Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder

Abstract

Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.

Keywords: Adipose triglyceride lipase; Atherosclerosis; Rare disease; Triglyceride metabolism; Triglyceride-deposit cardiomyovasculopathy.

Fig. 1

Pathological analysis of the autopsied heart of a 38-year-old man with TGCV phenotype without PNPLA2 mutation. Panel a The transverse section of the autopsied heart stained with Masson’s trichrome showed circumferential patchy fibrosis of the left ventricular wall. The letters A, L, R, and P denotes anterior, left, right, and posterior, respectively. Panel b Lipid droplets (LDs) stained with oil red O in the cytoplasm of cardiomyocytes. Panel c Immunostaining for ATGL (Cell Signaling, Danvers, MA). Cardiomyocytes showed positive reactivity for ATGL. Panel d Coronary arteries with diffuse concentric-type stenosis. Panel e The transverse section of coronary artery was stained with Masson’s trichrome. Coronary artery revealed intimal thickening and fibroatheromatous lesions. Panel f Double-staining of Sudan black B and α-smooth muscle actin (Dako, Tokyo, Japan). Smooth muscle cells (brown color) with lipid droplet (blue color) distributed diffusely in the media and intima (arrows in Panel f). Asterisk represents the vascular lumen. Panel g TG (m/z 879.7) was identified as green and blue colors depending on the intensity. TG signals were diffusely detected in the arterial wall by imaging mass spectrometry. Green color denotes relatively higher intensity of TG than blue color. Myocardial and coronary TG contents (3.64 and 19.44 mg/g of tissue, respectively) were higher in this patient, compared with each of control group (1.4 ± 1.0, and 6.2 ± 4.8 mg/g of tissue, respectively). The detailed clinical profile of this patient is reported as Case 10 in the reference [29]. Scale bars: 1 cm in Panel a, 20 μm in Panel b and c, 5 mm in Panel d, 1 mm in Panel e, 20 μm in Panel f, 200 μm in Panel g

Fig. 2

Schematic presentation of the disease concept for TGCV

Fig. 3

A pathophysiological model for TGCV. Genetic and acquired ATGL deficiency and other causes result in abnormal intracellular metabolism of TG and LCFA, leading to cardiomyocyte steatosis and TG-deposit SMCs. In normal condition (left panel), LCFA is taken up through LCFA transporters and receptors such as CD36 and some of them are transported to mitochondria for β-oxidation and the remaining LCFAs are utilized as a source for TG and rapidly hydrolyzed by intracellular lipases such as ATGL. In TGCV (right panel), LCFAs are taken up and used for the synthesis of TG which can not be hydrolyzed, leading to massive TG accumulation

Fig. 4

Schemes for cholesterol- (Left) and TG-deposit atherosclerosis (Right). In cholesterol-deposit atherosclerosis, cholesterol (green) accumulates in macrophages, leading to eccentric stenosis. In TG-deposit atherosclerosis, TG (red) accumulates in SMCs, leading to concentric stenosis, which is a major feature of TGCV

Fig. 5

Laboratory and imaging examinations for TGCV. a Representative images of May-Giemsa staining of blood smears were shown from patients with P-TGCV and I-TGCV. b Bull’s eye images for BMIPP scintigrams from patients with P-TGCV and I-TGCV. The first scan was performed 20 min post-injection to determine early BMIPP uptake, and the second scan was performed 200 min later to study delayed uptake using myocardial SPECT after patients were injected with ¹²³I-BMIPP. WOR was calculated with the Hear Risk View-S (HRSV) software as the difference between early and delayed images (reference value, 19.4 ± 3.2%). c A patient with P-TGCV showed numerous vacuoles (Panel a, H&E) in cardiomyocytes that stained positively for oil red O (ORO) (inset in Panel b). Furthermore, no positive reactivity for ATGL observed in any of cell types (Panel b, ATGL). Cardiomyocytes of patients with I-TGCV showed numerous vacuoles (Panel c, HE) filled with stained lipid (inset in Panel d, ORO), whereas positive reactivity for ATGL observed not only in adipocytes but also in cardiomyocytes (arrows in Panel d, ATGL). Scale bars: Panels a-d, 30 μm. d Coronary CT angiograms (CTA) from patients with P-TGCV and I-TGCV are shown. Bars in CTA correspond to Panels a-d, which are short axial sections of the left anterior descending coronary artery. The segmentation of the coronary artery lumen and wall was done using a workstation (Ziostation 2, Ziosoft, Japan). Constitutive components were classified into 4 colors with the original analysis software as follows. Colors indicate the CT number (yellow, − 25–0; orange, 0–40; green, 40–215; red, 215–700 Hounsfield unit [HU] (M@XNET, Tokyo, Japan) in Panels a-d. Yellow or orange areas indicate lipid components, red shows blood, and green shows the arterial wall without calcification or lipids. Black arrows in Panels a, b, and c indicate outside-in protrusion, which is the characteristics for TGCV

Fig. 6

Relationship between TGCV and NLSDs. Comparison of phenotype and genotype between NLSD-I, NLSD-M and TGCV