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

Grape seed extract (GSE) from Vitis vinifera L., rich in oligomeric proanthocyanidins, has shown cardioprotective activity at the molecular level and on surrogate clinical endpoints. This narrative review, appraised with SANRA and based on 166 sources identified through a reproducible PubMed/MEDLINE search (759 records, 2000–January 2026) and citation chasing, synthesizes the phytochemistry, mechanisms, interaction evidence and clinical relevance of GSE. Experimental data support modulation of six interconnected pathways; induction of endogenous antioxidant defenses through Nrf2, including glutathione synthesis, is proposed to be more relevant than direct radical scavenging. In silico profiling shows that the fractions most active in vitro (procyanidin C1: TPSA 310.9 Å2, four Lipinski violations) are the least likely to be absorbed. Meta-analyses report modest blood-pressure reductions (systolic −6.08 and diastolic −2.80 mmHg in one; diastolic −2.20 mmHg, I2 = 88.8%, in another) of uncertain individual clinical significance; GSE is not an alternative to guideline-recommended antihypertensive therapy. No GSE–drug interaction has been demonstrated clinically; warfarin warrants precaution on preclinical evidence. The Romanian cultivar Fetească Neagră shows a distinctive phytochemical profile and is proposed for dedicated investigation not ranked. A staged pathway from winemaking by-product to characterized supplement is outlined; therapeutic claims require outcome trials not yet performed.