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Cardiovascular Research 2004 63(2):256-263; doi:10.1016/j.cardiores.2004.04.019
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Copyright © 2004, European Society of Cardiology

Mechanoenergetic inefficiency in the septic left ventricle is due to enhanced oxygen requirements for excitation–contraction coupling

Ebrahim Aghajani*,a, Dag Nordhaugb, Christian Korvaldb, Tor Steensrudb, Kjell Husnesa, Ole Ingebretsenc, Arthur Revhauga and Truls Myrmelb

aDepartment of Digestive Surgery, University Hospital North Norway, Sykehusveien 38, N-9038 Tromsø, Norway
bDepartment of Cardiothoracic and Vascular Surgery, University Hospital North Norway, N-9038 Tromsø, Norway
cDepartment of Clinical Chemistry, University Hospital North Norway, N-9038 Tromsø, Norway

* Corresponding author. Tel.: +47-776-26000; fax: +47-776-26605. Email address: ebrahim.aghajani{at}fagmed.uit.no

Received 14 January 2004; revised 16 April 2004; accepted 19 April 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objective: Myocardial oxygen consumption (MVO2) in the septic myocardium is increased despite reduced left ventricular mechanical work. We investigated the mechanism behind this energetic inefficiency in the septic myocardium. Methods: To clarify whether energy consumption in basal metabolism or excitation–contraction (EC) coupling is elevated in the septic myocardium, we separated MVO2 used for these two processes. We assessed hemodynamics, left ventricular pressure–volume area, left ventricular MVO2, myocardial substrate metabolism and the inflammatory response in eight control pigs and in eight septic pigs receiving E. coli endotoxin. Using cardiopulmonary bypass (CPB), unloaded MVO2 was assessed before and after arrest of electromechanical activity using KCl infusions. Results: Unloaded MVO2 was significantly higher in the septic group compared to the control group (65.7±12.9 vs. 43.3±15.1 J·min–1·100 g LV–1, p<0.005), but basal MVO2 after 5 min KCl arrest was equal in the two groups. No difference in mechanical energy consumption or substrate metabolism was observed between groups. Conclusion: Basal MVO2 in the septic myocardium is not elevated, but an increased MVO2 for EC coupling is responsible for the energetic inefficiency.

KEYWORDS Endotoxins; Hemodynamics; Oxygen consumption; EC coupling; Septic shock


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The hemodynamic pattern in early septic shock is generally characterized by preserved or increased cardiac output (CO) and reduced systemic vascular resistance (SVR). An accompanying, but not fully understood, intrinsic myocardial dysfunction also contributes to circulatory derangements [1,2]. This myocardial dysfunction seems not to be caused by coronary hypoperfusion since coronary blood flow (CBF) is elevated and there is a net myocardial consumption of lactate [3,4]. However, although ventricular function is depressed, myocardial oxygen consumption (MVO2) in the septic myocardium is at least normal, and in some studies, MVO2 even exceeds control levels [3,5]. Hence, the septic myocardium is energetically inefficient.

We recently reported a 60% increase in MVO2 for non-mechanical work in the left pig ventricle during early E. coli sepsis [5]. In the present study, to further assess the mechanism for this energetic inefficiency, we separated this surplus energy consumption into basal metabolic oxygen consumption and energy used for excitation–contraction (EC) coupling. As shown, the increased energy consumption in this in vivo model of septic pig hearts is due to an increased oxygen consumption in electrical work or EC coupling [6].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Animals and surgical preparation
The experimental protocol was approved by the local steering committee of the Norwegian Animal Research Authority (NARA). All animals received care in compliance with the European Convention on Animal Care, and the investigation conformed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

We used an open chest pig model, described in detail earlier [5,7]. Briefly, 16 pigs (Norwegian Landrace, castrated males, 30–35 kg) were habituated in the animal department for 4–6 days and fasted overnight with free access to water. The pigs were premedicated with intramuscular ketamine (20 mg/kg, Warner Lambert Nordic, Sweden) and atropine (1 mg, Nycomed Pharma, Norway). Anesthesia was induced by intravenous pentobarbital sodium (10 mg/kg, Nycomed Pharma) and fentanyl (0.01 mg/kg, Pharmlink, Sweden) and maintained with continuous infusion of pentobarbital sodium (4.0 mg kg–1 h–1), fentanyl (0.02 mg kg–1 h–1) and midazolam (0.3 mg kg–1 h–1, Alpharma, Norway). Animals were tracheostomized, intubated and ventilated with 60% oxygen.

