Cuilan Li

Inhibition of Late Sodium Current by Mexiletine: A Novel Pharmotherapeutical Approach in Timothy Syndrome

Background— Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A (TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an INa blocker, mexiletine, to improve clinical manifestations in TS. Methods and Results— A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C . Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father’s oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470–490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT–RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late INa with IC50 of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT–RR slope in the TS model using BayK 8644. Conclusions— Mexiletine shortened QTc, attenuated QT–RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late INa.Background—Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A (TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an INa blocker, mexiletine, to improve clinical manifestations in TS. Methods and Results—A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father’s oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470–490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT–RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late INa with IC50 of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT–RR slope in the TS model using BayK 8644. Conclusions—Mexiletine shortened QTc, attenuated QT–RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late INa.

Mutation Spectrum in a Large Cohort of Unrelated Chinese Patients With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HC) is a hereditary heterogeneous cardiovascular disorder. Existing data have been of predominantly Caucasian samples, and a large study is needed in Chinese population. The present study was intended to explore the genetic basis and clinical characteristics correlated with different genotypes in a large cohort of Chinese patients. Direct gene sequencing of β-myosin heavy chain (MYH7), myosin binding protein-C (MYBPC3), and cardiac troponin T (TNNT2) was performed in 136 unrelated Chinese HC patients. Clinical evaluations were conducted. In total, 32 mutations were identified in 36 patients (27%), including 10 novel ones. Distribution of mutations was 56% (MYBPC3), 31% (MYH7), and 13% (TNNT2), respectively. Double mutations were identified in 3% patients. The occurrence of HC-associated sarcomeric mutations was associated with an earlier age of onset, increased left ventricular hypertrophy, a higher incidence of syncope, previous family history, and sudden cardiac death. No statistical difference was identified in patients carrying MYBPC3 and MYH7 mutations with regard to clinical characteristics and outcomes. Patients with double mutations were associated with malignant progression in the study. In conclusion, MYBPC3 is the most predominant gene in HC. Multiple mutations are common in MYH7, MYBPC3, and TNNT2. The present study suggests a large diversity of HC and a prognostic role of genotype.

Surgical left cardiac sympathetic denervation for long QT syndrome: effects on QT interval and heart rate.

The primary aim of the present study was to investigate the short-term effects of surgical left cardiac sympathetic denervation (LCSD) on the QT interval and heart rate in patients with congenital long QT syndrome (LQTS). Left cardiac sympathetic denervation was performed in five LQTS patients who had a history of syncope. The patients’ 12-lead and 24-h Holter monitoring ECG was recorded 24 h before and 24 h after LCSD. Treadmill exercise tests were also performed before and 6 days after surgery to assess changes in heart rate and the QT interval after surgery. Left cardiac sympathetic denervation was successful in all patients. The mean value of the corrected QT interval (QTc) in the five patients decreased from 0.59 ± 0.05 to 0.48 ± 0.04 s (P = 0.006) immediately after the procedure and remained short (0.47 ± 0.04, P < 0.05) after a 21-month follow-up. The mean value of QTc on the 24-h Holter monitoring ECG also decreased in all patients (0.67 ± 0.07 vs 0.60 ± 0.05 s, P < 0.01). The mean, maximum, and minimum heart rate on the 24-h ECG remained unchanged (P > 0.05). The maximum heart rate during the exercise tests decreased from 162 ± 4 beats/min before surgery to 129 ± 10 beats/min (P < 0.01). The exercise-induced increase in QTc remained unchanged after the surgery (P > 0.05). Although four of the five patients were syncope-free until 21 months postoperatively, the remaining patient had a recurrence of syncope, requiring an increased dose of β blocker. These findings indicate that LCSD shortens QTc and diminishes the exercise-induced increase in heart rate whereas the resting heart rate and exercise-induced increase in QTc remain unchanged. These results may have implications for the effectiveness and limitations of LCSD.

