Supplementary material online
The prognostic impact of thyroid function in pulmonary hypertension
Manuel J. Richter, MD, Natascha Sommer, MD, Ralph Schermuly, MD, Birk Grimminger, Werner Seeger, MD, Khodr Tello, MD, Hossein A. Ghofrani, MD, and Henning Gall, MD
Supplementary appendix 1
Thyroid-stimulating hormone (TSH) quartiles
In the overall study population with pulmonary hypertension (PH), TSH quartiles were defined as follows: Q1: ≤ 0.66 mIU/L; Q2: 0.66–1.2 mIU/L; Q3: 1.2–1.94 mIU/L; Q4: ≥ 1.94 mIU/L.
In pulmonary arterial hypertension (PAH), TSH quartiles were defined as follows: Q1: ≤ 0.87 mIU/L; Q2: 0.87–1.55 mIU/L; Q3: 1.55–2.64 mIU/L; Q4: ≥ 2.64 mIU/L.
In PH due to left heart disease, TSH quartiles were defined as follows: Q1: ≤ 0.75 mIU/L; Q2: 0.75–1.31 mIU/L; Q3: 1.31–1.94 mIU/L; Q4: ≥ 1.94 mIU/L.
In PH due to interstitial lung disease (ILD), TSH quartiles were defined as follows: Q1: ≤ 0.55 mIU/L; Q2: 0.55–0.87 mIU/L; Q3: 0.87–1.44 mIU/L; Q4: ≥ 1.44 mIU/L.
In PH due to chronic obstructive pulmonary disease (COPD), TSH quartiles were defined as follows: Q1: ≤ 0.54 mIU/L; Q2: 0.54–0.98 mIU/L; Q3: 0.98–1.48 mIU/L; Q4: ≥ 1.48 mIU/L.
In chronic thromboembolic PH (CTEPH), TSH quartiles were defined as follows: Q1: ≤ 0.68 mIU/L; Q2: 0.68–1.26 mIU/L; Q3: 1.26–1.97 mIU/L; Q4: ≥ 1.97 mIU/L.
In idiopathic PAH (iPAH), TSH quartiles were defined as follows: Q1: ≤ 0.89 mIU/L; Q2: 0.89–1.68 mIU/L; Q3: 1.68–2.65 mIU/L; Q4: ≥ 2.65 mIU/L.
Free triiodothyronine (fT3) quartiles
In PAH, fT3 quartiles were defined as follows: Q1: ≤ 2.8 ng/dL; Q2: 2.8–3.0 ng/dL; Q3: 3.0–3.3 ng/dL; Q4: ≥ 3.3 ng/dL.
In CTEPH, fT3 quartiles were defined as follows: Q1: ≤ 2.8 ng/dL; Q2: 2.8–3.1 ng/dL; Q3: 3.1–3.3 ng/dL; Q4: ≥ 3.3 ng/dL.
Supplementary appendix 2
Survival analysis
In PAH (PH group 1), patients were followed over a mean period of 46.3 ± 38.1 months (median [interquartile range (IQR)]: 37 [63] months), and the overall 1-, 3- and 5-year transplant-free survival was 89.6%, 73.6% and 59.7%, respectively (124 patients died).
In PH due to left heart disease (PH group 2), 115 patients died during a mean follow-up of 23.8 ± 29.4 months (median [IQR]: 12 [37] months), and the overall 1-, 3- and 5-year transplant-free survival was 87.9%, 69.8% and 56.2%, respectively.
In PH due to ILD (PH group 3.2), 177 patients died during a mean follow-up of 26.0 ± 23.8 months (median [IQR]: 21 [31] months), and 1-, 3- and 5-year overall transplant-free survival was 75.0%, 39.2% and 21.2%, respectively.
In PH due to COPD (PH group 3.1), 86 patients died during a mean follow-up of 31.7 ± 29.6 months (median [IQR]: 24 [46] months), and the overall 1-, 3- and 5-year transplant-free survival was 86.7%, 66.7% and 52.8%, respectively.
In CTEPH (PH group 4), the overall 1-, 3- and 5-year transplant-free survival was 89.7%, 75.0% and 67.0%, respectively; 106 patients died during a mean follow-up of 42.3 ± 36.3 months (median: 35 [58.3] months) (Figure S1).
