Overactive bladder (OAB) is a heterogenous condition that encompasses urgency urinary incontinence (UUI) and urinary urgency without incontinence (URG).  Though UUI and URG are commonly grouped together within the OAB spectrum, emerging evidence suggests that distinct biologic mechanisms may underlie these clinical phenotypes. Vascular disease has been proposed as a contributor to bladder dysfunction, potentially through mechanisms such as pelvic ischemia, endothelial dysfunction, or systemic metabolic dysregulation.  We sought to evaluate whether urgency status and phenotypes are associated with vascular comorbidity, erectile dysfunction (a proxy or harbinger for vascular comorbidity), and distinct cardiometabolic proteomic profiles.

A secondary analysis of the LURN1/2 cohorts was performed of participants categorized as controls,  URG, and UUI.  Vascular comorbidity included angina, congestive heart failure, myocardial infarction, stroke, and peripheral vascular disease.  Multivariable regression was performed adjusting for age, sex, and nonvascular comorbidity burden.  We performed cardiometabolic proteomic profiling on baseline serum samples using the Olink platform (false discovery rate [FDR] <0.05).  Among LURN2 cases vascular and non-vascular predictors of 12-month symptomatic improvement based on PGI-I score were evaluated.

Among the 2,116 included participants (268 controls; 1,848 cases [1,239 UUI; 609 UU]), those with urgency syndromes (UUI+URG combined) had 3.2-fold higher odds of vascular comorbidity compared with controls (OR 3.2, 95% CI 1.7–6.2; p<0.001) when adjusting for age, sex, and non-vascular comorbidity burden.  Among 762 men, ED was more prevalent in urgency (UUI+URG combined) cases than controls (53% vs. 29%) and highest in UUI (64% vs 41% in UU). The combined urgency syndromes (UUI+URG) group had lower IIEF erectile function score than controls (-3.64, p=0.001) on linear regression adjusting for age and non-vascular comorbidity burden.  When the urgency phenotypes of UUI and UU were modeled together, UUI had a larger IIEF reduction than URG (UUI: -5.71, p<0.001; UU: -2.14, p<0.001).  Proteomic profiling identified 23 cardiometabolic proteins that differed between UUI and URG (FDR<0.05) including those involved in lipid metabolism (ANGPTL3, APOM) and inflammation (CCL18).  Only one protein differed between UUI and controls, and none differentiated pooled URG/UUI cases from controls. Vascular comorbidity did not predict 12-month improvement, whereas surgery/invasive therapy did.

These findings support biologic heterogeneity amongst urinary urgency syndromes and suggest a systemic, vascular associated urgency urinary incontinence subtype distinct from urgency without incontinence, with implications for mechanism based phenotyping and management.

Urgency urinary incontinence is associated with increased vascular comorbidity, ED, and a distinct cardiometabolic proteomic profile compared with urgency without incontinence.