Association of Triglyceride Deposit Cardiomyovasculopathy With Drug-Eluting Stent Restenosis Among Patients With Diabetes | Acute Coronary Syndromes | JAMA Network Open | JAMA Network
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Figure.  Comparison of ISLL and the Cumulative Distribution Curve of ISLL Between the TGCV and Control Groups
Comparison of ISLL and the Cumulative Distribution Curve of ISLL Between the TGCV and Control Groups

A. ISLL, a parameter determined by caliper measurements using the known diameter of the angiographic catheter as a reference, was significantly higher in the TGCV group than in the control group. B. The cumulative distribution of ISLL revealed a greater value of ISLL in the TGCV group than in the control group. P value was calculated using ANCOVA with the following variables: American College of Cardiology/American Heart Association classification type B2/C, DES type, and TGCV diagnosis. ANCOVA indicates analysis of covariance; DES, drug-eluting stent; ISLL, in-stent late loss; IQR, interquartile range; ISR, in-stent restenosis; TGCV, triglyceride deposit cardiomyovasculopathy. P < .0001 vs control.

Table.  Patients Characteristics, Lesion Characteristics, and QCA and Restenosis Dataa
Patients Characteristics, Lesion Characteristics, and QCA and Restenosis Dataa
1.
Hirano  K, Ikeda  Y, Zaima  N, Sakata  Y, Matsumiya  G.  Triglyceride deposit cardiomyovasculopathy.   N Engl J Med. 2008;359(22):2396-2398. doi:10.1056/NEJMc0805305 PubMedGoogle ScholarCrossref
2.
Li  M, Hirano  KI, Ikeda  Y,  et al; Japan TGCV study group.  Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder.   Orphanet J Rare Dis. 2019;14(1):134. doi:10.1186/s13023-019-1087-4 PubMedGoogle ScholarCrossref
3.
Greenberg  AS, Coleman  RA, Kraemer  FB,  et al.  The role of lipid droplets in metabolic disease in rodents and humans.   J Clin Invest. 2011;121(6):2102-2110. doi:10.1172/JCI46069 PubMedGoogle ScholarCrossref
4.
Ikeda  Y, Zaima  N, Hirano  K,  et al.  Coronary triglyceride deposition in contemporary advanced diabetics.   Pathol Int. 2014;64(7):325-335. doi:10.1111/pin.12177 PubMedGoogle ScholarCrossref
5.
Lin  Y, Chiba  S, Suzuki  A,  et al.  Vascular smooth muscle cells isolated from adipose triglyceride lipase-deficient mice exhibit distinct phenotype and phenotypic plasticity.   Biochem Biophys Res Commun. 2013;434(3):534-540. doi:10.1016/j.bbrc.2013.03.109 PubMedGoogle ScholarCrossref
6.
Singh  R, Kaushik  S, Wang  Y,  et al.  Autophagy regulates lipid metabolism.   Nature. 2009;458(7242):1131-1135. doi:10.1038/nature07976 PubMedGoogle ScholarCrossref
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    Research Letter
    Cardiology
    August 7, 2020

    Association of Triglyceride Deposit Cardiomyovasculopathy With Drug-Eluting Stent Restenosis Among Patients With Diabetes

    Author Affiliations
    • 1Department of Cardiology, Aichi Medical University, Nagakute, Aichi, Japan
    • 2Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics, Triglyceride Research Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
    • 3Fujita Health University School of Medical Science, Kutsukake, Toyoake, Aichi, Japan
    JAMA Netw Open. 2020;3(8):e2012583. doi:10.1001/jamanetworkopen.2020.12583
    Introduction

    Type 2 diabetes remains an independent risk factor for vascular failure even in the setting of advanced medical treatment approaches and technologies for vascular disease, such as percutaneous coronary intervention. Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare cardiovascular disorder caused by defective hydrolysis of intracellular triglycerides and newly encoded as an orphan disease in Europe in 2019 (Orphanet ORPHAcode No. 565612).1,2 Orphan diseases are rare diseases that affect only a small number of individuals. TGCV is characterized by diffuse narrowing of the coronary arteries due to atherosclerosis with triglyceride deposits within the endothelial and smooth muscle cells.1,2 It is well known that diabetes leads to cellular TG deposition3, and our previous postmortem study revealed that some patients with diabetes who had died of cardiovascular diseases exhibited the TGCV phenotype.4 Therefore, we investigated the extent to which a TGCV comorbidity is associated with outcomes after percutaneous coronary intervention in patients with diabetes.

