Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients.
Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist.
Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc.
Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.
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A number of recent large patient series analyses have shown that systemic sclerosis (SSc) confers a high risk of death1 and that internal organ involvement is an important determinant of mortality.1–4 The cardiovascular system is one of the major systems involved in SSc, with pulmonary arterial hypertension (PAH) being a severe complication of the disease. SSc patients displaying PAH are at high risk of death with a 55% 1-year survival rate.5–8 Screening of SSc patients for diagnosis of PAH is thus warranted in order to initiate specific management, and international guidelines recommend systematic screening with annual Doppler echocardiography.9
At the time we designed our study, the published literature describing the prevalence of PAH in SSc populations included only monocentric studies with relatively low numbers of patients, enrolled over periods of 3 to 9 years.5 10–12 We aimed to assess the prevalence of PAH in France by screening a large number of SSc patients using a standardised algorithm based on symptoms and Doppler echocardiography, and by confirming the diagnosis with right heart catheterisation.
There have also been recent reports of left ventricular (LV) diastolic dysfunction in SSc identified by Doppler echocardiography; therefore, a second objective of our study was to describe left and right heart echoDoppler parameters in our cohort of patients.
The methodology of this study has been fully described in our previous article reporting the prevalence of PAH in SSc,13 and is thus summarised below, with additional information provided for the echoDoppler analysis.
This prospective study was conducted in 21 French university hospitals that have departments with expertise in the management of SSc and follow large SSc active files. Each centre established a multidisciplinary team that included SSc experts, echocardiographers and PAH specialists. All adult SSc patients without known severe pulmonary function abnormalities (FEV1<60%, forced vital capacity <60%, total lung capacity <60%) or known significant cardiac diseases (such as systolic or diastolic left heart failure, right heart failure other than secondary to PAH, organic right or left valvular disease) in these centres were invited to participate in the study as part of their regular follow-up. Patients were classified as having diffuse or limited cutaneous SSc according to the LeRoy et al classification.14 15 Patients were evaluated for dyspnoea according to NYHA functional class and underwent a Doppler echocardiography. Baseline demographic data were recorded together with SSc characteristics.
The study protocol was approved by the independent Ethics Committee of the Centre Hospitalier Universitaire de Lille, Lille, France. All patients provided written informed consent before undergoing any study-specific procedure.
All patients satisfying the selection criteria and without a known diagnosis of PAH were referred to a senior cardiologist in each centre for a complete time-motion (TM)-bidimensional and Doppler echocardiography examination with standard views and procedures after 20 min of rest. Echocardiography was performed according to a pre-defined protocol and particular attention was paid to the identification and quantification of tricuspid regurgitation for detection of PAH, LV hypertrophy (LVH) and mitral flow pattern. All echocardiography results were reviewed by one cardiologist (PdeG) for quality and consistency. All results were the average of at least three different beats. The LV internal dimension and wall thickness were measured at end-diastole and end-systole according to the recommendations of the American Society of Echocardiography.16 End diastolic and end systolic LV volumes were calculated using the modified Simpson rule from the apical four-chamber view. Longitudinal and transversal right atrium diameters were measured in the apical view. The right to left end-diastolic diameter ratio was determined as the ratio between transversal diameters of the right and the left ventricles measured in the apical view at the level of the tricuspid and mitral valves. A complete valvular evaluation was performed with morphological, as well as Doppler and colour-flow imaging assessments. The mitral flow pattern was analysed using the pulsed-wave Doppler technique, with the sample volume located between the tips of the mitral leaflets. For valvular regurgitation, colour-flow Doppler was used to achieve the best alignment between the regurgitation and Doppler ultrasound beam, followed by a continuous wave Doppler analysis. Valvular regurgitations were assessed qualitatively with a visual appreciation of the extension of the regurgitation and, when indicated, quantitatively using the volumetric method, the area method and the proximal isovelocity surface area method for mitral regurgitation. Regurgitant volume and effective regurgitant orifice were determined for the quantification of valvular regurgitations when indicated. For aortic stenosis the mean pressure gradient and the aortic valve area were determined. Continuous wave Doppler was used for acquisition of spectral envelopes of the highest quality to measure the peak velocity of tricuspid regurgitation (VTR). PAH was suspected for patients with VTR >2.5–3 m/s and associated with unexplained dyspnoea, or with VTR >3 m/s, and warranted confirmatory right heart catheterisation. An enlarged left atrium was defined as a left atrial diameter ⩾40 mm, measured in the parasternal long axis view. LV mass was estimated using the Devereux equation.17 LVH was defined as an LV mass index ⩾134 g/m2 in males and ⩾110 g/m2 in females. LV systolic dysfunction was defined as a LV ejection fraction (LVEF) ⩽45%. A delayed relaxation of LV was defined as an E/A ⩽1 and a mitral deceleration time >240 ms. A restrictive mitral flow pattern was defined as an E/A ratio >2 or an E/A ratio >1 with a mitral deceleration time ⩽140 ms.18–20
Patients with each echocardiographic abnormality are presented as number and percentage of the whole population (n = 570). Results are expressed as mean (SD) for continuous variables, and as numbers (percentages) for binary and categorical variables. All comparisons were two-sided. The significance threshold was set at 0.05. Continuous variables were compared with Student t test or analysis of variance (ANOVA) or covariance (ANCOVA) if there were more than two groups. Categorical variables were compared using a χ2 test or a Fisher’s exact test. All statistical analyses were performed using SAS software version 8.2 (SAS Institute, Cary, North Carolina, USA).
