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Brain natriuretic peptide and NT-proBNP levels reflect pulmonary artery systolic pressure 1 in trekkers at high altitude.

Our objective was to evaluate the utility of the natriuretic peptides BNP (brain natriuretic 2 peptide) and NT-proBNP as markers of pulmonary artery systolic pressure (PASP) in trekkers 3 ascending to high altitude (HA). 20 participants had BNP and NT-proBNP assayed and 4 simultaneous echocardiographic assessment of PASP performed during a trek to 5150 m. PASP 5 increased significantly (p=0.006) with ascent from 24±4 to 39±11 mm Hg at 5150 m. At 5150 m 6 those with a PASP ≥ 40 mm Hg (n=8) (versus those with PASP <40 mm Hg) had higher post- 7 exercise BNP (pg/ml): 54.5±36 vs 13.4±17 (p=0.012). Their resting BNP at 5150 m was also 8 higher: 57.3±43.4 vs 12.6±13 (p=0.017). In those with a pathological ( ≥ 400 pg/ml) rise in NT- 9 proBNP at 5150 m (n=4) PASP was significantly higher: 45.9±7.5 vs 32.2±6.2 mm Hg 10 (p=0.015). BNP and NT-proBNP may reflect elevated PASP, a central feature of high altitude 11 pulmonary oedema, at HA. 12 14 15 16 17 18


Introduction
Large numbers of people trek to high altitude (HA) each year, of which a significant number 2 develop pulmonary hypertension and succumb to HA illnesses such as high altitude pulmonary 3 oedema (HAPE). Currently there is no useful bed-side blood test that can aid in the diagnosis of 4 pulmonary hypertension or HAPE. 5 The cardiac natriuretic peptides, BNP (active) and NT-proBNP (inactive), are derived from a 6 prohormone, proBNP, stored in cardiomyocytes (Hall 2005). Their release is stimulated 7 primarily by myocardial wall tension related to cardiomyocyte stretch and as such they are 8 classically associated with congestive cardiac failure (CCF) secondary to left ventricular 9 dysfunction (LVD) (Hall 2005). However, it is increasingly recognized that hypoxia may also

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The hypoxia of HA leads to pulmonary vasoconstriction, which in turn contributes to an increase 16 in PASP, which may be associated with elevated natriuretic peptides at SL. An exaggerated Early detection of HAPE is therefore challenging and any simple test with the potential to 3 facilitate early diagnosis and treatment could be life-saving. 4 Conventionally, assessment of PASP either requires invasive assessment, not practical in the 5 field, or non-invasive assessment using trans-thoracic echocardiography that requires a skilled 6 operator and expensive equipment not usually available on conventional expeditions to HA. BNP 7 and NT-proBNP can be assayed on a small venous blood sample and BNP results can be readily 8 available in the field with little expertise using a point-of-care (POC) testing device.

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Although we have previously reported an association between BNP and NT-proBNP and acute us to establish if NT-proBNP/BNP could also be driven by, and act as a marker for, an elevated 12 PASP in previously healthy individuals exposed to HA.

1
The study was approved by the Ministry of Defence Research Ethics Committee (MODREC), 2 UK and conformed to the standards set in the Declaration of Helsinki. All participants gave 3 written informed consent.  were studied immediately on arrival after a day of trekking ("post-exercise") and the following 11 morning at rest. 12 Echocardiography and venous blood samples (from antecubital fossa) were performed post-13 exercise and at rest at the main study altitudes. Oxygen saturation (digitally on warm hands at 14 rest) was measured using a Nellcor NP-20 pulse oximeter (Covidian, MA, USA). BNP was 15 assayed using a point-of-care analyzer (Biosite Triage Meter with BNP tests strips, Alere Ltd, 16 Cheshire, UK) in the field and NT-proBNP was assayed on frozen samples on return to the UK 17 using the Roche NT-proBNP assay (Roche Diagnostics, Mannheim, Germany). As NT-proBNP 18 is renally cleared renal function was assessed by serum creatinine. PASP was estimated from the processing was carried out by a consultant cardiologist (CB), who was blinded to any of the 1 other data, to ascertain PASP.

