Why Blockbuster Drugs Fail the Microvessels: Herbal Multi-Target Chemistry Enters the ANOCA Debate

Between one-third and one-half of patients who arrive at the cardiac catheterization laboratory with crushing chest pain, breathlessness, or documented ischemia walk away with a perplexing answer: their coronary arteries are not blocked. This condition, now formally called angina with non-obstructive coronary arteries (ANOCA), was long dismissed as atypical or low-risk chest pain, but cardiology has come to recognize it as a genuine ischemic syndrome rooted in the smallest vessels of the heart. A comprehensive review published in Frontiers in Molecular Biosciences argues that the molecular machinery behind ANOCA is so tangled—so richly interconnected across inflammation, oxidative stress, metabolism, and structural remodeling—that single-target drugs may be structurally incapable of fixing it, and that traditional Chinese medicine (TCM) deserves systematic examination as a multi-component, multi-target alternative.

The pathobiology is anything but simple. In healthy coronary microvessels, endothelial nitric oxide synthase (eNOS) generates nitric oxide from L-arginine, with tetrahydrobiopterin as an essential cofactor; nitric oxide diffuses to vascular smooth muscle and produces vasodilation. In ANOCA, oxidative stress depletes the cofactor, and eNOS becomes ‘uncoupled,’ perversely churning out superoxide instead of nitric oxide. NADPH oxidase activity rises, feeding a self-sustaining redox-inflammatory loop centered on the transcription factor NF-κB. Mitochondrial injury erodes the endothelium’s repair capacity, and chronic remodeling produces capillary rarefaction—loss of the very vessels that perfuse the heart. The result is reduced coronary flow reserve, exaggerated vasoconstriction, and the persistent chest pain that defines the syndrome.

What makes this network vicious is that the pathways are coupled. The PI3K/Akt-eNOS axis maintains endothelial tone; AMPK and SIRT1 link metabolic stress to redox balance; HIF-1α and VEGF govern compensatory angiogenesis; and Nrf2/HO-1 coordinates antioxidant defense. These systems cross-talk continuously: metabolic stress activates AMPK, which regulates eNOS phosphorylation; eNOS uncoupling generates reactive oxygen species, which activate NF-κB, which amplifies endothelial inflammation. Blocking one node—an eNOS recoupler here, an NF-κB inhibitor there—leaves the feedback loops elsewhere in the circuit fully operational. Conventional cardiovascular drugs were engineered for obstructive disease, slowing heart rate and dilating conduit arteries, and were simply never designed for this integrated microvascular pathology.

This is where the review, authored by Yingkai Duan, Kaifeng Yu, and colleagues at Liaoning University of Traditional Chinese Medicine, makes its central conceptual argument. A single TCM formulation contains dozens of plant-, mineral-, and animal-derived constituents whose known molecular targets distribute across the disease modules that conventional polypharmacy tries to cover by co-administering separate pills. Classical pairing principles, the authors note, appear to select components for complementary rather than redundant actions. Modern systems pharmacology—mapping compounds to targets via databases such as DrugBank and TCMSP, then intersecting those targets with disease gene sets—has made this structure computationally visible, and machine-learning approaches are extending the paradigm into drug discovery.

Critically, the authors refuse to let mechanistic plausibility masquerade as clinical proof. They impose an explicit five-tier evidence hierarchy throughout the review. Tier 1 is reserved for randomized trials in formally defined ANOCA populations; Tier 2 covers invasively confirmed microvascular angina or INOCA; Tier 3 covers general coronary disease or diabetic cohorts; Tier 4 is animal data; Tier 5 is cell culture and computational work. Language is calibrated accordingly, so that a network-pharmacology prediction is described as ‘hypothesized’ and never as ‘demonstrated.’ The point is sharpened by a blunt admission: the TCM literature has historically conflated these tiers, claiming microvascular protection from cardiomyocyte data or efficacy from preclinical results.

