Ewa Moric-Janiszewska

The Risk of Cardiac Events and Genotype-Based Management of LQTS Patients

This review discusses the risk of cardiac events and genotype‐based management of LQTS. We describe here the genetic background of long QT syndrome and the eleven different genes for ion‐channels and a structural anchoring protein associated with that disorder. Clinical Background section discusses the risk of cardiac events associated with different LQTS types. Management and Prevention section describes in turn gene‐specific therapy, which was based on the identification of the gene defect and the dysfunction of the associated transmembrane ion channel. In patients affected by LQTS, genetic analysis is useful for risk stratification and for making therapeutic decisions. A recent study reported a quite novel pathogenic mechanism for LQTS and suggested that treatments aimed at scaffolding proteins rather than specific ion channels may be an alternative to antiarrhythmic strategy in the future.

Challenges of diagnosis of long-QT syndrome in children.

We describe the clinical and genetic characteristics of the family, in which the diagnosis of LQT1 had been made. The electrocardiogram (ECG) characteristics of this patient indicated the likelihood of LQTS1. Polymorphic ventricular extrasystolies and episodes of polymorphic non‐sustained ventricular tachycardia were confirmed by Holter ECG monitoring. On the exertional electrocardiogram polymorphic ventricular tachycardia (torsade de pointes) was recorded. Direct sequencing of both DNA strands revealed the absence of mutations or polymorphisms in the KCNQ1, HERG, and SCN5A genes.

Age-and sex-dependent mRNA expression of KCNQ1 and HERG in patients with long QT syndrome type 1 and 2.

Introduction The main goal of this study was to examine the patient age and sex dependent expression of KCNQ1 and HERG genes that encode potassium channels responsible for the occurrence of long QT syndrome (LQTS). Material and methods The study enrolled 43 families whose members suffered from LQTS type 1 (LQTS1) or 2 (LQTS2) or were healthy. The study attempted to prove that β-actin is a good endogenous control when determining the expression of the studied genes. Examination of gene expression was achieved with quantitative real-time PCR (QRT-PCR). Expression of the investigated genes was inferred from the analysis of the number of mRNA copies per 1 μg total RNA isolated from whole blood. Results Significantly lower KCNQ1 and KCNH2 mRNA levels in healthy females than healthy males were observed (p = 0.032; p = 0.02). In male patients both transcripts were expressed at a lower level (p = 0.0084; p = 0.035). The comparison of transcriptional activity of KCNQ1 and KCNH2 in healthy adults and children revealed higher KCNQ1 and lower KCNH2 mRNA levels in healthy adults (p = 0.033; p = 0.04), higher KCNQ1 and lower KCNH2 mRNA levels in adult patients below 55 years old than in adults over 55 years old (p=0.036; p = 0.044), and significantly higher KCNQ1 and lower KCNH2 mRNA levels in adult patients (over 55 years) than in paediatric patients (below 15 years) (p=0.047; p = 0.08). Conclusions The results support the hypothesis that KCNQ1 and HERG gene expression is influenced by age and gender in human patients with long QT syndrome and in healthy subjects.

Molecular diagnostics of families with long-QT syndrome

The Department of Pediatric Cardiology, Medical University of Silesia in Katowice-Ligota, studied 24 patients with clinically diagnosed (using ECG) long-QT syndrome (LQTS) in 18 cases. Nine patients were diagnosed with LQT1 and nine with LQT2. The other six individuals were healthy, with no symptoms characteristic for prolonged QT syndrome, but came from families with confirmed disease occurrence. The study was conducted on members of four families. In order to search for mutations (using mSSCP and sequencing), genomic DNA was obtained from patients to determine the expression levels of the genes KCNQ1 and KCNH2 (HERG), involved in the occurrence of clinical signs of disease. Total RNA was extracted from peripheral blood. Consent to the use of blood samples of patients had been given by the Bioethics Commission of the Medical University of Silesia. mSSCP analysis and sequencing did not confirm the occurrence of mutations in KCNQ1 and HERG associated with the occurrence of LQTS. Analysis of gene expression profile of KCNQ1 and HERG confirmed the presence of disease in people with a known clinical diagnosis. Overexpression, as well as reduced expression, was observed for the examined genes. KCNQ1 was inhibited in two families, whereas HERG was reduced in one and overexpressed in the other. Gene expression profile analysis showed abnormal expressions of KCNQ1 and HERG in healthy subjects, which may be a sign of predisposition to develop the disease. The novelty of our study involved the use of total mRNA isolated from human peripheral blood, and the very limited evidence in the literature to date regarding the assessment of gene expression profile of HERG and KCNQ1 in relation to the presence of prolonged QT syndrome.

