Patient Population

This was an observational retrospective cohort study. A total of 130 patients with sarcoidosis attending our referral center (Leiden University Medical Center, Leiden, The Netherlands) and undergoing 2D echocardiography at the time of or following their diagnoses were identified using the departmental cardiology information system (EPD-Vision). The diagnosis of sarcoidosis was made in the setting of a compatible clinical picture and the absence of an alternative disease process capable of producing a similar clinical syndrome, with or without histologic confirmation of the presence of noncaseating granulomas. Given that the aim of the present study was to identify the prevalence of RV dysfunction in patients with sarcoidosis independent of manifest systolic LV impairment or other clinical evidence of cardiac involvement, patients with known or suspected cardiac sarcoidosis on the basis of the Japanese Ministry of Health and Welfare diagnostic criteria were excluded ( n = 5 definite cardiac sarcoidosis, n = 9 one major criterion alone). Similarly, those with non-sarcoid-related etiologies of structural heart disease ( n = 16) were also excluded. Finally, patients with noncardiac conditions associated with pulmonary hypertension were also excluded to avoid possible confounding in the setting of differential causes of afterload-associated RV dysfunction ( Figure 1 ).

Study flowchart illustrating patient selection process. CS , Cardiac sarcoidosis.

Control subjects were identified from the departmental echocardiographic database (EchoPAC version 112.0.0; GE Vingmed Ultrasound AS, Horten, Norway) using a dedicated search code defining the absence of cardiac structural abnormalities in subjects without histories of cardiac disease, typically referred for echocardiography in the setting of cardiovascular risk stratification or the finding of a murmur on auscultation. An age- and gender-matched comparator group ( n = 50) was selected on the basis of published comparability principles.

The current retrospective evaluation of clinically acquired data was approved by the institutional review board of the Leiden University Medical Center, which waived the need to obtain written informed consent.

Study Protocol and Clinical End Points

Clinical data, including organs involved, mode of diagnosis, serum angiotensin-converting enzyme and lysozyme levels, and results of chest radiography and pulmonary function testing, were recorded for all patients. Pulmonary function parameters were measured according to American Thoracic Society and European Respiratory Society recommendations. RV GLS was measured by 2D speckle-tracking analysis applied to baseline echocardiographic images alongside comprehensive 2D and Doppler analysis in all patients and control subjects. The main outcome measure was prespecified as a composite end point of all-cause mortality or clinical heart failure, defined as heart failure–related hospitalization, New York Heart Association (NYHA) functional class III or IV symptoms, or deterioration of NYHA functional class by one or more classes from baseline. Outcome data were assessed by retrospective review of electronic medical data and the official Dutch National Survival Registry. Follow-up was available for all included patients.

Conventional Echocardiography

Two-dimensional grayscale and Doppler images were acquired with patients in the left lateral decubitus position using a commercially available system (Vivid 7 and e9; GE Vingmed Ultrasound AS) equipped with 3.5-MHz or M5S transducers. Image analysis was performed offline using EchoPAC version 112.0.0. LV chamber and wall thickness quantification were performed according to standard recommendations. LV ejection fraction (LVEF) was derived from LV volumes quantified according to the Simpson biplane method, as recommended. Left atrial volume was also measured using the Simpson biplane technique and subsequently indexed to body surface area. Severity of mitral regurgitation and tricuspid regurgitation was graded according to recent guidelines. For diastolic function, mitral inflow was analyzed using pulsed-wave Doppler and early (E) and late (A) diastolic velocities; E-wave deceleration time was also assessed. Mitral annular peak early velocity (average E′) was derived from color-coded tissue Doppler imaging at both the septal and lateral site of the mitral annulus, with individual site values averaged to give an overall value. The ratio of E-wave velocity to average E′ (E/E′) was subsequently calculated. Tricuspid annular plane systolic excursion (TAPSE) was measured at the RV free wall as the conventional measure of RV function. Pulmonary artery systolic pressure was estimated using RV systolic pressure calculated from the tricuspid regurgitation peak gradient added to assessment of right atrial pressure using inferior vena cava size and collapsibility, as previously described.

Two-Dimensional Speckle-Tracking Analysis

Speckle-tracking analysis was performed using commercially available software (EchoPAC version 112.0.0). For analysis of the right ventricle, the standard apical four-chamber view was used, as previously described. The endocardial border of the entire right ventricle was manually defined at end-systole, and the automatically created region of interest was then adjusted to the thickness of the myocardium. Longitudinal strain curves were generated for all six segments (basal, mid, and apical segments of both the septum and RV free wall). RV free wall longitudinal strain (FWS) was calculated as the average of the basal, mid, and apical segments of the RV free wall. RV GLS was then calculated as the average peak longitudinal systolic strain across the six regional curves ( Figure 2 ). Both measures represent the percentage of longitudinal shortening in systole relative to the original length and are expressed by convention as negative values. Therefore, a less negative value implies reduced magnitude of longitudinal strain, and a more negative value indicates greater magnitude of strain. The patient population was stratified into two groups (preserved RV function [RV GLS < −19%] and impaired RV function [RV GLS ≥ −19%]) on the basis of the previous demonstration of this cutoff for RV GLS to accurately differentiate between normal and impaired RV contractility (sensitivity, 95%; specificity, 85%).

Two-dimensional speckle-tracking strain assessment of the right ventricle. ( Left ) The region of interest created by manual delineation of the RV septal and free wall endocardial borders. From this six-segment model, longitudinal strain curves are generated ( top right ). RV GLS represents the average peak longitudinal systolic strain across the six regional curves ( dotted line curve, arrow ). RV FWS is also shown as the average of the three segments (basal, mid, and apical) of the RV free wall.