Mutations of Plakophilin-2 in Chinese With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart muscle disease associated with increased risks of sudden death, particularly in young, otherwise healthy, patients. The pathologic features are progressive myocardial atrophy and fibrofatty replacement. Plakophilin-2 (PKP2) is reported as the most common ARVD/C-causing gene in Western countries. In this study we aimed to determine the prevalence of PKP2 mutations in Chinese patients with ARVD/C and their phenotype characteristics. Genotype and phenotype were investigated in a cohort of 18 unrelated Chinese patients with a clinical diagnosis of ARVD/C. Direct sequencing of PKP2 led to the identification of 5 novel heterozygous mutations (R158K, Q211X, L419S, A793D, and N852fsX930) in 39% of patients (7 of 18) with ARVD/C. Among them, N852fsX930 was found in 3 unrelated young patients who presented with symptomatic ventricular tachyarrhythmia. Nevertheless, no significant difference could be detected between patients with ARVD/C with (n = 7) and without (n = 11) PKP2 mutations with regard to the phenotype characteristics and clinical outcomes. Decreased penetrance was prominent in family members. In conclusion, 5 novel PKP2 mutations were identified in a cohort of symptomatic Chinese patients with ARVD/C. N852fsX930 appeared to be a hot-spot mutation in which patients presented with a severe ARVD/C phenotype, and 2/3 had early onset of arrhythmic events. No significant difference was found in phenotype characteristics between patients with ARVD/C with and without PKP2 mutations. The decreased penetrance indicated that an ARVD/C diagnosis cannot solely rely on genotyping results.

Variation of Intrarenal Angiotensin II and Angiotensin II Receptors by Acute Renal Ischemia in the Aged Rat

The properties of Ang II receptors in the aged kidney and their changes after acute renal ischemia are rarely known. The aim of this study was to examine the expression of Ang II receptor mRNA and characteristics of Ang II receptors in the aged kidney and to compare different responsiveness to 45 min of acute renal ischemia in young (3-4 months) and aged (23-24 months) rats. In the normal condition, AT1 mRNA expression was much lower in the aged than that in the young rats. Maximal binding (Bmax) was also lower in the aged (1315 +/- 48 vs. 2035 +/- 257 fmol/mg, p < 0.05). The dissociation constant (KD) of glomerular Ang II receptors, however, was significantly lower in the aged rats compared to the young (6.8 +/- 1.6 vs. 17.4 +/- 2.5 nM). After acute ischemia, the expression of AT1 mRNA decreased in the young rats but increased in the aged rats. Interestingly, Bmax of glomerular Ang II receptors was significantly increased in the aged ischemic rats (1852 +/- 94 vs. 1315 +/- 48 fmol/mg) with unchanged KD. These results show that: (a) the AT1 mRNA expression and the Ang II receptor binding site are decreased with the aging process in the rat kidney; (b) the acute renal ischemia effect on different age groups has a greatly discrepant pattern in respect of Ang II receptor modulation, which may provide a potential therapeutic future for the receptor antagonists in acute renal ischemia in the aged.

Genetic analysis of Brugada syndrome and congenital long-QT syndrome type 3 in the Chinese

Background: Brugada syndrome and congenital long-QT syndrome (LQTS) type 3 (LQT3) are 2 inherited conditions of abnormal cardiac excitability characterized clinically by an increased risk of ventricular tachyarrhythmias. SCN5A gene that encodes the cardiac sodium channel α subunit is responsible for the 2 diseases, and more work is needed to improve correlations between SCN5A genotypes and associated clinical syndromes. Methods and Results: Four patients diagnosed as having Brugada syndrome, 9 patients suspected to have Brugada syndrome, and 3 LQTS patients suspected to be LQT3 without mutations in KCNQ1 and HERG participated in the study. DNA samples from these patients were analyzed using direct sequencing. One patient with Brugada syndrome had 2 novel mutations, V95I and A1649V. The former was identified in the N-terminus of SCN5A and the latter was in the DIVS4/S5 linker of SCN5A. One patient suspected to have Brugada syndrome had a mutation, delF1617, in the DIIIS3/S4 linker of SCN5A. A novel mutation in the C-terminus of SCN5A, delD1790, was found in a patient with LQT3. No other mutations of SCN5A were found in the remaining patients. These 4 mutations were not detected in 50 unrelated control subjects. Conclusions: Two novel and a reported SCN5A mutations were found in Chinese patients with Brugada syndrome, and a novel SCN5A mutation was found in a Chinese patient with LQT3.

Clinical features and management of congenital long QT syndrome: a report on 54 patients from a national registry.

To assess the clinical features and the management of congenital long QT syndrome (LQTS) in China, we collected the clinical data of 54 LQTS patients (14 males and 40 females) from our newly established national registry. All patients were symptomatic, with syncope being the most common symptom. The average age when the first symptoms occurred was 17.9 ± 15.6 (range, 0.5–62) years; 55.6% of them had the first symptoms before the age of 20. The most common triggers of the symptoms were physical exercise or emotional stress. The average corrected QT interval was 0.55 ± 0.08 s. Using ECG criteria, there were 14 (25.9%) LQT1 patients, 28 (51.9%) LQT2, and 2 (3.7%) LQT3. Thirty (55.6%) patients were treated with Β-blockers at the time of enrollment, with propranolol being the most commonly used drug, with an average daily dose of 57.5 ± 39.1 mg. Four patients underwent left cardiac sympathectomy. After an average follow-up of 24.9 ± 13.2 months, 3.1% (1/32) of patients with antiadrenergic therapy and 9.1% (2/22) without antiadrengergic therapy died of sudden cardiac death (P ≪ 0.05). We concluded that LQT2 might be the most common subtype in these patients. Antiadrenergic treatment was underused, raising the urgent need for educating both physicians and patients on the nature of the disease and its optimal antiadrenergic therapy.

