Author + information
- Received July 2, 2018
- Accepted July 3, 2018
- Published online October 1, 2018.
- Anders H. Tennøe, MDa,b,
- Klaus Murbræch, MD, PhDc,
- Johanna C. Andreassen, BScc,
- Håvard Fretheim, MDa,b,
- Torhild Garen, MSca,
- Einar Gude, MD, PhDc,
- Arne Andreassen, MD, PhDc,
- Svend Aakhus, MD, PhDd,e,
- Øyvind Molberg, MD, PhDa,b and
- Anna-Maria Hoffmann-Vold, MD, PhDa,b,∗ (, )@hoffmann_vold@Oslounivsykehus
- aDepartment of Rheumatology, Oslo University Hospital, Oslo, Norway
- bInstitute of Clinical Medicine, University of Oslo, Oslo, Norway
- cDepartment of Cardiology, Oslo University Hospital, Oslo, Norway
- dDepartment of Circulation and Imaging, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- eClinic of Cardiology, St. Olav’s Hospital, Trondheim, Norway
- ↵∗Address for correspondence:
Dr. Anna-Maria Hoffmann-Vold, Oslo Universitetssykehus HF, Rikshospitalet, Postboks 4950, Nydalen, 0424 Oslo, Norway.
Background Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality.
Objectives The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality.
Methods SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted.
Results Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84).
Conclusions DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.
Systemic sclerosis (SSc) is a severe and progressive, but heterogeneous systemic connective tissue disease characterized by vasculopathy, dysregulation of the immune system, and extensive fibrous tissue formation. Among the systemic connective tissue diseases, SSc presents the highest mortality (1).
Estimates from the European Scleroderma Trials and Research Group database indicate that the excessive mortality in SSc is mainly due to pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and disease-related cardiac causes, with cardiac causes accounting for 26% of the mortality defined as SSc-related (2).
Previous autopsy studies indicate that cardiac fibrosis is highly common in SSc (3,4). Mechanistically, it appears that disease-related loss-of-function of small coronary arteries and arterioles leads to ischemia and reperfusion injury, driving cardiac fibrotic tissue formation (5,6). Most cardiac affection is assumed to develop over the first years of the disease (7). Yet, most previous studies on cardiac function in SSc have not included serial measurements, making it challenging to elucidate how cardiac dysfunction evolves from baseline and onwards (8–13).
Diastolic dysfunction (DD) is regarded a precursor of heart failure with preserved ejection fraction (HFpEF) (14). Prior studies applying different combinations of echo parameters have reported reduced diastolic function in 18% to 62% of SSc cases (8,10,15), and DD assessed by the single parameter eʹ was reported to be a predictor of mortality in 2 smaller SSc cohorts (9,15).
To simplify and standardize the evaluation of diastolic function, the American Society of Echocardiography and the European Association of Cardiovascular Imaging established new guidelines in 2016 (16). To our knowledge, there are to date no studies estimating DD by these guidelines in a large and unselected SSc cohort.
The present study aimed to: 1) evaluate the frequency of DD at baseline and follow-up in a large unselected SSc cohort; and 2) determine the effect of diastolic function on mortality, applying the new criteria for diastolic function.
All SSc patients followed at the Oslo University Hospital are included in the prospective Oslo SSc cohort. Patients are followed on an annual basis by a rheumatologist, and data on demographic, clinical, laboratory, and imaging parameters are registered. Echocardiographies are performed routinely on all SSc patients to detect occult pulmonary hypertension (PH).
The present study involved patients registered between 2003 and 2016 with the following inclusion criteria: 1) fulfillment of the 2013 European League Against Rheumatism/American College of Rheumatology criteria (17) or the 1980 criteria (18) for SSc; and 2) at least 1 available echocardiography with adequate image quality. This study complied with the Declaration of Helsinki. The Regional Committee of Health and Medical Research Ethics in South-East Norway approved the research protocol (No. 2017/1815). Informed consent was obtained from all included subjects.
