Summary
Background
Early detection of pulmonary arterial hypertension (PH) is crucial in systemic scleroderma. However, predictors of new onset of resting PH during follow-up (FUPH) have been poorly explored.
Aim
To determine whether nailfold videocapillaroscopy (NVC) grade and exercise echocardiographic variables are predictors of FUPH.
Methods
We prospectively enrolled 40 patients with systemic sclerosis (age 54 ± 13 years; 68% women). All patients underwent graded semisupine exercise echocardiography and NVC. Baseline resting PH and FUPH were defined as systolic pulmonary arterial pressure (sPAP) > 35 mmHg, and exercise-induced PH (EIPH) as exercise sPAP > 50 mmHg.
Results
Seventeen patients developed EIPH (43%). During follow-up (FU) (25 ± 15 months), 11 patients without baseline PH developed FUPH (28%), all from the EIPH group. Patients with FUPH were significantly older (60 ± 14 vs 50 ± 12 years; P = 0.04), had higher resting and exercise sPAP (30 ± 4 vs 22 ± 5 and 60 ± 12 vs 40 ± 11 mmHg, respectively; P < 0.0001) and a higher exercise E/e’ ratio (9.4 ± 0.7 vs 5.8 ± 0.4; P = 0.0003) and presented more frequently NVC grade > 2 (90% vs 35%; P = 0.0009). After adjustment for age, resting sPAP, exercise sPAP and NVC grade > 2 were associated with maximal resting sPAP during follow-up and FUPH ( P < 0.05). Patients with both EIPH and NVC grade > 2 had a very high incidence of FUPH (82%), and both variables remained strongly associated with FUPH after adjustment for age (hazard ratio 11.6, 95% confidence interval 2.4–55.3; P = 0.002).
Conclusion
Exercise echocardiography and NVC can identify a subgroup of patients with systemic sclerosis who are at risk of developing FUPH.
Résumé
Contexte
Les facteurs prédictifs d’apparition d’HTAP pendant le suivi (HTAPsuivi), dans la sclérodermie systémique, demeurent mal connus.
Objectif
Étudier si le stade de la capillaroscopie digitale (CD) et l’échocardiographie d’effort peuvent prédire l’HTAPSuivi.
Méthodes
Quarante patients avec sclérodermie systémique ont été inclus (âge 54 ± 13 ans ; 68 % femme). Tous bénéficiaient d’une échocardiographie d’effort, et d’une CD. L’HTAP de repos était définie par une pression artérielle pulmonaire systolique (PAPs) > 35 mmHg, l’HTAP d’effort (HTAPeffort) par une PAPs d’effort > 50 mmHg.
Résultats
Dix-sept patients (43 %) développaient une HTAPeffort. Pendant le suivi (25 ± 15 mois), 11 patients sans d’HTAP à l’inclusion, développaient une HTAPsuivi (28 %), tous avaient une HTAPEffort. Les patients avec une HTAPsuivi étaient plus âgés (60 ± 14 vs 50 ± 12 ans ; p = 0,04) avaient une PAPs de repos et d’effort plus hautes (respectivement, 30 ± 4 vs 22 ± 5 and 60 ± 12 vs 40 ± 11 mmHg ; p < 0,0001), un E/e’ d’effort plus élevé (9,4 ± 0,7 vs 5,8 ± 0,4 ; p = 0,0003) et présentaient plus fréquemment un stade CD > 2 (90 % vs 35 % ; p = 0,0009). Après ajustement à l’âge, les PAPs de repos et d’effort ainsi que le stade CD > 2 étaient associées à la PAPs maximale de repos pendant le suivi et à l’apparition d’HTPSuivi ( p < 0,05). Les patients avec une HTAPEffort et un stade CD > 2 avaient une incidence d’HTPsuivi très élevée (82 %). Après ajustement à l’âge, l’association de ces paramètres étaient fortement associée à l’HTPsuivi (HR 11,6, IC 2,4–55,3 ; p = 0,002).
Conclusion
Dans la sclérodermie systémique, l’échocardiographie d’effort et la CD sont utiles pour identifier un groupe de patients à risque de développer une HTAPSuivi.
