Sex difference in nocturnal blood pressure dipping in adolescents with varying degrees of adiposity.

BACKGROUND: For adolescents, abnormal dipping patterns in blood pressure (BP) are associated with early-onset organ damage and a higher risk of cardiovascular disorders in adulthood. Obesity is one of the most common reasons for abnormal BP dipping in young people. However, it is unknown whether the severity of obesity is associated with BP dipping status and whether this association is sex-dependent. METHODS: 499 participants between 12 and 17 years old with overweight or obesity underwent ambulatory blood pressure monitoring (ABPM) between April 2018 and January 2019 in Beijing and Baoding. Participants were grouped by body mass index (BMI) into overweight (BMI 85th-95th percentile), obese (BMI ≥ 95th percentile) and severely obese (BMI ≥ 120% of 95th percentile or ≥ 35 kg/m2) groups. Non-dipping was defined as a < 10% reduction in BP from day to night. The interaction effect between sex and obesity degree was also analyzed. RESULTS: 326 boys and 173 girls were included, of whom 130 were overweight, 189 were obese, and 180 were severely obese. Girls with severe obesity had a higher prevalence of non-dipping, but boys showed no significant differences in BP dipping status between obesity categories. In addition, as obesity severity went up, a more evident increase in night-time SBP was observed in girls than in boys. CONCLUSIONS: Severely obese is associated with a higher prevalence of non-BP dipping patterns in girls than in boys, which suggests that the relationship between the severity of obesity and BP dipping status might be sex-specific.

A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND: Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described. METHODS: Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review. RESULTS: The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome. CONCLUSIONS: The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment. IMPACT: First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing NF1 Mutation.

INTRODUCTION: Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis. METHODS: Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression, and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK methods, respectively. RESULTS: A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused the skipping of exon 4, leading to a glutamine-to-valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modeling showed that several major domains were missing in the truncated neurofibromin protein. CONCLUSION: The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused the skipping of exon 4 and a truncated protein. Our findings offer new evidence for the molecular diagnosis of NF-1.

Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

Clinical characteristics of concurrent primary aldosteronism and renal artery stenosis: A retrospective case-control study.

Background: Rare cases of concurrent primary aldosteronism (PA) and renal artery stenosis (RAS) have been reported. Methods: In this retrospective case-control study, we selected a cohort of 10 PA with RAS patients and a control group of 20 PA without RAS patients from January 1, 2006, to January 1, 2016.  Results: All patients presented with refractory hypertension, and a nonstatistically significant trend toward lower mean serum potassium was seen in the PA with RAS group (p =.07). PA with RAS patients had lower mean orthostatic aldosterone-to-renin ratios (38.4 ± 41.4 ng dL-1/ng mL-1 h-1 vs. 87.4.4 ± 38.4 ng dL-1/ng mL-1 h-1, respectively; p < .01) and a higher false-negative rate (50% vs. 15%, respectively; p < .05) compared with controls. All misdiagnosed patients had the diagnosis of PA confirmed when we revaluated the repeated screening and confirmative tests because of residual hypertension or hypokalemia after successful revascularization of renal artery stenosis.  Conclusions: PA is easily missed in patients with RAS because of the high false-negative rate for screening tests. RAS patients with residual hypertension after successful renal angioplasty should be monitored for coexisting PA. Reevaluation of screening and confirmatory tests is helpful in establishing the correct diagnoses.

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation.

INTRODUCTION: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS: Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of ß-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS: We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.

Truncated Epithelial Sodium Channel ß Subunit Responsible for Liddle Syndrome in a Chinese Family.

BACKGROUND/AIMS: Liddle syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. METHODS: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the ß-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. RESULTS: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated ß-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. CONCLUSIONS: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of ß-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.

Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome.

BACKGROUND: Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age. OBJECTIVES: To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome. METHODS: Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed. RESULTS: A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature. CONCLUSIONS: Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension.

Transcatheter closure or surgical repair of right pulmonary artery-left atrial fistula.

Right pulmonary artery-left atrial fistula is a rare congenitalcardiac anomaly, and only a few articles published so far have reported the diagnosis and treatment of right pulmonary artery-left atrial fistula. In this study, we report three cases of successful transcatheter closure or surgical repair of right pulmonary artery-left atrial fistula.

Lack of association between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, IL-23R genes and Takayasu arteritis in a Chinese population.

OBJECTIVE: The goal of this study was to investigate the relationship between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, and IL-23R genes and Takayasu arteritis (TA) in a Chinese population. METHODS: A case-control study was performed to investigate the associations of 19 single nucleotide polymorphisms (SNPs) mapping to IL12A, IL12B, IL12RB1, IL12RB2 and IL23R with susceptibility to TA in 145 Chinese TA patients and 300 healthy controls. Genotype identification was performed with the MassARRAY system from Sequenom. The statistical analysis was conducted by Chi square test and unconditional logistic regression with plink. RESULTS: No significant differences were found for the distribution of allele and genotype frequencies of these SNPs between TA patients and healthy controls. However, a trend for IL12A rs582054 and IL23R rs1004819 in association with the TA phenotype was detected. TA patients carrying the rs582054/rs568408 haplotype (P' = 0.019) appeared less likely to progress to a more severe form of disease. And the C allele (P' = 0.082) of IL23R rs1004819 appeared to be a protective factor to refractory disease. CONCLUSIONS: These findings suggest that the polymorphisms of IL12A, IL12B, IL12RB1, IL12RB2 and IL23R might make no contribution to the susceptibility of TA in the Chinese population.

