Longitudinal Comorbidity Patterns Prior to Pulmonary Hypertension Diagnosis

BACKGROUND Pulmonary hypertension (PH) is a progressive and life-threatening condition that is often diagnosed late due to nonspecific symptoms shared with other cardiopulmonary diseases. The temporal relationship between comorbidities and PH diagnosis remains poorly understood, particularly regarding how disease order may influence diagnosis delays and prognosis. METHODS Pulmonary hypertension (PH) is a progressive and life-threatening condition that is often diagnosed late due to nonspecific symptoms shared with other cardiopulmonary diseases. The temporal relationship between comorbidities and PH diagnosis remains poorly understood, particularly regarding how disease order may influence diagnosis delays and prognosis. RESULTS The most common comorbidities among PH patients included hypertension (59.1%), heart failure (43.2%), and atrial fibrillation (31.8%). Pathway analysis revealed that PH diagnosis occurred 2.75 years earlier when diabetes preceded hypertension compared to the reverse order. In another pathway, advancing the position of hypercholesterolemia before hypertension and diabetes significantly shortened the progression time to PH across all three disease cohorts. Mortality risk varied by sequence type; a cardiometabolic trajectory involving diabetes, hypertension, and hypercholesterolemia was associated with a significantly higher mortality risk (HR = 1.97; P = 0.001). The relative order of metabolic conditions and comorbidity clusters was also associated with mortality. CONCLUSIONS Comorbidity order and sequence significantly affect the timeline and risk associated with PH diagnosis. Our findings demonstrate that earlier occurrence of certain metabolic conditions may determine disease progression speed and prognosis. These results support the utility of temporal disease trajectory modeling for risk stratification and early intervention of patients at risk for PH. Clinical Perspective WHAT IS NEW? Using process mining, we identified how the order and sequence of comorbidities influence the speed of pulmonary hypertension (PH) diagnosis in a large real-world UK Biobank cohort. Patients who were diagnosed with type 2 diabetes before hypertension reached a PH diagnosis significantly faster (by 2.75 years) than those with reversed comorbidity order. Certain metabolic pathways were associated with significantly higher mortality risk (HR = 1.97), highlighting the prognostic importance of comorbidity sequences in PH. WHAT ARE THE CLINICAL IMPLICATIONS? The sequence of cardiometabolic comorbidities can impact diagnostic delays and survival outcomes in PH. This temporal patterning could support earlier diagnosis or risk stratification of patients suspected of having PH. Incorporating comorbidity sequence logic into electronic health record systems may help improve clinical decision support for timely PH diagnosis.