Tissue Doppler imaging in systemic sclerosis: A 3-year longitudinal study

Seminars in Arthritis and Rheumatism 43 (2014) 673–680

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Tissue Doppler imaging in systemic sclerosis: A 3-year longitudinal study Michele D’Alto, MD, PhDa, Giovanna Cuomo, MDb, Emanuele Romeo, MD, PhDa, Paola Argiento, MD, PhDa, Michele Iudici, MDb, Serena Vettori, MD, PhDb, Maria Giovanna Russo, MDa, Raffaele Calabrò, MDa, Gabriele Valentini, MDb,n a b

Department of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy Rheumatology Unit, Second University of Naples, II Policlinico, Via Pansini 5, Naples 80131, Italy

a r t i c l e in fo

Keywords: Systemic sclerosis Tissue Doppler imaging Ventricular function Pulmonary artery systolic pressure

a b s t r a c t Objectives: To investigate by standard echocardiography and pulsed-tissue Doppler imaging (TDI) the course of systemic sclerosis (SSc) heart disease and its correlation with epidemiological, clinical, and serological features of the disease and drug treatment. Methods: A total of 74 consecutive patients (69 females, between the ages of 19 and 71 years, and disease duration 1–43 years) and 71 controls underwent cardiac assessment at baseline and at 3-year follow-up. Results: At baseline, compared to controls, patients showed post-Bonferroni correction, impaired left (LV) and right ventricular (RV) diastolic function (Em/Am 0.85 7 0.4 vs 1.5 7 0.7, p ¼ 0.0003; Et/At 0.9 7 0.3 vs 1.3 7 0.4, p ¼ 0.0003), subtle LV and RV systolic dysfunction (Sm 13.7 7 2.7 vs 15.4 7 3.2 cm/s, p ¼ 0.031; St o 11.5 cm/s in 16/74 patients vs 0 controls, p ¼ 0.0031), and higher pulmonary artery systolic pressure (sPAP) (26.1 7 6.0 vs 24.1 7 5.1, p ¼ 0.040). At 3-year follow-up, SSc patients showed a further deterioration of biventricular diastolic and systolic function and a further sPAP increase. At multiple regression analysis of baseline data, Em/Am o 1 was detected in 55/74 patients vs 25/71 controls (p o 0.0001) and was associated with age (p ¼ 0.030); Et/At o 1 was detected in 16/74 patients vs 7/71 controls (p o 0.0001), was associated with NYHA class Z II (p ¼ 0.033), late capillaroscopic pattern (p ¼ 0.029), and a baseline cardiac Medsger severity score Z 1 (p ¼ 0.029). TDI evidence of new abnormalities in RV and/or LV diastolic function was associated with a baseline cardiac Medsger severity score Z 1 (p ¼ 0.01). Neither diastolic or systolic abnormalities nor sPAP changes correlated with treatment. Conclusions: Our study confirms that SSc patients exhibit biventricular systolic and diastolic dysfunction and increased sPAP and reveals further deterioration at 3-year follow-up. & 2014 Published by Elsevier Inc.

Introduction Systemic sclerosis (SSc) is a clinically heterogeneous, multisystem autoimmune disorder characterized by widespread vascular lesions and fibrosis of the skin and internal organs [1] and a shortened survival rate due to SSc heart disease (HD) in approximately 30% of patients [2]. Formerly, the prevalence of HD in SSc patients estimated from autopsy studies [3] was higher than that detected by clinical examination and routine investigations [4]. However, subsequently, standard echocardiography (SE) [5–10], 24-h Holter electrocardiography [11], myocardial perfusion scintigraphy [12,13], and magnetic resonance imaging [14] have greatly improved the diagnostic accuracy of SSc-HD, so that its prevalence in the clinical setting now approximates that reported

n

Corresponding author. E-mail address: [email protected] (G. Valentini).

0049-0172/$ - see front matter & 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.semarthrit.2013.10.004

in autopsy studies [3,15]. Cross-sectional studies based on SE have repeatedly shown a high prevalence of left and right relaxation abnormalities and a very low frequency of depressed systolic function [5–10]. Tissue Doppler imaging (TDI) is a widely available, non-invasive technique that detects left and right diastolic and systolic functional abnormalities with a higher sensitivity and specificity than SE [16,17]. Various cross-sectional studies have investigated SSc-HD using TDI [18–24]. In a previous retrospective analysis of 77 prospectively enrolled SSc patients undergoing 2 or more SE examinations, we found that left ventricular (LV) filling dysfunction is progressive and precedes the occurrence of LV remodeling, and that systolic dysfunction, defined as LV ejection fraction o55%, is infrequent [25]. More recently, we used SE and pulsed TDI to evaluate pulmonary vascular response to exercise in consecutive SSc patients from 2 Italian centers (Naples and Pavia) to evaluate pulmonary vascular response to exercise [26]. In that study, SE and pulsed TDI were performed in all the SSc patients enrolled. Given the lack of

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M. D’Alto et al. / Seminars in Arthritis and Rheumatism 43 (2014) 673–680

longitudinal studies in SSc using TDI, we evaluated by both SE and TDI the Naples patients 3 years later to investigate the course of SSc-HD and look for correlations between SSc-HD and epidemiological, clinical, and serological features of the disease and drug treatment.

The epidemiological, clinical, and serological characteristics of SSc patients are listed in Table 1. This series mainly consisted of patients with lc-SSc (85%) with a disease duration 45 years (84%), a slow course (EScSG activity index o3 in 89% of cases), and a prevalence of HD, as determined by history, clinical examination, and ECG and ejection fraction assessment, as low as 22 out of 74 patients (29.7%).

