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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular inflammation and fibrosis. Visceral involvement, including cardiac manifestations, can lead to severe clinical complications, such as congestive heart failure, arrhythmias, and sudden death. Conventional echocardiography parameters have limited sensitivity to detect subtle myocardial dysfunction in patients with SSc. The aim of this study was to assess, using novel speckle-tracking strain analysis, the presence of myocardial dysfunction in patients with SSc, and to investigate its relationship to functional capacity and ventricular arrhythmias.

Methods

A total of 104 patients with SSc (mean ± SD age 54 ± 12 years, 77% female) were included and underwent cardiopulmonary exercise testing, 24-hour electrocardiography (EKG) Holter monitoring, and transthoracic echocardiography. For comparison, 37 matched healthy control subjects were included.

Results

The total patient population consisted of 51 patients with limited cutaneous SSc and 53 with diffuse cutaneous SSc. Peak VO2 was a mean ± SD 91 ± 20% predicted, and 28 patients had abnormal findings (ventricular tachycardia or ventricular ectopics >100/day) on EKG Holter monitoring. Patients with SSc, as compared with controls, had impaired global longitudinal and circumferential strains (mean ± SD −18.2 ± 1.8% versus −21.3 ± 1.7% and −18.2 ± 2.3% versus −21.3 ± 2.1%, respectively; each P < 0.01), but there was no difference in the left ventricular ejection fraction between patients and controls (mean ± SD 63.5 ± 7.2% versus 64.6 ± 4.4%; P = 0.20). In patients with SSc, global longitudinal and circumferential strains each correlated with the peak VO2 (r = −0.46 and r = −0.41, respectively; both P < 0.01), and multivariate analysis confirmed the independent association of each strain measure with the peak VO2. Compared to SSc patients with normal results on EKG Holter monitoring, SSc patients with abnormal results showed impaired global longitudinal strains (−18.5 ± 1.5% versus −17.1 ± 2.1%; P < 0.01) and circumferential strains (−18.7 ± 2.0% versus −17.3 ± 2.5%; P = 0.01), and each strain measure was independently associated with abnormal Holter findings.

Conclusion

Speckle-tracking strain analysis can detect subtle myocardial dysfunction in patients with SSc. Importantly, decreased global longitudinal and circumferential strains are associated with lower functional capacity and rhythm disturbances in patients with SSc.

Systemic sclerosis (SSc) is an autoimmune disease that is characterized by deposition of collagen in multiple organs and is associated with significant disability and reduced life expectancy (1). Cardiovascular involvement has been shown to be one of the leading causes of mortality in SSc (2) and can occur in up to 70% of patients as a finding on autopsy (3). Early diagnosis and accurate staging of myocardial involvement are therefore crucial for the management of these patients and for therapeutic strategies.

Conventional echocardiographic assessment of left ventricular (LV) systolic function is based on measurement of the LV ejection fraction (LVEF). This approach, however, has shown limited sensitivity for the assessment of myocardial abnormalities in patients with SSc, being able to identify only 5% of patients with cardiac involvement (4). More sophisticated and sensitive techniques for the assessment of LV function are therefore needed to improve the detection of subclinical myocardial dysfunction in patients with SSc. Results of initial studies using tissue Doppler imaging suggested that myocardial velocity and deformation (strain) might be more sensitive than conventional measures in identifying subtle cardiac dysfunction in asymptomatic patients with SSc (5–7). However, the clinical implications of this alternative approach for LV function assessment have not been evaluated.

Recently, 2-dimensional (2-D) speckle-tracking strain analysis has been proposed as a sensitive and accurate method for the evaluation of subclinical myocardial dysfunction, providing measures of LV regional and global strain in 3 orthogonal directions (longitudinal, circumferential, and radial) (8). The aim of this study was therefore to apply this novel technique to assess the presence of LV systolic dysfunction in a large cohort of patients with SSc. Furthermore, the clinical value of measurement of the LV global strain by 2-D speckle-tracking analysis was evaluated in relation to functional capacity and ventricular arrhythmias in these patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Patient population and protocol.

The present study included 113 consecutive patients with SSc referred to the Department of Rheumatology at Leiden University Medical Center. The patients were recruited from 2 prior studies: a randomized controlled trial evaluating the effectiveness of a multidisciplinary-team care program (9) and a study evaluating the outcomes of a 2-day diagnostic, multidisciplinary day care program (10). All patients underwent an extensive screening, including detailed physical examination, modified Rodnan skin thickness score assessment (maximum total score of 51) (11), laboratory testing (including determination of the erythrocyte sedimentation rate and levels of antinuclear, anti–topoisomerase I, anti-RNP, and anticentromere antibodies), chest radiography, and lung function tests. Interstitial lung disease was diagnosed by chest radiography and by lung function test, and also with computed tomography when indicated.