LV GLS analysis was similarly performed by tracing the LV endocardial border at end-systole in apical four-, two-, and three-chamber views stored as digital cine loops and processed offline. LV GLS was provided by the software as the average value of peak systolic longitudinal strain across all three apical views using a 17-segment model.

Statistical Analysis

Continuous variables are presented as mean ± SD and categorical variables as frequencies and percentages. Variables were compared across patient and control or RV function groups using either the unpaired Student’s t test or the χ ² test. Univariate and multivariate linear regression analyses were then performed to assess the independent correlates of RV GLS in the total patient population. All parameters achieving significance levels of P < .10 between RV GLS groups were selected for linear regression analysis; those parameters achieving significance at the univariate level ( P < .05) were subsequently entered into the multivariate analysis. Collinearity between individual univariate parameters was checked for using the Pearson correlation coefficient. Receiver operating characteristic curve analyses were then performed to determine the area under the curve for each of the RV function parameters (TAPSE, RV GLS, and RV FWS) for association with the clinical composite end point. Sensitivity and specificity of the predefined cutoff for RV GLS of ≥−19% were determined for this outcome. Finally, event rates for the risk for death or clinical heart failure were plotted in Kaplan-Meier curves and compared between RV GLS groups using the log-rank test.

Statistical analyses were performed with SPSS Statistics (IBM, Armonk, New York). All tests were two sided, and P values < .05 were considered to indicate statistical significance.

Reproducibility

Reproducibility of RV GLS and RV FWS were expressed as both interclass correlation coefficients and as a percentage of the absolute difference divided by the mean of the pair-repeated observations (absolute difference). For intra- and interobserver variability, 15 patients were selected at random, and measurements were repeated by the same observer on the same echocardiographic images ≥2 weeks apart, and by another independent observer.

Patients

RV GLS assessment was feasible in 91% of patients ( n = 88) eligible for inclusion, who constituted the final patient population ( Figure 1 ). The mean frame rate for the total study population was 64 ± 16 frames/sec. Baseline demographic and clinical characteristics of the patient population are shown in Table 1 . The mean age was 54 ± 13 years (control subjects, 54 ± 13 years; P = .25), and 51% of patients (control subjects, 46%; P = .56) were men. Patients and control subjects did not differ in terms of the presence of cardiovascular risk factors (hypertension, P = .22; diabetes, P = .59; hyperlipidemia, P = .08). Pulmonary involvement was present in the majority of patients (89%). Median estimated pulmonary artery systolic pressure for the overall patient population was 24 mm Hg (interquartile range, 18–32 mm Hg).

Regarding 2D echocardiographic parameters compared between patients and control subjects, as illustrated in Table 2 , patients with sarcoidosis had significantly lower LVEF and TAPSE, although for both parameters, mean values for patients remained within the normal ranges. Both quantitative global and regional RV function using RV GLS and RV FWS, respectively, were significantly reduced in patients with sarcoidosis compared with control subjects; however, 47% of the patient population ( n = 41) had impaired RV function according to the previously defined cutoff for GLS.

Table 2

Echocardiographic characteristics compared between patient and control populations and further stratified according to RV function

Variable	Control population ( n = 50)	Patient population ( n = 88)	Impaired RV function ( n = 41)	Preserved RV function ( n = 47)	P ∗
LVEDD (cm)	5.1 ± 0.51	4.9 ± 0.51	4.9 ± 0.56	5.0 ± 0.45	.29
LVESD (cm)	3.1 ± 0.41	3.2 ± 0.46	3.2 ± 0.50	3.2 ± 0.43	.67
LVESV (mL)	40 ± 10	46 ± 14 †	45 ± 14	47 ± 15	.45
LVEDV (mL)	107 ± 21	106 ± 30	103 ± 28	108 ± 31	.42
LVEF (%)	63 ± 6	57 ± 5 †	57 ± 5	57 ± 5	.29
MR grade ≥ 2	1 (2%)	4 (5%)	1 (2%)	3 (6%)	.38
LAVI (mL/m 2 )	25 ± 8	24 ± 8	24 ± 8	24 ± 7	.71
E (cm/sec)	79 ± 19	75 ± 17	72 ± 16	79 ± 17	.06
A (cm/sec)	67 ± 16	70 ± 16	72 ± 17	69 ± 16	.32
DT (msec)	204 ± 42	199 ± 41	198 ± 37	200 ± 44	.79
Average E′ (m/sec)	8.3 ± 2.3	7.5 ± 2.0	6.7 ± 1.9	8.1 ± 1.9	.002
Average E/E′ ratio	10 ± 3	11 ± 3	12 ± 4	10 ± 2	.046
TAPSE (cm)	2.4 ± 0.36	2.1 ± 0.33 †	2.0 ± 0.27	2.2 ± 0.35	.02
TR grade ≥ 2	2 (4%)	6 (7%)	3 (8%)	3 (7%)	.83
PASP (mm Hg)	22 ± 7	26 ± 15	28 ± 18	25 ± 12	.36
RV FWS (%)	−30.6 ± 4.2	−23.9 ± 6.7 †	−19.7 ± 6.0	−27.5 ± 4.8	<.001
RV GLS (%)	−24.6 ± 1.8	−20.1 ± 4.6 †	−16.1 ± 2.8	−23.6 ± 2.5	<.001

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