Original paper
NT-proBNP in patients after acute coronary syndrome with ST segment elevation subjected to early posthospitalization cardiologic rehabilitation

Introduction
Brain natriuretic peptide (BNP) represents a family of natriuretic peptides which also includes: atrial natriuretic peptide (ANP), secreted in the atria; C-type natriuretic peptide (CNP), secreted at the level of the vascular epithelium; and dendroapsis natriuretic peptide (DNP), discovered not long ago in viper venom [1]. Biological activity of natriuretic peptides is realized through a system of peripheral receptors (type A, B and C) localized in various tissues, among others in epithelial cells and renal tubules [2]. Natriuretic peptides neutralize the effects of excessive activation of the renin- -angiotensin-aldosterone system (RAA). BNP acting natriuretically, similarly as ANP, takes part in the body’s water balance. Its diuretic activity reduces the volume of the vascular bed and is an important element of the mechanism of arterial pressure endogenic regulation [3]. BNP is released from ventricular myocardium cadriomyocytes in response to increasing pressure or volume overload. Elevated BNP concentration was observed in circulatory system diseases with increased ventricular overload, e.g. in heart failure being the consequence of right and left ventricular dysfunction resulting from acute coronary syndromes (with and without ST segment elevation) [4]. Elevation of plasma BNP concentration is a recognized index of the degree of left ventricular dysfunction and has proved to be of high prognostic value, enabling the prediction of death due to heart failure or acute coronary syndrome not resulting in death [5, 6]. Every rehabilitation procedure aims to restore optimal fitness or at least develop the body’s compensatory functions. This principle also concerns the cardiovascular system. Exercise training through periodic increase of heart rate is a factor intensifying angiogenesis, which results in exercise-induced increase of the left ventricular ejection fraction (EF) and in the improvement of global myocardial contractility [7]. Furthermore, exercise restores endothelial balance: there is an increase in endothelium-derived relaxing factor (EDRF) and endothelium-derived hyperpolarizing factor (EDHF) synthesis and endothelin-1 (ET-1) release inhibition [8]. Fundamental studies of Sullivan from Duke University, in patients with heart failure, determined the effect of controlled exercise training on the increase of pulmonary ventilation capacity and the increase of blood flow in extremities [9]. The beneficial effect of physical training – increased cardiac output or oxygen consumption by myocardium – has also been confirmed by other authors [10]. Numerous researchers have observed the beneficial effect of cardiologic rehabilitation in reducing left ventricular systolic dysfunction expressed by ejection fraction improvement and decreased plasma NT-proBNP concentration. The aim of the study was to estimate NT-proBNP concentration under the effect of exercise training in patients after myocardial infarction with ST segment elevation, treated with primary PTCA with a stent.
Material and methods
Two groups of subjects were studied. Group I included 17 men, mean age 53.6 years, who within the last 2-3 weeks had acute coronary syndrome with ST segment elevation and were treated with primary angioplasty and intracoronary stent placement. These patients were qualified for 12-day exercise training. Group II comprised 14 men, mean age 64.3, who for the same reasons were treated with primary angioplasty but according to the risk stratification criteria for patients qualified for rehabilitation were not included into the training group. The following qualification criteria were considered: EF <40%, the occurrence of complex ventricular arrhythmia at rest and on exertion, horizontal depression of ST segment on exertion, physical efficiency <5 MET, pathological reaction to exercise, that is lack of increase or decrease of systolic arterial pressure or heart rate proportionally to the increase of load, and finally clinical data – ischaemia after revascularization or heart failure. A rule was accepted that when one of the above was observed, the patient was qualified to group II. A set of exercises such as breathing, isometric, of small muscular groups, and relaxation considered to be safe while undertaking rehabilitation treatment in the group of high risk patients, was suggested to all group II patients. Patients in both groups were subjected to simultaneous pharmacological therapy according to currently in force standards of the Polish Cardiac Society. Patients from both groups were subjected to exercise test on a moving track to estimate the level of tolerated exercise. A modified Bruce’s protocol was applied in group II. In this group in four cases the patients were not qualified on the basis of exercise test owing to weak tolerance of exercise. In both groups echocardiography was performed twice with a 3.5 MHz transducer: before and on completion of the training cycle. In each case the same person performed the examination. Ejection fraction (EF) was investigated with Simpson’s method. Means from the measurements in three cardiac cycles were accepted for estimation according to the recommendations of the American Society of Echocardiography. Group I patients were subjected to rehabilitation in 12-day exercise training. Interval training was applied on a cycloergometer with increasing load from 25 to 40 watts. The level of NT-proBNP was tested twice in all patients with ready immunoenzymatic kits by ELISA method (Biomedica). In group I blood was collected from the basilic vein at rest, before and after the training cycle, while in group II before and after a comparable period of observation (12 days). The investigated groups were compared taking into account parameters which could affect the level of NT-proBNP secretion. The following parameters were compared: myocardial infarction location, risk factors and also the level of troponin release. Statistical analysis was performed with STATISTICA PL. 5.1 on the basis of the determination of means of the variables and their standard deviations. Differences between the investigated groups were estimated with chi-square test. To find the normal distribution, variation of the distribution of the investigated variables was checked with W. Shapiro-Wilk test, and variances homogeneity with F test. Further analysis was performed with Student’s t-test for unmatched pairs. Correlation between the tested parameters was analysed by calculating Pearson’s correlation coefficient (r). The results are considered statistically significant at the level of significance <0.05 (p<0.05).
