FEV1 ↓ PaCO2 Worse respiratory system fitness for pH ↓ PaCO2 Better respiratory system fitness for pH ↓ PaCO2 Worse respiratory system fitness for pO2 ↓ PaCO2 Better respiratory system fitness for pCO2 ↑ PaO2 Better respiratory system fitness for pCO2 ↓ PaCO2 Worse respiratory system fitness for CVRR ↓ PaCO2 Better respiratory system fitness for CVRR ↓ PaCO2 Table 3. Effect of pH increase on PaCO2 or PaO2 for the different groups of COPD patients. Better respiratory system fitness for FVC ↑ CVRR Better respiratory system fitness for FEV1 ↑ CVRR Worse respiratory system fitness for pH ↓ PaCO2 Better respiratory system fitness for pH ↑ PaCO2 Better respiratory system fitness for pH ↑ CVRR Better respiratory system fitness for PaCO2 ↓ PaCO2 Better respiratory system fitness for PaCO2 ↑ CVRR Table 4. Effect of PaO2 increases on the PaCO2 and CVRR of COPD patients.