September 2nd, 2013

What You See Is Not Always What You Get

Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy BarrettLouis Handoko, and  Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.

Today’s late-breaking sessions included the much-anticipated COMPARE trial assessing the efficacy of losartan in reducing aortic root dilatation rates in patients with Marfan syndrome. Although losartan is already a recommended therapy in the guidelines on Marfan disease, the recommendation was based solely on promising pediatric and mouse-model data.

In COMPARE, losartan therapy resulted in significant reductions in aortic root dilatation in both native and post-surgically corrected Marfan patients. This study is truly a welcome addition to the management options for an often fatal condition in the young.

However, this trial raises two very important issues. First, surgical correction is one of the only therapies available that reduce mortality from aortic dissection or rupture, but losartan therapy continues to demonstrate benefit post-surgery. Why is this worrisome? We still have progression of the underlying disease even after our most effective therapy; we are treating a symptom and not the actual disease pathology. This is where losartan is different — it targets the very core of the disease.

Second, this study raises an even broader scientific question about how we characterize, classify, and target diseases. Marfan syndrome is characterized by over 30 signs and symptoms, and its diagnosis is based on fulfilling a set of — often contentiously — agreed-upon criteria. Almost all of these criteria qualify the phenotypic manifestations of the disease rather than the molecular or genetic features of the condition. This is not to say that a single genetic mutation equals the diagnosis of a disease, but I believe in the era of molecular medicine, we need to reassess classifying disease primarily based on clinical signs and symptoms and consider doing so by precise molecular pathophysiological hallmarks.

Such an approach has profound consequences for how we target the disease itself. The COMPARE trial included patients with Marfan syndrome who fulfilled the prespecified diagnostic criteria but may or may not have been carriers of the fibrillin-1 gene mutation. It is this gene mutation that results in abnormal TGF-B function and is probably the reason why losartan therapy in Marfan syndrome reduces aortic root dilatation, even post-surgical correction. By including Marfan patients without FBN-1 gene mutations, one runs the very real risk of diluting the beneficial effect of losartan in those who carry the gene mutation.

Furthermore, Marfan syndrome presents as a continuum of disease states and severity. This range of presentation is likely to result from the almost 700 different gene mutations that have been identified and their varied expression in Marfan syndrome. Even in patients with the FBN-1 gene mutation, there may be a variety of different pathophysiological processes at play, which may or may not be likely to respond to therapies that influence TGF-B function.

In other words, not all Marfan patients are FBN-1 gene mutation carriers, and not all FBN-1 gene mutations in Marfan patients result in the same pathophysiological consequences.

The COMPARE data add substantially more weight to the use of losartan in Marfan syndrome patients. However, maybe it is time we design and conduct more trials based on the molecular features of the disease rather than the clinical features. Such an approach may substantially amplify the beneficial effect of therapies we test and in such a fashion that matches the likely molecular mechanism of the disease to the molecular mechanism of the therapy.

To read CardioExchange’s news story on COMPARE, click here.

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