Background: Various ECG abnormalities are commonly observed in obesity and in metabolic syndrome. Summary: Some of these abnormalities are caused by the pushed-up position of the diaphragm due to obesity and others occur as a result of the complications of the condition. The position of the R wave may change, various arrhythmias may develop or the QT interval may be prolonged, which increases the tendency to malignant arrhythmias. In obesity, the ECG signs of ventricular hypertrophy are less informative due to the accumulation of epicardial and subcutaneous adipose tissue. In general, it can be concluded that a microcirculation disorder is present in metabolic syndrome that may primarily be associated with ST-T wave abnormalities. Key Messages: Body surface potential mapping is a more sensitive method than traditional ECG with potentially greater use for diagnosis mainly in the early phase of non-ST elevation myocardial infarctions.

The epidemic of obesity has spread throughout the world. Obesity-induced insulin resistance and hyperinsulinaemia make type 2 diabetes mellitus a more and more frequent problem, and atherogenic dyslipidaemia occurs as well. The increased sympathetic activity in obesity triggers an elevation of blood pressure. The presence of three of the aforementioned factors at a time is defined as metabolic syndrome, where the cardiovascular risk associated with each factor is not simply added up but multiplied [1].

A number of ECG abnormalities may be associated with obesity of various causes. A left shift of the P, QRS and T axes, morphological deviation of the P wave, low QRS amplitude, flattening of T waves (mainly in inferolateral leads) and potentially prolonged QT and QTc intervals are present at a significantly higher rate in obese than in non-obese individuals. The prolongation of the QT and QTc intervals is caused by the heightened sympathetic activity characteristic of obesity that increases the reduced heart rate variability; all these elements have the potential to cause arrhythmia [2]. Various arrhythmias occur more commonly in obese individuals, especially in those with co-existing sleep apnoea or left ventricular hypertrophy. Many ECG abnormalities are reversible, since they may change proportionately with reduced body weight, as was confirmed in a study demonstrating a reduction of the mild left shift of the P and QRS axes after weight loss [3]. In obesity, ECG may change in many ways (table 1) due to an elevation of the diaphragmatic level, left ventricular hypertrophy caused by increased cardiac output, the presence of epicardial and subcutaneous adipose tissue - functioning as electric insulation layers - as well as sleep apnoea/hypoventilation syndrome [4].

Table 1

Common ECG abnormalities in obesity

Common ECG abnormalities in obesity
Common ECG abnormalities in obesity

Complete bundle branch blocks caused by elevated pressure are easy to recognise, but the diagnosis of, for instance, an incomplete right bundle branch block is often wrong [5]. The assessment of right ventricular pressure elevation is even more difficult [6].

Left ventricular hypertrophy is a significant predictor of cardiovascular morbidity and mortality [7]. In one study, the sensitivity of the ECG criteria for left and right ventricular hypertrophy was investigated in abnormally obese patients and compared with echocardiography [8]. The results demonstrated that the sensitivity of the ECG criteria for three different left ventricular hypertrophies ranged between 0 and 20%, while their specificity was within the range of 73-100%. Similarly, the sensitivity of the ECG criteria for right ventricular hypertrophy was quite low (0-16%), while their specificity ranged between 95 and 100%. The combination of ECG criteria did not increase their sensitivity and actually caused a significant decrease in their specificity.

Another study showed that the use of the Cornell voltage criteria was much more useful than that of the Sokolow-Lyon voltage criteria [9]. The Cornell voltage criteria [10] showed sensitivity in obese and non-obese subjects, while the sensitivity of the Sokolow-Lyon voltage criteria was demonstrated to be quite low in obese individuals [11]. ECG as the first cardiological examination method is inexpensive, accessible and easy to perform; however, in obese individuals, it is not always the most preferred tool for the diagnosis of ventricular hypertrophies. Thus, it can be concluded that ECG has very limited use in the diagnosis of left and right ventricular hypertrophy in obese subjects (particularly in abnormally obese patients).

