To those of us involved in clinical research it seldom happens to begin working on a rather obscure disease, still largely unexplored, and to follow its ripening into a medical entity of large ...interest to clinicians and basic scientists alike, and moreover to do so for exactly 50 years. This is what has been my privilege in the relentless pursuit of the intriguing disease known as the long QT syndrome (LQTS). This essay begins with the encounter with my first patient affected by LQTS when just a handful of cardiologists had seen similar cases and continues with the series of efforts, some sound some amateurish, which eventually led-together with many brilliant partners and associates-to describe and understand the natural history of the disease and the most effective therapies. It then touches on how our International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, my own interest focused first on the intriguing genotype-phenotype correlation and then on 'modifier genes', in the attempt of understanding why family members with the same disease-causing mutation could have an opposite clinical history. And from there on to iPS-derived cardiomyocytes, used to unravelling the specific mechanisms of action of modifier genes and to exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination and the attraction of the unknown are irresistible.
Experimental and clinical evidence indicating an antiarrhythmic effect of cardiac sympathetic denervation has been available for 100 years. Experimental data show that left cardiac sympathetic ...denervation (LCSD), in particular, is not only antiarrhythmic, but also antifibrillatory-an effect exquisitely important for any clinical condition associated with a high risk of ventricular fibrillation and sudden cardiac death. LCSD has additional effects on both the coronary circulation and the mechanical performance of the left ventricle, with important implications for patients with ischaemic cardiomyopathy. Evidence also shows that LCSD increases the vagal activity directed to the heart, which has potential implications for the management of heart failure. In this Review, the current and novel clinical indications for LCSD are discussed, particularly in the context of results obtained in patients with channelopathies, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.
Drug-induced long QT syndrome (diLQTS) and congenital LQTS (cLQTS) share many features, and both syndromes can result in life-threatening torsades de pointes (TdP). Our understanding of their ...mechanistic and genetic similarities has led to their improved clinical management. However, our inability to prevent diLQTS has resulted in removal of many medicines from the market and from development. Genetic and clinical risk factors for diLQTS and TdP are well known and raise the possibility of TdP prevention. Clinical decision support systems (CDSS) can scan the patient's electronic health records for clinical risk factors predictive of diLQTS and warn when a drug that can cause TdP is prescribed. CDSS have reduced prescriptions of QT-prolonging drugs, but these relatively small changes lack the power to reduce TdP. The growing genetic evidence linking diLQTS to cLQTS suggests that prevention of TdP in the future may require inclusion of both genetic and clinical predictors into CDSS.
Abstract
Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk ...stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.
The mind-boggling progress in the understanding of the molecular mechanisms underlying the long QT syndrome (LQTS) has been the subject of many articles and reviews. Still, when it comes to the ...management of the patients affected by this life-threatening disorder, too many errors still take place, both in the diagnostic process and in the therapeutic choices. The price of these errors is paid by the patients and their families. This review is not directed to the relatively small number of LQTS experts who know what to do. It does not deal with genetics, with epidemiology, or with the well-known clinical manifestations. We have focused solely on the approach to diagnosis and therapy and we have directed this review to the average clinical cardiologist who, in his/her practice, sees occasionally patients affected or suspected to be affected by LQTS; the cardiologist who may know enough to manage them but not enough to be completely confident on his/her most critical choices. We have provided our personal views without making any attempt to blend differences whenever present. On most issues we agree fully but where we do not, we make it clear to the reader by indicating who is thinking what. The result may be unconventional, but it mirrors the challenges, often severe, that we all face in managing and protecting these patients from sudden death while also helping them live and thrive despite their diagnosis. We trust that this unabashed presentation of our clinical approach will be useful for both cardiologists and patients.
There are few areas in cardiology in which the impact of genetics and genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin ...related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, 3 are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these 3 diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care.
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