Correspondence

Triglyceride Deposit Cardiomyovasculopathy

N Engl J Med 2008; 359:2396-2398November 27, 2008

Article

To the Editor:

A 41-year-old man was admitted to our hospital with ventricular tachycardia in 2003. Biopsy specimens obtained from the right ventricle showed neutral lipid deposition in cardiomyocytes. In 2004, the patient had catecholamine-dependent congestive heart failure, and a left ventricular assist system was implanted. Skeletal-muscle atrophy in the arms became evident, and staining of biopsy specimens with oil red O showed droplets of predominantly type I fibers (Figure 1AFigure 1Oil Red O Staining of Biopsy Specimens from the Patient and Measures of Triglycerides and Cholesterol.). Levels of plasma lipids and carnitine were normal.

In June 2007, the patient underwent cardiac transplantation. Microscopical examination of the explanted heart revealed numerous vacuoles that stained positive for oil red O in the cytoplasm of cardiomyocytes (Figure 1B). The triglyceride content in the left ventricles was markedly increased, as compared with that in three control subjects without heart disease (data not shown). The patient's coronary arteries showed diffuse intimal thickening and fibroatheromatous lesions. Vacuoles were observed in the cytoplasm of endothelial cells, in the smooth-muscle cells in the media of the coronary arteries (Figure 1C), and in the foam cells in the intima. Cells that were positive for oil red O staining were seen in the endothelium, intima (Figure 1C, upper inset), and media (Figure 1C, lower inset). Surprisingly, the triglyceride content (Figure 1D), but not the cholesterol content (Figure 1E), in the patient's atherosclerotic coronary arteries was much higher than that in two control subjects and in two patients with ischemic cardiomyopathy.

To determine the molecular mechanism for this triglyceride deposition, we sequenced the adipose triglyceride lipase gene (ATGL, also known as PNPLA2), which encodes an essential intracellular triglyceride lipase.1 The patient was homozygous for a point mutation in exon 7 of ATGL (c.865C→T; p.Gln289X), which is identical to a mutation reported by Fischer et al.2 in a patient with mild myopathy.

The atherosclerotic lesion that we observed in this patient was unusual3 because the accumulated lipid was triglyceride rather than cholesterol, lipid-laden cells were distributed through all layers of the arterial wall, and the patient had normal plasma triglyceride levels. These phenotypes may result from the mutation in ATGL.4

Ken-ichi Hirano, M.D., Ph.D.
Osaka University, Osaka 565-0871, Japan
khirano@imed2.med.osaka-u.ac.jp

Yoshihiko Ikeda, M.D.
National Cardiovascular Center, Osaka 565-8565, Japan

Nobuhiro Zaima, Ph.D.
Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan

Yasuhiko Sakata, M.D., Ph.D.
Goro Matsumiya, M.D., Ph.D.
Osaka University, Osaka 565-0871, Japan

4 References

1. 1

   Haemmerle G, Lass A, Zimmermann R, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006;312:734-737
   CrossRef | Web of Science | Medline

2. 2

   Fischer J, Lefevre C, Morava E, et al. The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 2007;39:28-30
   CrossRef | Web of Science | Medline

3. 3

   Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med 1999;340:115-126
   Full Text | Web of Science | Medline

4. 4

   Schweiger M, Schoiswhol G, Lass A, et al. The C-terminal region of human adipose triglyceride lipase affects enzyme activity and lipid droplet binding. J Biol Chem 2008;283:17211-17220
   CrossRef | Web of Science | Medline

Citing Articles (13)

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   G Wölkart, A Schrammel, K Dörffel, G Haemmerle, R Zechner, B Mayer. (2012) Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist. British Journal of Pharmacology 165:2, 380-389
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   Rosalind A. Coleman, Douglas G. Mashek. (2011) Mammalian Triacylglycerol Metabolism: Synthesis, Lipolysis, and Signaling. Chemical Reviews 111:10, 6359-6386
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9. 9

   T. Skuban, T. Klopstock, B. Schoser. (2010) Lipidspeichermyopathien. Der Nervenarzt 81:12, 1460-1466
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    Ryan T. Birse, Joan Choi, Kathryn Reardon, Jessica Rodriguez, Suzanne Graham, Soda Diop, Karen Ocorr, Rolf Bodmer, Sean Oldham. (2010) High-Fat-Diet-Induced Obesity and Heart Dysfunction Are Regulated by the TOR Pathway in Drosophila. Cell Metabolism 12:5, 533-544
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    Ken-ichi Hirano. (2009) A Novel Clinical Entity: Triglyceride Deposit Cardiomyovasculopathy Implications and Perspectives from ''Obesity of the Heart''. Journal of Atherosclerosis and Thrombosis 16:5, 702-705
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