{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:27:48Z","timestamp":1790015268068,"version":"4.0.1"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic calcium channel blockers (CCBs) are indicated in children with idiopathic\/heritable pulmonary arterial hypertension (IPAH\/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients aged 3 months to 18 years who were diagnosed with IPAH\/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty-two eligible children were enrolled in the study, with a median age of 9 (6\u201311) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8\u201316.8) mg\/kg\/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5\u201328.5) mg\/kg\/day vs. 12.7 (6.6\u201314.4) mg\/kg\/day, <jats:italic>P<\/jats:italic> &amp;lt; 0.05. Patients were followed up for a median period of 6.2 (2.6\u201310.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Diltiazem was used in a very high dose for eligible children with IPAH\/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2022.918735","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T05:30:57Z","timestamp":1662528657000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Safety of chronic high-dose calcium channel blockers exposure in children with pulmonary arterial hypertension"],"prefix":"10.3389","volume":"9","author":[{"given":"Yan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Hua","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Xin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"FengWen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-Shan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202110-2428OC","article-title":"Twenty-year experience and outcomes in a National Pediatric Pulmonary Hypertension Service","author":"Constantine","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1161\/CIRCULATIONAHA.110.969584","article-title":"Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005","volume":"124","author":"van Loon","year":"2011","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"343","DOI":"10.7326\/0003-4819-115-5-343","article-title":"Survival in patients with primary pulmonary hypertension. 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