Pulmonary hypertension- a novel phenotypic hypothesis of Kabuki syndrome: a case report and literature review.

BACKGROUND: Pediatric pulmonary hypertension (PH) is a serious and rare disease that is often derived from genetic mutations. Kabuki syndrome (KS) is a chromosomal abnormality disease that has its origin in the mutation of lysine methyltransferase 2D(KMT2D). Recent evidence has shown that KMT2D mutations are associated with pediatric pulmonary disorders. However, the relationship between the clinical courses of PH and the KMT2D mutation is reported in extremely few cases. Therefore, in this paper, a case was presented and previous literature was reviewed for better understanding of the correlation between pediatric PH and KMT2D mutations. CASE PRESENTATION: A 3-year-old girl was transferred to our center for severe cough, shortness of breath, fatigue and fever. Physical examination revealed facial deformities and growth retardation. Echocardiography showed a small atrial septal defect (ASD), and right heart catheterization indicated a significant increase in pulmonary vascular pressure and resistance. The genetic test suggested that she had a KMT2D gene mutation. The patient was finally diagnosed with KS. She was given targeted drugs to reduce pulmonary vascular pressure, but the effect was unsatisfactory. CONCLUSIONS: KS can be complicated with multiple organ malformations and dysfunction. With the progress of next generation sequencing, an increasing number of new phenotypes related to KMT2D mutations have been reported. A bold hypothesis is proposed in this article, that is, PH may be a new phenotype associated with KMT2D mutations. It is suggested that KS and PH should be differentiated from each other to avoid delayed diagnosis and treatment in clinical practice. There is no specific drug for KS treatment. The prognosis of children with inherited PH is usually poor, and lung transplantation may increase their survival rates.

Agitated saline with 10% blood increases number and stability of microbubbles in detection right-to-left shunt by contrast-enhanced transcranial Doppler: an in vitro and in vivo observational study.

Background: Agitated saline (AS) with blood has been shown to have good tolerance and increased efficacy when used in contrast-enhanced transcranial Doppler (c-TCD) to detect right-to-left shunt (RLS). However, little is known about the effects of blood volume on c-TCD results. Our study investigated the characterization of AS with different blood volumes in vitro and compared the c-TCD results in vivo. Methods: In vitro, AS without blood, AS with 5% blood (5% BAS), and AS with 10% blood (10% BAS) were prepared based on previous studies and observed under microscopy. The numbers and sizes of the microbubbles from different contrast agents were compared immediately, 5 min, and 10 min post-agitation. In vivo, 74 patients were recruited. c-TCD was repeated 3 times using AS with different blood volumes in each patient. Signal detection times, positive rates, and classifications of RLS were compared among the 3 groups. Results: In vitro, the AS without blood produced 5.4±2.4/field microbubbles after agitation, the 5% BAS produced 30.4±4.2/field, and the 10% BAS produced 43.9±12.7/field. More microbubbles remained in the 10% BAS than the 5% BAS within 10 min (18.5±6.1 vs. 7.1±2.0/field, P<0.001). The size of the microbubbles from the 5% BAS increased from 9.2±8.2 to 22.1±10.6 µm within 10 min post-agitation (P=0.014), while the 10% BAS changed insignificantly. In vivo, the signal detection times of the 5% BAS (1.1±0.7 s) and 10% BAS (1.0±0.8 s) were significantly shorter than the AS without blood (4.0±1.5 s, P<0.0001). The RLS positive rates were 63.5%, 67.6% and 71.6% in AS without blood, 5% BAS and 10% BAS respectively; however, the differences were not statistically significant. The AS without blood reached 12.2% level III RLS, while the 5% BAS reached 25.7%, and the 10% BAS reached 35.1% (P=0.005). Conclusions: The 10% BAS would be suggested in c-TCD as it addressed larger RLS by increasing the number and stability of microbubbles, and it improves the diagnosis of patent foramen ovale (PFO).