A total of 570 patients were enrolled over the 11-month period from September 2002 to July 2003 and were suitable for evaluation for echocardiography. Clinical characteristics of the entire population and of subgroups of patients divided according to type of SSc are summarised in table 1.
During the study period, 114 additional patients had been enrolled but were further excluded from the analysis, of whom only 16 had severe pulmonary function abnormalities and 5 significant cardiac diseases. Other main exclusion criteria were refusal of the patients (n = 48) and other concomitant diseases (n = 14).
All different right heart parameters were in normal ranges, without difference between patients divided according to the type of SSC (data not shown).
PAH was suspected in 33 patients, which was confirmed by right heart catheterisation in 18 patients. PAH was not confirmed in 12 cases, and the remaining three cases displayed LV dysfunction.13 These latter patients had no or minor echocardiographic abnormalities: one patient had a normal LVEF but a left ventricle diameter normalised to body weight at the upper limit of the normal, one patient had a minor LVH, and the last one a normal echocardiogram.
Results of left heart parameters are shown in table 2.
LV systolic dysfunction was rare (eight patients; 1.4%) and observed more frequently in those with diffuse SSc (4.7%) than with limited SSc (0.2%) (p<0.001). Grade III–IV and II mitral regurgitations were found in two (0.4%) and 38 (6.7%) patients, respectively. Grade III–IV and II aortic regurgitations were found in 0 (0%) and 14 (2.5%) patients, respectively. Aortic stenosis <1 cm2 was noted in 19 (3.3%) patients. Conversely, other abnormalities were frequent. LVH was found in 129 (22.6%) patients. LV diastolic dysfunction was observed in 17.7%, with 48 patients (8.4%) having a restrictive mitral flow pattern and 53 (9.3%) a delayed relaxation of LV. A dilated left atrium was observed in 67 (11.8%) patients.
We performed subgroup analyses according to the most common left cardiac abnormalities. Thus, we compared patients with and without LVH (table 3), and patients according to their diastolic function (table 4).
Compared with those with no LVH, patients with LVH were less likely to be male, were older, had a higher systolic or diastolic blood pressure. In addition, they presented with greater left atrium and LV end diastolic diameters, and presented more frequently with a relaxation disorder or PAH (table 3). The type of SSc and the duration of the SSc disease did not differ between the two subgroups of patients.
Patients were divided according to mitral flow pattern. Most of the patients had a normal mitral flow pattern (n = 433, 76%), whereas 53 (9%) had a delayed relaxation and 48 (8%) had a restrictive pattern. There were some significant differences between subgroups with regard to sex, age, indices of LVH and of PAH, percentage of patients receiving antihypertensive drugs with the differences being most marked in those with delayed relaxation (data not shown). Blood pressure and type of SSc were similar in these 3 subgroups.
Because mitral flow patterns are highly dependent of some other parameters such as LVH, hypertension, age, LVEF and PAH, we excluded all the patients with cardiac or pulmonary diseases and patients receiving antihypertensive drugs except calcium channel blockers used for Raynaud symptoms. Characteristics of these patients, according to mitral flow pattern are summarised in table 4
The only significant difference between patients with a delayed mitral flow pattern and patients with a normal mitral flow was with regard to age. In patients with a restrictive mitral flow pattern, the only difference was female gender, with no male patients in this subgroup. Age, blood pressure, heart rate, type of SSc were similar in these two subgroups.