Data on demographics, date of diagnosis, and clinical presentation (including SSc subtype, modified Rodnan skin score, digital ulcers, ILD, and PH) were collected from the Oslo SSc cohort and from electronic patient journals. SSc subsets were evaluated as limited cutaneous SSc and diffuse cutaneous SSc based on extent of skin involvement (19). ILD was defined as the presence of >10% pulmonary fibrosis on high resolution computer tomography or 2 consecutive measurements of forced vital capacity <70% in the absence of imaging (20,21).
Right heart catheterization was performed on patients suspected of PH, based on echocardiography findings, clinical suspicion, or the DETECT algorithm (22). PH was defined as a mean pulmonary arterial pressure ≥25 mm Hg according to the European Society of Cardiology guidelines (23). Comparing the effect of primary cardiac and pulmonary disease on mortality, we defined PH as pre-capillary PH, excluding post-capillary PH from analyses. Pre-capillary PH was defined PH with a pulmonary capillary wedge pressure ≤15 mm Hg (23). PAH and PH-ILD were defined as pre-capillary PH in the absence or presence of ILD, respectively (24). Serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) values at baseline were collected. Disease duration was defined as time from diagnosis to baseline echocardiography, and the observation period as time from baseline echocardiography to date of death or study end (April 2017). Systemic hypertension was defined as the composite of both a hypertension diagnosis by the International Classification of Diseases-10th Revision code registered at Oslo University Hospital and a systolic blood pressure ≥140 mm Hg at the time of baseline echocardiography. Data on ischemic heart disease (IHD), heart failure, and atrial fibrillation was collected from electronic patient journals. At study end, vital status was available for all patients.
In total, 65 control subjects were collected from the Nord-Trøndelag Health Study (25). This population-based study contained echocardiographies from 1,266 participants without recognized systemic hypertension, cardiovascular disease, or diabetes mellitus. Control subjects were matched to the SSc patients with respect to age, sex, systolic blood pressure, and body mass index at time of baseline echocardiography.
The earliest accessible echocardiography from each patient was considered baseline echocardiography, and the most recent echocardiography was considered follow-up echocardiography. All examinations were performed at a single center, Oslo University Hospital, Rikshospitalet. Ultrasound recordings were obtained using GE Vivid 7 or Vivid E9 (GE Vingmed Ultrasound, Horten, Norway). Patients were examined in the left decubitus position, and software analyses were performed using EchoPAC version 201 (GE Healthcare, Chicago, Illinois). All examinations were reanalyzed for the present study between September 2016 and July 2017 by the same investigator (A.H.T.), blinded for patient clinical status. To ensure adequate interobserver variability, 43 examinations were analyzed by a second observer (J.C.A.), and 19 examinations were reanalyzed to ensure adequate intraobserver variability.
Diastolic function was assessed measuring transmitral flow pattern by pulsed Doppler, tissue Doppler displacement of the septal mitral annulus during early diastole (eʹ and E/eʹ), body surface indexed left atrial volumes by the biplane area length method (LAVI), and tricuspid regurgitant maximum velocity (TRV) by continuous Doppler (16). The 2016 guidelines on diastolic function were applied to evaluate diastolic function as a composite outcome (16). All 4 parameters were used for evaluation of diastolic function in the entire cohort, including TRV in patients with pre-capillary PH and LAVI in patients with mitral regurgitation. DD was defined as abnormality in >50% of the available parameters, whereas abnormality in <50% indicated normal diastolic function. In cases of 50% abnormal parameters, status was considered inconclusive. We applied these guidelines on all patients with ≥2 evaluable parameters. To compare patients clearly segregated by diastolic function, patients with inconclusive diastolic function were excluded from analyses on mortality. Patients with normal or inconclusive diastolic function at baseline and a DD diagnosis at the follow-up echocardiography were defined as new-onset DD.
DD was segregated into 3 severity grades: I, II, and III, using early and late transmitral flow velocities and number of abnormal diastolic parameters, as recommended by the guidelines (16).
