Accepted Manuscript

Title: Iron Deficiency in COPD Associates with Increased

Pulmonary Artery Pressure Estimated by Echocardiography

Author: Louis L. Plesner Mikkel M. Schoos Morten

Dalsgaard Jens P. Goetze Erik Kjøller Jørgen Vestbo Kasper
Iversen

PII: S1443-9506(16)30230-X
DOI: http://dx.doi.org/doi:10.1016/j.hlc.2016.04.020
Reference: HLC 2122

To appear in:

Received date: 31-1-2016

Revised date: 6-4-2016
Accepted date: 17-4-2016

Please cite this article as: Plesner LL, Schoos MM, Dalsgaard M, Goetze JP, Kjøller E,
Vestbo J, Iversen K, Iron Deficiency in COPD Associates with Increased Pulmonary
Artery Pressure Estimated by Echocardiography, Heart, Lung and Circulation (2016),
http://dx.doi.org/10.1016/j.hlc.2016.04.020

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Iron Deficiency in COPD Associates with Increased Pulmonary Artery Pressure Estimated by

Echocardiography

Louis L. Plesner MB1, Mikkel M. Schoos MD PhD 2, Morten Dalsgaard MD PhD1, Jens P. Goetze

MD DMSc3, Erik Kjøller MD DMSc1, Jørgen Vestbo MD DMSc4, Kasper Iversen MD DMSc1

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Department of Cardiology, Herlev Hospital, Copenhagen University Hospital, Copenhagen,

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Denmark.
2
Department of Cardiology, Roskilde Hospital, Copenhagen University Hospital, Roskilde,

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Denmark
3
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital,

Copenhagen, Denmark.
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Centre for Respiratory Medicine and Allergy, Manchester Academic Health Science Centre.

University Hospital South Manchester NHS Foundation Trust and the University of Manchester,
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Manchester, UK.
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SHORT TITLE: Iron status and pulmonary artery pressure in COPD

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CORRESPONDING AUTHOR: Louis Lind Plesner, Department of Cardiology, Herlev Hospital,

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Herlev Ringvej 75, DK-2730, Herlev, Denmark TELEPHONE: 0045 2294 8550 E-MAIL:

louislindplesner@gmail.com.
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FUNDING: This work was performed without external funding.

ABBREVIATIONS:

ID: Iron deficiency.

SPAP: Systolic pulmonary artery pressure.

TR Vmax: Tricuspid regurgitation maximum velocity.

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ABSTRACT

Objectives

Iron deficiency (ID) might augment chronic pulmonary hypertension in chronic

obstructive pulmonary disease (COPD). This observational study investigates the

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association between ID and systolic pulmonary artery pressure estimated by

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echocardiography in non-anaemic COPD outpatients.

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Methods

Non-anaemic COPD patients (GOLD II-IV) with no history of cardiovascular disease

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were recruited from outpatient clinics. Iron deficiency [d1]was defined as ferritin < 100

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μg/L. Pulmonary artery pressure was estimated from the tricuspid regurgitation maximum

velocity (TR Vmax). TR Vmax indicative of pulmonary hypertension was considered present
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for values ≥ 2.9 m/s.

Results
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In a total of 75 included patients, 31 (41%) had ID. These patients had a significantly
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higher TR Vmax (3.02 vs. 2.77 m/s, p=0.01) and lower diffusion capacity of carbon

monoxide (40% vs. 50% of predicted, p<0.01), though similar in age, sex, body mass
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index, pack years, FEV1 and high-sensitive CRP (p>0.05). Ferritin inversely correlated
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with TR Vmax in ID patients (-0.37 (p=0.04)). The prevalence of TR Vmax ≥ 2.9 m/s was

twice as high in patients with ID (58% vs. 29%) and odds ratio of pulmonary hypertension
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in ID (compared to no ID) was 3.3 (95% CI 1.3-8.6, p=0.015).

Conclusion

Iron deficiency in non-anaemic COPD patients was associated with a modest increase in

systolic pulmonary artery pressure and limitation of diffusion capacity.

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KEYWORDS

Chronic obstructive pulmonary disease, Iron deficiency, Pulmonary hypertension,

Echocardiography, Systolic pulmonary artery pressure, Ferritin.