    Methods

    This retrospective single-center cohort study included data from the cardiac catheter database at Aichi Medical University Hospital between May 1, 2010, and March 31, 2018. Among 526 consecutive patients with diabetes implanted with second-generation drug-eluting stents (DESs), which are a type of medical device used in percutaneous coronary intervention, data from 81 patients were allocated to either the TGCV group or the control group for subsequent comparative analyses (eFigure and eTable in the Supplement). The primary end point was a binary in-stent restenosis (ISR) assessed using quantitative coronary angiography. The secondary end points were an in-stent late loss, a parameter used to quantify the degree of neointimal hyperplasia after coronary stenting, a target lesion revascularization, and an evaluation of angiographic ISR morphology. Follow-up coronary angiography was usually performed 8 to 12 months after percutaneous coronary intervention (eMethods in the Supplement). The study protocol was approved by the ethics committee of Aichi Medical University, and written informed consent was obtained from all patients and their families. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Continuous variables were analyzed using t tests and the Mann-Whitney U test; categorical data were analyzed using Fisher exact test. In-stent late loss between the 2 groups was compared using analysis of covariance. Univariate and multivariate logistic regression analyses were performed to study the influence of TGCV on outcomes. Statistical significance was set at a 2-tailed P value <.05. SPSS Statistics software, version 25.0 (IBM Corp), was used for statistical analyses.

    Results

    This cohort study included a total of 81 patients: 7 and 74 patients with and without TGCV, each of them having 15 and 111 lesions, respectively. Overall, the mean (SD) age was 66 (11) years; 63 were men (77.8%) and 18 were women (22.2%) Demographics include Asian race/ethnicity: 7 (100%) in the TGCV group vs 74 (100%) in the control group (P > .99). (Table). In-stent late loss was greater in the TGCV group than in the control group (0.91 mm [interquartile range, 0.27-2.39 mm] vs 0.15 mm [interquartile range, 0.03-0.35 mm]; P < .001) (Figure), with a higher incidence of binary ISR and target lesion revascularization in the former than in the latter group (46.7% vs 9.0% [P < .001] and 33.3% vs 6.3% [P = .006], respectively). Multivariate analysis showed that TGCV was significantly and independently associated with ISR after DES implantation (odds ratio, 5.31; 95% CI, 1.32-21.4; P = .02). Diffuse or occlusive restenosis patterns were more frequent in the TGCV group than in the control group (100.0% vs 20.0%; P = .003).

    Discussion

    To our knowledge, this is the first study to assess the association of TGCV with 1-year outcomes after second-generation DES implantation. Study results suggest that a higher in-stent late loss at the 1-year follow-up, with a subsequently increased rate of ISR, was observed in the TGCV group than in the control group. Furthermore, TGCV was found to be independently associated with ISR even after adjustment for confounding factors. Diffuse or occlusive restenosis morphology was more frequently observed in the TGCV group than in the control group. The plausible mechanisms for the clinical deficiency of DESs in the setting of TGCV may be associated with an increased amount of inflammatory cytokines and growth factors that are expressed in TGCV mouse models.5 Furthermore, mammalian target of rapamycin inhibitors used in DESs might locally affect lipolysis in triglyceride-harboring smooth muscle cells and other vascular cells within the target lesion in TGCV.6 This study has several limitations, including potential bias due to the retrospective nature of the analysis and a small number of patients with TGCV resulting in the multivariate analysis being potentially overadjusted.

    In conclusion, comorbidity of TGCV with diabetes was associated with an increased incidence of vascular failure. These findings warrant future prospective clinical studies with larger cohorts.

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    Article Information

    Accepted for Publication: May 24, 2020.