Patients with iPAH receiving thyroid hormone replacement (THR) therapy (n = 38) had a 1-, 3- and 5-year transplant-free survival of 97.1%, 87.4% and 72.6%, respectively; nine of the patients (23.7%) died. Patients with iPAH who did not receive THR therapy (n = 154) had a 1-, 3- and 5-year transplant-free survival of 88.9%, 73.8%, and 60.7%, respectively; 54 of the patients (35.5%) died.
Supplementary tables
Table S1. TSH, fT3 and fT4 levels according to prostanoid treatment in patients with PAH without thyroid hormone replacement therapy
PAH (n = 281)No prostanoid treatment
(n = 203) / Inhaled iloprost
(n = 49) / Intravenous iloprost
(n = 11) / Parenteral trepostinil
(n = 18) / p-value
TSH, mIU/L / 1.40 [1.53] / 1.77 [1.91] / 1.98 [1.67] / 2.40 [2.02] / 0.126a
fT3, ng/dL / 3.02 ± 0.44 / 3.05 ± 0.38 / 3.35 ± 0.32 / 2.98 ± 0.18 / 0.175b
fT4, ng/dL / 1.32 ± 0.30 / 1.35 ± 0.24 / 1.36 ± 0.21 / 1.31 ± 0.27 / 0.91b
fT3, free triiodothyronine; fT4, free thyroxine; PAH, pulmonary arterial hypertension; TSH, thyroid-stimulating hormone.
Values represent mean ± standard deviation or median [interquartile range].
aKruskal-Wallis Test. bOne way ANOVA.
Table S2. Baseline characteristics, thyroid hormone test results and pulmonary hemodynamics of patients with iPAH with and without THR therapy
/ All / Without THR therapy / With THR therapy / p-value /
Patients, n / 192 / 154 / 38
Male/Female, n/n / 70/122 / 64/90 / 6/32 / 0.017a
Age, years / 53.0 ± 17.6 / 51.7 ± 17.5 / 56.9 ± 17.6 / 0.22
BMI, kg/m2 / 26.4 ± 4.8 / 26.5 ± 4.9 / 26.8 ± 4.3 / 0.94
Systolic BP, mmHg / 125 ± 21 / 124 ± 20 / 124 ± 24 / 0.72
Diastolic BP, mmHg / 77 ± 15 / 77 ± 16 / 74 ± 14 / 0.59
Laboratory
TSH, mIU/L / 1.68 [1.76] / 1.50 [1.59] / 2.47 [3.33] / 0.000b
fT3, ng/dL / 3.0 ± 0.44 / 3.1 ± 0.40 / 2.8 ± 0.42 / 0.06
fT4, ng/dL / 1.35 ± 0.27 / 1.33 ± 0.23 / 1.44 ± 0.39 / 0.33
TPOAbs, n (%) / 3 (2.8) / 3 (4.2) / none / -
TgAbs, n (%) / 4 (3.8) / 2 (2.8) / 2 (6.3) / 0.98
Mean L-thyroxine dosage, μg / - / - / 83.5 ± 40.4 / -
WHO functional class / 0.36a
I, % / 3.0 / 3.9 / none
II, % / 13.6 / 15.7 / 7.1
III, % / 65.2 / 62.7 / 78.6
IV, % / 18.2 / 17.6 / 14.3
RHC
mPAP, mmHg / 48.5 ± 15.8 / 48.9 ± 16.5 / 47.1 ± 12.5 / 0.53
PVR, dyne•s/cm5 / 911.8 ± 456.6 / 935.1 ± 508.6 / 880.0 ± 434.0 / 0.57
PAWP, mmHg / 7.7 ± 3.1 / 7.6 ± 2.9 / 8.2 ± 3.5 / 0.77
Cardiac index, L/min/m2 / 2.19 ± 0.6 / 2.18 ± 0.6 / 2.21 ± 0.7 / 0.93
Heart rate, beats/min / 78.9 ± 14.2 / 79.4 ± 14.2 / 77.7 ± 14.1 / 0.6
SvO2, % / 62.2 ± 9.4 / 62.2 ± 9.4 / 62.0 ± 9.8 / 0.98
pO2, mmHg / 68.7 ± 13.9 / 69.2 ± 13.9 / 66.9 ± 14 / 0.54
pCO2, mmHg / 32.9 ± 6.4 / 32.9 ± 6.8 / 32.6 ± 5 / 0.95
6MWD, m / 352 ± 123 / 354 ± 123 / 338 ± 124 / 0.75
Thyroid dysfunction, n (%) / 53 (27.6) / 15 (9.7) / 38 (100) / 0.001a