The impact of various risk factors in metabolic syndrome primarily manifests in various forms of myocardial ischaemia which may be caused by coronary artery disease facilitated by those risk factors and the microcirculation disorder of the myocardium [12]. The different risk factors may trigger various abnormal myocardial changes including, for example, myocyte hypertrophy, the accumulation of interstitial connective tissue (together called ‘stiffness' development) and narrowing of the capillary lumen. Myocardial ischaemia induced by reduced microcirculation and its consequences may be detected with several electrocardiological methods. The worsening of myocardial function and compliance may lead to elevated end-diastolic pressure, atrial load, elevated right ventricular pressure and arrhythmias. The question is which electrocardiological method is suitable for the detection of the different abnormal changes - the cardiac impact of risk factors - associated with the early and late phases of myocardial damage.

The risk of arrhythmias and sudden death is higher in obese individuals even without cardiac dysfunction. The Framingham Study has shown that the mortality rate is increased 6- to 12-fold in seriously obese men [13]. QT prolongation was observed in 30% of the patients with impaired glucose tolerance in the NHANES III (Third National Health and Nutrition Examination Survey) [14].

The high blood glucose level increases vasomotor tone and ventricular instability, since it reduces the accessibility of nitrogen monoxide [15]. In extremely obese patients, fatal arrhythmia and sudden cardiac death caused by the common dilated cardiomyopathy are not rare [16]. Serious hypoglycaemic episodes requiring intervention occur with a frequency of 62-170 episodes/100 patient-years with the treatment of type 1 diabetes mellitus [17,18], while in type 2 diabetes mellitus, the frequency of serious hypoglycaemic episodes may be nearly 73/100 patient-years. Enhanced sympathoadrenergic activity induced by hypoglycaemia results in tachycardia, feeling of stress and vasoconstriction. As a sign of this, the systolic blood pressure increases while the diastolic value tends to decrease [19]. Previous reports have shown a relationship between hypoglycaemia and atrial fibrillation. However, the changes in repolarisation (prolongation of the QT interval) during hypoglycaemia have greater clinical significance. The significance of the prolongation of the QT interval during hypoglycaemia lies in the fact that it is an independent risk factor of sudden death and Torsade de pointes [20]. The ‘late potential' test is less frequently used, although a positive result indicates ‘late' depolarisation induced by ischaemia or myocardial disorder [21] and thereby susceptibility to arrhythmia (e.g. it yields positive results in 100% of extreme obesity cases).

Hyperinsulinaemia-induced hypoglycaemia prolongs the QTc interval and decreases the T wave amplitude (even in healthy individuals). In the EURODIAB (Europe and Diabetes Study), a higher HbA1c value, female sex and an elevated systolic blood pressure have been shown to be related to QTc prolongation in subjects with normal baseline QTc intervals, but physical activity and normal body weight had a protective effect against this prolongation. Sawicki et al. [22] have found the degree of QT distribution to be the most important independent risk factor for all-cause, cardiac and cerebrovascular death. Many studies in either healthy subjects or (type 1 and 2) diabetic patients have investigated the effect of hypoglycaemia on the QT interval. Marques et al. [23] and Lee et al. [24] have demonstrated a significant QTc prolongation during hypoglycaemia episodes in patients with type 1 diabetes mellitus, and other investigators have found consistent results [25,26].

There are two basic mechanisms in the background of the prolongation of the QT interval. One is the hypoglycaemia-induced activation of the sympathoadrenergic system where epinephrine and norepinephrine are released into the bloodstream. The other includes the reduced potassium level caused by elevated insulin and epinephrine levels. Studies in healthy subjects and patients with type 1 diabetes mellitus have shown that QTc prolongation caused by hypoglycaemia-induced activation of the sympathoadrenergic system could be successfully treated with beta-blockade [27]. In a study by Robinson et al. [28], the QTc prolongation was slightly decreased by the administration of potassium infusions.