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction

Objectives: Genetic testing, a gold standard for long QT syndrome (LQTS) diagnosis, is time-consuming and costly when all the 15 candidate genes are screened. Since genotype-specific ECG patterns are present in most LQT1-3 mutation carriers, we tested the utility of ECG-guided genotyping in a large cohort of Chinese LQTS patients. Methods and Results: We enrolled 230 patients (26 ± 17 years, 66% female) with a clinical diagnosis of LQTS. Genotypes were predicted as LQT1-3 based on the presence of ECG patterns typical for each genotype in 200 patients (85 LQT1, 110 LQT2 and 5 LQT3). Family-based genotype prediction was also conducted if gene-specific ECG patterns were found in other affected family members. Mutational screening identified 104 mutations (44% novel), i.e. 46 KCNQ1, 54 KCNH2 and 4 SCN5A mutations. The overall predictive accuracy of ECG-guided genotyping was 79% (157/200) and 79% (67/85), 78% (86/110) and 80% (4/5) for LQT1, LQT2 and LQT3, respectively. The predictive accuracy was 98% (42/43) when family-based ECG assessment was performed. Conclusions: From this large-scale genotyping study, we found that LQT2 is the most common genotype among the Chinese. Family-based ECG-guided genotyping is highly accurate. ECG-guided genotyping is time- and cost-effective. We therefore recommend it as an optimal approach for the genetic diagnosis of LQTS.

Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome

Background: Long QT syndrome (LQTS) is characterized by QT prolongation, syncope and sudden death. This study aims to explore the causes, clinical manifestations and therapeutic outcomes of Jervell and Lange-Nielsen syndrome (JLNS), a rare form of LQTS with congenital sensorineural deafness, in Chinese individuals. Materials and Methods: Three JLNS kindreds from the Chinese National LQTS Registry were investigated. Mutational screening of KCNQ1 and KCNE1 genes was performed by polymerase chain reaction and direct DNA sequence analysis. LQTS phenotype and therapeutic outcomes were evaluated for all probands and family members. Results: We identified 7 KCNQ1 mutations. c.1032_1117dup (p.Ser373TrpfsX10) and c.1319delT (p.Val440AlafsX26) were novel, causing JLNS in a 16-year-old boy with a QTc (QT interval corrected for heart rate) of 620 ms and recurrent syncope. c.605-2A>G and c.815G>A (p.Gly272Asp) caused JLNS in a 12-year-old girl and her 5-year-old brother, showing QTc of 590 to 600 ms and recurrent syncope. The fourth JLNS case, a 46-year-old man carrying c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) and with QTc of 460 ms, has been syncope-free since age 30. His 16-year-old daughter carries novel missense mutation c.574C>T (p.Arg192Cys) and c.1032G>A(p.Ala344Alasp) and displayed a severe phenotype of Romano-Ward syndrome (RWS) characterized by a QTc of 530 ms and recurrent syncope with normal hearing. Both the father and daughter also carried c.253G>A (p.Asp85Asn; rs1805128), a rare single nucleotide polymorphism (SNP) on KCNE1. Bizarre T waves were seen in 3/4 JLNS patients. Symptoms were improved and T wave abnormalities became less abnormal after appropriate treatment. Conclusion: This study broadens the mutation and phenotype spectrums of JLNS. Compound heterozygous KCNQ1 mutations can result in both JLNS and severe forms of RWS in Chinese individuals.

Patient with obstructive sleep apnea-hypopnea syndrome and SCN5A mutation (R1193Q polymorphism) associated with Brugada type 2 electrocardiographic pattern

We describe a 45-year-old Asian man with Brugada-type 2 electrocardiogram and probable nocturnal agonal respiration. After genetic screening, drug challenge test and polysomnography examination, we ruled out Brugada syndrome and identified obstructive sleep apnea-hypopnea syndrome. Therefore, obstructive sleep apnea-hypopnea syndrome should be considered as a rare differential diagnosis for Brugada syndrome.