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INTRODUCTION

Chronic pulmonary hypertension increases mortality and risk of hospitalisation in COPD

and is partly attributable to hypoxic pulmonary vasoconstriction [1]
. Studies have shown

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that iron supplementation alleviates 40-65% of the rise in systolic pulmonary artery

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pressure (SPAP) during hypoxia and iron chelation increases SPAP with 4-5 mmhg during

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normoxia in healthy humans
[ 2–4]
. Up-regulation of hypoxia inducible factors

subsidiary to iron depletion may augment hypoxic pulmonary vasoconstriction [2–4]
.

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Several other mechanisms may exist for iron to affect the pulmonary vasculature [5]
.

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Paradoxically, one interventional study in rats has found iron chelation protective against

pulmonary remodelling during severe hypoxia [6]
while another found severe ID during
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normoxia to increase SPAP and right ventricular remodulation [7]
. We examined the

association between iron status and echocardiographic parameters including pulmonary

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artery pressure in non-anaemic COPD outpatients.

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MATERIAL AND METHODS

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This is an observational study of a previously described cohort of COPD outpatients with

no history of cardiovascular disease [8]
. The COPD diagnosis was made according to
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GOLD criteria. Transthoracic echocardiography (Vivid 7, GE Healthcare) was performed

and lung function was assessed with spirometry, body plethysmography and diffusion

capacity of carbon monoxide during a single breath (DLCO). Six minute walking distance

(6MWD) was assessed and peripheral oxygen saturation (SpO2) was measured with pulse

oximetry. Detailed methods of echocardiographic measurements have been previously

described [8]
. Left ventricular ejection fraction (LVEF) was evaluated by Simpson’s

biplane method. Systolic pulmonary artery pressure was assessed using the peak systolic

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velocity of the tricuspid regurgitation jet (TR Vmax). TR Vmax indicative of pulmonary

hypertension was considered present for values ≥ 2.9 m/s [9]
. We excluded patients with

congestive heart failure (CHF) (defined as LVEF < 50% or restrictive left ventricular

filling pattern) or haemoglobin < 8.0 mmol/l. The study was approved by the local ethics

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committee (H-A-2008-138). We quantified serum concentrations of ferritin, transferrin

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saturation (TSAT) and high-sensitive CRP (HsCRP) using an automated platform

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(COBAS, Roche Diagnostics). Iron deficiency was defined as ferritin < 100 μg/L [10]
.

Continuous variables were compared using Students t-test (normally distributed data) or

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Mann-Whitney U test (non-normally distributed data), and categorical values using chi-

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square test. Serum ferritin levels were non-normally distributed after log transformation so

non-parametric tests were used to assess correlations (Spearman’s rho). Differences were
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considered statistically significant at p0.05. Calculations were done with SPSS 22.0

(IBM corporation, USA).

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RESULTS
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Twenty-six of 101 included patients were excluded due to CHF (4 patients), no available
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TR jet measurement (7), no biomarker analysis (1) or haemoglobin < 8.0 mmol/L (14). In

75 remaining patients; mean age was 69 years and 44% were male. Five patients were in
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GOLD class I (6.6%), 25 in GOLD II (32%), 35 in GOLD III (46%) and 8 in GOLD IV

(10.5%). Mean FEV1 was 48.2% of predicted.

Iron deficiency was present in 31 patients (41%) who had significantly higher TR Vmax,

lower DLCO, and higher residual volume (RV) (Table 1). There were no associations with

ID and age, pack years, HsCRP, 6MWD, SpO2 or other lung function indices (p>0.05 for

all). No parameters of left or right ventricular function other than TR Vmax associated

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significantly with ID. Iron deficiency was present in none of GOLD I patients, 48% of

GOLD II, 41% of GOLD III and 43% of GOLD IV patients (p=0.26). TR Vmax > 2.9 m/s

indicative of pulmonary hypertension was present in 31 patients (41%); 18 (58%) of ID

patients had TR Vmax > 2.9 m/s versus 13 (29.5%) in the iron sufficient. Odds ratio (OR)

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of pulmonary hypertension in iron deficient compared to iron sufficient was 3.3 (95% CI

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1.3-8.6, p=0.015).

