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Johns Hopkins Medicine
Office of Corporate Communications
Media contact: David March
February 20, 2006

- Research advances possibility of blood screening test

A baker’s dozen mutations in a gene called plakophilin-2 (PKP2) have been identified by Johns Hopkins scientists as the most likely origins of a rare heart condition, arrhythmogenic right ventricular dysplasia (ARVD).  The condition, which runs in families, is among the top causes of sudden cardiac death among young athletes. 

Daniel P. Judge, M.D.
Daniel P. Judge, M.D.

In a report on what is believed to be the first comprehensive analysis of these genetic mutations in patients with the disease, to be published in the journal Circulation online Feb. 20, the Hopkins scientists say that some combination of the PKP2 mutations was commonly found in 43 percent of them.  ARVD is marked by a poorly functioning right ventricle that beats irregularly and over time weakens the muscle from the buildup of excess fatty and scar tissue.  Untreated ARVD can trigger a fatal heart rhythm disturbance. 

Senior study author and cardiac geneticist Daniel P. Judge, M.D., says, “We believe we have pinpointed the genetic mutations responsible for the syndrome in many people, and we expect to have a blood test to identify those at greater risk of developing ARVD clinically available within the next couple of months.”

According to Judge, an assistant professor at The Johns Hopkins University School of Medicine and its Heart Institute, it makes sense to screen the immediate family members of those already diagnosed with ARVD and PKP2 mutations for the presence of these mutations, but he cautions that the mere presence of mutations does not indicate an urgent risk of a fatal arrhythmia or need of preventive therapy, such as implantation of a defibrillator. 

Chromatogram DNA analysis shows with arrow where m

Chromatogram DNA analysis shows with arrow where mutation has been identified in gene plakophilin-2, in a patient with ARVD.

Estimates from researchers and the Heart Rhythm Society suggest that ARVD accounts for up to 5 percent of the 300,000 deaths each year in the United States from sudden cardiac death. 

As part of the study, the Hopkins team analyzed blood samples from 58 patients, including men and women, previously diagnosed with ARVD, sequencing the genetic content, or DNA, from each sample to determine any common genetic mutations in PKP2. 

Study participants, 30 of whom were involved in competitive sports, were part of Hopkins’ registry of U.S. patients with the condition, which appears on MRI scans as either a protruding, pouch-like bulge from the right side of the heart, or a dilated, malfunctioning right ventricle. 

Researchers then compared patients with PKP2 mutations to those without.  They also compared what happened in those who had received preventive therapy for the disease and those who had not received any.  The leading therapy for ARVD is an implantable defibrillator, which delivers a mild shock to the heart to correct irregular rhythms and prevents the heart from suddenly ceasing to function as result of a runaway heartbeat.

PKP2 was selected for initial analysis as a possible source of ARVD because the gene is known to be more common in patients with the condition, although previous research did not identify how many mutations or describe them.

In the Hopkins study, researchers found a total of 13 different mutations in PKP2, with 25 patients (43 percent) having one each.  Five of the mutations were new discoveries, with four of them appearing in different, unrelated families.  Three of the mutations were determined to be critical to overall gene translation, with another two altering the gene’s components.  Two others led to production of completely different proteins than originally intended.  These proteins act like “glue,” the researchers say, binding heart cells together.  But abnormalities make the heart more vulnerable to mechanical stresses, such as those experienced during intense exercise.

Those with PKP2 mutations were found more likely to develop symptoms of ARVD almost a decade earlier than those without, at age 28 for those with mutations compared to age 36 for those without.  Arrhythmias were also more likely to happen earlier, by age 32 if mutations were present, but not until age 40 if they were absent.  However, the disease appeared the same in both groups, producing similar symptoms and clinical testing results.

Initial symptoms include palpitations, dizziness and fainting after exercise.  Previous research by the Hopkins team, also published in Circulation, showed that ARVD frequently strikes people who are relatively young, after puberty and before age 50, and its symptoms may appear up to 15 years before diagnosis. 

Of the 48 patients in the latest study who had an implanted defibrillator, patients with and without PKP2 mutations had statistically similar rates for device firings, at 52 percent and 63 percent, respectively. 

“Preventive treatment with an implantable defibrillator appears to eliminate the risk of sudden death,” says study lead author Darshan Dalal, M.D., M.P.H., a cardiology research fellow at Hopkins.  “This highlights why it would be a life-saving advance to have a test for identifying precisely who should get one and who is most at risk for this serious disease, which can suddenly and unexpectedly strike apparently healthy individuals.”

Dalal adds that a screening test could also help improve diagnosis of ARVD, which is often misdiagnosed based on single diagnostic tests, such as MRI showing fatty tissue in the heart muscle.  He says that a screening test could add a more decisive and powerful tool to confirmation of the diagnosis, currently based on a four-point scale and up to 10 cardiac tests.  Electrocardiograms, or EKGs, and echocardiograms are performed along with MRI tests and tissue biopsy to confirm the buildup of fat and fibrous tissue in the right ventricle.

Researchers say their next steps are to identify the presence of PKP2 mutations in families of patients with ARVD and to more precisely define the genetic mutations and any additional environmental factors likely to trigger the disease.  “We are also going to closely monitor the remaining 57 percent of patients without PKP2 mutations for other possible genetic links to ARVD,” adds Judge.

Funding for this study, conducted at Hopkins during 2005, was provided by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, the National Institutes of Health, the Donald W. Reynolds Foundation and the W.W. Smith Charitable Trust. 

Besides Judge and Dalal, other researchers involved in this study, conducted solely at Hopkins, were Lorraine Molin, B.S., M.S.; Jonathan Piccini, M.D.; Crystal Tichnell, M.G.C; Cynthia James, Ph.D., Sc.M.; Chandra Bomma, M.D.; Kalpana Prakasa, M.D.; Philip Spevak, M.D.; David Bluemke, M.D., Ph.D.; Theodore Abraham, M.D.; Stuart Russell, M.D.; and Hugh Calkins, M.D.  Additional research assistance was provided by Frank Marcus, M.D., in Tucson, Ariz., and Jeffrey Towbin, M.D., in Houston, Texas.  Calkins receives research support from device manufacturers Guidant, Medtronic and St. Jude.  The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.


- JHM -