The disease in patients was classified as either limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc), according to the classification system described by LeRoy et al (12). In addition, cardiopulmonary exercise testing (CPET) and 24-hour electrocardiography (EKG) Holter monitoring were performed to assess patient functional capacity and potential ventricular arrhythmias, respectively. None of the patients had angina pectoris or symptoms attributable to cardiovascular disease, and therefore specific tests for microvascular and macrovascular ischemia were not performed. Transthoracic echocardiography was performed to evaluate conventional parameters of cardiac function and to assess subclinical LV systolic dysfunction using novel speckle-tracking analysis. The relationship of LV function with measurements of functional capacity and ventricular arrhythmias was evaluated.

Seven patients were not able to perform CPET (because of severe pulmonary hypertension in 4 patients, severe aortic valve stenosis in 1 patient, and severity of SSc in 2 patients), and therefore these patients were excluded from the analysis. In addition, 2 patients were excluded because of an incomplete clinical assessment. The final study population consisted of 104 patients.

For comparison purposes, 37 normal healthy individuals were matched with the patients (in a 1:3 ratio) for age and sex, as a control group. These subjects were referred for atypical chest pain, palpitations, or syncope without murmur, and were found to have a normal structural heart on echocardiography.

The study protocol was approved by the Ethics Committee of the Leiden University Medical Center. All participants provided written informed consent for the studies in which they participated

Lung function testing.

Lung function tests were performed in all patients with SSc, and included spirometry and single-breath diffusing capacity for carbon monoxide (DLCO). Spirometry measurements included the % predicted values for the forced vital capacity and total lung capacity (TLC), measured according to the American Thoracic Society/European Respiratory Society recommendations (13–15).

Conventional echocardiography.

All patients with SSc and controls were imaged in the left lateral decubitus position, using a commercially available system (Vingmed Vivid 7; General Electric Vingmed Ultrasound). Images were obtained using a 3.5-MHz transducer and digitally stored in cine-loop format; offline analysis was performed using EchoPAC version 108.1.5 (General Electric-Vingmed). LV dimensions, LV volumes, and the LVEF were measured according to the current recommendations (16). Evaluation of LV diastolic function was based on pulsed-wave Doppler imaging of mitral valve inflow, as recommended by the American Society of Echocardiography (17), measuring peak early diastolic velocity (E), peak late diastolic velocity (A), their ratio (E/A), and the E-wave deceleration.

Pulmonary venous flow velocities during systole (S) and diastole (D) were also recorded. Using tissue Doppler imaging, the early diastolic velocity (E′) and systolic velocity (S′) were measured at the level of the LV basal lateral segment. In addition, the E/E′ ratio was calculated as an estimation of LV filling pressure (18). LV diastolic dysfunction was therefore categorized as previously described: normal, mild (defined as LV impaired relaxation without evidence of increased filling pressure), moderate (defined as LV impaired relaxation associated with moderate elevation of filling pressures or pseudo-normal filling), and severe (defined as restrictive LV filling) (17). Pulmonary arterial systolic pressure (PASP) was estimated by determining the right ventricular systolic pressure, which was calculated from the tricuspid regurgitation peak gradient using the Bernoulli equation, and adding the right atrial pressure, estimated using the dimension and the degree of inferior vena cava respiratory collapse (19).

Two-dimensional speckle-tracking strain analysis.

Two-dimensional speckle-tracking analysis is a novel imaging technique that allows the assessment of LV myocardial deformation by tracking natural acoustic markers (speckles) in a frame-to-frame basis within the cardiac cycle. The speckles are visible in the standard gray-scale 2-D images and are equally distributed within the myocardium. As represented in Figure 1, LV deformation can be assessed in 3 orthogonal directions, as longitudinal, circumferential, and radial strains (20).

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Figure 1. Schematic representations of the 3 orthogonal directions of strain measured with 2-dimensional speckle-tracking analysis. Global longitudinal strain evaluates the shortening/lengthening of the myocardial wall. Radial strain evaluates the thickening and thinning of the myocardial wall. Circumferential strain assesses the shortening/lengthening along the curvature of the left ventricle.

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Longitudinal strain, evaluating the shortening/lengthening of the myocardial wall, was measured from the 3 apical views: 2-chamber view (including anterior and inferior walls), 4-chamber view (posteroseptal and lateral walls), and long-axis view (anteroseptal and posterior walls). Each wall was divided into 3 levels (basal, mid, and apical), and subsequently, 18 segmental strain curves were obtained. Global longitudinal strain was calculated as the average value of peak systolic strain for the 18 segments (Figure 2a).