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There was a significant negative association between ferritin and TR Vmax (Spearman's rho

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= -0.28, p=0.02,), which was stronger in ID patients (-0.37, p=0.04, n=31). The most iron

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deficient had the highest TR Vmax, and patients with ferritin between 69-100 μg/L had

similar values as iron sufficient (Figure 1). This relationship was not seen for DLCO.
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However, DLCO correlated with TR Vmax (Pearson’s r = 0.46, p<0.001) (Supplementary

Figure S1). Ferritin did not correlate with FEV1, haemoglobin, RV or 6MWD (0.01,
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p=0.974) (0.02, p=0.90), (-0.18, p=0.13) (0.13, p=0.27), respectively. In the lowest half of
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ID patients (ferritin < 69 μg/L, median ferritin 49 μg/L, n=15), TSAT was significantly

lower than in the highest half (ferritin 70-100, median ferritin 84 μg/L, n=16): TSAT:
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18.2% and 23.9% (p=0.04). The correlation between TSAT and ferritin in ID patients was
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0.364 (p=0.04).
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DISCUSSION

Iron deficiency might augment pulmonary hypertension in COPD since the human

hypoxic vasoconstrictory response has been shown to depend on iron [11]. One study is

currently investigating the response of iron on functional outcomes in COPD [12].

However, the association between iron status and echocardiographic indices of pulmonary

hypertension could have potential clinical significance and should be further investigated,

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preferably using invasive measurements. Studies should ultimately determine whether iron

supplementation reduces SPAP in iron deficient COPD patients.

Intravenous iron improves functional outcomes in CHF patients with ID and underlying

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mechanisms are unclear [8]. No studies have yet investigated the effects of ID on

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pulmonary pressure or right heart function in CHF. A small study of 15 patients with ID

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and idiopathic pulmonary arterial hypertension showed improvement in quality of life and

6MWD with iron supplementation, however no data on pulmonary pressure was reported

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[14]
.

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There is no consensus on how to define ID in COPD. One recent study of ID in stable

COPD patients used a stricter definition including soluble transferrin receptor and found a
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prevalence of 18% and a median ferritin of 28 μg/L in ID patients [11]
. We might

overestimate the prevalence of ID with a cut-off of ferritin < 100 μg/L and mean TSAT
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was only < 20% in patients with lowest ferritin (<69 μg/L) indicating restricted iron
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delivery to tissues might only be present in these patients. In CHF, a diagnosis of

functional ID is made with ferritin between 100-300 μg/L and TSAT < 20% [13]
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Though functional ID can be present in COPD [15]
this cut-off has not been sufficiently
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validated in COPD patients and a study is ongoing [12]
. TR Vmax is the preferred non-

invasive method for estimation of SPAP in patients with COPD [1]
, though lung
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hyperinflation makes this method less feasible in these patients. Low haemoglobin levels

might increase TR Vmax due to increased cardiac output, but haemoglobin was not

associated to TR Vmax. Further limitations include the relatively small sample size of

mainly GOLD II and III patients and the cross-sectional study design.

CONCLUSION

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Iron deficiency was associated with a modest increase in pulmonary pressure measured by

echocardiography and limitation of diffusion capacity in stable non-anaemic COPD

patients without cardiovascular disease.

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AUTHOR DISCLOSURE

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All authors declare no conflicts of interest regarding the submitted article. Dr. Vestbo

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reports personal fees from GlaxoSmithKline, personal fees from Chiesi Pharmaceuticals,

personal fees from Boehringer-Ingelheim, personal fees from Novartis, personal fees from

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AstraZeneca, all outside the submitted work.

CONTRIBUTIONS
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LP wrote the manuscript and performed the statistical analyses. LP, MS, MD, KI and JPG

participated in the acquisition of data. EK, KI and JV participated in the interpretation of

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data. LP and KI had the original idea for the study. All authors critically revised the
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manuscript for intellectual content and approved the final version.

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iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized

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increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J

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4. Balanos GM, Dorrington KL, Robbins PA: Desferrioxamine elevates pulmonary

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pulmonary vascular remodeling. Free Radic Biol Med 2012, 53:1738–47.

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7. Cotroneo E, Ashek A, Wang L, Wharton J, Dubois O, Bozorgi S et al.: Iron

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homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular

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9. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A et al.: 2015 ESC/ERS

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Stable COPD Patients [clinicaltrials.gov/show/NCT02416778].
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13. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P: Iron
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deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J

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14. Ruiter G, Manders E, Happé CM, Schalij I, Groepenhoff H, Howard LS et al.:

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iron deficiency. Pulm Circ 2015, 5:466–72.