2
For statistical calculations the software package SPSS 14.0 was used. Parametric or non-3 parametric statistical tests were applied after performing the Shapiro-Wilks statistic. 4 Changes in dependent variables between altitudes were initially tested by Student's paired t test 5 or Wilcoxon signed ranks test. For independent variables an independent-samples t test or Mann 6 Whitney test was used. Either a within participants ANOVA or a Friedman test was performed to 7 investigate any serial changes in measures (eg PASP or BNP) with ascent. BNP and NT-proBNP  Spearman's rank correlation between BNP, NT-proBNP and PASP was performed, as was a 11 ROC (receiver operating characteristic) analysis to investigate the utility of the natriuretic 12 peptides in identifying a PASP >40 mmHg.

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A p value <0.05 was considered significant throughout. All data are reported as mean±SD (± 14 range where appropriate) except for figure 1 (mean±SEM).

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Participants were excluded from analysis once they took drugs to aid acclimatization. The main, novel, finding of this study is that at HA those with a markedly elevated PASP appear 2 to have higher BNP and NT-proBNP than those with a more moderate PASP.  14 diagnose CCF (>100 and >400 pg/ml respectively). The levels we report associated with PASP 15 ≥40 mm Hg are above the normal range, occasionally above the diagnostic level for CCF, and 16 consistent with those seen in other states of pulmonary hypertension.

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Only one previous study has examined the relationship between NT-proBNP and PASP at HA  reported an NT-proBNP of 12.9 pg/ml on arrival compared to the 301 pg/ml we recorded at a 21 very similar altitude using the same assay. A critical difference between these studies may be the 22 exercise stimulus involved: our participants trekked to 5150 m, as opposed to arriving at 5200 m 23 by vehicle (Toshner et al. 2008). The fact that they reported very similar PASP to that which we 1 observed suggests that exercise, which also increases PASP, may be a key factor in the rise in 2 NT-proBNP at altitude. This is supported by our group's previous work that has shown no rise in initial rise in BNP and NT-proBNP following exercise at SL or HA may be due to release of 1 proBNP from the small stored pool in cardiomyocytes. If there has been sufficient stimulus then 2 in hypoxic conditions there may then be rapid up-regulation of BNP gene transcription that 3 accounts for the persisting and elevated levels at rest. 4 It also makes physiological sense that the stressed and hypoxic myocardium should release BNP 5 as it induces a natriuresis and is a vasodilator thereby acting to reduce myocardial wall stress. 6 Infused BNP is known to attenuate hypoxaemia-induced increases in PASP and pulmonary 7 vascular resistance (Cargill and Lipwoth 1995) and BNP levels are also employed to guide 8 vasodilator therapy in pulmonary artery hypertension (Yap 2004). 9 We are not proposing that a high PASP is the sole determinant of a high BNP level at HA. BNP BNP but that there is some relationship between high PASP and a high BNP or NT-proBNP at 20 HA that may ultimately prove useful in detecting not only high PASP but also cases of HAPE.
Limitations to our study include that although high PASP is a critical factor in the 1 pathophysiology of HAPE our study does not include overt, clinical cases of HAPE. As such this 2 report can only record an association between BNP and NT-proBNP and high PASP. Further 3 work is needed to establish any relationship with subsequent HAPE. In addition, creatinine rose 4 statistically significantly and theoretically a change in renal function could effect NT-proBNP 5 levels (since NT-proBNP is renally cleared). However, since the absolute rise was marginal and 6 only 1 subject had a creatinine >125µmol/l (142 µmol/l) we feel this is unlikely to have a 7 significant effect on the overall levels of NT-proBNP and the findings of this study. 8 The correlation between PASP and BNP and NT-proBNP were moderate but highly significant 9 and the ROC analysis suggests that both natriuretic peptides should be further evaluated for their 10 utility in identifying a high PASP at HA in a larger cohort. While an NT-proBNP cut-off of 133 11 pg/ml that gives a sensitivity of 70% and a specificity of 83% for identifying a high PASP may 12 not be perfect, in the context of the cohort studied it is encouraging.

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In conclusion, HAPE is a serious condition with an incidence estimated at up to 4% at 4559m and as such, particularly with near-patient testing, may facilitate identification of a 1 pathophysiological state that without appropriate management may be life-threatening.      Table 1 Oxygen saturation, PASP, BNP and NT-proBNP with ascent to 5150 m in the Khumbu