    Published: August 7, 2020. doi:10.1001/jamanetworkopen.2020.12583

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Nakano Y et al. JAMA Network Open.

    Corresponding Author: Yusuke Nakano, MD, PhD, Department of Cardiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan (nakanoy@aichi-med-u.ac.jp).

    Author Contributions: Drs Nakano and Amano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Nakano, Hirano, Amano.

    Acquisition, analysis, or interpretation of data: Nakano, Suzuki, Hirano, Ando, Takashima, Takahashi.

    Drafting of the manuscript: Nakano, Hirano, Takashima, Amano.

    Critical revision of the manuscript for important intellectual content: Nakano, Suzuki, Hirano, Ando, Takahashi, Amano.

    Statistical analysis: Nakano, Takahashi.

    Obtained funding: Nakano, Hirano.

    Administrative, technical, or material support: Suzuki, Hirano, Takashima, Amano.

    Supervision: Hirano, Ando, Amano.

    Conflict of Interest Disclosures: Dr Hirano reported receiving a licensed patent (WO2013031729) during the conduct of this study and a research grant from Nihon Medi-Physics Co Ltd outside of the submitted work. Dr Nakano reported receiving lecture fees from Otsuka Pharm Co, Ltd, Bristol-Myers Squibb, and Kowa Co, Ltd. and grants from the Japan Society for the Promotion of Science outside of the submitted work. Dr Amano reported receiving lecture fees from Astellas Pharma, AstraZeneca, Bayer, Daiichi Sankyo, and Bristol-Myers Squibb. No other disclosures were reported.

    Funding/Support: This study was supported by grant 17ek0109092h0003 from the Ministry of Health, Labour and Welfare and the Japan Agency of Medical Research and Development (Dr Hirano) and grant 19K11705 from Grant-in-Aid for Scientific Research (Dr Nakano).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank the following collaborators for their support: Toru Niwa, MD, and Ms Kana Yamamoto, BA, assisted in data collection; Katsuhisa Waseda, MD, assisted in interpretation of data; and Hirofumi Ohashi, MD, and Masahiro Shimoda, MD, assisted in data analysis. They received no financial compensation for their contributions outside their normal salaries.

    Additional Information: Dr Hirano is the principle investigator for the Japan Triglyceride Deposit Cardiomyovasculopathy study group.

    References
    1.
    Hirano  K, Ikeda  Y, Zaima  N, Sakata  Y, Matsumiya  G.  Triglyceride deposit cardiomyovasculopathy.   N Engl J Med. 2008;359(22):2396-2398. doi:10.1056/NEJMc0805305 PubMedGoogle ScholarCrossref
    2.
    Li  M, Hirano  KI, Ikeda  Y,  et al; Japan TGCV study group.  Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder.   Orphanet J Rare Dis. 2019;14(1):134. doi:10.1186/s13023-019-1087-4 PubMedGoogle ScholarCrossref
    3.
    Greenberg  AS, Coleman  RA, Kraemer  FB,  et al.  The role of lipid droplets in metabolic disease in rodents and humans.   J Clin Invest. 2011;121(6):2102-2110. doi:10.1172/JCI46069 PubMedGoogle ScholarCrossref
    4.
    Ikeda  Y, Zaima  N, Hirano  K,  et al.  Coronary triglyceride deposition in contemporary advanced diabetics.   Pathol Int. 2014;64(7):325-335. doi:10.1111/pin.12177 PubMedGoogle ScholarCrossref
    5.
    Lin  Y, Chiba  S, Suzuki  A,  et al.  Vascular smooth muscle cells isolated from adipose triglyceride lipase-deficient mice exhibit distinct phenotype and phenotypic plasticity.   Biochem Biophys Res Commun. 2013;434(3):534-540. doi:10.1016/j.bbrc.2013.03.109 PubMedGoogle ScholarCrossref
    6.
    Singh  R, Kaushik  S, Wang  Y,  et al.  Autophagy regulates lipid metabolism.   Nature. 2009;458(7242):1131-1135. doi:10.1038/nature07976 PubMedGoogle ScholarCrossref
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