Bile acid predicts congenital portosystemic venous shunt in patients with pulmonary arterial hypertension.

The etiology of pulmonary arterial hypertension (PAH) is complex, especially the investigation of rare pathogeny is difficult. Congenital portosystemic venous shunt (CPSS) is a rare congenital anomaly in which the portal blood completely or partially bypasses the liver through a congenital portosystemic shunt, and drains directly into the inferior vena cava (IVC) (Howard and Davenport in J Pediatr Surg 32:494-497, 1997).CPSS is an uncommon cause of PAH (Christiane et al. in J Pediatr Gastroenterol Nutr 56:675-681, 2013), and often covered by other pathogenic factors. The clinical manifestations of CPSS-associated PAH are not specific, thus making it difficult to distinguish from PAH caused by other pathogenetic factors based on clinical presentations alone. This is a retrospective analysis of data from six patients with CPSS at a single center. Of these, five were diagnosed as PAH: four were also associated with other predisposing factors of pulmonary hypertension (PH). All patients had high serum bile concentration and high cardiac output. The aim of this retrospective study was to investigate the clinical recognition of PAH secondary to CPSS. The concentration of serum bile acid and cardiac output can be used as two important non-invasive indicators in clinical practice. Thus far, few studies have reported the clinical outcomes of CPSS-associated PAH specifically (Anna et al. in Hepatology 71:658-669, 2020;Franchi-Abella et al. in J Pediatr Gastroenterol Nutr 51:322-330, 2010;Uike et al. in Pediatr Pulmonol 53:505-511, 2018;). In the current study, such patients carried a poor prognosis if left untreated, or treated with pulmonary vasodilators alone.

Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review.

BACKGROUND: Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. CASE PRESENTATION: The patient was a 8-month-old female with repeated episodes of pneumonia. Physical examination revealed cleft lip, cleft palate and developmental retardation. Imaging examination showed a small atrial septal defect (ASD), central pulmonary artery enlargement, left upper lobe of lung atelectasis, and pulmonary infiltration. Genetic test showed she carried a de novo pathogenic variant of FLNA gene (c.5417-1G > A, p.-). Oral medications didn't slow the progression of PAH in the patient, and she died two years later. CONCLUSIONS: FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other comorbidities in pediatric patients. We highly recommend genetic testing for pediatric patients when suspected with PAH. Given the high mortality in this group, lung transplantation may offer a better outcome.

Understanding the current status of patients with pulmonary hypertension during COVID-19 outbreak: a small-scale national survey from China.

Pulmonary hypertension is a chronic disease developing progressively with high mortality. Pulmonary hypertension patients need persistent medical care; however, limited reports focused on them when there was an outbreak of coronavirus disease 2019 in China. This national survey was aimed to evaluate the overall condition of pulmonary hypertension patients during this period. A questionnaire regarding the living condition of pulmonary hypertension patients during coronavirus disease 2019 was designed by pulmonary hypertension diagnostic experts in Wuhan Asia Heart Hospital. Pulmonary hypertension patients and their family members were invited to participate in this survey online. One-hundred twenty pulmonary hypertension patients and 23 family members participated in the survey; 64.8% (n = 87) participants came from Hubei, and others were from 15 other provinces; 98.6% (n = 141) participants were in home quarantine; 65.8% (n = 79) were pulmonary arterial hypertension associated with congenital heart disease; and 76.7% (n = 92) patients proclaimed their heart function was well maintained at class I or II. One (0.8%) patient was confirmed severe acute respiratory syndrome coronavirus 2 infection. Two (1.7%) patients were hospitalized due to heart function worsening. Nearly 70% (n = 100) participants implied shortage in medications during coronavirus disease 2019 outbreak. A total of 24.2% (n = 29) patients indicated that medications were discontinued due to the insufficient supply. Most of the participants stayed optimistic on either coronavirus disease 2019 outbreak or their pulmonary hypertension disease, and 61.7% (n = 74) patients would go to the hospital for follow-up immediately after outbreak. These preliminary data show pulmonary hypertension patients are able to avoid severe disease when they are in home quarantine. Medication supplement is important for pulmonary hypertension patients when their heart function is well maintained. In addition, there might be increasing requirements of medical care for pulmonary hypertension patients after the outbreak.