Results
The studied groups were comparable as regards infarction location (p=0.998), risk factors (p=0.774) and troponin release (p<0.684). In group I the determined NT-proBNP concentration was 192.09 fmol/ml before rehabilitation. After completion of the training cycle a statistically significant decrease in NT-proBNP concentration was observed to the value 99.91 fmol/ml. In group I initial NT-proBNP concentration was 267.58 fmol/ml. After completion of the period of observation a statistically insignificant decrease in NT-proBNP was noted to the value 243.80 fmol/ml (Table I, Figure 1). After completion of the training cycle a significant improvement in physical fitness was observed. Mean efficiency in group I before rehabilitation was 6 MET, while on completion it was 9 MET. In group II no significant improvement was observed in the range of physical efficiency after the period of observation. Mean efficiency in this group was 3 MET and after the observation period 4 MET. In group I, EF calculated before the training cycle was 53.65%, while after rehabilitation the value of EF increased statistically significantly to 56.65%. In group II, at the beginning of observation EF was 38.40% and after completion no significant improvement of EF was noted (Table II, Figure 2). Both in group I and II a significant negative correlation was observed between NT-proBNP concentration and EF: respectively in group I: r=0.872 (Figure 3) and in group II r=0.755 (Figure 4), p<0.05.
Discussion
The principle goal in rehabilitation of patients after myocardial infarctions is to restore the organ’s optimal efficiency, in this case of heart lesioned by acute ischaemia, or to develop its compensatory function. This aim can be achieved by selecting exercises and load adequate for the age and the organism efficiency, indispensable for activation of the organ to restore its primary efficiency [12]. Systolic dysfunction is a clinical equivalent of myocardial ischaemia because to maintain normal contractility the heart must continuously restore energetic reserves. Prolonged ischaemia causes gradual endogenic glycogen utilization [13]. Excessive supply of free fatty acids (FFA) and mininal oxygen metabolism cause increased oxidation of fatty acids [14]. In ischaemic myocardium, energetically little effective and consuming about 10% of oxygen, the process of FFA oxidation remains the main source of energy. Reversal of energetic substrates metabolism for the benefit of FFA results in quicker exhaustion of already poor oxygen reserves and rapid decrease of ATP production which is not sufficient for preservation of normal function of cardiomyocyte [15]. In clinical practice metabolic disorders lead to left ventricular systolic dysfunction with hypokinesis or akinesis of ischaemic segments [16]. Lack of radical improvement in oxygen supply to the myocardium leads to its irreversible damage. On the other hand, restoration of coronary perfusion is not equivalent to the normalization of metabolism. Increased oxygen availability activates an enzymatic complex related to carnitine responsible for FFA transport to mitochondria and thus limiting the rate of glucose oxidation [17]. The role of oxygen free radicals should not be neglected either. They are produced excessively in the period of reperfusion. Free radicals effectively change the properties of the sarcolemma by lipid peroxidation in the cell membrane, making it more permeable to calcium ions [18]. Excess of ionized calcium activates proteolytic enzymes responsible for the formation of microlesions in the area of contractile elements. They are reversible, although their restitution is slow. Paradoxically, after coronary flow restoration the normal function of previously ischaemic left ventricular segments is not necessarily restored because altered contractility is associated with transient myofilament dysfunction [19]. The aim of angioplasty is to recanalize an oblitarated coronary artery responsible for myocardial infarction. The blood flow is radically restored in the main coronary vessels, but usually with perfusion disturbances in small coronary arteries [20]. In the ischaemic heart, a poorly developed system of arterial anastomoses is also observed, particularly in subjects with a short history of the disease. Together with persisting impairment