Methods Patients The study group consisted of 74 patients with SSc (69 females, 5 males; between the ages of 19 and 71 years, median ¼ 54 years; with a disease duration between 1 and 43 years, median ¼ 12 years), all of whom satisfied the 1980 ACR preliminary criteria for classification of the disease [27]. Of the original Naples series consisting of 87 patients, 13 were not reinvestigated at the end of follow-up. Of these 13 patients, 2 died (1 from lung cancer and 1 from sudden death), 1 suffered a myocardial infarction, 1 was undergoing hemodialysis after a scleroderma renal crisis, 1 became pregnant, 4 withdrew consent, and 4 moved out of Naples and declined to return for follow-up. However, these patients did not differ from the 74 patients included in the present study in terms of epidemiological, clinical, and serological features and SE and TDI parameters at baseline. All patients were assessed using the EUSTAR Minimal Essential Data Set [28]. Patients were divided into 2 subsets (diffuse or limited cutaneous, dc- and lc-SSc) according to the classification of LeRoy et al. [29]. Autoantibody profile and capillaroscopic abnormalities were investigated as previously described [30]. Disease duration was calculated from the appearance of Raynaud's phenomenon. Disease activity was assessed with the EScSG activity index [31,32], and disease extent and severity were assessed with the revised Medsger scale [33]; a score Z1 was considered indicative of each organ/system involvement (i.e., for cardiac disease, the presence of a conduction defect and/or a left ventricle ejection fraction less than 50%, and for lung disease, the presence of a lung diffusion for carbon monoxide and/or a forced vital capacity o 80% of the respective predicted values). Of the 74 patients, 9 (12%) exhibited systemic arterial hypertension at baseline and after 3 years. Moreover, since diastolic and systolic right and left heart function might be affected by age, sex, body mass index, and blood pressure in both patients and controls and by disease duration and the severity of cardiac and lung disease in SSc patients, we evaluated the correlation among each of these features and SE and TDI parameters.

Medications During the interval between the 2 observations, all patients were treated with low-dose aspirin, nifedipine (20–60 mg), and proton pump inhibitors. In addition, 11/74 (15%) patients were also treated with ACE inhibitors for systemic hypertension, 56/74 (76%) received low-dose corticosteroids ( r10-mg prednisone equivalent) and vitamin D supplementation, 33/74 (45%) received lowdose pulse cyclophosphamide (500 mg upto a cumulative dose of 10 g) administered for either active alveolitis or early diffuse disease and followed by either azathioprine or mycophenolate mofetil, and 14/74 (19%) received intercurrent iloprost infusion for ischemic ulcers developed despite treatment with calcium channel blockers. Any medication affecting heart rate or vascular function (i.e., nifedipine and iloprost) was discontinued at least 7 days before SE and TDI examination. This washout period was chosen to ensure that heart rate was not influenced by these drugs, because heart rate can affect some SE and TDI parameters [34,35].

Controls A total of 71 patients' sex-, age-, weight-, and body surface area-matched controls (66 females, 5 males; between the ages of 18 and 72 years, median ¼ 54 years) who were admitted to the cardiology unit for a cardiologic assessment before undergoing a minor surgical intervention and who agreed to participate in the study were selected for comparison. At the first evaluation, clinical examination, ECG, and chest X-ray were unremarkable. Of the 71 controls, 8 (11%) exhibited mild or moderate systemic arterial hypertension. Similar to SSc patients, any medication affecting heart rate or vascular function was discontinued at least 7 days before SE and TDI examination. Echocardiography Echocardiographic examination was performed by 2 highly trained, independent cardiologists (M.D. and P.A.), blinded to the clinical characteristics of the study population, using commercially available equipment with a phased array system (Philips iE33 ultrasound machine, Philips Medical Systems, Andover, MA) and a 2.5- or 3.5-MHz transducer. The procedure was performed in accordance with international recommendations [36,37]. Specific views included the parasternal long- and short-axis views (at the mitral valve and papillary muscle level); apical 4-, 2-, and 3-chamber views; and subcostal views, including respiratory motion of the inferior vena cava. Pulsed, continuous wave and color Doppler interrogation was performed on all 4 cardiac valves. Tissue Doppler imaging was performed to evaluate diastolic and systolic function of both the left and right ventricle from the 4-chamber view. Specific measurements were made by the average of 3–5 cardiac cycles.

M- and B-mode measurements Left ventricular diastolic and systolic diameters, interventricular septum, and posterior wall thickness were assessed in the parasternal long-axis view with the patient in the left lateral position. Left ventricular ejection fraction was calculated with the biplane Simpson's rule in the apical 4- and 2-chamber views. Left atrial maximal volume was measured at the point of mitral valve opening using the biplane area–length method, and was corrected for body surface area [36]. Right ventricular (RV) end-diastolic chamber size was assessed accurately according to the American Society of Echocardiography guidelines for the echocardiographic assessment of the right heart in adults [38]. Right atrial (RA) measurements were obtained in the apical 4-chamber view. Right atrial area was estimated by planimetry at end systole (largest volume), tracing from the lateral aspect of the tricuspid annulus to the septal aspect, excluding the area between the leaflets and annulus, following the RA endocardium, excluding the inferior and superior vena cava and the RA appendage [38]. Tricuspid annular plane systolic excursion (TAPSE) was calculated as an index of RV longitudinal systolic function by placing an M-mode cursor through the tricuspid annulus in a standard apical 4-chamber window and measuring the difference between end-diastolic and end-systolic amount of longitudinal motion of the annulus.

