Next Article in Journal
Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension
Next Article in Special Issue
Mapping the Gut Microbiota Composition in the Context of Raltegravir, Dolutegravir, and Bictegravir—A Scoping Review
Previous Article in Journal
An Autocrine Regulator Loop Involving Tumor Necrosis Factor and Chemokine (C-C motif) Ligand-2 Is Activated by Transforming Growth Factor-β in Rat Basophilic Leukemia-2H3 Mast Cells
Previous Article in Special Issue
Effects of Aneurysmal Subarachnoid Hemorrhage in Patients Without In-Hospital Infection on FABP-I, LBP, and sCD-14
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites

by
Barathan Muttiah
1,* and
Alfizah Hanafiah
1,2,*
1
Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
2
GUT Research Group, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(9), 4264; https://doi.org/10.3390/ijms26094264
Submission received: 9 April 2025 / Revised: 29 April 2025 / Accepted: 29 April 2025 / Published: 30 April 2025
(This article belongs to the Special Issue Interplay Between the Human Microbiome and Diseases)

Abstract

Cardiovascular diseases (CVDs), including heart failure (HF), hypertension, myocardial infarction (MI), and atherosclerosis, are increasingly linked to gut microbiota dysbiosis and its metabolic byproducts. HF, affecting over 64 million individuals globally, is associated with systemic inflammation and gut barrier dysfunction, exacerbating disease progression. Similarly, hypertension and MI correlate with reduced microbial diversity and an abundance of pro-inflammatory bacteria, contributing to vascular inflammation and increased cardiovascular risk. Atherosclerosis is also influenced by gut dysbiosis, with key microbial metabolites such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) playing crucial roles in disease pathogenesis. Emerging evidence highlights the therapeutic potential of natural compounds, including flavonoids, omega-3 fatty acids, resveratrol, curcumin, and marine-derived bioactives, which modulate the gut microbiota and confer cardioprotective effects. These insights underscore the gut microbiota as a critical regulator of cardiovascular health, suggesting that targeting dysbiosis may offer novel preventive and therapeutic strategies. Further research is needed to elucidate underlying mechanisms and optimize microbiome-based interventions for improved cardiovascular outcomes.

1. Introduction

Noncommunicable diseases like cardiovascular diseases (CVDs), cancers, respiratory diseases, and diabetes cause over 63% of total mortality [1], and CVDs accounted for ~19 million deaths in 2021 [2] alone, followed by cancers (10 million) [3], respiratory diseases (4 million) [4], and diabetes (>2 million) [5]. Tobacco smoking, unhealthy diet, physical inactivity, alcohol consumption, and air pollution are some common risk factors, which affected disproportionately low- and middle-income countries (LMICs) [6]. Chronic diseases will be responsible for 75% of all deaths worldwide by 2030 [7] because of age, physical inactivity, poor diet, and environmental exposure, further weakening health systems [8]. They are overlooked at the global level due to myths, risk underestimation, and a lack of investment in prevention [9]. LMICs struggle with chronic disease prevention due to limited access to care, shortages of trained professionals, and inadequate infrastructure [10], while high-income countries (HICs) face rising healthcare costs, health disparities, and challenges integrating preventive care [11]. Conventional therapies such as drugs, chemotherapy, and immunotherapy have improved disease control but are limited by resistance, side effects, and incomplete efficacy [12], necessitating alternative approaches. Emerging evidence indicates the etiology of metabolic disease by the microbiome through metabolic, immune, and neuroendocrine modulation [13].
Gut dysbiosis may contribute to metabolic diseases, chronic inflammation, and even tumorigenesis through immune dysregulation [14,15]. Chronic infections including Helicobacter pylori lead to gastric cancer [16,17], hepatitis B virus/hepatitis C virus (HBV/HCV) to hepatocellular carcinoma [18,19], and Epstein–Barr virus (EBV) reprograms immune pathways leading to lymphoma [20]. These infections induce inflammation, oxidative stress, immune suppression, and genetic/epigenetic alterations [21], resulting in obesity, diabetes, and metabolic dysfunction [22]. Microbiome targeting can enhance existing treatments and curtail disease progression [23]. Natural products like polyphenols (curcumin, resveratrol, and quercetin), probiotics, and microbial metabolites have therapeutic value via microbiota modulation, anti-inflammation, and drug metabolism enhancement [24,25]. The role of the microbiome in chronic disease pathogenesis has been emphasized in recent research, with dysbiosis linked to obesity, type 2 diabetes, inflammatory bowel disease (IBD), and cancer [26,27]. Understanding microbiome-mediated mechanisms could uncover new interventions, including probiotics, prebiotics, and fecal microbiota transplantation. This review is centered on CVDs and microbiome-focused natural products as adjuvants to traditional treatments. Due to the high global load of CVDs and their metabolic and inflammatory associations, it is important to investigate microbiome-based therapies for new treatment options [28].

2. Human Microbial Contributions

The gut microbiota is a diverse microbial community that is essential for human health, and is linked with improved metabolism, immune function, and decreased chronic disease risk. It mostly consists of Bacillota and Bacteroidota which make up about 90% of the microbes in a healthy adult [29]. The microbiota has over 1000 species with a predicted 150-fold more genes than the human genome [30]. Each individual has a unique microbiome with less than 10% commonality between two individuals [31]. Bacillota, including Lactobacillus, Clostridium, Ruminococcus, and Faecalibacterium, are accountable for fiber fermentation and SCFA production, stimulating colonocyte energy and immune control [32]. Bacillota are also engaged in energy metabolism, and increased levels are linked with obesity. Bacteroidota, including Bacteroides and Prevotella, are involved in carbohydrate metabolism, SCFA production, and gut barrier integrity [33]. A balanced ratio of Bacillota to Bacteroidota is critical since its disruption has been associated with metabolic disease [34]. Actinobacteria, particularly Bifidobacterium, are probiotic, exerting immune modulation and pathogen suppression [35]. Proteobacteria, including Escherichia, Enterobacter, and Helicobacter, occur in low numbers by nature, but overgrowth has been associated with inflammation of the intestine and diseases such as IBD and colorectal cancer [36].
Diet affects gut microbiota diversity by providing nutrients for microbial metabolism, regulating bacterial composition [37]. High-fiber diets, common in non-Western populations, encourage beneficial bacteria like Prevotella to ferment complex carbohydrates into SCFAs like butyrate, acetate, and propionate [38]. These metabolites strengthen gut barrier function, anti-inflammatory responses, and metabolic homeostasis. Meanwhile, Western diets, which are rich in fat and processed food and poor in fiber, reduce microbial diversity, promote pro-inflammatory taxa (Bacteroides), and lower beneficial bacteria (Akkermansia muciniphila and Faecalibacterium prausnitzii) and may predispose to obesity, type 2 diabetes, and cardiovascular disease [39]. The polyphenols found in fruit and vegetables have prebiotic actions, promoting beneficial bacteria selectively. High-protein diets, particularly diets high in red meat, increase Odoribacter splanchnicus and trimethylamine-N-oxide (TMAO), a metabolite linked to cardiovascular risk [40]. Fermented foods like yogurt, kefir, kimchi, and sauerkraut introduce probiotics (Lactobacillus and Bifidobacterium), which boost microbial diversity and intestinal health [41]. Other than diet, gut microbiota populations are influenced by several lifestyle, genetic, and environmental determinants [42]. Aging comes with declines in protective bacteria like Bifidobacteria and rises in pathogenic taxa that cause inflammation and reduced gut resilience [43]. Exercise raises microbial diversity and SCFA output, but lifestyle sedentism promotes gut dysbiosis [44]. Smoking and alcohol abuse negatively influence microbiota by raising pro-inflammatory bacteria and intestinal permeability [45]. Agents such as antibiotics, PPIs, and NSAIDs cause chronic microbial dysbiosis, which enhances susceptibility to infections such as Clostridioides difficile [46]. Genetic predisposition regulates microbial colonization, which affects immune function and metabolic competence [47]. Geographical settings, cultural habits, and environmental toxins (e.g., heavy metals, pesticides, and microplastics) also regulate microbiome composition, potentially leading to inflammation and metabolic disease [48]. Early-life exposures, including birth mode, breastfeeding, and early-life antibiotic exposure, have a profound impact on microbiota diversity, influencing immune development and disease susceptibility [49].

3. Cardiovascular Diseases (CVDs) and Gut Microbiota

CVDs are a leading cause of morbidity and mortality worldwide, with multifactorial etiologies rooted in genetic, lifestyle, and environmental determinants [50]. There is growing evidence to support the notion that the gut microbiota, the vast array of microorganisms within the gastrointestinal tract, plays a significant role in modulating cardiovascular health [51]. The host metabolism–microbial composition interaction has been highlighted more and more, particularly in relation to dysbiosis and its contribution to CVD pathogenesis [52]. The gut microbiota plays a critical role in the pathophysiology of CVDs such as atherosclerosis, hypertension, myocardial infarction, and heart failure (HF), through intricate mechanisms involving inflammation, metabolism, and microbial dysbiosis [51].

4. HFs and Gut Microbial Changes

Heart failure (HF) is a clinical syndrome of impaired cardiac performance, leading to reduced blood flow. There were over 64 million cases worldwide in 2017; HF remains a significant health emergency, and its prevalence is estimated to rise due to increased survival and aging populations [53]. Its economic burden is also high, with U.S. healthcare spending projected to reach $69.8 billion by 2030 [54].
There is growing evidence that gut dysbiosis is involved in HF progression through the disruption of homeostasis, increased intestinal permeability, and the induction of systemic inflammation [51]. HF-related structural and functional gastrointestinal alterations, including systemic redistribution of blood, reduced cardiac output, and neuro-humoral activation, cause the thickening of the intestinal wall, edema, and barrier dysfunction [55]. This allows for microbial translocation and systemic inflammation, and elevated inflammatory markers are predictive of worse HF prognosis [56]. Also, increased concentrations of bacteria and adhesion to intestinal mucosa further increase inflammation, and HF patients have greater rates of infection with Clostridium difficile, which add to inflammatory load [57,58]. Gut microbiota metabolites have significant influences on the pathogenesis of HF.
SCFAs like acetate, propionate, and butyrate have protective effects by promoting intestinal barrier function, modulating immune response, and managing glucose and lipid metabolism. SCFAs activate G-protein coupled receptors (GPR41, GPR43, and GPR109A), leading to immune modulation by upregulating anti-inflammatory cytokines (IL-10) and decreasing systemic inflammation, a characteristic of HF [59]. They also inhibit histone deacetylases (HDACs), which affect gene expression to upregulate anti-inflammatory genes, improve gut barrier function, and prevent bacterial endotoxin translocation, all of which are involved in HF [60]. SCFAs thus maintain the integrity of the gut epithelium and reduce microbial translocation, which promotes additional systemic inflammation and endothelial function [57,58,59].
On the other hand, TMAO, a gut-derived metabolite of dietary choline and carnitine, induces NF-κB activation to induce pro-inflammatory cytokine generation; worsens endothelial dysfunction, oxidative stress, and atherosclerosis; and facilitates the progression of HF [61]. TMAO also alters mitochondrial function and reduces myocardial contractility with cardiac dysfunction [62]. TMAO also activates the ROS/TXNIP/NLRP3 inflammasome and TGF-β1/Smad3 signaling pathways to cause fibrosis and maladaptive cardiac remodeling. Increased TMAO levels are associated with higher HF mortality, and pharmacologic inhibition of TMAO pathways has been shown to prevent the progression of HF [63,64].
Bile acids (BAs), branched-chain amino acids (BCAAs), and tryptophan derivatives are also involved in HF through diverse mechanisms. Bile acids activate the FXR pathway, modulating lipid metabolism and immune responses [65], while BCAAs activate the mTOR pathway, causing oxidative stress and inflammation [66]. Tryptophan metabolites, like indole derivatives, modulate the NLRP inflammasome and the PERK pathway, influencing immune responses, inflammation, and cellular stress, all of which dictate the severity of HF [67]. BAs also experience compositional alterations in HF patients, and a higher secondary-to-primary BA ratio is a predictor of poor survival. BA overload induces cardiac hypertrophy and metabolic derangement by inhibiting PGC-1α and repressing fatty acid oxidation [68]. In addition, excessive intracellular BA accumulation also activates AIM2 inflammasomes and type I interferon pathways, inducing chronic myocardial inflammation, mitochondrial dysfunction, and fibrosis [69].
Another key stimulus of HF progression is gut-derived lipopolysaccharide (LPS). LPS translocation into the circulatory system triggers systemic inflammation, oxidative stress, and fibrosis. LPS signals via Toll-like receptor 4 (TLR4) to trigger cytokine release, arrhythmias, and cardiac injury, whereas oxidative imbalance and MMP-mediated remodeling exacerbate contractility [70]. Gut dysbiosis also sustains systemic inflammation by increasing immune cell infiltration, compromising gut barrier integrity, and increasing inflammatory signaling [71]. With the pivotal role of inflammation in HF development, the pharmacological targeting of inflammatory pathways potentially provides new therapeutic options [70]. The gut microbiota collectively modulates key pathways, emphasizing the gut microbiota’s importance in HF pathophysiology. Table 1 explains the various pathway modulations by metabolites in HF.

5. Hypertension and Gut Microbial Changes

Hypertension, or high blood pressure, is one of the world’s most significant public health challenges and a leading risk factor for cardiovascular morbidity, stroke, and kidney disease [72]. It accounts for approximately 8.5 million deaths annually, highlighting the need for urgent action in prevention and treatment. Despite being a preventable and manageable condition, hypertension often remains undiagnosed or inadequately controlled, particularly in low- and middle-income countries [73]. Effective screening, early detection, and cost-effective treatment strategies are crucial in reducing its burden [74]. Recent studies have established a strong connection between gut microbiota dysbiosis and hypertension in both animal models and humans. The gut–brain axis directly influences blood pressure regulation, as microbiota-induced gut alterations can enhance sympathetic drive through either direct intestinal wall nerve–brain interactions or neuroinflammation, consequently modulating central blood pressure control pathways [75]. Compositional changes in the gut microbiota have been linked to increased sympathetic outflow, contributing to elevated blood pressure [76]. Hypertensive individuals often exhibit reduced microbial richness, diversity, and evenness, along with an increased Firmicutes/Bacteroidetes ratio [76]. A decrease in acetate- and butyrate-producing bacteria has also been implicated in hypertension [77]. For example, human studies indicate that hypertensive patients have elevated levels of Klebsiella, Streptococcus, and Parabacteroides, whereas beneficial bacteria such as Roseburia and Faecalibacterium are significantly reduced [78]. Beyond microbial composition, gut dysbiosis promotes systemic inflammation by activating T-helper 17 (Th17) cells and stimulating the release of pro-inflammatory cytokines [79]. This immune imbalance contributes to T-cell infiltration in vascular tissues, leading to inflammation, endothelial dysfunction, and ultimately, hypertension [80]. Additionally, gut microbial metabolites influence critical physiological processes, including energy balance, catecholamine metabolism, and ion transport, all of which impact blood pressure regulation [81]. Mechanistically, gut dysbiosis is associated with an increase in LPS-producing bacteria, leading to low-grade endotoxemia and vascular inflammation [82]. These factors contribute to endothelial dysfunction, a key driver of hypertension. SCFAs stimulate these receptors, notably GPR43, to influence vasodilation, inhibit inflammatory cytokine production, and regulate sympathetic nervous system activity [77]. SCFAs also inhibit components of the renin–angiotensin–aldosterone system (RAS), a central controller of blood pressure [83]. Meanwhile, butyrate increases endothelial nitric oxide synthase (eNOS) expression, increasing the availability of nitric oxide (NO), leading to vasodilation [84]. An emerging mechanism involves the role of olfactory receptors (ORs) in the cardiovascular system, which are influenced by gut microbiota-derived metabolites such as SCFAs. These ORs help regulate blood pressure by modulating sympathetic nervous activity and vascular tone. For example, Olfr78 responds to SCFAs by regulating renin secretion, while OR10J5 is expressed in endothelial cells, further emphasizing the gut–heart connection in hypertension [85]. TMAO is synthesized from dietary substrates like choline, carnitine, and betaine through microbial metabolism to trimethylamine (TMA) that undergoes further oxidation in the liver by flavin monooxygenase 3 (FMO3). TMAO elevation is linked to hypertension through the activation of NF-κB signaling that enhances vascular inflammation and endothelial dysfunction [86]. TMAO increases platelet hyperresponsiveness, increasing the risk of thrombotic events [87]. Tryptophan degradation by gut microbiota yields indole derivatives, kynurenine, and serotonin, all of which exert influences on vascular and renal function. Indole derivatives stimulate the aryl hydrocarbon receptor (AhR), influencing immune responses and maintaining vascular integrity [88]. Polyamines such as putrescine and spermidine either activate or inhibit nitric oxide production, controlling vascular tone and blood pressure [89]. These findings underscore the critical role of the gut microbiota in hypertension and suggest that targeting gut dysbiosis may offer novel therapeutic strategies for its management, as shown in Table 2.

