TGCV and atherosclerosis

The principal disorder in TGCV is defective intracellular lipolysis, which causes excessive triglyceride accumulation in the myocardium and coronary artery vascular smooth muscle cells, leading to heart failure and coronary artery disease with a poor prognosis.

The total number of patients diagnosed with TGCV in Japan between 2008 and 2014 was <10 according to a report published by the Japan TGCV study group.4 Thereafter, the number increased to 226; among whom, 45 were deceased by the end of 2019, indicating a high-risk profile. The rapid increase in the number of patients might have been partly due to the fact that the diagnostic criteria have piqued public and cardiologist interest in enhancing awareness of TGCV. The prevalence of TGCV awareness is low outside of Japan. Diffuse atherosclerotic lesions associated with multivessel coronary artery disease should be carefully excluded by identifying coronary artery narrowing using coronary CT and coronary angiography. Atherosclerotic lesions due to familial hypercholesterolemia can be differentiated by serum lipid profiles. Other disease entities that require exclusion include4 hypertrophic, dilated, arrhythmogenic right ventricular, diabetic and mitochondrial cardiomyopathies, alcoholic heart disease, metabolic myocardial disorders such as Fabry, Pompe, Danon, mitochondrial and cholesteryl ester storage diseases and a CD36 deficiency, as well as a drug-induced or dialysis-associated carnitine deficiency, and excessive epicardial fat deposition.

Prognosis of TGCV and haemodialysis

Onishi et al reported the prevalence and prognosis of TGCV among patients on haemodialysis in this issue of Heart.5 The prevalence of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death for patients with definitive TGCV was 53% in contrast to patients without TGCV (9%). The 20% frequency of definitive TGCV in patients with haemodialysis and suspected of having coronary artery disease might have been partly attributed to author selection bias for iodine-123-β-methyl-iodophenyl pentadecanoic acid (¹²³I-BMIPP) imaging and a diagnosis of diffuse coronary artery narrowing. Thus, whether the frequency of TGCV can be extrapolated to patients on haemodialysis in other communities and nations is not clear. In addition, their study was based on diagnostic criteria defined in 2016, when myocardial triglyceride deposition or impaired long-chain fatty acid (LFCA) metabolism and diffuse coronary narrowing were considered as major components (two points each), whereas the Jordan anomaly and diabetes were considered as minor components (one point each). Scores of ≥4 and 3 were taken as definitive and probable TGCV, respectively. The 2020 diagnostic criteria for TGCV include the modifications discussed below (box 1). However, their diagnosis of definitive TGCV would not be changed even with the new criteria, and the present study suggests that a diagnostic combination of ¹²³I-BMIPP and diffuse narrowing of coronary arteries is effective for the diagnosis.

¹²³I-BMIPP fatty acid imaging

Long-chain fatty acids (LCFA) comprise the major energy source of the normally contracting heart. They are incorporated into the cellular triglyceride pool after uptake into cardiomyocytes (figure 1A), with enzymes such as adipose triglyceride lipase and hydrolyse triglycerides. Released fatty acid is subsequently oxidised in the mitochondria to produce ATP. Metabolic processes can be visualised using the unique radiotracer, ¹²³I-BMIPP. This tracer has been widely applied in Japan since the Ministry of Health and Welfare approved ¹²³I-BMIPP with wide indications for cardiac diseases in 1993. After uptake into myocytes, ¹²³I-BMIPP is transferred to the triglyceride pool and then to mitochondria, but it is not immediately metabolised by β oxidation, due to having branched structures in the beta position. It is therefore regarded as a retention-type radiotracer that undergoes slow α oxidation followed by β oxidation, which differs from LCFA that are a major cardiac source of energy. However, slow clearance from the heart is convenient for nuclear single-photon emission CT (SPECT) imaging. Images are obtained early (15 min) and late (3–4 hours) after intravenous injection of the tracer to calculate washout rates. The average washout rate in 3 hours is 10%–30% in coronary artery disease and even under normal conditions. Thus, a low washout rate (<10%) can be an important indicator of TGCV metabolism. While reduced ¹²³I-BMIPP clearance might have a diagnostic role in TGCV, BMIPP kinetics are not yet fully understood and are considered to be a composite of backdiffusion, α and β oxidation and intermediate metabolites. Since washout can vary depending on the algorithm used to calculate it, a standardised method applicable to heterogeneous distribution and focal defects should be investigated from a technological viewpoint to determine the optimal diagnostic threshold. Figure 1B,C shows typical ¹²³I-BMIPP clearance in patients with and without TGCV.

