EDITORIAL

European Heart Journal (2024) 00, 1–3
https://doi.org/10.1093/eurheartj/ehae253

Miscellaneous

Hiroaki Shimokawa

1,2*1

Graduate School, International University of Health and Welfare, Kozunomori 4-3, Narita 286-8686, Japan; and 2Department of Cardiovascular Medicine, Tohoku University, Seiryo-machi
1-1, Sendai 980-8574, Japan

This editorial refers to ‘Cardiac shockwave therapy in addition to coronary bypass surgery improves myocardial function inischaemic heart failure: the CAST-HF trial’, by J. Holfeld et al., https://doi.org/10.1093/eurheartj/ehae341.

Graphical Abstract

Therapeutic potentials of sound waves in cardiovascular medicine
Low-intensity shockwave (SW)

Activation ofself-healing abilities

Broad indications

Low-intensity pulsed
ultrasound (LIPUS)

Alzheimer’s disease
Brain

Vascular dementia
StrokeAngiogenesis

AnginaLymphangiogenesis

Acute MI (AMI)
HeartHeart failure (HFpEF)
Pulmonary HT
Microvascular angina

Neurogenesis
KidneyOthers
Peripheral

Chronic kidneydiseaseAtherosclerotic
obliterans
Erectile dysfunction

Therapeutic potentials of sound wave therapies with shock wave (SW) and low-intensity pulsed ultrasound (LIPUS). The SW and LIPUS therapies could
activate self-healing abilities depending on disease-specific conditions, including angiogenesis in ischaemic tissue, lymph-angiogenesis in oedematous tis­sue, neurogenesis in damaged nervous tissue, and others. These sound therapies appear to have broad indications for the brain, heart, kidney and per­ipheral arteries in cardiovascular medicine. AMI, acute myocardial infarction; HFpEF, heart failure with preserved LV ejection fraction.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +81 476 20 7701, Email: shimo@iuhw.ac.jp, Tel: +81 22 717 7153, Email: shimo@cardio.med.tohoku.ac.jp© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com forreprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further informationplease contact journals.permissions@oup.com.

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Therapeutic potentials of sound waves
in cardiovascular medicine: further importantevidence

2demonstrated with the LIPUS therapy.11 Third, it remains to be exam­
ined whether this intraoperative SW therapy actually improves longterm prognosis of patients with ischaemic heart failure.
Some comments should be made on the LIPUS therapy.1 Specific irradi­
ation conditions of LIPUS (32 cycles, 0.25 W/cm2, 1.875 MHz for the heartand 0.5 MHz for the brain) have been demonstrated to induce similar bio­
logical effects as SW.1 LIPUS therapy may have some advantages over SW
therapy in terms of efficacy and safety, including shorter treatment time (ascompared with extracorporeal SW therapy) and no harmful effects on thelung, etc. LIPUS therapy has been suggested to be effective and safe forsevere angina12,13 and also Alzheimer’s disease.14,15 For Alzheimer’s dis­ease, it has been demonstrated that multiple neuroprotective responses
are up-regulated in the whole brain in response to the LIPUS stimulation.14
This is in contrast to the fact that drug therapies need a certain therapeutictarget for drug development, which may cause polypharmacy issue, andcell therapies, where the fate of exogenously administered cells may not
be completely controlled. Currently, new therapies remain to be devel­
oped for major organ diseases, including dementia in the brain, heart failurein the heart and chronic kidney disease in the kidney, where microvascular
dysfunction plays a major pathogenetic role.1 Sound-wave therapies ap­
pear to be promising modalities to treat these diseases through improve­
ment of microvascular dysfunction (Graphical Abstract).1
In conclusion, sound-wave therapies with SW or LIPUS are a new
emerging class of therapy to activate self-healing abilities depending
on disease-specific conditions with reasonable efficacy and safety andappear to have broad indications as compared with current drug ther­
apies and cell therapies (Graphical Abstract).

Declarations
Disclosure of Interest
HS is the founder and executive chairman of the Sound WaveInnovation, Ltd. (https://sw-innovation.com/).