6. Myocardial Infarction and Gut Dysbiosis

Globally, myocardial infarction (MI) is a significant cause of death, affecting an estimated 3 million people worldwide, with over a million annual deaths in the US alone [90]. The global burden of MI is 3.8% among individuals younger than 60 years and rises to 9.5% among those older than 60 years. In 2019, MI caused an estimated 8.9 million deaths, accounting for 16% of total global mortality [91]. Risk factors include high blood pressure, smoking, diabetes, physical inactivity, obesity, high cholesterol levels, poor diet, and excessive alcohol consumption [92]. While the incidence of MI is declining in developed countries due to improved healthcare and public health interventions, it is increasing in developing regions such as South Asia, parts of Latin America, and Eastern Europe [93].
Recent research highlights the relationship between the gut microbiota and MI, emphasizing how gut dysbiosis influences cardiovascular health [94]. MI patients exhibit significant alterations in gut microbiota composition, including a decreased Firmicutes-to-Bacteroidetes ratio and an increased abundance of pro-inflammatory bacteria such as Desulfovibrio and Acidaminococcus [95]. In acute myocardial infarction (AMI) patients, a distinct microbial shift has been observed, with notable reductions in beneficial genera such as Prevotella and Parabacteroides known for maintaining gut homeostasis and regulating inflammation alongside increases in genera like Bifidobacterium and Dorea [96]. These microbial changes correlate with metabolic dysregulation, particularly in lipid metabolism. In early AMI patients, gut dysbiosis has been associated with high concentrations of long-chain fatty acids (LCFAs), which promote platelet aggregation, a critical step in thrombus formation and MI initiation [97]. Additionally, an altered gut microbiota composition contributes to systemic inflammation through elevated LPS levels, which enter the circulatory system and activate inflammatory pathways via TLR4, exacerbating cardiovascular disease and MI outcomes [98]. Beyond inflammation, gut dysbiosis affects lipid homeostasis, glucose metabolism, and vascular integrity, further increasing cardiovascular risk [99]. Notably, LCFAs have been proposed as potential early biomarkers for early AMI (eAMI), underscoring the gut microbiome’s diagnostic potential in cardiovascular disease [98].
Following MI, intestinal permeability increases, allowing gut bacteria to translocate into the circulatory system, exacerbating inflammation. Studies indicate that over 12% of blood bacteria in ST elevation MI (STEMI) patients originate from the gut, correlating with elevated LPS levels that drive systemic inflammation and worsen cardiovascular prognosis [100]. The gut-derived metabolite TMAO is produced from the microbial metabolism of dietary choline and L-carnitine and has been implicated in promoting atherosclerosis and increasing MI risk [101]. Another notable microbial metabolite, phenylacetylglutamine (PAGln), derived from phenylalanine metabolism, influences MI severity by activating adrenergic receptors on platelets, thereby enhancing platelet responsiveness and promoting thrombosis. Elevated PAGln levels are associated with increased thrombotic risk, potentially worsening MI outcomes [102].
Conversely, SCFAs, beneficial microbial metabolites that regulate inflammation and blood pressure, are often reduced in MI-related dysbiosis, potentially impairing recovery. Although plasma SCFA levels may not differ significantly in acute MI patients, fecal SCFA profiles often show alterations, reflecting microbial shifts during MI. Additionally, aromatic amino acid metabolites have been linked to oxidative stress and myocardial infarct size, further influencing post-MI outcomes [103].
Gut dysbiosis in MI patients triggers several pathological pathways. Firstly, inflammation and immune activation are enhanced because TMAO and LPS of gut microbiota stimulate NF-κB signaling, leading to the release of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), which enhance myocardial injury and inhibit cardiac repair [104]. Secondly, TMAO and LPS promote oxidative stress and endothelial dysfunction by augmenting ROS production, disrupting eNOS activity, and reducing NO bioavailability, worsening ischemic and reperfusion damage [105]. Thirdly, calcium signaling and cardiac contractility are disrupted, whereby TMAO augments the intracellular calcium level, deranging excitation–contraction coupling, disrupting myocardial contractility, and elevating arrhythmogenicity [106]. Also, MI-associated gut hypoperfusion and ischemia result in compromised gut barrier integrity (“leaky gut”) allowing the entry of microbial products like LPS into the circulatory system, which worsens systemic inflammation and myocardial damage [107]. Understanding the intricate relationships between gut microbiota, inflammation, and cardiovascular health remains a critical research area, offering insights into innovative microbiome-based strategies for MI prevention and treatment in Table 3.

7. Atherosclerosis and Gut Microbiota Composition

Atherosclerosis, which is an inflammatory disease of large and medium-sized arteries that advances progressively, is a major cause of ischemic heart disease (IHD), ischemic stroke, and peripheral arterial disease (PAD) [108]. Despite spectacular reductions in IHD- and stroke-related mortality in rich countries since the middle of the 20th century, IHD is the single most significant cause of early adult death in the world [109]. Low- and middle-income countries, in contrast, have reported varied trends where a few nations recorded decreased stroke mortality, but others continue to be affected by rising IHD mortality [110].
The pathogenesis of gut dysbiosis and its contribution to atherosclerosis is characterized by distinctive microbial patterns and metabolic derivatives that directly influence cardiovascular health [111]. Notably, studies have identified distinctive microbial alterations that are associated with atherosclerosis. Pathogenic bacteria such as Megamonas, Veillonella, and Streptococcus are found in higher concentrations in atherosclerosis patients, whereas the beneficial genera Bifidobacterium and Roseburia, which exert anti-inflammatory and protective actions on the gut, are significantly reduced [112]. In addition, fungal dysbiosis, encompassing high Candida albicans, has been linked with dyslipidemia and atherosclerosis development via the modulation of the HIF-2α–ceramide pathway, which indicates the cardiovascular disease function of the gut mycobiome [113]. Patients with atherosclerotic cardiovascular disease (ACVD) exhibit pronounced alterations in gut microbiota profiles. All the studies describe elevated levels of pro-inflammatory and potentially pathogenic bacterial taxa, such as Enterobacteriaceae (with Escherichia coli), Streptococcus spp., Eggerthella, and Ruminococcus gnavus. These bacteria are associated with elevated inflammatory potential and systemic immune activation [114].
Beyond microbial composition, the metabolic byproducts of the gut microbiota are mediators that have a prime function in atherosclerosis development. High-fat diets can induce gut dysbiosis, compromising intestinal integrity and promoting atherosclerosis through metabolism-independent and metabolite-dependent pathways [115]. Moreover, gut lymphocytes affected by diet-induced dysbiosis proliferate in mesenteric lymph nodes and migrate to atherosclerotic plaques, fueling T-cell accumulation [116].
TMAO is a gut microbiota metabolite produced from dietary precursors like choline, phosphatidylcholine, and L-carnitine. TMAO pathways are key inducers of atherosclerosis, and elevated TMAO impairs the bioavailability of nitric oxide (NO), a molecule central to endothelial function and vascular health. This leads to endothelial dysfunction, a key early event in atherogenesis [117]. TMAO also enhances foam cell formation, which is a key process in the formation of atherosclerotic plaques. Foam cells are macrophages laden with lipids that accumulate in arterial walls, leading to plaque expansion and instability [118]. In addition, TMAO also triggers mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, both of which are involved in inflammatory responses. The resulting oxidative stress and inflammation destabilize the endothelial lining further and cause plaque rupture [119]. TMAO has also been shown to inhibit the reverse transport of cholesterol, a process by which cholesterol is moved from the peripheral tissues to the liver for excretion. Such inhibition leads to increased deposition of cholesterol in the arterial walls, encouraging atherosclerosis [120].
SCFAs, including butyrate, acetate, and propionate, on the other hand, have been reported to have protective roles in the regulation of inflammation, the maintenance of the intestinal barrier, and the regulation of lipid metabolism, specifically by tightening the gut lining, and SCFAs also prevent the translocation of harmful microbial components (LPS) into the circulatory system, thus reducing systemic inflammation [121]. SCFAs also activate peroxisome proliferator-activated receptor gamma (PPARγ), which plays an important part in the control of lipid metabolism and the minimization of inflammation within the vasculature [122]. Nonetheless, dysbiosis tends to be characterized by a considerable decrease in SCFA-producing bacteria, and this causes higher inflammation, weakened immune function, and elevated cardiovascular risk [123]. Table 4 shows the pathways of gut-derived metabolites that orchestrate complex pathological changes during atherosclerosis. In summary, these results highlight the complex interplay between the gut microbiota and atherosclerosis and offer new therapeutic opportunities for interventions into microbial composition and function. Figure 1 describes gut microbiota changes in CVDs (heart failure, hypertension, myocardial infarction, and atherosclerosis); meanwhile, Table 5 explains the impact of the composition of the gut microbiota and its metabolites on various CVDs.

8. Natural Products and Their Potential in CVD

CVDs remain the leading cause of morbidity and mortality worldwide, imposing an enormous global health burden. These conditions, such as coronary artery disease, heart failure, and hypertension, are managed with pharmacological agents, surgery, and lifestyle modification [124]. Statins (Atorvastatin, Rosuvastatin, and Simvastatin) lower LDL cholesterol to restrict atherosclerosis [125], while beta-blockers (Metoprolol, Carvedilol, and Bisoprolol) decrease the heart rate and blood pressure, reducing cardiac workload [126]. Angiotensin-converting-enzyme (ACE) inhibitors (Enalapril, Lisinopril, and Ramipril) and ARBs (Losartan, Valsartan, and Candesartan) control blood pressure and avoid cardiac remodeling [127]. Antiplatelets (Aspirin, Clopidogrel, and Ticagrelor) and anticoagulants (Warfarin, Rivaroxaban, and Apixaban) avert clot formation and stroke, respectively [128]. PCSK9 inhibitors (Alirocumab and Evolocumab) further reduce LDL cholesterol by allowing receptor recycling, while SGLT2 inhibitors (Empagliflozin, Dapagliflozin, and Canagliflozin) increase glucose excretion and reduce cardiovascular events in diabetes [129]. Surgical interventions such as Coronary Artery Bypass Grafting (CABG) restore blood flow in ischemic heart disease [130], and Transcatheter Aortic Valve Replacement (TAVR) with artificial valves (e.g., Edwards Sapien) and mechanical or biologic valve replacements manage heart valve dysfunction [131]. In addition to surgical and medical treatment, lifestyle modification, including adherence to heart-healthy diets like the Mediterranean diet and DASH diet, and attending formal cardiac rehabilitation programs, is also necessary to maximize cardiovascular health and patient recovery [132]. However, the long-term use of these cardiovascular drugs can lead to adverse effects, such as muscle pain and liver toxicity (statins), fatigue and bronchospasm (beta-blockers), cough and hyperkalemia (ACE inhibitors), and bleeding risks (antiplatelets/anticoagulants). PCSK9 inhibitors may cause injection site reactions, while SGLT2 inhibitors increase the risk of urinary infections and ketoacidosis [133,134]. These concerns have driven interest in alternative therapies like nutraceuticals (omega-3 and polyphenols) and plant-derived compounds (berberine and resveratrol), which have garnered attention due to their bioactive compounds with potential cardioprotective properties [135,136]. These compounds exhibit diverse mechanisms of action, such as antioxidant, anti-inflammatory, antihypertensive, and lipid-lowering effects, making them attractive candidates for CVD management.

8.1. Flavonoids

Flavonoids, a diverse group of naturally occurring polyphenolic compounds, are widely distributed in the plant kingdom and possess significant antioxidant, anti-inflammatory, and cardioprotective properties [137]. They share a common 15-carbon skeleton comprising two aromatic rings linked by a heterocyclic ring, and are categorized into flavonols, flavanols, flavones, isoflavones, and anthocyanins [138]. Key flavonoids include quercetin, kaempferol, myricetin, rutin, hesperidin, and naringenin, each with distinct biological effects. Rich dietary sources include berries (anthocyanins), citrus fruits (hesperidin, naringenin), onions (flavonols), and tea, particularly black and green tea, which are abundant in total flavonoids [139,140].
Flavonoids modulate oxidative stress, inflammation, and endothelial dysfunction, key drivers of CVDs, making them promising therapeutic agents [141,142]. Oxidative stress, a major contributor to CVD pathogenesis, results from excess ROS, leading to endothelial dysfunction, vascular inflammation, and tissue damage [143]. Flavonoids mitigate oxidative stress by scavenging ROS, enhancing endogenous antioxidant defenses, and inhibiting ROS-generating enzymes such as xanthine oxidase and NADPH oxidase. Their phenolic rings neutralize ROS like superoxide and peroxynitrite, preventing cellular injury. Additionally, flavonoids activate nuclear factor erythroid 2-related factor 2 (Nrf2), which upregulates antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) [144]. They also prevent low-density lipoprotein (LDL) oxidation, a key factor in atherosclerosis [145].
Beyond antioxidation, flavonoids possess strong anti-inflammatory effects, inhibiting vascular inflammation by suppressing pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-8) and enzymes such as cyclooxygenase-2 (COX-2) and lipoxygenase [146]. They improve endothelial function by enhancing NO bioavailability, promoting vasodilation, and reducing blood pressure [147]. Their anti-thrombotic effects prevent clot formation by inhibiting platelet aggregation and coagulation factor activation. Anti-atherogenic properties limit arterial plaque formation, reducing the risk of coronary heart disease [148]. By modulating the NF-κB, PI3K-AKT, and Nrf2/HO-1 pathways, flavonoids suppress inflammation, oxidative stress, and macrophage-mediated endothelial dysfunction, thereby preventing atherosclerosis and hypertension [149].
In myocardial infarction and ischemia–reperfusion injury, flavonoids offer cardioprotection via antioxidative, anti-inflammatory, and anti-apoptotic mechanisms [150]. Preclinical studies highlight the efficacy of morin and isoliquiritigenin in reducing myocardial damage and improving cardiac function [151]. Their antioxidant actions involve free radical scavenging and upregulation of SOD and catalase. Isoliquiritigenin activates Nrf2/HO-1 signaling, suppressing oxidative stress and ferroptosis in cardiomyocytes [152]. Flavonoids also downregulate the NF-κB and SAPK pathways (p38, JNK), reducing inflammation [153]. Their anti-apoptotic effects involve the regulation of survival pathways such as the RISK pathway (ERK, eNOS), with morin significantly inhibiting apoptosis in ischemia–reperfusion models [154]. Additionally, they modulate MAPK and NF-κB signaling, regulate calcium homeostasis, and protect mitochondria and autophagic pathways, enhancing cardioprotection [155]. However, clinical translation remains challenging, necessitating further research on their mechanisms and therapeutic interactions [155].
Flavonoids also influence mitochondrial function by activating mitochondrial potassium (mitoK) channels, which reduce calcium overload, stabilize membrane potential, and prevent ischemia–reperfusion-induced apoptosis [155,156]. Flavonoids like naringenin, quercetin, and epigallocatechin gallate enhance mitoK channel activity, reducing oxidative damage and supporting cardiovascular health [155]. Additionally, they improve vasodilation by enhancing endothelial nitric oxide synthase (eNOS) activity, reducing vascular stiffness, and lowering blood pressure [157]. Their inhibition of the angiotensin-converting enzyme (ACE) reduces vasoconstriction, further benefiting cardiovascular function [158]. Flavonoids prevent cardiomyocyte apoptosis by modulating apoptotic proteins, inhibiting JNK and p38 MAPK signaling, and promoting survival pathways like PI3K/Akt [159,160]. Their antioxidant actions prevent mitochondrial dysfunction by reducing ROS generation, maintaining membrane potential, and preventing mitochondrial permeability transition pore (MPTP) opening, which is particularly beneficial in diabetic cardiomyopathy and myocardial ischemia–reperfusion injury [161]. These broad molecular targets make flavonoids promising candidates for preventing oxidative stress-induced myocardial damage and CVD progression [162].

8.2. Omega-3 Fatty Acids

Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a crucial role in cardiovascular health [163]. A systematic review found that marine omega-3 fatty acids significantly reduce the risk of cardiovascular events by 10%, cardiac death by 9%, and coronary events by 18%, particularly in high-risk individuals [164]. These benefits stem from their ability to improve lipid profiles, reduce blood pressure, enhance vascular function, and exert anti-inflammatory effects [165]. Furthermore, omega-3 supplementation has been shown to lower the incidence of sudden cardiac death and all-cause mortality in post-myocardial infarction patients.
Current dietary recommendations advocate for at least two servings of fatty fish per week for the general population to maintain cardiovascular health. Individuals diagnosed with coronary heart disease are advised to consume approximately 1 g/day of EPA and DHA, while those with hypertriglyceridemia benefit from higher doses of 3–5 g/day under medical supervision to achieve significant triglyceride-lowering effects. Epidemiological studies consistently demonstrate that populations with high fish consumption exhibit lower rates of CVD morbidity and mortality [166]. Omega-3 fatty acids exert cardioprotective effects through multiple mechanisms. They regulate lipid metabolism by lowering triglyceride levels, inhibiting diacylglycerol O-acyltransferase (DGAT), and activating peroxisome proliferator-activated receptors (PPAR-α), leading to decreased triglyceride accumulation [167]. These effects are particularly beneficial for individuals with hypertriglyceridemia, a known risk factor for atherosclerosis. Beyond lipid metabolism, omega-3 fatty acids modulate inflammatory pathways that contribute to atherosclerosis. EPA and DHA inhibit the conversion of arachidonic acid into pro-inflammatory eicosanoids by downregulating cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) enzyme activity [168]. Instead, they promote the production of specialized pro-resolving lipid mediators such as resolvins, protectins, and maresins, which reduce endothelial activation and suppress pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). This mitigates chronic vascular inflammation, helping to prevent atherosclerotic plaque formation and rupture [169,170].
Additionally, omega-3 fatty acids exhibit antithrombotic properties by reducing platelet aggregation and altering membrane phospholipid composition. They lower thromboxane A2 (TXA2) synthesis while increasing prostacyclin (PGI2) production, thereby reducing the likelihood of thrombosis [170,171]. Omega-3s also improve endothelial function by enhancing nitric oxide (NO) bioavailability, which promotes vasodilation, reduces arterial stiffness, and lowers blood pressure [172]. Moreover, omega-3 fatty acids influence cardiac electrophysiology, stabilizing sodium and calcium ion channels to reduce arrhythmias, a major cause of sudden cardiac death [173]. Clinical trials indicate that omega-3 supplementation significantly lowers the incidence of atrial fibrillation and ventricular arrhythmias, particularly in post-myocardial infarction patients. Despite strong observational and mechanistic evidence, some clinical trials have reported mixed results regarding omega-3 supplementation in CVD prevention [174], potentially due to variations in dosage, baseline omega-3 levels, genetic factors, and concurrent lipid-lowering therapies. Further research is needed to refine optimal dosing strategies and identify patient subgroups who may derive the greatest benefit. Nonetheless, the overall evidence supports the inclusion of omega-3 fatty acids in dietary and pharmacological strategies aimed at reducing CVD risk.

8.3. Resveratrol

Resveratrol, another polyphenolic stilbenoid found in grapes and peanuts, has shown significant cardioprotective action through various mechanisms, including antioxidant, anti-inflammatory, vasoprotective, and anti-atherosclerotic effects [175]. It reduces oxidative stress by inhibiting LDL oxidation and activating endogenous antioxidant enzymes, thereby preventing endothelial dysfunction and vascular damage [176]. Moreover, it enhances NO production, endothelial function, platelet aggregation inhibition, and reduced vascular inflammation that account for its vasoprotective effect [177]. Resveratrol is also very active in expressing anti-inflammatory activities by downregulating central inflammatory markers and enhancing the signaling cascade of SPMs, such as resolvins, that contribute to countering chronic inflammation in cardiovascular diseases [178]. It controls vascular smooth muscle cell (VSMC) function by suppressing lipid uptake and migration, thereby limiting atherosclerotic growth [179]. Resveratrol is also ischemia–reperfusion injury and cardiac hypertrophy protective, and its cardioprotective action is due to the activation of central molecular targets, including sirtuins (SIRT1), AMPK, and estrogen receptor α, which control oxidative stress, vascular function, and inflammatory responses [180]. Preclinical studies point to the potential of resveratrol in the prevention and treatment of hypertension, atherosclerosis, and heart failure, with synthetic analogs under investigation to enhance its bioavailability and clinical efficacy [181]. However, despite promising accounts, clinical evidence remains elusive due to concerns of bioavailability and study design but, at the same time, emphasizes the need for further studies in the formulation of optimal resveratrol-based interventions. As a result of the etiologically complex nature of cardiovascular disease, an integrated approach incorporating resveratrol with other therapies might be the most effective way of reducing cardiovascular risk [182].

