Hereditary ventricular arrhythmias can be divided into two main categories: primary electrocardiographic diseases and arrhythmogenic cardiomyopathies. Primary electrocardiographic diseases refer to a group of diseases characterized by electrocardiographic disturbances in the absence of organic heart disease, including long QT syndrome (LQTS), Brugada syndrome, idiopathic ventricular fibrillation (IVF), catecholamine-mediated polymorphic ventricular tachycardia (CPVT), isolated ventricular fibrillation, and possibly It also includes hereditary heart block, unpredictable sudden nocturnal death syndrome, sudden infant death syndrome, and short QT syndrome.
Arrhythmogenic cardiomyopathies are cardiomyopathies with ventricular tachycardia and include arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM). In the last decade or so, the combination of molecular genetics, genetic techniques and cardiology has led to the elucidation of the molecular pathogenesis of these diseases. To date, it is known that the majority of primary cardiac diseases are caused by mutations in genes encoding the major ion channel subunits, and therefore these diseases are commonly referred to as “channelopathies”. In contrast, the causative genes found in arrhythmogenic cardiomyopathies mainly affect myofibrillar membranes and cytoskeletal proteins, and the progression of the major cardiac ion channelopathies is outlined below.
I. Long QT syndrome
LQTs syndromes are a group of syndromes with prolonged QT interval on ECG, abnormal T waves, predisposition to ventricular arrhythmias, especially tip-twisting ventricular tachycardia (TdP), manifesting as syncope and sudden death. The syndromes can be divided into two types, acquired and hereditary, according to their etiology. Acquired LQTS is usually associated with localized myocardial ischemia, bradycardia, electrolyte abnormalities and the application of certain drugs. There are two forms of hereditary LQTS, Romano-Ward (RWS) syndrome and JervellLange-Nielsell (JLN) syndrome, in which only prolonged QT intervals on ECG and occasional non-cardiac abnormalities occur. JLN syndrome is relatively uncommon and is autosomal recessive. JLN syndrome has a longer OT interval than RWS syndrome and a higher probability of malignant events such as syncope and sudden death. Seven genes have been found to be associated with LOTS, they are KCNQl (LQTI), KCNH2 (LQT2), SCNSA (LQT3 (LQT4),KCNEI (LQT5), KCNE2 (LQT6),KCNJ2 (LQT7) (Table 1). The main genotype is LQT3, but recently Dr. Li Zhang from the United States believes that LQT4 and LQT7 should not actually be included in LQTS because these two types are characterized by u-wave abnormalities rather than T-wave abnormalities.
II. Brugada syndrome.
1, BRS has the following characteristics:
①Specific ST-segment elevation in the anterior thoracic leads (V1-V3) with or without RBBB;
(ii) Normal cardiac structure;
(iii) a tendency for recurrent fatal ventricular tachyarrhythmias. On the ECG of patients with BRS, the QRS complex wave ends in a positive skew (or prominent J wave), followed by oblique downward ST-segment elevation, with generally normal or even shortened OT intervals and inverted T waves. v” lead changes are prominent, i.e., the degree of ST-segment elevation in the adjacent leads gradually decreases, and can be associated with varying degrees of RBBB in v, leads. the terminal portion of the QRS complex wave is ~an r-type The elevated or negatively skewed portion of the QRS complex wave ends in an oblique downward elevation of the ST segment followed by a J wave, with similar changes in the adjacent leads, but the elevation of the sT segment is usually less pronounced than in the v, leads. ST-segment elevation in the right thoracic lead without ST-segment depression in the corresponding lead is the most distinctive feature of BRS.
It has been determined that BRS can have the following three types of ECG changes: type 1, characterized by prominent “dome type” ST-segment elevation, manifested by a J-wave or elevated ST-segment apex greater than 0,2 mV, accompanied by T-wave inversion with little or no isotonic line separation; type 2, with a J-wave amplitude greater than 0,2 mV, causing gradual ST-segment In type 3, ST segment elevation is less than 0,1mv, which can be “saddle type” or “dome type”, or both. “The ST-segment changes in BRS ECG are dynamic, and different patterns can be observed in the same patient or after the application of specific drugs such as sodium channel blockers.
The molecular biology of Brugada syndrome has shown that BRS is autosomal dominant with incomplete epistasis, and the only gene confirmed is the sodium channel gene SCN5A. 8 mutation sites have been identified on SCN5A that cause Bs, mostly located between regions I and 11, the intracellular junctions between regions 1II and IV, the P-loop of region DIII, and the C-terminus. terminal.
The mutation sites on SCN5A that can cause Bs can be broadly classified into two types, one is to cause a decrease in the number of functional Na+ channels in the cardiomyocyte membrane, and the other is to cause changes in the biophysical properties of Na+ channels. The Na+ currents were not detected by injecting the eDNA of SCNSA into Xenopus oocytes or by expressing the R1432G mutated channel in tsA-201 cells. The exact manner in which the splice site mutation affects the channel is not known, but a decrease in Nat channel density is expected to reduce the AP amplitude, resulting in a negative voltage at the onset of phase 1 repolarization. As a consequence of this change and the more pronounced instantaneous outward potassium current on epicardial cells (110), flucarbamate selectively shortens the epicardial AP, causing a phase 2 foldback. Moreover, the reduced sodium current (INa) may be responsible for the presence of conduction disturbances in a significant proportion of patients.
Some family members with ECG features of Brugada syndrome have prolonged asymptomatic episodes, suggesting incomplete episodes of causative genes in patients with Brugada syndrome. Currently, progress in the molecular biology of Brugada syndrome has been relatively slow, mainly because, compared with congenital long QT syndrome, Brugada syndrome has a smaller family line and involves fewer family members, which does not facilitate chain analysis.