ECG actually records the electric activity (potential) of the heart. The principle of this method is that the electric activity of the heart detectable on the body surface (ECG leads) is used to draw conclusions on various cardiac events and the underlying anatomical and pathological changes of the heart. In his first tests, Waller [29] essentially performed body surface potential mapping (BSPM) and assumed the presence of an electric dipole in the background of the potential distribution, and this is why the measurement of the summation vector had been the objective of electrocardiological examination for a long time. In many instances, specific calculated parameters of vectorcardiography (change in spatial size of the summation vector, change in azimuth angle, spatial velocity and spatial angular velocity) indicate the change in the order of electric depolarisation more reliably. In such cases, the underlying cause may either be a bundle branch block or a change in the myocardium [30].

Later, numerous attempts have made to find which leads may be the most informative ones. Wilson et al. [31] introduced the 12-lead ECG, consisting of 3 dipolar, 1 frontal (modified extremity unipolar) and 6 chest unipolar leads. In the extremity leads used by Wilson et al. (VR, VL and VF), only small surface amplitudes could be detected. Therefore, Goldberger [32] amplified them (aVR, aVL and aVF), and these are the leads that are in use today.

Due to numerous electrodes (63 in the Montreal system) placed on the body surface (even on the back), minor electrocardiological events can also be detected that are less detectable or non-detectable with 12-lead ECG [33,34]. In general, qualitative and quantitative evaluations of isopotential maps provide the most information, but they are also the most time-consuming procedures. The assessment of isoareal maps is faster [35]. Purely quantitative parameters may also provide useful information [36,37]. By using BSPM, the ratio of dipolar to non-dipolar forces during depolarisation can be determined, and with an increased non-dipolar activity, this may indicate myocardial inhomogeneity and major malignant arrhythmias [38,39,40,41]. There are some specific clinical alternatives for the use of BSPM that may be useful for the examination of outcomes of metabolic syndrome: minor electric potential losses [42,43,44,45], the presence and location of coronary artery stenoses [46], the electric viability of the myocardium [47,48], electric changes following revascularisation [49,50], various intervals [51] and the electric activity of the left atrium [52] can be accurately determined, or clinical indices such as overload [53] or even haemodynamic information can be obtained [54].

It is a well-known fact that micro- and macrovascular complications are often present at the time of the first diagnosis of diabetes. Ždarská et al. [55] studied patients with type 1 diabetes without cardiovascular symptoms by using BSPM. Elevated heart rate, QRS and QT changes as well as depolarisation and significant changes in repolarisation were found compared with the non-diabetic controls.

Approximately 15-20% of patients hospitalised with chest symptoms suffer from acute coronary syndrome, while in diabetic patients, the evaluation of clinical symptoms is much more difficult due to autonomic neuropathy [56]. The 1-year mortality after acute coronary syndrome is significantly higher in diabetic patients than in non-diabetic subjects [57] despite up-to-date treatment.

An evaluation of non-ST elevation myocardial infarction in diabetic patients may be even more difficult, due to the often atypical symptoms and non-specific ECG changes and since cardiac necroenzyme kinetics may only surely indicate the problem within 14-16 h. McClelland et al. [58] studied patients examined due to chest pain by using BSPM evaluated with an automated program (in addition to the standard diagnostic procedures of ECG and assessment of cardiac necroenzymes). Acute myocardial infarction confirmed by biochemical markers was found in 53 of the 103 patients. It was diagnosed with a significantly better specificity by BSPM than by standard 12-lead ECG (45 vs. 64%, p < 0.001), while no significant difference in sensitivity was shown (98 vs. 94%) [58].

There are various ECG abnormalities observed in obesity and in metabolic syndrome. In these conditions, we have several difficulties to evaluate the ECG features. One of the most important factors includes the amount of thoracic and epicardial adipose tissue (functioning as electric insulation layers), which lowers the electric potentials from unipolar leads. Therefore, the ECG criteria for left and right ventricular hypertrophy have a poor sensitivity but strong specificity. The elevated diaphragmatic level results in changes in the position of the R axis. The enhanced sympathetic activity characteristic of obesity increases the risk of malignant arrhythmias via a prolongation of the QTc interval. The importance of BSPM is high because the method has a greater sensitivity than traditional ECG, and since BSPM is evaluated by computer, it is now cheap and cost effective; however, specific knowledge is required, and its availability is very limited in general practice.

