The next piece of the titin puzzle

Dr. Paz Tayal

In our last post you heard a bit about the role of titin truncating variants (TTNtv) in dilated cardiomyopathy, but we had lots more questions at the end.

Well, we’ve now completed a major study of the clinical outcomes of patients with TTNtv. In the research, recently published in the Journal of the American College of Cardiology, 716 patients with DCM, including 83 patients with TTNtv, were followed up for a primary composite outcome of cardiovascular death, major heart failure events and major arrhythmic events. We found that there was no difference in outcomes between patients with and without TTNtv (5 year event rate for TTN positive/negative patients: 10.4%/13.6%, p=0.65).

So, what does this mean?

This study suggests that having a TTNtv doesn’t affect your outcome in DCM. It shows that TTNtv DCM doesn’t have the adverse event profile associated with other genetic cardiomyopathies such as lamin cardiomyopathy. This is potentially really useful information for patients and clinicians.

But does that mean there is no role for titin in risk stratification in DCM? Not quite.

The first point to note is that the patients in the study were largely in NYHA class I/II, with moderately impaired ventricular function. Secondly, whilst this was the largest single center study of patients with TTNtv DCM with independently adjudicated outcomes and CMR phenotyping, the overall follow up time was 3.9 years (median). This is considered medium term follow up. Maybe we were a little early and longer term follow up will reveal differences that this study did not. Finally the number of the events within the cohort was lower than previous studies, not just from registry data but also historic studies in our institution. This suggests an improvement in DCM outcomes overall (note – this is a good thing for patients). Therefore it is possible that longer follow up in patients with a higher risk for adverse events could reveal subtle differences between titin positive and negative patients.

Some previous studies have suggested that there is a difference in outcome in male patients with TTNtv compared to female patients with TTNtv. TTNtv may well have a different effect in some groups e.g. women, patients with fibrosis, but the number of events in our study meant that we could not definitively analyse this. Multicenter studies will be the way forward.

On a general point, I would advise caution when interpreting studies that analyse data in only a subset of their cohort (e.g. survival analysis in only the patients with TTN and not compared to the entire DCM cohort – you may end up just picking up a DCM effect and not a TTN specific effect) or those that present survival analysis from birth (this works for hard outcomes e.g. death, but doesn’t work for outcomes such as heart failure hospitalisations, as you can’t be sure the patient didn’t have an event before they enrolled in your study).

Another important finding of the study was that prognostic indicators for all-cause DCM also predict outcome in TTNtv DCM. This means that the factors that predict outcome in DCM such as LVEF, mid wall fibrosis late gadolinium enhancement, and left atrial size, are still valid in patients with TTNtv DCM. This information is important as we move towards multi-modality risk stratification in DCM – the next part of the DCM jigsaw…