Coronary blood flow (CBF) was measured by transit time flow probes (CardioMed CM-4000, Medi-Stim, Horten, Norway) on the main stem of the right, the left anterior descending and the circumflex coronary arteries. A flow probe was also placed on the pulmonary artery for measurement of cardiac output (CO). A catheter was advanced to the great cardiac vein via the superior caval vein and the coronary sinus for myocardial venous blood sampling. A catheter was also inserted into the pulmonary trunk to measure mean pulmonary artery pressure (MPAP). Both femoral arteries were cannulated for measurements of mean arterial pressure (MAP) and blood resistivity (rho). Central venous pressure (CVP) was monitored through the right jugular vein. A 7 Fr balloon catheter was advanced to the inferior caval vein, for preload alterations. A 7 Fr, 12-electrode, dual-field, combined pressure–volume conductance catheter (Sentron, AC Roden, The Netherlands) was advanced through the left carotid artery into the left ventricle (LV) for assessment of left ventricular pressure–volume relationships. Heparin (2500 IU) was administered prior to venous catheterization. Conductance-derived volumes were adjusted for parallel conductance (Vp, non-LV cavity-derived conductance) determined by the hypertonic saline technique [5,7,8]. Left ventricular conductance and pressure signals were sampled and digitized at 250 Hz during 10–12-s runs (Leycom Sigma 5 and Conduct PC, CD Leycom, Leiden, The Netherlands) and stored for computerized calculations (CircLab 4.8, Leiden).

The bladder was drained by cystostomy and the diuresis was carefully measured every hour before urine samples for biochemical analyses were drawn. Blood volume was maintained by infusion of 0.9% NaCl enriched with glucose (1.25 g·l–1). The infusion rate was 20 ml kg–1 h–1 throughout the experiment. Rectal temperature was monitored and maintained constant near 37.5 °C throughout the experiment with a heating pad or ice bags. After the surgical preparation, the animals were allowed to stabilize for 30 min.

2.2. Experimental protocol
In septic pigs (n=8), an iv endotoxin infusion, E. coli lipopolysaccharide (serotype 0111; B4; Sigma, St Louis, MO, USA) dissolved in saline, was started at 0 h at a rate of 0.5 µg kg–1·h–1 and was increased gradually over 30 min until reaching 5 µg kg–1·h–1. The endotoxin infusion was discontinued after 1 h, or if MPAP exceeded 50 mm Hg. In this experimental series, each septic pig was matched with a control animal with an identical heart rate. These control pigs (n=8) were paced from the right atrium using an identical heart rate to their matched septic pigs throughout the experiment.

After the stabilization period, a set of baseline data, including blood analyses and mechanoenergetic variables, was recorded. In addition, repeated biochemical analyses and mechanoenergetic variables were measured 2 h (T1) after the start of endotoxin or saline infusion. Measurements included rectal temperature and simultaneous arterial and cardiac venous blood sampling for assessment of tumor necrosis factor alpha (TNF-{alpha}), interleukin-1 (IL-1), glucose, free fatty acid (FFA), lactate, Hb, and white blood cell count (WBC). After T1 measurements were taken, the animals received 10000 IU heparin intravenously.

