Low‐intensity pulsed ultrasound attenuates cardiac inflammation of CVB3‐induced viral myocarditis via regulation of caveolin‐1 and MAPK pathways

Q: What are the key findings of this study?

Low-intensity pulsed ultrasound on days 1, 3, and 5 improved 14-day survival from 40% to 70% and attenuated cardiac inflammation in CVB3-induced viral myocarditis mice.

Q: What is the clinical evidence from this study?

Population: Coxsackievirus B3 (CVB3)-induced acute viral myocarditis. Intervention: Low-intensity pulsed ultrasound (LIPUS) vs. Sham LIPUS (ultrasound device applied under 1.2% isoflurane anaesthesia without ultrasound delivery on days 1, 3, and 5). Primary outcome: 14-day survival rate (in VMC + Day 1, 3, 5 LIPUS group vs untreated VMC group) (p=0.013).

Q: What does this research mean for the field?

Low-intensity pulsed ultrasound treatment significantly improves survival and attenuates cardiac inflammation in CVB3-induced viral myocarditis by upregulating caveolin-1 and suppressing MAPK signaling pathways. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Cheng Zheng; Senmin Wu; Hao Lian; Yuan‐Zheng Lin; Rong Zhuang; Saroj Thapa; Quan‐Zhi Chen; Yi‐Fan Chen; Jiafeng Lin

doi:10.1111/jcmm.14098

December 27, 2018Journal of Cellular and Molecular MedicineOpen Access

Low‐intensity pulsed ultrasound attenuates cardiac inflammation of CVB3‐induced viral myocarditis via regulation of caveolin‐1 and MAPK pathways

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Key result

Low-intensity pulsed ultrasound improves 14-day survival by ~30 percentage points in murine viral myocarditis.

P=0.013

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Why the study?

Acute viral myocarditis triggers aggressive immunological activity causing cardiomyocyte loss, and it was unknown whether low-intensity pulsed ultrasound could attenuate CVB3-induced injury by regulating inflammation.

Does low-intensity pulsed ultrasound (LIPUS) improve survival and attenuate cardiac inflammation and ventricular dysfunction in a mouse model of CVB3-induced acute viral myocarditis?

Key Points

To investigate whether low-intensity pulsed ultrasound (LIPUS) can attenuate cardiac injury induced by coxsackievirus B3 (CVB3) infection by modulating the inflammatory response.
Male BALB/c mice were inoculated intraperitoneally with CVB3 and received LIPUS treatment on Day 1, Days 1 and 3, or Days 1, 3, and 5 post-inoculation, followed for 14 days (n=40 per group for survival; n=6 per group for tissue and functional assays).
RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) with or without LIPUS exposure and caveolin-1 siRNA transfection.
Day 1, 3, 5 LIPUS treatment significantly increased 14-day survival to 70% (28/40) compared with 40% (16/40) in the untreated CVB3 myocarditis group (P=0.013), without altering myocardial CVB3 replication on days 7 and 14.
LIPUS given on Days 1, 3, and 5 significantly decreased heart weight/body weight ratio, Day 7 plasma Troponin I, brain natriuretic peptide (BNP), and left ventricular end-diastolic and end-systolic diameters, while increasing left ventricular ejection fraction (P<0.05).
Day 1, 3, 5 LIPUS suppressed myocardial infiltration, decreased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ, ICAM-1, and MCP-1), increased caveolin-1 activation, and suppressed p38 MAPK and ERK signaling (P<0.05).

Structured PICO

Does low-intensity pulsed ultrasound (LIPUS) improve survival and attenuate cardiac inflammation and ventricular dysfunction in a mouse model of CVB3-induced acute viral myocarditis?

P

Population

Male BALB/c mice (5 weeks old) with coxsackievirus B3-induced acute viral myocarditis (40 mice per group for survival analysis; 6 per group at days 7 and 14 for tissue analysis) followed for 14 days, alongside in vitro LPS-treated RAW264.7 macrophage experiments.

I

Intervention

Transthoracic low-intensity pulsed ultrasound (LIPUS; 1 MHz frequency, 20% duty cycle, 100 Hz pulse repetition frequency, 0.5 W/cm2 output intensity, 100 mW/cm2 spatial average-temporal average intensity) applied to the heart in the parasternal short-axis view at papillary muscle levels for 20 minutes/day under 1.2% isoflurane inhalation anaesthesia on Day 1, Days 1 and 3, or Days 1, 3, and 5 post-inoculation.

C

Comparator

Sham LIPUS therapy in CVB3-infected mice (VMC group received the LIPUS device under 1.2% isoflurane anaesthesia without ultrasound delivery on days 1, 3, and 5) and uninfected PBS-injected control groups (with and without LIPUS).

