Exploring the Potential of Energy-Based Therapeutics (Photobiomodulation/Low-Level Laser Light Therapy) in Cardiovascular Disorders: A Review and Perspective

Based on the review of the literature, this article examines the potential therapeutic benefits of photobiomodulation therapy (PBMT) or low-level laser therapy (LLLT) for the treatment of cardiovascular disorders. The methodology involved searching PubMed, Google Scholar, and Central databases for relevant articles published from inception till date. The articles included in this review were preclinical and clinical studies investigating the effects of PBMT and LLLT on the heart. The article summarizes the findings of nineteen studies investigating the effects of PBMT and LLLT on various parameters related to heart failure (HF) and myocardial infarction (MI), including inflammation, oxidative stress, angiogenesis, cardiac function, and remodeling. The studies suggest that PBMT and LLLT have potential therapeutic benefits for the treatment of cardiovascular diseases and could be used in combination with traditional pharmacological therapies to enhance their effects or as a stand-alone treatment for patients who are not responsive to or cannot tolerate traditional therapies. In conclusion, this review article highlights the promising potential of PBMT for the treatment of HF and MI and the need for further research to fully understand its mechanisms of action and optimize treatment protocols.


Introduction And Background
Introduction Photobiomodulation (PBM) or low-level laser therapy (LLLT) is a non-invasive therapeutic approach that uses low-level light sources, typically in the form of low-power lasers or light-emitting diodes (LEDs), to stimulate cellular responses and promote healing. The process involves the absorption of red or nearinfrared (NIR) light by specific cellular components, mainly the mitochondria, resulting in a cascade of biological reactions that enhance cellular function and overall tissue health. Photobiomodulation (PBM) or low-level laser therapy (LLLT) was demonstrated in numerous in vitro studies to exhibit unique biological effects with a dose-dependent cellular action mechanism [1]. Since its inception in the year 1967, more than 400 randomized, double-blinded clinical trials, some featuring placebo controls, have been published for various employments [2]. The intricate biological mechanisms responsible for LLLT/PBM's therapeutic effects have not been entirely understood, and these mechanisms might differ among cell types and tissue conditions, such as healthy versus stressed or hypoxic states. Nevertheless, both laboratory and clinical investigations indicate that LLLT/PBM effectively diminishes inflammation, prevents fibrosis [3][4][5][6][7][8][9], alleviates pain, and enhances overall organism function when applied appropriately [1,[10][11][12].
Emerging evidence suggests that PBM primarily acts on Cytochrome c Oxidase (CcO) in the mitochondrial respiratory chain, facilitating electron transport and subsequently increasing adenosine triphosphate (ATP) production by boosting the transmembrane proton gradient [13]. As ATP is the universal energy source for all biological activities in living cells, even a minor upsurge in ATP levels can improve bioavailability for cellular metabolism functions [1]. Furthermore, red or NIR light absorption may cause a brief, transient surge of reactive oxygen species (ROS), followed by an adaptive decrease in oxidative stress [1]. The low ROS concentrations activate numerous cellular processes, including transcription factors such as nuclear factor kappa B (NF-κB), which in turn upregulate stimulatory and protective genes [14]. These genes produce fibroblast growth factors, cytokines and chemokines involved in tissue regeneration.