Eckel RH, York DA, Rossner S, et al; American Heart Association: Prevention Conference VII: obesity, a worldwide epidemic related to heart disease and stroke - executive summary. Circulation 2004;110:2968-2975.
Mathew B, Francis L, Kayalar A, Cone J: Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med 2008;21:562-568.
Fraley MA, Birchem JA, Senkottaiyan N, et al: Obesity and the electrocardiogram. Obes Rev 2005;6:275-281.
Eisenstein I, Edelstein J, Sarma R, Sanmarco M, Selvester RH: The electrocardiogram in obesity. J Electrocardiol 1982;15:115-118.
Medvegy M, Antalóczy Z: Clinical significance of incomplete right bundle branch block (in Hungarian). Orv Hetil 1993;134:1525-1528.
Medvegy M, Antalóczy Z, Préda I: Connection between right ventricular pressure and the ECG. J Electrocardiol 1994;27:23-27.
Kannel WB, Gordon T: Left ventricular hypertrophy by electrocardiogram: prevalence, incidence, and mortality in the Framingham Study. Ann Intern Med 1969;71:89-105.
Nath A, Alpert MA, Terry BE, et al: Sensitivity and specificity of electrocardiographic criteria for left and right ventricular hypertrophy in morbid obesity. Am J Cardiol 1988;62:126-130.
Sokolow M, Lyon TP: The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949;37:161-186.
Casale P, Devereux R, Kligfield P, Eisenberg R, Miller D, Chaudhary B, Phillips M: Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria. J Am Coll Cardiol 1985;6:572-580.
Abergel E, Tase M, Menard J, Chatellier G: Influence of obesity on the diagnostic value of electrocardiographic criteria for detecting left ventricular hypertrophy. Am J Cardiol 1996;77:739-744.
Medvegy M, Simonyi G, Medvegy N, Pécsvárady Z: Non-ST elevation myocardial infarction: a new pathophysiological concept could solve the contradiction between accepted cause and clinical observations. Acta Physiol Hung 2011;98:252-261.
Kannel WB, Plehn JF, Cupples LA: Cardiac failure and sudden death in the Framingham Study. Am Heart J 1988;115:869-875.
Brown DW, Giles WH, Greenlund KJ, et al: Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey. J Cardiovasc Risk 2001;8:227-233.
D'Amico M, Marfella R, Nappo F, et al: High glucose induces ventricular instability and increases vasomotor tone in rats. Diabetologia 2001;44:464-470.
Messerli FH, Nunez BD, Ventura HO, Snyder DW: Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity. Arch Intern Med 1987;147:1725-1728.
Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
MacLeod KM, Hepburn DA, Frier BM: Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabet Med 1993;10:238-245.
Fisher BM, Gillen G, Hepburn DA, et al: Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol 1990;258:H1775-H1779.
Robinson RT, Harris ND, Ireland RH, et al: Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes 2003;52:1469-1474.
Lalani AP, Kanna B, John J, et al: Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res 2000;8:20-28.
Sawicki PT, Kiwitt S, Bender R, et al: The value of QT interval dispersion for identification of total mortality risk in noninsulin-dependent diabetes mellitus. J Intern Med 1998;243:49-56.
Marques JLB, George E, Peacey SR, et al: Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997;14:648-654.
Lee SP, Harris ND, Robinson RT, et al: Effect of atenolol on QTc interval lengthening during hypoglycaemia in type 1 diabetes. Diabetologia 2005;48:1269-1272.
Koivikko ML, Karsikas M, Salmela PI, et al: Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes. Diabetologia 2008;51:426-435.