Thyroidectomy, n (%) / 12 (6.3) / 1 (0.1) / 11 (29)
Goiter, n (%) / 6 (3.1) / 6 (3.9) / none
Hypothyroidism, n (%) / 25 (13) / 2 (1.2) / 23 (60.5)
Hyperthyroidism, n (%) / 3 (1.5) / 3 (1.9) / none
AITD, n (%) / 7 (3.6) / 3 (1.9) / 4 (10.5)
AITD, autoimmune thyroid diseases; BMI, body mass index; BP, blood pressure; fT3, free triiodothyronine; fT4, free thyroxine; iPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen; PVR, pulmonary vascular resistance; RHC, right heart catheterization; SvO2, mixed venous oxygen saturation; TgAbs, thyroglobulin antibodies; THR, thyroid hormone replacement; TPOAbs, thyroperoxidase antibodies; TSH, thyroid-stimulating hormone; WHO, World Health Organization; 6MWD, six-minute walk distance.
Unless otherwise specified, values represent mean ± SD or median [IQR].
aPearson Chi-Square Test.
bKruskal-Wallis Test.
Table S3. Comparison of selected baseline characteristics, thyroid hormone test results and hemodynamics between survivors and non-survivors with iPAH
/ Patients with iPAH // Survivors / Non-survivors / p-value /
Patients, n (%) / 128 (66.7) / 64 (33.3)
Male/Female, n/n / 40/88 / 30/34 / 0.34a
Age, years / 52.9 ± 16.4 / 53.2 ± 19.7 / 0.9
BMI, kg/m2 / 26.8 ± 4.8 / 25.8 ± 4.7 / 0.2
Systolic BP, mmHg / 127 ± 21 / 119 ± 22 / 0.04
Diastolic BP, mmHg / 77 ± 15 / 74 ± 14 / 0.31
Laboratory
TSH, mIU/L / 1.53 [1.68] / 1.81 [2.02] / 0.45b
fT3, ng/dL / 3.03 ± 0.4 / 3.02 ± 0.4 / 0.73
fT4, ng/dL / 1.3 ± 0.3 / 1.4 ± 0.2 / 0.8
THR therapy, n (%) / 29 (22.7) / 9 (14.1) / 0.39a
Mean dosage, μg / 84.5 ± 42.5 / 80.6 ± 34.9 / 0.8
WHO functional class / 0.18a
I, % / 4.5 / None
II, % / 13.6 / 13.6
III, % / 70.5 / 54.5
IV, % / 11.4 / 31.9
RHC
mPAP, mmHg / 45.7 ± 14.9 / 54.1 ± 16.0 / 0.001
PVR, dyne•s/cm5 / 818.4 ± 434.8 / 1111.9 ± 548.6 / 0.001
PAWP, mmHg / 7.6 ± 3.1 / 7.9 ± 2.9 / 0.48
Cardiac index, L/min/m2 / 2.3 ± 0.7 / 1.9 ± 0.5 / 0.002
Heart rate, beats/min / 76 ± 13 / 84 ± 15 / 0.001
SvO2, % / 64.3 ± 8.8 / 58.0 ± 9.3 / 0.001
pO2, mmHg / 70.7 ± 14.2 / 64.6 ± 12.2 / 0.006
pCO2, mmHg / 33.2 ± 6.6 / 32.4 ± 6.1 / 0.46
6MWD, m / 371 ± 120 / 309 ± 119 / 0.002
Thyroid dysfunction / 0.57a
Thyroidectomy, n (%) / 9 (7.0) / 3 (4.7)
Goiter, n (%) / 3 (2.3) / 3 (4.7)
Hypothyroidism, n (%) / 18 (14.1) / 7 (10.9)
Hyperthyroidism, n (%) / 2 (1.6) / 1 (1.6)
AITD, n (%) / 7 (5.5) / None
AITD, autoimmune thyroid diseases; BMI, body mass index; BP, blood pressure; fT3, free triiodothyronine; fT4, free thyroxine; iPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen; PVR, pulmonary vascular resistance; RHC, right heart catheterization; SvO2, mixed venous oxygen saturation; THR, thyroid hormone replacement; TSH, thyroid-stimulating hormone; WHO, World Health Organization; 6MWD, six-minute walk distance.
