A cluster of heritable pulmonary arterial hypertension cases in a family with all three siblings carrying the same novel AQP1 c.273C>G variant-a case report.

Approximately 25%-30% of patients diagnosed with idiopathic pulmonary arterial hypertension (PAH) have a clustered underlying Mendelian genetic cause and should be classified as heritable PAH (HPAH). The sixth World Symposium on Pulmonary Hypertension listed AQP1 as a PAH-related gene. AQP1 and its protein product Aquaporin-1 (AQP1) are found in abundance within pulmonary artery smooth muscle cells. Here, we report a family affected by HPAH with all three siblings carrying the same novel missense variant of AQP1 c.273C>G (p.Ile91Met). The youngest brother and the older sister both had dyspnea and edema and were diagnosed with HPAH about 10 years ago. In 2021, they received genetic tests that revealed all three siblings carried the same novel variant of AQP1 (c.273C>G). The brother in between these two siblings, although originally claimed to be asymptomatic, raised awareness. He then sought medical examination and confirmed the diagnosis of HPAH as well. This report on all three siblings carrying the same novel variant of AQP1 (c.273C>G) highlighted the importance of genetic testing and counseling for family members when PAH was first detected.

Case report: The impact of percutaneous atrial septal defect closure in pulmonary hypertension with co-existing cor triatriatum sinister and multiple cardiac comorbidities.

Cor triatriatum sinister is a rare congenital anomaly characterized by the left-sided triatrial form of the heart. Diverse theories have been proposed regarding its formation, and the failure of incorporation of the common pulmonary vein into the left atrium (LA) during embryogenesis is the most widely accepted theory. Accordingly, cor triatriatum sinister may be associated with pulmonary venous obstruction and post-capillary pulmonary hypertension in the setting of restricted fenestration. A high proportion of patients with cor triatriatum sinister also have an associated secundum atrial septal defect. Pre-capillary pulmonary hypertension, which is unusual in patients with small atrial septal defects (<2 cm), is probably not as rare as some reports indicate, especially when combined with complex comorbidities. The conventional treatment strategy of atrial septal defect closure in patients with pulmonary hypertension, whether associated with cor triatriatum sinister or co-existing multiple cardiac anomalies, involves simultaneous repair with other cardiac surgical procedures. To the best of our knowledge, there is no reported clinical experience of percutaneous atrial septal defect closure in the literature. Herein, we present the case of an elderly female with pulmonary hypertension and coexisting cor triatriatum sinister, secundum atrial septal defect, and multiple cardiac anomalies. Despite optimal medical therapy, the biventricular failure deteriorated, and clinical stabilization could not be achieved. Transcutaneous atrial septal defect closure was then performed. Subsequent investigations showed an initial improvement (perhaps due to elimination of the left-to-right shunt) from this intervention, but the long-term impact did not appear favorable, likely due to multiple uncorrected cardiac anomalies. To the best of our knowledge, this is the first clinical report showing that partial treatment of combined pre- and post-capillary pulmonary hypertension by eliminating the pre-capillary component may have an initial benefit; thus, total surgical correction should be considered a definite therapeutic strategy unless contraindicated.

Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan.

Background: Genetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce. Methods: Subjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers. Results: Eight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis. Conclusions: We identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

Serum Caveolin-1 as a Novel Biomarker in Idiopathic Pulmonary Artery Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease but with significant morbidity and high mortality. There is no specific way to diagnose PAH. Thus, an easy used with good sensitivity and specificity biomarker of PAH is highly desirable to aid in the screening, diagnosis, and follow-up. Caveolin-1 (Cav1) is the structural protein of caveolae and is highly expressed in type I pneumocytes. Lungs tissues from idiopathic PAH (IPAH) patients showed decreased expression of Cav1 in vascular endothelial cells. Therefore, we developed a direct sandwich immunoassay for the determination of Cav1 in IAPH patient's serum. The result disclosed serum Cav1 level was significantly lower in IPAH than control groups. Using serum Cav1, 17.17 pg/mL as a cutoff value, the sensitivity was 0.59 and the specificity was 1.0. There were two major findings in our results. First, serum Cav1 might be a novel biomarker in the diagnosis of IPAH with fare sensitivity and good specificity. Second, Cav1 might be used to make differential diagnosis between COPD-PH and IPAH group.

Heart rate variability parameters and ventricular arrhythmia correlate with pulmonary arterial pressure in adult patients with idiopathic pulmonary arterial hypertension.