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Figure 1

Metabolism of free fatty acid and ¹²³I-BMIPP and typical short-axis ¹²³I-BMIPP images in patients with and without TGCV. FFA and ¹²³I-BMIPP metabolism (A). Early (15 min) and late (3 hours) ¹²³I-BMIPP mid short-axis images of 35-year-old and 58-year-old men with primary TGCV (B) and aortic regurgitation (C), respectively. Actual range of ¹²³I-BMIPP activity is shown as standardised to maximum early count of 100%, and decay for 3 hours is corrected. Uptake is similar in the early and late images of patient with TGCV (B), but reduced in late image of patient without TGCV (C). Calculated washout rates of ¹²³I-BMIPP from whole heart counts were −0.7% and 17%, respectively. Original patient information was provided courtesy of Professor Ken-ichi Hirano, Osaka University, Japan. AMP, adenosine monophosphate; ATGL, adipose triglyceride lipase; ATP, adenosine triphosphate; FFA, free fatty acid; ¹²³I-BMIPP, iodine-123-β-methyl-iodophenyl pentadecanoic acid; TGCV, triglyceride deposit cardiomyovasculopathy.

New diagnostic criteria for TGCV

The revised 2020 diagnostic criteria conformed to this underlying pathophysiology (box 1).4 The essential diagnostic criteria comprise metabolic evidence of very slow or absent triglyceride clearance from the heart determined as ¹²³I-BMIPP washout rates on myocardial SPECT,6 direct histological evidence from biopsy specimens identified in the initial report about the patient1 and evidence of triglyceride deposits determined by X-ray CT or nuclear magnetic resonance (NMR) spectroscopy. The essential items associated with evidence of triglyceride deposition in the new guidelines are emphasised, and heart failure has been added. In addition, the major criteria include reduced left ventricular contractility associated with heart failure, which reflects the experiences of patients with TGCV, during which atypical courses might arise. Diffuse narrowing of coronary arteries with triglyceride deposition is also a feature.7 The Jordan anomaly in peripheral blood smears is also diagnostic, although neutral lipid storage disease with ichthyosis, and a carnitine palmitoyltransferase deficiency can also cause this anomaly. Primary and idiopathic TGCV can be differentially diagnosed based on the presence or absence, respectively, of a typical Jordan anomaly. Since TGCV cannot be diagnosed with conventional serum triglyceride, cholesterol profiles and body mass index, the new guidelines should help physicians to diagnose TGCV effectively.

What is the next step?

A new perspective and diagnostic procedures might be required to diagnose new disease entities. However, the first step is to become aware of a disease and try to visualise it. Even when diagnosed by contemporary techniques, therapeutic intervention will be the next important step. In this context, glyceryl decanoate (tricaprin) has been investigated as a nutritional therapeutic agent,8 as this medium-chain fatty acid eliminates myocardial triglyceride deposition. A diagnosis of TGCV might be more easily promoted using ¹²³I-BMIPP in Japan. However, ¹²³I-BMIPP might also be useful for research applications elsewhere, and the feasibility of approaches using X-ray CT and NMR spectroscopy should also be investigated to extend diagnostic capabilities worldwide. Accumulated experience with TGCV is definitely important to determine the next steps.