M. D’Alto et al. / Seminars in Arthritis and Rheumatism 43 (2014) 673–680

Table 1 Clinical and serological characteristics of patients with systemic sclerosis No. of patients dc-SSc/lc-SSc Autoantibody profile (n, %) ANA ACA Anti-Sc170 Capillaroscopic pattern Early Active Late Active disease (EScSG Z 3) (n, %)

74 11 (15%)/63 (85%)

Organ/system involvement

Prevalence (n, %) Severity (median; range)

General Peripheral vascular Skin Joint/tendon Muscle Gut Lung Heart Kidney

20 74 65 8 7 58 61 16 0

74 (100%) 32 (43.2%) 31 (41.9%) 39 12 18 8

(52.7%) (16.2%) (24.3%) (10.8%)

(27) (100) (87.8) (10.8) (9) (78) (82) (21.6) (0)

1; 0–2 1.5; 1–3 1; 0–2 0; 0–4 0; 0–2 1; 0–3 1.5; 0–4 0; 0–2 0

ACA ¼ anticentromere antibody; ANA ¼ antinuclear antibody; dc-SSc ¼ diffuse cutaneous systemic sclerosis; EScSG ¼ European Scleroderma Study Group; lc-SSc ¼ limited cutaneous systemic sclerosis.

Color Doppler analysis Valvular regurgitation was quantified from color Doppler imaging. Intermediate vena contracta values (3–7 mm) were confirmed with the proximal isovelocity surface-area method [39]. Pulsedwave Doppler-derived LV and RV diastolic inflow were recorded in the apical 4-chamber view by placing the sample volume at the level of the tip of the mitral and tricuspid valves. E and A peak velocities (m/s) and their ratio were measured for both ventricles [36]. Tissue Doppler Imaging To obtain a measure of LV and RV myocardial function by TDI, we assessed LV and RV peak systolic velocities (Sm and St, respectively) and LV and RV early- and late-diastolic velocities (Em, Am, Et, and At, respectively) from the apical 4-chamber view by placing the sample volume at the mitral and tricuspid annulus. Care was taken to ensure optimal image orientation and avoid underestimation of velocities. Care was also taken to ensure optimal image orientation and to avoid underestimation of velocities [37]. Non-invasive pulmonary artery systolic pressure Peak tricuspid regurgitant velocity was measured from the spectral profile of the tricuspid regurgitation jet in the RV inflow projection of the parasternal long-axis view, the parasternal shortaxis view, or the apical 4-chamber view. The highest transvalvular velocity was used for calculation of RV systolic pressure. Pulmonary artery systolic pressure (sPAP) was assumed to equate the RV systolic pressure in the absence of pulmonic stenosis and/or RV outflow tract obstruction. sPAP was then calculated as 4  V2 þ 5 mmHg assigned to RA pressure [40] (where V is the maximal velocity of tricuspid regurgitation jet). All data were analyzed offline by 2 observers (E.R. and A.D.) blinded to the clinical characteristics of the patients. Intra- and inter-observer variability was o1% and o4.0%, respectively. Statistical analysis Continuous variables were analyzed with the Student's t-test and with the Mann–Whitney test of medians for normally and

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non-normally distributed variables, respectively. The chi-square test or Fisher's exact test was applied for contingency tables and odds ratio evaluation. The relationships between each demographic, disease and treatment feature and each SE and TDI parameter were explored first by linear or biserial correlation, and subsequently with a multiple logistic model. Hazard ratios were calculated by a Cox proportional hazards model. The rates of SE and TDI changes over the 3-year follow-up were adjusted for baseline values as follows: (value at time 3 years – value at baseline)/value at baseline. A p value o 0.05 was considered statistically significant. Data are expressed as mean 7 SD, median, range, or percentages. Statistical analysis was performed using SPSS software, version 12.0.1 (SPSS Inc., Chicago, IL).

Results Baseline Table 2 shows the SE and TDI parameters recorded in the study population at baseline. Mean blood pressure did not differ significantly between SSc patients and controls (data not shown). None of the SSc patients or controls showed severe mitral or aortic valve regurgitation or stenosis; 3/74 SSc patients and 2/71 controls showed moderate mitral valve regurgitation, and 1/74 SSc patients showed moderate aortic valve regurgitation. Mild pericardial effusion was detected in 4/74 SSc patients and in none of the controls. At SE, LV-filling abnormalities were observed more frequently in SSc patients than in controls. Mitral E wave was significantly lower in SSc patients than in controls (p ¼ 0.07), whereas mitral A wave was significantly higher (p ¼ 0.02); an inverted E/A ratio was detected in 33/74 SSc patients vs 19/71 controls (p ¼ 0.0379). In addition, sPAP, though within the normal range, was higher in SSc patients than in controls (26.1 7 6.0 vs 24.1 7 5.1 mmHg; p ¼ 0.0013), exceeding 440 mmHg only in 2 patients. No cardiac chamber abnormalities were identified. As expected, TDI was more sensitive than SE in detecting LV-filling impairment. In fact, an inverted Em/Am was identified in 55/74 (74%) SSc patients vs 25/71 (35%) controls (p ¼ 0.000001). In addition, the prevalence of RVfilling abnormalities (p ¼ 0.000001) and of subtle RV and LV systolic impairment was significantly higher in patients than in controls (p ¼ 0.000001). Given the high number of parameters considered, we applied the Bonferroni correction. After correction, the following parameters still differed significantly between patients and controls: the E/A mitral ratio and sPAP at SE; and Sm, Em, Am, Em/Am, St o 11.5 cm/s, At, Et/At, and the prevalence of Em/Am o 1 and Et/At o 1 at TDI. These findings confirmed the impaired left ventricular filling and the increase of sPAP at SE, as well as the impairment of both left and right diastolic and systolic function. We also evaluated the correlations between each SE and TDI parameter and demographic and disease feature that could affect these parameters. We investigated the correlations between each SE and TDI parameter, age, and disease duration by linear correlation and the others by biserial correlation (Table 3). Significant correlations were found between: (i) SE-assessed E/A mitral ratio and age (r ¼  0.481, p ¼ 0.0001), disease duration (r ¼  0.233, p ¼ 0.04), and Medsger lung severity score Z 1 (r ¼  0.323, p ¼ 0.005); (ii) Em and age (r ¼  0.238, p ¼ 0.042) and dyspnea Z NYHA class II (r ¼  0.285, p ¼ 0.015); (iii) Em/Am and age (r ¼  0.266, p ¼ 0.023); (iv) At and Medsger heart severity scale Z 1 (r ¼  0.241, p ¼ 0.03); and (v) Et/At and age (r ¼  0.362, p ¼ 0.001), disease duration (r ¼  0.302, p ¼ 0.009), Medsger heart severity score Z 1 (r ¼  0.192, p ¼ 0.039), Medsger lung severity score Z 1 (r ¼  0.231, p ¼ 0.049), late pattern on

