CORRESPONDENCE Treprostinil Iontophoresis in Idiopathic Pulmonary Arterial Hypertension To the Editor: Idiopathic pulmonary arterial hypertension (PAH) is a progressive disease without identifiable etiology and is characterized by elevated pulmonary vascular resistance that can lead to right heart failure and death (1). Initial studies characterized idiopathic PAH (IPAH) as a disease of the pulmonary circulation; however, recent data from us (2, 3) and other investigators (4–6) showed evidence of extrapulmonary vascular involvement. The extrapulmonary microcirculation can be studied in vivo, using cutaneous laser Doppler flowmetry (7), a methodology that can measure changes in skin flow in response to vasoactive stimuli. One stimulus is the cutaneous administration of prostacyclin (PGI2 ), using iontophoresis. Patients with IPAH have a marked reduction in PGI2 synthase (8) and expression of prostaglandin I 2 receptors (9) in the lungs. More important, PGI2 analogs are potent medications to treat IPAH. Treprostinil is a PGI2 analog that increases cutaneous blood flow when administered by cathodal iontophoresis to healthy volunteers (10) and patients with systemic sclerosis (11). We hypothesize that patients with IPAH have systemic abnormalities in the PGI2 pathway that can be tested in vivo by cutaneous treprostinil iontophoresis. The research protocol was approved by the Cleveland Clinic Institutional Review Board, and all subjects provided written informed consent. We conducted this cross-sectional study between February 2013 and February 2015. We included consecutive patients who met hemodynamic criteria for PAH (12) and had the idiopathic or heritable (HPAH) forms of the disease. In addition, we studied age- and sex-matched control subjects without clinical evidence of pulmonary hypertension.
Supported by Clinical and Translational Science Collaborative KL2 (grant TR000440 to A.R.T.) from the National Center for Research Resources, a component of the National Institutes of Health, National Institutes of Health Roadmap for Medical Research. M.K.A. is supported by the Egyptian Cultural and Educational Research Scholar Program. A.R.T. participated in the conception and design of the study, data collection, statistical analysis, interpretation of the results, writing and critical revision of the manuscript for important intellectual content, and final approval of the manuscript submitted and is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. M.K.A. participated in performing the microvascular studies and laboratory determinations, data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. L.A. participated in performing the microvascular studies, data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. F.C. participated in the data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. K.A. participated in laboratory determinations, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. R.A.D. participated in the conception of the study, interpretation of the results, writing and critical revision of the manuscript for important intellectual content, and final approval of the manuscript submitted. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
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We used the PeriFlux system 5000 (Perimed, J¨arf¨alla, Sweden) to test the effects of treprostinil iontophoresis and local thermal hyperemia. Treprostinil iontophoresis in patients was performed within 1 hour after right heart catheterization. Treprostinil (Remodulin 1 mg/ml) and its placebo (only treprostinil buffer) were iontophoresed for 30 minutes at 20 mA with a negative polarity. Measures were expressed as arbitrary perfusion units (PUs) (Figure 1). A detailed description of the methods is presented in the online supplement. Safety of the methodology was ascertained by recording local and/or systemic adverse effects in all subjects and by measuring treprostinil levels in plasma (at 20 minutes of iontophoresis) in a subset of individuals (n = 5). Patients (n = 24; IPAH = 22, HPAH = 2) and controls (n = 25) were age- and sex-matched. We also matched conditions known to be associated with systemic microvascular dysfunction. Patients were in New York Heart Association functional class I (n = 4, 17%), II (n = 7, 29%), III (n = 12, 50%), and IV (n = 1, 4%). Three quarters of patients were receiving PAHspecific therapies at the time of iontophoresis. Five (21%) and 7 (29%) received inhaled or parenteral PGI2 analogs, respectively. Patients had a mean pulmonary artery pressure of 44.5 6 14 mm Hg, cardiac index (thermodilution) of 2.8 6 0.79 L/min/m 2 , and pulmonary vascular resistance of 7.5 6 4.3 Wood units. A total of 17 patients underwent inhaled nitric oxide challenge. With treprostinil iontophoresis, peak PUs, percentage change in PUs, and the percentage of peak PUs relative to the maximum value obtained by local hyperthermia were significantly reduced in patients compared with matched controls (Table 1). These relationships persisted after adjusting for skin resistance. The treprostinil buffer only minimally increased these determinations (n = 6), supporting the idea that the vasoactive effects are mostly a result of treprostinil. The receiver operating characteristic curve that tested the ability of the percentage change in PUs with treprostinil