Correspondence

Arrhythmogenic Right Ventricular Cardiomyopathy

N Engl J Med 2009; 360:2784-2786June 25, 2009

Article

To the Editor:

Although the article by Asimaki et al. (March 12 issue)1 is provocative, we remain unconvinced that arrhythmogenic right ventricular cardiomyopathy (ARVC) is caused by a primary defect in the intercalated disk.

No molecular studies reporting desmosomal mutations in autopsy tissues have shown images of morphologic changes indicating ARVC. There is little documentation of pathological features of ARVC in the tissue samples obtained from the subjects in the study by Asimaki et al.

We have been interested in ARVC for many years,2 and we have found no evidence of diffuse connexin 43 abnormalities in patients with ARVC who die suddenly3 (Figure 1Figure 1Histologic and Immunofluorescence Images from Biopsy Samples Obtained at Autopsy from Eight Subjects with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Who Died Suddenly.).

The recent discovery of mutations unrelated to desmosomes in families with ARVC is telling.4 There is an urgent need for published data that show clear postmortem findings of ARVC, with documented molecular findings supporting a specific genetic basis of this condition.

Fabio Tavora, M.D.
Nathaniel Creswell, M.S.
Allen P. Burke, M.D.
Armed Forces Institute of Pathology, Washington, DC 20306

4 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation 1998;97:1571-1580
   Web of Science | Medline

3. 3

   Burke AP, Cresswell N, Kutys R, Li L. Arrhythmogenic cardiomyopathy: a biventricular disease with predilection for African-Americans. Mod Pathol 2009;22:77A-77A
   CrossRef | Web of Science

4. 4

   Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 2008;82:809-821
   CrossRef | Web of Science | Medline

To the Editor:

Asimaki et al. introduce a new immunohistochemical test for ARVC. Without knowing whether the subjects had ARVC or not, they performed the analysis of specimens from subjects who underwent heart biopsies at Johns Hopkins Hospital.

We found some of the numbers in the article confusing. In the Abstract, the authors report that they correctly identified 10 of 11 subjects without ARVC, but they report a specificity of only 82%. Given the specificity in the Abstract and the confidence interval reported in the Results section, it appears that the test correctly identified 9 of 11 subjects without ARVC. But if that is the case, then Table 2 of their article should have one more row in which the “comparison with clinical diagnosis” says “disagree.”

Also, it is not clear whether samples from the subjects with ARVC and samples from the subjects without ARVC were obtained separately, or whether the sampling was cross-sectional. If the samples were obtained separately, then the prevalence of ARVC of 50% (11 of 22 subjects) is artificial, and the calculated predictive values may not be clinically relevant.1

Michael A. Kohn, M.D., M.P.P.
Thomas B. Newman, M.D., M.P.H.
University of California at San Francisco, San Francisco, CA 94107
michael.kohn@ucsf.edu

1 References

1. 1

   Newman TB, Kohn MA. Evidence-based diagnosis. Cambridge, United Kingdom: Cambridge University Press, 2009:41-2.
   

Author/Editor Response

If Tavora and colleagues are suggesting that because we did not include detailed descriptions of pathological findings, we did not actually analyze tissue samples from subjects with ARVC, they are mistaken. We have never claimed that connexin 43 is lacking from intercalated disks in ARVC — only that the signal is reduced as compared with that of controls. This finding has been confirmed by direct visualization on electron microscopy showing reduced gap-junction density in ARVC.1 Immunoreactive signal intensity is highly dependent on staining conditions. We can make the difference disappear by simply manipulating antibody concentrations. Because no information was provided about methods and no controls were included, we cannot interpret Figure 1 in the letter by Tavora and colleagues. However, substantial independent data link gap-junction remodeling to ARVC. Since our original articles described this phenomenon in recessive forms of ARVC, gap-junction remodeling has been shown in ARVC caused by dominant mutations in plakophilin 2,2,3 in a naturally occurring animal model of ARVC,4 and in cardiac myocytes in which the expression of desmosomal protein has been knocked down by small interfering RNA.5

Regarding Kohn and Newman's query about sampling: each biopsy specimen was evaluated four times. The evaluations were highly consistent except in one specimen in which two evaluations indicated ARVC and two ruled out ARVC. The tie was broken after further evaluation that ruled out ARVC. When our final diagnoses were compared with clinical diagnoses, we correctly ruled out ARVC in 10 of 11 subjects. However, in our statistical analysis, we opted for the worst-case scenario and used the individual evaluations in calculating sensitivity, specificity, and positive and negative predictive values. We did not use the terms sensitivity and specificity in our tie-breaker situation, but we did use them in the worst-case scenario. Finally, the biopsy specimens were obtained from a restricted population of patients referred to the Johns Hopkins ARVC Registry for further diagnostic workup.

Jeffrey E. Saffitz, M.D., Ph.D.
Angeliki Asimaki, Ph.D.
Shiva Gautam, Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
jsaffitz@bidmc.harvard.edu

5 References

1. 1

   Basso C, Czarnowska E, Della Barbera M, et al. Ultrastructural evidence of intercalated disk remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies. Eur Heart J 2006;27:1847-1854
   CrossRef | Web of Science | Medline

2. 2

   Fidler LM, Wilson GJ, Liu F, et al. Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations. J Cell Mol Med 2008 July 26 (Epub ahead of print).
   

3. 3

   Tandri H, Asimaki A, Dalal D, et al. Gap junction remodeling in a case of arrhythmogenic right ventricular dysplasia due to plakophilin-2 mutation. J Cardiovasc Electrophysiol 2008;19:1212-1214
   CrossRef | Web of Science | Medline

4. 4

   Oxford EM, Everitt M, Coombs W, et al. Molecular composition of the intercalated disc in a spontaneous canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Heart Rhythm 2007;4:1196-1205
   CrossRef | Web of Science | Medline

5. 5

   Oxford EM, Musa H, Maass K, Coombs W, Taffet SM, Delmar M. Connexin43 remodeling caused by inhibition of plakophilin-2 expression in cardiac cells. Circ Res 2007;101:703-711
   CrossRef | Web of Science | Medline