Short-Term Toll-Like Receptor 9 Inhibition Leads to Left Ventricular Wall Thinning After Myocardial Infarction

Q: What is the clinical evidence from this study?

Population: Myocardial ischaemia-reperfusion injury (IRI) in a rat model (n=49). Intervention: Oligonucleotide (ODN) 2088 (Toll-like receptor 9 antagonist) or DNase-1 vs. Control-ODN (400 μg bolus plus 66.667 μg/h for 24 h via mini-osmotic pump) or sham (physiological saline solution). Primary outcome: Left ventricular wall thickness at 4 weeks after ischaemia-reperfusion (p=0.003).

Q: What does this research mean for the field?

Short-term pharmacological inhibition of TLR9 during myocardial ischaemia-reperfusion leads to enhanced neutrophil infiltration and significant left ventricular wall thinning. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Max Lenz; Attila Kiss; Patrick Haider; Manuel Salzmann; Mira Brekalo; Konstantin A. Krychtiuk; Ouafa Hamza; Kurt Huber; Christian Hengstenberg; Bruno K. Podesser; Johann Wojta; Philipp J. Hohensinner; Walter S. Speidl

doi:10.1002/ehf2.14403

May 16, 2023ESC Heart FailureOpen Access

Short-Term Toll-Like Receptor 9 Inhibition Leads to Left Ventricular Wall Thinning After Myocardial Infarction

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Key result

Short-term TLR9 inhibition with ODN 2088 reduced left ventricular wall thickness at 4 weeks after ischaemia-reperfusion compared with control-ODN.

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Why the study?

Ischaemia-reperfusion injury after myocardial infarction remains challenging in acute cardiac care, with neutrophil infiltration and neutrophil-mediated cellular damage thought to aggravate primary tissue injury. Toll-like receptor 9 is involved in neutrophil activation and chemotaxis, making its pharmacological inhibition a potential target for modulating ischaemia-reperfusion injury.

Does short-term pharmacological inhibition of Toll-like receptor 9 with ODN 2088 during the first 24 hours of reperfusion affect left ventricular remodelling and neutrophil infiltration after myocardial ischaemia-reperfusion injury in rats?

Key Points

To examine the effects of transient pharmacological inhibition of toll-like receptor 9 on neutrophil infiltration and ventricular remodeling during ischaemia–reperfusion injury.
In 49 male Sprague–Dawley rats, myocardial ischaemia–reperfusion injury was induced by 30 min of left coronary artery occlusion followed by reperfusion.
Animals received a 400 μg intravenous bolus of the toll-like receptor 9 inhibitor ODN 2088, control-ODN, or DNase, followed by continuous delivery via mini-osmotic pump (66.667 μg/h) for 24 h.
Hearts were assessed at 24 h or 4 weeks post-reperfusion by echocardiography, histological and immunohistochemical staining, and circulating troponin T quantification.
Inhibition with ODN 2088 significantly decreased left ventricular wall thickness at 4 weeks compared with control-ODN (0.888 mm ± 0.334 mm vs. 2.089 mm ± 0.633 mm, P = 0.003) and reduced left ventricular mass (82.2% ± 9.6% vs. 100% ± 8.7%, P = 0.011).
ODN 2088-treated rats exhibited larger areas of neutrophil infiltration at 24 h compared with control-ODN (18.77% ± 4.271% vs. 10.56% ± 4.71%, P = 0.005) and an increased estimated infarct area (21.35% ± 5.69% vs. 7.05% ± 3.81%, P < 0.001).
Receptor inhibition was accompanied by up-regulation of the chemotactic receptor CXCR2 (P = 0.046) and elevated circulating troponin T levels (73.56 ± 24.65 pg/mL vs. 43.10 pg/mL ± 20.01 pg/mL in control-ODN), with no changes observed in monocyte content.

Structured PICO

Does short-term pharmacological inhibition of Toll-like receptor 9 with ODN 2088 during the first 24 hours of reperfusion affect left ventricular remodelling and neutrophil infiltration after myocardial ischaemia-reperfusion injury in rats?

