Maarten K. Ninaber

Left ventricular dysfunction assessed by speckle‐tracking strain analysis in patients with systemic sclerosis: Relationship to functional capacity and ventricular arrhythmias

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 VO(2) 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 VO(2) (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 VO(2). 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.

Subclinical left ventricular dysfunction by echocardiographic speckle-tracking strain analysis relates to outcome in sarcoidosis.

Limited data exist on the risk of developing cardiac sarcoidosis (CS) and/or adverse events in sarcoidosis patients. Using LV global longitudinal strain (GLS), an emerging sensitive parameter of LV function, we evaluated the prevalence of subclinical cardiac dysfunction in sarcoidosis and investigated whether LVGLS predicts adverse outcomes in this population.

Randomized Comparison of a Multidisciplinary Team Care Program With Usual Care in Patients With Systemic Sclerosis

To compare the effectiveness of a multidisciplinary team care program with usual outpatient care in patients with systemic sclerosis (SSc; scleroderma).

Predicting cardiopulmonary involvement in patients with systemic sclerosis: complementary value of nailfold videocapillaroscopy patterns and disease-specific autoantibodies.

Objective To evaluate the prevalence of anti-extractable nuclear antigen (anti-ENA) antibodies in Dutch SSc patients and the predictive power of the combination of specific anti-ENA antibodies and nailfold videocapillaroscopy (NVC) patterns to improve identification of patients with high risk for cardiopulmonary involvement. Methods A total of 287 patients (79%) from the Leiden SSc-Cohort had data available on NVC-pattern (no SSc-specific, early, active, late) and anti-ENA antibodies. Associations between anti-ENA/NVC combinations with cardiopulmonary parameters were explored using logistic regression. Results Prevalence of ACA was 37%, anti-Scl-70 24%, anti-RNP 9%, anti-RNAPIII 5%, anti-fibrillarin 4%, anti-Pm/Scl 3%, anti-Th/To 0.3% and anti-Ku 1.4%. NVC showed a SSc-specific pattern in 88%: 10% early, 42% active and 36% late. The prevalence of different NVC patterns was equally distributed among specific anti-ENA antibodies, except for the absence of early pattern in anti-RNP positive patients. Fifty-one percent had interstitial lung disease (ILD), 59% had decreased diffusion capacity for carbon monoxide and 16% systolic pulmonary artery pressure >35 mmHg (sPAP↑). Regardless of ENA-subtype, NVC-pattern showed a stable association with presence of ILD or sPAP↑. For ILD, the odds ratios (ORs) were 1.3-1.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). For diffusion capacity for carbon monoxide, the OR was 1.5 ( P < 0.05 for analyses with ACA, anti-Scl-70, anti-RNAPIII, anti-RNP). For sPAP↑, the ORs were 2.2-2.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). Conclusion In Dutch SSc patients, all SSc-specific auto-antibodies were found, with ACA and anti-Scl-70 being the most prevalent. Strikingly, the association between NVC-pattern and heart/lung involvement was independent of specific anti-ENA antibodies, which might indicate microangiopathy is an important cause of organ involvement.

Complete pathological resolution of pulmonary Langerhans cell histiocytosis.

Cigarette smoking is a major risk factor for pulmonary Langerhans cell histiocytosis (pLCH) and lung cancer. Resolution of pLCH may occur spontaneously, after smoking cessation or other interventions. However, despite clinicoradiological resolution, residual pulmonary Langerhans cells may be present and may lead to recurrent disease. We report the first case of pLCH with a complete histological resolution.

Carotid body tumors are not associated with an increased risk for sleep-disordered breathing

PurposeTumors in the carotid bodies may interfere with their function as peripheral chemoreceptors. An altered control of ventilation may predispose to sleep-disordered breathing. This study aimed to assess whether patients with unilateral or bilateral carotid body tumors (uCBT or bCBT, respectively) or bilateral CBT resection (bCBR) display sleep-disordered breathing and to evaluate the global contribution of the peripheral chemoreceptor to the hypercapnic ventilatory response.MethodsEight uCBT, eight bCBT, and nine bCBR patients and matched controls underwent polysomnography. The peripheral chemoreflex drive was assessed using euoxic and hyperoxic CO2 rebreathing tests. Daytime sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Multidimensional Fatigue Index.ResultsAll patient groups reported significant fatigue-related complaints, but no differences in excessive daytime sleepiness (EDS) were found. The apnea/hypopnea index (AHI) did not differ significantly between patient groups and controls. Only in bCBT patients, a trend towards a higher AHI was observed, but this did not reach significance (p = 0.06). No differences in the peripheral chemoreflex drive were found between patients and controls.ConclusionsPatients with (resection of) CBTs have more complaints of fatigue but are not at risk for EDS. The presence or resection of CBTs is neither associated with an altered peripheral chemoreflex drive nor with sleep-disordered breathing.

