Abstract
Summary
Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable disease characterized by massive triglyceride (TG) accumulation in the myocardium and coronary arteries caused by genetic or acquired dysfunction of adipose TG lipase (ATGL). A phase IIa trial has been conducted involving patients with idiopathic TGCV using CNT-01 (tricaprin/trisdecanoin) by the Japan TGCV study group, which showed that CNT-01 improved myocardial lipolysis as demonstrated by iodine-123-beta-methyl iodophenyl-pentadecanoic acid (BMIPP) scintigraphy. We evaluated changes in myocardial TG content using proton magnetic resonance spectroscopy (1H-MRS) before/after CNT-01. This report describes a male patient with hypertension, diabetes, angina pectoris, repeated percutaneous coronary intervention, chest pain, and exertional dyspnea that persisted despite standard medications and nitroglycerin. Idiopathic TGCV was diagnosed based on a remarkably reduced washout rate (WR) for BMIPP scintigraphy, high myocardial TG content on 1H-MRS, and no ATGL mutation. After an 8-week, 1.5 g/day CNT-01 administration, the WR of BMIPP increased from 5.1 to 13.3% and the myocardial TG content decreased from 8.4 to 5.9%, with no adverse effects. CNT-01 corrected myocardial lipolysis and subsequently reduced TG content in idiopathic TGCV as evaluated using 1H-MRS, which may be a useful, noninvasive evaluation of therapeutic efficacy.
Learning points
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Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable disease characterized by massive triglyceride accumulation in the myocardium and coronary arteries, caused by genetic or acquired dysfunction of adipose triglyceride lipase.
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Japan TGCV Study Group developed a specific treatment for idiopathic TGCV using CNT-01 (tricaprin/trisdecanoin), a type of medium-chain fatty acid.
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CNT-01 corrected myocardial lipolysis and reduced TG content in idiopathic TGCV using proton magnetic resonance spectroscopy, which may be a useful noninvasive evaluation of therapeutic efficacy.
Background
Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable disease characterized by massive triglyceride (TG) accumulation in the myocardium and coronary arteries, caused by genetic or acquired dysfunction of adipose TG lipase (ATGL) (1). This process leads to congestive heart failure and ischemic heart disease (2). Per the Japan TGCV Study Group, TGCV diagnostic criteria include impaired long-chain fatty acid (LCFA) metabolism on myocardial scintigraphy with iodine-123-β-methyl iodophenyl-pentadecanoic acid (BMIPP) or myocardial TG deposition on magnetic resonance spectroscopy (MRS) or biopsy (3). This group developed a specific treatment for TGCV using tricaprin/trisdecanoin, the TG form of capric acid, a type of medium-chain fatty acid (MCFA). A tricaprin/trisdecanoin diet facilitated myocardial lipolysis, reduced lipid deposition, and improved left ventricular (LV) function in an ATGL knockout mouse model for TGCV, suggesting tricaprin/trisdecanoin may be useful to treat TGCV (4, 5).
Osaka University Hospital manufactured CNT-01, which was used in a multicenter, placebo-controlled, double-blind, phase IIa study of idiopathic TGCV (UMIN000035403). It has been reported that CNT-01 improved myocardial lipolysis in idiopathic TGCV (6).
Our study evaluated changes in BMIPP washout rate (WR) and myocardial TG content using proton magnetic resonance spectroscopy (1H-MRS) in a patient with idiopathic TGCV after CNT-01 administration.
Case presentation
An 86-year-old man presented with hypertension, diabetes, exercise-induced angina pectoris, repeated percutaneous coronary intervention, persistent chest pain and exertional dyspnea despite standard medications and nitroglycerin. At the age of 82 years, coronary angiography showed multiple stenoses and diffuse narrowing of right and left coronary arteries (Fig. 1A). The BMIPP scintigraphy WR was 7.8%; (3) idiopathic TGCV was diagnosed. No ATGL mutation was identified. Cardiac magnetic resonance imaging (MRI) showed normal LV contraction, normal myocardial mass, and no delayed enhancement. Myocardial TG content was 3.21% using 1H-MRS (Fig. 1B and C). The patient was referred to our hospital 1 year later for phase IIa trial treatment with CNT-01.
