A comprehensive review of ischemic heart disease: pathophysiology, current treatments, natural products-based therapies, and nanotherapeutics

FIGURE 1. The figure depicts the interconnected drivers of the rising global IHD burden. Modifiable metabolic risk factors—particularly high systolic blood pressure, elevated LDL-c cholesterol, and high BMI—remain the dominant contributors and have fueled an estimated 67% increase in metabolic-attributable cardiovascular disease since 1990, largely driven by urbanization and dietary shifts toward ultra-processed foods. Non-modifiable determinants, including age, sex, genetics, ethnicity, and elevated lipoprotein(a), shape baseline susceptibility, with higher risk observed in South Asian populations and post-menopausal women. Environmental and psychosocial exposures—such as air pollution, lead exposure, and chronic stress—further amplify risk through inflammation, oxidative stress, and endothelial dysfunction. Together, these factors converge to drive the escalating global burden of IHD.

FIGURE 2. Pathophysiological mechanisms of ischemic heart disease. This figure summarizes the key processes driving ischemic heart disease, beginning with endothelial dysfunction, LDL-c oxidation, and monocyte recruitment, leading to foam cell formation, smooth muscle cell proliferation, necrotic core development, and plaque progression mediated by inflammatory cytokines such as IL-1β and IL-6, with systemic C-reactive protein (CRP) amplification. Prolonged ischemia results in irreversible myocardial injury: ST-elevation myocardial infarction (STEMI) causes transmural necrosis due to complete coronary occlusion, whereas Non-ST-elevation myocardial infarction (NSTEMI) produces subendocardial damage from partial obstruction. Although reperfusion restores blood flow, it may exacerbate injury through oxidative stress, calcium overload, mitochondrial dysfunction, apoptosis, necrosis, and ferroptosis, an iron-dependent lipid peroxidation–driven form of cell death.

FIGURE 3. Pharmacological therapy in the management of IHD. This figure summarizes pharmacologic strategies for IHD, highlighting complementary mechanisms that reduce ischemia, thrombosis, inflammation, and adverse remodeling. In addition to antiplatelet, anticoagulant, lipid-lowering, anti-anginal, and RAAS-modulating therapies, cardioprotective glucose-lowering agents have emerged as a major advance in integrated cardiometabolic care. SGLT2 inhibitors reduce preload and afterload, improve myocardial energetics, and attenuate fibrosis and inflammation, while GLP-1 receptor agonists exert anti-atherosclerotic and endothelial-protective effects with favorable impacts on weight and systemic inflammation. Together, these therapies provide cardiovascular protection beyond glycemic control and contribute to improved myocardial efficiency, plaque stabilization, and long-term risk reduction in IHD.

FIGURE 4. Future directions for the management of IHD. Future IHD therapy is shifting toward precision-based, mechanism-driven strategies that extend beyond conventional risk factor control. Emerging approaches incorporate personalized medicine using multi-omics profiling, pharmacogenomics, biomarkers, and artificial intelligence to refine risk stratification and treatment selection. Targeted immunomodulatory therapies aim to suppress residual vascular inflammation, while regenerative, metabolic, and mitochondrial interventions seek to restore myocardial integrity and energetic efficiency. Microvascular- and endothelial-focused therapies, advanced nanotherapeutics, and gut–heart axis modulation further expand the therapeutic landscape, highlighting a transition toward integrated and restorative cardiovascular care.

FIGURE 5. Lifestyle and environmental factors influencing IHD. Lifestyle habits and environmental exposures play central roles in the development and progression of ischemic heart disease by regulating endothelial function, inflammation, oxidative stress, metabolic balance, and myocardial resilience. Dietary quality, physical activity, psychosocial stress, sleep patterns, and substance exposure directly influence atherogenesis and vascular dysfunction, while environmental pollution and socioeconomic factors further modulate cardiovascular risk. Optimization of these factors enhances prevention, supports pharmacological therapy, and provides mechanistic insight into integrative and natural compound–based cardiovascular strategies.

FIGURE 6. Cardioprotective mechanisms of major phytochemical classes in ischemic heart disease (IHD). This figure summarizes the multitarget mechanisms by which major phytochemical classes confer cardioprotection in IHD. Polyphenols—including flavonoids, phenolic acids, tannins, stilbenes, and lignans—enhance endothelial nitric oxide (NO) production, improve vascular reactivity, reduce platelet aggregation, modulate lipid profiles, and attenuate oxidative stress and inflammation through pathways such as AMPK, SIRT1, PGC-1α, JAK2/STAT3, and Nrf2. Curcuminoids regulate epigenetic and pro-fibrotic signaling (p300-HAT, TGF-β/Smad), suppress apoptosis, and improve post-ischemic remodeling. Quinones, saponins, alkaloids, and terpenoids exert antioxidant, anti-inflammatory, mitochondrial-protective, anti-apoptotic, and ion-channel–modulating effects, targeting pathways including PI3K/Akt, MAPK, NF-κB, and NLRP3 inflammasome signaling. Organosulfur compounds and isothiocyanates activate cytoprotective Nrf2-dependent responses, improve calcium handling, and mitigate ischemia–reperfusion injury, while omega-3 and omega-9 fatty acids enhance endothelial integrity, reduce thrombosis, suppress adhesion…

FIGURE 7. Molecular mechanisms by which polyphenols and related phytochemicals attenuate atherosclerosis and vascular inflammation. This figure summarizes the integrated antioxidant, anti-inflammatory, metabolic, and survival pathways targeted by major phytochemicals in ischemic heart disease. Compounds such as resveratrol, curcumin, quercetin, and catechins reduce oxidative stress by inhibiting NADPH oxidase–derived ROS and activating AMPK/SIRT1/FOXO and Nrf2 signaling, enhancing antioxidant defenses (HO-1, NQO1, SOD, CAT, GPx) and preserving mitochondrial function. They suppress inflammatory cascades through inhibition of NF-κB, MAPK, TLR4, and NLRP3 inflammasome pathways, lowering TNF-α, IL-1β, and IL-6 production. Additional effects include activation of PI3K/Akt-mediated endothelial NO signaling, modulation of lipid metabolism via LDL-cR/PCSK9 pathways, inhibition of endothelin-induced vasoconstriction, and regulation of apoptosis through Bcl-2 family proteins and cytochrome c release.

FIGURE 8. Schematic illustration of nanoparticle-mediated cardioprotection mechanisms in IHD. This figure depicts how diverse nanoformulations—including lipid nanoparticles, solid lipid nanoparticles (SLNs), liposomes, lipid–polymer hybrids, metal–organic framework systems, polymeric nanoparticles, and targeted RGD- or mitochondria-modified carriers—enhance myocardial drug delivery and therapeutic efficacy in IHD. By optimizing physicochemical properties (size, PDI, zeta potential, drug loading, entrapment efficiency, and controlled release), these systems improve cardiac accumulation, bioavailability, and sustained drug action compared with free compounds. At the biochemical level, nanoformulations reduce cardiac injury markers (CK-MB, LDH, troponin-I, AST/ALT), suppress lipid peroxidation (MDA), and restore antioxidant defenses (SOD, CAT, GPx, GSH). Molecularly, they inhibit ROS generation, NF-κB, MAPK, NLRP3 inflammasome, COX-2, and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18), while modulating PI3K/Akt, AMPK, PPAR-γ, and Nrf2 pathways. They also regulate apoptosis (↓Bax, ↓caspase-3, ↑Bcl-2), enhance autophagy (Beclin-1, ULK1, LC3), promote mitochondrial protection and ATP…