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Figure 2. Left ventricle (LV) strain assessment in 3 orthogonal directions by 2-dimensional speckle-tracking analysis. a, Global longitudinal strain was calculated from the apical 4-chamber, 2-chamber, and long-axis views of the LV. Each color denotes a regional segmental strain (6 segments per view, for a total of 18 segments) and the white broken line represents the average strain value for each view. b and c, Global longitudinal strain was calculated as the average value for peak strain in the 3 apical views. From the mid-ventricular short-axis view of the LV, the global circumferential strain (b) and radial strain (c) were calculated, by averaging the peak strain of the 6 LV segments.

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From the LV mid-ventricular short-axis view, circumferential strain (evaluating myocardial shortening/lengthening along the LV curvature) and radial strain (evaluating myocardial thickening/thinning) were measured. The global values of circumferential and radial strains were derived from the average value of peak systolic strain for 6 segments, as illustrated in Figures 2b and 2c, respectively. Global longitudinal and circumferential strains are expressed as negative values, and a lower strain is represented by less-negative values. Global radial strain is expressed as positive values, and lower values indicate lower strain. The intra- and interobserver agreements for the measurements of longitudinal, circumferential, and radial strains have been reported previously (20).

Cardiopulmonary exercise testing.

All patients with SSc underwent CPET by performing a maximal exercise stress test on an electrically braked stationary cycle ergometer, using a ramp protocol in accordance with the American Thoracic Society/American College of Chest Physicians statement on cardiopulmonary testing (21). Briefly, a tight-fitting facemask was worn by the patients, which allowed ventilation and metabolic gas exchange measurements (Oxycon Pro; Jaeger-Viasys Healthcare). The initial work load was 30W, with further increments of 5W every 30 seconds. Patients were encouraged to exercise until exhaustion or until the supervising physician stopped the test because of significant symptoms, such as chest pain, dizziness, ST-segment deviations, or marked systolic hypotension or hypertension. Peak VO2 was defined as the highest oxygen consumption during any stage of maximal exercise. Furthermore, the peak VO2 was adjusted to each patient's age, sex, and weight, with results expressed as the % predicted.

Assessment of cardiac function by 24-hour EKG Holter monitoring.

To detect potential ventricular arrhythmias, 24-hour EKG Holter monitoring was performed in 100 of 104 patients. Abnormal Holter results were defined as the presence of intermittent bundle branch block, ventricular arrhythmias, including frequent monomorphic and/or polymorphic premature ventricular contractions at a rate of >100 per day, or nonsustained or sustained ventricular tachycardia detected by EKG Holter monitoring (22).

Statistical analysis.

Continuous variables are presented as the mean ± SD. Categorical data are presented as frequencies and percentages. Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test. Statistical comparisons were performed by using Student's t-test for continuous variables, and chi-square test for binary variables. Univariate linear regression analysis was used to identify potential determinants of peak VO2 % predicted. Correlations were expressed in terms of Pearson's correlation coefficients. Moreover, univariate binary logistic regression was used to determine the factors associated (using odds ratios [ORs] and 95% confidence intervals [95% CIs]) with abnormal EKG Holter results. The final multivariate models for peak VO2 % predicted and abnormal Holter results were obtained using the enter method, in which parameters that were statistically significant in univariate analysis were included.

To avoid bias from multicollinearity, multidirectional global strains were entered into the stepwise model individually. Analysis of covariance tests with inclusion of covariates to correct for significant differences in subpopulation characteristics were performed. All statistical analyses were performed using the statistical package SPSS for Windows (version 15.0). P values less than 0.05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Clinical characteristics of the patient population.

A total of 51 patients (49%) were classified as having lcSSc and 53 (51%) as having dcSSc. Clinical characteristics of the total patient population and of the 2 patient populations stratified by disease subtype (limited or diffuse) are shown in Table 1. According to the matching criteria, age (mean ± SD 54 ± 12 years versus 54 ± 10 years; P = 0.82) and sex (female 77% versus 73%; P = 0.66) were similar between patients with SSc and controls. Most of the patients with SSc were positive for antinuclear antibodies, and almost 50% of the patients had underlying interstitial lung disease. In addition, 24 patients (20 patients with dcSSc and 4 with lcSSc) had received treatment with cyclophosphamide, and 13 patients (all with dcSSC) had undergone stem cell transplantation. A total of 4 patients had mild pulmonary hypertension (2 due to underlying interstitial lung disease and 2 due to pulmonary arterial hypertension), 1 patient had a previous myocardial infarction, and 2 patients were known to have epicardial coronary artery disease.