O

Outcome

14-day survival rate, left ventricular function (LVEF, LVEDd, LVESd by transthoracic echocardiography at day 14), myocardial injury biomarkers (plasma Troponin I, cardiac BNP, HW/BW ratio), and cardiac histopathological inflammatory infiltration and signalling pathways (caveolin-1, p38 MAPK, ERK, and pro-inflammatory cytokines at days 7 and 14).hard clinical

Main Result

Absolute Event Rate: 70% vs 40%

p-value: p=0.013

This preclinical study demonstrates for the first time that noninvasive low-intensity pulsed ultrasound (LIPUS) improves survival and attenuates cardiac inflammation and left ventricular dysfunction in acute viral myocarditis via caveolin-1 activation and MAPK pathway suppression.

Limitations

LIPUS treatment was only performed within the first 5 days after virus inoculation, so the effect of a longer course of treatment was not investigated.
Caveolin-1 knockout (KO) mice were not utilized in vivo to verify the LIPUS mechanism, relying instead on siRNA knockdown in vitro.
The overactive immunological response in vitro was mimicked by LPS treatment on RAW264.7 cells rather than direct CVB3 infection.
In vitro experiments only investigated the effect of LIPUS on macrophages, leaving its effect on other cardiac resident cells (cardiomyocytes, endothelial cells, fibroblasts) unexplored.
LIPUS treatment was performed only within the first 5 days after virus inoculation, leaving the effect of a relatively longer treatment course uninvestigated.
Caveolin-1 knockout (KO) mice were not used in vivo to confirm the mechanism of LIPUS treatment.
The overactive immunological response in vitro was mimicked by LPS stimulation of RAW264.7 cells rather than CVB3 infection.
In vitro experiments only investigated macrophages and did not explore the effect of LIPUS on other cardiac resident cells such as cardiomyocytes, endothelial cells, or fibroblasts.

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Implication

Hypothesis-generating for LIPUS in viral myocarditis; leaves open translation from mice to clinical practice.

Abstract

The aggressive immunological activity elicited by acute viral myocarditis contributes to a large amount of cardiomyocytes loss and poor prognosis of patients in clinic. Low-intensity pulsed ultrasound (LIPUS), which is an effective treatment modality for osteoarthropathy, has been recently illustrated regulating the overactive inflammatory response in various diseases. Here, we aimed to investigate whether LIPUS could attenuate coxsackievirus B3 (CVB3) infection-induced injury by coordinating the inflammatory response. Male BALB/c mice were inoculated intraperitoneally with CVB3 to establish the model of acute viral myocarditis. LIPUS treatment was given on Day 1, Day 1, 3 and Day 1, 3, 5 post-inoculation, respectively. All mice were followed up for 14 days. Day 1, 3, 5 LIPUS treatment significantly improved the survival rate, attenuated the ventricular dysfunction and ameliorated the cardiac histopathological injury of CVB3-infected mice. Western blotting analysis showed Day 1, 3, 5 LIPUS treatment decreased pro-inflammatory cytokines, increased the activation of caveolin-1 and suppressed p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signallings in heart tissue. RAW264.7 cells were treated with lipopolysaccharides (LPS) to simulate the augmented inflammatory response in vivo. LIPUS treatment on RAW264.7 inhibited the expression of pro-inflammatory cytokines, activated caveolin-1 and suppressed p38 MAPK and ERK signallings. Transfecting RAW264.7 with caveolin-1 siRNA blunted the suppression of pro-inflammatory cytokines and MAPK signallings by LIPUS treatment. Taken together, we demonstrated for the first time that LIPUS treatment attenuated the aggressive inflammatory response during acute viral myocarditis. The underlying mechanism may be activating caveolin-1 and suppressing MAPK signallings.

Discussion

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Cite This Study

Zheng et al. (2018) studied Coxsackievirus B3 (CVB3)-induced acute viral myocarditis. Low-intensity pulsed ultrasound (LIPUS) vs. Sham LIPUS (ultrasound device applied under 1.2% isoflurane anaesthesia without ultrasound delivery on days 1, 3, and 5) was evaluated on 14-day survival rate (in VMC + Day 1, 3, 5 LIPUS group vs untreated VMC group) (p=0.013). Low-intensity pulsed ultrasound on days 1, 3, and 5 improved 14-day survival from 40% to 70% and attenuated cardiac inflammation in CVB3-induced viral myocarditis mice.

synapsesocial.com/papers/6a733fc34e82b1a46ac675a6 https://doi.org/10.1111/jcmm.14098

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Low‐intensity pulsed ultrasound attenuates cardiac inflammation of CVB3‐induced viral myocarditis via regulation of caveolin‐1 and MAPK pathways

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Low‐intensity pulsed ultrasound attenuates cardiac inflammation of CVB3‐induced viral myocarditis via regulation of caveolin‐1 and MAPK pathways

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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