Potential Applications of Artificial Intelligence (AI) in Managing Polypharmacy in Saudi Arabia: A Narrative Review.

Prescribing medications is a fundamental practice in the management of illnesses that necessitates in-depth knowledge of clinical pharmacology. Polypharmacy, or the concurrent use of multiple medications by individuals with complex health conditions, poses significant challenges, including an increased risk of drug interactions and adverse reactions. The Saudi Vision 2030 prioritises enhancing healthcare quality and safety, including addressing polypharmacy. Artificial intelligence (AI) offers promising tools to optimise medication plans, predict adverse drug reactions and ensure drug safety. This review explores AI's potential to revolutionise polypharmacy management in Saudi Arabia, highlighting practical applications, challenges and the path forward for the integration of AI solutions into healthcare practices.

OPTIMA-BP: empOwering PaTients in MAnaging Blood Pressure - protocol for a randomised parallel group study comparing use of Kvatchii web-based patient education portal as an addition to home blood pressure monitoring.

INTRODUCTION: Hypertension is the leading modifiable risk factor for cardiovascular disease and is implicated in half of all strokes and myocardial infarctions. One-third of the adults in Scotland have hypertension yet only a quarter of them have their blood pressure (BP) controlled to target (<140/90 mm Hg). Empowering patients to have a better understanding of their condition and becoming actively involved in the monitoring and management of hypertension may lead to improved patient satisfaction, improved BP control and health outcomes and reduction in the use of primary/secondary care hypertension clinics. METHODS AND ANALYSIS: OPTIMA-BP is a randomised parallel group pilot study comparing the use of home BP monitoring accompanied by access to the web-based cardiovascular educational portal (Kvatchii) and home BP monitoring (HBPM) alone in 200 patients with hypertension attending the Glasgow Blood Pressure Clinic, Queen Elizabeth University Hospital, Glasgow. Consented participants will be asked to complete surveys on lifestyle factors, medication adherence, quality of life and hypertension knowledge, understanding and home monitoring. The intervention group will be asked to complete a survey to help evaluate the Kvatchii portal. At 6 and 12 months, the surveys will be repeated via the CASTOR EDC. Both groups will input their HBPM results at 2-month intervals into a CASTOR-EDC survey. OPTIMA-BP will follow-up with participants over 12 months with the study running over 24 months. The primary outcome is HBPM systolic BP area under the curve between baseline and 6 months ETHICS AND DISSEMINATION: OPTIMA-BP was approved by the North of Scotland Research Ethics Committee 2 (22/NS/0095). Current protocol version 1.2 date 6 June 2023. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed journals and will be presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05575453. Registered 12 October 2022. https://clinicaltrials.gov/ct2/show/NCT05575453.

Scrutinizing science to save lives: uncovering flaws in the data linking L-type calcium channels blockers to CRAC channels and heart failure.

Hypertension is estimated to affect almost 1 billion people globally and significantly increases risk of myocardial infarction, heart failure, stroke, retinopathy and kidney disease. One major front line therapy that has been used for over 50 years involves L-type Ca 2+ channel blockers (LCCBs). One class of LCCBs is the dihydropyridine family, with amlodipine being widely prescribed regardless of gender, race, ethnicity or age. In 2020, Johnson et al. 7 reported that all LCCBs significantly increased the risk of heart failure, and attributed this effect to non-canonical activation of store-operated Ca 2+ entry. A major approach on which they based many of their arguments was to measure cytosolic Ca 2+ using the fluorescent Ca 2+ indicator dye fura-2. We recently demonstrated that amlodipine is highly fluorescent within cells and overwhelms the fura-2 signal, precluding the use of the indicator dye with amlodipine 24 . Our meta-analyses and prospective real world study showed that dihydropyridines were not associated with an increase in heart failure, likely explained by the lack of consideration by Johnson et al. 7 of well-known confounding factors such as age, race, obesity, prior anti-hypertensive treatment or diabetes 24 . Trebak and colleagues have responded to our paper with a forthright and unwavering defence of their work 27 . In this paper, we carry out a forensic dissection of Johnson et al., 7 and conduct new experiments that address directly points raised by Trebak et al. 27 . We show that there are major flaws in the design and interpretation of their key experiments, that fura-2 cannot be used with amlodipine, that there are fundamental mathematical misunderstandings and mistakes throughout their study leading to critical calculations on heart failure that are demonstrably wrong, and several of their own results are inconsistent with their interpretation. We therefore believe the study by Johnson et al. 7 is flawed at many levels and we stand by our conclusions.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

A Reappraisal of the Effects of L-type Ca2+ Channel Blockers on Store-Operated Ca2+ Entry and Heart Failure.

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca2+ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca2+ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use. Given that hypertension is the dominant "silent killer" across the globe affecting ∼1.13 billion people, removal of Ca2+ channel blockers as antihypertensive agents has major health implications. Here, we show that amlodipine has marked intrinsic fluorescence, which further increases considerably inside cells over an identical excitation spectrum as fura-2, confounding the ability to measure cytosolic Ca2+. Using longer wavelength Ca2+ indicators, we find that concentrations of Ca2+ channel blockers that match therapeutic levels in serum of patients do not activate store-operated Ca2+ entry. Antihypertensive Ca2+ channel blockers at pharmacological concentrations either have no effect on store-operated channels, activate them indirectly through store depletion or inhibit the channels. Importantly, a meta-analysis of published clinical trials and a prospective real-world analysis of patients prescribed single antihypertensive agents for 6 mo and followed up 1 yr later both show that dihydropyridines are not associated with increased heart failure or other cardiovascular disorders. Removal of dihydropyridines for treatment of hypertension cannot therefore be recommended.