We believe that one major interest of our study is that it was conducted on a nationwide and multicentric basis, and used a pragmatic but still harmonised approach with pre-defined echoDoppler parameters. In addition, it was designed and performed to ensure high-quality data: dedicated experienced cardiologists performed all echocardiography assessments and all results were subsequently reviewed by one cardiologist for quality and consistency. We studied 570 consecutive patients, a significant proportion of the estimated 7000 SSc patients in France.21 Patients were enrolled in the main French University Hospitals that have significant experience in SSc and follow a large number of patients. Thus, the cohort described in the article may be representative of a subgroup of the general SSc population in France, without any evidence of heart disease or severe pulmonary fibrosis; nevertheless, in the absence of any French nationwide epidemiological data on SSc, this cannot be ascertained. Furthermore, our patient population was recruited in less than one year, which, together with the subsequent data review by one individual, promoted consistency of patient assessments. We were able to determine VTR in 80% of our patients, which is in the range of best reports in the literature,22 23 highlighting the good quality of echocardiograms in the study.
As we have shown, LV abnormalities are frequent in SSc, underlining the fact that careful analysis of the LV is warranted in order to distinguish PAH from postcapillary pulmonary hypertension. Some postcapillary pulmonary hypertensions may still be missed on echoDoppler evaluation, confirming that, as recommended by international guidelines, right heart catheterisation is mandatory to establish the diagnosis of PAH.9–24 We commented in detail on the prevalence of PAH in SSc in our primary article.13
Our study shows that LV abnormalities, particularly LVH (22.6%) or abnormal mitral flow pattern (17.7%) are frequent in SSc patients whereas LV systolic dysfunction is rare (1.4%), as were significant valvular diseases. It is of note, however, that these frequencies are underestimated as we excluded some patients with a known severe cardiac disease from the study. We did not find any difference in standard echocardiographic parameters between patients with limited or diffuse SSc, except for LV systolic dysfunction. However, because of the limited number of patients with systolic LV dysfunction, this result must be interpreted with caution.
There is controversy in the literature about the cause of diastolic dysfunction in SSc, as it may be specific to SSc or alternatively secondary to other confounding factors (such as age, elevated blood pressure and associated cardiovascular conditions). A histological study suggested that cardiac abnormal collagen deposition was present in 94% of SSc patients without LVH, systemic hypertension or PAH.25 Some authors found that impaired relaxation of the LV was still present in the SSc groups compared with controls, after adjustment for age and blood pressure and even in patients without LVH or systolic dysfunction.26–30 Recently, Maione et al demonstrated that diastolic dysfunction, defined as an inverted E/A ratio, was significantly more frequent in a population of 77 SSc patients (30% and up to 37% prevalence during the follow-up) compared with a matched control group (2%, p<0.001).29 Conversely, in the larger study by Aguglia et al, LV diastolic dysfunction was found only in SSc patients with conditions potentially affecting LV diastolic function.31 In a recent study, comparing 50 patients with SSc-related PAH and 41 idiopathic PAH, Fisher and co-workers found that SSc patients had LV abnormalities (LVH, left atrium dilatation and LV diastolic dysfunction) more frequently than patients with idiopathic PAH.32 However, SSc patients were older than patients with idiopathic PAH.
In the present study, because of the large number of patients included, we were able to assess the characteristics of those with and without an abnormal mitral flow pattern after exclusion of those with left heart diseases, hypertension or PAH. We then observed that an abnormal mitral flow pattern was still present in 15% of these patients. Moreover, we used a more precise definition of the mitral flow pattern than in all previous studies, allowing us to describe two different mitral profiles in our population; 8% of the patients had a restrictive mitral flow pattern while 6% had a delayed mitral flow. This latter pattern was predominantly related to age. However, the 8% of the patients with a restrictive mitral flow pattern were similar to the patients with normal mitral flow except for male gender. Age, duration of SSc, blood pressure and heart rate were similar. It is possible that these patients represent a subgroup of patients with a significant specific cardiac involvement in SSc. However, the number of patients is limited and further studies are definitely required in order to confirm this hypothesis. New echoDoppler parameters or new techniques, such as magnetic resonance imaging, have already demonstrated their usefulness for a better understanding of cardiac involvement in SSc.33–35
We acknowledge that our study has some limitations. Firstly, we did not include a control group for this echocardiography study as this program was primarily dedicated to prospectively screen for PAH in a large population of SSc patients. Secondly, our study focused on a selected subset of SSc patients without severe pulmonary function abnormalities and severe cardiac disease. Consequently, our figures underestimate the true prevalence of PAH and cardiac abnormalities. Thirdly, we may have underestimated the proportion of patients with abnormal LV diastolic function as we included patients with a pseudo-normal mitral flow in the subgroup of patients with normal diastolic function. As LV diastolic dysfunction progresses, between the delayed relaxation and the restrictive pattern, patients with diastolic dysfunction have a pseudo-normal pattern of the mitral flow. In this case, new echocardiographic parameters, which were not analysed in our multicentric study, are required. Fourthly, one important confounding factor is arterial hypertension. Hypertension is, with age, one of the most important determinants of LVH and of LV diastolic dysfunction. In SSc population, it is very difficult to know the true proportion of patients with hypertension because a majority of patients with Raynaud phenomenon or with digital ulcers received vaosactive agents such as calcium channel blockers, which thus may control blood pressure and hide a possible hypertension. Lastly, we cannot exclude silent coronary ischaemia in some patients with diastolic dysfunction.
