Hemodynamic phenotypes linked to high-altitude subclinical organ damage

Abstract Background Chronic exposure to high-altitude hypoxia imposes sustained cardiovascular stress, yet hemodynamic adaptation among healthy high-altitude dwellers is heterogeneous and remains poorly characterized. This study aimed to identify distinct hemodynamic phenotypes in a healthy high-altitude population using unsupervised machine learning and to evaluate their association with multi-system subclinical target organ damage. Methods This cross-sectional study enrolled 694 healthy adults permanently residing at ≥3300 m on the Qinghai-Tibet Plateau. Unsupervised K-means clustering was performed on nine hemodynamic variables, including peripheral and central blood pressures, augmentation index (AIx), pulse pressure amplification ratio (pPP/cPP), and systolic pressure amplification (pSBP-cSBP). Differences across phenotypes in carotid intima-media thickness (IMT), estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and pulse wave velocity (PWV) were assessed using one-way ANOVA with Bonferroni-corrected post-hoc tests. Results Three distinct hemodynamic phenotypes were successfully identified. The C2 (Balanced Adaptation) phenotype (n = 245) demonstrated the most favorable hemodynamic profile, characterized by the lowest blood pressure and augmentation index (AIx) values, along with the highest peripheral-to-central pulse pressure ratio (pPP/cPP). The C1 (Vascular Stress) phenotype (n = 267) presented with normal peripheral systolic blood pressure (125.9 ± 11.3 mmHg) but exhibited markedly elevated wave reflection indices, including the highest heart rate-adjusted augmentation index (AIx@HR75: 31.9 ± 9.7%) and the lowest pPP/cPP ratio (1.29 ± 0.08). The C3 (High-Load Decompensation) phenotype (n = 182) displayed significantly elevated blood pressures and the greatest overall hemodynamic load. Regarding target organ damage, a clear gradient was observed across the three phenotypes. The C3 phenotype showed the highest carotid intima-media thickness (IMT: 1.162 ± 0.23 mm) and left ventricular mass index (LVMI: 69.18 ± 40.73 g/m²). Conversely, the C2 phenotype exhibited the highest estimated glomerular filtration rate (eGFR: 97.38 ± 16.38 mL/min/1.73m²) and the lowest IMT (0.994 ± 0.26 mm). The C1 phenotype consistently displayed intermediate values for all organ damage indicators. After Bonferroni correction, all pairwise comparisons for LVMI and pulse wave velocity (PWV) reached statistical significance (all P < 0.05). Conclusions Healthy high-altitude individuals manifest three distinct hemodynamic phenotypes arrayed along a cardiovascular risk continuum. The novel Vascular Stress (C1) phenotype represents a “masked” high-risk state characterized by normal peripheral blood pressure but elevated arterial stiffness and wave reflection, challenging sole reliance on brachial pressure for risk assessment. This phenotype-based stratification provides a framework for precision prevention and early intervention in high-altitude populations.