Larsen A, Højlund K, Poulsen MK, et al: Hypoglycemia-associated electroencephalogram and electrocardiogram changes appear simultaneously. J Diabetes Sci Technol 2013;7:93-99.
Heller SR: Abnormalities of the electrocardiogram during hypoglycaemia: the cause of the dead in bed syndrome? Int J Clin Pract Suppl 2002;129:27-32.
Robinson RT, Harris ND, Ireland RH, et al: Comparative effect of human soluble insulin and insulin aspart upon hypoglycaemia-induced alterations in cardiac repolarization. Br J Clin Pharmacol 2003;55:246-251.
Waller AD: A demonstration on man of electromotive changes accompanying the heart's beat. J Physiol 1887;8:229-234.
Medvegy M, Regős L, Antalóczy Z, et al: Analysis of conduction disturbances in right ventricule of heart based on spatial velocity curve [Jobb kamrai vezetési zavarok elemzése a térbeli sebességgörbe alapján]. Proc Appl Comput Cybern Methods Med Biol, 12th Coll, Szeged, 1984, pp 254-261.
Wilson FN, Johnston FD, Cotrim N, Rosenbaum FF: Relations between the potential variations of the ventricular surfaces and the form of the ventricular electrocardiogram in leads from the precordium and the extremities. Trans Assoc Am Physicians 1941;56:258.
Goldberger E: The aVR, aVL, and aVF leads. A simplification of standard electrocardiography. Am Heart J 1942;24:378-396.
Préda I, Medvegy M, Duray G: Clinical value of body surface potential maps: new diagnostic challenges; in Pastore CA (ed): Electrocardiology 2001. Proc 28th Int Congr ECG, Sao Paulo, 2001. Athens, World Scientific, 2002, pp 21-27.
Medvegy M, Duray G, Pintér A, Préda I: Body surface potential mapping: historical background, present possibilities, diagnostic challenges. Ann Noninvasive Electrocardiol 2002;7:139-151.
Medvegy M, Préda I, Nadeau R, et al: Diagnosis of non-Q wave myocardial infarction by isoarea departure maps using different time periods; in Bacharova L, Macfarlane PW (eds): Electrocardiology '97. Proc 24th Int Congr ECG, Bratislava, 1997. Singapore, World Scientific, 1998, pp 210-213.
Medvegy M, Savard P, Pintér A, et al: Simple, quantitative body surface potential map parameters in the diagnosis of remote Q-wave and non-Q-wave myocardial infarction. Can J Cardiol 2004;20:1109-1115.
Medvegy M, Préda I, Savard P, et al: New quantitative parameters in the diagnosis of the myocardial infarction. 26th Int Congr Int Med, Global Physicians Network: A Challenge for the New Century, Kyoto, 2002.
Antalóczy Z, Medvegy M, Endrőczy G: A new approach in the study of electrical activity of the heart; in Antalóczy Z, Préda I, Kékes E (eds): Advances in Electrocardiology. Amsterdam, Elsevier, 1990, pp 19-22.
Endrőczy G, Antalóczy Z, Medvegy M: A practical new method for the complete determination of the equivalent dipole; in Antalóczy Z, Préda I, Kékes E (eds): Advances in Electrocardiology. Amsterdam, Elsevier, 1990, pp 23-26.
Medvegy M, Antalóczy Z, Endrőczy G: The dipole aspect in the clinical practice; in Antalóczy Z, Préda I, Kékes E (eds): Advances in Electrocardiology. Amsterdam, Elsevier, 1990, pp 27-30.
Medvegy M, Antalóczy Z, Cserjés Z: A new possibility in the study of heart activation: the nondipolar body surface map. Can J Cardiol 1993;9:215-218.
Medvegy M, Préda I, Savard P, et al: A new body surface isopotential map evaluation method to detect minor potential losses in non-Q wave myocardial infarction. Circulation 2000;101:1115-1121.