Left ventricular systolic function was evaluated by ejection fraction using the Simpson biplane method and by global longitudinal strain averaging values from apical long-axis, 4-chamber, and 2-chamber views (26). Right-sided parameters such as tricuspid annular plane systolic excursion, fractional area change, right ventricular free wall longitudinal strain, right ventricular dimensions, and right atrial area were all evaluated in the 4-chamber view. Mitral regurgitation was categorized as mild, moderate, or severe. Pericardial effusion was categorized as mild (<5 mm), moderate (5 to 15 mm), or severe (≥ 15 mm).
Statistical analyses were performed using SPSS version 23 (IBM, Armonk, New York) and STATA version 14 (StataCorp LLC, College Station, Texas). Paired and independent t-tests, nonparametric tests, and chi-square tests were applied as appropriate for continuous and categorical data, respectively. For analyzing correlations, Pearson or Spearman coefficients were applied as appropriate. Parameters with >2 variables were analyzed with 1-way analysis of variance, and post hoc tests were applied. Logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs) were applied to investigate associations between DD and clinical characteristics. Cox regressions with hazards ratios (HRs) and 95% CIs were applied for prediction of mortality. Clinical, laboratory, and echocardiographic parameters of relevance were assessed. Only factors presenting significance levels <20% in univariable analyses, along with variables of clinical known importance, were allowed for inclusion in multivariable Cox regression analyses. A manual backward stepwise elimination procedure was performed to identify independent risk factors for mortality. To determine independent predictor variables and control for confounding from other parameters of the multivariable models, parameters with significance levels >0.05 (27) were eliminated from the models. Multiple regression analyses were preceded by estimation of correlation between the respective parameters. To avoid multicollinearity, parameters presenting high correlations were not included in common models. Multivariable Cox models were discriminated by the c-index (values >0.7 were considered acceptable). Cumulative survival rates were computed by the Kaplan-Meier method and significance was tested with the log-rank test.
We included 333 consecutive SSc patients with baseline echocardiographies available for analyses. Mean age was 58 ± 14 years, 83% were female, and 71% had limited cutaneous SSc. Median disease duration at baseline echocardiography was 1.6 years (interquartile range: 0.3 to 7.4 years) (Table 1). Data on IHD, systemic hypertension, right heart catheterization, heart failure, PH, and medication are presented in Table 1. As detailed later, a follow-up echocardiography was available for analyses in 207 of the 333 patients (62%) with baseline echocardiographies.
Systolic function at baseline
Left ventricular systolic function, measured by left ventricular ejection fraction (LVEF), was reduced in SSc patients compared with control subjects (Table 2). A midrange LVEF of 40% to 49% (28) was present in 21 patients (8%) of the entire cohort, and 9 patients (3%) had LVEF <40%. All control subjects had LVEF >50%.
Left ventricular diastolic function at baseline
At least 2 of the required parameters for DD were available and evaluated in 275 of 333 of the cohort patients (83%), and 241 patients presented a conclusive either normal diastolic function or DD (Tables 1 and 2). There were no differences between these 275 patients and the 58 patients who did not have evaluable diastolic function with respect to age at echocardiography, sex, SSc subtype, disease duration, systemic hypertension, IHD, body mass index, PH, or ILD. We did, however, find that mortality was higher in the 58 patients with nonevaluable diastolic function than in the 275 with evaluable function (55% vs. 24%; p < 0.001), and they had numerically lower mean LVEF (55% vs. 58%; p = 0.075).
At baseline, 46 of the 275 patients (17%) with evaluable diastolic function fulfilled the criteria for DD, 34 (12%) had an inconclusive evaluation and 195 (71%) had normal diastolic function. Of the 46 patients with DD, 41 were possible to categorize; 15% had DD grade I, 54% grade II, and 5% grade III; the last 27% were inconclusive between grades I and II.
