© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Transgenic models in cardiac arrhythmias: how close can we get to the bedside?
Molecular Cardiology Laboratories, IRCCS Fondazione S Maugeri, Via Ferrata 8, 27100 Pavia, PV, Italy
* Tel.: +39-382-592050; fax: +39-382-592094. cnapolitano{at}fsm.it
Received 30 November 2003; accepted 2 December 2003
See article by Tian et al. [8] (pages 256–267) in this issue.
The exponential growth of studies exploring the molecular bases of arrhythmogenesis is one of the most relevant trends recently taking place in the area of cardiovascular pathophysiology. The starting point of this line of research was the discovery of the DNA coding abnormalities causing Mendelian diseases (such as the Long QT syndrome (LQTS), the Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) that alter cardiac excitability and cause sudden cardiac death. This step constituted the inception of a novel type of research aimed at dissecting out the molecular pathways leading from a genetic defect to a clinical phenotype, the so-called "translational research". Two major strategies have been undertaken: the first is "molecular epidemiology" that is aimed at linking the genotype (mutation) to the presentation of a disease; the second uses various cellular models in order to link the genotype to its cellular or sub-cellular functional counterpart at the protein level.
These strategies provided valuable information both for the understanding of the pathophysiology and about the ways we are treating our patients. However, it is becoming clear that even using this novel "molecular knowledge", human biology is quite resistant to categorization, and linking a DNA alteration with the phenotype is not straightforward. Variable penetrance [1], genetic modifiers [2–4] and complex biophysical features (only partially explaining the "whole heart" phenotype) [5–7] are strongly challenging the interpretation skills of scientists working in the field. Thus, many issues remain open and more comprehensive models are needed.
In general, subsequent attempts to further expand our investigational capabilities depend mainly on the possibility of following, step by step, the entire path from the DNA to the protein, the cell, the whole heart and finally to the clinical manifestations. Integrative experimental models such as computer modeling or transgenic mice might represent a way to reach, or at least to get close to, this objective.
The study by Tian et al. [8], published in this issue of Cardiovascular Research, is an example of how the combination of animal physiology and genomic manipulation may provide novel information to help understand how a genetic defect causes a life-threatening arrhythmogenic substrate. In this study, transgenic technology has been applied to characterize the N1325S mutation in the cardiac sodium channel-encoding gene (SCN5A). Unlike other mice with LQTS, a clearly abnormal phenotype was observed, including QT interval prolongation, ventricular arrhythmias and sudden death. The availability of this model allowed the authors to perform a wide spectrum of assays spanning from voltage clamping to action potential recordings to in vivo electrocardiographic assessment.
An interesting finding was the evidence of a non-bradycardic mechanism of arrhythmias suggested by the ECG data and in vitro action potential measurements. In the clinical setting, LQTS patients harboring a SCN5A mutation (LQT3) usually experience cardiac events at rest that are thought to be triggered by bradycardia. This evidence is supported by recent experimental findings in transgenic animals [9]. However, it is also known that approximately 15% of these patients have cardiac arrests during exercise or acute emotion [10]. It is tempting to speculate that the data by Tian et al. provide the first clue of a novel arrhythmogenic mechanism specific for a subset of SCN5A mutations.
However, as the authors correctly stated in the text, there are limitations that are difficult to interpret in the light of the clinical phenotype. For example, the faster heart rate and shorter PR interval in the study by Tian et al. are not consistent with LQT3 patients who, if any, present with PR prolongation and low heart rate.
The detection of "unexpected" phenotypes or a poor correlation with the clinical findings is not new among the LQTS mice so far produced [11–13] and highlights the general concept that mice primarily provide answers relevant to mouse physiology. Therefore, if some findings indicate that mouse models may become key components in transitional research, on the other hand, it is evident they the same models are also likely to generate a certain amount of "background noise" that may blur the information relevant to the human being. This may be primarily due to the fact that different patterns of development and expression of several genes controlling cardiac excitability translate into a markedly different electrophysiological milieu [14], suggesting that similar genetic defects may induce different consequences according to their surrounding environment.
In extrapolating from the animal models to humans, technical considerations are also crucial. In this study, the abnormal phenotype was observed only in the strain expressing a high copy number (n = 10) of the transgene, while the strain with one to two copies, which more closely resembles the genetic background occurring in humans, only showed mild abnormalities. Thus, it becomes important to define whether it would be more relevant to use the transgenic techniques to generate a manifest phenotype or to produce a mouse closely resembling the human genetic substrate. Probably, both strategies may provide useful information to better understand pathophysiology and, in the future, to design novel therapeutic strategies, but this issue needs further investigation.
In summary, the elegant paper by Tian et al. has hit its target of providing a possible explanation to previously open issues and to generate novel questions to be addressed in future research.
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