Pulmonary Hypertension in Pulmonary sarcoidosis - optimizing the diagnostic strategy. Acroniem: PULSAR

BACKGROUND: Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by formation of non-caseating granulomas in affected tissues, particularly the lung and lymphatic system. Pulmonary hypertension (PH) is a serious complication of sarcoidosis with a suggested prevalence between 5 and 74% in patients with pulmonary involvement. The cornerstone in the diagnosis of PH is the right heart catheterization (RHC). Treatment decision should be made on a case by case basis.PH is associated with an increased morbidity and mortality in affected patients. Different pathophysiologic mechanisms involved in sarcoidosis associated pulmonary hypertension (SAPH) are suggested. For example pulmonary fibrosis, extrinsic compression of the pulmonary vessels by lymphadenopathy or fibrosis, pulmonary veno-occlusive disease, left ventricular dysfunction, porto-pulmonary hypertension, hypoxemia and intrinsic sarcoid vasculopathy. The management of PH associated sarcoidosis depends on the underlying mechanism. OBJECTIVES: Objective 1: To investigate whether the addition of right ventricle (RV) measurements by three-dimensional transthoracic echocardiography (3D-TTE) to two-dimensional transthoracic echocardiography (2D-TTE) is superior to 2D-TTE alone to select patients for RHC in order to reduce both the number of false negatives and false positives. Objective 2: To investigate and specify the role of 3D-TTE measurements in the initial work-up and follow-up of all patients with pulmonary sarcoidosis and perform follow-up to determine the development of PH on long-term for patients initially classified as PH unlikely by TTE or PH absent by RHC. Objective 3: To generate further insight into the etiology and different mechanisms involved in SAPH using intravascular ultrasound (IVUS) and pressure/flow measurements. HYPOTHESIS: Firstly, non-invasive diagnostic tools can optimize the diagnostic strategy, in order to minimize the number of invasive diagnostic procedures. Secondly, invasive imaging of the pulmonary artery can further differentiate the mechanisms involved in PH associated sarcoidosis. STUDY DESIGN: Cross-sectional diagnostic research STUDY POPULATION/DATASET: All consecutive sarcoidosis patients with pulmonary involvement stage I-IV INTERVENTION: All patients will be screened for the presence of PH by a standardized diagnostic strategy (Local standard protocol) including history taking and physical examination, electrocardiogram (ECG) and biomarkers related to PH (NT–pro BNP, troponin and uric acid) and 2D-TTE with additional 3D-TTE right ventricle volume and function measurements (Ventripoint® system). In a subgroup of patients with the diagnosis “PH possible or likely” based on the diagnostic strategy (as suggested by the international guidelines for PH), RHC will be performed to measure pulmonary hemodynamics. Additionally, this will include intravascular imaging of the pulmonary artery using IVUS (Revolution® 45 MHz Rotational IVUS Imaging Catheter) and measurements of pressure/flow in the pulmonary arteries (Combowire® pressure/flow guide wire Reef 9500 series). OUTCOME MEASURES: For the first objective: Relative differences in sensitivity and specificity between 2D-TTE alone based on the ESC guideline and 2D-TTE combined with 3D-TTE evaluating increase in RV volumes and decrease in function. For the second objective: Association of various 3D-TTE parameters reflecting the RV volumes and function with the presence or absence of PH in all patients. The final diagnosis of PH will be based on either the results of RHC (mPAP≥25mmHg) or classification as PH unlikely by echocardiography in those without RHC. For the third objective: Comparing measurements by RHC, IVUS and local flow and pressure assessing extrinsic compression with a local luminal loss of > 50%, vessel diameter/area and wall thickness, pulsatility, compliance and distensibility to examine differences in patients diagnosed as PH present or PH absent. SAMPLE SIZE: We will examine a total of 400 consecutive patients with pulmonary sarcoidosis in whom both 2D-TTE and 2D-TTE combined with 3D-TTE will be performed. The expected prevalence of PH is 15% (n=60). This will allow us to demonstrate absolute differences in sensitivity of around 15-20% and specificity of around 10%. The expected percentage of indication for RHC based on TTE is 25% (n=100). The expected prevalence of PH in this subgroup is 60%. DATA ANALYSIS: For data analysis, we will use different test where appropriate. We will calculate sensitivities and specificities with 95% CI. We will also use ROC analysis of single parameters using both crude and smoothed fitting, and multivariable logistic regression models to examine multiple parameters jointly using the 1:10 rule. COLLABORATION/CONNECTION: Samenwerking tussen onderzoek en praktijk / Cooperation between research and practice: Ja / Yes TIME SCHEDULE: 48 Months