Cardiopulmonary bypass (CPB) was initiated in order to assess oxygen consumption in both the completely unloaded and arrested heart (the CPB circle is outlined in Fig. 1). The ascending aorta was cannulated using a 9 Fr arterial cannula with a side branch for cardioplegia infusion. Venous return was through a 28 Fr two-stage cannula in the right atrium. The extracorporeal circuits were primed with Ringers acetate solution 37 °C. Blood gasses were maintained using a membrane oxygenator (Monolyth, Sorin Biomedica, Saluggia, Italy) and a baby-sized reservoir. CPB was initiated with flow rates sufficient to give an MAP of 50 mm Hg, and the left ventricle was vented using a 9 Fr needle inserted through the apex. Unloaded MVO2 was measured by simultaneous arterial and cardiac venous blood samples for oxygen saturation measurement, and LV coronary blood flow in the empty beating LV. To assess basal metabolism in the empty arrested heart with no electromechanical work, the ascending aorta and the inferior and superior caval veins were clamped and 30 ml KCl (1 mol/l) was given through the side branch of the arterial cannula until the heart stopped. Blood samples for oxygen saturation measurements were taken after 5 min at the stable LV coronary blood flow rate. During this period, perfusion pressure was adjusted to give approximately the same flow rates as under unloaded conditions. If the heart resumed electrical activity, a bolus of KCl was given.


Figure 1
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  		Fig. 1 Schematic diagram showing the cardiopulmonary bypass circuit as well as the cardioplegia circuit. Note that by clamping the ascending aorta distally to the arterial cannula, only the heart was perfused during basal metabolism measurements. These were done as the final part of the experiments.

 
Staining of the left coronary artery perfusion area (Evans blue, 1%) was used to relate the weight of the myocardium to coronary perfusion. Cardiac arrest was then induced at the end of the experiment using a bolus of KCl (1 mol/l). The weights of the entire LV and stained myocardium were used for normalization of flow and energetic indexes to weight.

2.3. Determination of substrate oxidation
In order to assess the influence of metabolic substrates on left ventricular oxygen consumption, infusion of isotopes was started 45 min before baseline with a bolus of 30 ml h–1 for 15 min, and continued by steady-state infusion of 8 ml h–1 throughout the experiment. We used [3H]oleate (NET-289 [9,10-3H(N)]-oleic acid) and [14C]glucose (NEC-042X D[14C(U)]-glucose) (NEN Research Products, DuPont, Germany), and (nec [3H]lactate). The substrate oxidation rate in four septic pigs and their matched controls were monitored by 14C-glucose/3H-oleate. The remaining four septic pigs and their controls were monitored with 3H-lactate. Details of trapping technique, and analysis of isotope degradation products (3H2O and 14CO2), have been described earlier [9].

2.4. Assessment of inflammatory mediators and stress-response
To determine the systemic inflammatory response in this model, the production of the mediators TNF-{alpha}, IL-1, and WBC were analyzed at both baseline and T1. TNF-{alpha} and IL-1 levels were measured with enzyme-linked immunosorbent assay kits specific for pigs (TNF-{alpha}, Nordic BioSite, Täby, Sweden and IL-1B, BioSource International, California, USA). The minimum detectable dose for TNF-{alpha} and IL-1 was >6.0 and >15 pg·ml–1, respectively. The systemic stress-response in the septic state was determined by measuring catecholamine output in the urine [HPLC with fluorescence detection HPLC and electrochemical detection using CleanRep-Complete Kit (Recipe, Munich, Germany)].

2.5. Other chemical analyses
Blood gases were analyzed with a standard blood gas lab (BGM 1312, Allied Instrumentation Laboratory). Hemoglobin was analyzed from EDTA blood with a cell analyzer (CA 460, Medonic). Plasma levels of glucose and FFA were determined on a centrifugal analyzer (Cobas Fara II, Roche Diagnostica; kits and quality controls from Boehringer Mannheim, Germany). Lactate was analyzed on a Bio-Rad aminex HPX-87H HPLC column and UV detection [10].

2.6. Calculation
Left ventricular contractility was assessed using several indices. Load-insensitive contractility indexes were calculated on a beat-to-beat basis from PV data recorded during 12-s inferior caval vein occlusions (VCO). The slope of the end-systolic pressure–volume relation (Ees) and slope of the stroke work–Ved relation (PRSW) have been described in details elsewhere [6,11]. We assessed Ees both as the slope of linear ESPVR and the slope of a fitted second order polynomial curve (y=ax2+bx+c) in V0 [12].