Patients with DD were older at baseline and had higher accumulated frequencies of systemic hypertension, IHD, and PH at study end compared with patients with normal diastolic function. DD patients also exhibited reduced right ventricular function (Table 2). There were no differences between the groups stratified by diastolic function regarding sex, SSc subset, LVEF, body mass index, or ILD (Table 1).
We found that the 34 patients with inconclusive diastolic function differed from the 195 patients with normal diastolic function regarding age at baseline (63 ± 11 years vs. 54 ± 13 years; p < 0.001), frequency of hypertension (24% vs. 8%; p = 0.045), PH (35% vs. 15%; p = 0.031), and all-cause mortality (44% vs. 13%; p = 0.001), but there were no differences with respect to sex, disease duration, IHD, ILD, body mass index, or LVEF.
Among the control subjects, 4 individuals (6%) fulfilled the DD criteria. In terms of the diastolic parameters eʹ, E/eʹ, and left atrial area, we found no difference between control subjects and SSc patients with normal diastolic function, whereas SSc patients with DD differed from the control subjects (Table 2). Patients presented a higher rate of pathological TRV.
Factors associated with DD
In univariable logistic regression, baseline DD was associated with age at baseline, systemic hypertension, calcinosis, PH, New York Heart Association functional class, 6-min walk test, NT-proBNP, and IHD. In multivariable logistic regression, adjusted for sex, baseline DD was associated with age at baseline (OR: 1.09; 95% CI: 1.03 to 1.15; p = 0.004), NT-proBNP (OR: 1.01; 95% CI: 1.01 to 1.02; p = 0.001), PH (OR: 3.03; 95% CI: 1.01 to 9.17; p = 0.049), and calcinosis (OR: 5.86; 95% CI: 1.74 to 19.71; p = 0.004).
DD and mortality
In total, 98 of the 333 patients (29%) died during the observation period. The 5- and 10-year survival rates for the entire cohort were 76% and 54%, respectively (Central Illustration). Among patients with PH at baseline, 26 of 43 (60%) were dead at study end. Stratification by baseline diastolic function revealed higher death rates in patients with DD (26 of 46; 57%) than in patients with normal diastolic function, (25 of 195; 13%; p < 0.001). The 26 deceased DD patients did not differ from the 20 DD survivors regarding LVEF or observation period, but showed a numerical, nonsignificant lower age at baseline compared with DD survivors (age 66 years vs. 69 years; p = 0.293). Six of the DD patients had moderate or severe mitral regurgitation, of which 1 died during the observation period.
DD patients had a higher frequency of cumulative cardiovascular medication than patients with normal diastolic function (Table 1). However, no significant differences were found between subsets of deceased patients from the 2 groups (Figure 1).
Risk factors for mortality in the study cohort
In univariable Cox regression analysis, mortality was predicted by higher age at baseline echocardiography, presence of DD, PH, ILD, calcinosis, pericardial effusion and tendon friction rubs, absence of anticentromere antibodies, lower diffusing capacity of the lung for carbon monoxide and LVEF, higher modified Rodnan skin score, creatinine and NT-proBNP, abnormal left sided diastolic parameters, abnormal right-sided systolic parameters, and larger right atrial area. In the final multivariable regression model, DD was an independent predictor of mortality (Table 3).
Predicting mortality in SSc-PH
TRV approximates pressure of the pulmonary arteries during systole and is considered a valid marker of left atrial pressure in patients without pulmonary vascular disease. By excluding TRV from the DD algorithm in patients with established PH, DD remained a highly significant predictor of mortality, increasing c-index to 0.90 in multivariable Cox regression. PH independently predicted mortality (HR: 2.0; 95% CI: 1.1 to 3.9; p = 0.039) in a model including age, sex, modified Rodnan skin score, and NT-proBNP (c-index 0.84).