Simultaneous Bilateral vs Unilateral Carotid Artery Stenting: 30-Day and 1-Year Results.

PURPOSE: To evaluate clinical outcomes of simultaneous bilateral carotid artery stenting (sbCAS) compared with unilateral CAS (uCAS). METHODS: The database in our institution was queried to identify all patients treated with CAS from January 2005 to December 2012. In this time frame, 120 (18.8%) patients (mean age 64.9 ± 7.7 years; 96 men) underwent sbCAS and 517 (81.2%) patients (mean age 65.7 ± 7.7 years; 421 men) received uCAS. The primary endpoint was the composite of stroke, myocardial infarction, or death within 30 days or any ipsilateral stroke within 1 year. RESULTS: There was no significant difference in the rates of the primary endpoint between the sbCAS and uCAS groups (6.7% vs 4.6%, p=0.358). The rates of the primary endpoint among symptomatic patients was 8.0% in the sbCAS group and 5.0% in the uCAS group (p=0.299) and 3.1% and 4.0%, respectively (p=0.821) among asymptomatic patients. During the 30-day periprocedural period, the rates of the primary endpoint did not differ significantly between the sbCAS and uCAS groups among all patients (5.8% vs 4.4%, p=0.479), symptomatic patients (6.8% vs 5.0%, p=0.594), or asymptomatic patients (3.1% vs 3.5%, p>0.999). After this period, the incidences of any ipsilateral stroke were similarly low (0.8% and 0.2%, respectively; p=0.342). CONCLUSION: The study showed that simultaneous bilateral CAS had no more adverse events than unilateral CAS during the periprocedural period or within 1 year. This 1-stage strategy may become a valuable alternative in the treatment of patients with severe bilateral carotid stenosis.

A novel frameshift mutation of epithelial sodium channel ß-subunit leads to Liddle syndrome in an isolated case.

OBJECTIVE: Liddle syndrome, an autosomal dominant form of monogenic hypertension, is attributed to mutations in the genes encoding ß and γ subunits (SCNN1B and SCNN1G) of the epithelial sodium channel (ENaC). The aim of this study was to search for pathogenic mutations of SCNN1B and SCNN1G in an adolescent under the impression of Liddle syndrome and no family history of hypertension. DESIGN AND PATIENTS: We screened the C-terminus of SCNN1B and SCNN1G in an adolescent with poorly controlled hypertension who was clinically diagnosed as having Liddle syndrome. We also screened for the mutation in his parents, 100 hypertensive patients and 100 controls. RESULTS: Genetic analysis of SCNN1B revealed a frameshift mutation induced by insertion of an additional cytosine into a string of six located between codons 617 and 618, which is predicted to introduce a new termination codon at position 621 and produce a protein truncated by 20 amino acids. This frameshift mutation was not detected in the patient's parents, the 100 hypertensive patients or the 100 controls, indicating that this is a de novo mutation and not a common genetic polymorphism. There was no mutation of SCNN1G in any of the individuals examined. CONCLUSION: Based on direct DNA sequencing, we identified a novel frameshift mutation in the ßENaC gene in an isolated case of Liddle syndrome. Confirmation of the diagnosis and effective tailored treatment in the patient were achieved, implying that genetic testing is a useful tool to diagnose Liddle syndrome.

Predicting stroke and myocardial infarction risk in Takayasu arteritis with automated machine learning models.

Few models exist for predicting severe ischemic complications (SIC) in patients with Takayasu arteritis (TA). We conducted a retrospective analysis of 703 patients with TA from January 2010 to December 2019 to establish an SIC prediction model for TA. SIC was defined as ischemic stroke and myocardial infarction. SIC was present in 97 of 703 (13.8%) patients with TA. Common iliac artery, coronary artery, internal carotid artery, subclavian artery, vertebral artery, renal artery involvement, chest pain, hyperlipidemia, absent pulse, higher BMI, vascular occlusion, asymmetric blood pressure in both upper limbs, visual disturbance, and older age were selected as predictive risk factors. Considering both discrimination and calibration performance, the Weighted Subspace Random Forest model was the most optimal model, boasting an area under the curve of 0.773 (95% confidence interval [0.652, 0.894]) in the validation cohort. Effective models for predicting SIC in TA may help clinicians identify high-risk patients and make targeted interventions.

Intestinal Cckbr-specific knockout mouse as a novel model of salt-sensitive hypertension via sodium over-absorption.