And/or taking anti-hypertensive drugs. a

p ¼ 0.009 r ¼  0.302 p ¼ 0.810 p ¼ 0.810 p ¼ 0.234 p ¼ 0.227 p ¼ 0.912 Et/At

p ¼ 0.001 r¼  0.362

p ¼ 0.908 p ¼ 0.928

SSc ¼ systemic sclerosis; BMI ¼ body mass index; F ¼ female; M ¼ male; dc ¼ diffuse cutaneous subset; lc ¼ limited cutaneous subset; NVC ¼ nailfoldvideocapillaroscopy; E ¼ E wave; A ¼ A wave; TDI ¼ tissue Doppler imaging; Sm ¼ S wave at mitral annulus; Em ¼ E wave at mitral annulus; Am ¼ A wave at mitral annulus; Et ¼ E wave at tricuspid annulus; At ¼ A wave at tricuspid annulus; sPAP ¼ pulmonary artery systolic pressure.

p ¼ 0.02 r ¼  0.272 p ¼ 0.006 r ¼  0.316 p ¼ 0.049 r ¼  0.231

p ¼ 0.878 p ¼ 0.08 p ¼ 0.761 p ¼ 0.051 p ¼ 0.329 p ¼ 0.353

0.564 0.03  0.241 0.049  0.192 p ¼ p ¼ r ¼ p ¼ r ¼ p ¼ 0.108 p ¼ 0.479 p ¼ 0.278 p ¼ 0.422 p ¼ 0.278 p ¼ 0.422 p ¼ 0.586 p ¼ 0.893 p ¼ 0.776 p ¼ 0.846

p ¼ 0.081 p ¼ 0.06 p ¼ 0.156 p ¼ 0.423 p ¼ 0.558 p ¼ 0.228 p ¼ 0.228 p ¼ 0.344

p ¼ 0.084 p ¼ 0.349 p ¼ 0.234 p ¼ 0.397 p ¼ 0.252

St (cm/s) At (cm/s)

capillaroscopy (r ¼  0.272, p ¼ 0.02), and dyspnea Z NYHA class II (r ¼  0.316, p ¼ 0.006); St o 11.5 cm/s and disease duration (r ¼ 0.240, p ¼ 0.04). At multiple regression analysis of baseline data adjusted for age, sex, disease duration, blood pressure, and body mass index, the following correlations remained significant: Em/Am o 1 and age (OR ¼ 1.19; 95% CI: 1.01–1.40; p ¼ 0.030); Et/At o 1 and dyspnea NYHA class Z II (OR ¼ 1.11; 95% CI: 1.06–1.33; p ¼ 0.033), late capillaroscopic pattern (OR ¼ 1.19; 95% CI: 1.11–1.36; p ¼ 0.029), and a Medsger heart severity score Z 1 (OR ¼ 1.49; 95% CI: 1.19–1.79; p ¼ 0.0459). These data confirm the expected influence of age on left ventricular filling and the hitherto unreported associations of microvascular alterations and routinely detected cardiac disease with altered right ventricular filling.

p ¼ 0.401

According to Bonferroni.

p ¼ 0.885

a

Em/Am

SSc ¼ systemic sclerosis; RVD basal ¼ right ventricular basal dimensions; TAPSE ¼ tricuspid annulus plane systolic excursion; RV ¼ right ventricle; LVEDd ¼ left ventricular end-diastolic diameter; LVESd ¼ left ventricular end-systolic diameter; IVS ¼ interventricular septum; PW ¼ posterior wall; EF ¼ ejection fraction; LA ¼ left atrium; PA ¼ pulmonary artery; PW ¼ pulsed wave; E ¼ E wave; A ¼ A wave; TDI ¼ tissue Doppler imaging; Sm ¼ S wave at mitral annulus; Em ¼ E wave at mitral annulus; Am ¼ A wave at mitral annulus; St ¼ S wave at tricuspid annulus; Et ¼ E wave at tricuspid annulus; At ¼ A wave at tricuspid annulus; sPAP ¼ pulmonary artery systolic pressure.