8.4. Curcumin

The active compound of turmeric has predominantly cardiovascular protective effects through various mechanisms. It normalizes the levels of lipids by reducing total LDL cholesterol and triglycerides but increasing HDL cholesterol [183]. Through its potent antioxidant and anti-inflammatory activities, it inactivates ROS and regulates inflammation pathways, reducing oxidative stress and vascular inflammation, which are at the epicenter of the etiopathogenesis of CVD [184]. Curcumin possesses anti-thrombotic and anti-atherosclerotic effects by inhibiting platelet aggregation, preventing endothelial dysfunction, and slowing the development of atherosclerosis [185]. It is protective against drug-induced cardiotoxicity, such as adriamycin-induced damage, and inhibits ischemia–reperfusion (I/R) injury by stimulating SIRT1, which decreases myocardial damage and oxidative stress [186]. Additionally, curcumin exerts cardioprotective actions in diabetic cardiomyopathy (DCM) by activating SIRT1/FoxO1 and PI3K/Akt and the Nrf2/ARE pathway, inhibiting oxidative damage and improving cardiac function. In myocardial ischemia–reperfusion (MI/R) injury, it stimulates the JAK2/STAT3 pathway, enhancing cardiac repair mechanisms [187]. Additionally, curcumin delays cardiac aging by inhibiting the p53/p21 pathway, which prevents cellular senescence and oxidative damage [188]. Curcumin suppresses cardiac hypertrophy and heart failure by downregulating the p300-HAT enzyme that regulates cardiac remodeling, thereby attenuating hypertrophy and fibrosis [189]. Curcumin improves endothelial function and vascular health via increased NO bioavailability, improved arterial compliance, and reduced arterial stiffness, rendering it beneficial for hypertension and vascular disease [190]. Curcumin also controls metabolic syndrome by increasing insulin sensitivity, improving glucose metabolism, and facilitating weight regulation—major participants in averting the cardiovascular complications associated with diabetes [191]. Despite these favorable actions, curcumin’s therapeutic application is limited by its poor bioavailability. More recent formulations such as nano-curcumin and curcumin derivatives are under development to enhance its cardiovascular action.

8.5. Coenzyme Q10 (CoQ10)

This is a promising cardiovascular disease prevention and therapeutic drug due to its antioxidant, anti-inflammatory, and mitochondrial-supportive actions in enhancing cellular energy production and inhibiting oxidative stress [192]. As a potent antioxidant, CoQ10 can neutralize ROS that induce oxidative damage to lipids, proteins, and DNA, which is significant in the pathologies of cardiovascular diseases such as atherosclerosis and endothelial dysfunction [193]. In addition, CoQ10 improves mitochondrial function by increasing ATP synthesis, particularly in energy-demanding tissues such as the heart, while maintaining mitochondrial membrane stability and blocking apoptosis resulting from mitochondrial damage [194]. Its protective effects against vessels are also highlighted through its ability to improve endothelial function with increased nitric oxide (NO) bioavailability and reduced superoxide anion production, leading to increased vasodilation and lowered blood pressure [195]. Clinical evidence has shown the effects of CoQ10 supplementation on various cardiovascular illnesses, particularly heart failure, wherein trials like the Q-SYMBIO trial have revealed reductions in major adverse cardiovascular events and mortality [196]. For myocardial infarction, CoQ10 may enhance the survival of cardiomyocytes during ischemia and decrease remodeling following infarction, and antihypertensive effects have been proven using meta-analyses with a reduction in systolic and diastolic blood pressure [197]. The protective effect of CoQ10 against atherosclerosis is because it can inhibit the oxidation of LDL, reducing arterial plaque accumulation and improving vascular compliance [198]. Moreover, in diabetes, CoQ10 has been associated with improvements in lipid profiles, including reductions in LDL and total cholesterol levels, as well as potential impacts on glucose control [199]. While randomized controlled trials (RCTs) have been promising, particularly in improving systolic function and endothelial function, more large-scale clinical studies are needed to confirm the optimum dosage, duration, and long-term impact of CoQ10 supplementation in CVDs. Despite its superb safety record, CoQ10 can interact with anticoagulants like warfarin and may be of benefit in statin-treated patients as statins lower endogenous CoQ10 levels to cause myopathy [200,201]. Also, because variation in absorption, metabolism, and action of CoQ10 occurs between individuals, the personalized management of supplementation has to be used, and there is some evidence that the reduced form, ubiquinol, will yield superior bioavailability [202]. Overall, CoQ10 is a viable adjunctive therapy for cardiovascular disease, considering its ability to enhance mitochondrial bioenergetics, reduce oxidative stress, improve endothelial function, and support general cardiac health, and therefore additional clinical investigation of its applications is warranted.

8.6. Marine-Derived Compounds

These have gained huge attention regarding CVD prevention and management owing to their rich bioactive properties like antioxidant, anti-inflammatory, lipid-lowering, and antihypertensive activities. Marine microalgae, rich in polysaccharides, peptides, and carotenoids, have been reported to possess strong antioxidant and anti-inflammatory activity, which may protect against CVD by inhibiting oxidative stress and endothelial dysfunction [203]. Among the carotenoids derived from marine origins, astaxanthin and fucoxanthin stand out for their potential to scavenge free radicals, increase lipid metabolism, and increase the level of HDL cholesterol that exhibits major functions towards averting cardiovascular hazards [204]. Bioactive metabolites of marine origin include xyloketal B, asperlin, saringosterol, and omega-3 acid ethyl esters with cardioprotection, evidenced as acting through the major mechanisms for dealing with hypertension, ischemic heart disease, atherosclerosis, and myocardial infarction [205]. Phlorotannins, new seaweed polyphenols, possess promise regarding the modulation of CVD and metabolic disorder risk factors such as hyperglycemia, hyperlipidemia, inflammation, and oxidative stress, and they are potentially good candidates for the development of functional foods [206]. Seaweeds, collectively, are rich sources of bioactive compounds such as soluble dietary fiber, peptides, lipids, and minerals that have been shown to regulate lipid profiles, lower blood pressure, and improve vascular function, hence preventing CVD [207]. Fresh evidence also suggests the interactions among seafood-derived compounds, the gut microbiota, and cardiovascular health, highlight the influence of fish-derived proteins, peptides, and algal constituents on gut microbiome diversity, intestinal wall integrity, and systemic inflammation, which are crucial to CVD pathogenesis [208]. Despite strong preclinical and epidemiological evidence for the cardiovascular protective action of marine-derived products, variability among clinical trial results suggests that bioavailability, individual metabolic heterogeneity, dosage, and dietary interaction must be kept in mind to ensure the highest therapeutic benefit [209]. More large, well-designed clinical trials are essential to validate such findings and establish standardized protocols for the use of marine-derived constituents in CVD prevention and cure. Table 6 explains the various bioactive compounds with cardioprotective impacts.

9. Natural Products as Microbial Modulators for Cardioprotection

Natural products are potent microbial modulators with the potential to affect cardiovascular health by remodeling the gut microbiota environment [210]. The gut microbiota plays a crucial role in modulating cardiovascular homeostasis as well as in disease development, such as that of atherosclerosis, hypertension, and heart failure. Natural compounds can modulate the composition and function of the gut microbiota, inhibit systemic inflammation, regulate lipid metabolism, and improve the gut barrier, ultimately exerting significant cardioprotective effects [211].
Various bioactive natural compounds possess cardioprotective action through modulating the gut microbiota and host metabolic functions. Berberine, an isoquinoline alkaloid isolated from the Coptis chinensis and Berberis plants, promotes the growth of health-promoting SCFA-producing bacteria (Roseburia, Blautia, and Alistipes), strengthens intestinal barrier function, suppresses LPS-induced inflammation through TLR4/NF-κB, and improves lipid profiles, all providing overall cardiovascular protection [212]. Berberine improves lipid profiles by reducing serum cholesterol, triglycerides, and LDL levels, further protecting against CVD [213], while increasing high-density lipoprotein cholesterol (HDL-C) in individuals with hyperlipidemia.
Polymethoxyflavones (PMFs) from aged citrus peel support the increase in beneficial bacteria such as Akkermansia and Bifidobacterium, inhibit the production of TMA by targeting TMA-producing bacteria and hepatic FMO3, and decrease the NF-κB/MAPK signaling pathways, thus preventing vascular inflammation and atherosclerosis (AS) formation [214]. Resveratrol, a polyphenol found in grapes, modulates the gut microbiota by promoting beneficial bacteria like Bacteroides, Lactobacillus, and Bifidobacterium, which support gut homeostasis and reduce inflammation [215], while lowering pathogenic bacteria like Enterococcus faecalis, improving the bile acid metabolism, lowering TMAO, and exhibiting protective action against oxidative stress and endothelial dysfunction. It enhances endothelial function by increasing NO bioavailability, improving vascular health, and lowering the risk of atherosclerosis and hypertension. Its antioxidant and anti-inflammatory properties further protect against cardiovascular diseases by reducing oxidative stress and chronic inflammation [216]. While promising for gut and cardiovascular health, further clinical studies are needed to fully understand its therapeutic potential.
Moreover, quercetin, a flavonoid, possesses prebiotic functions by modulating gut microbiota, enhancing gut barrier function, and generating bioactive metabolites. It activates health-promoting bacteria, strengthens tight junctions to suppress inflammation, and generates antioxidant and anti-inflammatory metabolites that have beneficial effects on overall health [217]. Quercetin has prebiotic-like effects, which help restore gut microbiota after antibiotic exposure [218]. Thirty-two metabolic parameters, including BA biosynthesis intermediates 3,7,12,26-tetrahydroxy-5-cholestane (C27H48O4), are linked to its effect [218]. Quercetin indirectly regulates bile acid profiles through microbiota reshaping, contributing significantly to its anti-obesity and metabolic benefits in abdominal obesity-related metabolic syndrome (MetS) [219]. Quercetin also causes intestinal antioxidant enzyme upregulation and nutrient uptake transporters, reverses GM imbalance, and blocks inflammasome activation and TLR-4 signaling pathway stimulation [220]. Quercetin combined with resveratrol corrects HFD-induced dysbiosis by decreasing the density of pathogenic bacteria and the F/B ratio [221].
Ferulic acid (FA), a phenolic acid, exhibits anti-inflammatory, antioxidant, and cardioprotective effects. FA promotes lipid metabolism, inhibits the risk of thrombosis, and regulates diabetes [222]. FA decreases cholesterol, triglyceride, and LDL levels, and increases the F/B ratio in gut microbiota composition. FA regulates fat metabolism by promoting PPAR-α expression and inhibiting PPAR-β/γ expression [223]. In mice, FA reshapes the gut microbiota and fecal metabolites, diminishes pro-inflammatory cytokines (IL-1β, IL-2, IL-6, and TNF-α), decreases Prevotellaceae, and enhances beneficial Lachnospiraceae family abundance [224]. Other phytochemicals, such as apigenin and silibinin, also help by triggering SCFA production, regulating lipid metabolism and blocking oxidative stress and vascular inflammation, and thus promoting cardiovascular resilience [225].
Curcumin, the bioactive compound in turmeric, exerts anti-inflammatory and antioxidant effects by modulating the gut microbiota and promoting beneficial bacteria while suppressing harmful ones, thereby reducing systemic inflammation [226]. It strengthens the intestinal barrier, preventing the leakage of harmful substances like LPS into the bloodstream, which can trigger inflammation. Curcumin also inhibits pro-inflammatory pathways such as NF-κB and regulates lipid metabolism, lowering the risk of atherosclerosis and CVD [227]. These combined actions make curcumin a promising natural compound for gut and cardiovascular health.
Pomegranate juice is rich in polyphenols and exhibits anti-inflammatory properties [228]. Pomegranate juice significantly reduces atherosclerotic lesion size and intima-media thickness, decreases LDL uptake by macrophages, increases HDL levels by 27%, and lowers CVD risk by 12–18% [229]. Anthocyanins are flavonoid polyphenols that possess antioxidant activity and are associated with reduced CVD risk [230,231]. Anthocyanins favorably regulate the gut microbiota by increasing the counts of Bifidobacterium, Lactobacillus, Roseburia, Akkermansia, and Parabacteroides [232]. Anthocyanins enhance vascular function through enhanced production of NO, decreased oxidative stress, and inhibited aortic inflammation, leading to decreased leukocyte infiltration, reduced plaque formation, and decreased levels of inflammatory cytokines in the blood [233]. They also affect the NF-κB inflammatory pathway, liver lipid metabolism, and redox homeostasis [234]. In addition, anthocyanins also regulate gene expression linked to atherosclerosis in macrophages, endothelial cells, and the aorta, and evidence suggests that they regulate over 1200 genes [235]. Metabolites like protocatechuic acid also inhibit atherosclerosis by activating the miRNA-10b-ABCA1/ABCG1 cholesterol efflux pathway [236]. Nevertheless, although there is potential in the emphasis on natural products, it should be mentioned that not every microbial metabolite is beneficial; certain compounds, like LPS, are pro-inflammatory and are involved in cardiovascular disease. How these natural products are manifested in real-world environments where there is gut microbiota variability remains to be fully understood. Table 7 summarizes the role of natural products in modulating cardiovascular microbial activity.

10. Synergistic Effects of Phytochemicals in CVD

The integration of phytochemicals with conventional pharmaceuticals offers a multi-targeted approach to managing CVDs and enhancing therapeutic efficacy while potentially mitigating adverse effects [237]. Phytochemicals interact with various molecular pathways, complementing the mechanisms of cardiovascular drugs [238,239]. Flavonoids, phenolic acids, and polyphenols, commonly present in fruits, vegetables, tea, and medicinal plants, have remarkable antioxidant and anti-inflammatory activity that can enhance the therapeutic efficacy of traditional drugs like statins, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors [240]. For instance, polyphenols like resveratrol and quercetin exhibit anti-inflammatory and antioxidant properties that enhance statin-induced cholesterol reduction [241,242], while curcumin and berberine improve endothelial nitric oxide production, supporting the vascular benefits of ACE inhibitors [243,244]. Many conventional drugs suffer from limited bioavailability, which can be improved through phytochemical co-administration. Curcumin enhances the intestinal absorption of statins by inhibiting P-glycoprotein efflux pumps, and piperine from black pepper increases metformin bioavailability, enhancing its glucose-lowering effects [245]. Phytochemicals may also reduce the required dosage of conventional drugs, minimizing side effects [243]. Berberine combined with metformin achieves similar glucose-lowering effects at lower metformin doses, reducing gastrointestinal discomfort [246], while quercetin co-administration with beta-blockers helps mitigate oxidative stress-induced cardiac dysfunction, improving patient compliance [247]. Clinical studies highlight the benefits of phytochemical–drug combinations in enhancing endothelial function, lipid metabolism, and glucose control. For example, resveratrol and statins improve endothelial nitric oxide bioavailability and reduce vascular inflammation [248], berberine combined with statins offers superior LDL cholesterol-lowering effects, and green tea catechins enhance the antiplatelet activity of aspirin while reducing gastric irritation [249]. Specific phytochemical-drug combinations with demonstrated synergistic effects include resveratrol with statins, which enhances endothelial nitric oxide synthase (eNOS) activation and reduces oxidative stress, improving LDL reduction and vascular function [250]; curcumin with ACE inhibitors, which counteracts angiotensin II-mediated oxidative stress, aiding blood pressure control and cardiac remodeling [244]; quercetin with beta-blockers, which increases nitric oxide bioavailability and reduces adrenergic stress [251], leading to better blood pressure regulation; berberine with metformin, which activates AMPK to mimic metformin’s effects while lowering lipogenesis and insulin resistance [252]; and green tea catechins with aspirin or clopidogrel, which enhance platelet inhibition and reduce oxidative damage, strengthening antiplatelet activity and lowering thrombotic risk [253]. Moreover, when used alongside statins, garlic supplementation has also been observed to increase the improvements in lipid profiles without increasing the risk of hepatotoxicity [254]. With continued scientific investigation and clinical approval, the combination of phytochemicals with conventional pharmacological treatments has the potential to revolutionize cardiovascular medicine, offering a more effective, safer, and holistic treatment paradigm for diseases of the heart. Figure 2 shows the integration of phytochemicals with conventional pharmaceuticals for CVD management.

11. Challenges and Future Directions

Although phytochemical–drug combinations show promising evidence in terms of treating CVDs, several initial problems discourage their implementation on a regular basis, including the inadequacies of large studies, regulatory problems, variation in the composition of phytochemicals, and herb–drug interactions [255]. Well-designed large-scale randomized clinical trials are needed to prove efficacy and safety before clinical application since most of them are observational or pilot-based with lower methodological rigor and short follow-up intervals [256], making it impossible to assess long-term cardiovascular effects. In addition, the heterogeneity of the patient population, genetic diversity, comorbid conditions, and food intake, also limit clinical evidence, necessitating larger and more heterogeneous study populations to be examined [257].
Mechanistic research that utilizes omics-based methods (metabolomics, proteomics, and transcriptomics) can supply clues on how phytochemicals interact with traditional drugs at the molecular level and further augment precision medicine practices [258]. Furthermore, regulatory and standardization issues as phytochemicals typically fail to meet requirements for quality control and dosage standardization demanded for drugs [259]. Plant species variation, cultivation practices, extraction methods, and storage methods all play a huge role in contributing to variations in the concentrations of bioactive compounds, making it difficult to achieve consistent therapeutic effects [260]. The regulatory classification issues are also part of the scenario, with most phytochemicals being classified as dietary supplements rather than pharmaceuticals and therefore restricted from use in evidence-based clinical care [261]. Pharmaceutical-quality material with defined bioactive content and stability must be formulated to enable regulatory approval and clinical use [262].
Another important issue is drug–herb interaction, since certain phytochemicals can influence drug metabolism through the inhibition of cytochrome P450 (CYP) enzymes and drug transporters such as P-glycoprotein (P-gp) [263]. For instance, grapefruit polyphenols inhibit CYP3A4, thereby increasing plasma concentrations and toxicity of statins and calcium channel blockers [264], whereas St. John’s Wort stimulates CYP3A4, reducing the efficacy of warfarin and beta-blockers [265]. Furthermore, curcumin and quercetin inhibit P-gp, affecting drug absorption; whereas, phytochemicals such as garlic, ginseng, and ginger exhibit anticoagulant activity that can enhance bleeding risks when co-administered with warfarin or aspirin [266]. Therefore, standardized protocols are required to guide clinicians on the safe co-administration of phytochemicals with cardiovascular drugs.
Pharmacogenomic factors add additional complexity to the clinical application of phytochemical–drug combinations because CYP450 enzyme polymorphisms (e.g., CYP2C19, CYP2D6, and CYP3A4) can influence drug metabolism and impact the efficacy of statins, beta-blockers, and antiplatelet drugs [267]. The genetic screening of response markers to phytochemicals may be able to forecast individual responses, and new evidence highlights the gut microbiota as the central player in phytochemical metabolism and the regulation of bioavailability and therapeutic effects [268]. Future research will have to center on microbiome-based precision medicine strategies to optimize phytochemical–drug interactions within clearly defined patient subgroups. Additionally, the development of personalized dosing regimens via genetic, metabolic, and gut microbiome profiling can potentially enhance efficacy and safety even further, leading towards the successful application of phytochemicals to mainstream cardiovascular medicine.
In summary, in the face of gigantic hurdles, progress in precision medicine, regulation standardization, and microbiome sciences offer hopeful fields to overcome today’s limitations. Future endeavors would have to include the incorporation of phytochemicals into evidence-based cardiovascular prevention and treatment in large, well-designed clinical trials, mechanistic studies, and the creation of patient-specified therapeutic regimens.

