Close connections between contraction and rhythm: a new genetic cause of atrial fibrillation/cardiomyopathy and what it can teach us

This editorial refers to ‘A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation’†, by D.F. Gudbjartsson et al., on page 27. A review of the literature published a decade ago reported that almost nothing was known about the genetics of atrial fibrillation (AF), but suggested that ‘Identifying the gene of susceptibility, coupled with defining the sequence and function of the protein that it encodes, has the potential to provide both insight into the pathophysiology of the arrhythmia and diagnostic tools with which to identify susceptible individuals’.1 Subsequent work has richly confirmed the validity of this statement. A recent review listed 33 rare variants and 14 genetic loci associated with AF, and discussed the importance of their discovery for pathophysiological understanding and clinical practice.2 Of the rare variants, the most common motifs are variants in ion-channel subunits (in 21) and transcription factors (in 6). AF clearly has a strong heritable basis2 and it is likely that the discovery of novel AF-associated loci will continue to occur and to improve our understanding of this widely prevalent condition. In the present issue of the journal, Gudbjartsson et al. report just such a finding.3 They used highly sophisticated whole-genome sequencing and statistical genetics methods to identify sequence variants linked to early-onset AF in 1799 Icelanders. These approaches revealed a rare frameshift deletion in the atrial myosin light-chain gene MYL4 associating with early-onset AF under recessive inheritance models. Eight homozygous carriers all had early-onset AF, three required pacemakers for sick sinus syndrome, three had strokes (without non-AF risk factors), and one experienced sudden death. ECG intervals were generally unremarkable. The only abnormalities present on early echocardiograms were left atrial dilation in two patients. Late echocardiograms showed disease progression, with left atrial enlargement in all, mild ventricular dilation in 4/6 individuals, and reduced ejection fraction in 2. Overall, the findings indicate atrial-selective abnormalities associated with conduction system disease, stroke, and eventually mild ventricular dysfunction. These results position MYL4 mutations as a novel cause of atrial cardiomyopathy. Schematic representation of the localization of MYL4 in the cardiac contractile protein apparatus, and how MYL4 dysfunction might lead to electrical dysfunction and arrhythmias via impaired contractility and disruption of sarcomere integrity, with loss of co-ordination of contractile, structural, and signalling proteins leading to dramatic electrical consequences. Red arrows indicate causal sequences; solid arrows are already demonstrated mechanisms, while dashed arrows are speculated mechanisms. Loss of MYL4 function is known to impair contractility. Sarcomere disruption probaby results from altered atrial contractility and could also be a direct consequence of altered contractile protein interactions due to abnormal essential light chain function. Loss of Z-disk proteins alters cell signalling. actin+, actin and associated proteins such as troponin and tropomyosin; AF, atrial fibrillation; AV, atroventricular; myosin+, myosin and associated proteins. The mechanistic link between MYL4 and AF remains to be clarified. The clinical phenotype points to an atrial cardiomyopathy, with associated conduction system abnormalities,3 consistent with prior evidence of highly atrial-selective expression and contractile effects.6,–8 A very recent study reported a family presenting early-onset AF, with all afflicted members carrying a MYL4 mutation (E11K) that substitutes the basic amino acid lysine for glutamic acid.11 Affected individuals had AF onset between 22 and 32 years of age, depressed atrial contractile function, and evidence of conduction system disease including profound sinus node dysfunction. P-wave amplitude became extremely small prior to AF onset and the atria showed large areas of electrical silence. The authors created a transgenic zebrafish line expressing a corresponding mutation (E17K) in the zebrafish MYL4 orthologue under control of an atrial-specific myh6 promoter. E17K transgenics showed abnormal sinus node function, prolonged PR interval, and substantial atrial dilation. Their Z-disks were largely absent, and sarcomere structure was severely disturbed. The finding of a clear link between MYL4 mutations and early-onset AF provides new insights into the genetic basis of