of metabolism in the area of myocardial infarction, the described factors to a great extent are responsible for left ventricular systolic dysfunction after infarction. BNP is a biochemical marker of systolic dysfunction. In the group of patients with acute coronary syndromes both BNP and NT-proBNP submit independent and additional diagnostic information and have high predictive value in this group of patients [21]. The authors of the Val-Heft trial recommend the use of both neurohormonal markers in clinical practice for monitoring the effectiveness of the treatment and mortality prognostication in the group of patients with heart failure [22]. In our own studies a significant decrease in NT-proBNP concentration was observed after rehabilitation in patients treated with PTCA. In the control group, the patients were not subjected to rehabilitation and a significant decrease in plasma NT-proBNP concentration was not observed. Also in the group of patients subjected to rehabilitation a significant increase in EF was observed, while in the control group after the period of observation EF practically did not change. Ginuzzi et al. investigated changes of NT-proBNP concentration in the group of patients after transmural myocardial infarction, who were included in the training programme. The interests of the authors focused on the effect of physical training on left ventricle dimension and its systolic function – postinfarction contractility disorders. Significant increase in end-diastolic volume and EF was observed as compared to the control group [23]. Condraads et al. observed a significant decrease in plasma NT-proBNP concentration in patients with postinfarction heart failure after rehabilitation with increasing training load at the end of the programme. A significant decrease in left ventricular end-systolic dimension was also observed [24]. The results of other studies also confirm beneficial effect of exercise training in patients after myocardial infarction. Numerous authors indicate that programmed physical exercise in this group of patients markedly increases left ventricular function after infarction, which is reflected by proportional increase in EF [25]. Improvement of myocardial contractility results from better metabolism of cardiomyocytes through restoration of balance in the range of FFA oxidation and simultaneous increase in the share of oxygen metabolism in ATP synthesis. Normal phosphorylation of high-energy residues increases energy reserves indispensable for activation of repair processes in damaged myofilaments and thus contributes to quicker restoration of normal systolic function of the damaged segment of the left ventricle. Opening of the artery responsible for myocardial infarction in the course of PTCA significantly improves perfusion of the ischaemic area. However, medium and small coronary vessels should be mentioned. They are responsible for blood supply to distant segments of the myocardium. The role of collaterals in the heart is emphasized particularly in relation to hypertrophic myocardium [26]. Furthermore, their importance also in non-hypertrophic myocardium exposed to extreme ischaemia during infarction before restoration of artery patency should not be underestimated. Physical exercise and regular controlled acceleration of heart rate in the course of rehabilitation of patients increases the secretion of vascular growth factors, intensifying at the same time angiogenesis. This process distributed in time contributes additionally to heart perfusion improvement after myocardial infarction [27]. The increase in EF in correlation with the decrease in NT-proBNP concentration observed in our study seems to confirm the regression of myocardial degeneration after infarction. The significant increase in exercise efficiency in group I after rehabilitation is clinical evidence of the improvement of left ventricular systolic function associated with rehabilitation. Such a dependency was not observed in group II.
Conclusions
The results of the study allow us to state that exercise training applied in patients after myocardial infarction within the range of cardiologic rehabilitation contributes to the improvement of left ventricular systolic function, which is reflected by increased EF with accompanying decrease in plasma NT-proBNP concentration.