12. Conclusions

Growing evidence highlights the intricate relationship between gut microbiota dysbiosis and CVDs, including HF, hypertension, MI, and atherosclerosis. Dysbiosis contributes to systemic inflammation, vascular dysfunction, and disease progression through microbial-derived metabolites such as TMAO and SCFAs. The potential of natural compounds, including flavonoids, omega-3 fatty acids, resveratrol, curcumin, and marine-derived bioactives to restore microbial balance and confer cardioprotective effects presents a promising therapeutic avenue. Targeting gut microbiota offers novel strategies for CVD prevention and management, yet further research is needed to elucidate mechanistic pathways and develop microbiome-based interventions. Figure 3 shows the understanding the interplay between the gut microbiota and cardiovascular health may pave the way for personalized therapeutic approaches, ultimately improving patient outcomes.

Author Contributions

B.M. and A.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing. A.H.: conception and design, assembly of data, data analysis, final approval of manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by research grants from the Centre for Research and Instrumentation Management (CRIM), Universiti Kebangsaan Malaysia (Grant ID: DIP-2024-005). The funder had no role in the manuscript submission and publication.

Data Availability Statement

Data sharing is not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Hacker, K. The Burden of Chronic Disease. Mayo Clin. Proc. Innov. Qual. Outcomes 2024, 8, 112–119. [Google Scholar] [CrossRef] [PubMed]
  2. Di Cesare, M.; Perel, P.; Taylor, S.; Kabudula, C.; Bixby, H.; Gaziano, T.A.; McGhie, D.V.; Mwangi, J.; Pervan, B.; Narula, J.; et al. The Heart of the World. Glob. Heart 2024, 19, 11. [Google Scholar] [CrossRef] [PubMed]
  3. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  4. GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med. 2020, 8, 585–596. [Google Scholar] [CrossRef] [PubMed]
  5. GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 2023, 402, 203–234. [Google Scholar] [CrossRef]
  6. Ndubuisi, N.E. Noncommunicable Diseases Prevention In Low- and Middle-Income Countries: An Overview of Health in All Policies (HiAP). Inq. A J. Med. Care Organ. Provis. Financ. 2021, 58, 46958020927885. [Google Scholar] [CrossRef]
  7. NCD Countdown 2030 collaborators. NCD Countdown 2030: Worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet 2018, 392, 1072–1088. [Google Scholar] [CrossRef]
  8. Budreviciute, A.; Damiati, S.; Sabir, D.K.; Onder, K.; Schuller-Goetzburg, P.; Plakys, G.; Katileviciute, A.; Khoja, S.; Kodzius, R. Management and Prevention Strategies for Non-communicable Diseases (NCDs) and Their Risk Factors. Front. Public Health 2020, 8, 574111. [Google Scholar] [CrossRef]
  9. Miranda, J.J.; Kinra, S.; Casas, J.P.; Davey Smith, G.; Ebrahim, S. Non-communicable diseases in low- and middle-income countries: Context, determinants and health policy. Trop. Med. Int. Health 2008, 13, 1225–1234. [Google Scholar] [CrossRef]
  10. Phelan, H.; Yates, V.; Lillie, E. Challenges in healthcare delivery in low- and middle-income countries. Anaesth. Intensiv. Care Med. 2022, 23, 501–504. [Google Scholar] [CrossRef]
  11. Piot, P.; Caldwell, A.; Lamptey, P.; Nyrirenda, M.; Mehra, S.; Cahill, K.; Aerts, A. Addressing the growing burden of non-communicable disease by leveraging lessons from infectious disease management. J. Glob. Health 2016, 6, 010304. [Google Scholar] [CrossRef]
  12. Khan, S.U.; Fatima, K.; Aisha, S.; Malik, F. Unveiling the mechanisms and challenges of cancer drug resistance. Cell Commun. Signal. 2024, 22, 109. [Google Scholar] [CrossRef]
  13. Gebrayel, P.; Nicco, C.; Al Khodor, S.; Bilinski, J.; Caselli, E.; Comelli, E.M.; Egert, M.; Giaroni, C.; Karpinski, T.M.; Loniewski, I.; et al. Microbiota medicine: Towards clinical revolution. J. Transl. Med. 2022, 20, 111. [Google Scholar] [CrossRef]
  14. Kandpal, M.; Indari, O.; Baral, B.; Jakhmola, S.; Tiwari, D.; Bhandari, V.; Pandey, R.K.; Bala, K.; Sonawane, A.; Jha, H.C. Dysbiosis of Gut Microbiota from the Perspective of the Gut-Brain Axis: Role in the Provocation of Neurological Disorders. Metabolites 2022, 12, 1064. [Google Scholar] [CrossRef]
  15. Furman, D.; Campisi, J.; Verdin, E.; Carrera-Bastos, P.; Targ, S.; Franceschi, C.; Ferrucci, L.; Gilroy, D.W.; Fasano, A.; Miller, G.W.; et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 2019, 25, 1822–1832. [Google Scholar] [CrossRef]
  16. Lim, K.G.; Palayan, K. A Review of Gastric Cancer Research in Malaysia. Asian Pac. J. Cancer Prev. 2019, 20, 5–11. [Google Scholar] [CrossRef]
  17. Hanafiah, A.; Binmaeil, H.; Raja Ali, R.A.; Mohamed Rose, I.; Lopes, B.S. Molecular characterization and prevalence of antibiotic resistance in Helicobacter pylori isolates in Kuala Lumpur, Malaysia. Infect. Drug Resist. 2019, 12, 3051–3061. [Google Scholar] [CrossRef]
  18. Fung, J.; Lai, C.L.; Yuen, M.F. Hepatitis B and C virus-related carcinogenesis. Clin. Microbiol. Infect. 2009, 15, 964–970. [Google Scholar] [CrossRef]
  19. Barathan, M.; Mohamed, R.; Yong, Y.K.; Kannan, M.; Vadivelu, J.; Saeidi, A.; Larsson, M.; Shankar, E.M. Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion. Cells 2018, 7, 165. [Google Scholar] [CrossRef]
  20. Hatton, O.L.; Harris-Arnold, A.; Schaffert, S.; Krams, S.M.; Martinez, O.M. The interplay between Epstein-Barr virus and B lymphocytes: Implications for infection, immunity, and disease. Immunol. Res. 2014, 58, 268–276. [Google Scholar] [CrossRef]
  21. Greten, F.R.; Grivennikov, S.I. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity 2019, 51, 27–41. [Google Scholar] [CrossRef] [PubMed]
  22. Lin, K.; Zhu, L.; Yang, L. Gut and obesity/metabolic disease: Focus on microbiota metabolites. MedComm 2022, 3, e171. [Google Scholar] [CrossRef]
  23. Oka, A.; Sartor, R.B. Microbial-Based and Microbial-Targeted Therapies for Inflammatory Bowel Diseases. Dig. Dis. Sci. 2020, 65, 757–788. [Google Scholar] [CrossRef] [PubMed]
  24. Plamada, D.; Vodnar, D.C. Polyphenols-Gut Microbiota Interrelationship: A Transition to a New Generation of Prebiotics. Nutrients 2021, 14, 137. [Google Scholar] [CrossRef] [PubMed]
  25. Sorrenti, V.; Burò, I.; Consoli, V.; Vanella, L. Recent Advances in Health Benefits of Bioactive Compounds from Food Wastes and By-Products: Biochemical Aspects. Int. J. Mol. Sci. 2023, 24, 2019. [Google Scholar] [CrossRef]
  26. Ogunrinola, G.A.; Oyewale, J.O.; Oshamika, O.O.; Olasehinde, G.I. The Human Microbiome and Its Impacts on Health. Int. J. Microbiol. 2020, 2020, 8045646. [Google Scholar] [CrossRef]
  27. DeGruttola, A.K.; Low, D.; Mizoguchi, A.; Mizoguchi, E. Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflamm. Bowel Dis. 2016, 22, 1137–1150. [Google Scholar] [CrossRef]
  28. Vaduganathan, M.; Mensah, G.A.; Turco, J.V.; Fuster, V.; Roth, G.A. The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health. J. Am. Coll. Cardiol. 2022, 80, 2361–2371. [Google Scholar] [CrossRef]
  29. Gomaa, E.Z. Human gut microbiota/microbiome in health and diseases: A review. Antonie Leeuwenhoek 2020, 113, 2019–2040. [Google Scholar] [CrossRef]
  30. Afzaal, M.; Saeed, F.; Shah, Y.A.; Hussain, M.; Rabail, R.; Socol, C.T.; Hassoun, A.; Pateiro, M.; Lorenzo, J.M.; Rusu, A.V.; et al. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022, 13, 999001. [Google Scholar] [CrossRef]
  31. Gilbert, J.A.; Blaser, M.J.; Caporaso, J.G.; Jansson, J.K.; Lynch, S.V.; Knight, R. Current understanding of the human microbiome. Nat. Med. 2018, 24, 392–400. [Google Scholar] [CrossRef]
  32. Yüksel, E.; Voragen, A.G.J.; Kort, R. The pectin metabolizing capacity of the human gut microbiota. Crit. Rev. Food Sci. Nutr. 2024, 1–23. [Google Scholar] [CrossRef] [PubMed]
  33. Tufail, M.A.; Schmitz, R.A. Exploring the Probiotic Potential of Bacteroides spp. Within One Health Paradigm. Probiotics Antimicrob. Proteins 2025, 17, 681–704. [Google Scholar] [CrossRef]
  34. Petakh, P.; Oksenych, V.; Kamyshnyi, A. The F/B ratio as a biomarker for inflammation in COVID-19 and T2D: Impact of metformin. Biomed. Pharmacother. 2023, 163, 114892. [Google Scholar] [CrossRef] [PubMed]
  35. Plaza-Diaz, J.; Ruiz-Ojeda, F.J.; Gil-Campos, M.; Gil, A. Mechanisms of Action of Probiotics. Adv. Nutr. 2019, 10 (Suppl. 1), S49–S66. [Google Scholar] [CrossRef]
  36. Moon, C.D.; Young, W.; Maclean, P.H.; Cookson, A.L.; Bermingham, E.N. Metagenomic insights into the roles of Proteobacteria in the gastrointestinal microbiomes of healthy dogs and cats. MicrobiologyOpen 2018, 7, e00677. [Google Scholar] [CrossRef] [PubMed]
  37. Zhang, P. Influence of Foods and Nutrition on the Gut Microbiome and Implications for Intestinal Health. Int. J. Mol. Sci. 2022, 23, 9588. [Google Scholar] [CrossRef]
  38. Fu, J.; Zheng, Y.; Gao, Y.; Xu, W. Dietary Fiber Intake and Gut Microbiota in Human Health. Microorganisms 2022, 10, 2507. [Google Scholar] [CrossRef]
  39. Shin, Y.; Han, S.; Kwon, J.; Ju, S.; Choi, T.G.; Kang, I.; Kim, S.S. Roles of Short-Chain Fatty Acids in Inflammatory Bowel Disease. Nutrients 2023, 15, 4466. [Google Scholar] [CrossRef]
  40. Sejbuk, M.; Mirończuk-Chodakowska, I.; Karav, S.; Witkowska, A.M. Dietary Polyphenols, Food Processing and Gut Microbiome: Recent Findings on Bioavailability, Bioactivity, and Gut Microbiome Interplay. Antioxidants 2024, 13, 1220. [Google Scholar] [CrossRef]
  41. Leeuwendaal, N.K.; Stanton, C.; O’Toole, P.W.; Beresford, T.P. Fermented Foods, Health and the Gut Microbiome. Nutrients 2022, 14, 1527. [Google Scholar] [CrossRef] [PubMed]
  42. Strasser, B.; Wolters, M.; Weyh, C.; Krüger, K.; Ticinesi, A. The Effects of Lifestyle and Diet on Gut Microbiota Composition, Inflammation and Muscle Performance in Our Aging Society. Nutrients 2021, 13, 2045. [Google Scholar] [CrossRef]
  43. Nagpal, R.; Mainali, R.; Ahmadi, S.; Wang, S.; Singh, R.; Kavanagh, K.; Kitzman, D.W.; Kushugulova, A.; Marotta, F.; Yadav, H. Gut microbiome and aging: Physiological and mechanistic insights. Nutr. Healthy Aging 2018, 4, 267–285. [Google Scholar] [CrossRef] [PubMed]
  44. Monda, V.; Villano, I.; Messina, A.; Valenzano, A.; Esposito, T.; Moscatelli, F.; Viggiano, A.; Cibelli, G.; Chieffi, S.; Monda, M.; et al. Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxidative Med. Cell Longev. 2017, 2017, 3831972. [Google Scholar] [CrossRef] [PubMed]
  45. Bishehsari, F.; Magno, E.; Swanson, G.; Desai, V.; Voigt, R.M.; Forsyth, C.B.; Keshavarzian, A. Alcohol and Gut-Derived Inflammation. Alcohol Res. Curr. Rev. 2017, 38, 163–171. [Google Scholar]
  46. Bruno, G.; Zaccari, P.; Rocco, G.; Scalese, G.; Panetta, C.; Porowska, B.; Pontone, S.; Severi, C. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J. Gastroenterol. 2019, 25, 2706–2719. [Google Scholar] [CrossRef]
  47. Juarez, V.M.; Montalbine, A.N.; Singh, A. Microbiome as an immune regulator in health, disease, and therapeutics. Adv. Drug Deliv. Rev. 2022, 188, 114400. [Google Scholar] [CrossRef]
  48. Bora, S.S.; Gogoi, R.; Sharma, M.R.; Anshu Borah, M.P.; Deka, P.; Bora, J.; Naorem, R.S.; Das, J.; Teli, A.B. Microplastics and human health: Unveiling the gut microbiome disruption and chronic disease risks. Front. Cell. Infect. Microbiol. 2024, 14, 1492759. [Google Scholar] [CrossRef]
  49. Zhang, L.; Agrawal, M.; Ng, S.C.; Jess, T. Early-life exposures and the microbiome: Implications for IBD prevention. Gut 2024, 73, 541–549. [Google Scholar] [CrossRef]
  50. Ojeda-Granados, C.; Campisi, E.; Barchitta, M.; Agodi, A. Genetic, lifestyle and metabolic factors contributing to cardiovascular disease in the Italian population: A literature review. Front. Nutr. 2024, 11, 1379785. [Google Scholar] [CrossRef]
  51. Tang, W.H.; Kitai, T.; Hazen, S.L. Gut Microbiota in Cardiovascular Health and Disease. Circ. Res. 2017, 120, 1183–1196. [Google Scholar] [CrossRef]
  52. Xu, H.; Wang, X.; Feng, W.; Liu, Q.; Zhou, S.; Liu, Q.; Cai, L. The gut microbiota and its interactions with cardiovascular disease. Microb. Biotechnol. 2020, 13, 637–656. [Google Scholar] [CrossRef] [PubMed]
  53. Shahim, B.; Kapelios, C.J.; Savarese, G.; Lund, L.H. Global Public Health Burden of Heart Failure: An Updated Review. Card. Fail. Rev. 2023, 9, e11. [Google Scholar] [CrossRef] [PubMed]
  54. Heidenreich, P.A.; Albert, N.M.; Allen, L.A.; Bluemke, D.A.; Butler, J.; Fonarow, G.C.; Ikonomidis, J.S.; Khavjou, O.; Konstam, M.A.; Maddox, T.M.; et al. Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association. Circ. Heart Fail. 2013, 6, 606–619. [Google Scholar] [CrossRef] [PubMed]
  55. Borovac, J.A.; D’Amario, D.; Bozic, J.; Glavas, D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J. Cardiol. 2020, 12, 373–408. [Google Scholar] [CrossRef]
  56. Fukui, H. Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation? Inflamm. Intest. Dis. 2016, 1, 135–145. [Google Scholar] [CrossRef]
  57. Trehan, S.; Singh, G.; Bector, G.; Jain, P.; Mehta, T.; Goswami, K.; Chawla, A.; Jain, A.; Puri, P.; Garg, N. Gut Dysbiosis and Cardiovascular Health: A Comprehensive Review of Mechanisms and Therapeutic Potential. Cureus 2024, 16, e67010. [Google Scholar] [CrossRef]
  58. Méndez-Bailón, M.; Jiménez-García, R.; Hernández-Barrera, V.; Miguel-Díez, J.; Miguel-Yanes, J.M.; Muñoz-Rivas, N.; Lorenzo-Villalba, N.; Carabantes-Alarcon, D.; Zamorano-León, J.J.; Astasio-Arbiza, P.; et al. Heart Failure Is a Risk Factor for Suffering and Dying of Clostridium difficile Infection. Results of a 15-Year Nationwide Study in Spain. J. Clin. Med. 2020, 9, 614. [Google Scholar] [CrossRef]
  59. Duan, H.; Wang, L.; Huangfu, M.; Li, H. The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: Mechanisms and therapeutic potentials. Biomed. Pharmacother. 2023, 165, 115276. [Google Scholar] [CrossRef]
  60. Patil, R.S.; Maloney, M.E.; Lucas, R.; Fulton, D.J.R.; Patel, V.; Bagi, Z.; Kovacs-Kasa, A.; Kovacs, L.; Su, Y.; Verin, A.D. Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology. Biomolecules 2024, 14, 140. [Google Scholar] [CrossRef]
  61. Nagatomo, Y.; Tang, W.H. Intersections Between Microbiome and Heart Failure: Revisiting the Gut Hypothesis. J. Card. Fail. 2015, 21, 973–980. [Google Scholar] [CrossRef] [PubMed]
  62. Jing, L.; Zhang, H.; Xiang, Q.; Hu, H.; Zhai, C.; Xu, S.; Tian, H. Role of Trimethylamine N-Oxide in Heart Failure. Rev. Cardiovasc. Med. 2024, 25, 240. [Google Scholar] [CrossRef]
  63. Palm, C.L.; Nijholt, K.T.; Bakker, B.M.; Westenbrink, B.D. Short-Chain Fatty Acids in the Metabolism of Heart Failure—Rethinking the Fat Stigma. Front. Cardiovasc. Med. 2022, 9, 915102. [Google Scholar] [CrossRef] [PubMed]
  64. Riehle, C.; Abel, E.D. PGC-1 proteins and heart failure. Trends Cardiovasc. Med. 2012, 22, 98–105. [Google Scholar] [CrossRef]
  65. Li, Y.; Wang, L.; Yi, Q.; Luo, L.; Xiong, Y. Regulation of bile acids and their receptor FXR in metabolic diseases. Front. Nutr. 2024, 11, 1447878. [Google Scholar] [CrossRef] [PubMed]
  66. Zhenyukh, O.; González-Amor, M.; Rodrigues-Diez, R.R.; Esteban, V.; Ruiz-Ortega, M.; Salaices, M.; Mas, S.; Briones, A.M.; Egido, J. Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation. J. Cell Mol. Med. 2018, 22, 4948–4962. [Google Scholar] [CrossRef]
  67. Li, S. Modulation of immunity by tryptophan microbial metabolites. Front. Nutr. 2023, 10, 1209613. [Google Scholar] [CrossRef]