OBJECTIVES: To investigate the value of CCKBRfl/fl villin-Cre mice as a mouse model of salt-sensitive hypertension (SSH). METHODS: In the first part, 2-month-old CCKBRfl/fl villin-Cre mice (CKO) and control CCKBRfl/fl mice (WT) were fed with normal diet (0.4% NaCl) or high salt diet (4% NaCl), separately for 6 weeks. In the rescue study, one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet. The blood pressure, biochemical indexes, and the expression of small intestinal sodium transporters (NHE3, NKCC1, eNaC) was detected. The organ injury markers (MMP2/MMP9) and the histopathological changes of kidneys were observed, whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo. RESULTS: The CCKBRfl/fl villin-Cre mice with high salt intake exhibited high blood pressure, increased duodenal sodium absorption and urinary sodium excretion, and with renal injury. The protein expression of NHE3, NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice. Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBRfl/fl villin-Cre mice, but no significant histopathological changes were observed. CONCLUSIONS: These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBRfl/fl villin-Cre mice. The CCKBRfl/fl villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.

Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described. METHODS: Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further. RESULTS: Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events. CONCLUSIONS: The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study.

PURPOSE: Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. METHODS: Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. RESULTS: The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. CONCLUSIONS: The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-ß) signaling-related disorders.

RET c.1901G>A and Novel SLC12A3 Mutations in Familial Pheochromocytomas

Familial PHEOs (pheochromocytomas) are inherited as an autosomal dominant trait, and inherited PHEOs can be one clinical phenotype of clinical syndromes, such as multiple endocrine neoplasia type 2A (MEN2A). In recent years, there has been a lot of controversy about the factors affecting the penetrance of PHEOs in MEN2A, of which the effects of RET (rearranged during transfection) proto-oncogene mutations are the primary concern. In this report, we performed genetic screening of patients in one family presenting with PHEOs and found they carried a RET c.1901G>A mutation. They were ultimately diagnosed with familial MEN2A. We found that MEN2A patients with the RET c.1901G>A mutation tended to have bilateral PHEOs that appeared earlier than medullary thyroid carcinoma. Genetic analysis showed that the patients also carried novel SLC12A3 (solute carrier family 12 member 3) variants, which are highly associated with Giteman syndrome. The results of protein structure prediction models suggest this SLC12A3 mutant has altered both the protein structure and the interaction with surrounding amino acids. Further studies of the phenotypes and related mechanisms of the gene mutations are required to guide individual assessment and treatment.

Percutaneous Transluminal Renal Angioplasty for Fibromuscular Dysplasia and Prognostic Risk Factors: A Retrospective Chinese Cohort Study.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disease involving small-to-medium-sized arteries. The characteristics of Chinese patients with FMD remain unclear. We retrospectively analyzed the data of patients with renal FMD who underwent percutaneous transluminal renal angioplasty (PTRA) for the first time at Fuwai Hospital between 2010 and 2021. The variables were selected through least absolute shrinkage and selection operator regression (LASSO), and logistic regression models were constructed to identify independent risk factors. A total of 116 patients (52 males, median age at diagnosis, 25.0 years) were enrolled. Elevated blood pressure was the leading complaint. After a median follow-up period of 18.0 months (interquartile range: 6.0-48.0 months), hypertension recurred in 34 patients and restenosis in nine patients, among whom four patients underwent secondary intervention and one patient underwent surgical revascularization. Bilateral renal artery involvement (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.11-6.15; p = 0.028) and age at hypertension onset (OR: 0.93, 95% CI: 0.88-0.99; p = 0.018) were independent prognostic factors for adverse outcomes. The results indicate that patients with bilateral renal artery involvement and younger age at hypertension onset are more likely to have poorer clinical outcomes after PTRA, and should be more closely monitored.

Seasonal variation of ambulatory blood pressure in Chinese hypertensive adolescents.

Background: Blood pressure (BP) exhibits seasonal variation with lower levels at higher temperatures and vice versa. This phenomenon affects both sexes and all age groups. So far, only a few research studies have investigated this condition in adolescents and none of them were based on hypertensive population or ever applied ambulatory blood pressure monitor (ABPM). Therefore, we carried out the first study that used ABPM to record seasonal variation of blood pressure in hypertensive adolescents. Methods: From March 2018 to February 2019, 649 ABPMs from hypertensive adolescents between 13 and 17 years who were referred to wear an ABPM device in Beijing and Baoding were extracted. Seasonal change in ambulatory BP value, dipping status, and prevalence of different BP phenotypes were analyzed and compared. Results: Mean age of participants was 14.9 ± 1.5 years and 65.8% of them were boys. Of the participants, 75.3% met the criteria of overweight or obesity. From summer to winter, average 24-hour, day-time, and night-time BP showed significant rise, which was 9.8/2.8, 9.8/3.0, and 10.9/3.4 mmHg, respectively. This seasonal effect on BP was not dependent on the obesity degree. In addition, higher prevalence of nondippers and risers existed in winter while white coat hypertension was more frequent in warmer seasons. Conclusion: Hypertensive adolescents showed evident seasonal change in their ABPM results, which was featured by elevated BP level and more frequent abnormal dipping patterns in winter. On the contrary, higher prevalence of white coat hypertension was found in warmer seasons. Physicians should take seasonal variation into consideration when managing adolescent hypertension.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction.

BACKGROUND: Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS: The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS: A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS: The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.