Therapeutic and diagnostic outcomes of a standardised, comprehensive care pathway for patients with systemic sclerosis

Objectives To determine the outcomes, including number of medical interventions and initiation of immunosuppressive treatment of a standardised, comprehensive, diagnostic care pathway for patients with systemic sclerosis (SSc). Patient characteristics associated with need for medical interventions and with need for immunosuppressive treatment were determined. Methods Data were routinely gathered in connection with a 2-day care pathway combining multidisciplinary care and complete diagnostic work-up of organ involvement in SSc. The number of patients in whom the pathway resulted in medical interventions, and/or initiation of immunosuppressives was recorded. Patient characteristics and diagnostic tests results were compared between patients with and without medical interventions, and patients with and without initiation of immunosuppressives by means of multivariable logistic regression analyses. Results During a period of 44 months, 226 patients with SSc were referred to the care pathway. They included 186 (82%) women with mean age of 54 (SD 14.5) years, and median disease duration of 4 years (range 1–11); 73 (32%) of them had diffuse cutaneous SSc. Medical interventions were initiated in 191 (85%) patients, including initiation of immunosuppressive treatment in n=49 (22%). Presence of telangiectasias and higher erythrocyte sedimentation rate were associated with any medical intervention. Of commonly available variables, lower age, higher skin score and absence of anticentromere antibody were associated with initiation of immunosuppressives. Conclusions A standardised comprehensive 2-day care pathway for patients with SSc resulted in additional diagnostic or therapeutic interventions in 85% of the patients, regardless of SSc subtype and disease duration. In 22% of the patients, immunosuppressive treatment was initiated.

Rituximab in early systemic sclerosis

Objectives (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). Methods A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. Results In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated. Conclusions No unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement. Trial registration number EudraCT 2008-07180-16; Results.

Lung structure and function relation in systemic sclerosis: application of lung densitometry.

INTRODUCTION Interstitial lung disease occurs frequently in patients with systemic sclerosis (SSc). Quantitative computed tomography (CT) densitometry using the percentile density method may provide a sensitive assessment of lung structure for monitoring parenchymal damage. Therefore, we aimed to evaluate the optimal percentile density score in SSc by quantitative CT densitometry, against pulmonary function. MATERIAL AND METHODS We investigated 41 SSc patients by chest CT scan, spirometry and gas transfer tests. Lung volumes and the nth percentile density (between 1 and 99%) of the entire lungs were calculated from CT histograms. The nth percentile density is defined as the threshold value of densities expressed in Hounsfield units. A prerequisite for an optimal percentage was its correlation with baseline DLCO %predicted. Two patients showed distinct changes in lung function 2 years after baseline. We obtained CT scans from these patients and performed progression analysis. RESULTS Regression analysis for the relation between DLCO %predicted and the nth percentile density was optimal at 85% (Perc85). There was significant agreement between Perc85 and DLCO %predicted (R=-0.49, P=0.001) and FVC %predicted (R=-0.64, P<0.001). Two patients showed a marked change in Perc85 over a 2 year period, but the localization of change differed clearly. CONCLUSIONS We identified Perc85 as optimal lung density parameter, which correlated significantly with DLCO and FVC, confirming a lung parenchymal structure-function relation in SSc. This provides support for future studies to determine whether structural changes do precede lung function decline.

A Syringe Simulation of Biological Controls for Quality Assessment of Prospective Lung Volume Measurements

Background: At present a syringe is being used for calibration of lung function devices, but biological controls are used to detect prospectively the variability and reproducibility of lung volumes measured by spirometers. Laboratory personnel is often used as biological control and therefore the cost for these measurements is substantial and may be reduced by replacement of a syringe procedure to increase the capacity of the laboratory to measure more patients. Objectives: To develop a mechanical syringe procedure for identification of instrument problems. Methods: A commercial 3-liter precision syringe is used to simulate breathing maneuvers (inspiratory vital capacity, functional residual capacity, residual volume and total lung capacity) on a spirometer. Three healthy males representing biological controls performed spirometry, maximum expiratory flow volume and helium dilution forced residual capacity at bimonthly intervals for 3 years. Confidence intervals and interval widths are calculated for each parameter. Levene’s test for equality of variances was used to test for significance between standard deviations. Results: The interval width of inspiratory vital capacity, functional residual capacity, total lung capacity and residual volume of repeated measurements obtained from the syringe was significantly narrower than those of biological controls. In addition, almost all standard deviations from lung volumes obtained from the syringe were smaller and significantly different from those of the biological control. Conclusion: Our syringe procedure may replace biological controls for detection of variability of lung volumes. This will result in cost reduction and improve quality assessment of lung function devices.