Vascular dysfunction and increased cardiovascular risk in hypospadias

Lucas-Herald, A. K. et al. (2022) Vascular dysfunction and increased cardiovascular risk in hypospadias. European Heart Journal, 43(19), pp. 1832-1845. (doi: 10.1093/eurheartj/ehac112) (PMID:35567552) (PMCID:PMC9113289)

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Aims Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease. Methods and results Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4–5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5–11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7–114.3, P = 0.02). Conclusion Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males. Key question Is hypospadias associated with vascular dysfunction? Key finding Boys with hypospadias have evidence of hypercontractility and impaired vasodilation secondary to increased Rho kinase activation and oxidative stress. This leads to raised systolic blood pressure in adolescence and increased risk of admission to hospital for cardiovascular diseases in adulthood. Take-home message Hypospadias is a risk factor for cardiovascular dysfunction in males.

Item Type:Articles
Additional Information:ALH, RAL, LH, CD and KB and RMT are supported by grants from the British Heart Foundation (BHF) (RE/13/5/30177; RE/18/6/34217). RMT is supported by a BHF Chair Award (CH/12/4/29762). ACM is supported by a University of Glasgow Walton fellowship. ALH received funding from the Mason Medical Research Foundation.
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Brooksbank, Dr Katriona and Delles, Professor Christian and Alimussina, Dr Malika and Haddow, Mrs Laura and Mccallum, Dr Linsay and Ahmed, Professor Syed Faisal and Steven, Miss Mairi and Flett, Mr Martyn and Montezano, Dr Augusto and Lucas-Herald, Dr Angela and Touyz, Professor Rhian
Authors: Lucas-Herald, A. K., Montezano, A. C., Alves-Lopes, R., Haddow, L., Alimussina, M., O’Toole, S., Flett, M., Lee, B., Amjad, S. B., Steven, M., Brooksbank, K., McCallum, L., Delles, C., Padmanabhan, S., Ahmed, S. F., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:European Heart Journal
Publisher:Oxford University Press
ISSN (Online):1522-9645
Published Online:17 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in European Heart Journal 43(19): 1832-1845
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences
300689Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762CAMS - Cardiovascular Science