References
1. Shindo T, Shimokawa H. Therapeutic angiogenesis with sound waves. Ann Vasc Dis 2020;
13:116–25. https://doi.org/10.3400/avd.ra.20-00010
2. Huang C, Hlfeld J, Schaden W, Orgill D, Ogawa R. Mechanotherapy: revisiting physicaltherapy and recruiting mechanobiology for a new era in medicine. Trends in Mol Med
2013;19:555–64. https://doi.org/10.1016/j.molmed.2013.05.005
3. Davies MJ, Earley S, Li Y-S, Chien S. Vascular mechanotransduction. Physiol Rev 2023;
103:1247–421. https://doi.org/10.1152/physrev.00053.2021
4. Hatanaka K, Ito K, Shindo T, Kagaya Y, Ogata T, Eguchi K, et al. Molecular mechanismsof the angiogenic effects of low-energy shock wave therapy: roles of mechanotrans­
duction. Am J Physiol Cell Physiol 2016;311:C378–85. https://doi.org/10.1152/ajpcell.
00152.2016
5. Shindo T, Ito K, Ogata T, Hatanaka K, Kurosawa R, Eguchi K, et al. Low-intensity pulsed
ultrasound enhances angiogenesis and ameliorates left ventricular dysfunction in amouse model of acute myocardial infarction. Arterioscler Thromb Vasc Biol 2016;36:1220–9. https://doi.org/10.1161/ATVBAHA.115.306477
6. Nishida T, Shimokawa H, Oi K, Tatewaki H, Uwatoku T, Abe K, et al. Extracorporeal
cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dys­function in pigs in vivo. Circulation 2004;110:3055–61. https://doi.org/10.1161/01.CIR.
0000148849.51177.97
7. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, et al. Extracorporeal
cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe
coronary artery disease. Coron Artery Dis 2006;17:63–70. https://doi.org/10.1097/00019501-200602000-00011
8. Kikuchi Y, Ito K, Ito Y, Shiroto T, Tsuburaya R, Aizawa K, et al. Double-blind andplacebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock
wave therapy for severe angina pectoris. Circ J 2010;74:589–91. https://doi.org/10.1253/
circj.CJ-09-1028
9. Holfeld J, Nagele F, Polzl L, Engler C, Graber M, et al. Direct cardiac shockwave ther­apy in addition to coronary bypass surgery for improvement of myocardial function inischemic heart failure (CAST-HF): an investigator-initiated, sham-controlled trial. EurHeart J.

