Triglyceride (TG) deposit cardiomyovasculopathy (TGCV) was first identified in Japanese patients with homozygous mutations in PNPLA2 encoding adipose triglyceride lipase. TGs and fatty acids released by lipolytic action are major energy substrates in a normal heart. In TGCV, the defective intracellular lipolysis of long-chain TGs causes cellular steatosis and energy failure mainly in cardiomyocytes and vascular smooth muscle cells. One of the major characteristics is diffuse narrowing TG-deposited coronary atherosclerosis which is distinct from classic cholesterol-induced focal lesions. TGCV comprises primary and idiopathic subtypes with and without homozygous PNPLA2 mutations, respectively. Genetic causes or backgrounds of idiopathic TGCV (I-TGCV) remain undetermined. We established the diagnostic criteria without requirement of genetic tests, including the reduced washout rate (<10%) of iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid in myocardial single-photon emission computed tomography, which reflects defective lipolysis, as an essential item. Serum TG level and body mass index are irrelevant to the diagnosis. As of October 2024, 15 primary TGCV (P-TGCV) and 976 I-TGCV cases were diagnosed across all Japanese prefectures. The cardiac symptoms of P-TGCV and I-TGCV occurred in patients aged in their 30s and 50s, respectively. The patients exhibited heart failure (HF), diffuse coronary artery disease including vasospastic angina, and ventricular arrhythmia. The prognosis was very severe in patients with P-TGCV manifesting HF with reduced ejection fraction unless receiving cardiac transplantation. In I-TGCV, the 5-year-overall and cardiovascular event-free survival rates were 71.8% and 54.0%, respectively, with standard remedies. Tricaprin/trisdecanoin, a medium-chain TG that facilitates myocardial lipolysis, is being developed as a first-in-class orphan drug for TGCV. TGCV is a novel class of adult-onset cardiovascular disease caused by the defective lipolysis of long-chain TGs. Many patients with TGCV exhibiting high cardiovascular risk remain undiagnosed; thus, increased awareness of this emerging disease is required among cardiologists of all subspecialties.