OBJECTIVE: This aim of this study was to correlate heart rate variability (HRV) parameters to pulmonary arterial pressure (PAP) in patients with purely idiopathic pulmonary arterial hypertension (IPAH). BACKGROUND: HRV is decreased in patients with PAH. Whether HRV indices can be used to assess PAP in IPAH patients remains unclear. METHODS: HRV parameters obtained by 24-h ECG were evaluated in 26 IPAH patients and 51 controls. RESULTS: Time-domain HRV parameters (SDNN, p < 0.0001; SDANN, p < 0.0001; RMSSD, p = 0.006) were lower in IPAH patients. Frequency-domain indices (high-frequency power, HFP, p = 0.001; low-frequency power, LFP, p = 0.003; total power, TP, p = 0.001) were also decreased in IPAH patients. In IPAH patients, RMSSD (p = 0.001), HFP (p = 0.015), and LFP (p = 0.027) were significantly correlated with PAP. IPAH patients had longer QTc intervals (p < 0.0001) and more premature ventricular contractions (p < 0.0001) than controls. CONCLUSIONS: IPAH is associated with autonomic dysfunction. RMSSD, HFP, and LFP may be used as a supplemental tool to assess PAP in IPAH patients. IPAH patients with autonomic dysfunction are at high risk for ventricular arrhythmia.

Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.

Valproic acid induced teratogenicity at genetic and somatic levels, the action mechanism is still unclear. We hypothesized that folate receptor gene (folr1) and others may be interacting to elicit neural tube defect (NTD), while N-acetylcysteine (NAC) may be beneficial for protection. In chicken embryo model, the experiment was conducted in two parts. The first part was carried out to test the optimum dose of VPA. The second part was conducted to test the protective effect of NAC at doses 10 and 20 mM. VPA induced dysvascularization, incomplete somite enclosure, histone deacetylase (HDAC) inhibition, folate deficiency, homocysteine accumulation, SOD inhibition, glutathione depletion, elevated MDA and hydrogen peroxide. NAC alleviated most of these adverse effects. The microarray analysis revealed 17 genes downregulated and four upregulated. The relevancy covered translation (23%), signal transduction (23%), transcription (16%), cell adhesion (16%), neural cell migration (8%), transport (7%), and organismal development (7%). The genes insulin-like growth factor 2 receptor gene (IGF2R), regulator of G-protein signaling 4 gene (RGS4), alpha 3 (VI) collagen gene (COL6A3), endothelin receptor type b gene (EDNRB), and Krüppel-like factor 6 gene (KLF6) substantially downregulated in reality were directly intermodulating and associated with NTD. VPA downregulated folr1 gene in a dose responsive manner without affecting pax-3 gene, which was ascribed to the metahypoxic state. Conclusively, VPA affects 21 genes: 17 downregulated and four upregulated. VPA dose responsively downregulates gene folr1 without affecting pax-3 gene. These adverse effects can be partially alleviated by N-acetylcysteine.

Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model.

The teratogenicity of antiepilepsy drug valproic acid (VPA) mostly is found in genetic and somatic levels, causing teratogenesis involving neurotubular defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta. A diversity of nutraceutics have been tried to alleviate the risk of VPA-teratogenicity. The effect was varying. In order to promote the preventive prescription, to find out its action mechanism can be rather crucial. We used chicken embryo model to try the effect of folic acid (FA), ascorbic acid (AA), and N-acetyl cysteine (NAC). VPA at 30mM showed the higher malformation rate (66.7%) with the least mortality (22.2%). Pathological findings indicated that the cervical muscle was more susceptible to VPA injury than the ankle muscle. VPA downregulated levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate, and upregulated H(2)O(2) and homocysteine. FA, AA, and NAC significantly upregulated SOD, but only AA alone activated GSH. AA and NAC downregulated H(2)O(2), while FA was totally ineffective. All three nutraceutics comparably rescued HDAC with simultaneously suppressed homocysteine accumulation and folate re-elevation, although less effectively by NAC. Based on these data, we conclude VPA possesses "Multiple Point Action Mechanism". In addition to affecting the cited transcription and translation levels, we hypothesize that VPA competitively antagonize the glutamic acid to couple with pteroic acid in biosynthesis of dihydrofolic acid (DHFA). H(2)O(2) directly destroyed the NADPH reducing system at dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) levels, while completely restored by AA, an implication in preservation of intact apoenzymes. In addition, the GSH-GSSG system is sandwiched between the reducing systems NADPH/NADP and DHA-AA, its net balance is highly dependent on in situ in vivo Redox state, hence folic acid transformation is varying. To rescue the VPA-induced teratogenicity, simultaneous multiple prescriptions are suggested.