Myocardial oxygen consumption (MVO2) was assessed as ml O2·min–1·100 g LV–1 from LV blood flow (ml·min–1·100 g–1) and arterial to cardiac venous O2-content difference. When calculating LV mechanoenergetics, MVO2 was converted to joules (1 ml O2=20.2 J) and corrected for heart rate (HR). Stroke work (SW, mm Hg·ml) was assessed from the area of the pressure volume loop. The area bounded by the ESPVR and end-diastolic pressure–volume relationship (EDPVR) bordered by the PV-loop represents potential energy (PE). The PVA was calculated as the sum of SW and PE (mm Hg·ml), and converted to J·beat–1·100 g–1 using the constant 1.33·10–4 J·mm Hg–1·ml–1. The preload-varied steady-state MVO2 and PVA points assessed at each sampling period were used to obtain a MVO2–PVA relationship by linear regression [6]. Systemic vascular resistance (dyne·s·cm–5) was calculated as: SVR=(MAP–CVP)/CO·80. Diastolic LV function was measured by the time constant of isovolumic LV pressure decay (tau) and Eed, the slope of a linear EDPVR. For calculation details and equations, see our earlier studies [5,7,9].

2.7. Statistical analysis
All data are shown as mean±S.D. unless stated otherwise. Linear, curvilinear and exponential relationships were estimated by least squares fit regression, and all data were further analyzed in a statistical software package (SPSS 11.0, SPSS, Chicago, IL). Overall differences between and within groups were tested using analysis of variances for repeated measurements (RANOVA). We tested for within-group time effects, and time x group interaction. A non-parametric test (Wilcoxon sign rank) was used when non-normal distribution was observed (such data are presented as median with 95% confidence limits). Significance was assumed at p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Hemodynamic variables and left ventricular contractility
At baseline, i.e., before the infusion of endotoxin, there were no differences between the control and septic groups in any hemodynamic or other measured variables (Tables 1 and 2)Go. The hemodynamic alterations in septic pigs were characterized by reduced MAP, increased HR, unaltered CO, reduced SVR, and an increased MPAP. By atrial pacing, the design of the experiment aimed to match the control pigs to the increased heart rate due to E. coli sepsis. The control pigs therefore had heart rates equal to the septic pigs. Apart from this, the controls had only minimally altered MAP, CO, SVR, and MPAP throughout the experimental period (from baseline to T1). In two pigs, short periods of critical hypotension were seen during the first 30 min of endotoxin infusion. However, they recovered quickly with a bolus of 0.25 mg adrenaline intravenously. The same adrenaline bolus was given to their matched control pigs at the same time point.


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  		Table 1 General hemodynamic variables

 

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  		Table 2 Left ventricular measurements and urine catecholamine output

 
Correlation coefficients for left ventricular elastance (Ees), both linear and curvilinear, and pre-load recruitable stroke work (Mw), ranged from 0.97 to 0.99 in both groups. There was an increase in Ees in both groups after induction of sepsis or pacing tachycardia, and both Ees and Mw were equal in the two groups. The V0 value was shifted to the right in the sepsis group but was not significantly different from controls (Table 2). Curvilinear—Ees in the control group (5.83±0.9 and 6.93±0.9 mm Hg·ml–1, baseline vs. T1, respectively) was not significantly different from the septic group (5.82±1.3 and 7.16±1.4 mm Hg·ml–1, baseline vs. T1, respectively). Curvilinear—V0 in the control group (–1.35±6.7 vs. –2.49±3.4 ml, baseline vs. T1, respectively) was not significantly different from the septic group (–3.16±5.1 vs. –0.86±3.9 ml, baseline vs. T1, respectively). However, both the maximum first derivative of pressure rise (dP/dtmax) and SW were reduced in the septic group compared to the control animals (Table 2).

Diastolic function was unaltered in both groups throughout the experiment. The tau value in the control group (31.7±3.5 vs. 29.1±4.2 ms, baseline vs. T1, respectively) was not significantly different from the septic group (30.5±4.1 vs. 27.9±4.4 ms, baseline vs. T1, respectively). The slope of the linear EDPVR (Eed) did not decrease significantly from 0.27±0.05 to 0.24±0.07 mm Hg·ml–1 in the septic group or from 0.26±0.1 to 0.22±0.1 mm Hg·ml–1 in the control group.

