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Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress

Veeraveedu PT, Sanada S, Okuda K, Fu HY, Matsuzaki T, Araki R, et al.

Biochem Pharmacol, 2017 Aug 15;138:73-80.
PMID: 28450225 DOI: 10.1016/j.bcp.2017.04.022

BACKGROUND AND PURPOSE: ST2 is one of the interleukin (IL)-1 receptor family members comprising of membrane-bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non-ischemic HF. Here, we tested whether IL-33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL-33(-/-)) mice.
METHODS AND RESULTS: Transverse aortic constriction (TAC)/sham surgery were carried out in both IL-33 and WT-littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF-α were enhanced in IL-33(-/-) mice than in WT mice. After 8-weeks, IL-33(-/-) mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c-Myc/BNP) molecular markers were also significantly enhanced in IL-33(-/-) mice than those in WT mice.
CONCLUSIONS: We report for the first time that ablation of IL-33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL-33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL-33 in non-ischemic HF.
Fulltext Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats

Okuda K, Fu HY, Matsuzaki T, Araki R, Tsuchida S, Thanikachalam PV, et al.

PLoS One, 2016;11(8):e0160944.
PMID: 27501378 DOI: 10.1371/journal.pone.0160944

Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.
Fulltext An international, stepped wedge, cluster-randomized trial investigating the 0/1-h algorithm in suspected acute coronary syndrome in Asia: the rational of the DROP-Asian ACS study

Inoue K, Chieh JTW, Yeh LC, Chiang SJ, Phrommintikul A, Suwanasom P, et al.

Trials, 2022 Dec 07;23(1):986.
PMID: 36476401 DOI: 10.1186/s13063-022-06907-4

BACKGROUND: More than half of the world's population lives in Asia. With current life expectancies in Asian countries, the burden of cardiovascular disease is increasing exponentially. Overcrowding in the emergency departments (ED) has become a public health problem. Since 2015, the European Society of Cardiology recommends the use of a 0/1-h algorithm based on high-sensitivity cardiac troponin (hs-cTn) for rapid triage of patients with suspected non-ST elevation acute coronary syndrome (NSTE-ACS). However, these algorithms are currently not recommended by Asian guidelines due to the lack of suitable data.
METHODS: The DROP-Asian ACS is a prospective, stepped wedge, cluster-randomized trial enrolling 4260 participants presenting with chest pain to the ED of 12 acute care hospitals in five Asian countries (UMIN; 000042461). Consecutive patients presenting with suspected acute coronary syndrome between July 2022 and Apr 2024 were included. Initially, all clusters will apply "usual care" according to local standard operating procedures including hs-cTnT but not the 0/1-h algorithm. The primary outcome is the incidence of major adverse cardiac events (MACE), the composite of all-cause death, myocardial infarction, unstable angina, or unplanned revascularization within 30 days. The difference in MACE (with one-sided 95% CI) was estimated to evaluate non-inferiority. The non-inferiority margin was prespecified at 1.5%. Secondary efficacy outcomes include costs for healthcare resources and duration of stay in ED.
CONCLUSIONS: This study provides important evidence concerning the safety and efficacy of the 0/1-h algorithm in Asian countries and may help to reduce congestion of the ED as well as medical costs.
Fulltext Correction: An international, stepped wedge, cluster-randomized trial investigating the 0/1-h algorithm in suspected acute coronary syndrome in Asia: the rational of the DROP-Asian ACS study

Inoue K, Chieh JTW, Yeh LC, Chiang SJ, Phrommintikul A, Suwanasom P, et al.

Trials, 2023 May 17;24(1):335.
PMID: 37198646 DOI: 10.1186/s13063-023-07342-9