  68. Pereira, R.O.; Wende, A.R.; Crum, A.; Hunter, D.; Olsen, C.D.; Rawlings, T.; Riehle, C.; Ward, W.F.; Abel, E.D. Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2014, 28, 3691–3702. [Google Scholar] [CrossRef]
  69. Cianci, R.; Franza, L.; Borriello, R.; Pagliari, D.; Gasbarrini, A.; Gambassi, G. The Role of Gut Microbiota in Heart Failure: When Friends Become Enemies. Biomedicines 2022, 10, 2712. [Google Scholar] [CrossRef]
  70. Mamic, P.; Snyder, M.; Tang, W.H.W. Gut Microbiome-Based Management of Patients With Heart Failure: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2023, 81, 1729–1739. [Google Scholar] [CrossRef]
  71. Huang, Y.J.; Ferrari, M.W.; Lin, S.; Wang, Z.H. Recent advances on the Role of Gut Microbiota in the Development of Heart Failure by Mediating Immune Metabolism. Curr. Probl. Cardiol. 2024, 49, 102128. [Google Scholar] [CrossRef] [PubMed]
  72. Singh, S.; Shankar, R.; Singh, G.P. Prevalence and Associated Risk Factors of Hypertension: A Cross-Sectional Study in Urban Varanasi. Int. J. Hypertens 2017, 2017, 5491838. [Google Scholar] [CrossRef] [PubMed]
  73. Mills, K.T.; Stefanescu, A.; He, J. The global epidemiology of hypertension. Nat. Rev. Nephrol. 2020, 16, 223–237. [Google Scholar] [CrossRef]
  74. Lu, J.; Lu, Y.; Wang, X.; Li, X.; Linderman, G.C.; Wu, C.; Cheng, X.; Mu, L.; Zhang, H.; Liu, J.; et al. Prevalence, awareness, treatment, and control of hypertension in China: Data from 1·7 million adults in a population-based screening study (China PEACE Million Persons Project). Lancet 2017, 390, 2549–2558. [Google Scholar] [CrossRef]
  75. Yang, Z.; Lin, S.; Liu, Y.; Song, Z.; Ge, Z.; Fan, Y.; Chen, L.; Bi, Y.; Zhao, Z.; Wang, X.; et al. Targeting intestinal microecology: Potential intervention strategies of traditional Chinese medicine for managing hypertension. Front. Pharmacol. 2023, 14, 1171119. [Google Scholar] [CrossRef]
  76. Cai, M.; Lin, L.; Jiang, F.; Peng, Y.; Li, S.; Chen, L.; Lin, Y. Gut microbiota changes in patients with hypertension: A systematic review and meta-analysis. J. Clin. Hypertens 2023, 25, 1053–1068. [Google Scholar] [CrossRef] [PubMed]
  77. Fusco, W.; Lorenzo, M.B.; Cintoni, M.; Porcari, S.; Rinninella, E.; Kaitsas, F.; Lener, E.; Mele, M.C.; Gasbarrini, A.; Collado, M.C.; et al. Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients 2023, 15, 2211. [Google Scholar] [CrossRef]
  78. Verhaar, B.J.H.; Prodan, A.; Nieuwdorp, M.; Muller, M. Gut Microbiota in Hypertension and Atherosclerosis: A Review. Nutrients 2020, 12, 2982. [Google Scholar] [CrossRef]
  79. Mousa, W.K.; Chehadeh, F.; Husband, S. Microbial dysbiosis in the gut drives systemic autoimmune diseases. Front. Immunol. 2022, 13, 906258. [Google Scholar] [CrossRef]
  80. Drożdż, D.; Drożdż, M.; Wójcik, M. Endothelial dysfunction as a factor leading to arterial hypertension. Pediatr. Nephrol. 2023, 38, 2973–2985. [Google Scholar] [CrossRef]
  81. Al Khodor, S.; Reichert, B.; Shatat, I.F. The Microbiome and Blood Pressure: Can Microbes Regulate Our Blood Pressure? Front. Pediatr. 2017, 5, 138. [Google Scholar] [CrossRef]
  82. Violi, F.; Cammisotto, V.; Bartimoccia, S.; Pignatelli, P.; Carnevale, R.; Nocella, C. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat. Rev. Cardiol. 2023, 20, 24–37. [Google Scholar] [CrossRef] [PubMed]
  83. Pawlonka, J.; Buchalska, B.; Buczma, K.; Borzuta, H.; Kamińska, K.; Cudnoch-Jędrzejewska, A. Targeting the Renin–angiotensin–aldosterone System (RAAS) for Cardiovascular Protection and Enhanced Oncological Outcomes: Review. Curr. Treat. Options Oncol. 2024, 25, 1406–1427. [Google Scholar] [CrossRef] [PubMed]
  84. Dias, M.T.S.; Aguilar, E.C.; Campos, G.P.; do Couto, N.F.; Capettini, L.D.S.A.; Braga, W.F.; Andrade, L.O.; Alvarez-Leite, J. Butyrate inhibits LPC-induced endothelial dysfunction by regulating nNOS-produced NO and ROS production. Nitric Oxide Biol. Chem. 2023, 138–139, 42–50. [Google Scholar] [CrossRef]
  85. Beito, M.R.; Ashraf, S.; Odogwu, D.; Harmancey, R. Role of Ectopic Olfactory Receptors in the Regulation of the Cardiovascular–Kidney–Metabolic Axis. Life 2024, 14, 548. [Google Scholar] [CrossRef] [PubMed]
  86. Janeiro, M.H.; Ramírez, M.J.; Milagro, F.I.; Martínez, J.A.; Solas, M. Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target. Nutrients 2018, 10, 1398. [Google Scholar] [CrossRef]
  87. Zhu, W.; Gregory, J.C.; Org, E.; Buffa, J.A.; Gupta, N.; Wang, Z.; Li, L.; Fu, X.; Wu, Y.; Mehrabian, M.; et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 2016, 165, 111–124. [Google Scholar] [CrossRef]
  88. Hubbard, T.; Murray, I.; Bisson, W.; Lahoti, T.S.; Gowda, K.; Amin, S.G.; Patterson, A.D.; Perdew, G.H. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 2015, 5, 12689. [Google Scholar] [CrossRef]
  89. Xuan, M.; Gu, X.; Li, J.; Huang, D.; Xue, C.; He, Y. Polyamines: Their significance for maintaining health and contributing to diseases. Cell Commun. Signal. 2023, 21, 348. [Google Scholar] [CrossRef]
  90. Salari, N.; Morddarvanjoghi, F.; Abdolmaleki, A.; Rasoulpoor, S.; Khaleghi, A.A.; Hezarkhani, L.A.; Shohaimi, S.; Mohammadi, M. The global prevalence of myocardial infarction: A systematic review and meta-analysis. BMC Cardiovasc. Disord. 2023, 23, 206. [Google Scholar] [CrossRef]
  91. Rajati, F.; Rajati, M.; Chegeni, M.; Kazeminia, M. The prevalence of myocardial infarction in the elderly: A systematic review and meta-analysis. ARYA Atheroscler. 2024, 20, 61–73. [Google Scholar] [CrossRef] [PubMed]
  92. Wereski, R.; Kimenai, D.M.; Bularga, A.; Taggart, C.; Lowe, D.J.; Mills, N.L.; Chapman, A.R. Risk factors for type 1 and type 2 myocardial infarction. Eur. Heart J. 2022, 43, 127–135. [Google Scholar] [CrossRef]
  93. Gaziano, T.A.; Bitton, A.; Anand, S.; Abrahams-Gessel, S.; Murphy, A. Growing epidemic of coronary heart disease in low- and middle-income countries. Curr. Probl. Cardiol. 2010, 35, 72–115. [Google Scholar] [CrossRef] [PubMed]
  94. Papadopoulos, P.D.; Tsigalou, C.; Valsamaki, P.N.; Konstantinidis, T.G.; Voidarou, C.; Bezirtzoglou, E. The Emerging Role of the Gut Microbiome in Cardiovascular Disease: Current Knowledge and Perspectives. Biomedicines 2022, 10, 948. [Google Scholar] [CrossRef]
  95. Han, Y.; Gong, Z.; Sun, G.; Xu, J.; Qi, C.; Sun, W.; Jiang, H.; Cao, P.; Ju, H. Dysbiosis of Gut Microbiota in Patients With Acute Myocardial Infarction. Front. Microbiol. 2021, 12, 680101. [Google Scholar] [CrossRef]
  96. Hills, R.D., Jr.; Pontefract, B.A.; Mishcon, H.R.; Black, C.A.; Sutton, S.C.; Theberge, C.R. Gut Microbiome: Profound Implications for Diet and Disease. Nutrients 2019, 11, 1613. [Google Scholar] [CrossRef]
  97. Bijla, M.; Saini, S.K.; Pathak, A.K.; Bharadwaj, K.P.; Sukhavasi, K.; Patil, A.; Saini, D.; Yadav, R.; Singh, S.; Leeuwenburgh, C.; et al. Microbiome interactions with different risk factors in development of myocardial infarction. Exp. Gerontol. 2024, 189, 112409. [Google Scholar] [CrossRef] [PubMed]
  98. An, L.; Wirth, U.; Koch, D.; Schirren, M.; Drefs, M.; Koliogiannis, D.; Nieß, H.; Andrassy, J.; Guba, M.; Bazhin, A.V.; et al. The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases. J. Gastrointest. Surg. Off. J. Soc. Surg. Aliment. Tract. 2022, 26, 671–683. [Google Scholar] [CrossRef]
  99. Novakovic, M.; Rout, A.; Kingsley, T.; Kirchoff, R.; Singh, A.; Verma, V.; Kant, R.; Chaudhary, R. Role of gut microbiota in cardiovascular diseases. World J. Cardiol. 2020, 12, 110–122. [Google Scholar] [CrossRef]
  100. Zhou, X.; Li, J.; Guo, J.; Geng, B.; Ji, W.; Zhao, Q.; Li, J.; Liu, X.; Liu, J.; Guo, Z.; et al. Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction. Microbiome 2018, 6, 66. [Google Scholar] [CrossRef]
  101. Shanmugham, M.; Bellanger, S.; Leo, C.H. Gut-Derived Metabolite, Trimethylamine-N-oxide (TMAO) in Cardio-Metabolic Diseases: Detection, Mechanism, and Potential Therapeutics. Pharmaceuticals 2023, 16, 504. [Google Scholar] [CrossRef] [PubMed]
  102. Krishnamoorthy, N.K.; Kalyan, M.; Hediyal, T.A.; Anand, N.; Kendaganna, P.H.; Pendyala, G.; Yelamanchili, S.V.; Yang, J.; Chidambaram, S.B.; Sakharkar, M.K.; et al. Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases. ACS Omega 2024, 9, 3164–3172. [Google Scholar] [CrossRef]
  103. Peng, J.; Xiao, X.; Hu, M.; Zhang, X. Interaction between gut microbiome and cardiovascular disease. Life Sci. 2018, 214, 153–157. [Google Scholar] [CrossRef] [PubMed]
  104. Shen, Y.; Fan, N.; Ma, S.X.; Cheng, X.; Yang, X.; Wang, G. Gut Microbiota Dysbiosis: Pathogenesis, Diseases, Prevention, and Therapy. MedComm 2025, 6, e70168. [Google Scholar] [CrossRef]
  105. Oktaviono, Y.H.; Dyah Lamara, A.; Saputra, P.B.T.; Arnindita, J.N.; Pasahari, D.; Saputra, M.E.; Suasti, N.M.A. The roles of trimethylamine-N-oxide in atherosclerosis and its potential therapeutic aspect: A literature review. Biomol. Biomed. 2023, 23, 936–948. [Google Scholar] [CrossRef]
  106. Eisner, D.A.; Caldwell, J.L.; Kistamás, K.; Trafford, A.W. Calcium and Excitation-Contraction Coupling in the Heart. Circ. Res. 2017, 121, 181–195. [Google Scholar] [CrossRef]
  107. Soranno, D.E.; Coopersmith, C.M.; Brinkworth, J.F.; Factora, F.N.F.; Muntean, J.H.; Mythen, M.G.; Raphael, J.; Shaw, A.D.; Vachharajani, V.; Messer, J.S. A review of gut failure as a cause and consequence of critical illness. Crit. Care 2025, 29, 91. [Google Scholar] [CrossRef]
  108. Badimon, L.; Padró, T.; Vilahur, G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur. Heart J. Acute Cardiovasc. Care 2012, 1, 60–74. [Google Scholar] [CrossRef] [PubMed]
  109. Finegold, J.A.; Asaria, P.; Francis, D.P. Mortality from ischaemic heart disease by country, region, and age: Statistics from World Health Organisation and United Nations. Int. J. Cardiol. 2013, 168, 934–945. [Google Scholar] [CrossRef]
  110. Trimarchi, G.; Pizzino, F.; Paradossi, U.; Gueli, I.A.; Palazzini, M.; Gentile, P.; Di Spigno, F.; Ammirati, E.; Garascia, A.; Tedeschi, A.; et al. Charting the Unseen: How Non-Invasive Imaging Could Redefine Cardiovascular Prevention. J. Cardiovasc. Dev. Dis. 2024, 11, 245. [Google Scholar] [CrossRef]
  111. Jin, L.; Shi, X.; Yang, J.; Zhao, Y.; Xue, L.; Xu, L.; Cai, J. Gut microbes in cardiovascular diseases and their potential therapeutic applications. Protein Cell 2021, 12, 346–359. [Google Scholar] [CrossRef] [PubMed]
  112. Alexandrescu, L.; Suceveanu, A.P.; Stanigut, A.M.; Tofolean, D.E.; Axelerad, A.D.; Iordache, I.E.; Herlo, A.; Nelson Twakor, A.; Nicoara, A.D.; Tocia, C.; et al. Intestinal Insights: The Gut Microbiome’s Role in Atherosclerotic Disease: A Narrative Review. Microorganisms 2024, 12, 2341. [Google Scholar] [CrossRef] [PubMed]
  113. Wang, X.; Zhou, S.; Hu, X.; Ye, C.; Nie, Q.; Wang, K.; Yan, S.; Lin, J.; Xu, F.; Li, M.; et al. Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling. Cell Host Microbe 2024, 32, 964–979.e7. [Google Scholar] [CrossRef] [PubMed]
  114. Jie, Z.; Xia, H.; Zhong, S.L.; Feng, Q.; Li, S.; Liang, S.; Zhong, H.; Liu, Z.; Gao, Y.; Zhao, H.; et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 2017, 8, 845. [Google Scholar] [CrossRef]
  115. Malesza, I.J.; Malesza, M.; Walkowiak, J.; Mussin, N.; Walkowiak, D.; Aringazina, R.; Bartkowiak-Wieczorek, J.; Mądry, E. High-Fat, Western-Style Diet, Systemic Inflammation, and Gut Microbiota: A Narrative Review. Cells 2021, 10, 3164. [Google Scholar] [CrossRef]
  116. Laurans, L.; Mouttoulingam, N.; Chajadine, M.; Lavelle, A.; Diedisheim, M.; Bacquer, E.; Creusot, L.; Suffee, N.; Esposito, B.; Melhem, N.J.; et al. An obesogenic diet increases atherosclerosis through promoting microbiota dysbiosis-induced gut lymphocyte trafficking into the periphery. Cell Rep. 2023, 42, 113350. [Google Scholar] [CrossRef]
  117. Caradonna, E.; Abate, F.; Schiano, E.; Paparella, F.; Ferrara, F.; Vanoli, E.; Difruscolo, R.; Goffredo, V.M.; Amato, B.; Setacci, C.; et al. Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health. Metabolites 2025, 15, 220. [Google Scholar] [CrossRef]
  118. Gui, Y.; Zheng, H.; Cao, R.Y. Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms. Front. Cardiovasc. Med. 2022, 9, 845942. [Google Scholar] [CrossRef]
  119. Seldin, M.M.; Meng, Y.; Qi, H.; Zhu, W.; Wang, Z.; Hazen, S.L.; Lusis, A.J.; Shih, D.M. Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-κB. J. Am. Heart Assoc. 2016, 5, e002767. [Google Scholar] [CrossRef]
  120. Canyelles, M.; Borràs, C.; Rotllan, N.; Tondo, M.; Escolà-Gil, J.C.; Blanco-Vaca, F. Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease? Int. J. Mol. Sci. 2023, 24, 1940. [Google Scholar] [CrossRef]
  121. Nogal, A.; Valdes, A.M.; Menni, C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes 2021, 13, 1897212. [Google Scholar] [CrossRef] [PubMed]
  122. Christofides, A.; Konstantinidou, E.; Jani, C.; Boussiotis, V.A. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metab. Clin. Exp. 2021, 114, 154338. [Google Scholar] [CrossRef] [PubMed]
  123. Lange, O.; Proczko-Stepaniak, M.; Mika, A. Short-Chain Fatty Acids-A Product of the Microbiome and Its Participation in Two-Way Communication on the Microbiome-Host Mammal Line. Curr. Obes. Rep. 2023, 12, 108–126. [Google Scholar] [CrossRef]
  124. Strauss, M.H.; Hall, A.S.; Narkiewicz, K. The Combination of Beta-Blockers and ACE Inhibitors Across the Spectrum of Cardiovascular Diseases. Cardiovasc. Drugs Ther. 2023, 37, 757–770. [Google Scholar] [CrossRef] [PubMed]
  125. Niazi, M.; Galehdar, N.; Jamshidi, M.; Mohammadi, R.; Moayyedkazemi, A. A Review of the Role of Statins in Heart Failure Treatment. Curr. Clin. Pharmacol. 2020, 15, 30–37. [Google Scholar] [CrossRef]
  126. Roghani, S.H.; Khan, D.S.; Shafiq, A.; Akbar, A.; Mustafa, W.; Shah, S.Q.A.; Khan, M., Jr.; Ali, H. Efficacy of Different Beta Blockers in Reducing Mortality in Heart-Failure Patients. Cureus 2024, 16, e74171. [Google Scholar] [CrossRef]
  127. Alcocer, L.A.; Bryce, A.; De Padua Brasil, D.; Lara, J.; Cortes, J.M.; Quesada, D.; Rodriguez, P. The Pivotal Role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension Management and Cardiovascular and Renal Protection: A Critical Appraisal and Comparison of International Guidelines. Am. J. Cardiovasc. Drugs Drugs Devices Other Interv. 2023, 23, 663–682. [Google Scholar] [CrossRef]
  128. Patail, H.; Sharma, T.; Bali, A.D.; Isath, A.; Aronow, W.S.; Haidry, S.A. Dual antiplatelet therapy with concomitant anticoagulation: Current perspectives on triple therapy. Arch. Med. Sci. Atheroscler. Dis. 2023, 8, e13–e18. [Google Scholar] [CrossRef]
  129. Velidakis, N.; Stachteas, P.; Gkougkoudi, E.; Papadopoulos, C.; Kadoglou, N.P.E. Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease—A Narrative Clinical Review. Pharmaceuticals 2024, 17, 568. [Google Scholar] [CrossRef]
  130. Zuo, L.; Yue, X.; Bian, T.; Cai, Y.; Wang, L.; Zeng, L.; He, H.; Wang, L.; Ioannou, A.; Li, S. Coronary artery bypass surgery versus medical therapy alone for ischaemic heart disease. Cochrane Database Syst. Rev. 2021, 2021, CD013645. [Google Scholar] [CrossRef]
  131. Dasi, L.P.; Hatoum, H.; Kheradvar, A.; Zareian, R.; Alavi, S.H.; Sun, W.; Martin, C.; Pham, T.; Wang, Q.; Midha, P.A.; et al. On the Mechanics of Transcatheter Aortic Valve Replacement. Ann. Biomed. Eng. 2017, 45, 310–331. [Google Scholar] [CrossRef] [PubMed]
  132. Ghodeshwar, G.K.; Dube, A.; Khobragade, D. Impact of Lifestyle Modifications on Cardiovascular Health: A Narrative Review. Cureus 2023, 15, e42616. [Google Scholar] [CrossRef] [PubMed]