Unless otherwise specified, values represent mean ± SD or median [IQR].
aPearson Chi-Square Test.
bMann-Whitney U Test;
Table S4. Hazard ratios and 95% confidence intervals for mortality in patients without THR therapy calculated by univariate Cox regression analysis
/ Patients with PH without THR therapy / Patients with iPAH without THR therapy /Variables / Mortality /
/ HR [95% CI] / p-value / HR [95% CI] / p-value /
Thyroid-related parameters
TSH dichotomized
(Q1 + Q4 vs Q2 + Q3) / 1.16 [0.98–1.39] / 0.09 / 2.14 [1.25–3.69] / 0.006
fT3, ng/dLa / 1.72 [1.37–2.13] / < 0.0001 / 1.61 [0.75–3.45] / 0.22
fT4, ng/dL / 2.04 [1.40–2.90] / < 0.0001 / 3.09 [0.71–13.49] / 0.13
TPOAbs / 1.87 [0.77–4.50] / 0.16 / 22.66 [0.20–24.26] / 0.38
TgAbs / 1.85 [0.77–4.54] / 0.17 / 1.6 [0.22–12.04] / 0.64
Thyroid dysfunction / –b / –b / –b / –b
Other parameters
Gender (male vs female) / 1.56 [1.30–1.86] / < 0.0001 / 1.32 [0.77–2.25] / 0.31
Age, years / 1.03 [1.03–1.04] / < 0.0001 / 1.01 [0.99–1.03] / 0.18
BMI, kg/m2 / 0.97 [0.95–0.99] / 0.001 / 0.97 [0.92–1.03] / 0.34
Systolic BP, mmHg / 0.99 [0.98–0.99] / < 0.0001 / 0.98 [0.97–0.99] / 0.02
Diastolic BP, mmHg / 0.98 [0.97–0.99] / < 0.0001 / 0.98 [0.96–1.00] / 0.03
WHO functional class
II vs I / 2.99 [1.45–6.18] / 0.003 / 1.96 [0.47–8.33] / 0.35
III vs I / 5.00 [2.40–10.6] / < 0.0001 / 1.89 [0.06–5.55] / 0.27
IV vs I / –b / –b / –b / –b
RHC
mPAP, mmHg / 1.01 [0.99–1.01] / 0.07 / 1.02 [1.01–1.04] / 0.03
PVR, dyne•s/cm5 / 1.00 [1.00–1.00] / 0.046 / 1.01 [1.00–1.01] / 0.049
PAWP, mmHg / 1.02 [0.99–1.03] / 0.08 / 1.04 [0.95–1.14] / 0.43
Cardiac index, L/min/m2a / 1.2 [1.04–1.39] / 0.014 / 1.85 [1.09–3.13] / 0.024
Heart rate, beats/min / 1.01 [1.00–1.01] / 0.007 / 1.02 [1.01–1.04] / 0.03
SvO2, % / 0.97 [0.96–0.98] / < 0.0001 / 0.97 [0.94–0.99] / 0.01
pO2, mmHg / 1.01 [0.99–1.01] / 0.39 / 0.99 [0.96–1.01] / 0.21
pCO2, mmHg / 1.03 [1.01–1.04] / < 0.0001 / 0.99 [0.95–1.05] / 0.88
6MWD, m / 0.99 [0.99–1.00] / < 0.0001 / 0.99 [0.99–1.00] / 0.001
BMI, body mass index; BP, blood pressure; CI, confidence interval; fT3, free triiodothyronine; fT4, free thyroxine; HR, hazard ratio; iPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; pCO2, partial pressure of carbon dioxide; PH, pulmonary hypertension; pO2, partial pressure of oxygen; PVR, pulmonary vascular resistance; Q, quartile; RHC, right heart catheterization; SvO2, mixed venous oxygen saturation; TgAbs, thyroglobulin antibodies; THR, thyroid hormone replacement; TPOAbs, thyroperoxidase antibodies; TSH, thyroid-stimulating hormone; WHO, World Health Organization; 6MWD, six-minute walk distance.
aHR > 1 indicates increased mortality with decreased levels of the measured parameter.
bModel did not converge.