iontophoresis to discriminate between patients and controls showed an area under the curve of 0.75 (95% confidence interval [CI], 0.60–0.86; P = 0.0007). Patients treated with PGI2 analogs had higher baseline PUs (median [interquartile range], 7 [4–10] vs. 3 [2–6]; P = 0.04) and higher cardiac indexes (3.2 [2.8–3.6] vs. 2.4 [1.8–3.1] L/min/m2; P = 0.01) than those not receiving this treatment. In addition, those receiving PGI2 analogs had a higher percentage change in PUs (517 [202–672] vs. 225 [86–274]%; P = 0.004) during treprostinil iontophoresis compared with individuals not receiving this treatment. In patients with IPAH not receiving PGI2 analogs (n = 12), the receiver operating characteristic curve of percentage change in PUs for discriminating patients versus controls showed an area under the curve of 0.87 (95% CI, 0.72–0.96; P , 0.0001). In this analysis, a cutoff of
Supported by Clinical and Translational Science Collaborative KL2 (grant TR000440 to A.R.T.) from the National Center for Research Resources, a component of the National Institutes of Health, National Institutes of Health Roadmap for Medical Research. M.K.A. is supported by the Egyptian Cultural and Educational Research Scholar Program. A.R.T. participated in the conception and design of the study, data collection, statistical analysis, interpretation of the results, writing and critical revision of the manuscript for important intellectual content, and final approval of the manuscript submitted and is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. M.K.A. participated in performing the microvascular studies and laboratory determinations, data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. L.A. participated in performing the microvascular studies, data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. F.C. participated in the data collection, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. K.A. participated in laboratory determinations, interpretation of the results, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. R.A.D. participated in the conception of the study, interpretation of the results, writing and critical revision of the manuscript for important intellectual content, and final approval of the manuscript submitted. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
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We used the PeriFlux system 5000 (Perimed, J¨arf¨alla, Sweden) to test the effects of treprostinil iontophoresis and local thermal hyperemia. Treprostinil iontophoresis in patients was performed within 1 hour after right heart catheterization. Treprostinil (Remodulin 1 mg/ml) and its placebo (only treprostinil buffer) were iontophoresed for 30 minutes at 20 mA with a negative polarity. Measures were expressed as arbitrary perfusion units (PUs) (Figure 1). A detailed description of the methods is presented in the online supplement. Safety of the methodology was ascertained by recording local and/or systemic adverse effects in all subjects and by measuring treprostinil levels in plasma (at 20 minutes of iontophoresis) in a subset of individuals (n = 5). Patients (n = 24; IPAH = 22, HPAH = 2) and controls (n = 25) were age- and sex-matched. We also matched conditions known to be associated with systemic microvascular dysfunction. Patients were in New York Heart Association functional class I (n = 4, 17%), II (n = 7, 29%), III (n = 12, 50%), and IV (n = 1, 4%). Three quarters of patients were receiving PAHspecific therapies at the time of iontophoresis. Five (21%) and 7 (29%) received inhaled or parenteral PGI2 analogs, respectively. Patients had a mean pulmonary artery pressure of 44.5 6 14 mm Hg, cardiac index (thermodilution) of 2.8 6 0.79 L/min/m 2 , and pulmonary vascular resistance of 7.5 6 4.3 Wood units. A total of 17 patients underwent inhaled nitric oxide challenge. With treprostinil iontophoresis, peak PUs, percentage change in PUs, and the percentage of peak PUs relative to the maximum value obtained by local hyperthermia were significantly reduced in patients compared with matched controls (Table 1). These relationships persisted after adjusting for skin resistance. The treprostinil buffer only minimally increased these determinations (n = 6), supporting the idea that the vasoactive effects are mostly a result of treprostinil. The receiver operating characteristic curve that tested the ability of the percentage change in PUs with treprostinil iontophoresis to discriminate between patients and controls showed an area under the curve of 0.75 (95% confidence interval [CI], 0.60–0.86; P = 0.0007). Patients treated with PGI2 analogs had higher baseline PUs (median [interquartile range], 7 [4–10] vs. 3 [2–6]; P = 0.04) and higher cardiac indexes (3.2 [2.8–3.6] vs. 2.4 [1.8–3.1] L/min/m2; P = 0.01) than those not receiving this treatment. In addition, those receiving PGI2 analogs had a higher percentage change in PUs (517 [202–672] vs. 225 [86–274]%; P = 0.004) during treprostinil iontophoresis compared with individuals not receiving this treatment. In patients with IPAH not receiving PGI2 analogs (n = 12), the receiver operating characteristic curve of percentage change in PUs for discriminating patients versus controls showed an area under the curve of 0.87 (95% CI, 0.72–0.96; P , 0.0001). In this analysis, a cutoff of