P

Population

49 male adult Sprague-Dawley rats (10-12 weeks old, 260-400 g) subjected to 30-minute left coronary artery occlusion and reperfusion (n=46) or sham surgery (n=3), followed for 24 hours or 4 weeks.

I

Intervention

Oligonucleotide (ODN) 2088 (TLR9 antagonist) administered at onset of reperfusion as a 400 μg IV bolus via the femoral vein followed by 66.667 μg/h (1600 μg over 24 h) via implanted mini-osmotic pump; or DNase-1 (20 μg initial bolus and 20 μg over 24 h).

C

Comparator

Control-ODN (negative control for ODN 2088) administered as a 400 μg bolus and simultaneously 66.667 μg/h for 24 h via mini-osmotic pump, or sham surgery receiving 400 μL physiological saline bolus and saline-filled mini-osmotic pump.

O

Outcome

Left ventricular (LV) wall thickness (thinning) measured histologically 4 weeks after ischaemia-reperfusion.surrogate

Main Result

Absolute Event Rate: 0.888% vs 2.089%

p-value: p=0.003

Short-term pharmacological TLR9 inhibition during the first 24 hours after myocardial ischaemia-reperfusion prevents CXCR2 down-regulation, exacerbating neutrophil infiltration, acute myocardial damage, and subsequent left ventricular wall thinning in rats.

Limitations

Use of male rats only, representing a potential selection bias due to the lacking representation of female physiology
ODN 2088 was also reported to interact with TLR7 and TLR8, so TLR7- and TLR8-mediated effects leading to adverse remodelling cannot be ruled out
The use of male rats only represents a potential selection bias due to the lacking representation of female physiology
ODN 2088 is reported to also interact with and inhibit TLR7 and TLR8, so TLR7- and TLR8-mediated effects leading to adverse remodelling cannot be ruled out

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Implication

TLR9 inhibition may worsen post-MI remodeling in rats; hypothesis-generating and should not change practice.

Abstract

Aims Ischaemia–reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long-term consequence. The extent of neutrophil infiltration and neutrophil-mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll-like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor. Methods and results Forty-nine male adult Sprague–Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30 min. Oligonucleotide (ODN) 2088, a toll-like receptor 9 (TLR9) antagonist, control-ODN, or DNase, were administered at the time of reperfusion and over 24 h via a mini-osmotic pump. The hearts were harvested 24 h or 4 weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4 weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P = 0.003) in association with drastically enhanced neutrophil infiltration (P = 0.005) and increased markers of tissue damage. Additionally, an up-regulation of the chemotactic receptor CXCR2 (P = 0.046) was found after TLR9 inhibition. No such effects were observed in control-ODN or DNase-treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury. Conclusions Our data indicate a TLR9-dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down-regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR−/− mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24 h following IRI.

Discussion

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Cite This Study

Lenz et al. (2023) studied Myocardial ischaemia-reperfusion injury (IRI) in a rat model (n=49). Oligonucleotide (ODN) 2088 (Toll-like receptor 9 antagonist) or DNase-1 vs. Control-ODN (400 μg bolus plus 66.667 μg/h for 24 h via mini-osmotic pump) or sham (physiological saline solution) was evaluated on Left ventricular wall thickness at 4 weeks after ischaemia-reperfusion (p=0.003). Short-term TLR9 inhibition with ODN 2088 reduced left ventricular wall thickness at 4 weeks after ischaemia-reperfusion compared with control-ODN.

synapsesocial.com/papers/6a9056c46419f6799027a3e0 https://doi.org/10.1002/ehf2.14403

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Short-Term Toll-Like Receptor 9 Inhibition Leads to Left Ventricular Wall Thinning After Myocardial Infarction

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Short-Term Toll-Like Receptor 9 Inhibition Leads to Left Ventricular Wall Thinning After Myocardial Infarction

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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