3.2. Biochemical mediators (white blood cells (WBC), TNF-{alpha}, IL-1, and catecholamines)
Detectable IL-1 levels were present in only a few of the animals at baseline. Both IL-1 and TNF-{alpha} increased significantly in the sepsis group 2 h after endotoxin administration (Table 3). There was no difference in arterial to coronary venous TNF-{alpha} concentration to indicate that the heart produced TNF-{alpha} during early sepsis. The white blood cell count was decreased in the septic pigs, and all these parameters document the systemic inflammatory response in the septic animals. Table 2 shows the urine catecholamine levels in the experiment. There were no significant changes over time between the groups.


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  		Table 3 Biochemical markers of inflammation

 
3.3. Energetics
The relationships between oxygen consumption and the total mechanical work produced by the left ventricle (MVO2–PVA) were highly linear in both control and sepsis groups at baseline and T1 (range 0.94–0.96). The reduction of left ventricular total mechanical energy output (PVA) in the septic animals was significantly higher than controls. In the septic group at T1, the y-axis intercept (i.e., unloaded MVO2) of the MVO2–PVA relationship was increased significantly compared to the control group (p<0.001) (Table 4).


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  		Table 4 Left ventricular energetic

 
The unloaded MVO2, representing the non-mechanical energy consumption consisting of both basal metabolism and excitation–contraction coupling, obtained in the empty beating LV, was significantly higher at T1 in the septic group compared to the control group (65.7±12.9 and 43.3±15.1 J·min–1·100 g LV–1, respectively) (Fig. 2). KCl arrested basal metabolic MVO2 (non-electrical metabolism) at 5 min was (8.3±5.0 J·min–1·100 g LV–1) in septic hearts. This value did not significantly differ from that in the control group (11.8±4.8 J·min–1·100 g LV–1). Therefore, MVO2 for electrical work or excitation–contraction coupling was significantly higher in the septic group and responsible for increased unloaded MVO2 (Fig. 2).


Figure 2
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  		Fig. 2 Left ventricular non-mechanical oxygen consumption (unloaded MVO2), i.e., excitation–contraction (EC) coupling plus basal metabolism at T1 in the sepsis and control groups. Error bars indicate S.D. Basal MVO2 after 5-min KCl arrest (basal metabolism only) was unchanged between groups. The increased MVO2 in septic myocardium is therefore due to EC coupling only (p<0.005, paired t-test).

 
3.4. Substrate metabolism
Table 5 shows arterial levels, left ventricular uptake and oxidation rates of glucose, FFA, and lactate. During sepsis, systemic arterial lactate levels increased at T1 (p=0.003), but left ventricular lactate uptake and oxidation rates did not change significantly between groups despite large increases in numerical values in the septic animals. There were no significant changes in arterial to coronary venous lactate concentration in the septic group at baseline and T1 (0.70±0.58 and 0.95±0.61 mmol·l–1, respectively), and there were also no significant differences in other substrate parameters between the groups.


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  		Table 5 Arterial levels, uptake and oxidation rates of main myocardial substrates

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
This study is the first to indicate that an increased energy consumption in excitation–contraction coupling can explain the inefficient energy state in the septic heart. In the septic animals, we observed a substantial increase in non-mechanical oxygen consumption (unloaded MVO2) and an unchanged basal metabolism. Thus, in this clinically relevant model, the LV is in a state of considerable "oxygen waste" due to an increased energy utilization for electronic work, a finding that may have implication for our understanding and treatment of sepsis.

Basal MVO2 in non-ischemic, arrested hearts from different species varies from 2.0 to 3.5 ml·min–1·100 g–1 [13]. These different levels depend on several factors such as time of measurement after cardiac arrest, perfusion pressure, temperature, and type of arrest, conditions that were comparable between the groups in our study.