p ¼ 0.252

0.031 – 0.0003 0.0012 0.0003 0.0003 0.890 0.0003 0.229 0.0018 0.0003 0.0003

p ¼ 0.635

0.001 – 0.000001 0.000004 0.000001 0.000001 0.03 0.000001 0.0074 0.00006 0.000001 0.000001

p ¼ 0.712

15.4 7 3.2 0 18.2 7 6.7 12.5 7 3.4 1.5 7 0.7 25 (35%) 15.7 7 4.7 0 15.9 7 3.2 12.3 7 4.5 1.3 7 0.4 18 (25%)

p ¼ 0.928

13.7 7 2.7 0 12.9 7 3.4 17.1 7 5.4 0.85 7 0.4 55 (74%) 14.4 7 3.5 16 (22%) 13.8 7 3.2 16.7 7 4.7 0.9 7 0.3 49 (66%)

Am (cm/s)

TDI Sm (cm/s) Sm o 7.5 Em (cm/s) Am (cm/s) Em/Am Em/Am o 1 St (cm/s) St o 11.5 Et (cm/s) At (cm/s) Et/At Et/At o 1

p ¼ 0.799 p ¼ 0.965 p ¼ 0.622

0.217 0.620 0.031 0.007 – – – – 0.040

0.811 0.756 0.015  0.285 0.382

0.007 0.02 0.001 0.037 0.11 0.64 0.13 0.33 0.0013

p ¼ p ¼ p ¼ r ¼ p ¼

86.8 7 15.2 65.3 7 21.1 1.3 7 0.4 19 (27%) 58.4 7 16.3 40.9 7 13.3 1.5 7 0.6 7 (10%) 24.1 7 5.1

p ¼ 0.560 p ¼ 0.087 p ¼ 0.754

77.8 7 17.1 75.4 7 18.1 1.1 7 0.4 33 (45%) 55.2 7 11.4 42.1 7 11.9 1.4 7 0.4 12 (16%) 26.1 7 6.0

p ¼ 0.799 p ¼ 0.754 p ¼ 0.669

Pulsed wave Doppler E mitral (cm/s) A mitral (cm/s) E/A mitral E/A o 1 mitral E tricuspid (cm/s) A tricuspid (cm/s) E/A tricuspid E/A o 1 tricuspid sPAP (mmHg)

p ¼ 0.799 p ¼ 0.754 p ¼ 0.669

–

p ¼ 0.941 p ¼ 0.145 p ¼ 0.857

0.08

p ¼ 0.312 p ¼ 0.234 p ¼ 0.895

23.2 7 4.6

p ¼ 0.186 p ¼ 0.465 p ¼ 0.395

25.2 7 4.8

Left atrium LA volume index (ml/m2)

sPAP (mmHg) Sm (cm/s) Em (cm/s)

– – – – –

p ¼ 0.417

0.09 0.16 0.57 0.21 0.47

p ¼ 0.06

46.8 7 4.1 29.7 7 3.2 9.6 7 1.9 8.4 7 3.2 62.1 7 4.3

0.005  0.323 0.767 0.654 0.427

45.8 7 3.9 28.6 7 4.2 9.9 7 2.9 8.7 7 2.8 61.4 7 5.1

p ¼ r ¼ p ¼ p ¼ p ¼

Left ventricle LVEDd (mm) LVESd (mm) IVS (mm) PW (mm) EF (%)

p ¼ 0.232

–

0.04  0.233 0.389 0.453 0.550

0.35

p ¼ r ¼ p ¼ p ¼ p ¼

14.8 7 3.5

p ¼ 0.427

15.2 7 3.8

p ¼ 0.427

Right atrium RA area (cm2)

p ¼ 0.388

– – –

0.0001  0.481 0.674 0.812 0.042  0.238 0.002  0.262 0.023  0.266 0.497 0.626

0.16 0.69 0.23

p ¼ r ¼ p ¼ p ¼ p ¼ r ¼ p ¼ r ¼ p ¼ r ¼ p ¼ p ¼

33.9 7 5.1 22.1 7 4.8 5.1 7 0.3

p ¼ 0.351

34.4 7 4.1 22.1 7 3.1 5.2 7 0.4

E/A mitral

Right ventricle RVD basal (mm) TAPSE (mm) RV free wall (mm)

Medsger lung severity score Z 1

–

Medsger heart severity score Z 1

0.12

Disease duration

76.6 7 12.1

dcSSc

79.9 7 11.3

lcSSc

Heart rate (bpm)

Hypertensiona

p Correcteda

BMI Z 25 kg/m2

p

Age

Controls (n ¼ 71)

Table 3 Relationships between each baseline SE and TDI echocardiographic parameter and possible demographic and disease factors

SSc (n ¼ 74)

Dyspnea NYHA class Z II

Table 2 Baseline echocardiographic findings in SSc patients and controls

p ¼ 0.881

Late pattern on NVC

M. D’Alto et al. / Seminars in Arthritis and Rheumatism 43 (2014) 673–680

Sex

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M. D’Alto et al. / Seminars in Arthritis and Rheumatism 43 (2014) 673–680

Follow-up The SE and TDI parameters evaluated at 3-year follow-up are detailed in Table 4. Notably, no significant changes in any echocardiographic parameter were observed in controls. On the contrary, SSc patients showed a further deterioration of biventricular systolic and diastolic function. In particular, SE revealed a significant decrease in mitral and tricuspid E/A ratios and a significant increase Table 4 Echocardiographic and tissue Doppler findings at 3 years of follow-up p

p Correcteda

SSc (n ¼ 74)

