Long QT syndrome LQTS a rare inheritable arrhythmia first de

Long QT syndrome (LQTS), a rare inheritable arrhythmia first described by Romano and Ward et al. in the 1960s, is characterized by the prolongation of the QT interval on surface ECGs and an increased risk of potentially fatal ventricular arrhythmias, especially torsade de pointes . In 1995, after years of extensive clinical investigation and linkage analysis, several research groups, including Keating et al., successfully identified three distinct LQTS phenotypes (LQT1, LQT2, and LQT3) associated with mutations in genes encoding plasma membrane ion buy Atglistatin (, , and , respectively) . These seminal studies motivated further extensive genetic screening in LQTS patients using a candidate gene approach and functional analyses of the mutant genes. These efforts provided evidence that ion channel genes represent the genetic basis for several other arrhythmogenic syndromes that occur in the structurally intact heart, often referred to as idiopathic ventricular fibrillation. At present, 13 genes responsible for LQTS have been identified. Approximately 90% of the genotyped LQTS subjects belong to the three major subtypes (LQT1-3) in which numbers of distinct genotype-specific clinical characteristics have been demonstrated, including T-wave morphology , triggers for cardiac events , response to the epinephrine provocation test and drug therapy . Genetic testing for known arrhythmia susceptibility genes has become the standard-of-care for a number of disorders, including LQTS. Considering the remarkable progress of research in this area, there is no doubt that 1995 was the year in which genetic technologies experienced a paradigm shift with respect to both the understanding and clinical management of inherited arrhythmias. However, it should be noted that despite the rapid progress in understanding the genetic basis, the etiology still remains unknown in approximately 20% of LQTS conditions . Therefore, additional studies are needed to reveal the missing heritable factors associated with these syndromes.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Although AF prevalence is lower in Asian populations (~1%) than in Caucasians, the absolute numbers of patients in Asia suggest that the overall disease burden attributable to AF may eclipse that found in Western countries . To combat this surging regional AF epidemic, new strategies resting on a more detailed understanding of the AF pathophysiology will be needed. A fundamental challenge in the field is that arrhythmia dynamics during AF remain unclear, despite over a century of research . AF has been hypothesised to involve a combination of local drivers, including re-entrant circuits known as and focal sources, or due to multiple simultaneous re-entrant wavelets, with a related postulated role for endo-epicardial wavefront dissociation . It is clear that AF arises in the context of electrophysiological and structural remodelling occurring in the context of clinical risk factors including aging, heart failure, valvular heart disease, sinus node disease, hypertension, obesity and obstructive sleep apnoea. These factors are known to modulate local conduction velocity, refractoriness and heterogeneity to create the critical substrate for AF arrhythmogenesis. Recently, increasing attention has been paid to the role of detailed muscular architecture of the atrium in providing the substrate for AF re-entrant circuits. The complex interlacing myoarchitecture of the atrium, whose detailed structure was first outlined by Papez , may provide a functional substrate for AF, even in the absence of disease. Specific attention has been focused on the histoanatomy of the pulmonary vein (PV)–posterior left atrium (LA) junction. Klos et al. identified source–sink mismatch at the PV–LA junction as a possible mechanism for wavebreak at the onset of AF in the sheep heart . Simulation studies have further delineated the 3-dimensional nature of myofiber orientation as a critical player. In humans, the PV–LA junction and posterior LA have similarly been determined as locations for conduction delay and block, providing an intrinsic histologically pre-determined substrate for re-entry .