FIGURE 1: The intracellular events in a stressed/hypoxic cell
The figure depicts the intracellular events that occur in a stressed or hypoxic cell. The figure shows that in a hypoxic cell, mitochondria generate excess nitric oxide (NO), that binds to Cytochrome c Oxidase (CcO) and displaces oxygen. The displacement of oxygen from CcO leads to inhibited cellular respiration, reduced ATP generation and increased oxidative stress. This state activates various intracellular signalling pathways and transcription factors such as redox factor-1, hypoxia-inducible factor-1, HIF-like factor 17, activator protein-1, nuclear factor-kB, p53, activating transcription factor/cyclic adenosine monophosphate (cAMP)-response elementbinding protein (ATF/CREB), inducing the downstream production of inflammatory mediators like interleukins IL-1 and IL-6, tumor necrosis factor-alpha, cyclooxygenase (COX)-2, and prostaglandin E2. The inflammatory milieu delays or halts cellular repair and tissue healing. ATP (Adenosine Triphosphate), HIF (Hypoxia Inducible Factor), HIFLF (Hypoxia Inducible Factor Like Factor), NF (Nuclear Factor), TNF (Tumor Necrosis Factor), Cox (Cyclooxygenase) Evidence indicates that administering LLLT/PBM with appropriate parameters to stressed cells can dissociate NO from its competitive binding to CcO, increase ATP production, and restore the balance between pro and antioxidant mediators, reducing oxidative stress [20]. For instance, LLLT/PBM has been demonstrated to attenuate ROS production in neutrophils [21] and reduce ROS in an animal model of traumatic tissue injury [22]. Additionally, PBM has been found to decrease the generation of tumor necrosis factor alpha (TNF-α) and increase IL-10, an anti-inflammatory cytokine, in a model of acute lung inflammation [23]. Furthermore, NO's vasodilatory properties [24] can enhance blood supply to illuminated tissue, while LLLT-mediated vascular regulation increases tissue oxygenation and immune cell trafficking [1]. These two effects may contribute to promoting wound repair and regeneration ( Figure 2) [16]. The analgesic effects of PBM are likely induced by additional mechanisms beyond the increased ATP/reduced oxidative stress model. PBM with a relatively high-power density can inhibit A and C neuronal pain fibers when absorbed by nociceptors, slowing neural conduction velocity, reducing compound action potential amplitude, and suppressing neurogenic inflammation [12]. PBM has the potential to modulate almost all pathogenic mechanisms in the body (e.g., inflammation, edema, pain, fibrosis, ulceration, and neuropathy and myopathy) [1].

FIGURE 2: Mechanism of action of photobiomodulation in biological tissue
The mechanism of action of PBMT/LLLT for promoting cell repair involves the mitochondrial electron transport chain (ETC). The chromophores (e.g. Cytochrome c Oxidase) are iron/copper-containing molecules that can absorb red/infrared light spectrum. Upon absorbing the incoming energy from a light-emitting device, Cytochrome c Oxidase (CcO) a critical enzyme in ETC gets activated. This results in the dissociation of NO from CcO which in turn reverses the hypoxic cell cascade explained in Figure 1. Free NO causes vasodilation increasing tissue oxygenation. On the other hand, CcO activation also increases ATP production and reduces ROS. The net effects promote cell survival and tissue repair. Consequently, LLLT has been identified as a promising approach for mitigating various cardiac pathologies [25]. Intriguing evidence suggests that LLLT's beneficial effects could persist long-term even after treatment cessation, warranting further systematic evaluation [25]. LLLT has recently been employed as an antiinflammatory treatment in numerous diseases, including myocardial infarction (MI), where it may exert a cardioprotective effect [26]. LLLT's cardioprotective role is mediated by anti-inflammatory, antioxidant and pro-angiogenic actions [27].
Low-level laser therapy (LLLT) can alter the expression of cardiac cytokines and assists in the reversal of ventricular remodeling following myocardial injury [26]. Moreover, photobiomodulation (PBM) therapy has been shown to be effective in several age-associated chronic cardiovascular conditions, such as hypertension and atherosclerosis [28]. In this review, the focus is on examining the evidence-based investigations concerning the application of photobiomodulation therapy in cardiovascular diseases and to analyze their major propositions and recommendations.

Methodology
For this review, a comprehensive search was conducted in the PubMed, Google Scholar and Central databases using the following keywords: "low-level laser therapy," "photobiomodulation therapy," "PBM," "cardiovascular disease," "heart failure," "myocardial infarction," "cardiac remodeling," "angiogenesis," "inflammation," "oxidative stress," "aging," and "energy-based therapeutics" (Appendices). Articles published in the English language from inception till date were included. A total of nineteen relevant articles were selected for this review based on their relevance to the research question and inclusion criteria. The selected articles included randomized controlled trials, observational studies, and animal experiments. Based on the analysis of the available evidence, a perspective was presented on the potential role of energy-based therapeutics, specifically LLLT/PBM, in the prevention and management of cardiovascular disorders.

Review
The experimental and clinical investigations were carefully considered and the mechanistic basis of lowlevel laser therapy, its positive influence on cardiac remodeling, reducing infarct area, restenosis prevention and other presented cardioprotective effects were examined. The summary of the salient findings of the studies are presented in Table 1.   In this comprehensive review, the therapeutic potential of energy-based modalities, specifically low-level laser therapy (LLLT) and photobiomodulation (PBM), for cardiovascular disorders is investigated. A total of 19 studies were examined, and their findings are summarized as follows.