Unloaded MVO2 (non-mechanical MVO2) consists mainly of oxygen used for EC coupling (2/3 of unloaded MVO2) and basal metabolic processes. A decreased efficiency of the mitochondria could explain part of inefficient oxygen consumption, but several studies have demonstrated that myocardial ATP is well preserved during sepsis [14]. Furthermore, the contractile efficiency was unaffected, indicating unaltered mitochondrial oxidative phosphorylation and ATP consumption for myofibrillar cross-bridge cycling. "Oxygen waste" may also be present in response to inotropic drugs [6] or during an extremely high rate of fatty acid oxidation, a setting where increased oxygen consumption is likely to be due to an increased energy demand of basal metabolic processes [7]. We could, however, neither show an increased inotropic state nor presume an increased rate of fatty acid utilization in the septic animals relative to their matched controls. Although not significant, our measurements do indicate an increased consumption of lactate in the septic myocardium, in agreement with the previous reports [3]. Such a preference for lactate would, if anything, reduce the oxygen cost of metabolism due to the high P/O ratio for lactate. As stated, no indication for increased fatty acid consumption was observed, and an overall metabolic energetic disadvantage was therefore not induced [7]. Also, since there was no difference in arterial to coronary venous lactate concentration in the septic group, myocardial metabolism was aerobic in sepsis, and cellular hypoxia cannot explain any contractile derangement.

In the septic state, temperature may have a key impact on MVO2 alone, as increasing body temperature increases MVO2 by 10–13% per degree. The identical temperature in the two groups in this study excludes this explanation of increased unloaded MVO2.

Although the precise mechanism for the increased oxygen used for EC coupling in this study remains unclear, it could theoretically occur in sarcoplasmatic Ca2+-ATPase (SERCA) and/or sarcolemmal Na+/K+-ATPase. Whether an impaired Ca2+ uptake in sarcoplasmic reticulum or a futile calcium cycling can be found in the septic myocardium [15] is unclear at the present time.

4.1. Model considerations
The endotoxin challenge to the animals induced a systemic response characterized by tachycardia and increased MPAP, unchanged CO, and a reduced SVR and MAP. These acute effects mark a severe hemodynamic derangement affecting both the heart and the peripheral circulation. Pulmonary vasoconstriction during early endotoxemia (0–2 h) appears to be mediated by thromboxane A2 [16,17]. The combined increase in MPAP and HR gave reduced LV filling and stroke volume. Combined with the reduced MAP, these alterations induced a reduced LV mechanical energy output (PVA) in the septic animals.

We did not observe any fall in Ees or Mw to indicate a reduced inotropic state of the LV in sepsis. This contrasts with most, but not all, previous publications in this field. Some studies have reported decreased LV contractility [16,18], while others have shown no change [19] or even increased LV contractility [20] in early sepsis. These disparities may reflect differences in experimental methodology, species, anesthetic regimens, and phases of the septic response being studied. Although the Ees has been shown to be curvilinear during extreme alterations of pre and/or afterload [21], no additional information concerning changes in LV contractility was achieved using a curvilinear approach to our data. However, both the septic and control groups had a marked increase in heart rate, and the Ees index is particularly sensitive to tachycardia demonstrating a marked force–frequency response [22]. Furthermore, we observed a reduced dP/dtmax and SW in the septic group, and an unchanged or even increased Ees could therefore in fact be a "hidden" reduced contractile function in animals with marked tachycardia and a possible state of low filling. Importantly, however, there was no difference in Ees between control and septic animals thereby ruling out a difference in contractility being the reason for the oxygen waste in the septic hearts.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
We have shown that endotoxemia increases energy for excitation–contraction coupling. In the treatment of septic shock, inotropic agents yield short-term hemodynamic improvement, but they also increase MVO2 further by increasing oxygen utilization for Ca2+ handling. The large increase in MVO2 caused by sepsis and pressors in conjunction is particularly critical in patients with coronary artery disease since the energy supply to the myocardium is limited. To what extent this mechanoenergetic inefficiency contributes to the organ dysfunction and myocardial failure in lethal septic states is presently unknown.


   Acknowledgements
 
This study was supported in part by a grant from the Research Council of Norway. We would like to tank the staff at the Surgical Research Laboratory and special analysis section of the Department of Clinical Chemistry at the University of Tromsø for their technical assistance.


   Notes
 
Time for primary review 29 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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