Zheng, TenghaoTavares, Leticia CamargoD’Amato, MauroMarques, Francine Z.2026-06-112026-06-110363-6135PubMed:39150392ORCID:/0000-0001-7278-0999/work/219172347https://hdl.handle.net/1885/733810233Traditional cardiovascular risk factors, including hypertension, only explain part of major adverse cardiac events (MACEs). Understanding what other risk factors contribute to MACE is essential for prevention. Constipation shares common risk factors with hypertension and is associated with an increased risk of several cardiovascular diseases. We hypothesized that constipation is an underappreciated risk factor for MACE. We used the population healthcare and genomic data in the UK Biobank (n = 408,354) to study the contribution of constipation (ICD10 K59.0) to the risk of MACE, defined by any episode of acute coronary syndrome (ACS), ischemic stroke, and heart failure (HF). Analyses were controlled for traditional cardiovascular risk factors. We also assessed genetic correlations (rg) between constipation and MACE. Constipation cases (n = 23,814) exhibited a significantly higher risk of MACE compared with those with normal bowel habits [odds ratio (OR) = 2.15, P < 1.00 × 10-300]. Constipation was also significantly associated with individual MACE subgroups, in order: HF (OR = 2.72, P < 1.00 × 10-300), ischemic stroke (OR = 2.36, P = 2.02 × 10-230), and ACS (OR = 1.62, P = 5.82 × 10-113). In comparison with patients with constipation-free hypertension, patients with hypertension with constipation showed significantly higher odds of MACE (OR = 1.68, P = 1.05 × 10-136) and a 34% increased risk of MACE occurrence (P = 2.3 × 10-50) after adjustment for medications that affect gut motility and other traditional cardiovascular risk factors. Finally, we detected positive genetic correlations between constipation and MACE subgroups ACS (rg = 0.27, P = 2.12 × 10-6), ischemic stroke (rg = 0.23, P = 0.011), and HF (rg = 0.21, P = 0.0062). We identified constipation as a potential risk factor independently associated with higher MACE prevalence. These findings warrant further studies on their causal relationship and identification of pathophysiological mechanisms.F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation, a National Heart Foundation of Australia Future Leader Fellowship Grant 105663, and a National Health & Medical Research Council (NHMRC) Emerging Leader Fellowship Grant GNT2017382. M.D. is supported by a PRIN 2022 Grant, financed by the Italian Ministry of University and Research (MUR) and the NextGenerationEU program Grant 2022PMZKEC–CUP E53D23004910008.enPublisher Copyright: Copyright © 2024 the American Physiological Society.constipationgenomicsMACEriskUK Biobank202410.1152/ajpheart.00519.202485204819931