the condition and underlying pathophysiological mechanisms. Atrial cardiomyopathy is becoming increasingly recognized as an important entity,12 and MYL4 dysfunction is an interesting new paradigm for primary atrial cardiomyopathies. At the same time, the work raises a host of new and stimulating questions. The properties of MYL4 as an important atrial-specific contractile protein account for the abnormal atrial mechanical function observed with MYL4 mutation. What causes the profound associated electrophysiological abnormalities, including severe sinus node dysfunction, atrioventricular block, and ultimately AF, is unclear. Heart failure is clearly an important cause of AF.13 This association is generally attributed to the substantial atrial remodelling caused by the haemodynamic and neurohumoral consequences of heart failure.14 However, MYL4 dysfunction is not expected to disrupt ventricular function; indeed, ventricular dysfunction is unusual in patients bearing MYL4 mutations and is a mild and late manifestation when it does occur.3 Thus, the atrial electrical disturbances noted with MYL4 mutations must be due to changes resulting from primary atrial contractile dysfunction, and not secondary consequences of heart failure. What these changes are and why they happen are presently unclear—discovery and clarification of the mechanisms might lead to important new insights into atrial physiology and AF pathophysiology. MYL4 dysfunction greatly alters atrial cardiomyocyte ultrastructure, presumably via the effects of altered mechanical stresses.11 Z-disks, located at the lateral disks of sarcomeres, are extremely complex macromolecular complexes containing hundreds of proteins that serve crucial roles in contraction, cell structure, and signalling.15 Loss of integrin-linked kinase, an important Z-disk protein, causes arrhythmogenic cardiomyopathy.16 The severe disruption of atrial Z-disk integrity observed in MYL4-mutated zebrafish11 might therefore cause signalling and transcriptional changes that grossly affect electrical function. On the other hand, altered mechanical forces may affect crucial subcellular structures and protein functions that are not within the Z-disks to interfere with electrophysiological properties. A schematic representation of the possible pathophysiological mechanisms is shown in Figure 1. Discovering precisely how and why the atrial electrophysiological changes occur with MYL4 abnormalities could provide novel insights relevant not only to the mechanisms of MYL4-associated cardiomyopathy, but also more broadly to atrial and even ventricular cardiomyopathy in general. If cardiac remodelling and electrical disturbances can be a direct result of mechanical dysfunction (and not simply secondary changes due to cardiac failure), the important rhythm disturbances associated with ventricular cardiomyopathies may also directly result from the electrophysiological consequences of anomalous contraction properties. Detailing the underlying mechanisms might have important pathophysiological and clinical implications. While the treatment of arrhythmias has advanced enormously over the past decades, major challenges remain.17 AF remains a particularly difficult and important clinical problem. New mechanistic insights have the potential to advance greatly the risk prediction, prevention, and management of AF. Therefore, discoveries of novel molecular AF paradigms, such as that of MYL4 dysfunction, are crucially important. An interesting aspect of the Gudbjartsson report is the very high prevalence of stroke in MYL4 mutation carriers (3/8, 37.5%) despite the absence of risk factors. This observation probably reflects the important atrial contractile disturbances caused by dysfunctional MYL4, and is reminiscent of amyloid cardiomyopathy, another form of atrial cardiomyopathy with strongly reduced atrial contractility and a high risk of stroke.18 Further work on the basis for the high stroke risk in MYL4 mutation patients may lead to improved mechanistic understanding and management of this crucially important AF-related complication. Mechanical–electrical interactions are known to be potentially significant controllers of cardiac physiology.19 The MYL4 atrial cardiomyopathy is a striking exemplar of dramatic and clinically important cardiac electrical dysfunction resulting from a primary abnormality in the contractile apparatus. We look forward to the exciting new insights that will surely emerge from its discovery. Supported by the Canadian Institutes of Health Research and the Quebec Heart and Stroke Foundation. Conflict of interest: none declared.