Chronic nicotine exposure drives dose-dependent pulmonary hypertension and cardiopulmonary remodeling: Preclinical and clinical validation.

Pulmonary hypertension (PH) is a severe and life-threatening pulmonary vascular disease. Cigarette smoking is a significant environmental risk factor for PH, and nicotine, a primary toxic component of cigarettes, is closely associated with the development and progression of PH. This study aimed to elucidate the pathological progression of PH induced by chronic nicotine exposure and its dose-dependent effects. We established a murine model of PH by intranasal nicotine instillation in C57BL/6 J mice, coupled with a clinical cohort study of smokers. Using high-resolution echocardiography, right heart catheterization, microvascular tension measurement, and histopathological techniques, we systematically assessed nicotine's dose-dependent effects on pulmonary hemodynamics, vascular function, and cardiac structure and function. Results demonstrated right ventricular systolic pressure (RVSP)-a surrogate for pulmonary arterial (PA) systolic pressure without pulmonary valve stenosis-increased from 18.09 ± 0.28 mmHg (Control) to 31.99 ± 0.21 mmHg (High-dose, P < 0.01). RV hypertrophy and dilation were accompanied by dose-dependent impairment in tricuspid annular plane systolic excursion (TAPSE), declining from 1.83 ± 0.05 mm to 1.15 ± 0.03 mm (P < 0.01). PA abnormalities included shortened acceleration time (PAT), reduced PAT/ejection time ratio, increased PA diameter (PAD), vascular wall thickening, and inflammatory infiltration. Microvascular tension studies confirmed functional impairment. Clinical validation mirrored core findings: in PH patients, smoking index correlated positively with PAD (R2 = 0.8553, P < 0.01) and negatively with TAPSE (R2 = 0.7523, P < 0.01), strongly corroborating animal data and underscoring nicotine's clinical hazards. Our research demonstrates chronic nicotine exposure induces dose-dependent PH through elevated PA pressure, pulmonary vascular remodeling, and RV dysfunction, providing mechanistic insights for smoking-related PH prevention and treatment.