Controls (n ¼ 71)

Right ventricle RVD basal (mm) TAPSE (mm) RV free wall (mm) IVC (mm)

35.1 7 4.6 21.9 7 3.4 5.3 7 0.5 13.8 7 2.5

34.0 75.2 21.9 7 3.4 5.2 7 0.5 13.7 7 2.5

0.42 0.49 0.62 0.71

– – – –

Right atrium RA area (cm2)

15.4 7 2.9

15.1 7 3.9

0.57

–

Left ventricle LVEDd (mm) LVESd (mm) IVS (mm) PW (mm) EF (%)

46.9 7 4.6 28.7 7 3.6 10.0 7 3.1 8.6 7 3.0 60.9 7 5.7

47.7 7 4.6 29.4 7 3.8 9.9 7 3.2 8.6 7 2.8 61.9 7 4.8

0.15 0.23 0.37 0.74 0.48

– – – – –

Left atrium LA volume index (ml/m2) 25.8 7 5.8

24.8 7 6.2

0.16

–

Pulsed-wave Doppler E mitral (cm/s) A mitral (cm/s)b E/A mitralc E/A o 1 mitral E tricuspid (cm/s)d A tricuspid (cm/s)e E/A tricuspide sPAP (mmHg)f

76.4 7 16.3 77.9 7 19.6 1.0 7 0.3 37 (50%) 52.3 7 10.4 46.8 7 12.5 1.2 7 0.3 28.8 7 6.3

88.5 7 17.7 68.9 7 18.3 1.3 7 0.6 21 (14%) 55.1 7 12.8 41.8 7 11.7 1.3 7 0.4 25.1 7 4.3

0.0001 0.0047 0.00001 0.0193 0.048 0.0021 0.0001 0.0002

0.0026 0.12 0.00026 0.501 0.13 0.054 0.0026 0.0052

TDI Sm (cm/s)g Sm o7.5 cm/s Em (cm/s)h Am (cm/s)i Em/Ami Em/Am o 1 St (cm/s)j St o 11.5 cm/s Et (cm/s)k At (cm/s)l Et/Atm Et/At o 1

12.6 7 2.6 5 (7%) 11.5 7 4.0 18.8 7 4.5 0.6 7 0.2 71 (96%) 13.9 7 3.4 18 (24%) 13.3 7 3.3 17.7 7 5.2 0.8 7 0.4 55 (77%)

14.7 7 3.7 0 17.8 7 4.2 13.7 7 5.2 1.3 7 0.9 26 (37%) 15.9 7 4.4 0 15.1 7 5.2 13.5 7 3.2 1.1 7 0.5 20 (28%)

0.00001 0.076 0.00001 0.00001 0.00001 0.0001 0.0027 0.0001 0.00001 0.00001 0.00001 0.00001

0.00026 – 0.00026 0.00026 0.00026 0.00026 0.070 0.00026 0.00026 0.00026 0.00026 0.0052

SSc ¼ systemic sclerosis; RVD basal ¼ right ventricular basal dimensions; TAPSE ¼ tricuspid annulus plane systolic excursion; RV ¼ right ventricle; IVC ¼ inferior vena cava; LVEDd ¼ left ventricular end-diastolic diameter; LVESd ¼ left ventricular end-systolic diameter; IVS ¼ interventricular septum; PW ¼ posterior wall; EF ¼ ejection fraction; LA ¼ left atrium; PA ¼ pulmonary artery; PW ¼ pulsed wave; E ¼ E wave; A ¼ A wave; TDI ¼ tissue Doppler imaging; Sm ¼ S wave at mitral annulus; Em ¼ E wave at mitral annulus; Am ¼ A wave at mitral annulus; St ¼ S wave at tricuspid annulus; Et ¼ E wave at tricuspid annulus; At ¼ A wave at tricuspid annulus; sPAP ¼ pulmonary artery systolic pressure. a

According to Bonferroni. p ¼ 0.029. p ¼ 0.01. d p ¼ 0.0050. e p ¼ 0.0001. f p ¼ 0.0013. g p ¼ 0.033. h p ¼ 0.020. i p ¼ 0.00001. j p ¼ 0.0013. k p ¼ 0.0074. l p ¼ 0.00006. m p ¼ 0.0007 vs SSc patients at baseline. b c

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Table 5 Differences between adjusted changes (adjusted Δ) in SE and TDI parameters in patients and controls Adjusteda ΔSSc patients Adjusteda ΔControls p Pulsed-wave Doppler E mitral (cm/s) A mitral (cm/s) E/A mitral

 0.006 7 0.09 0.04 7 0.16  0.022 7 0.22

E tricuspid (cm/s) A tricuspid (cm/s) E/A tricuspid sPAP (mmHg)

 0.036 0.123  0.116 0.193

7 7 7 7

0.14 0.23 0.19 0.32

0.013  0.038 0.049 0.016

7 7 7 7

0.007 0.013 0.151 0.107

0.004 0.0001 0.0001 0.002

TDI Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am St (cm/s) Et (cm/s) At (cm/s) Et/At