Impact of dehydroepianrosterone (DHEA) supplementation on serum levels of insulin-like growth factor 1 (IGF-1): A dose-response meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Inconsistencies exist with regard to the influence of dehydroepiandrosterone (DHEA) supplementation on insulin-like growth factor 1 (IGF-1) levels. The inconsistencies could be attributed to several factors, such as dosage, gender, and duration of intervention, among others. To address these inconsistencies, we conducted a systematic review and meta-analysis to combine findings from randomized controlled trials (RCTs) on this topic. METHODS: Electronic databases (Scopus, PubMed/Medline, Web of Science, Embase and Google Scholar) were searched for relevant literature published up to February 2020. RESULTS: Twenty-four qualified trials were included in this meta-analysis. It was found that serum IGF-1 levels were significantly increased in the DHEA group compared to the control (weighted mean differences (WMD): 16.36 ng/ml, 95% CI: 8.99, 23.74; p = .000). Subgroup analysis revealed that a statistically significant increase in serum IGF-1 levels was found only in women (WMD: 23.30 ng/ml, 95% CI: 13.75, 32.87); in participants who supplemented 50 mg/d DHEA (WMD: 15.75 ng/ml, 95% CI: 7.61, 23.89); in participants undergoing DHEA intervention for >12 weeks (WMD: 17.2 ng/ml, 95% CI: 8.02, 26.22); in participants without an underlying comorbidity (WMD: 19.11 ng/ml, 95% CI: 10.69, 27.53); and in participants over the age of 60 years (WMD: 19.79 ng/ml, 95% CI: 9.86, 29.72). CONCLUSION: DHEA supplementation may increase serum IGF-I levels especially in women and older subjects. However, further studies are warranted before DHEA can be recommended for clinical use.

Guideline implementation and early risk assessment in pulmonary arterial hypertension associated with congenital heart disease: A retrospective cohort study.

INTRODUCTION: Current guidelines emphasize that accurate risk stratification is important for patients with pulmonary arterial hypertension (PAH), however, few suggestions have been specified for PAH associated with congenital heart disease (PAH-CHD). OBJECTIVES: The aim of this study was to propose an accurate and simple system based on current guidelines for risk stratification in PAH-CHD patients during 12-month follow-up. METHODS: We reviewed 288 Chinese PAH-CHD patients between January 2014 and December 2016 in this retrospective cohort study. The low-risk criteria according to 2015 European Society of Cardiology guidelines and the adverse events (AEs) during follow-up were collected. The association between low-risk criteria and AEs was assessed with Cox regression, and a simplified risk stratification system was proposed. RESULTS: There were 105 PAH-CHD patients included in the final analysis. Twenty-nine patients had AEs defined as death, initiation of new or combined medication treatment, or re-hospitalisation because of the PAH worsening. Among the low-risk criteria, WHO/NYHA functional class, 6-minute walking distance (6MWD), NT-proBNP and SvO2 were significantly different between AE and AE-free groups. However, 6MWD (HR = 0.08, 95% CI: 0.03-0.19, P < 0.001) and NT-proBNP (HR = 0.35, 95% CI: 0.16-0.78, P = 0.01) were the only independent predictors of AEs in multivariable model. When taking them into a simplified system for risk stratification, the number of low-risk criteria at diagnosis discriminated the risk of AEs (P < 0.001). CONCLUSIONS: Among the low-risk criteria proposed by current guidelines, 6MWD and NT-proBNP predicted AEs independently for PAH-CHD patients. Simplified risk stratification system by taking these two parameters numerically provides accurate prognostic information in PAH-CHD patients.

[Clinical characteristics of 195 Chinese patients with WHO Class I pulmonary hypertension].