Table 1. Clinical characteristics of the patients with systemic sclerosis (SSc), in total and by subset of limited cutaneous SSc (lcSSc) versus diffuse cutaneous SSc (dcSSc)*
 Total SSc (n = 104)SSc subset
lcSSc (n = 51)dcSSc (n = 53)P
  • *

    Except where indicated otherwise, values are the mean ± SD. ESR = erythrocyte sedimentation rate; FVC = forced vital capacity; TLC = total lung capacity; DLCO = diffusing capacity for carbon monoxide; ACE = angiotensin-converting enzyme.

  • Chronic kidney disease was defined as an estimated glomerular filtration clearance rate of <60 ml/minute/1.73 m2 for more than 3 months.

Age, years54 ± 1258 ± 1250 ± 12<0.01
Female sex, no. (%)80 (77)43 (84)37 (70)0.08
Time since diagnosis, years5.1 ± 2.37.1 ± 3.54.1 ± 2.5<0.01
Time since onset of Raynaud's phenomenon, years8.6 ± 6.315.0 ± 5.85.8 ± 4.2<0.01
Time since onset of skin manifestations, years5.6 ± 3.57.1 ± 6.24.7 ± 2.80.02
Modified Rodnan skin thickness score5.6 ± 6.12.8 ± 2.28.3 ± 7.4<0.01
Systolic blood pressure, mm Hg122 ± 18125 ± 18119 ± 180.08
Diastolic blood pressure, mm Hg71 ± 970 ± 872 ± 110.23
Systemic hypertension, no. (%)11 (11)2 (18)9 (82)0.03
ESR, mm/hour20.5 ± 17.620.7 ± 19.820.3 ± 15.40.91
Immune marker, no. (%)    
 Antinuclear antibodies94 (90)46 (90)48 (91)0.61
 Anti–topoisomerase I antibodies36 (35)7 (14)29 (58)<0.01
 Anticentromere antibodies25 (24)21 (41)4 (7)<0.01
 Anti-RNP antibodies7 (7)5 (10)2 (4)0.38
Interstitial lung disease, no. (%)49 (47)15 (28)34 (64)<0.01
Pulmonary hypertension, no. (%)4 (4)1 (2)3 (6)0.62
Chronic kidney disease, no. (%)10 (10)6 (12)4 (8)0.52
Lung function, % predicted    
 FVC94.4 ± 14.494.9 ± 12.493.9 ± 15.90.73
 TLC86.9 ± 18.192.7 ± 17.282.1 ± 17.5<0.01
 DLCO63.3 ± 16.865.4 ± 17.561.2 ± 16.10.22
Current immunosuppressive medication, no. (%)    
 Corticosteroids15 (14)6 (12)9 (17)0.45
 Methotrexate4 (8)3 (6)4 (8)0.52
 Azathioprine2 (4)4 (8)2 (4)0.32
Current cardiovascular medication, no. (%)    
 Calcium antagonists46 (44)17 (33)29 (55)0.03
 ACE inhibitors42 (40)12 (24)30 (57)<0.01

On average, patients with dcSSc, compared with those with lcSSc, had a younger age, shorter time since diagnosis, and shorter time since onset of Raynaud's phenomenon and skin manifestations. Moreover, patients with dcSSc were more likely to have underlying interstitial lung disease, to have a lower TLC % predicted, and to receive angiotensin-converting enzyme inhibitors (mainly to prevent renal crisis) as compared to patients with lcSSc. Patients with lcSSc had a significantly lower prevalence of anti–topoisomerase I antibodies and a lower modified Rodnan skin thickness score (Table 1).

Echocardiographic characteristics of the patient population.

Conventional echocardiographic measurements of LV systolic and diastolic function in patients with SSc and controls are shown in Table 2. No significant differences in the LV volumes or in the LVEF were noted between patients with SSc and controls (Table 2). Moreover, the S′ velocity derived from tissue Doppler imaging was similar between patients and controls. However, the estimated PASP was significantly higher in patients with SSc as compared to controls, and the E/E′ ratio and grade of LV diastolic dysfunction were significantly worse in patients with SSc. When comparing the 2 different subtypes of SSc, both groups showed similar values for all conventional echocardiographic parameters.