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the Potential Role of Iron Deficiency. COPD 2016, 13:100–9.

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TABLE 1: Association between clinical, spirometric and echocardiographic parameters

and presence of iron deficiency in patients with chronic obstructive pulmonary disease

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All variables presented as means unless specified. LVEDDi: left ventricle end-diastolic

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diameter indexed, LVESDi: left ventricle end-systolic diameter indexed, BSA: body

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surface area, E/A ratio: ratio of early to atrial transmitral diastolic filling, e': tissue-

Doppler derived early diastolic velocity, DT: decelleration time of transmitral flow, GLS:

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global longitudinal strain, S' (RV): tissue-Doppler derived systolic velocity in right

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ventricle free wall, RA: right atrium, TAPSE: tricuspid annular plane systolic excursion,

TR Vmax: tricuspid regurgitation maximum velocity.

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 All patients ID present ID absent p-value
(n=75) (n=31) (n=44)
Age, years (SD) 69.4 (9) 69.7 (8) 69.1 (9) 0.81
Male sex, n (%) 33 (44) 12 (39) 21 (48) 0.28
Body Mass Index, kg/m2 (SD) 24 (5) 23 (5) 26 (6) 0.04
Smoking, pack years (SD) 39 (17) 38 (18) 42 (16) 0.43
6MWD, metres (SD) 417 (107) 388 (108) 431 (109) 0.10

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SpO2, median % (IQR) 95 (93-96) 95 (92-96) 94 (93-96) 0.42

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TSAT%, percentage (SD) 23 (8) 21 (8) 24 (8) 0.17
Ferritin, μg/L median (IQR) 103 (70-203) 69 (52-84) 176 (139-251) <0.01

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Haemoglobin, mmol/L median 8.9 (8.4-9.3) 8.6 (8.2-9.1) 9.1 (8.5-9.4) 0.20
(IQR)
HsCRP, mg/L median (IQR) 2.7 (1.2-5.8) 2.6 (1.0-5.5) 2.9 (1.3-6.2) 0.48

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Pulmonary function
FEV1, % predicted value (SD) 49 (16) 45.9 (14) 51.1 (18) 0.16
FVC, % predicted value (SD) 85 (19) 83 (19) 88 (20) 0.25

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TLC, % predicted value (SD) 122 (21) 127 (21) 120 (21) 0.20
GOLD class III-IV, n (%) 44 (59) 18 (58) 26 (59) 0.94
DLCO, % predicted value (SD) 49.8 (16) 40.2 (14) 51.4 (16) <0.01
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RV, % predicted value (SD) 184 (54) 201 (55) 172 (50) 0.03
Left ventricular function
LVEDDi, mm/BSA, (SD) 25.0 (3.4) 25.5 (3.4) 24.7 (3.5) 0.39
LVESDi, mm/BSA, (SD) 16.7 (2.8) 17.6 (2.8) 16.2 (2.7) 0.08
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LVEF, % (SD) 64 (8) 65 (10) 64 (8) 0.50

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E/A ratio (SD) 0.95 (0.5) 1.0 (0.5) 0.91 (0.5) 0.41
Lateral e', cm/s (SD) 9 (3) 9 (2) 9 (3) 0.36
E/e' ratio (SD) 8.9 (2.5) 8.7 (2.8) 9.0 (2.3) 0.56
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DT, ms (SD) 234 (52) 231 (47) 235 (56) 0.76

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Right ventricular function

GLS (RV) (SD) 25 (6) 26 (6) 24 (6) 0.27
S' (RV), cm/s (SD) 13 (3) 13 (2) 14 (3) 0.07
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RA volume index, ml/BSA (SD) 20 (6) 20 (6) 20 (6) 0.84

TAPSE, cm (SD) 2.3 (0.3) 2.2 (0.3) 2.3 (0.3) 0.60
TR Vmax, m/s (SD) 2.87 (0.43) 3.02 (0.36) 2.77 (0.44) 0.01

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FIGURE 1: Tricuspid regurgitant jet maximum velocity, diffusion capacity and FEV1

according to ferritin level

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Mean tricuspid regurgitation maximum velocity (TR Vmax), diffusion of carbon monoxide

during a single breath (DLCO) and forced expiratory volume 1 second (FEV1) in iron
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deficient and sufficient patients, further divided at median serum ferritin into 4 groups.

DLCO and FEV1 are shown in percentage of predicted values.

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