  133. Golomb, B.A.; Evans, M.A. Statin adverse effects: A review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs Drugs Devices Other Interv. 2008, 8, 373–418. [Google Scholar] [CrossRef]
  134. Sethi, Y.; Patel, N.; Kaka, N.; Kaiwan, O.; Kar, J.; Moinuddin, A.; Goel, A.; Chopra, H.; Cavalu, S. Precision Medicine and the future of Cardiovascular Diseases: A Clinically Oriented Comprehensive Review. J. Clin. Med. 2023, 12, 1799. [Google Scholar] [CrossRef]
  135. Sharifi-Rad, J.; Rodrigues, C.F.; Sharopov, F.; Docea, A.O.; Can Karaca, A.; Sharifi-Rad, M.; Kahveci Karıncaoglu, D.; Gülseren, G.; Şenol, E.; Demircan, E.; et al. Diet, Lifestyle and Cardiovascular Diseases: Linking Pathophysiology to Cardioprotective Effects of Natural Bioactive Compounds. Int. J. Environ. Res. Public Health 2020, 17, 2326. [Google Scholar] [CrossRef]
  136. Méndez, L.; Medina, I. Polyphenols and Fish Oils for Improving Metabolic Health: A Revision of the Recent Evidence for Their Combined Nutraceutical Effects. Molecules 2021, 26, 2438. [Google Scholar] [CrossRef] [PubMed]
  137. Panche, A.N.; Diwan, A.D.; Chandra, S.R. Flavonoids: An overview. J. Nutr. Sci. 2016, 5, e47. [Google Scholar] [CrossRef] [PubMed]
  138. Dias, M.C.; Pinto, D.C.G.A.; Silva, A.M.S. Plant Flavonoids: Chemical Characteristics and Biological Activity. Molecules 2021, 26, 5377. [Google Scholar] [CrossRef]
  139. Ullah, A.; Munir, S.; Badshah, S.L.; Khan, N.; Ghani, L.; Poulson, B.G.; Emwas, A.H.; Jaremko, M. Important Flavonoids and Their Role as a Therapeutic Agent. Molecules 2020, 25, 5243. [Google Scholar] [CrossRef]
  140. Drețcanu, G.; Știrbu, I.; Leoplold, N.; Cruceriu, D.; Danciu, C.; Stănilă, A.; Fărcaș, A.; Borda, I.M.; Iuhas, C.; Diaconeasa, Z. Chemical Structure, Sources and Role of Bioactive Flavonoids in Cancer Prevention: A Review. Plants 2022, 11, 1117. [Google Scholar] [CrossRef]
  141. Zahra, M.; Abrahamse, H.; George, B.P. Flavonoids: Antioxidant Powerhouses and Their Role in Nanomedicine. Antioxidants 2024, 13, 922. [Google Scholar] [CrossRef] [PubMed]
  142. Ciumărnean, L.; Milaciu, M.V.; Runcan, O.; Vesa, Ș.C.; Răchișan, A.L.; Negrean, V.; Perné, M.G.; Donca, V.I.; Alexescu, T.G.; Para, I.; et al. The Effects of Flavonoids in Cardiovascular Diseases. Molecules 2020, 25, 4320. [Google Scholar] [CrossRef]
  143. Scioli, M.G.; Storti, G.; D’Amico, F.; Rodríguez Guzmán, R.; Centofanti, F.; Doldo, E.; Céspedes Miranda, E.M.; Orlandi, A. Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets. J. Clin. Med. 2020, 9, 1995. [Google Scholar] [CrossRef] [PubMed]
  144. Bellavite, P. Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action. Antioxidants 2023, 12, 280. [Google Scholar] [CrossRef]
  145. Mucha, P.; Skoczyńska, A.; Małecka, M.; Hikisz, P.; Budzisz, E. Overview of the Antioxidant and Anti-Inflammatory Activities of Selected Plant Compounds and Their Metal Ions Complexes. Molecules 2021, 26, 4886. [Google Scholar] [CrossRef]
  146. Al-Khayri, J.M.; Sahana, G.R.; Nagella, P.; Joseph, B.V.; Alessa, F.M.; Al-Mssallem, M.Q. Flavonoids as Potential Anti-Inflammatory Molecules: A Review. Molecules 2022, 27, 2901. [Google Scholar] [CrossRef]
  147. Jomova, K.; Raptova, R.; Alomar, S.Y.; Alwasel, S.H.; Nepovimova, E.; Kuca, K.; Valko, M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging. Arch. Toxicol. 2023, 97, 2499–2574. [Google Scholar] [CrossRef] [PubMed]
  148. Zhang, W.; Zheng, Y.; Yan, F.; Dong, M.; Ren, Y. Research progress of quercetin in cardiovascular disease. Front. Cardiovasc. Med. 2023, 10, 1203713. [Google Scholar] [CrossRef]
  149. Cavalier, A.N.; Clayton, Z.S.; Wahl, D.; Hutton, D.A.; McEntee, C.M.; Seals, D.R.; LaRocca, T.J. Protective effects of apigenin on the brain transcriptome with aging. Mech. Ageing Dev. 2024, 217, 111889. [Google Scholar] [CrossRef]
  150. Kozłowska, A.; Szostak-Węgierek, D. Targeting Cardiovascular Diseases by Flavonols: An Update. Nutrients 2022, 14, 1439. [Google Scholar] [CrossRef]
  151. Khan, J.; Deb, P.K.; Priya, S.; Medina, K.D.; Devi, R.; Walode, S.G.; Rudrapal, M. Dietary Flavonoids: Cardioprotective Potential with Antioxidant Effects and Their Pharmacokinetic, Toxicological and Therapeutic Concerns. Molecules 2021, 26, 4021. [Google Scholar] [CrossRef] [PubMed]
  152. Yao, J.; Peng, T.; Shao, C.; Liu, Y.; Lin, H.; Liu, Y. The Antioxidant Action of Astragali radix: Its Active Components and Molecular Basis. Molecules 2024, 29, 1691. [Google Scholar] [CrossRef] [PubMed]
  153. Zawawi, N.A.; Ahmad, H.; Madatheri, R.; Fadilah, N.I.M.; Maarof, M.; Fauzi, M.B. Flavonoids as Natural Anti-Inflammatory Agents in the Atopic Dermatitis Treatment. Pharmaceutics 2025, 17, 261. [Google Scholar] [CrossRef] [PubMed]
  154. Verma, V.K.; Bhardwaj, P.; Prajapati, V.; Bhatia, A.; Purkait, S.; Arya, D.S. Flavonoids as therapeutics for myocardial ischemia-reperfusion injury: A comprehensive review on preclinical studies. Lab. Anim. Res. 2024, 40, 32. [Google Scholar] [CrossRef]
  155. Kampa, R.P.; Sęk, A.; Bednarczyk, P.; Szewczyk, A.; Calderone, V.; Testai, L. Flavonoids as new regulators of mitochondrial potassium channels: Contribution to cardioprotection. J. Pharm. Pharmacol. 2023, 75, 466–481. [Google Scholar] [CrossRef]
  156. Kulawiak, B.; Bednarczyk, P.; Szewczyk, A. Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels. Cells 2021, 10, 1554. [Google Scholar] [CrossRef]
  157. Si, H.; Wyeth, R.P.; Liu, D. The flavonoid luteolin induces nitric oxide production and arterial relaxation. Eur. J. Nutr. 2014, 53, 269–275. [Google Scholar] [CrossRef]
  158. Guerrero, L.; Castillo, J.; Quiñones, M.; Garcia-Vallvé, S.; Arola, L.; Pujadas, G.; Muguerza, B. Inhibition of angiotensin-converting enzyme activity by flavonoids: Structure-activity relationship studies. PLoS ONE 2012, 7, e49493. [Google Scholar] [CrossRef]
  159. Ross, J.A.; Kasum, C.M. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr. 2002, 22, 19–34. [Google Scholar] [CrossRef]
  160. Ahmed, K.R.; Rahman, M.M.; Islam, M.N.; Fahim, M.M.H.; Rahman, M.A.; Kim, B. Antioxidants activities of phytochemicals perspective modulation of autophagy and apoptosis to treating cancer. Biomed. Pharmacother. 2024, 174, 116497. [Google Scholar] [CrossRef]
  161. Jubaidi, F.F.; Zainalabidin, S.; Mariappan, V.; Budin, S.B. Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids. Int. J. Mol. Sci. 2020, 21, 6043. [Google Scholar] [CrossRef]
  162. Jia, J.Y.; Zang, E.H.; Lv, L.J.; Li, Q.Y.; Zhang, C.H.; Xia, Y.; Zhang, L.; Dang, L.S.; Li, M.H. Flavonoids in myocardial ischemia-reperfusion injury: Therapeutic effects and mechanisms. Chin. Herb. Med. 2020, 13, 49–63. [Google Scholar] [CrossRef] [PubMed]
  163. Swanson, D.; Block, R.; Mousa, S.A. Omega-3 fatty acids EPA and DHA: Health benefits throughout life. Adv. Nutr. 2012, 3, 1–7. [Google Scholar] [CrossRef] [PubMed]
  164. Delgado-Lista, J.; Perez-Martinez, P.; Lopez-Miranda, J.; Perez-Jimenez, F. Long chain omega-3 fatty acids and cardiovascular disease: A systematic review. Br. J. Nutr. 2012, 107 (Suppl. 2), S201–S213. [Google Scholar] [CrossRef]
  165. Rauch, B.; Senges, J. The effects of supplementation with omega-3 polyunsaturated Fatty acids on cardiac rhythm: Anti-arrhythmic, pro-arrhythmic, both or neither? It depends…. Front. Physiol. 2012, 3, 57. [Google Scholar] [CrossRef]
  166. Bowen, K.J.; Harris, W.S.; Kris-Etherton, P.M. Omega-3 Fatty Acids and Cardiovascular Disease: Are There Benefits? Curr. Treat. Options Cardiovasc. Med. 2016, 18, 69. [Google Scholar] [CrossRef] [PubMed]
  167. Rundblad, A.; Sandoval, V.; Holven, K.B.; Ordovás, J.M.; Ulven, S.M. Omega-3 fatty acids and individual variability in plasma triglyceride response: A mini-review. Redox Biol. 2023, 63, 102730. [Google Scholar] [CrossRef]
  168. Calder, P.C. Omega-3 polyunsaturated fatty acids and inflammatory processes: Nutrition or pharmacology? Br. J. Clin. Pharmacol. 2013, 75, 645–662. [Google Scholar] [CrossRef]
  169. Jannas-Vela, S.; Espinosa, A.; Candia, A.A.; Flores-Opazo, M.; Peñailillo, L.; Valenzuela, R. The Role of Omega-3 Polyunsaturated Fatty Acids and Their Lipid Mediators on Skeletal Muscle Regeneration: A Narrative Review. Nutrients 2023, 15, 871. [Google Scholar] [CrossRef]
  170. Adili, R.; Hawley, M.; Holinstat, M. Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids. Prostaglandins Other Lipid Mediat. 2018, 139, 10–18. [Google Scholar] [CrossRef]
  171. Sherratt, S.C.R.; Libby, P.; Budoff, M.J.; Bhatt, D.L.; Mason, R.P. Role of Omega-3 Fatty Acids in Cardiovascular Disease: The Debate Continues. Curr. Atheroscler. Rep. 2023, 25, 1–17. [Google Scholar] [CrossRef]
  172. Zanetti, M.; Grillo, A.; Losurdo, P.; Panizon, E.; Mearelli, F.; Cattin, L.; Barazzoni, R.; Carretta, R. Omega-3 Polyunsaturated Fatty Acids: Structural and Functional Effects on the Vascular Wall. BioMed Res. Int. 2015, 2015, 791978. [Google Scholar] [CrossRef]
  173. Jayedi, A.; Shab-Bidar, S.; Eimeri, S.; Djafarian, K. Fish consumption and risk of all-cause and cardiovascular mortality: A dose-response meta-analysis of prospective observational studies. Public Health Nutr. 2018, 21, 1297–1306. [Google Scholar] [CrossRef]
  174. Moreno, C.; Macías, A.; Prieto, A.; de la Cruz, A.; González, T.; Valenzuela, C. Effects of n-3 Polyunsaturated Fatty Acids on Cardiac Ion Channels. Front. Physiol. 2012, 3, 245. [Google Scholar] [CrossRef]
  175. Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines 2018, 6, 91. [Google Scholar] [CrossRef]
  176. Yan, Q.; Liu, S.; Sun, Y.; Chen, C.; Yang, S.; Lin, M.; Long, J.; Yao, J.; Lin, Y.; Yi, F.; et al. Targeting oxidative stress as a preventive and therapeutic approach for cardiovascular disease. J. Transl. Med. 2023, 21, 519. [Google Scholar] [CrossRef]
  177. Xia, N.; Förstermann, U.; Li, H. Resveratrol and endothelial nitric oxide. Molecules 2014, 19, 16102–16121. [Google Scholar] [CrossRef]
  178. Meng, T.; Xiao, D.; Muhammed, A.; Deng, J.; Chen, L.; He, J. Anti-Inflammatory Action and Mechanisms of Resveratrol. Molecules 2021, 26, 229. [Google Scholar] [CrossRef]
  179. Salazar, J.; Pirela, D.; Nava, M.; Castro, A.; Angarita, L.; Parra, H.; Durán-Agüero, S.; Rojas-Gómez, D.M.; Galbán, N.; Añez, R.; et al. Specialized Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis. Int. J. Mol. Sci. 2022, 23, 3133. [Google Scholar] [CrossRef] [PubMed]
  180. Matsushima, S.; Sadoshima, J. The role of sirtuins in cardiac disease. Am. J. Physiol. Heart Circ. Physiol. 2015, 309, H1375–H1389. [Google Scholar] [CrossRef] [PubMed]
  181. Zordoky, B.N.; Robertson, I.M.; Dyck, J.R. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim. Biophys. Acta 2015, 1852, 1155–1177. [Google Scholar] [CrossRef]
  182. Bonnefont-Rousselot, D. Resveratrol and Cardiovascular Diseases. Nutrients 2016, 8, 250. [Google Scholar] [CrossRef]
  183. Cox, F.F.; Misiou, A.; Vierkant, A.; Ale-Agha, N.; Grandoch, M.; Haendeler, J.; Altschmied, J. Protective Effects of Curcumin in Cardiovascular Diseases-Impact on Oxidative Stress and Mitochondria. Cells 2022, 11, 342. [Google Scholar] [CrossRef] [PubMed]
  184. Młynarska, E.; Hajdys, J.; Czarnik, W.; Fularski, P.; Leszto, K.; Majchrowicz, G.; Lisińska, W.; Rysz, J.; Franczyk, B. The Role of Antioxidants in the Therapy of Cardiovascular Diseases-A Literature Review. Nutrients 2024, 16, 2587. [Google Scholar] [CrossRef]
  185. Singh, L.; Sharma, S.; Xu, S.; Tewari, D.; Fang, J. Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review. Molecules 2021, 26, 4036. [Google Scholar] [CrossRef]
  186. Wang, A.J.; Tang, Y.; Zhang, J.; Wang, B.J.; Xiao, M.; Lu, G.; Li, J.; Liu, Q.; Guo, Y.; Gu, J. Cardiac SIRT1 ameliorates doxorubicin-induced cardiotoxicity by targeting sestrin 2. Redox Biol. 2022, 52, 102310. [Google Scholar] [CrossRef]
  187. Wei, Z.; Pinfang, K.; Jing, Z.; Zhuoya, Y.; Shaohuan, Q.; Chao, S. Curcumin Improves Diabetic Cardiomyopathy by Inhibiting Pyroptosis through AKT/Nrf2/ARE Pathway. Mediat. Inflamm. 2023, 2023, 3906043. [Google Scholar] [CrossRef]
  188. Bahrami, A.; Montecucco, F.; Carbone, F.; Sahebkar, A. Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence. BioMed Res. Int. 2021, 2021, 8972074. [Google Scholar] [CrossRef]
  189. Sunagawa, Y.; Funamoto, M.; Shimizu, K.; Shimizu, S.; Sari, N.; Katanasaka, Y.; Miyazaki, Y.; Kakeya, H.; Hasegawa, K.; Morimoto, T. Curcumin, an Inhibitor of p300-HAT Activity, Suppresses the Development of Hypertension-Induced Left Ventricular Hypertrophy with Preserved Ejection Fraction in Dahl Rats. Nutrients 2021, 13, 2608. [Google Scholar] [CrossRef] [PubMed]
  190. Santos-Parker, J.R.; Strahler, T.R.; Bassett, C.J.; Bispham, N.Z.; Chonchol, M.B.; Seals, D.R. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging 2017, 9, 187–208. [Google Scholar] [CrossRef] [PubMed]
  191. Nurcahyanti, A.D.R.; Cokro, F.; Wulanjati, M.P.; Mahmoud, M.F.; Wink, M.; Sobeh, M. Curcuminoids for Metabolic Syndrome: Meta-Analysis Evidences Toward Personalized Prevention and Treatment Management. Front. Nutr. 2022, 9, 891339. [Google Scholar] [CrossRef] [PubMed]
  192. Roşian, Ş.H.; Boarescu, I.; Boarescu, P.-M. Antioxidant and Anti-Inflammatory Effects of Bioactive Compounds in Atherosclerosis. Int. J. Mol. Sci. 2025, 26, 1379. [Google Scholar] [CrossRef]
  193. Rabanal-Ruiz, Y.; Llanos-González, E.; Alcain, F.J. The Use of Coenzyme Q10 in Cardiovascular Diseases. Antioxidants 2021, 10, 755. [Google Scholar] [CrossRef]
  194. Garrido-Maraver, J.; Cordero, M.D.; Oropesa-Ávila, M.; Fernández Vega, A.; de la Mata, M.; Delgado Pavón, A.; de Miguel, M.; Pérez Calero, C.; Villanueva Paz, M.; Cotán, D.; et al. Coenzyme q10 therapy. Mol. Syndromol. 2014, 5, 187–197. [Google Scholar] [CrossRef]
  195. Cyr, A.R.; Huckaby, L.V.; Shiva, S.S.; Zuckerbraun, B.S. Nitric Oxide and Endothelial Dysfunction. Crit. Care Clin. 2020, 36, 307–321. [Google Scholar] [CrossRef] [PubMed]
  196. Mortensen, S.A.; Rosenfeldt, F.; Kumar, A.; Dolliner, P.; Filipiak, K.J.; Pella, D.; Alehagen, U.; Steurer, G.; Littarru, G.P.; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial. JACC Heart Fail. 2014, 2, 641–649. [Google Scholar] [CrossRef] [PubMed]
  197. Zozina, V.I.; Covantev, S.; Goroshko, O.A.; Krasnykh, L.M.; Kukes, V.G. Coenzyme Q10 in Cardiovascular and Metabolic Diseases: Current State of the Problem. Curr. Cardiol. Rev. 2018, 14, 164–174. [Google Scholar] [CrossRef]
  198. Suárez-Rivero, J.M.; Pastor-Maldonado, C.J.; de la Mata, M.; Villanueva-Paz, M.; Povea-Cabello, S.; Álvarez-Córdoba, M.; Villalón-García, I.; Suárez-Carrillo, A.; Talaverón-Rey, M.; Munuera, M.; et al. Atherosclerosis and Coenzyme Q10. Int. J. Mol. Sci. 2019, 20, 5195. [Google Scholar] [CrossRef]
  199. Zahedi, H.; Eghtesadi, S.; Seifirad, S.; Rezaee, N.; Shidfar, F.; Heydari, I.; Golestan, B.; Jazayeri, S. Effects of CoQ10 Supplementation on Lipid Profiles and Glycemic Control in Patients with Type 2 Diabetes: A randomized, double blind, placebo-controlled trial. J. Diabetes Metab. Disord. 2014, 13, 81. [Google Scholar] [CrossRef]
  200. Martelli, A.; Testai, L.; Colletti, A.; Cicero, A.F.G. Coenzyme Q10: Clinical Applications in Cardiovascular Diseases. Antioxidants 2020, 9, 341. [Google Scholar] [CrossRef]