Table 2. Conventional echocardiographic parameters and 2-dimensional speckle-tracking strain measurements in patients with SSc, in total and by disease subset, as compared with healthy control subjects*
 Controls (n = 37)Total SSc (n = 104)P, total SSc versus controlslcSSc (n = 51)dcSSc (n = 53)P, lcSSc versus dcSSc
  • *

    Except where indicated otherwise, values are the mean ± SD. LV = left ventricular; PASP = pulmonary arterial systolic pressure; E′ = early diastolic velocity at basal mitral annulus; E/E′ = ratio of peak early diastolic velocity to early diastolic velocity at basal mitral annulus; S′ = early systolic velocity at basal mitral annulus (see Table 1 for other definitions).

Conventional echocardiographic parameter      
 LV end diastolic volume, ml70.6 ± 20.676.0 ± 25.40.2172.9 ± 22.478.9 ± 23.00.24
 LV end systolic volume, ml26.6 ± 5.729.1 ± 13.10.1328.8 ± 13.929.4 ± 12.50.82
 LV ejection fraction, %64.6 ± 4.463.5 ± 7.20.2064.6 ± 7.963.4 ± 6.40.19
 PASP, mm Hg21.7 ± 6.328.9 ± 8.7<0.0129.5 ± 8.328.3 ± 9.10.48
 LV diastolic function, no. (%)      
  Normal21 (62)35 (34)<0.0118 (35)17 (32)0.62
  Mild9 (24)24 (23) 12 (24)12 (23) 
  Moderate5 (14)30 (29) 16 (31)14 (26) 
  Severe0 (0)15 (14) 5 (10)10 (19) 
 E′ velocity, cm/second9.8 ± 2.08.5 ± 2.80.038.8 ± 2.78.1 ± 3.00.22
 E/E′ ratio7.7 ± 1.910.1 ± 3.8<0.0110.2 ± 3.810.0 ± 3.70.73
 S′ velocity, cm/second6.4 ± 1.46.3 ± 2.10.816.8 ± 2.05.7 ± 2.0<0.01
Speckle-tracking measure      
 Global longitudinal strain, %−21.3 ± 1.7−18.2 ± 1.8<0.01−18.6 ± 1.6−17.9 ± 1.90.02
 Global circumferential strain, %−21.3 ± 2.1−18.2 ± 2.3<0.01−19.0 ± 2.0−17.5 ± 2.3<0.01
 Global radial strain, %40.3 ± 12.437.0 ± 13.90.1837.6 ± 13.136.3 ± 14.70.65

In order to detect subtle LV dysfunction, myocardial strain values in 3 orthogonal directions were measured by speckle-tracking analysis (Table 2). Both the global longitudinal strain and the global circumferential strain were significantly impaired in patients with SSc as compared to controls. However, no difference in global radial strain was noted between patients with SSc and normal healthy subjects. Of note, patients with dcSSc showed worse values for both global longitudinal and global circumferential strains, as compared to patients with lcSSc.

Cardiopulmonary function.

All patients with SSc completed CPET, at an exercise level of at least 50W, and reached anaerobic threshold. The heart rate recovery was >12 beats/minute and the respiratory exchange ratio was >1.00, suggesting a satisfactory exercise capacity in the study population. The mean ± SD peak VO2 % predicted was 90.6 ± 20.4% and the maximum exercise time was 9.9 ± 3.6 minutes, suggesting a relatively preserved functional capacity in the SSc patient population. Patients with dcSSc had a significantly lower peak VO2 % predicted compared to those with lcSSc (mean ± SD 83.2 ± 21.1% versus 99.7 ± 24.7%; P < 0.01).

According to Pearson's correlation analysis, the peak VO2 % predicted was not related to conventional echocardiographic measurements, including the LV dimensions, LVEF, and LV diastolic function (each P > 0.05). However, the peak VO2 % predicted was significantly correlated with the global longitudinal strain (r = −0.46, P < 0.01), circumferential strain (r = −0.41, P < 0.01), and radial strain (r = −0.20, P = 0.05) (Figures 3A–C).

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Figure 3. Correlation between the peak VO2 % predicted and global longitudinal (A), circumferential (B), and radial (C) strains as measured by 2-dimensional speckle-tracking analysis in patients with systemic sclerosis. Broken lines correspond to the 95% confidence intervals.

