An assay aimed at myocardial intercellular adhesion proteins appeared to be
highly accurate in identifying cases of arrhythmogenic right ventricular
cardiomyopathy (ARVC) in a small laboratory study [1]. Researchers hope the
immunohistochemical test, if commercially developed, will help in diagnosing the
rare genetic disorder in its early stages, when noninvasive tests such as ECG,
echocardiography, and MRI are the least helpful.

The study, which appears in the March 12, 2009 New England Journal of Medicine,
was performed using biopsy specimens from individuals primarily with advanced
ARVC, caution the authors, led by Dr Angeliki Asimaki (Beth Israel Deaconess
Medical Center, Boston, MA).

ARVC, also frequently called right ventricular dysplasia, is a degenerative
process in which right ventricular myocardium is gradually replaced by
fibrofatty tissue, explained principal author Dr Jeffrey E Saffitz (Beth Israel
Deaconess Medical Center) to heartwire. The changes can also occur elsewhere in
the heart

Conventional biopsy analysis is unreliable in early-stage ARVC and not very
helpful in the later stages, according to Saffitz. In early disease, biopsy is
too likely to capture normal myocardium and miss the disease; in advanced ARVC,
the diagnosis is usually apparent by other means, he said.

"This is a familial disease that can have a very lethal phenotype," Saffitz
said. "The first and only manifestation can be sudden death." If the test
ultimately proves useful in early-stage disease, it could be used to confirm the
diagnosis in patients with otherwise-suspected ARVC so they can get preventive
therapy, typically an implantable defibrillator.

The test could also help the relatives of patients with the ARVC genotype who
are asymptomatic but concerned about whether they might have the disease,
according to Dr Frank I Marcus (University of Arizona Sarver Heart Center,
Tucson), an expert in the disorder who did not participate in the study. "This
would be most helpful in advising family members," he told heartwire.

"I have been following this work carefully and am most enthusiastic about the
possibility of making an accurate diagnosis in this disease, which has been very
difficult to diagnose with a high degree of certainty using conventional
methods," Marcus said. "If the results can be confirmed by these investigators
or by others in larger series of patients in the early stages of the disease, it
would be a significant medical advance."

The group first performed the test on myocardial tissue obtained at biopsy or on
autopsy of 11 persons known to have ARVC and 10 others without clinical or
pathological heart disease. All ARVC tissue samples showed sharply lower
immunoreactivity for plakoglobin, a protein constituent of the cell-surface
desmosome structures central to myocyte adhesion, compared with the control
samples.

"Plakoglobin signal levels were reduced not only in right ventricular regions
showing typical pathological changes of fibrofatty replacement, but also in
normal-appearing left ventricle and interventricular septum, including the
subendocardium," the authors write.

Myocardium from 15 hearts from patients who had undergone transplantation for
end-stage disease, including ischemic heart disease, hypertrophic
cardiomyopathy, and dilated cardiomyopathy, showed high plakoglobin levels that
"were indistinguishable from the signal levels in control samples."

Applied to myocardial biopsy samples from participants in the Johns Hopkins ARVC
Registry, the test showed a sensitivity of 91%, specificity of 82%, an 83%
positive predictive value, and a 90% negative predictive value for ARVC.

The authors acknowledge their study's important limitations--for example, its
limited size, need for validation, predominant use of tissue with advanced
disease, and questions about whether plakoglobin is similarly reduced in all
forms of ARVC. But if validated in early-stage disease, the test could be
performed easily on a routine basis, Saffitz said. "We envision that it could be
done in any hospital pathology department."

The study was partially funded by the St Jude Medical Foundation. According to
the paper, "Beth Israel Deaconess Medical Center has filed patents covering
methods of diagnosing ARVC." Marcus discloses that he may partner with Saffitz
and others on proposed, future ARVC research.


Asimaki A, Tandri H, Huang H, et al. A new diagnostic test for arrhythmogenic
right ventricular cardiomyopathy. N Engl J Med 2009; 360:1075-1084.