12 Jul Genetic Variants Linked to Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators
MedicalResearch.com Interview with:
Ben Cordon, PhD
NIHR Post-doctoral Academic Clinical Fellow
Specialist Registrar training in cardiology
James S. Ware, PhD, MRCP
Reader in Genomic Medicine
Group head within the Cardiovascular Genetics & Genomics Unit
Imperial College London
MedicalResearch.com: What is the background for this study?
Response: Non-ischaemic dilated cardiomyopathy is a common cause of heart failure and carries the risk of life-threatening ventricular arrhythmia. An implantable cardioverter defibrillator (ICD) can be life-saving in this condition. However, the decision to implant an ICD is not one that can be taken lightly – ICD insertion carries its own risks, such as infection or inappropriate shocks, and our ability to predict who will benefit from a device is currently far from perfect. Genetic sequencing is affordable and widely available and for DCM, like many diseases, it is hoped that genetic stratification may one day help deliver personalised management. In DCM, variants in the Lamin A/C gene for example are known to cause a phenotype with early and severe arrhythmias and, as a result, international guidelines advocate a lower threshold for ICD insertion in these patients. However, Lamin A/C is an infrequent cause of DCM. The commonest known genetic cause of DCM are protein-truncating variants in the gene encoding Titin (TTNtv), accounting for ~15% of DCM cases. We wanted to know if this group had a higher risk of arrhythmia than the general DCM population.
Earlier work from our group on this topic found that patients with TTNtv-associated DCM were more likely to have a clinical history of arrhythmia (composite of atrial and ventricular arrhythmia, including NSVT), at the time of their initial DCM diagnosis. But it was unclear if this was driven by ventricular arrhythmia, atrial arrhythmia, or both or if it would translate into a long-term risk of potentially dangerous ventricular arrhythmia of the sort for which an ICD can be life-saving. In another study we analysed a larger cohort of ambulant DCM patients but did not find an increased risk of ventricular arrhythmia – but this was a relatively low-risk group, with comparatively mild symptoms (NHYA I/II heart failure) and moderately impaired LV function. As a result, the overall arrhythmic event rate was low, meaning that the power to detect differences between the TTNtv and non-TTNtv groups was reduced.
To investigate further, we studied a group of DCM patients with implantable devices (an ICD or CRTD, 91% of which were for primary prevention). Not only do this group have a higher baseline risk of arrhythmia (the devices are typically inserted because the patients continue to have severe LV impairment despite optimal medical therapy) but they also allowed us to capture complete, 24-hour, 7-days-a-week arrhythmia data for all patients over a long-follow-up (median 4.2 years). Both of these factors helped us to capture more events and therefore have more power to detect differences between the TTNtv and non-TTNtv groups.
Our primary hypothesis was that TTNtv would be associated with a higher risk of significant ventricular arrhythmia. Importantly, we chose a relatively strict definition of this, only counting VF or sustained VT >200bpm (meeting MADIT-RIT high-rate criteria) which resulted in anti-tachycardia pacing (ATP) or a shock. A secondary hypothesis was that TTNtv would be associated with new, persistent atrial fibrillation.
MedicalResearch.com: What are the main findings?
Response: TTNtv were associated with a 4.9-fold increased risk of receiving an appropriate ICD therapy (shock or ATP) for VT or VF (P<0.0001). Importantly, this association remained after adjusting for co-variants already known to increase the risk of ventricular arrhythmia, including age, male sex, lower LV ejection fraction and the presence of fibrosis on cardiac MRI (adjusted hazard ratio [HR] = 8.3, P = 0.006).
A notable finding was that patients with both a TTNtv and fibrosis on their cardiac MRI were at a markedly greater risk of ventricular arrhythmia than those with neither (62% vs 5%), suggesting a potential additive effect of these risk factors.
TTNtv were also a risk factor for developing new, persistent AF (HR = 3.9, P = 0.01).
MedicalResearch.com: Who should be tested for this gene variant?
Response: Clinically, the main motivation for genetic testing in DCM is to help identify family members who may be at risk of developing the disease, since it can run in families. Usually, once an individual is diagnosed with DCM we would offer evaluation to their immediate relatives. Often healthy relatives end up being followed up in the cardiology clinic for a long time, since even if they have a reassuring normal evaluation, they may still be at risk of developing it later – as many people don’t develop problems until later in life.
Genetic testing can provide a much quicker definitive answer – if we know the precise genetic cause in one member of the family, then we can directly test for the genetic predisposition in others. Family members who are shown not to carry the underlying genetic problem can be reassured and safely discharged, freeing them from the burden of long-term follow up. Conversely, relatives who do share the gene variant can be offered close surveillance.
In some cases, genetic testing can also guide management of the patient themselves – as in the case of a Lamin A/C variant described above – which is managed a bit differently from other causes of DCM. This ss an emerging area, as our study and others are suggesting that genetic testing will increasingly help in risk stratification or in delivering personalised medicine.
MedicalResearch.com: What should readers take away from your report?
Response: Our main take-home message is that TTNtv are a risk factor for clinically important ventricular and atrial arrhythmia in patients with DCM and a CRT-D/ICD device. Going further, it may be that knowledge of TTNtv-status is complementary to fibrosis imaging by CMR in predicting arrhythmic risk in DCM patients, but this is a hypothesis at this stage and requires further testing in larger, prospective studies.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: One next step is to see if this association holds in larger studies and studies including different patient populations from other parts of the world. As part of this, TTNtv could be tested along with other factors for their utility in multi-modality risk stratifying algorithms for DCM.
Another strand of research will focus on the mechanisms by which a TTNtv could lead to increased arrhythmia risk. Our group has previously shown that the hearts of DCM patients with a TTNtv compared to those without a TTNtv have thinner LV walls and lower LV mass for the same degree of dilatation. This combination is predicted to result in higher LV wall stress, which has been linked to a greater risk of arrhythmia through promotion of triggered activity (via early and late after-depolarisations) and through the facilitation of re-entry circuits. Understanding these, or other potential mechanisms will require a significant amount of basic research.
Dr Ware has acted as a consultant for MyoKardia. This work is entirely unrelated to this study.
We are grateful to the Wellcome Trust, the British Heart Foundation, the NIHR Imperial Biomedical Research Centre, the NIHR Royal Brompton Cardiovascular Biomedical Research Unit, and the Leducq Foundation for their generous support of our research.
Corden B, Jarman J, Whiffin N, et al. Association of Titin-Truncating Genetic Variants With Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators. JAMA Netw Open. Published online June 28, 20192(6):e196520. doi:10.1001/jamanetworkopen.2019.6520
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