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Univariate analysis revealed that among all of the clinical and echocardiographic characteristics, patients' age (β = 0.24, 95% CI 0.09, 0.83, P = 0.02), subtype of dcSSc (β = 0.40, 95% CI 0.30, 0.79, P < 0.01), presence of underlying interstitial lung disease (β = 0.24, 95% CI 0.10, 0.81, P = 0.02), TLC % predicted (β = 0.40, 95% CI 0.30, 0.79, P < 0.01), and DLCO % predicted (β = 0.49, 95% CI 0.46, 0.96, P < 0.01) were each significantly associated with the peak VO2 % predicted. After adjusting the model for the aforementioned parameters in a multivariate analysis, we found that the global longitudinal strain (β = −0.36, 95% CI −0.21, −0.72, P < 0.01) and circumferential strain (β = −0.34, 95% CI −0.19, −0.75, P < 0.01) were both independently associated with the peak VO2 % predicted, together with age and the DLCO % predicted.

Findings on 24-hour EKG Holter monitoring.

Among the 100 patients with SSc who underwent 24-hour EKG Holter monitoring, 28 (28%) had abnormal results. In particular, 9 patients presented with nonsustained ventricular tachycardia and 19 patients had ventricular ectopics at a rate of >100 per day. No atrial arrhythmias were recorded.

Differences in clinical and echocardiographic measurements between patients with and those without abnormal EKG Holter results are shown in Table 3. Patients with abnormal Holter results were more likely to be male and to have underlying interstitial lung disease. Conventional LV systolic function, LV diastolic dysfunction grade, and S′ velocity were similar between patients with and those without abnormal Holter results. However, the E/E′ ratio was significantly higher in patients with abnormal Holter results. Moreover, global longitudinal and circumferential strains, but not the global radial strain, were each significantly impaired in patients with abnormal Holter results.

Table 3. Clinical and echocardiographic characteristics of SSc patients with and those without abnormal results on 24-hour electrocardiographic (EKG) Holter monitoring*
 Normal EKG Holter results (n = 72)Abnormal EKG Holter results (n = 28)P
  • *

    Except where indicated otherwise, values are the mean ± SD. LV = left ventricular; PASP = pulmonary arterial systolic pressure; E′ = early diastolic velocity at basal mitral annulus; E/E′ = ratio of peak early diastolic velocity to early diastolic velocity at basal mitral annulus; S′ = early systolic velocity at basal mitral annulus (see Table 1 for other definitions).

Clinical characteristic   
 Age, years54 ± 1356 ± 120.45
 Female sex, no. (%)59 (81.9)17 (60.7)0.04
 Interstitial lung disease, no. (%)9 (32.1)19 (67.9)0.01
 dcSSc, no. (%)35 (48.6)19 (67.9)0.12
 Modified Rodnan skin thickness score5.1 ± 5.87.2 ± 7.10.16
 Immune marker, no. (%)   
  Antinuclear antibodies65 (90.3)26 (92.9)1.00
  Anti–topoisomerase I antibodies22 (31.4)13 (46.4)0.17
  Anticentromere antibodies17 (26.2)7 (25)1.00
  Anti-RNP antibodies6 (8.6)1 (3.6)0.67
 Lung function, % predicted   
  FVC89.0 ± 17.883.2 ± 18.50.17
  TLC64.6 ± 17.260.4 ± 16.10.25
  DLCO95.4 ± 13.793.6 ± 15.00.58
Conventional echocardiographic parameter   
  LV end diastolic volume, ml73.5 ± 22.479.4 ± 28.70.34
  LV end systolic volume, ml27.5 ± 9.932.1 ± 18.80.23
  LV ejection fraction, %63.9 ± 6.662.8 ± 9.10.57
  PASP, mm Hg28.0 ± 7.530.1 ± 10.20.36
  LV diastolic function, no. (%)   
   Normal26 (36)8 (29)0.36
   Mild17 (24)5 (18) 
   Moderate21 (29)8 (29) 
   Severe8 (11)7 (25) 
  E′ velocity, cm/second8.6 ± 2.98.1 ± 2.60.35
  E/E′ ratio9.4 ± 3.811.7 ± 4.00.04
  S′ velocity, cm/second6.3 ± 2.06.2 ± 2.20.79
Speckle-tracking measure   
 Global longitudinal strain, %−18.5 ± 1.5−17.1 ± 2.1<0.01
 Global circumferential strain, %−18.7 ± 2.0−17.3 ± 2.50.01
 Global radial strain, %37.8 ± 14.033.7 ± 13.10.17