Table S5. Hazard ratios and 95% confidence intervals for mortality calculated by univariate Cox regression analysis.
/ All patients with PH / All patients with iPAH /Variables / Mortality /
/ HR [95 % CI] / p-value / HR [95 % CI] / p-value /
Thyroid-related parameters
THR therapy (absence vs presence) / 1.38 [1.12–1.69] / 0.003 / 1.99 [0.98–4.05] / 0.05
fT3, ng/dLa / 1.56 [1.28–1.89] / < 0.0001 / 1.45 [0.72–2.86] / 0.31
fT4, ng/dL / 1.73 [1.30–2.30] / < 0.0001 / 1.87 [0.68–5.12] / 0.23
TPOAbs / 2.36 [1.06–5.29] / 0.04 / –b / –b
TgAbs / 1.85 [0.89–4.00] / 0.1 / 1.72 [0.24–12.5] / 0.59
Hyperthyroidismc / 1.49 [1.05–2.10] / 0.024 / –b / –b
Other parameters
Gender (male vs female) / 1.64 [1.40–1.92] / < 0.0001 / 1.74 [1.06–2.86] / 0.03
Age, years / 1.03 [1.02–1.04] / < 0.0001 / 1.01 [0.99–1.03] / 0.31
BMI, kg/m2 / 0.97 [0.96–0.99] / 0.001 / 0.97 [0.92–1.03] / 0.35
Systolic BP, mmHg / 0.99 [0.98–0.99] / < 0.0001 / 0.98 [0.97–0.99] / 0.007
Diastolic BP, mmHg / 0.98 [0.98–0.99] / < 0.0001 / 0.98 [0.97–1.01] / 0.06
WHO functional class
III vs II / 4.55 [2.33–9.09] / < 0.0001 / 2.38 [0.63–9.09] / 0.42
IV vs II / 1.59 [1.18–2.17] / < 0.0001 / 2.18 [0.83–5.56] / 0.46
RHC
mPAP, mmHg / 1.01 [1.01–1.02] / 0.013 / 1.02 [1.01–1.04] / 0.02
PVR, dyne•s/cm5 / 1.00 [1.00–1.00] / 0.02 / 1.01 [1.00–1.01] / 0.03
PAWP, mmHg / 1.02 [1.01–1.04] / 0.012 / 1.03 [0.95–1.12] / 0.43
Cardiac index, L/min/m2a / 1.15 [1.01–1.31] / 0.032 / 1.59 [0.99–2.56] / 0.05
Heart rate, beats/min / 1.01 [1.00–1.02] / 0.001 / 1.02 [1.01–1.04] / 0.01
SvO2, % / 0.98 [0.97–0.98] / < 0.0001 / 0.97 [0.95–0.99] / 0.006
pO2, mmHg / 1.01 [0.99–1.01] / 0.76 / 0.98 [0.96–1.01] / 0.05
pCO2, mmHg / 1.03 [1.02–1.04] / < 0.0001 / 1.01 [0.96–1.05] / 0.87
6MWD, m / 0.99 [0.99–1.00] / < 0.0001 / 0.99 [0.99–1.00] / 0.001
BMI, body mass index; BP, blood pressure; CI, confidence interval; fT3, free triiodothyronine; fT4, free thyroxine; HR, hazard ratio; iPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; pCO2, partial pressure of carbon dioxide; PH, pulmonary hypertension; pO2, partial pressure of oxygen; PVR, pulmonary vascular resistance; RHC, right heart catheterization; SvO2, mixed venous oxygen saturation; TgAbs, thyroglobulin antibodies; THR, thyroid hormone replacement; TPOAbs, thyroperoxidase antibodies; TSH, thyroid-stimulating hormone; WHO, World Health Organization; 6MWD, six-minute walk distance.