Background
Systemic sclerosis is a rare and complex autoimmune disease characterized by widespread vascular lesions and fibrosis leading to multiple organ impairment for the most severe presentation of the disease . Lung, pulmonary circulation and myocardium impairment can lead to the development of pulmonary arterial hypertension (PH) caused by precapillary and/or post-capillary mechanisms. Early detection and treatment of PH is crucial in systemic sclerosis, as it is a main cause of death and poor outcome . In systemic sclerosis, nailfold videocapillaroscopy (NVC) is an interesting tool for identifying microvascular impairment. Although some studies have shown the association of NVC with severe organ involvement , it has not been shown to be linked to the new onset of resting PH during follow-up (FUPH). Exercise-induced PH (EIPH) has recently been suggested as a potential highly sensitive tool for the early identification of patients with systemic sclerosis who are at risk of developing resting PH . However, probably due to lack of specificity, it seems that the incidence of EIPH may overestimate the percentage of FUPH . Although an examination of the haemodynamics of pulmonary circulation is of value , exercise echocardiography was not included in the last European Society of Cardiology recommendations , because of the ongoing debate about its usefulness in daily-life practice.
The present study sought to evaluate the usefulness of exercise echocardiography, B-type natriuretic peptide (BNP) blood concentration and NVC in an integrated screening approach for patients at risk of FUPH in systemic sclerosis.
Methods
From January 2008 to November 2012 we prospectively studied 68 consecutive patients with a diagnosis of systemic sclerosis followed in the rheumatology centre of CHU Sart-Tilman in Liège. Five patients refused to participate in the study. Exclusion criteria were inability to provide informed consent; previous ischaemic heart or valvular heart disease; inability to perform an exercise test; baseline resting PH; and unquantifiable systolic pulmonary arterial pressure (sPAP). Fifteen patients were excluded from the population ( n = 63) because of unquantifiable sPAP (24% of the population), one for ≥ moderate mitral regurgitation, two for coronary artery disease and three for baseline resting PH (7% of patients with registrable tricuspid regurgitation). Finally, two patients were lost during follow-up, so the final analysis included 40 patients ( Fig. 1 ). The relevant institutional review board approved the protocol, and all patients gave written informed consent.
Echocardiographic examination
All patients underwent comprehensive resting echocardiography, using a conventional method, with a Vivid 9 ultrasound system (General Electric Healthcare, Little Chalfont, UK), at baseline and during follow-up (twice a year), blinded for NVC results at baseline. Offline analysis was performed retrospectively using a customized software package (EchoPac). Left ventricular (LV) stroke volume was calculated as the difference between LV end-diastolic and end-systolic volumes assessed by the biapical Simpson’s disc method, and LV ejection fraction was derived from the stroke volume/LV end-diastolic volume ratio. Cardiac output was obtained by multiplying LV, stroke volume and heart rate. Peak E wave and A wave velocities of the mitral inflow were measured with pulsed-wave Doppler. Tissue Doppler imaging was applied for the measurement of e’ wave at the lateral mitral annulus aspect. Both measurements of E and A waves and tissue Doppler imaging at the mitral annulus level were performed during exercise, just before fusion of E and A waves. Right ventricular fractional area change, tricuspid annular plane systolic excursion and maximal systolic velocity of the tricuspid annulus (s’) were assessed in all patients. The systolic pulmonary arterial pressure (sPAP) was derived from the maximal velocity of the tricuspid regurgitant jet, according to the simplified Bernoulli equation, with the addition of right atrial pressure, estimated from the dimension and collapsibility of the inferior vena cava . A peak value > 35 mmHg was considered to define resting PH at baseline and FUPH. At peak exercise, sPAP was derived from the tricuspid regurgitant jet velocity, with the addition of 10 mmHg for the estimation of right atrial pressure . EIPH was defined as sPAP > 50 mmHg . mPAP was estimated using the Chemla formula: mPAP = 0.61 × sPAP + 2. The slope of the mPAP/LVCO relationship was estimated as the ratio between changes (peak – rest value) in mPAP and changes in LVCO . All echocardiographic variables were acquired at peak exercise, except for mitral inflow velocities and tissue Doppler imaging at the mitral annulus.