I. Effects of LLLT/PBM on cardiac function and remodeling
Several studies have explored the effects of Low-Level Laser Therapy (LLLT) and Photobiomodulation (PBM) on cardiac function and remodeling following myocardial infarction (MI). Biasibetti et al. [29] revealed that LLLT altered oxidative balance in skeletal muscle of heart failure (HF) rats by reducing superoxide dismutase (SOD) activity and dichlorofluorescein (DCFH) oxidation levels. However, high LLLT doses led to increased DNA damage [29]. Meanwhile, Blatt et al. [30] established that applying LLLT to bone marrow resulted in diminished scarring, enhanced angiogenesis, and functional improvement following MI in a porcine model [30]. Bublitz et al. [31] concluded that while LLLT did not enhance functional capacity in HF patients, it potentially modulated blood lactate metabolism and decreased perceived muscle fatigue [31].
Capalonga et al. [32] demonstrated that light-emitting diode therapy (LEDT) elevated functional capacity in heart failure (HF) rats, as evidenced by improved distance, time, and speed during exercise [32]. Feliciano et al. [35] discovered that photobiomodulation therapy (PBMT) reversed alterations in myocardial extracellular matrix gene mRNA expression, modified cardiac microRNAs (miRNAs) expression associated with fibrosis replacement, and identified correlations between specific miRNAs and mRNA [35]. Feliciano et al. [36] in their 2021 study found that MI led to modified mRNA expression of various biomarkers linked to detrimental cardiac activity, and PBMT reverted most of these transcriptional changes, particularly decreasing mRNA expression of IL-6, tumor necrosis factor (TNF) receptor, transforming growth factor β 1 (TGF-β1), and collagen I and III. PBMT also reduced miR-221, miR-34c, and miR-93 expression post-MI [36].
Syed et al. [28] discovered that early PBM treatments reduced age-associated increases in left ventricular (LV) mass, decreased LV end-diastolic volume (EDV) in AC8, lowered left atrial dimension, enhanced LV ejection fraction, alleviated aortic wall stiffness, and improved gait symmetry. These effects persisted after the pause, and cumulative survival increased in PBM-treated AC8 mice. PBM treatment was found to mitigate age-associated cardiovascular remodeling, reduce cardiac function, enhance neuromuscular coordination, and increase longevity in an experimental animal model, with responses correlating with elevated TGF-β1 in circulation [28].
However, some studies reported contradictory results. For instance, Manchini et al. [25] in their 2017 study found that the beneficial effects of LLLT on left ventricular (LV) systolic function may be dependent on the maintenance of phototherapy [25]. LLLT reduced MI size, attenuated systolic dysfunction, and decreased myocardial mRNA expression of interleukin-1 beta and interleukin-6, as reported by Manchini et al. [41] in 2014, but did not show significant changes in vascular endothelial growth factor (VEGF) expression or capillaries' density [41]. More research is needed to confirm these findings and to determine the optimal dose and wavelength of LLLT for disease treatment.

II. Anti-inflammatory effects of LLLT/PBM
The anti-inflammatory effects of LLLT/PBM have been demonstrated in various studies, showcasing their potential in mitigating inflammation in injured cardiovascular tissues. Hentschke et al. [39] found that LLLT reduced plasma IL-6 levels, TNF-α/IL-10, and IL-6/IL-10 ratios while increasing IL-10 levels in rats with heart failure [39]. Manchini et al. [25] in his 2017 study observed that laser light treatment influenced numerous biomarkers associated with inflammation and myocardial repair, although no significant changes were detected in VEGF expression or capillary density [25]. Wang et al. [43] revealed that LED therapy significantly attenuated microglial activation and reduced IL-18, IL-1β, and nerve growth factor (NGF) expression in the peri-infarct myocardium [43].

III. Effects of LLLT/PBM on angiogenesis
Blatt et al. [30] established that applying LLLT to bone marrow resulted in enhanced angiogenesis [30]. Tuby et al. [42] demonstrated that laser-irradiated rat hearts post-infarction and intact hearts exhibited a significant increase in VEGF and inducible nitric oxide synthase (iNOS) expression compared to non-laserirradiated hearts. LLLT also caused a significant elevation in angiogenesis, and the upregulated VEGF and iNOS expression in the infarcted rat heart was associated with enhanced angiogenesis and cardioprotection [42].