Longitudinal assessment of DD
Among patients with follow-up echocardiographies available, 186 (90%) had an echocardiography that was evaluable for diastolic function. Median time from baseline to follow-up echocardiography was 3.4 years (interquartile range: 1.6 to 6.2 years). Individual DD parameter analyses showed that the frequencies of patients with pathological eʹ, LAVI, TRV, and E/eʹ were higher at follow-up than at baseline (Table 4).
DD was diagnosed in 54 patients (29%) at follow-up. Patients with new-onset DD at follow-up showed a trend toward higher mortality (8 of 26; 31%) than patients with normal diastolic function at follow-up (12 of 106; 11%; p = 0.055).
Interobserver and intraobserver variability
Interclass and intraclass correlations coefficients for eʹ, E/eʹ, and left atrial area in 4-chamber view were 0.98 and 0.97, 0.98 and 0.99, and 0.94 and 0.94, respectively. Interclass correlation coefficient for TRV was 0.99.
Previous studies, mostly investigating smaller cohorts, indicated high frequencies of reduced diastolic function in SSc, but did not apply newly established DD definitions (8,9,11,15,29). Here, we show in a large and unselected SSc cohort that DD, defined by the 2016 echocardiographic guidelines on diastolic function, increases in frequency and severity during the disease course and has a high impact on mortality in SSc patients, which appears to exceed that of pre-capillary PH (Central Illustration).
Prevalence of DD
We consider the current SSc study cohort to be largely unselected, as most patients in South East Norway (with a population of 2.7 million) are referred to Oslo University Hospital for an interdisciplinary evaluation. In this cohort, we found a 17% cumulative incidence of DD at baseline and 29% at follow-up after a median follow-up time of 3.4 years. These DD frequencies are in the lower range of previous reports and may represent actual divergence from other cohorts. It may, however, also be due to the stricter definitions of DD applied, short disease duration at baseline, and that many earlier studies were from tertiary centers, potentially excluding patients with milder disease.
DD, cardiovascular risk factors, and mortality
In 2011, Hinchcliff et al. (9) showed that the diastolic parameter eʹ was predictive for mortality in SSc patients; this was further supported by Faludi et al. (15) in 2014. Although eʹ is a marker of left ventricular relaxation, evaluation of diastolic function is today recommended to also rely on parameters of ventricular filling pressure (LAVI, TRV, and E/eʹ) (16).
The DD group in our cohort was 13 years older at baseline than patients with normal diastolic function, and a higher mortality would be expected. However, in Norway, female life expectancy exceeds 84 years (30). This illustrates that the mortality rate in our cohort is very high considering their median age of 67 years and a median follow-up of 2.5 years. Finally, in the final Cox regression model, both age and DD predicted mortality independently. If the effect on mortality from DD was due to higher age, we would expect age to remain an independent predictor, whereas DD would lose significance. However, in the model, both remained significant predictors.
Creatinine was not permitted for inclusion in a common multivariable model with NT-proBNP due to high correlation. However, when replacing NT-proBNP with creatinine in the multivariable model, creatinine failed to predict mortality independently, adjusted for other parameters of the model.
Among DD patients, 13 of 46 (28%) were registered with a code of IHD at some time during the study period. Five of these 13 patients died during the study period. The DD subset with IHD presented a lower mortality (38%; n = 13) than the rest of the DD group (64%; n = 33). The DD group presented a higher amount of IHD compared with the group with normal diastolic function. However, in Cox regression, IHD failed to predict mortality, even at a univariable level. This supports the notion that mortality in SSc is highly dominated by other causes, outweighing the effect of IHD.
The current study design does not allow for assessment of causality between DD and death. Patients might die due to other SSc complications, or even non-SSc–related events, but DD seems to be either a primary or a contributing cause of death.
DD, a primary cardiomyopathy or due to right-sided dysfunction?
Patients with idiopathic pulmonary arterial hypertension are known to present a high prevalence of DD, associated with worse hemodynamics and outcome (31). Elevated right ventricular pressure may bulge the interventricular septum toward the left side (32,33), impairing left ventricular filling (34). It is therefore not surprising that many PH patients in our cohort also show a high coexistence of DD. In our study, 52% of patients with baseline DD developed PH during the disease course. Surprisingly, DD exceeded PH in respect of predicting mortality. Although effective treatment of DD is awaited, our study proposes that patients who display DD may require a closer follow-up.