A symptom-limited graded bicycle exercise test was performed in a semisupine position on a tilted table. After an initial workload of 25 W maintained for 2 minutes, the workload was gradually increased by 25 W every 2 minutes. A 12-lead electrocardiogram was monitored continuously, and blood pressure was measured at rest and at each level of exercise. All patients presented normal tests, defined as the absence of the occurrence of: angina; ≥2 mm ST-segment depression compared with baseline level; or complex ventricular arrhythmias.
NVC and lung function assessment
Using an optical probe videocapillaroscope, the nailfold of the second, third, fourth and fifth fingers was examined bilaterally in each patient as described previously . NVC grades were qualitatively assessed as normal (grade 1: normal capillary morphology, regular distribution and no capillary loss), early (grade 2: few capillary microhaemorrhages and giant capillaries, no loss of capillaries and preserved distribution), active (grade 3: frequent capillary microhaemorrhages and giant capillaries, moderate loss of capillaries, mild disorganization of the microvascular architecture and absent or mild ramified capillaries) and late (grade 4: irregular enlargement of capillaries, few or absent giant capillaries and microhaemorrhages, severe loss of capillaries and large avascular areas, disorganization of capillary and ramified capillary).
All patients underwent standard pulmonary function tests, with assessment of total lung capacity, vital capacity, forced vital capacity, forced expiratory volume in 1 second, ratio of forced expiratory volume in 1 second to vital capacity and diffusing capacity of the lung for carbon monoxide.
BNP blood concentration assessment
BNP blood concentration was assessed at rest, just before echocardiography examination, in a subset of 30 patients. Venous blood samples were drawn before echocardiography, after 10 minutes of supine rest. Chilled ethylenediaminetetraacetic acid tubes were centrifuged immediately at 4000 rpm (4–8 °C) for 15 minutes.
Statistical analysis
Continuous variables are expressed as means ± standard deviations; categorical variables are presented as numbers and percentages. Data comparisons were performed according to the presence or absence of FUPH using Student’s unpaired and paired t tests, the χ 2 test or Fisher’s exact test, as appropriate. The relationships between maximal sPAP during follow-up and other continuous variables (i.e. demographic data, resting and exercise echocardiographic data) were evaluated by simple linear regression. Predictors of highest sPAP during follow-up were identified with the use of univariate and multivariable linear regressions. Univariate and multivariable logistic regression and Cox proportional-hazards models analyses were performed to define predictors of FUPH. In all multivariable analyses, because of the sample size and the limited number of outcome data, adjustments were performed with only two variables in order to limit statistical power reduction and to avoid type II error. The value of χ 2 for each variable defined its prognostic value. Sequential Cox models were performed to determine the incremental prognostic benefit of different variables over age. A statistically significant increase in the global log-likelihood χ 2 of the model defined incremental prognostic value. Probabilities of FUPH-free survival were obtained by Kaplan-Meier estimates, and then compared using a two-sided log-rank test. Values of P < 0.05 were considered statistically significant. All statistical analyses were performed with SPSS software, version 16.0.
Results
Population characteristics
The mean age of the population was 54 ± 13 years; 68% were women. sPAP increased significantly during exercise (from 24 ± 6 to 46 ± 14 mmHg; P < 0.0001). Seventeen (43%) patients developed EIPH. After a mean follow-up of 25 ± 15 months (median 28 months), 11 patients (28%) had FUPH, all in the EIPH group. Patients with EIPH and FUPH were significantly older (62 ± 12 vs 48 ± 11 years and 60 ± 14 vs 50 ± 12 years, respectively; P < 0.05 in both cases). Female sex was more frequent in the EIPH group (90% vs 62%; P = 0.03), but not in the FUPH group (64% vs 69%; P = 0.69. There were no significant differences between the two groups regarding medication and lung function test variables ( Table 1 ). There were no significant differences between the two groups in terms of Raynaud’s phenomenon (82% vs 87%; P = 1.00 or the presence of Scl-70 antibodies (36% vs 31%; P = 0.70. Patients with FUPH had a higher BNP blood concentration (79 ± 86 vs 23 ± 21 pg/mL; P = 0.01).