IV. Other effects of LLLT/PBM
Derkacz et al. [33] observed that LLLT contributed to reduced TGF-β1 and fibroblast growth factor-2 (FGF-2) levels, consequently leading to smaller neointima formation, decreased late lumen loss, and a lower restenosis rate [33]. In a subsequent study, Derkacz et al. [34] reported not only elevated nitrite/nitrate concentrations but also a transient increase in endothelin-1 in the laser group, which was accompanied by a reduced restenosis rate [34]. Lohr et al. [24] elucidated that R/NIR light could decay nitrosyl hemes and release NO, thereby augmenting the cardioprotective effects of nitrite [24]. Furthermore, Malinovskaya et al. [40] highlighted that wideband red light irradiation resulted in decreased mortality compared to laser irradiation and control groups, restored heart rate, diminished lipid peroxidation (LPO) products, and increased SOD activity in myocardial tissues [40]. Additionally, Wang et al. [43] unveiled that LED therapy significantly reduced the incidence of acute myocardial infarction (AMI)-induced ventricular arrhythmias (VAs) and decreased left stellate ganglion (LSG) neural activity in the AMI+LED group compared to the AMI group. Of note, LED therapy significantly attenuated inflammatory cytokine expression in the peri-infarct myocardium, suggesting a potential protective effect against AMI-induced VAs through the suppression of sympathetic neural activity and the inflammatory response [43]. Lastly, Yang et al. [26] employed a cytokine antibody array to identify cytokines involved in the response to therapeutic laser irradiation, finding that low-level laser irradiation (LLLI) did not improve damaged heart function but reduced infarct area expansion [26].
Despite showing promising results in pre-clinical investigations, it is important to note that the small sample sizes and varied methodological approaches of available literature may be the Achilles' heel of this study, making it difficult to draw definitive conclusions. The studies were also of limited scope because they had a short follow-up period and were conducted in different animal models and human populations. The studies also used different doses and wavelengths of LLLT. As a result, the long-term safety and efficacy of LLLT could not be assessed. The studies were conducted in different animal models, including mice, rats, and rabbits. The studies used different doses of LLLT, ranging from 1 to 22 J/cm2. The studies also used different wavelengths of LLLT, ranging from 630 to 900 nm. The results may vary depending on the type of animal model, the human population, the dose of LLLT, and the wavelength of LLLT. More research is needed to determine the long-term safety and efficacy of LLLT.

Future implications
The studies discussed here demonstrate the potential of photobiomodulation therapy (PBMT) in treating various aspects of heart failure and acute myocardial infarction. Although the mechanisms of action of PBMT are still not fully understood, it is clear that it has a beneficial effect on several biomarkers and processes related to cardiac function and remodeling. The findings suggest that PBMT could be used in combination with traditional pharmacological therapies to enhance their effects or as a standalone treatment for patients who are not responsive to or cannot tolerate traditional therapies.
Moreover, future studies should focus on optimizing PBMT protocols, including the timing, frequency, and duration of treatments, as well as the use of different types of light sources and wavelengths. Furthermore, PBM has been used to delay the presentation of age-related cardiac disorders. A recent study by Syed et al. [28] suggests that PBM therapy could mitigate age-associated cardiovascular remodeling and improve cardiac function, neuromuscular coordination, and longevity in an experimental animal model. Additionally, the observed responses correlated with increased TGF-β1 levels in circulation [28]. These findings indicate that PBM therapy may have promising benefits in preventing or slowing cardiovascular aging and may serve as a potential therapeutic strategy for age-related cardiovascular diseases in the future.
Finally, larger-scale randomized controlled trials are needed to validate the findings of these studies and to investigate the long-term safety and efficacy of PBMT in different patient populations.
In conclusion, the studies discussed in this article suggest that PBMT has promising potential in the treatment of heart failure and acute myocardial infarction. The mechanisms of action of PBMT appear to involve anti-inflammatory, anti-fibrotic, and pro-angiogenic effects, which could help mitigate the downward spiral of heart failure and promote tissue repair and regeneration. While further research is needed to fully understand the mechanisms of action of PBMT, and its potential adverse effects and to optimize treatment protocols, the findings to date are encouraging and suggest that PBMT could be a valuable addition to the armamentarium of therapies available for heart failure and acute myocardial infarction.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.