 0.016  0.050 0.184  0.123  0.030  0.030 0.08  0.081

7 7 7 7 7 7 7 7

0.10 0.41 0.391 0.529 0.11 0.133 0.188 0.17

0.031  0.03 0.069  0.08  0.005 0.033 0.073  0.021

7 7 7 7 7 7 7 7

0.08 0.08 0.115 0.111 0.07 0.12 0.12 0.188

0.029 0.487 0.09 0.009 0.049 0.003 0.569 0.115

0.022 7 0.08 0.008 7 0.08 0.020 7 0.12

0.015 0.049 0.002

SSc ¼ systemic sclerosis; PW ¼ pulsed wave; E ¼ E wave; A ¼ A wave; TDI ¼ tissue Doppler imaging; Sm ¼ S wave at mitral annulus; Em ¼ E wave at mitral annulus; Am ¼ A wave at mitral annulus; St ¼ S wave at tricuspid annulus; Et ¼ E wave at tricuspid annulus; At ¼ A wave at tricuspid annulus; sPAP ¼ pulmonary artery systolic pressure. a

For basal values.

in the prevalence of both mitral and tricuspid E/A o 1, and a further increase in sPAP. An estimated sPAP 4 40 mmHg was detected in 9 of the 72 SSc patients with a baseline sPAP o 40 mmHg vs no controls (p ¼ 0.03). Tissue Doppler imaging revealed a significant decrease in Em, Et, Em/Am, Et/At, Sm, and St and a further increase in Am, At and in the prevalence of Em/Am o 1, Et/At o 1, and St o1. At TDI, 16/19 SSc patients with basal Em/Am 4 1 (84%) showed mitral Em/Am o 1 vs 1/36 controls (3%) (p o 0.0001); 9/62 SSc patients with basal Et/At 4 1 (15%) showed Et/At o 1 vs 2/46 controls (4%) (p ¼ 0.11); 5/74 (7%) SSc patients showed Sm o 7.5 cm/s vs no control (p ¼ 0.058); and 2/58 (3%) SSc patients showed St o 11.5 cm/s vs no controls (p ¼ 0.2). After Bonferroni correction, all parameters remained significant except for the mean Et, At, St, and the prevalence of E/A o 1. These data show that the deterioration of left and right diastolic and systolic function is greater in SSc patients than in controls. As shown in Table 5, we evaluated the entity of changes in each SE and TDI parameter in patients and controls adjusted for basal values. It is noteworthy that almost all changes were greater in patients. At multiple logistic regression analysis adjusted for age, sex, disease duration, blood pressure, body mass index, and the use of immunosuppressive drugs (not proton pump inhibitors, calcium channel blockers, or anti-platelet agents because all patients were taking these drugs) a correlation between the inversion of the tricuspid E/A ratio and age (OR ¼ 1.10; 95% CI: 1.02–1.34; p ¼ 0.027) and female sex was detected (OR ¼ 0.018; 95% CI: 0.011– 0.067; p ¼ 0.035). New abnormalities in RV and/or LV diastolic function were associated with a baseline Medsger cardiac severity score Z 1 (HR ¼ 6.53; 95% CI: 1.53–27.8; p ¼ 0.01). These data show that SSc patients undergoing immunosuppressive therapy do not present a distinct SSc-HD disease course. Moreover, they show that the presence of routinely detected cardiac disease (i.e., a Medsger cardiac severity score Z 1) at baseline is predictive of the development of new diastolic alterations. Discussion This is the first longitudinal study to evaluate echocardiographic alterations in patients with SSc using both SE (M-mode,

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B-mode, and pulsed- and continuous-wave Doppler) and pulsed TDI. The latter procedure can be performed in 3 modalities: spectral pulsed-wave Doppler, 2-dimensional, and M-mode color Doppler [36–38]. Pulsed TDI is available in most echocardiography laboratories and allows accurate measurement of global and regional LV and RV function [36–38]. Nevertheless, in pulsed TDI, peak amplitudes of velocity and strain variables are influenced by the angle of the incident beam with the myocardial wall and depend on image quality [37]. In fact, it is frequently difficult to use TDI to evaluate apical segments. A number of studies have investigated HD patients in SSc patients by pulsed TDI [18–24], but most included only small case series [18–22,24]. Lindqvist et al. [18] evaluated 26 asymptomatic SSc patients using both SE and TDI and demonstrated normal RV systolic function but altered RV diastolic function together with an increase in RV wall thickness and RA area. In a series of 23 SSc patients undergoing SE, pulsed TDI and strain rate imaging, D'Andrea et al. [19] reported an independent inverse association of RV relaxation with skin disease, sPAP, and pulmonary fibrosis. In 20 SSc patients, Poanta et al. [21] found neither any signs of cardiac involvement nor any ECG or SE abnormalities or impaired LV filling. In 26 SSc patients with no clinical evidence of pulmonary hypertension and normal global systolic and diastolic function at conventional echocardiography, Aktoz et al. [22] identified an impairment of systolic and diastolic function by TDI. In the study of Shattke et al. [24], which included 20 SSc patients, isovolumetric acceleration was found to be a useful tool with which to detect early RV systolic impairment. In the only published report with a sample size comparable to ours, Meune et al. [23] prospectively evaluated 100 consecutive SSc patients without pulmonary arterial hypertension or clinical signs of heart failure undergoing SE and pulsed TDI. Compared with controls, SSc patients showed a wider left atrial diameter, impaired LV function, RV diastolic function, and a higher prevalence of depressed LV and RV contractility. At TDI, Sm was o7.5 cm/s in 14 SSc patients vs no control (p ¼ 0.040), and St was o 11.5 cm/s in 15 SSc patients vs no control (p ¼ 0.039). No correlation was found between TDI parameters and disease features. In our study, baseline SE showed: (i) impaired LV filling in SSc patients, as documented by an inverted E/A ratio in a significantly higher percent of SSc patients vs controls (45% vs 27%, p ¼ 0.007) even after Bonferroni correction; (ii) a significantly higher sPAP in SSc patients (p ¼ 0.040); and (iii) no anatomical alterations or any left or right systolic dysfunction. However, sPAP values in SSc patients were in the normal range and the small difference detected might depend on intra-inter observer variability. On the other hand, a subtle RV systolic dysfunction may have been missed. Although TAPSE is a reliable echocardiographic feature that reflects RV dysfunction, it has various limitations: it ignores the outlet portion and septal contribution to RV ejection, is angle dependent, is influenced by LV function, is load dependent, and is influenced by the degree of tricuspid regurgitation. Using TDI, we observed an even greater prevalence of both LV and RV diastolic abnormalities together with impaired RV systolic function as defined by St o 11.5 (22% of SSc patients vs no controls, p ¼ 0.0003). Moreover, 74% of SSc patients and 35% of controls showed mitral Em/Am o 1 (p o 0.0003) and 66% of SSc patients and 25% of controls showed Et/At o 1 (p ¼ 0.0003). No patients or controls had impaired systolic function as defined by Sm o 7.5 cm/s. Our results are consistent with those of previous studies that assessed diastolic function in SSc patients by both SE and pulsed TDI. An impaired LV diastolic function has been reported in approximately 40% and 75% of SSc patients by SE [18,19] and TDI [23], respectively, whereas an impaired RV diastolic function has been reported in approximately 15% and 65% of SSc patients by SE