| Variables | Whole cohort ( n = 40) | No FUPH ( n = 29, 72%) | FUPH ( n = 11, 28%) | P |
|---|---|---|---|---|
| Demographic, clinical and biological data | ||||
| Age (years) | 54 ± 13 | 50 ± 12 | 60 ± 14 | 0.04 |
| Female sex | 27 (68) | 20 (69) | 7 (64) | 0.69 |
| Body mass index (kg/m 2 ) | 24 ± 5 | 24 ± 5 | 25 ± 6 | 0.72 |
| Heart rate (bpm) | 74 ± 14 | 73 ± 13 | 74 ± 16 | 0.72 |
| Systolic arterial pressure (mmHg) | 128 ± 19 | 126 ± 19 | 134 ± 16 | 0.36 |
| Diastolic arterial pressure (mmHg) | 73 ± 9 | 73 ± 10 | 74 ± 7 | 0.90 |
| Raynaud’s phenomenon | 34 (85) | 25 (87) | 9 (82) | 1.00 |
| Delay between diagnosis and TTE (months) | 36 ± 36 | 37 ± 39 | 31 ± 28 | 0.62 |
| NYHA class > II | 3 (8) | 3 (10) | 0 (0) | 0.26 |
| Presence of Scl-70 antibodies | 13 (33) | 9 (31) | 4 (36) | 0.70 |
| BNP (pg/mL) | 41 ± 61 | 23 ± 21 | 79 ± 86 | 0.01 |
| Risk factors | ||||
| Systemic hypertension | 4 (10) | 2 (7) | 2 (11) | 0.33 |
| Hypercholesterolaemia | 9 (23) | 7 (25) | 2 (18) | 0.64 |
| Smoker | 10 (24) | 9 (31) | 1 (9) | 0.08 |
| Family history of CV disease | 2 (5) | 2 (7) | 0 (0) | 0.24 |
| Pulmonary function | ||||
| Total lung capacity (% predicted) | 93 ± 21 | 95 ± 21 | 82 ± 16 | 0.15 |
| Vital capacity (% predicted) | 104 ± 24 | 105 ± 26 | 96 ± 17 | 0.32 |
| Force vital capacity (% predicted) | 101 ± 25 | 102 ± 21 | 93 ± 17 | 0.30 |
| FEV1 (% predicted) | 95 ± 20 | 96 ± 20 | 87 ± 22 | 0.27 |
| FEV1/vital capacity (% predicted) | 99 ± 12 | 100 ± 12 | 96 ± 13 | 0.38 |
| DLCO (% predicted) | 65 ± 14 | 66 ± 15 | 60 ± 12 | 0.33 |
| Medication | ||||
| ACE inhibitors | 2 (5) | 1 (4) | 1 (10) | 0.51 |
| Beta-blockers | 3 (8) | 1 (4) | 2 (9) | 0.15 |
| Diuretics | 2 (5) | 1 (4) | 1 (10) | 0.51 |
| Calcium inhibitors | 20 (50) | 13 (52) | 7 (70) | 0.32 |
| Corticoids | 9 (23) | 5 (20) | 4 (40) | 0.23 |
| Immunosuppressors | 6 (16) | 4 (16) | 2 (20) | 0.77 |
| Exercise data | ||||
| Workload (W) | 75 ± 31 | 81 ± 30 | 65 ± 36 | 0.22 |
| Duration of exercise (minutes) | 4.9 ± 1.3 | 4.7 ± 1.3 | 5.1 ± 1.6 | 0.55 |
| Heart rate (bpm) | 119 ± 17 | 119 ± 16 | 122 ± 21 | 0.65 |
| Systolic arterial pressure (mmHg) | 168 ± 23 | 163 ± 23 | 176 ± 21 | 0.19 |
| Diastolic arterial pressure (mmHg) | 82 ± 12 | 81 ± 11 | 84 ± 13 | 0.55 |
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