Longitudinal Comorbidity Patterns Prior to Pulmonary Hypertension Diagnosis

BACKGROUNDPulmonary 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. METHODSPulmonary 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. RESULTSThe 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. CONCLUSIONSComorbidity 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 PerspectiveO_ST_ABSWHAT IS NEW?C_ST_ABSO_LIUsing 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. C_LIO_LIPatients 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. C_LIO_LICertain metabolic pathways were associated with significantly higher mortality risk (HR = 1.97), highlighting the prognostic importance of comorbidity sequences in PH. C_LI WHAT ARE THE CLINICAL IMPLICATIONS?O_LIThe sequence of cardiometabolic comorbidities can impact diagnostic delays and survival outcomes in PH. C_LIO_LIThis temporal patterning could support earlier diagnosis or risk stratification of patients suspected of having PH. C_LIO_LIIncorporating comorbidity sequence logic into electronic health record systems may help improve clinical decision support for timely PH diagnosis. C_LI