Untangling the heart-brain connection in Parkinson's disease: emerging mechanisms and models

Cardiovascular autonomic dysfunction (CVAD) is a prevalent yet underrecognized nonmotor manifestation of Parkinson's disease (PD) that adversely affects morbidity, prognosis, and quality of life. Framed by the heart-brain axis, this review examines bidirectional interactions between neurodegeneration and cardiovascular control, synthesizing clinical and preclinical evidence from 2015 to 2025. We searched PubMed for English-language studies addressing autonomic involvement in PD and cardiovascular outcomes; of 1035 records identified, more than 240 met inclusion criteria following removal of duplicates, commentaries, and off-topic articles. Consistent clinical observations include orthostatic hypotension, diminished heart rate variability, impaired baroreflex sensitivity, and blood pressure lability, though heterogeneity in acquisition protocols and analytics limits comparability. Experimental models reveal mechanistic leads but often lack integration of central and peripheral endpoints, sex-inclusive cohorts, aging variables, and longitudinal designs. We highlight methodological constraints, particularly the interpretive limits of HRV, anesthesia effects in preclinical work, and inconsistent preprocessing, and outline priorities for standardized, multimodal approaches that couple neural markers with cardiovascular readouts. Advancing an integrative, translational framework may enable earlier diagnosis, robust autonomic biomarkers, risk stratification across "body-first" and "brain-first" trajectories, and targeted interventions, including neuromodulation and metabolic strategies, aimed at mitigating CVAD and potentially modifying PD progression.