Traditionally, few SSc-PH cases are thought to arise from left-sided heart disease (35), and our cohort included only 14 patients (4%) with post-capillary PH. However, a Canadian study showed that although the majority of SSc-PH patients initially were considered pre-capillary PH, fluid-challenge revealed occult left-heart disease, making post-capillary the dominant PH group (36). It is possible that some patients diagnosed with pre-capillary PH may in fact experience post-capillary PH secondary to DD (37). Further studies are warranted to clarify this important issue.
HFpEF in SSc, an underestimated complication?
DD is the hallmark of HFpEF (38), which appears to have equal morbidity and mortality as heart failure with reduced ejection fraction (39). Data on HFpEF in SSc are limited, but Bourji et al. (40) showed a 2-fold increased risk of death in SSc patients with combined PH and HFpEF compared with isolated SSc pulmonary arterial hypertension. HFpEF is more difficult to disclose than heart failure with reduced ejection fraction, as patients show normal ejection fractions and levels of natriuretic peptides are significantly lower (41). Patients experiencing heart failure may present lower-range NT-proBNP (42), and natriuretic peptide levels have been reported to be especially low in patients of female sex and lower age (43); both features are common in SSc patients. Heart failure symptoms in SSc may resemble pulmonary complications, and dyspnea related to heart failure may be misinterpreted as ILD or PH, leaving HFpEF underdiagnosed in SSc. Further studies on the impact and treatment of these conditions in SSc are therefore in demand.
A potential limitation is that the echocardiographies were re-evaluated for the present study and not originally recorded with respect to the present guidelines for diastolic assessment. Hence, 58 cohort patients were excluded because they had inadequate images for baseline diastolic evaluation. This group accounted for 32 deceased patients and was not used in analyses on DD and mortality. As the groups mostly showed resemblance, we consider our analyses generalizable for the entire cohort.
Second, apart from NT-proBNP values, our cohort did not include data on HFpEF. Such data would have made it possible to differentiate between symptomatic and asymptomatic DD in the predictive analyses.
When evaluating PH as a predictor variable, complete data on invasive measurements of all patients would be ideal. We still consider right heart catheterization in 51% of the cohort a high percentage.
Last, although our cohort is fairly large, there were fairly few outcomes in categories as DD and new-onset DD. This limits the ability to draw conclusions on predicting new-onset DD and prognosis.
Our study, applying the 2016 echocardiographic guidelines for DD on a large unselected cohort, implies a high frequency of DD in SSc, and a more detrimental impact on mortality than assumed from previous reports. DD strongly predicts mortality, even exceeding the role of pre-capillary PH.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with SSc, left ventricular diastolic dysfunction is associated with decreased survival.
TRANSLATIONAL OUTLOOK: Further studies are needed to evaluate potential treatment modalities for patients with SSc and diastolic ventricular dysfunction.
The authors thank The Nord-Trøndelag Health study (The HUNT Study), which is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology [NTNU]), Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The authors also appreciate the collaboration with Cathrine Brunborg, MSc, Oslo Centre for Biostatistics & Epidemiology, Oslo University Hospital.
The Norwegian Extra Foundation for Health and Rehabilitation and the Norwegian Women’s Public Health Association made this project possible. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- diastolic dysfunction
- heart failure with preserved ejection fraction
- ischemic heart disease
- interstitial lung disease
- left atrial volume index
- left ventricular ejection fraction
- N-terminal prohormone of brain natriuretic peptide
- odds ratio
- pulmonary hypertension
- systemic sclerosis/scleroderma
- tricuspid regurgitant maximum velocity
- Received July 2, 2018.
- Accepted July 3, 2018.
- 2018 American College of Cardiology Foundation
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