III. Idiopathic ventricular fibrillation fIVF.
IVF with unexplained cardiac arrest is rare in the absence of significant structural lesions, myocardial ischemia, drug effects, electrolyte or metabolic abnormalities, and the presence of intoxication, but in reality it seems to be more common than one might originally expect. fIVF accounts for approximately 6% to 12% of total sudden death cases (incidence 5/10,000 in the total population), but the percentage is higher in younger individuals younger than 40 years. Of these, Brugada syndrome accounts for 20% to 40% as a special case of 1VF. class Ia antiarrhythmic drugs are highly preventive of re-induction of ventricular tachycardia, with a sudden death rate of 11% 1 year after diagnosis. these pre-term beats occur within 40 ms of the previous T-wave peak, and no interval-dependent arrhythmias are found. Similar to Brugada syndrome fIVF has a high morbidity and mortality rate, and the 5-year recurrence rate of patients surviving cardiac arrest is higher than 30%.
IV. Catecholamine-mediated polymorphic ventricular tachycardia (CPVT).
CPVT is a malignant ventricular arrhythmia, which was first proposed by Leenhardt in 1995. It refers to exercise or catecholamines in more than 3 consecutive beats that can cause two or more ventricular tachycardia patterns, mostly bidirectional (bVT) and/or polymorphic ventricular tachycardia (pVT); in the absence of electrolyte disturbances, drugs or organic heart disease that can cause polymorphic ventricular tachycardia/ventricular fibrillation.
The ECG should be distinguished from Brugada syndrome and short intercohorticulitis with tip-twist ventricular tachycardia. The distinction between these three disorders is important not only because they are all associated with sudden death in children and adolescents, but also because only buried cardioverter-defibrillators (ICDs) are effective in the latter two, whereas most patients with CPVT can be treated with β-blockers, which reduce arrhythmias but still require ICDs in about 30% of patients. 100% success rate of exercise-induced CPVT, Catecholamines have a 75% success rate, and programmed stimulation does not induce CPVT.
The autosomal recessive form of CPVT is associated with mutations in conserved regions of the calcium storage protein 2 gene. These mutations appear to interfere with the binding of ca2+ and calcium storage protein, thereby causing free ca2+ leakage from the sarcoplasmic reticulum during exercise, while catecholamines drive the opening of RyR2.3. Mechanism of CPVT by RyR2 mutations.
DAD may be the cause of bidirectional ventricular tachycardia in CPVT. Recently, it has been found that cardiac glycosides can lead to an increase in channel opening through the direct action of RyR2. mutations in RyR2 channels or by cardiac glycosides, abnormal channel function occurs and excessive Can is released from the diastolic sarcoplasmic reticulum, causing DAD, which is manifested as bidirectional ventricular tachycardia on the ECG. Several factors can increase the amplitude of DAD and thus potentially bring it to the threshold potential. These factors include an increase in the frequency of triggered action potentials (AP) (corresponding to an increase in heart rate), an increase in intracellular c mineral+ load. Cardiac glycosides and catecholamines alone can increase the amplitude of DAD through both of these pathways. Direct evidence from electrophysiological studies demonstrates that the administration of catecholamines to CPVT patients to produce DAD does induce bidirectional ventricular tachycardia. In CPVT patients carrying a mutation in the RyR2 gene, the mutation results in a reduction in the release of ca2+ through the RyR2 channel, and as a feedback mechanism, the cell will take up more ca2+ into the sarcoplasmic reticulum via the Ca”/ATPase pump to compensate for this lack of release. This results in the sarcoplasmic reticulum Cal+ content being maintained at a higher steady state concentration. In response to catecholamine-induced phosphorylation, RyR2 may acquire its normal function, with the resulting changes being sufficient to overcome the inhibitory effects of the mutation. The sarcoplasmic reticulum is made to release all the overloaded ca2+. Then, the phosphorylation effect during exercise will further promote the ca2+ loading of the sarcoplasmic reticulum to overcome the inhibitory effect of the mutated ca2′ release, and the excessive ca2+ release triggered by these processes will cause DAD and trigger arrhythmias.
The key to the treatment of CPVT is to maintain complete and continuous beta blockade. It is difficult to do both, especially in children, who metabolize most of the current β-blockers too quickly, and the combination of Class 1 drugs or amiodarone is not beneficial or even harmful.
V. Short QT syndrome (SQTS).
All patients showed a constant short QT interval on the ECG. Extensive invasive and meta-invasive examinations, including serial resting ECG, color Doppler echocardiography, cardiac MRl, exercise testing, Holter’s dynamic ECG, and signal-averaged ECG, were performed in 6 patients from 2 families. Four of them underwent electrophysiological evaluation, including programmed ventricular stimulation, and all individuals were excluded from structural heart disease. The base-case ECG showed that all patients exhibited OT intervals ≤280 ms. Sudden death with short OT intervals occurred in both sexes in all generations, suggesting an autosomal dominant mode of inheritance.
In early 2004, it was found that SQTS can be caused by the N588K mutation in the HEItG gene. In contrast to the mechanism of the mutation causing LQT2, the N588K mutation leads to a functional amplification of the Ikr current, which causes an increase in the repolar phase outward current. V307L on the KCNQI gene was also found to cause SQTS, suggesting genetic heterogeneity in the pathogenesis of SQTS.
As the study of hereditary arrhythmias with normal cardiac structure progresses, it is increasingly common to find that different loci of the same gene cause different diseases, and even different mutations at the same locus can cause two diseases with completely opposite pathogenesis, suggesting that the exact mechanism of human diseases caused by gene mutations is complex, and there is a long way to go for its in-depth study.