Intractable Coronary Artery Disease in a Patient With Type 2 Diabetes Presenting With Triglyceride Deposit Cardiomyovasculopathy

• A 51-year-old man with sudden cardiac death despite multiple percutaneous coronary interventions (PCIs) and coronary artery bypass graft surgery

• The patient was overweight since adolescence and diagnosed with type 2 diabetes at age 26

• Severely deteriorated insulin sensitivity indicated by the rate constant for plasma glucose disappearance by the insulin tolerance test (K_ITT) (0.87%) and endogenous hyperinsulinemia suspected from total daily urinary C-peptide excretion (242.8 μg) at age 35. K_ITT value progressively deteriorated to 0.49, 0.32, and 0.25% at ages 38, 39, and 40, respectively

• High dosage (320 units) of total daily insulin injection at age 49

• Acute myocardial infarction at age 36 and multiple PCIs at ages 36, 47, and 48

• Diffuse narrowing of coronary arteries accompanying abundant triglyceride deposition within coronary wall demonstrated by coronary computed tomography (CT) angiography with color-coded display

• A remarkably reduced washout rate (−11%) in myocardial scintigraphy with [¹²³I]-β-methyl iodophenyl-pentadecanoic acid (BMIPP) at age 50

• The above two features were consistent with triglyceride deposit cardiomyovasculopathy (TGCV)

• His younger brother also died of acute myocardial infarction at age 38

• He had nonalcoholic steatohepatitis (NASH) and multiple diabetic microvascular complications, including visual loss and end-stage nephropathy

The patient was a 51-year-old man who had been overweight since adolescence and was diagnosed with type 2 diabetes at age 26. He had been treated with a sulfonylurea, but his glycemic control was poor. When his medication was replaced with insulin injection at age 35, K_ITT, a marker of insulin sensitivity (1), was severely deteriorated to 0.87%, and resulting endogenous hyperinsulinemia was suspected from total daily urinary C-peptide excretion (242.8 μg). At that time, he was overweight by BMI (27.1 kg/m²). Lipid profiles showed mild hypertriglyceridemia with apolipoprotein E3/3 phenotype. His K_ITT value progressively deteriorated to 0.49, 0.32, and 0.25% at ages 38, 39, and 40, respectively, which were extremely low values compared with our previous data from Japanese patients with type 2 diabetes (2). His total daily insulin dosage was 28 units initially and increased to 320 units owing to severe insulin resistance at age 49. He was diagnosed with NASH by liver biopsy at age 40 and showed liver cirrhosis at age 49 (Fig. 1A). He lost left visual acuity at age 41 and received hemodialysis at age 43 due to diabetic microvascular complications.

The patient underwent PCI for ST-segment elevation myocardial infarction in the right coronary artery (RCA) at age 36. However, his frequent chest pain, discomfort, and palpitations due to ventricular tachycardia persisted and remained intractable under standard medication including hypolipidemic drugs (Fig. 1B). He underwent PCI twice, at ages 47 (for proximal RCA) and 48 (for left anterior descending artery [LAD]). Coronary angiography at age 50 showed multiple significant stenoses in the middle RCA, distal LAD, and proximal left circumflex artery in addition to in-stent restenosis in the middle LAD (Fig. 1C). Finally, he underwent coronary artery bypass graft surgery at age 51.

The clinical features of this patient were quite peculiar, as follows: 1) relatively early onset and long duration of type 2 diabetes; 2) overweight since adolescence; 3) severely deteriorated insulin sensitivity, leading to hyperinsulinemia; 4) requirement of high dosage of insulin injections for glycemic control; 5) advanced diabetic microvascular complications; 6) comorbidity for NASH as a sign of ectopic triglyceride (TG) deposition; 7) premature coronary artery disease (CAD), resistant to multiple PCIs; and 8) a positive family history in that his younger brother died of myocardial infarction at age 38.