References
1. Stein BC, Levin RI. Natriuretic peptides: Physiology, therapeutic potential and risk stratification in ischemic heart disease. Am Heart J 1998; 135: 914-23. 2. Nakao K, Ogawa Y, Suga S, Imura H, et al. Molecular biology and biochemistry of the natriuretic peptide system II: natriuretic peptide receptors. J Hypertens 1992; 10: 1111-4. 3. Holmes SJ, Espiner EA, Richards AM, Yandle TG, Frampton C. et al. Renal, endocrine and hemodynamic effect of human brain natriuretic peptide in normal man. J Clin Endocr Metab 1993; 76: 91-6. 4. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, et al. The prognostic value of b-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345: 1014-21. 5. Maeda K, Tsutamoto T, Wada A, Mabuchi N, Hayashi M, Tsutsui T, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 2000; 36: 1587-93. 6. Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes. Simultaneous assessment of troponin I, C-reactive protein and B-type natriuretic peptide. Circulation 2002; 105: 1760-3. 7. Verani MS, Hartung GH, Hoepfel-Harris J, Welton DE, Pratt CM, Miller RR. Effects of exercise training on left performance and myocardial perfusion in patients with coronary artery disease. Am J Cardiol 1981; 47: 797-803. 8. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454-60. 9. Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in patients with severe left ventricular dysfunction: hemodynamic and metabolic effects. Circulation 1988; 78: 506-15 10. Coats AJ, Adamopoulos S, Radaelli A, McCance A, Meyer TE, Bernardi L, et al. Controlled trial of physical training in chronic heart failure: exercise performance, hemodynamics, ventilation, and autonomic function. Circulation 1992; 85: 2119–31. 11. Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: a randomized trial JAMA 2000; 283: 3095-101. 12. Balady GJ, Ades PA, Comoss P, Limacher M, Pina IL, Southard D, et al. Core components of cardiac rehabilitation/secondary prevention programs: a statement for healthcare professional from the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation Writing Group. Circulation 2000; 102: 1069-73. 13. Opie LH, King LM. Glukose and glycogen utilization in myocardial ischaemia changes in metabolism and consequences for the myocyte. Moll Cell Biochem 1998; 180: 3-26. 14. Benzi RH, Lerch R. Dissociation between contractile function and oxidative metabolism in post-ichaemic myocardium. Circ Res 1992; 71: 567-76. 15. Ferrari R, Pedersini P, Bongrazio M, Gaia G, Bernocchi P, Di Lisa F, et al. Mitochondrial energy production and cation control in myocardial ischaemia and reperfusion. Basic Res Cardiol 1993; 88: 495-512. 16. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, et al. Symptomatic and asymptomatic left ventricular systolic dysfunction in urban population. Lancet 1997; 350: 829-33. 17. Kudo N, Gillespie JG, Kung L, Witters LA, Schulz R, Clanachan AS, et al. Heart contains an active 5`-AMP-activated protein kinase that is involved in the regulation of fatty acid oxidation. Circulation 1996; 92: 1771-7. 18. Kowalski J, Kosmider M, Baj Z et al. Plasma concentrations of selected cytokines in patients with unstable angina pectoris during percutaneous transluminal coronary angioplasty (PTCA). Int Rev Allergol Clin Immunol 1997; 3: 139-141. 19. Gao WD, Atar D, Backx PH, Marban E. Relationship between intracellular calcium and contractile force in stunned myocardium. Direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ Res 1995; 76: 1036-48. 20. Voci P, Mariano E, Pizzuto F, Puddu PE, Romeo F. Coronary recanalization in anterior myocardial infarction. The open perforator hypothesis. J Am Coll Cardiol 2002; 40: 1205-13. 21. Bazzino O, Fuselli JJ, Botto F, Perez De Arenaza D, Bahit C, Dadone J; PACS group of investigators. Relative value of N-terminal probrain natriuretic peptide, TIMI risk score, ACC/AHA prognostic classification and other risk markers in patients with non ST-elevation acute coronary syndromes. Eur Heart J 2004; 25: 859-66. 22. Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, et al.; Val-HeFT Investigators Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT) Circulation 2003; 107: 1278-83. 23. Giannuzzi P, Temporelli PL, Corra U, Gattone M, Giordano A, Tavazzi L. Attenuation of unfavorable remodeling by exercise training in postinfarction patients with left ventricular dysfunction: results of the Exercise in Left Ventricular Dysfunction (ELVD) trial. Circulation 1997; 96: 1790-7. 24. Conraads VM, Beckers P, Vaes J, Martin M, Van Hoof V, De Maeyer C, et al. Combined endurance/resistance training reduces NT-proBNP levels in patients with chronic heart failure. Eur Heart J 2004; 20: 1797-805. 25. Ades PA, Maloney A, Savage P, Carhart RL Jr. Determinants of physical functioning in coronary patients: response to cardiac rehabilitation. Arch Intern Med 1999; 159: 2357-60. 26. Ito N, Nitta Y, Ohtani H, Ooshima A, Isoyama S. Remodelling of microvessels by coronary hypertension or cardiac hypertrophy. J Mol Cell Cardiol 1994; 26: 49-59. 27. Niebauer J, Hambrecht R, Velich T, Hauer K, Marburger C, Kalberer B, et al. Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention: role of physical exercise. Circulation 1997; 96: 2534-41.