Electrocardiographic Abnormalities in Young Athletes with Mitral Valve Prolapse

Mitral valve prolapse (MVP) is the most common primary valvular abnormality in a young population. In some individuals, MVP is silent or associated with palpitations, dizziness, chest pain, and abnormal electrocardiogram (ECG) repolarization with or without ventricular arrhythmias.

Arrhythmogenic right ventricular dysplasia:clinical study.

Arrhythmogenic right ventricular dysplasia (ARVD) is a complex arrhythmogenic cardiomyopathy, characterized by a partial or total replacement of the right ventricular myocytes by fatty and fibrous tissue. In this study, we present a case of ARVD in 17 year old girl, who was admitted to the hospital after syncope with ventricular arrhythmia. The echocardiography did not demonstrate structural cardiac abnormalities but the magnetic resonance recently showed thinning of the right ventricular wall. The girl was treated with the lidocaine, amiodarone and next, after radiofrequency catheter ablation she was receiving metoprolol. The girl has remained asymptomatic for four years of follow‐up.

Left Ventricular Diastolic Dysfunction Assessed by Conventional Echocardiography and Spectral Tissue Doppler Imaging in Adolescents With Arterial Hypertension

AbstractCompared to conventional echocardiography, spectral tissue Doppler imaging (s-TDI) allows more precise evaluation of diastolic cardiac function. The purpose of this study was to conduct s-TDI to analyze the slow movement of the left ventricular (LV) myocardium in adolescents with systemic arterial hypertension (HT) and to determine whether patients with HT suffer from LV diastolic dysfunction. The study group comprised 69 consecutive patients (48 boys and 21 girls aged 14–17 years [mean, 15.5 ± 1.1 years]) with primary HT, and the control group comprised 48 healthy participants (24 boys and 24 girls aged 14–17 years [mean, 15.8 ± 1.3 years]). Physical examinations, 24-hour arterial blood pressure monitoring, conventional 2-dimensional and Doppler echocardiography, and s-TDIs were performed. Analysis revealed that study group participants were significantly heavier and had greater LV mass indices than controls (P < 0.001). There were no differences between the velocities of E waves (peak early filling of mitral inflow), but the deceleration times of the mitral E waves were significantly shorter whereas the A waves survived longer in the study group than in the control group. The velocities of A waves (peak late filling of mitral inflow) were elevated (P = 0.041), and the E/A wave pattern (E/A = 1.8 ± 0.4) was normal. These results suggest pseudonormalization, a type of LV diastolic dysfunction in adolescents with HT.In the study group, when the sample volume was positioned at the septal or lateral insertion site of the mitral leaflet, the e′ wave velocity was significantly depressed whereas the a′ wave velocity was elevated, compared to those of the control group (P < 0.001).The e′/a′ ratios from the septal and lateral insertion sites were lower, whereas the E/e′ ratio from the septal insertion site was significantly higher in the study group, similar to that seen in atrial reversal velocity (P < 0.001).These findings indicate that using sTDI to find and measure diastolic LV failure is valuable when the probe is placed at the septal and lateral mitral valve annuli during examination.Changes in the myocardium appear similar to those seen in adults.

Microarray Analysis in Cardiac Arrhythmias: A New Perspective?