Univariate analysis demonstrated that the presence of abnormal Holter results was associated with male sex (OR 2.94, 95% CI 1.12, 7.69, P < 0.01), the presence of interstitial lung disease (OR 3.32, 95% CI 1.32, 8.36, P < 0.01), a higher E/E′ ratio (OR 1.15, 95% CI 1.02, 1.32, P = 0.04), and lower values for the global longitudinal strain (OR 1.71, 95% CI 1.24, 2.38, P < 0.01) and global circumferential strain (OR 1.55, 95% CI 1.18, 2.03, P < 0.01). After multivariate adjustment, both the global longitudinal strain (OR 1.47, 95% CI 1.05, 2.07, P = 0.03) and the global circumferential strain (OR 1.35, 95% CI 1.01, 1.82, P = 0.04) remained the only independent predictors of abnormal Holter results in patients with SSc.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The results of the present study demonstrate that patients with SSc can exhibit subtle LV systolic dysfunction, as assessed by 2-D speckle-tracking strain analysis, despite having a normal LVEF and normal LV dimensions. More importantly, LV global longitudinal and circumferential strains, but not conventional echocardiographic parameters, were independently associated with functional capacity, as assessed by CPET, and ventricular arrhythmias, as detected by 24-hour EKG Holter monitoring.

Cardiac involvement in patients with SSc has been characterized mainly by the presence of an elevated PASP and LV diastolic dysfunction (5, 6). Results of recent studies using tissue Doppler imaging in relatively small groups of patients with SSc (5–7) have also suggested an impairment in myocardial systolic deformation (strain), despite a preserved LVEF and LV dimensions (4, 23). However, strain analysis by tissue Doppler imaging is significantly limited by angle dependency (the measure changes with the insonation angle) and does not allow for the evaluation of all LV segments and of different directions of myocardial deformation. The advent of 2-D speckle-tracking analysis overcomes these limitations and allows angle-independent, direct evaluation of LV global strain in all 3 orthogonal directions, providing more accurate assessment of LV function (8).

The present study applied this novel analytic technique in a large cohort of patients with SSc, and found that both LV global longitudinal and global circumferential strains were modestly, but significantly, impaired in patients with SSc as compared to healthy control subjects. The relatively small difference in strain values noted between the 2 groups could be explained by the fact that patients with SSc in the present cohort were asymptomatic and had a relatively preserved functional capacity, suggestive of mild and subclinical cardiovascular involvement. Furthermore, patients with dcSSc showed worse values for global longitudinal and circumferential strains as compared to patients with lcSSc, confirming a more common and severe cardiac involvement in the diffuse form of the disease (5, 24).

Therefore, the use of more sensitive echocardiographic parameters may enable the detection of subtle LV systolic dysfunction, i.e., an abnormality not identified by conventional approaches, before the manifestation of clinical signs and symptoms. Of note, both the present results and those from the studies by Mele et al (5) and Kepez et al (6) failed to show a significant difference in myocardial function between patients with SSc and controls, when tissue Doppler imaging was used to derive the S′ velocity. These findings therefore suggest that for the detection of subtle myocardial dysfunction in patients with SSc, 2-D speckle-tracking analysis of global strain, which allows angle-independent and global LV functional assessment, is superior to tissue Doppler imaging to derive the S′ velocity.

Although the mechanism underlying LV systolic dysfunction is unknown, previous studies have demonstrated the presence of significant myocardial fibrosis in patients with SSc, using delayed gadolinium-enhanced magnetic resonance imaging (25, 26). These structural alterations, mainly caused by repeated focal ischemia due to abnormal vasoreactivity, may be responsible for the myocardial dysfunction. Interestingly, in the present study, multidirectional strain analysis demonstrated significant impairment of longitudinal and circumferential strains (shortening), but not of radial strain (thickening). This finding may suggest that myocardial involvement of the subendocardial layer (responsible for longitudinal and circumferential shortening) occurs earlier than that in the subepicardial layer (responsible for radial deformation), since the subendocardium is more susceptible to ischemia and fibrosis phenomena. Nevertheless, the exact mechanism of myocardial dysfunction requires further studies.

Patients with SSc were shown to have reduced cardiopulmonary exercise capacity, as measured by the VO2 % predicted, which could be attributed to multiple factors (27–30). Previous studies have suggested that pathologic features of the lung are one of the main determinants of impaired cardiopulmonary functional capacity in these patients (28, 31). Similarly, the present study also showed the important role of lung function as assessed by the DLCO % predicted, which was independently associated with the VO2 % predicted (31). In addition, a recent study by Walkey and colleagues has also suggested that exercise-induced LV diastolic dysfunction, undetected by resting echocardiography, was a cause of impaired exercise capacity (29). However, the potential role of LV systolic dysfunction as an important contributing factor to functional capacity has not been demonstrated before. Importantly, the present study demonstrated that LV global longitudinal and circumferential strains were significantly correlated with the VO2 % predicted, independent of age, SSc subtype, and lung function. This observation thus provided direct evidence that LV systolic dysfunction significantly contributes to impaired functional capacity in patients with SSc. Therefore, novel 2-D speckle-tracking strain analysis may be used in conjunction with lung function testing in order to provide a global assessment and monitoring of the cardiopulmonary status in patients with SSc.