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In our body, many potential self-healing abilities remain and could be
activated in response to exercise and other adequate physical stimuli.
Sound waves, such as low-intensity shock wave (SW) and low-intensity
pulsed ultrasound (LIPUS), provide such adequate mechanical stimuli
to promote various self-healing responses through the so-called ‘me­chanotransduction’ mechanism.1–3 Indeed, it is interesting to note thatsound-wave therapies with SW or LIPUS induce disease-specific re­generative responses, including angiogenesis in ischaemic tissue,
lymph-angiogenesis in oedematous tissue, neurogenesis in damaged
nervous tissues, and others through improvement of microvascular
dysfunction (Graphical Abstract).1 This therapeutic approach to stimu­
late endogenous self-healing abilities with sound waves appears to befeasible and promising in terms of efficacy, safety and medical cost ascompared with the molecular biological approach with exogenous ma­
terials, such as genes or cells.1 Interestingly, SW and LIPUS share thesame intracellular molecular mechanisms for mechanotransduction, in­volving the β1-integrin/caveolin-1 complex in the endothelial caveolae fol­
lowed by up-regulation of endothelial nitric oxide synthase (eNOS).4,5
Angiogenic and thus anti-ischaemic effects of low-energy SW were firstdescribed in a porcine model of chronic myocardial ischaemia6 andthen in patients with severe coronary artery disease.7,8
In this issue of the Journal,9 Holfeld et al. added important evidence
to the literature of therapeutic potentials of sound waves in cardiovas­
cular medicine. In their single-blind, parallel-group, sham-controlled trial(CAST-HF), patients with left ventricular ejection fraction (LVEF) <40% requiring surgical revascularization were enrolled. The patientswere randomly assigned to undergo direct cardiac SW therapy (n =30) or sham treatment (n = 28) in addition to coronary artery bypass
grafting (CABG) surgery and were followed up for one year. The results
showed that improvement in LVEF measured by cardiac MRI (primaryendpoint) was greater in the SW group than in the sham treatmentgroup (△ from baseline to 360 days: SW 11.3% vs. Sham 6.3%,
P = .0146), which was also the case for improvement in 6-min walk dis­
tance (△ from baseline to 360 days: SW 127.5 m vs. Sham 43.6 m,
P = .028), whereas no difference was noted between the two groups
for Minnesota Living with Heart Failure Questionnaire (SW 11.0 pointvs. Sham 17.3 point, P = .15). In contrast to the previous studies withextracorporeal cardiac SW therapy,7,8 the authors employed direct
SW therapy during CABG surgery after complete revascularization,
while still on cardiopulmonary bypass.9 The SW irradiation conditions
were also different; in this study by Holfeld et al., 300 impulses for cor­
onary supply territory for all three coronary territories due to threevessel disease, intensity of 0.38 mJ/mm2 and a frequency of 3 Hz,9
whereas in the previous studies, 200 shots/spot for 20∼40 spots(depending on the extent of ischaemic myocardium), intensity of
0.09 mJ/mm2 and in a manner of heart rate synchronization.7,8
Nonetheless, the impact of the SW therapy on cardiac function inthe study by Holfeld et al. is meaningful in daily practice, suggesting
the usefulness of the routine use of the SW therapy during CABG sur­gery for patients with ischaemic heart failure. It is also interesting tonote that the authors demonstrated the involvement of innate im­mune receptor Toll-like receptor 3 (TLR3) pathway in the effectsof the SW therapy.10 This suggests the cross-talk between theTLR3 and the eNOS pathways in the effects of the SW therapy. Inaddition to the discussion by the authors on the study limitations,9several points remain to be examined. First, the potential usefulnessof additional extracorporeal cardiac SW therapy after this intraopera­
tive SW therapy remains to be examined in future studies. Second, it
remains to be elucidated whether the intraoperative therapy im­
proves cardiac diastolic function in addition to systolic function, as

EditorialEditorial

13. Shindo T, Ito K, Ogata T, Kurosawa R, Eguchi K, Kagaya Y, et al. A randomized, doubleblind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for re­fractory angina pectoris. PLoS One 2023;18:e0287714. https://doi.org/10.1371/journal.
pone.0287714
14. Eguchi K, Shindo T, Ito K, Ogata T, Kurosawa R, Kagaya Y, et al. Whole-brain lowintensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mousemodels of dementia—crucial roles of endothelial nitric oxide synthase. Brain Stim 2018;
11:959–73. https://doi.org/10.1016/j.brs.2018.05.012
15. Shimokawa H, Shindo T, Ishiki A, Tomita N, Ichijyo S, Watanabe T, et al. A pilot study ofwhole-brain low-intensity pulsed ultrasound therapy for early stage of Alzheimer’s dis­ease (LIPUS-AD): a randomized, double-blind, placebo-controlled trial. Tohoku J ExpMed 2022;258:167–75. https://doi.org/10.1620/tjem.2022.J078

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10. Holfeld J, Tepekoylu C, Reissig C, Lobenwein D, Scheller B, Kirchmar E, et al.
Toll-like receptor 3 signalling mediates angiogenic response upon shock wave
treatment of ishaemic muscle. Cardiovasc Res 2016;109:331–43. https://doi:10.1093/
cvr/cvv272
11. Monma Y, Shindo T, Eguchi K, Kurosawa R, Kagaya Y, Ikumi Y, et al. Low-intensity pulsed
ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy forheart failure with preserved left ventricular ejection fraction. Cardiovasc Res 2017;117:1325–38. https://doi.org/10.1093/cvr/cvaa221
12. Hanawa K, Ito K, Aizawa K, Shindo T, Nishimiya K, Hasebe Y, et al. Low-intensity pulsed
ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine
model of chronic myocardial ischemia. PLoS One 2014;9:e104863. https://doi.org/10.
1371/journal.pone.0104863

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