Préda I, Medvegy M, Savard P, et al: Body surface isopotential maps to detect minor potential losses in non-Q-wave myocardial infarction. Proc 30th Int Congr ECG, Helsinki, 2003. Int J Bioelectromagn 2003;5:337-339.
Medvegy M, Préda I, Nadeau R, Savard P, Pintér A, Tremblay G, Nasmith J, Palisaitis D: Investigation of old non-Q wave myocardial infarction by body surface potential mapping. Circ Suppl 1996;94:4276.
Préda I, Medvegy M: Body surface potential mapping in the diagnosis of non-Q wave myocardial infarction. Lecture. J Kardiol, 5th Alpe-Adria Cardiol Meet, Austria, 1997, pp 161-162.
Szűcs E, Szakolczai K, Simonyi G, Bauernfeind T, Pintér A, Préda I, Medvegy M: Diagnostic value of body surface potential mapping in assessment of the coronary artery lesion after angina pectoris and without repolarization changes on the ECG. J Electrocardiol 2010;43:326-335.
Medvegy M, Duray G, Pintér A, Préda I: Evaluation of the electrical viability by nitroglycerin test in ischemic heart disease. 9th Int Congr Cardiovasc Pharmacother, Salvador. Cardiovasc Drugs Ther 2000;14:195.
Medvegy M, Duray G, Bauernfeind T, Szűcs E, Pintér A, Préda I: Electrical viability: a new term by body surface potential mapping. 14th World Congr Cardiol, Sydney. JACC 2002;39(suppl B):399B, 4532.
Medvegy M, Préda I, Nadeau R, Savard P, Pintér A, Tremblay G, Nasmith J, Palisaitis D: Changes of potential losses due to revascularisation attempt of coronary arteries. 16th Interam Congr Cardiol, Fajardo. PR Health Sci J 1997;16(suppl A):30.
Medvegy M, Préda I, Nadeau R, Savard P, Pintér A, Tremblay G, Nasmith J, Palisaitis D, Sándor G: Alterations of depolarisation pattern detected by body surface potential mapping due to different revascularisation methods. 13th World Congr Cardiol, Rio de Janeiro. JACC 1998;31(suppl C):20C.
Duray G, Medvegy M, Préda I: Repolarization time intervals in ischemic heart disease in acute nitroglycerin effect; in DeAmbroggi L (ed): Electrocardiology 2000. Proc 27th Int Congr ECG, Milan, 2000. Rome, Casa Editrice Scientifica Internationale, 2001, pp 159-161.
Bauernfeind T, Medvegy M, Duray G, Pintér A, Borsányi T, Préda I: Relationship between the left atrial activity and the positivity of the exercise test. 14th World Congr Cardiol, Sydney. JACC 2002;39(suppl B):116B, 2664.
Medvegy M, Préda I, Nadeau RA, et al: Relationship between the response to exercise test and the extension of potential loss in non-Q wave myocardial infarction; in Roshchevsky MP (ed): Electrocardiology '99. Proc 26th Int Congr Electrocardiol, Syktyvkar, 1999. Syktyvkar, Institute of Physiology, 2000, pp 172-176.
Medvegy M, Duray G, Nasmith J, Nadeau RA, Pintér A, Bauernfeind T, Szűcs E, Préda I: Minor electrical potential losses can provide hemodynamic information in unstable coronary artery disease. 14th World Congr Cardiol, Sydney. JACC 2002;39(suppl B):113B, 2649.
Ždarská D, Pelisková P, Charvát J, et al: ECG body surface mapping (BSM) in type 1 diabetic patients. Physiol Res 2007;56:403-410.
Pope JH, Aufderheide TP, Ruthazer R, et al: Missed diagnosis of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163-1170.
Donahoe SM, Stewart GC, McCabe CH, et al: Diabetes and mortality following acute coronary syndromes JAMA 2007;298:765-775.
McClelland AJ, Owens CG, Menown IB, et al: Comparison of the 80-lead body surface map to physician and to 12-lead electrocardiogram in detection of acute myocardial infarction. Am J Cardiol 2003;92:252-257.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.