Ventricular arrhythmias commonly occur in patients with SSc (32) and are responsible for up to 6% of deaths, as demonstrated by a recent study (2). In particular, the presence of nonsustained ventricular tachycardias has been reported in 6–10% of patients with SSc, and this has been shown to be significantly associated with total mortality and sudden death (31, 32). In the present study, 24-hour EKG Holter monitoring was systematically performed in a large group of patients with SSc, and nonsustained ventricular tachycardias were identified in 9% of the patients. Importantly, in the multivariate analysis, LV systolic dysfunction, as assessed by LV global longitudinal and circumferential strains, was the only independent predictor of ventricular arrhythmias (ventricular ectopics and nonsustained ventricular tachycardia). These results suggest that subtle LV systolic dysfunction is per se an important factor associated with ventricular arrhythmias and may also reflect the extent of myocardial fibrosis, which is a well-known arrhythmogenic substrate (25). These novel echocardiographic parameters therefore represent a valuable tool to improve the risk stratification among patients with SSc. The present results underscore the need for implementing speckle-tracking strain analysis in larger SSc cohort studies, investigating risk stratification and potential protective effects of antiarrhythmic strategies.

The present study was a cross-sectional analysis, and therefore a causal relationship between impaired 2-D speckle-tracking–derived strain and impaired functional capacity and ventricular arrhythmias in patients with SSc could not be established. Moreover, the current population included patients with SSc whose functional capacity was preserved and in whom there was a low prevalence of pulmonary hypertension; therefore, the results of the present study cannot be extrapolated to SSc patients with severe cardiopulmonary involvement. Furthermore, neither microvascular nor macrovascular ischemia was fully documented, since all of the patients had no clinical evidence of myocardial ischemia (nor were there any indications observed during CPET), and therefore invasive evaluations and/or vasoreactivity tests were not performed. Future studies are required to evaluate the impact of both microvascular and macrovascular ischemia on 2-D speckle-tracking–derived multidirectional strain in patients with SSc.

In conclusion, patients with SSc can have subtle LV systolic dysfunction as measured by 2-D speckle-tracking strain analysis. Importantly, LV global longitudinal and circumferential strains were independent predictors of impaired functional capacity, as measured by CPET, and ventricular arrhythmias, detected by 24-hour EKG Holter monitoring. The use of this novel imaging technique may therefore improve risk stratification and monitoring of the cardiovascular involvement in patients with SSc.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Schuerwegh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Yiu, Schouffoer, Marsan, Ninaber, Stolk, Vliet Vlieland, Scherptong, Delgado, Holman, Bax, Schuerwegh.

Acquisition of data. Yiu, Schouffoer, Marsan, Ninaber, Scherptong, Delgado, Holman, Huizinga, Bax, Schuerwegh.

Analysis and interpretation of data. Yiu, Schouffoer, Marsan, Ninaber, Scherptong, Delgado, Holman, Tse, Huizinga, Bax, Schuerwegh.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We are grateful to Sole Mio chief Dr. Z. de Jong and clinical nurse specialists Mrs. L. Beaart-van de Voorde and Mrs. J. Tromp at Leiden University Medical Center, as well as the following referring rheumatologists in The Netherlands: Drs. J. Ewals, R. Goekoop, Y. Ruiterman, and H. Ronday at Haga Hospital, Dr. M. Kortekaas at Flevo Hospital, Drs. J. Peeters and C. Bijkerk at Reinier de Graaf Hospital, Drs. I. Tchetverikow, M. de Jager, S. Beer, and B. Van Schaeybroeck at Albert Schweitzer Hospital, Dr. P. van der Lubbe at Vlietland Hospital, Dr. D. van Zeeben at St. Franciscus Gasthuis, Dr. M. van Krugten at Admiraal De Ruyter Hospital, Drs. I. Speyer, G. Steup-Beekman, and M. Westedt at Bronovo Hospital, Dr. E. Ton at Utrecht University Medical Center, Dr. A. Voskuyl at VU University Medical Center, Drs. H. Boom and K. Steen at Spaarne Hospital, Dr. H. Nuver- Zwart at Deventer Hospital, Drs. M. Van Oosterhout and E. Molenaar at Groene Hart Hospital, and Drs. G. Collée, M. de Buck, W. de Beus, M. Dubois, and L. Lard at Westeinde Hospital.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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