[9] and TDI [18], respectively. In addition, our findings are consistent with those of Meune et al. [23] showing that SSc patients have increased sPAP, depressed RV systolic function, and subtle LV systolic dysfunction. Meune et al. [23] assessed LV diastolic function using the E/E ratio, while we used the Em/Am ratio. However, both methods are considered reliable [41,42]. Unlike Meune et al. [23], we did not observe a wider left atrial diameter nor an increased prevalence of pericardial effusions or Sm o 7.5 cm/s in any patient. These discrepancies may reflect differences in epidemiological and clinical characteristics. In fact, compared with our study, there was a higher prevalence of male sex and of patients with dc-SSc in the series of Meune et al.. In addition, in our study, several TDI-derived parameters correlated with epidemiological, capillaroscopic, and clinical features. At multiple regression analysis of baseline data, Em/Am o 1 was associated with age (p ¼ 0.030) and Et/At o 1 was associated with NYHA functional class Z II (p ¼ 0.018), late capillaroscopic pattern (p ¼ 0.022), and a Medsger cardiac severity score Z 1 (p ¼ 0.0459). The late capillaroscopic pattern was reported to be associated with the presence of digital ulcers and pulmonary hypertension [43]. Our results seem to be in line with this finding. The main objective of our study was to evaluate the disease course of SSc-HD by TDI. Interestingly, we confirm that TDI is more sensitive than SE in detecting subtle and subclinical LV and RV systolic and diastolic dysfunctions. In fact, differently from TDI, the vast majority of SE features were normal at baseline and unchanged at the end of follow-up. Indeed, at the 3-year followup, there was a further impairment of both diastolic and systolic function, as witnessed by significant changes in Em, Am, the Em/Am ratio, Et, Sm, and St. In addition, a further significant increase in sPAP ( þ0.193 7 0.32 vs þ0.016 vs 0.107; p ¼ 0.002) was detected at the 3-year follow-up, and 9 SSc patients vs no control developed a sPAP 4 40 mmHg. These findings confirm our previous SE-based observations [25] that suggested SSc patients undergo progressive diastolic impairment, and demonstrate the concomitant deterioration in these patients of RV and LV systolic function together with mild pulmonary artery disease, as documented by the increase in estimated sPAP. In the present study, we did not confirm the increase in interventricular septum and posterior wall thickness that was detected in our previous study [25]. However, it is noteworthy that this increased occurred only in patients who were monitored for 8–12 years. From a clinical point of view, these data and our previous data on the evolution of SSc-HD obtained using SE [25] suggest that SSc heart and pulmonary vessels undergo a progressive, albeit slow, deterioration that precedes the development of clinically significant manifestations (blocks, arrhythmias, and congestive heart failure), which might be contrasted by a therapy tailored to the single patient. The mechanisms underlying diastolic and systolic abnormalities in SSc are hotly debated. However, it is thought that Raynaud's phenomenon with the associated ischemic injury to the small coronary arteries and internal organs involved may precede and drive the development of fibrosis [44]. In line with this concept, increased myocardial fibrous tissue deposition was detected in endomyocardial biopsies of 94% of patients with no signs or symptoms of HD and/or pulmonary or arterial hypertension, LV hypertrophy, and LV systolic dysfunction [45]. It is should be noted that that our findings derive from prospectively recruited patients who were treated with calcium channel blockers, ACE inhibitors, or prostanoids. Both calcium channel blockers and ACE inhibitors have been shown to improve myocardial ischemia in short duration trials [46–49]. In addition, the use of calcium channel blockers was found to be an independent factor associated with LV dysfunction in the large retrospective

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EUSTAR cohort [50], whereas the use of ACE inhibitors was found to be negatively correlated with LV diastolic abnormalities [51]. Because our study was not designed to investigate the influence of currently used drugs on the course of SSc-HD, our data do not enable us to confirm or disprove these findings; however, they suggest that the current use of these drugs might not prevent the evolution of HD in SSc. Consequently, our results are consistent with those of a recent meta-analysis that demonstrated persistently high mortality rates of SSc patients in general and of SSc-HD patients in particular [2].

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