Sex differences in cardiovascular–kidney–metabolic risk factors associated with degenerative valvular heart disease

Abstract Aims The cardiovascular–kidney–metabolic (CKM) health approach emphasizes the importance of multidisciplinary early-stage disease prevention. This study aimed to explore sex differences in CKM risk factors associated with common degenerative valvular heart disease (VHD). Methods and results A total of 436 184 participants (54.4% women; mean age, 58 years) free of VHD or heart failure at baseline and with complete information about CKM risk factors were included from the UK Biobank cohort. We assessed sex differences in hazard ratios (HRs) and population-attributable risk (PAR) for incident VHD and VHD-related interventions or mortality, focusing on five CKM risk factors: hypertension, diabetes, obesity, hypertriglyceridaemia, and chronic kidney disease (CKD). At baseline, 81.06% of participants had one or more CKM risk factors: 75.61% had hypertension, 4.80% had diabetes, 24.14% had obesity, 22.26% had hypertriglyceridaemia, and 2.32% had CKD. Over a median follow-up period of 13.80 years, incidences of aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR) were 11.18 and 5.42, 3.64 and 2.19, and 10.39 and 6.94 events per 10 000 person-years for men and women, respectively. Hypertension was consistently the largest attributable risk factor for incident VHD in both sexes, with PARs of 29.07% and 25.17% for AS, 24.21% and 16.51% for AR, and 19.55% and 13.01% for MR in women and men, respectively. Compared with men, women had higher risks of AS with obesity [HR: 1.17 (1.04–1.32)], AR with CKD [1.59 (1.01–2.49)], and MR with either hypertension [1.25 (1.07–1.47)] or hypertriglyceridaemia [1.22 (1.07–1.39)]. Conclusion Tailoring the prioritization of CKM risk factors based on gender has the potential to enhance the effectiveness of VHD prevention strategies. Lay summary Despite the rising incidence of degenerative valvular heart disease (VHD), recommended preventive interventions are lacking. This large-scale study examined sex disparities in the relationship between the cardiovascular–kidney–metabolism (CKM) health construct, as proposed by the American Heart Association, and degenerative VHD in a cohort of UK adults. This study provided a comprehensive investigation into CKM risk factors for degenerative VHD. Hypertension was the largest attributable risk factor for incident VHD in both sexes. Females showed higher risks for specific VHD subtypes when certain CKM risk factors were present. Specifically, females had higher risks of aortic valve stenosis with obesity, aortic valve regurgitation with chronic kidney disease, and mitral valve regurgitation with either hypertension or hypertriglyceridaemia, compared with males. Our study findings indicate that customizing risk factor prioritization based on gender may enhance the precision and effectiveness of prevention strategies for degenerative VHD, with particular emphasis on female CKM health.