  201. Dohlmann, T.L.; Kuhlman, A.B.; Morville, T.; Dahl, M.; Asping, M.; Orlando, P.; Silvestri, S.; Tiano, L.; Helge, J.W.; Dela, F.; et al. Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial. Antioxidants 2022, 11, 1698. [Google Scholar] [CrossRef] [PubMed]
  202. Mantle, D.; Dybring, A. Bioavailability of Coenzyme Q10: An Overview of the Absorption Process and Subsequent Metabolism. Antioxidants 2020, 9, 386. [Google Scholar] [CrossRef]
  203. Yurika, N.; Montuori, E.; Lauritano, C. Marine Microalgal Products with Activities against Age-Related Cardiovascular Diseases. Mar. Drugs 2024, 22, 229. [Google Scholar] [CrossRef] [PubMed]
  204. Nishida, Y.; Berg, P.C.; Shakersain, B.; Hecht, K.; Takikawa, A.; Tao, R.; Kakuta, Y.; Uragami, C.; Hashimoto, H.; Misawa, N.; et al. Astaxanthin: Past, Present, and Future. Mar. Drugs 2023, 21, 514. [Google Scholar] [CrossRef]
  205. Akram, W.; Rihan, M.; Ahmed, S.; Arora, S.; Ahmad, S.; Vashishth, R. Marine-Derived Compounds Applied in Cardiovascular Diseases: Submerged Medicinal Industry. Mar. Drugs 2023, 21, 193. [Google Scholar] [CrossRef] [PubMed]
  206. Nagahawatta, D.P.; Liyanage, N.M.; Jayawardena, T.U.; Jeon, Y.J. Marine Polyphenols in Cardiovascular Health: Unraveling Structure-Activity Relationships, Mechanisms, and Therapeutic Implications. Int. J. Mol. Sci. 2024, 25, 8419. [Google Scholar] [CrossRef]
  207. Cardoso, S.M.; Pereira, O.R.; Seca, A.M.; Pinto, D.C.; Silva, A.M. Seaweeds as Preventive Agents for Cardiovascular Diseases: From Nutrients to Functional Foods. Mar. Drugs 2015, 13, 6838–6865. [Google Scholar] [CrossRef]
  208. Lamminpää, I.; Amedei, A.; Parolini, C. Effects of Marine-Derived Components on Cardiovascular Disease Risk Factors and Gut Microbiota Diversity. Mar. Drugs 2024, 22, 523. [Google Scholar] [CrossRef]
  209. Han, Y.; Kim, D.H.; Pack, S.P. Marine-Derived Bioactive Ingredients in Functional Foods for Aging: Nutritional and Therapeutic Perspectives. Mar. Drugs 2024, 22, 496. [Google Scholar] [CrossRef]
  210. Olas, B. Probiotics, Prebiotics and Synbiotics-A Promising Strategy in Prevention and Treatment of Cardiovascular Diseases? Int. J. Mol. Sci. 2020, 21, 9737. [Google Scholar] [CrossRef]
  211. López-Yerena, A.; de Santisteban Villaplana, V.; Badimon, L.; Vilahur, G.; Padro, T. Probiotics: A Potential Strategy for Preventing and Managing Cardiovascular Disease. Nutrients 2025, 17, 52. [Google Scholar] [CrossRef]
  212. Yang, F.; Gao, R.; Luo, X.; Liu, R.; Xiong, D. Berberine influences multiple diseases by modifying gut microbiota. Front. Nutr. 2023, 10, 1187718. [Google Scholar] [CrossRef] [PubMed]
  213. Zhang, M.; Feng, L.; Li, J.; Chen, L. Therapeutic Potential and Mechanisms of Berberine in Cardiovascular Disease. Curr. Pharmacol. Rep. 2016, 2, 281–292. [Google Scholar] [CrossRef]
  214. Deng, B.; Tao, L.; Wang, Y. Natural products against inflammation and atherosclerosis: Targeting on gut microbiota. Front. Microbiol. 2022, 13, 997056. [Google Scholar] [CrossRef] [PubMed]
  215. Wang, X.; Qi, Y.; Zheng, H. Dietary Polyphenol, Gut Microbiota, and Health Benefits. Antioxidants 2022, 11, 1212. [Google Scholar] [CrossRef]
  216. Hooshangi Shayesteh, M.R.; Hami, Z.; Chamanara, M.; Parvizi, M.R.; Golaghaei, A.; Nassireslami, E. Evaluation of the protective effect of coenzyme Q10 on hepatotoxicity caused by acute phosphine poisoning. Int. J. ImmunopathoL. Pharmacol. 2024, 38, 3946320241250286. [Google Scholar] [CrossRef] [PubMed]
  217. Aghababaei, F.; Hadidi, M. Recent Advances in Potential Health Benefits of Quercetin. Pharmaceuticals 2023, 16, 1020. [Google Scholar] [CrossRef]
  218. Mi, W.; Hu, Z.; Xu, L.; Bian, X.; Lian, W.; Yin, S.; Zhao, S.; Gao, W.; Guo, C.; Shi, T. Quercetin positively affects gene expression profiles and metabolic pathway of antibiotic-treated mouse gut microbiota. Front. Microbiol. 2022, 13, 983358. [Google Scholar] [CrossRef]
  219. Zhu, X.; Dai, X.; Zhao, L.; Li, J.; Zhu, Y.; He, W.; Guan, X.; Wu, T.; Liu, L.; Song, H.; et al. Quercetin activates energy expenditure to combat metabolic syndrome through modulating gut microbiota-bile acids crosstalk in mice. Gut Microbes 2024, 16, 2390136. [Google Scholar] [CrossRef]
  220. Junyuan, Z.; Hui, X.; Chunlan, H.; Junjie, F.; Qixiang, M.; Yingying, L.; Lihong, L.; Xingpeng, W.; Yue, Z. Quercetin protects against intestinal barrier disruption and inflammation in acute necrotizing pancreatitis through TLR4/MyD88/p38 MAPK and ERS inhibition. Pancreatology 2018, 18, 742–752. [Google Scholar] [CrossRef]
  221. Zhao, L.; Zhang, Q.; Ma, W.; Tian, F.; Shen, H.; Zhou, M. A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. Food Funct. 2017, 8, 4644–4656. [Google Scholar] [CrossRef] [PubMed]
  222. Neto-Neves, E.M.; da Silva Maia Bezerra Filho, C.; Dejani, N.N.; de Sousa, D.P. Ferulic Acid and Cardiovascular Health: Therapeutic and Preventive Potential. Mini Rev. Med. Chem. 2021, 21, 1625–1637. [Google Scholar] [CrossRef] [PubMed]
  223. d’Angelo, M.; Castelli, V.; Tupone, M.G.; Catanesi, M.; Antonosante, A.; Dominguez-Benot, R.; Ippoliti, R.; Cimini, A.M.; Benedetti, E. Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs. Int. J. Mol. Sci. 2019, 20, 5422. [Google Scholar] [CrossRef]
  224. Zhou, M.; Ma, J.; Kang, M.; Tang, W.; Xia, S.; Yin, J.; Yin, Y. Flavonoids, gut microbiota, and host lipid metabolism. Eng. Life Sci. 2023, 24, 2300065. [Google Scholar] [CrossRef]
  225. Javadi, B.; Sobhani, Z. Role of apigenin in targeting metabolic syndrome: A systematic review. Iran. J. Basic Med. Sci. 2024, 27, 524–534. [Google Scholar] [CrossRef] [PubMed]
  226. El-Saadony, M.T.; Yang, T.; Korma, S.A.; Sitohy, M.; Abd El-Mageed, T.A.; Selim, S.; Al Jaouni, S.K.; Salem, H.M.; Mahmmod, Y.; Soliman, S.M.; et al. Impacts of turmeric and its principal bioactive curcumin on human health: Pharmaceutical, medicinal, and food applications: A comprehensive review. Front. Nutr. 2023, 9, 1040259. [Google Scholar] [CrossRef]
  227. Ghosh, S.S.; He, H.; Wang, J.; Gehr, T.W.; Ghosh, S. Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects. Tissue Barriers 2018, 6, e1425085. [Google Scholar] [CrossRef]
  228. Zarfeshany, A.; Asgary, S.; Javanmard, S.H. Potent health effects of pomegranate. Adv. Biomed. Res. 2014, 3, 100. [Google Scholar] [CrossRef]
  229. Aviram, M.; Rosenblat, M. Pomegranate Protection against Cardiovascular Diseases. Evid.-Based Complement. Altern. Med. 2012, 2012, 382763. [Google Scholar] [CrossRef]
  230. Festa, J.; Hussain, A.; Al-Hareth, Z.; Singh, H.; Da Boit, M. Anthocyanins and Vascular Health: A Matter of Metabolites. Foods 2023, 12, 1796. [Google Scholar] [CrossRef]
  231. Xiong, H.H.; Lin, S.Y.; Chen, L.L.; Ouyang, K.H.; Wang, W.J. The Interaction between Flavonoids and Intestinal Microbes: A Review. Foods 2023, 12, 320. [Google Scholar] [CrossRef] [PubMed]
  232. Zhong, H.; Xu, J.; Yang, M.; Hussain, M.; Liu, X.; Feng, F.; Guan, R. Protective Effect of Anthocyanins against Neurodegenerative Diseases through the Microbial-Intestinal-Brain Axis: A Critical Review. Nutrients 2023, 15, 496. [Google Scholar] [CrossRef] [PubMed]
  233. Mozos, I.; Flangea, C.; Vlad, D.C.; Gug, C.; Mozos, C.; Stoian, D.; Luca, C.T.; Horbańczuk, J.O.; Horbańczuk, O.K.; Atanasov, A.G. Effects of Anthocyanins on Vascular Health. Biomolecules 2021, 11, 811. [Google Scholar] [CrossRef]
  234. Chen, K.; Kortesniemi, M.K.; Linderborg, K.M.; Yang, B. Anthocyanins as Promising Molecules Affecting Energy Homeostasis, Inflammation, and Gut Microbiota in Type 2 Diabetes with Special Reference to Impact of Acylation. J. Agric. Food Chem. 2023, 71, 1002–1017. [Google Scholar] [CrossRef]
  235. Mauray, A.; Felgines, C.; Morand, C.; Mazur, A.; Scalbert, A.; Milenkovic, D. Bilberry anthocyanin-rich extract alters expression of genes related to atherosclerosis development in aorta of apo E-deficient mice. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 72–80. [Google Scholar] [CrossRef] [PubMed]
  236. Rotllan, N.; Price, N.; Pati, P.; Goedeke, L.; Fernández-Hernando, C. microRNAs in lipoprotein metabolism and cardiometabolic disorders. Atherosclerosis 2016, 246, 352–360. [Google Scholar] [CrossRef]
  237. Chihomvu, P.; Ganesan, A.; Gibbons, S.; Woollard, K.; Hayes, M.A. Phytochemicals in Drug Discovery-A Confluence of Tradition and Innovation. Int. J. Mol. Sci. 2024, 25, 8792. [Google Scholar] [CrossRef]
  238. Roy, A.; Khan, A.; Ahmad, I.; Alghamdi, S.; Rajab, B.S.; Babalghith, A.O.; Alshahrani, M.Y.; Islam, S.; Islam, M.R. Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications. BioMed Res. Int. 2022, 2022, 5445291. [Google Scholar] [CrossRef]
  239. Shah, S.M.A.; Akram, M.; Riaz, M.; Munir, N.; Rasool, G. Cardioprotective Potential of Plant-Derived Molecules: A Scientific and Medicinal Approach. Dose-Response A Publ. Int. Hormesis Soc. 2019, 17, 1559325819852243. [Google Scholar] [CrossRef]
  240. Tungmunnithum, D.; Thongboonyou, A.; Pholboon, A.; Yangsabai, A. Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview. Medicines 2018, 5, 93. [Google Scholar] [CrossRef]
  241. Khatiwada, N.; Hong, Z. Potential Benefits and Risks Associated with the Use of Statins. Pharmaceutics 2024, 16, 214. [Google Scholar] [CrossRef]
  242. Hossain, M.S.; Wazed, M.A.; Asha, S.; Amin, M.R.; Shimul, I.M. Dietary Phytochemicals in Health and Disease: Mechanisms, Clinical Evidence, and Applications-A Comprehensive Review. Food Sci. Nutr. 2025, 13, e70101. [Google Scholar] [CrossRef] [PubMed]
  243. Alum, E.U. Role of phytochemicals in cardiovascular disease management: Insights into mechanisms, efficacy, and clinical application. Phytomed. Plus 2025, 5, 100695. [Google Scholar] [CrossRef]
  244. Li, K.X.; Wang, Z.C.; Machuki, J.O.; Li, M.Z.; Wu, Y.J.; Niu, M.K.; Yu, K.Y.; Lu, Q.B.; Sun, H.J. Benefits of Curcumin in the Vasculature: A Therapeutic Candidate for Vascular Remodeling in Arterial Hypertension and Pulmonary Arterial Hypertension? Front. Physiol. 2022, 13, 848867. [Google Scholar] [CrossRef]
  245. Chaachouay, N. Synergy, Additive Effects, and Antagonism of Drugs with Plant Bioactive Compounds. Drugs Drug Candidates 2025, 4, 4. [Google Scholar] [CrossRef]
  246. Wang, H.; Zhu, C.; Ying, Y.; Luo, L.; Huang, D.; Luo, Z. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget 2017, 9, 10135–10146. [Google Scholar] [CrossRef] [PubMed]
  247. Dagher, O.; Mury, P.; Thorin-Trescases, N.; Noly, P.E.; Thorin, E.; Carrier, M. Therapeutic Potential of Quercetin to Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases. Front. Cardiovasc. Med. 2021, 8, 658400. [Google Scholar] [CrossRef]
  248. Breuss, J.M.; Atanasov, A.G.; Uhrin, P. Resveratrol and Its Effects on the Vascular System. Int. J. Mol. Sci. 2019, 20, 1523. [Google Scholar] [CrossRef]
  249. Kong, W.J.; Wei, J.; Zuo, Z.Y.; Wang, Y.M.; Song, D.Q.; You, X.F.; Zhao, L.X.; Pan, H.N.; Jiang, J.D. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metab. Clin. Exp. 2008, 57, 1029–1037. [Google Scholar] [CrossRef]
  250. Penumathsa, S.V.; Thirunavukkarasu, M.; Koneru, S.; Juhasz, B.; Zhan, L.; Pant, R.; Menon, V.P.; Otani, H.; Maulik, N. Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J. Mol. Cell Cardiol. 2007, 42, 508–516. [Google Scholar] [CrossRef]
  251. Carrillo-Martinez, E.J.; Flores-Hernández, F.Y.; Salazar-Montes, A.M.; Nario-Chaidez, H.F.; Hernández-Ortega, L.D. Quercetin, a Flavonoid with Great Pharmacological Capacity. Molecules 2024, 29, 1000. [Google Scholar] [CrossRef]
  252. Babaei Khorzoughi, R.; Namvarjah, F.; Teimouri, M.; Hosseini, H.; Meshkani, R. In-vitro Synergistic Effect of Metformin and Berberine on High Glucose-induced Lipogenesis. Iran. J. Pharm. Res. 2019, 18, 1921–1930. [Google Scholar] [CrossRef] [PubMed]
  253. Kang, W.S.; Chung, K.H.; Chung, J.H.; Lee, J.Y.; Park, J.B.; Zhang, Y.H.; Yoo, H.S.; Yun, Y.P. Antiplatelet activity of green tea catechins is mediated by inhibition of cytoplasmic calcium increase. J. Cardiovasc. Pharmacol. 2001, 38, 875–884. [Google Scholar] [CrossRef] [PubMed]
  254. Zhao, X.; Cheng, T.; Xia, H.; Yang, Y.; Wang, S. Effects of Garlic on Glucose Parameters and Lipid Profile: A Systematic Review and Meta-Analysis on Randomized Controlled Trials. Nutrients 2024, 16, 1692. [Google Scholar] [CrossRef]
  255. Wang, H.; Chen, Y.; Wang, L.; Liu, Q.; Yang, S.; Wang, C. Advancing herbal medicine: Enhancing product quality and safety through robust quality control practices. Front. Pharmacol. 2023, 14, 1265178. [Google Scholar] [CrossRef]
  256. Tashkin, D.P.; Amin, A.N.; Kerwin, E.M. Comparing Randomized Controlled Trials and Real-World Studies in Chronic Obstructive Pulmonary Disease Pharmacotherapy. Int. J. Chronic Obstr. Pulm. Dis. 2020, 15, 1225–1243. [Google Scholar] [CrossRef]
  257. Gross, A.S.; Harry, A.C.; Clifton, C.S.; Della Pasqua, O. Clinical trial diversity: An opportunity for improved insight into the determinants of variability in drug response. Br. J. Clin. Pharmacol. 2022, 88, 2700–2717. [Google Scholar] [CrossRef]
  258. Resurreccion, E.P.; Fong, K.W. The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer. Metabolites 2022, 12, 488. [Google Scholar] [CrossRef]
  259. Edo, G.I.; Obasohan, P.; Makia, R.S.; Abiola, O.T.; Umelo, E.C.; Jikah, A.N.; Yousif, E.; Isoje, E.F.; Igbuku, U.A.; Opiti, R.A.; et al. The use of quality control parameters in the evaluation of herbal drugs. A review. Discov. Med. 2024, 1, 168. [Google Scholar] [CrossRef]
  260. Vaou, N.; Stavropoulou, E.; Voidarou, C.; Tsigalou, C.; Bezirtzoglou, E. Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives. Microorganisms 2021, 9, 2041. [Google Scholar] [CrossRef]
  261. Avigan, M.I.; Mozersky, R.P.; Seeff, L.B. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States. Int. J. Mol. Sci. 2016, 17, 331. [Google Scholar] [CrossRef] [PubMed]
  262. Tian, J.; Song, X.; Wang, Y.; Cheng, M.; Lu, S.; Xu, W.; Gao, G.; Sun, L.; Tang, Z.; Wang, M.; et al. Regulatory perspectives of combination products. Bioact. Mater. 2021, 10, 492–503. [Google Scholar] [CrossRef] [PubMed]
  263. Ondieki, G.; Nyagblordzro, M.; Kikete, S.; Liang, R.; Wang, L.; He, X. Cytochrome P450 and P-Glycoprotein-Mediated Interactions Involving African Herbs Indicated for Common Noncommunicable Diseases. Evid.-Based Complement. Altern. Med. 2017, 2017, 2582463. [Google Scholar] [CrossRef]
  264. Uno, T.; Yasui-Furukori, N. Effect of grapefruit juice in relation to human pharmacokinetic study. Curr. Clin. Pharmacol. 2006, 1, 157–161. [Google Scholar] [CrossRef]
  265. Borrelli, F.; Izzo, A.A. Herb-drug interactions with St John’s wort (Hypericum perforatum): An update on clinical observations. AAPS J. 2009, 11, 710–727. [Google Scholar] [CrossRef] [PubMed]
  266. Ge, B.; Zhang, Z.; Zuo, Z. Updates on the clinical evidenced herb-warfarin interactions. Evid.-Based Complement. Altern. Med. 2014, 2014, 957362. [Google Scholar] [CrossRef]
  267. Duarte, J.D.; Cavallari, L.H. Pharmacogenetics to guide cardiovascular drug therapy. Nat. Rev. Cardiol. 2021, 18, 649–665. [Google Scholar] [CrossRef]
  268. Santhiravel, S.; Bekhit, A.E.A.; Mendis, E.; Jacobs, J.L.; Dunshea, F.R.; Rajapakse, N.; Ponnampalam, E.N. The Impact of Plant Phytochemicals on the Gut Microbiota of Humans for a Balanced Life. Int. J. Mol. Sci. 2022, 23, 8124. [Google Scholar] [CrossRef]
Figure 1. Gut dysbiosis and cardiovascular diseases.
Figure 1. Gut dysbiosis and cardiovascular diseases.
Ijms 26 04264 g001
Figure 2. The central concept of phytochemical–pharmaceutical integration for CVD treatment.
