Prevalence and Clinical Characteristics of Heterozygous RNF213 p.Arg4810Lys Variant Carriers Diagnosed With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Ring finger protein 213 (RNF213) p.Arg4810Lys is a susceptibility gene for moyamoya disease, peripheral pulmonary artery stenosis (PPS), and other vascular diseases and thrombosis. We investigated the prevalence and clinical characteristics of RNF213 variant carriers diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: We retrospectively analyzed the prevalence of the RNF213 p.Arg4810Lys variant in patients diagnosed with CTEPH (n=112) and PPS (n=10). Clinical and angiographic characteristics were evaluated between RNF213 variant carriers diagnosed with CTEPH and noncarriers with CTEPH and homozygous variant carriers with PPS. Eight heterozygous RNF213 p.Arg4810Lys variant carriers (7.1%) were identified among patients diagnosed with CTEPH, while 5 patients with PPS (50%) carried the homozygous variant. The clinical characteristics of heterozygous variant carriers with CTEPH were not remarkably different from those of noncarriers with CTEPH. All heterozygous variant carriers with CTEPH showed webs/bands lesions at the segmental/subsegmental level, with 75% showing distal tortuous vessels. None of the heterozygous variant carriers with CTEPH exhibited the string-of-beads pattern or elongated stenosis. Homozygous variant carriers with PPS showed the string-of-beads pattern, elongated stenosis, and distal tortuous vessels without webs/bands lesions. CONCLUSIONS: A subset of patients diagnosed with CTEPH (7.1%) carried the heterozygous RNF213 p.Arg4810Lys variant. Clinical and angiographic characteristics of heterozygous variant carriers were not remarkably different from those of noncarriers of CTEPH. However, both heterozygous variant carriers with CTEPH and homozygous variant carriers with PPS showed tortuous vessels on angiography.

Effect of direct oral anticoagulant therapy on pulmonary artery clot dissolution in intermediate high-risk pulmonary thromboembolism.

BACKGROUND: Direct oral anticoagulants are the established drugs for treating pulmonary thromboembolism. The advantage of direct oral anticoagulants over conventional therapy for clot lysis and right ventricular unloading in the acute phase remains unclear. This study aimed to evaluate the effect of acute treatment with direct oral anticoagulants on clot dissolution and right ventricular unloading in intermediate high-risk pulmonary thromboembolism. METHODS: Thirty patients with intermediate high-risk pulmonary thromboembolism admitted between November 2012 and December 2018 were included; 21 and 9 were treated with direct oral anticoagulants and conventional therapy, respectively. We compared the efficacy of clot dissolution and right ventricular unloading for intermediate high-risk pulmonary thromboembolism between direct oral anticoagulant and conventional therapy in the acute phase. Efficacy was assessed by computed tomography obstruction index, right/left ventricular ratio, and brain natriuretic peptide levels between baseline and at discharge. RESULTS: Computed tomography obstruction index, right ventricular/left ventricular ratio, and brain natriuretic peptide levels were significantly lower at discharge than at admission in both groups. The rate of improvement in computed tomography obstruction index was significantly higher in the direct oral anticoagulant therapy group than in the conventional therapy group (64 ± 15% vs. 47 ± 16%; p = 0.01). There were no significant differences in the rate of improvement in right ventricular/ left ventricular ratio and brain natriuretic peptide levels between the two groups. CONCLUSIONS: Compared with conventional therapy, direct oral anticoagulants significantly reduced pulmonary artery clot burden conventional therapy in the acute treatment of intermediate high-risk pulmonary thromboembolism.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary disease without pulmonary hypertension.

Balloon pulmonary angioplasty (BPA) is beneficial for patients with chronic thromboembolic pulmonary disease (CTEPD) with pulmonary hypertension (PH). However, the clinical benefit of BPA for the patients with CTEPD without PH remains unknown. In this study, we aimed to evaluate the efficacy, safety, and long-term outcomes of BPA in patients with CTEPD without PH. We retrospectively analyzed the data from 84 CTEPD patients with mean pulmonary artery pressure (mPAP) < 25 mmHg and 39 CTEPD patients with mPAP ≤ 20 mmHg (without PH). Among the 39 patients with CTEPD without PH, 14 underwent BPA (BPA-treated group), and the remaining 25 received no treatment (untreated group). In the patients with CTEPD without PH, BPA led to improvements in symptoms, pulmonary vascular resistance (3.6 ± 1.6 to 2.6 ± 1.1 Wood units, p < 0.001), peak oxygen consumption (16.1 ± 4.0 to 18.8 ± 4.3 mL/kg/min, p = 0.033), minute ventilation versus carbon dioxide production slope (41.4 ± 12.2 to 35.1 ± 6.7, p = 0.026), and mPAP/cardiac output slope (7.0 ± 2.6 to 4.4 ± 2.0 mmHg/L/min, p = 0.004) and facilitated the discontinuation of home oxygenation therapy, with no serious complications. Kaplan-Meier analysis showed no significant difference in all-cause mortality between the untreated and BPA-treated groups. BPA may be a safe treatment option for the patients with CTEPD without PH that can alleviate symptoms, improve exercise capacity, and facilitate weaning from home oxygen therapy. Further prospective randomized trials are needed to confirm these findings.

Clinical outcomes of upfront combination therapy for portopulmonary hypertension.

Background: Limited data exists on upfront combination therapy for portopulmonary hypertension. We evaluated the clinical efficacy, long-term outcomes, and safety of upfront combination therapy in patients with portopulmonary hypertension. Methods: We performed a retrospective, single-center cohort study involving a final analysis of 33 consecutive patients diagnosed with portopulmonary hypertension who were taking pulmonary arterial hypertension-specific medication. We compared hemodynamic parameters, risk profiles, composite clinical worsening events, and safety between monotherapy (n = 23) and upfront combination therapy (n = 10). Results: Twenty-seven patients (82 %) were classified into the Child-Pugh A stage. The change ratios of pulmonary vascular resistance (-32 % vs. -57 %, P = 0.006) were significantly better with upfront combination therapy. Upfront combination therapy also showed significant improvement in risk profiles. Kaplan-Meier analysis showed that the composite event-free rate was significantly lower in patients who received upfront combination therapy than in those who received monotherapy (P = 0.016), although no statistical differences were observed in all-cause death. In the univariate Cox proportional hazards analysis, upfront combination therapy was a factor for decreasing composite clinical worsening outcomes (hazard ratio 0.190, 95 % confidence interval 0.042-0.854; P = 0.030). No significant hepatic impairments were observed over 2 years of follow-up in the upfront combination group. Conclusions: In patients with portopulmonary hypertension, upfront combination therapy significantly improved symptoms and short-term hemodynamics, and reduced long-term clinical worsening events without serious adverse effects. This study's findings suggest that patients with portopulmonary hypertension presenting with mild hepatic impairment benefit from upfront combination therapy.