Imaging examinations for TGCV. (A) Coronary angiogram. RCA, right coronary artery (left anterior oblique 30° and cranial 30° views); LCA, left coronary artery (cranial 45° view and caudal 30° view). (B) Myocardial voxel localization for proton magnetic resonance spectroscopy (1H-MRS) in four-chamber and short-axis views. A volume of interest (1 × 1 × 2 cm3) was localized within the ventricular septum from the systolic phase of cine-mode images. (C) 1H-MR spectra without and with water suppression. The left panel shows that water signals were acquired at 4.7 ppm from spectra without water suppression. The right panel shows that lipids signals were acquired at 1.4 ppm from spectra with water suppression. Myocardial triglyceride content was calculated as a ratio of lipid to water (%). (D) Bull’s eye images of iodine-123-β-methyl iodophenyl-pentadecanoic acid (BMIPP) scintigrams before CNT-01 administration: washout rate, 5.1%. (E) Bull’s eye images of BMIPP scintigrams after CNT-01 administration: washout rate, 13.3%.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0370
Before CNT-01 administration, the patient was taking multiple drugs (Table 1). Height was 157 cm; weight was 60 kg. The heart rate was 54 beats/min, blood pressure 132/78 mmHg, respiratory rate 18 breaths/min, and oxygen saturation 98% in room air. Lung sounds were bilaterally clear. A systolic murmur was auscultated loudest at the second right sternal border. No lower limb edema was noted.
Serial changes in clinical and laboratory parameters before and after CNT-01 administration.
Before | After | |
---|---|---|
Body weight (kg) | 60 | 59.8 |
Systolic blood pressure (mmHg) | 132 | 122 |
Diastolic blood pressure (mmHg) | 78 | 78 |
Pulse rate (beats/min) | 54 | 56 |
Laboratory data | ||
Hemoglobin (g/dL) | 12.8 | 13.3 |
Total protein (g/dL) | 6.6 | 6.6 |
Albumin (g/dL) | 4.0 | 3.9 |
AST (U/L) | 14 | 17 |
ALT (U/L) | 12 | 16 |
γ-GTP (U/L) | 25 | 23 |
Creatinine (mg/dL) | 0.77 | 0.84 |
eGFR (mL/min/1.73 m2) | 71.9 | 65.4 |
Total cholesterol (mg/dL) | 131 | 128 |
HDL cholesterol (mg/dL) | 48 | 46 |
LDL cholesterol (mg/dL) | 59 | 73 |
Triglyceride (mg/dL) | 51 | 44 |
Casual blood glucose (mg/dL) | 123 | 125 |
Hemoglobin A1c (%) | 6.0 | 6.4 |
BNP (pg/mL) | 172 | 106 |
Cardiac MRI variables | ||
LVEDV (mL) | 109.5 | 118.8 |
LVESV (mL) | 37.7 | 41.9 |
Stroke volume (mL) | 71.8 | 76.8 |
Ejection fraction (%) | 65.6 | 64.7 |
LV myocardial mass (g) | 126.1 | 115.6 |
Myocardial TG content (%) | 8.4 | 5.9 |
WR of BMIPP (%) | 5.1 | 13.3 |
NYHA functional classification | Ⅱ | Ⅱ |
Six-minute walk distance (m) | 165 | 120 |
Medication | ||
Aspirin | 100 mg | |
Bisoprolol | 2.5 mg | |
Benidipine | 8 mg | |
Telmisartan | 40 mg | |
Rosuvastatin | 2.5 mg | |
Isosorbide dinitrate | 40 mg | |
Nicorandil | 15 mg | |
Linagliptin | 5 mg |
γ-GTP, γ-glutamyl transpeptidase; ALT, alanine transaminase; AST, aspartate transaminase; BMIPP, iodine-123-β-methyl iodophenyl-pentadecanoic acid; BNP, B-type natriuretic peptide; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; MRI, magnetic resonance imaging; NYHA, New York Heart Association; TG, triglyceride; WR, washout rate.
Investigations
Chest radiography revealed slight cardiomegaly (cardio-thoracic ratio 51%). Electrocardiography confirmed first-degree atrioventricular block. No anemia was present; renal function was normal. High-density lipoprotein cholesterol (HDL-C) was 48 mg/dL, low-density lipoprotein cholesterol (LDL-C) 59 mg/dL, and serum TG 51 mg/dL. Hemoglobin A1c (HbA1c) was well controlled at 6.0%. Brain natriuretic peptide serum concentration was 172 pg/mL. Transthoracic echocardiography showed normal LV systolic function (estimated ejection fraction 69%), and calcified aortic valve with mild stenosis. No LV hypertrophy was detected. The BMIPP WR was 5.1% (Fig. 1D); myocardial TG content using 1H-MRS was 8.4%.
Treatment
The patient was orally administered 1.5 g/day of CNT-01 for 8 weeks. We evaluated changes in BMIPP WR and myocardial TG content using 1H-MRS before/after CNT-01.