Figure 2. The central concept of phytochemical–pharmaceutical integration for CVD treatment.
Ijms 26 04264 g002
Figure 3. The complex relationship between gut microbiota dysbiosis and CVDs.
Figure 3. The complex relationship between gut microbiota dysbiosis and CVDs.
Ijms 26 04264 g003
Table 1. The pathways of gut-derived metabolites orchestrate complex pathological changes during HF (↑: upregulation,↓: downregulation).
Table 1. The pathways of gut-derived metabolites orchestrate complex pathological changes during HF (↑: upregulation,↓: downregulation).
MetaboliteActivated PathwayKey EffectsImpact on Heart Failure
SCFAs (acetate, propionate, butyrate)GPR41, GPR43, GPR109A activation; HDAC inhibition↑ IL-10 (anti-inflammatory cytokine), ↓ systemic inflammation, improved gut barrier integrityProtective: maintains epithelial integrity, reduces microbial translocation, limits inflammation
TMAONF-κB activation; ROS/TXNIP/NLRP3 inflammasome; TGF-β1/Smad3 signaling↑ Pro-inflammatory cytokines, ↑ oxidative stress, endothelial dysfunction, fibrosisDetrimental: promotes atherosclerosis, cardiac dysfunction, and maladaptive remodeling
Bile Acids (BAs)FXR activation; AIM2 inflammasome; Type I interferon pathwaysModulation of lipid metabolism, immune responses, mitochondrial dysfunction, cardiac hypertrophyDetrimental: worsens inflammation, fibrosis, and metabolic derangement
BCAAsmTOR pathway activation↑ Oxidative stress, ↑ inflammationDetrimental: exacerbates cardiac stress and injury
Tryptophan Derivatives (e.g., indole derivatives)NLRP3 inflammasome modulation; PERK pathway activationImmune regulation, cellular stress responsesMixed: potential protective or harmful effects depending on balance
LPSTLR4 signaling activation↑ Cytokine release, oxidative stress, fibrosis, arrhythmiasDetrimental: drives systemic inflammation and cardiac remodeling
Table 2. The pathways of gut-derived metabolites orchestrate complex pathological changes during hypertension.
Table 2. The pathways of gut-derived metabolites orchestrate complex pathological changes during hypertension.
MetaboliteActivated PathwayKey EffectsImpact on Hypertension
Short-Chain Fatty Acids (SCFAs)GPR43 activation, inhibition of RAS, modulation of ORs (Olfr78, OR10J5)Vasodilation, reduced inflammation, regulation of sympathetic activity, enhanced NO productionLowers blood pressure; protective
Trimethylamine-N-oxide (TMAO)NF-κB activation, vascular inflammation pathwaysIncreases vascular inflammation, endothelial dysfunction, platelet hyperresponsivenessElevates blood pressure; pro-hypertensive
Indole Derivatives (from Tryptophan)Aryl hydrocarbon receptor (AhR) activationModulates immune responses, maintains vascular integrityGenerally protective; supports vascular health
KynurenineImmune and vascular modulationAffects vascular tone and renal functionVariable, depending on pathway balance
Serotonin (5-HT)Vascular and renal regulatory pathwaysModulates vascular contraction and renal functionComplex effects; can contribute to hypertension if dysregulated
Polyamines (Putrescine, Spermidine)NO synthesis modulationRegulates vascular tone through NO activation/inhibitionCan lower or raise blood pressure depending on balance
Lipopolysaccharides (LPS)TLR4-mediated inflammatory signalingInduces systemic inflammation, endothelial dysfunctionPromotes hypertension; detrimental
Table 3. The pathways of gut-derived metabolites orchestrate complex pathological changes during MI.
Table 3. The pathways of gut-derived metabolites orchestrate complex pathological changes during MI.
MetaboliteActivated PathwayKey EffectsImpact on MI
Trimethylamine N-oxide (TMAO)NF-κB activation; calcium signaling disruption; ROS generationPromotes inflammation, oxidative stress, endothelial dysfunction, arrhythmia, atherosclerotic plaque destabilizationIncreases MI risk, worsens myocardial injury and outcomes
Short-Chain Fatty Acids (SCFAs) (e.g., acetate, butyrate, propionate)GPR41/43 activation; HDAC inhibition; eNOS activationSuppress inflammation, improve gut barrier function, enhance vasodilationProtective role; their reduction may impair MI recovery
Phenylacetylglutamine (PAGln)Adrenergic receptor activation on plateletsEnhances platelet aggregation and thrombosisElevates thrombotic risk, worsens MI severity
Lipopolysaccharide (LPS)TLR4-NF-κB activation; ROS generationInduces systemic inflammation, oxidative stress, endothelial dysfunctionExacerbates myocardial injury and adverse remodeling
Long-Chain Fatty Acids (LCFAs)Metabolic dysregulation (lipid metabolism)Promote platelet aggregation and thrombus formationPotential biomarker for early AMI; contributes to MI initiation
Aromatic amino acid metabolitesOxidative stress pathwaysIncrease ROS generation, influence infarct sizeWorsen post-MI outcomes through increased oxidative damage
Table 4. The pathways of gut-derived metabolites that orchestrate complex pathological changes during atherosclerosis.
Table 4. The pathways of gut-derived metabolites that orchestrate complex pathological changes during atherosclerosis.
MetaboliteActivated PathwayKey EffectsImpact on Atherosclerosis
Trimethylamine N-oxide (TMAO)TMAO pathway, MAPK, NF-κB signaling, inhibition of reverse cholesterol transport
-
Impairs nitric oxide (NO) bioavailability, leading to endothelial dysfunction.
-
Enhances foam cell formation.
-
Increases oxidative stress and inflammation.
-
Promotes atherosclerosis by causing endothelial dysfunction, plaque instability, and elevated cholesterol deposition.
Short-Chain Fatty Acids (SCFAs)PPARγ activation, gut barrier integrity regulation
-
Regulates inflammation.
-
Maintains gut integrity by tightening the gut lining.
-
Regulates lipid metabolism and reduces systemic inflammation.
-
Protects against atherosclerosis by preventing LPS translocation and reducing vascular inflammation.
Lipopolysaccharides (LPS)TLR4 signaling, NF-κB pathway
-
Activates inflammatory response.
-
Increases endothelial activation and immune cell recruitment.
-
Promotes endothelial dysfunction and accelerates plaque formation due to systemic inflammation.
Table 5. Overall types of CVD-associated gut dysbiosis.
Table 5. Overall types of CVD-associated gut dysbiosis.
FeatureHealthy Gut MicrobiotaAtherosclerosis-Associated DysbiosisHypertension-Associated DysbiosisHeart Failure-Associated DysbiosisMyocardial Infarction (MI)-Associated Dysbiosis
Microbial DiversityHigh microbial richness and diversityReduced diversity, enrichment of pro-inflammatory speciesLower diversity, increased pathobiontsSignificant microbial imbalance, loss of beneficial bacteriaDecreased diversity, dominance of pro-inflammatory bacteria
Bacillota/Bacteroidota RatioBalanced ratio, supporting homeostasisIncreased Bacillota/Bacteroidota ratio (linked to inflammation)Increased Bacillota, decreased BacteroidotaElevated Bacillota levels, disrupting metabolic pathwaysIncreased Bacillota dominance, linked to inflammation
SCFA-Producing BacteriaHigh levels of Faecalibacterium, Roseburia, AkkermansiaDecreased Faecalibacterium, RoseburiaReduced Akkermansia muciniphila, impairing gut barrierLoss of Butyrivibrio and FaecalibacteriumDecreased Roseburia and Akkermansia
SCFA Levels (Butyrate, Acetate, Propionate)High, maintaining gut and vascular healthDecreased SCFA levels, leading to endothelial dysfunctionLower SCFA levels, contributing to vascular stiffnessMarkedly reduced SCFAs, worsening systemic inflammationReduced SCFAs, promoting pro-thrombotic environment
Inflammatory BacteriaLow levels of Escherichia, EnterobacterIncreased Escherichia coli, Enterobacter, ProteobacteriaOvergrowth of Desulfovibrio (H2S producer, causing damage)Elevated Klebsiella, Enterococcus, StaphylococcusIncreased Enterobacter and Fusobacterium
LPS-Producing BacteriaLow levels, preventing endotoxemiaIncreased Klebsiella, ParabacteroidesEnrichment of Proteobacteria, elevating systemic LPSHigh Enterobacteriaceae, promoting systemic inflammationIncreased Bacteroides and Proteobacteria
TMAO-Producing BacteriaLow levels, reducing cardiovascular riskEnrichment of Lachnoclostridium, Desulfovibrio (TMAO producers)Increased Clostridia and Fusobacterium, promoting TMAOElevated Eggerthella lenta and DesulfovibrioIncreased Lachnospiraceae and Clostridium
Bile Acid MetabolismNormal bile acid balance, supporting lipid metabolismIncreased secondary bile acids (pro-inflammatory effects)Altered bile acid conversion, affecting BP regulationElevated toxic bile acids, worsening cardiac functionDisrupted bile acid homeostasis, impairing heart recovery
Inflammatory MarkersLow levels of IL-6, TNF-α, CRPElevated IL-6, TNF-α, CRP, promoting plaque formationIncreased pro-inflammatory cytokines (IL-17, TNF-α)High IL-6, TNF-α, gut permeability worsensIncreased IL-1β, IL-18, contributing to clot formation
Endothelial FunctionIntact vascular endothelium, healthy BP regulationEndothelial dysfunction, leading to atherosclerotic plaqueReduced nitric oxide (NO), causing vascular constrictionEndothelial damage, exacerbating heart failure riskVascular inflammation, increasing thrombosis risk
Gut Barrier IntegrityStrong tight junctions, preventing microbial translocationImpaired barrier, microbial translocation fuels inflammationWeakened barrier, increasing BP-related damageSevere gut leakiness, endotoxemia worsens heart functionIncreased permeability, leading to systemic inflammation
Table 6. The key bioactive compounds with cardioprotective effects.
Table 6. The key bioactive compounds with cardioprotective effects.
CompoundSourcesCardioprotective MechanismsKey Molecular TargetsClinical ImplicationsReferences
FlavonoidsBerries, citrus fruits, onions, teaAntioxidant, anti-inflammatory, anti-atherosclerotic, anti-thrombotic, improves endothelial function, reduces blood pressureNrf2, NF-κB, PI3K-AKT, eNOS, COX-2, NADPH oxidase, MAPKPotential role in preventing atherosclerosis, hypertension, and MI; needs further clinical translation[137,138,139,140,141,142,143,144,145,146,147,148,149]
Omega-3 fatty acidsFatty fish (EPA, DHA), flaxseeds, walnutsReduces triglycerides, lowers blood pressure, is anti-inflammatory, improves endothelial function, stabilizes cardiac electrophysiologyPPAR-α, COX-2, LOX, resolvins, prostacyclin, NOBeneficial in reducing cardiovascular events, improving lipid profiles, and managing hypertriglyceridemia[163,164,165,166,167,168,169,170,171,172,173,174]
ResveratrolGrapes, peanuts, berriesAntioxidant, anti-inflammatory, anti-atherosclerotic, vasoprotective, inhibits LDL oxidation, enhances NO productionSIRT1, AMPK, estrogen receptor α, NF-κB, eNOSPotential in managing hypertension, atherosclerosis, and heart failure; concerns regarding bioavailability[175,176,177,178,179,180,181,182]
CurcuminTurmeric, gingerReduces oxidative stress, is anti-inflammatory and anti-thrombotic, regulates lipids, inhibits platelet aggregation, prevents atherosclerosisSIRT1, NF-κB, COX-2, NADPH oxidaseCardioprotective in conditions like ischemia–reperfusion injury, diabetic cardiomyopathy, and drug-induced toxicity[183,184,185,186]
Coenzyme Q10 (CoQ10)Meat, fish, nuts, spinach, broccoli, whole grainsAntioxidant, mitochondrial function support, reduces oxidative stress, enhances energy production, improves endothelial functionCytochrome c oxidase, Nrf2, ATP synthase, SIRT1Potential benefits in heart failure, ischemic heart disease, hypertension, and statin-induced myopathy[187,188,189,190,191,192,193]
Marine-derived compoundsFish oils, seaweed, marine algae, krill oilAnti-inflammatory, antioxidant, reduces cholesterol and triglycerides, protects against ischemic damage, improves endothelial healthPPAR-α, SIRT1, eNOS, COX-2, TLR4Protective effects in cardiovascular diseases like atherosclerosis, heart failure, and inflammation[194,195,196,197,198,199,200]
Table 7. Some natural products that modulate cardiovascular health through gut microbiota interactions.
Table 7. Some natural products that modulate cardiovascular health through gut microbiota interactions.
Natural ProductGut Microbiota ModulationCardiovascular BenefitsMechanism of ActionReferences
BerberinePromotes SCFA-producing bacteria (Roseburia, Blautia, Alistipes)Reduces cholesterol, triglycerides, and LDL; increases HDL-CIncreases beneficial bacteria, suppresses LPS-induced inflammation via TLR4/NF-κB, improves lipid profiles and strengthens intestinal barrier function[212,213]
Polymethoxyflavones (PMFs)Increases Akkermansia and Bifidobacterium; inhibits TMA-producing bacteriaPrevents vascular inflammation and atherosclerosis; reduces TMAOInhibits TMA production, reduces NF-κB/MAPK signaling, improves gut health and prevents atherosclerosis[214]
ResveratrolPromotes Bacteroides, Lactobacillus, Bifidobacterium; reduces Enterococcus faecalisLowers risk of atherosclerosis and hypertension; improves endothelial functionModulates gut microbiota to enhance NO bioavailability, reduces inflammation and oxidative stress, improves bile acid metabolism, and lowers TMAO[215,216]
QuercetinActivates health-promoting bacteria; restores gut microbiota after antibiotic exposureAnti-obesity, metabolic benefits in metabolic syndrome; reduces inflammationStrengthens tight junctions, generates antioxidant metabolites, regulates bile acid profiles, blocks inflammasome activation and TLR4 signaling pathway[217,218,219,220]
Ferulic Acid (FA)Increases Lachnospiraceae; reduces PrevotellaceaeLowers cholesterol, triglycerides, LDL; promotes fat metabolismReshapes gut microbiota, activates PPAR-α, inhibits PPAR-β/γ, decreases pro-inflammatory cytokines, and regulates lipid metabolism[222,223,224]
CurcuminPromotes beneficial bacteria; suppresses harmful bacteriaReduces inflammation and oxidative stress; lowers atherosclerosis riskInhibits NF-κB pathway, strengthens intestinal barrier, modulates lipid metabolism, reduces vascular inflammation, and prevents endotoxemia[226,227]
Pomegranate JuiceEnhances Bifidobacterium, Lactobacillus, Roseburia, AkkermansiaReduces atherosclerotic lesions; increases HDL-C and lowers CVD riskModulates gut microbiota, reduces atherosclerotic plaque size, enhances NO production, reduces oxidative stress and inflammatory cytokines[228,229]
AnthocyaninsIncreases Bifidobacterium, Lactobacillus, Roseburia, AkkermansiaEnhances vascular function; reduces plaque formation and aortic inflammationEnhances NO production, decreases oxidative stress, modulates NF-κB pathway, regulates gene expression linked to atherosclerosis, improves redox homeostasis[230,231,232,233,234,235]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Muttiah, B.; Hanafiah, A. Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. Int. J. Mol. Sci. 2025, 26, 4264. https://doi.org/10.3390/ijms26094264

AMA Style

Muttiah B, Hanafiah A. Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. International Journal of Molecular Sciences. 2025; 26(9):4264. https://doi.org/10.3390/ijms26094264

Chicago/Turabian Style

Muttiah, Barathan, and Alfizah Hanafiah. 2025. "Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites" International Journal of Molecular Sciences 26, no. 9: 4264. https://doi.org/10.3390/ijms26094264

APA Style

Muttiah, B., & Hanafiah, A. (2025). Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. International Journal of Molecular Sciences, 26(9), 4264. https://doi.org/10.3390/ijms26094264

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop