Grape Seed Extract as a Cardiovascular Adjunct: Molecular Targets, Drug Interactions, and Antioxidant-Mediated Cardioprotection

Cardiovascular disease (CVD) is one of the major causes of mortality worldwide and in Romania. Vitis vinifera L. seed extract (GSCE), rich in oligomeric proanthocyanidins (OPCs), has shown cardioprotective activity at the molecular level and on surrogate clinical endpoints. This interdisciplinary narrative review synthesizes the phytochemistry of GSCE, and its cardioprotective mechanisms through a network pharmacology lens, provides the first artificial intelligence (AI)-assisted systematic assessment of GSCE drug interactions in cardiovascular polypharmacy and proposes an exploratory precision-medicine framework based on patient phenotyping, with emphasis on the cultivar ‘Feteasca Neagra’. The review was conducted according to SANRA principles, included 162 studies identified from 2,200 records published between 2000 and 2026 in PubMed/MEDLINE, Scopus and Web of Science. AI tools served exclusively auxiliary roles, with all outputs fully validated by the authors. GSCE simultaneously modulates six interconnected cardioprotective pathways: Nrf2/HO-1 axis activation, suppression of vascular inflammation via NF-κB, stimulation of nitric oxide production through PI3K/Akt/eNOS, limitation of reperfusion injury via MAPK/JNK, protection of LDL from oxidation, and inhibition of platelet aggregation. Published meta-analyses (16 RCTs, n = 810) document reductions in systolic (WMD = − 6.08 mmHg) and diastolic blood pressure (WMD = −2.20 mmHg; p < 0.05) and in heart rate (WMD = − 1.25 bpm; p < 0.05), with high heterogeneity (I² = 88.8%). The first systematic assessment of potential drug interactions identifies warfarin as the highest-risk interaction, based on CYP2C9 inhibition. ‘Feteasca Neagra’ was identified as having the highest theoretical cardioprotective potential among Romanian viticultural cultivars, and is proposed as a priority subject for translational research. This inference cannot support a clinical recommendation without dedicated pharmacological and clinical studies.