Outcome and follow-up
After 8-week CNT-01 administration, no adverse effects occurred during follow-up. Weight was 59.8 kg, heart rate 56 beats/min, blood pressure 122/78 mmHg, HDL-C 46 mg/dL, LDL-C 73 mg/dL, serum TG 44 mg/dL, HbA1c 6.4%, and brain natriuretic peptide serum concentration 106 pg/mL. The BMIPP WR increased to 13.3% (Fig. 1E). On MRI, LV ejection fraction was not significantly changed, but LV myocardial mass was slightly decreased. Myocardial TG content decreased to 5.9%. New York Heart Association class was II with no changes after administration. Table 1 summarizes clinical and laboratory changes before/after CNT-01 administration.
Discussion
The BMIPP WR improved and myocardial TG accumulation decreased by 1H-MRS after CNT-01 administration in idiopathic TGCV. In TGCV, ectopic TG accumulation in cardiomyocytes and smooth muscle cells occurs due to abnormal intracellular TG and LCFA metabolism (1, 2). Some LCFAs (a major energy source in the normal heart) taken up by cardiomyocytes are immediately incorporated into the cytoplasmic TG pool; subsequently, intracellular lipases, such as ATGL, hydrolyze TG to release LCFAs, which are oxidized in mitochondria to produce ATP. However, in TGCV, caused by deficient ATGL activity, LCFAs are taken up and used to synthesize TG that cannot be hydrolyzed, leading to TG deposition, lipotoxicity, and energy failure (2).
The BMIPP WR is an essential indicator for the diagnosis of TGCV – a decrease indicates impaired myocardial lipolysis and TG deposition (5, 7). This patient had a WR of BMIPP decreased to 7.8% and myocardial TG content on 1H-MRS of 3.21%, which indicates impaired myocardial lipolysis and myocardial TG accumulation.
The MCFAs are readily oxidized by cells, including cardiomyocytes, as a very efficient source of energy production (8). Absorbed in the small intestine and directly transported via the portal vein, MCFAs are rapidly degraded by β-oxidation in the liver. Capric acid is used and oxidized as an alternative energy source for LCFAs in an ATGL-deficient state (9). Intracellular metabolism of MCFAs differs from LCFAs, and MCFAs are rapidly metabolized by β-oxidation in mitochondria, indicating that a tricaprin diet facilitated myocardial lipolysis, reduced fat deposition, and improved myocardial LV function in ATGL knockout mice (4). These results suggest the tricaprin diet may facilitate myocardial lipolysis and improve BMIPP WR. In this patient, it increased from 5.1 to 13.3% after CNT-01 administration. These results were similar to those in animal experiments, suggesting that MCFAs improved LCFA metabolism and myocardial TG accumulated in the cytoplasm were metabolized to LCFA for energy production.
In TGCV patients, 1H-MRS was useful to detect myocardial TG accumulation (7). We previously validated that myocardial TG content in idiopathic TGCV was extremely high compared with previous reports (10). In parallel with the improved BMIPP WR, myocardial TG content decreased from 8.4 to 5.9%, possibly because this decrease is associated with improved myocardial lipolysis, so 1H-MRS can monitor CNT-01 effects. Myocardial TG content remained high at 5.9% after CNT-01 administration; thus, the long-term CNT-01 treatment effect of TGCV needs further study. Primary TGCV with ATGL mutations has occurred with skeletal myopathy (neutral lipid storage disease) (7), which was not present in our case.
In conclusion, CNT-01 facilitated myocardial lipolysis and reduced TG content in idiopathic TGCV using 1H-MRS, which may be a useful noninvasive evaluation of therapeutic efficacy.
Declaration of interest
K-i Hirano holds the position of Joint Research Chair in collaboration with TOA EIYO LTD since February 2021 and medical adviser of TOA EIYO LTD since December 2021. K-i Hirano received a research grant from Nihon Medi-Physics Co. Ltd. Others have no conflict to declare.
Funding
This work was supported by research grants for rare diseases from the Japan Agency of Medical Research and Development (AMED) (18ek0109335h001) and the Ministry of Health, Labour, and Welfare, Japan (20FC1008).
Patient consent
Written informed consent has been obtained from the patient to publish this paper.
Author contribution statement
Conceptualization: TA, ES, SF, KS and KH; Methodology: TA, ES, SF, KS and KH; Formal analysis: TA, AK, YOK, KT, MH, TY and TM; Investigation: TA, AK, YOK, KT, MH, TY, TM and KS; Writing – Original Draft Preparation: TA and ES; Writing – Review & Editing: ES, TM, SF, KS, KH, HD and Tohru M; Supervision: KH, HD and Tohru M; Project Administration: SF, KS and KH; Funding Acquisition: KH; all authors read and approved the final manuscript.
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