The opportunity to distinguish an accurate set of genes associated with multigenic diseases such as cardiomyopathies or cardiac arrhythmias was very limited before the genomic era. Numerous methods of measuring RNA abundance exist, including northern blotting, multiplex polymerase chain reaction (PCR), and quantitative real‐time reverse transcriptase‐PCR. However, these techniques might be used to assess the expression levels of only 10–50 genes at time. Today, DNA microarrays provide us with opportunity to simultaneously analyze tens of thousands of genes, giving a remarkable possibility to investigate the genomic contribution to cardiovascular diseases. A particular tissue at any stage of health or disease may be used to generate a genomic profile. Microarray techniques are already used in infectious diseases, oncology, and pharmacology to facilitate clinicians, risk‐stratify patients, as well as to predict and assess therapeutic responses to drugs. In this paper, we describe recent advances in the use of various types of microarray technique in the diagnosis of arrhythmogenic heart disease. We also highlight other strategies and methods of differential gene typing comparing with pros and cons of microarray analysis.

Electrocardiographic T-wave parameters in families with long QT syndrome

BACKGROUND T-wave parameters, especially the Tpeak-Tend interval (TpTe), reflect the total dispersion of repolarization, whose amplification may lead to the development of life-threatening ventricular arrhythmias observed in the long QT syndrome (LQTS). OBJECTIVES The study attempted to evaluate QT, QTp (Q-Tpeak) and TpTe (Tpeak-Tend) intervals in unaffected and affected blood relatives of children with clinically confirmed LQTS as well as to determine whether the values of these repolarization parameters may be used in clinical practice. MATERIAL AND METHODS The study group included 47 affected blood relatives (27 LQTS1 and 20 LQTS2) and 68 unaffected family members without clinically confirmed LQTS symptoms. The TpTe, QT and QTp intervals were measured manually in the lead V5 of standard ECGs and corrected using Bazetts and Fridericias formulas. RESULTS The RR, QT, QTp and TpTe intervals with their corrected values were significantly longer (p < 0.0001) in the affected subjects than in the unaffected subjects and, similarly, in LQTS1 and LQTS2 patients compared with the unaffected family members. The TpTe interval in LQTS2 showed only a tendency to be longer compared to LQTS1, but did not reach statistical significance (p = 0.0933). For affected blood relatives, only the TpTe interval (p < 0.0409) and QT interval, corrected with Bazetts (p < 0.0393) and Fridericias (p < 0.0495) formulas, enabled differentiation between LQTS1 (mean TpTe = 103 ±15) and LQTS2 women (mean TpTe = 106 ±17). Moreover, there were statistically significant differences (p < 0.05) in the TpTe interval between the 6 sex subgroups: unaffected women and men as well as women and men with LQTS1 and LQTS2. CONCLUSIONS The electrocardiographic Tpeak-Tend parameter, in addition to the QT interval, is helpful in identifying affected blood relatives of children with LQTS, particularly for the group of LQTS1 and LQTS2 women. Further studies are required to assess the clinical importance of the TpTe interval in families with long QT syndrome.

Quantitative PCR as an Alternative in the Diagnosis of Long-QT Syndrome

Congenital long-QT syndrome is a genetic disorder associated with abnormalities in the function and/or structure of cardiac ion channels. Up to the present, 13 types of the disease have been described (LQTS1-13) which result from the fact that 13 genes of which mutations can have an influence on the occurrence of the disease have been identified. Characteristic symptoms of the disease include the changes in the ECG (QT interval prolonged above 450 ms), “torsade de pointes,” fainting, and even sudden cardiac death. The present study has been focused on two types of the disease, namely, LQTS1 and LQTS2. The examination of two appropriate genes expression (KCNQ1; KCNH2) at the transcription level by QRT-PCR in a group of LQTS patients and a healthy control group showed different transcriptional activities of KCNH2 gene in LQTS2 patients compared to the control individuals. KCNQ1 gene expression study did not reveal such differences between both groups. The results indicate that QRT-PCR may serve as a complimentary method to the identification of molecular alterations in genetic determinants of LQTS2 only, but it cannot be used as a sole diagnostic criterion.