OBJECTIVE: To analyze the clinical characteristics of WHO Class I pulmonary hypertension (PAH) in central China. METHODS: Data was collected as a part of prospective registry of PAH through Jan. 2009 to Oct. 2013 in Wuhan Asia Heart Hospital. A total of 195 patients were recruited including 144 cases with congenital heart disease with pulmonary hypertension (CHD-PAH) and 51 cases with idiopathic pulmonary hypertension (IPAH). RESULTS: The age of all patients ranged from 1 to 68 years (mean (27.5 ± 13.2) years), 129 cases were female (66.2%). WHO Class I PAH accounted for 91.1%, CHD-PAH 67.3%, IPAH 23.8%, and other 8.9%.WHO function class III/IV in newly diagnosed PAH accounted for 32.3%, the mean 6MWD was (397 ± 74) m. For patients with IPAH, the median time period between onset of symptoms and diagnosis by right heart catheterization was 38 months. The mean pulmonary pressure, pulmonary vascular resistance index, cardiac index of patients with IPAH and CHD-PAH were measured by the right heart catheterization and there was no difference between the two groups. Acute pulmonary vasodilator testing was negative in all patients in this cohort. Cardiac function was improved in the 121 cases who received the targeted drug treatment and 1 patient died out of these 121 patients while 5 cases died out of patients receiving conventional therapy. CONCLUSION: In Central China, Class I pulmonary hypertension is the most predominant type of PAH, the cardiac function and hemodynamic indexes of these patients were significantly impaired at the time of first PAH diagnosis. Most of the patients accepted targeted drug treatment of pulmonary hypertension, but the drug dose used for the targeted drug treatment is not effective enough in these patients.

[Efficacy of endothelin receptor antagonist bosentan on the long-term prognosis in patients after Fontan operation].

OBJECTIVE: To investigate the long-term effect of bosentan on outcome in patients after Fontan operation. METHODS: Patients after Fontan surgery were randomly divided into bosentan group (B, n = 16) and control group (C, n = 23). Bosentan was applied within 7 days after Fontan surgery as follows: at the first month, 7.8125 mg Bid for patients with body weight ≤ 10 kg; 15.625 mg Bid for patients with body weight between 10-20 kg; 31.25 mg Bid for patients with body weight 20-30 kg and 62.5 mg Bid for patients with body weight > 30 kg. At the second month, the bosentan dose was doubled and Bosentan therapy was continued for more than 1 year. Group C didn't take drugs affecting pulmonary artery pressure. All patients were followed up for 2 years and incidence of mortality, protein losing enteropathy, pulmonary arteriovenous fistulae, 6-minute walk test, heart function were compared between the two groups. RESULTS: After 2 years, mortality tended to be lower in group B compared to group C [6.25% (1/16) vs. 21.8% (5/23), P > 0.05]. Incidence of pulmonary arteriovenous fistulae and protein losing enteropathy were significantly lower in group B than in group C (6.25% vs. 34.78%, P = 0.01;6.25% vs. 39.13%, P = 0.02, respectively) . The results of 6-minute walk test[ (485 ± 44) m vs. (302 ± 183) m] and heart function in group B (3 NYHA III/IV patients in group B vs. 14 NYHA III/IV patients in group C, all P < 0.05) were all better than group C. The concentrations of vasoactive factors such as brain natriuretic peptide (BNP, 279.07 ± 128.17 vs. 457.67 ± 221.30), endothelin (ET, 3.30 ± 0.61 vs. 4.98 ± 1.24) and thromboxane (TXA2, 97.2 ± 24.0 vs. 163.22 ± 24.4) were also significantly lower in group B than in group C (all P < 0.05). Prostacyclin (PGI2) level and incidence of arrhythmias were similar between the two groups. There was no thrombotic event in both groups during follow up. CONCLUSION: Bosentan trerapy in patients post Fontan operation could reduce the incidence of pulmonary arteriovenous fistulae and protein losing enteropathy and improve heart function.