In conclusion, this large prospective nationwide multicentric study in SSc patients demonstrated that LV hypertrophy and diastolic dysfunction are frequent features of this disease. We found a small subgroup of patients (8%) without any concomitant cardiac or pulmonary diseases, with a mitral restrictive pattern. This subgroup could represent a small subset of patients with primary cardiac involvement related to SSc. The prognostic implications of these LV abnormalities will be evaluated in the 3-year follow-up of this cohort.
The authors thank Actelion Pharmaceuticals France for the grant to support this study.
List of ItinerAIR-Scleroderma investigators in alphabetical order by city
Bobigny, Avicenne: Loïc Guillevin, Luc Mouthon, Linda Nasciembeni, Jean-Marie Houeix; Bordeaux 1: Jean-François Viallard, Marie-Sylvie Doutre, Thierry Schaeverbeke, Marc-Alain Billès, Stéphane Lafitte, Virginie Bernard, Claire Dromer; Bordeaux 2: Joël Constans, Philippe Gosse, Philippe Lemetayer; Clamart, Antoine-Béclère: Marc Humbert, Olivier Sitbon, Xavier Jaïs, Abdul Monem Hamid, Vincent Ioos, Gérald Simonneau; Créteil, Henri-Mondor: Anne Cosnes, Pascal Guéret, Juliette Rousseau, Serge Adnot; Grenoble: Patrick Carpentier, Jean-Louis Cracowski, Christophe Pison; Lille: Eric Hachulla, Pierre-Yves Hatron, David Launay, Viviane Queyrel, Marc Lambert, Pascal de Groote, Nicolas Lamblin, Joël Dagorn; Lyon: Jacques Ninet, Fadi Jamal, Michel Ovize, Jean-Yves Bayle, Michèle Bertocchi, Jean-François Cordier; Marseille: Jean-Robert Harle, Fréderique Retornaz, Sylvie Hesse-Bonerandi, Gilbert Habib, Sébastien Renard, Martine Reynaud-Gaubert; Nancy: Claude Schmidt, Jean-Luc Schmutz, Christine Suty-Selton, François Chabot; Nantes: Christian Agard, Mohamed Hamidou, Jean-Marc Langlard, Erwan Bressolette, Alain Haloun; Paris, Bichat: Thomas Papo, Olivier Lidove, Catherine Picard-Dahan, Dominique de Zuttere, Eric Brochet; Paris, Cochin: André Kahan, Yannick Allanore, Laure Cabanes, Christophe Meune, Christian Spaulding; Paris, La Pitié-Salpêtrière: Camille Francès, Anne-Claude Koeger, Dominique de Zuttere; Paris, Saint-Antoine: Jean Cabane, Kiet Phong Tiev, Ariel Cohen; Paris, Saint-Joseph: Isabelle Lazareth, Ulrique Michon Pasturel, Yara Antakly-Hanon; Paris, Saint-Louis: Dominique Farge, Suzanne Ménasché; Rennes: Patrice Jego, Jacqueline Chevrant-Breton, Marcel Laurent, Philippe Delaval; Rouen: Isabelle Marie, Geneviève Dérumeaux, Fabrice Bauer, Hélène Etchaninoff; Strasbourg: Jean-Louis Pasquali, Jean Sibilia, Hélène Petit, Ari Chaouat; Toulouse: Daniel Adoue, Daniel Conte, Bruno Degano; Tours: Elisabeth Diot, Laurent Machet, Frédéric Patat, Véronique Eder, Christian Marchal, Olivier Marie.
Funding: A research grant from Actelion Pharmaceuticals France was obtained for the logistical support, monitoring, project management, data management and statistical analysis of the study.
Competing interests: None declared