Five formulations anchor the analysis, and only one has reached the top tier. Shexiang Baoxin Pill, a pharmacopoeia-listed patent medicine containing moschus, ginseng, bovine calculus artifactus, cinnamon, styrax, toad venom, and borneol, has been profiled to contain more than seventy non-volatile and forty volatile constituents. Its ginsenoside Rb1 enhances eNOS Ser1177 phosphorylation through PI3K/Akt; ginsenoside Rg1 promotes HIF-1α–VEGF–driven angiogenesis and supports mitochondrial quality control via AMPK/PINK1; muscone modulates connexin 43 and microvascular permeability; bufadienolides act on sodium-potassium ATPase; and borneol modulates tight junctions. These mechanisms, established in cell and animal models, now have a clinical counterpart: a multicenter, randomized, double-blind, placebo-controlled phase IV trial enrolling 239 ANOCA patients across eleven Chinese centers reported significant improvement in Seattle Angina Questionnaire scores over twelve weeks of treatment, with a safety profile comparable to placebo. Earlier, in the larger MUSKARDIA trial of 2,674 patients with stable coronary artery disease, the pill did not significantly reduce major adverse cardiovascular events at twenty-four months, though subgroup signals favored women and patients with lower body mass index.

The other four formulations illustrate the gap between plausibility and proof. Tongxinluo Capsule, built around ginseng, white peony, leech-derived antithrombotic peptides, and other ingredients, shows preclinical activity in thrombin inhibition, NF-κB suppression, and hypoxia-triggered autophagy in cardiac microvascular endothelial cells, but its clinical trials sit mostly in stable coronary disease and post-stenting populations—Tier 2 to Tier 3 at best. Shexiang Tongxin Dropping Pill promoted angiogenesis through VEGF/eNOS signaling in a diabetic microcirculation model, improving capillary density in animals, yet has no ANOCA-specific clinical evidence. Tongmai Jiangtang Capsule, whose berberine and astragaloside IV act on AMPK in hyperglycemic settings, has been studied in type 2 diabetes complicated by coronary heart disease—an overlapping but distinct population. Compound Danshen Dropping Pill, chemically the simplest of the five, concentrates salvianolic acids and notoginsenoside R1 on the eNOS-NO axis and adaptive angiogenesis, with meta-analytic support drawn largely from trials lacking invasive confirmation of microvascular dysfunction.

The review is equally candid about the translational obstacles. ANOCA itself is a heterogeneous syndrome encompassing microvascular spasm, endothelium-dependent and -independent flow reserve abnormalities, and coronary artery spasm, yet most TCM trials have never stratified by phenotype or used invasive measures such as coronary flow reserve, the index of microcirculatory resistance, or acetylcholine provocation. Multi-component formulations vary chemically between manufacturing batches, particularly when biological materials are involved, and trials that omit HPLC or LC-MS fingerprinting undermine reproducibility. The supportive clinical literature leans heavily on small, single-center studies with surrogate endpoints. Drug–drug interactions with standard antianginal therapy—via CYP enzymes and P-glycoprotein—remain systematically underreported. And even the best biomarker shifts, in nitric oxide or high-sensitivity C-reactive protein, may not translate into measurable functional improvement in the microcirculation.

The prescription the authors offer is methodological rather than mystical. Future trials should adopt the invasive COVADIS phenotyping framework as both entry criterion and endpoint, report chemical fingerprints of the actual trial product, support mechanistic claims with dose-response data on individual constituents, and test whether traditional syndrome patterns—qi deficiency, blood stasis, phlegm turbidity—correspond to invasively defined microvascular subtypes. Whether TCM earns a place in the evidence-based cardiology vocabulary, the review concludes, will depend on whether the field meets that standard. For now, one phase IV trial in 239 patients stands between a compelling systems-pharmacology hypothesis and a genuinely validated therapy for millions whose chest pain has no blocked artery to blame.

Subject of Research: Multi-target biochemical mechanisms of traditional Chinese medicine in coronary microvascular dysfunction of ANOCA

Article Title: Decoding protein signaling networks in microvascular angina: the multi-target biochemical actions of traditional Chinese medicine

Article References: Decoding protein signaling networks in microvascular angina: the multi-target biochemical actions of traditional Chinese medicine. (n.d.). https://doi.org/10.3389/fmolb.2026.1908353

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1908353

Keywords: ANOCA, coronary microvascular dysfunction, traditional Chinese medicine, endothelial dysfunction, oxidative stress, eNOS signaling, network pharmacology, Shexiang Baoxin Pill, inflammation, angiogenesis, mitochondrial dysfunction, phase IV trial