Dr. Sylvain Richard
Intense investigative efforts currently focus on better understanding of cardiomyopathies with high risk of sudden cardiac death (SCD). Current therapeutical strategies are most often palliative with modest success and drug side effects. Over the last decade, we have witnessed a revolution in the understanding of arrhythmias primarily related to ion channel disorders, thanks to the input of genetic approaches. Therefore, it was timely to review part of the spectrum and causes of arrhythmias in cardiomyopathies, with particular focus on SCD in this session.
Pr. G. Thiene (Padua, It) reviewed a number of heart muscle diseases traditionally classified as ‘dilated’, ‘hypertrophic’, ‘restrictive’, and ‘arrhythmogenic right ventricular’ cardiomyopathies. Based on the original World Health Organization (WHO, 1980; 1995) classifications, he presented hypertrophic and restrictive cardiomyopathies as sarcomeric (force generation) diseases, dilated cardiomyopathies as skeleton (force transmission) diseases, and arrhythmogenic right ventricular cardiomyopathy as cell junction disease. More importantly, Pr. Thiene reminded us that, based on the rapid evolution of molecular genetics, a panel of experts (AHA, 2006) updated the definition and classification of the cardiomyopathies as follows : “Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction the usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are a part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability". This definition truly incorporates channelopathies and ion channel related disorders (short and long QT, Brugada, catecholaminergic polymorphic ventricular tachycardia syndromes) as primary cardiomyopathies. Pr. Thiene, therefore, emphasized that ECG is, in addition to echocardiography, a must for diagnosis by the clinician.
Dr. B.C. Knollmann (Washington, USA) presented molecular mechanisms of arrhythmias in sarcomeric cardiomyopathy. He focussed on the cardiac troponin T (TnT)-I79N mutation, exhibiting high incidence of SCD in absence of cardiac hypertrophy. Transgenic mice expressing the human TnT-I79N mutation display stress-induced VT, even in absence of hypertrophy and/or fibrosis, which was proposed to arise from afterdepolarizations due to the combination of AP shortening, suppression of IK1 and Ca2+ transients reduction. He also showed that the diastolic dysfunction, due to increased left ventricular stiffness in these animals, leads to diastolic heart failure and SCD, which could be prevented by diltiazem. Finally, Dr. Knollmann presented data showing that increased myofilament Ca2+ sensitivity, in animal models with TnT mutations or using the Ca2+ sensitizer EMD 57033, may reduce the responsiveness of mouse hearts to inotropic stimuli, particularly at fast pacing rates.
Dr. C.R. Bezzina (Amterdam, NL) presented a state-of-the art review of Na+ channel channelopathies and the involvement in various types of ventricular arrhythmia. She showed the overall structure of the cardiac Na+ channel (Scn5a gene) and introduced the mutations responsible for various rhythm disorders. The long-QT syndrome (LQT3), associated with syncopes, bradycardia, and torsades de pointes, reflects a Gain-of-function mutation in the main α-subunit which induces a persistent late Na+ current. Involvement of a L179F (C535T) missense mutation in the 4 regulatory subunit and caveolin-3 mutations have been recently shown to constitute novel LQTS-susceptibility genes responsible for late Na+ current increase. In contrast, the Brugada syndrome, characterised by ST segment elevation with or without conduction abnormalities, significant risk of nocturnal sudden cardiac death in absence of structural heart disease, rather reflects a Loss-of-function due to alterations in Na+ channel gating. Defective traffiking for the endoplasmic reticulum/Golgi complex to the plasma membrane might be involved. Conduction slowing based on interstitial fibrosis, but not transmural repolarization differences has been reported. Finally, LQT3 Na+ channel mutations giving rise to late inward Na+ current can also underlie sinus bradycardia and sinus pauses as shown by the 1795insD mutant Na+ channels in rabbits. Mice carrying this mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similarly to the human phenotype.
Dr. M.H. Gollob (Ottwa, CA) introduced cardiac connexins as critical components of myocardial function, and reviewed experimental data demonstrating their key role in normal and diseased hearts. He reminded us that genetic defects in cardiac connexins predispose to arrhythmia vulnerability. There are at least 20 genes expressing connexin. Eight of them are involved in human diseases, with mutations leading to arrhythmias. GJA5, the gene encoding for the gap-junction protein connexin 40, can exhibit missense mutations altering the ability of connexin 40 to form gap junctions and to conduct current from one cell to another. Cells expressing a Pro88 Ser substitution in one mutant form of connexin 40 do not form gap junctions. This mutation predisposes primarily to idiopathic atrial fibrillation. Dr. Gollob also pointed out that Connexin43, the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction. Its absence in the mouse heart results in enhanced susceptibility to induced arrhythmias with no alteration of cardiac contractility.
In conclusion, this session underlined the tremendous potential of the ongoing molecular analyses of normal and diseased cardiac functions which will allow to identify the many causes involved in cardiomyopathies at risk of sudden death. We can expect a large body of information to increasingly become accessible for diagnosis, susceptibility testing and therapeutical strategies.
Molecular pathology of cardiomyopathies at risk of sudden death Basic Science Track
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