TGCV is a novel disease concept where the abnormal intracellular metabolism of TG results in ectopic TG deposition in vascular smooth muscle cells (SMCs) and cardiomyocytes, leading to a novel type of TG-deposit atherosclerosis with diffuse narrowing of coronary arteries and heart failure (3,4). SMCs with TG deposits exhibit proinflammatory and vulnerable phenotypes in vitro (5). The first identified patient who required cardiac transplantation carried a rare genetic mutation of PNPLA2 encoding adipose triglyceride lipase (ATGL), a rate-limiting enzyme of intracellular TG hydrolysis (3). Our retrospective postmortem studies also identified patients with diabetes with TGCV phenotype but with a conserved ATGL expression who died of severe CAD and heart failure (6). To elucidate the underlying mechanism and pathophysiology of severe CAD associated with diabetes, we analyzed whether the case patient presented the phenotype of TGCV.

Myocardial scintigraphy with BMIPP, a radioactive analog for long-chain fatty acid that can detect abnormal TG metabolism (7), revealed that the washout rate of BMIPP was remarkably reduced to −11% at age 50 (reference value, 19.4 ± 3.2%) (Fig. 1D). We applied coronary CT angiography with color-coded display (7) to this patient. This technique we had developed enabled us to differentiate coronary lesions in TGCV patients with PNPLA2 mutation from those in non-TGCV patients and control subjects (7). As shown in Video 1 with separated still images, abundant TG deposition can be observed as orange/yellow areas within this patient’s coronary arterial walls, distributing mainly in the adventitial side and protruding from outside to inside in a nodular, peninsular, or bridging pattern. These imaging data were consistent with those of TGCV patients with PNPLA2 mutations (7,8).

Furthermore, we planned a detailed analysis of ATGL activities and genetic tests for PNPLA2; the LIPE encoding hormone-sensitive lipase, which is another important intracellular lipase; and PNPLA3, a gene responsible for NASH. Unfortunately, however, the patient died suddenly before these analyses.

TG is a major energy source for the normal heart, in which TG is hydrolyzed by the action of intracellular lipases such as ATGL and hormone-sensitive lipase and released long-chain fatty acids are oxidized to produce ATP. Basic and clinical studies showed that these lipase activities and expressions can be regulated by insulin (9,10). Even though the exact mechanism could not be clarified, the long-term severe insulin resistance and resulting hyperinsulinemia in addition to high-dosage insulin injections might have partly contributed to the ectopic TG deposition and manifestation of TGCV phenotype in this patient. As CAD is a major cause of death in patients with diabetes worldwide, it would be of significance to determine the prevalence of TGCV among patients with diabetes with intractable CAD.

Acknowledgments. The authors thank Drs. Hiromi Iwahashi (Department of Metabolic Medicine and Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University), Yoshihiro Kamada (Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University), Hiroaki Naito (Department of Diagnostic and Interventional Radiology, Nippon Life Hospital), Ming Li (Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics [CNT], Graduate School of Medicine, Osaka University), Yoshihiko Ikeda (Department of Pathology, National Cerebral and Cardiovascular Center), and Yuichi Motoyama (Department of Pathology, Graduate School of Medicine, Osaka University) for their important comments according to their specialties.

Funding. This study was partially supported by research grants from the Ministry of Health, Labour and Welfare of Japan and the Japan Agency for Medical Research and Development (grant no. 17ek0109092h0003). This study was also supported by Nihon Medi-Physics Co., Ltd., in the form of donated supplies to K.-i.H.

Duality of Interest. K.-i.H. has a license for patent WO2013031729. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. J.K., M.H., and K.-i.H. wrote the manuscript. J.K. took care of the patient. I.S. contributed to the discussion. K.-i.H. is the principal investigator for the Japan TGCV study group. M.H. is the guarantor of and takes responsibility for the coronary CT angiography with color-coded display. J.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data (other than the coronary CT angiography with color-coded display) and the accuracy of the data analysis.