Establishing plausibility of cardiovascular adverse effects of immunotherapies using Mendelian randomisation.

Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%-89.10%; WHR: 42.92% (4.17%-81.67%); TG: 72.05% (10.63%-133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.

Long-Term Usage and Improved Clinical Outcomes with Adoption of a COPD Digital Support Service: Key Findings from the RECEIVER Trial.

Purpose: Digital tools may improve chronic obstructive pulmonary disease (COPD) management, but further evidence of significant, persisting benefits are required. The RECEIVER trial was devised to evaluate the Lenus COPD support service by determining if people with severe COPD would continue to utilize the co-designed patient web application throughout study follow-up and to explore the impact of this digital service on clinical outcomes with its adoption alongside routine care. Patients and Methods: The prospective observational cohort hybrid implementation-effectiveness study began in September 2019 and included 83 participants. Recruitment stopped in March 2020 due to COVID-19, but follow-up continued as planned. A contemporary matched control cohort was identified to compare participant clinical outcomes with and minimize biases associated with wider COVID-19 impacts. Utilization was determined by daily COPD assessment test (CAT) completion through the application. Survival metrics and post-index date changes in annual hospitalizations were compared between the RECEIVER and control cohorts. Longitudinal quality of life and symptom burden data and community-managed exacerbation events were also captured through the application. Results: High and sustained application utilization was noted across the RECEIVER cohort with a mean follow-up of 78 weeks (64/83 participants completed at least one CAT entry on ≥50% of possible follow-up weeks). Subgroup analysis of participants resident in more socioeconomically deprived postcode areas revealed equivalent utilization. Median time to death or a COPD or respiratory-related admission was higher in the RECEIVER cohort compared to control (335 days vs 155 days). Mean reduction in annual occupied bed days was 8.12 days vs 3.38 days in the control cohort. Quality of life and symptom burden remained stable despite the progressive nature of COPD. Conclusion: The sustained utilization of the co-designed patient application and improvements in participant outcomes observed in the RECEIVER trial support scale-up implementation with continued evaluation of this digital service.

Survey and Evaluation of Hypertension Machine Learning Research.

Background Machine learning (ML) is pervasive in all fields of research, from automating tasks to complex decision-making. However, applications in different specialities are variable and generally limited. Like other conditions, the number of studies employing ML in hypertension research is growing rapidly. In this study, we aimed to survey hypertension research using ML, evaluate the reporting quality, and identify barriers to ML's potential to transform hypertension care. Methods and Results The Harmonious Understanding of Machine Learning Analytics Network survey questionnaire was applied to 63 hypertension-related ML research articles published between January 2019 and September 2021. The most common research topics were blood pressure prediction (38%), hypertension (22%), cardiovascular outcomes (6%), blood pressure variability (5%), treatment response (5%), and real-time blood pressure estimation (5%). The reporting quality of the articles was variable. Only 46% of articles described the study population or derivation cohort. Most articles (81%) reported at least 1 performance measure, but only 40% presented any measures of calibration. Compliance with ethics, patient privacy, and data security regulations were mentioned in 30 (48%) of the articles. Only 14% used geographically or temporally distinct validation data sets. Algorithmic bias was not addressed in any of the articles, with only 6 of them acknowledging risk of bias. Conclusions Recent ML research on hypertension is limited to exploratory research and has significant shortcomings in reporting quality, model validation, and algorithmic bias. Our analysis identifies areas for improvement that will help pave the way for the realization of the potential of ML in hypertension and facilitate its adoption.

Effect of Sodium Bicarbonate on Systolic Blood Pressure in CKD: A Systematic Review and Meta-Analysis.

BACKGROUND: Individuals with CKD are at a higher risk of cardiovascular morbidity and mortality. Acidosis is positively correlated with CKD progression and elevated systolic BP. Sodium bicarbonate is an efficacious treatment of acidosis, although this may also increase systolic BP. In this systematic review and meta-analysis, we summarize the evidence evaluating systolic BP and antihypertensive medication change (which may indicate systolic BP change) in response to sodium bicarbonate therapy in individuals with CKD. METHODS: Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, and World Health Organization (WHO) trials registry databases were searched for randomized control trials where sodium bicarbonate was compared with placebo/usual care in CKD stage G1-5 non-dialysis-dependent populations. Random effects meta-analyses were used to evaluate changes in systolic BP and BP-modifying drugs after sodium bicarbonate intervention. RESULTS: Fourteen randomized control trials (2110 individuals, median follow-up 27 [interquartile range 97] weeks, mean age 60 [SD 10] years, mean systolic BP 136 [SD 17] mm Hg, mean eGFR 38 [SD 10] ml/min, mean serum bicarbonate 22 [SD 4] mmol/L) were eligible for inclusion. Meta-analysis suggested that sodium bicarbonate did not influence systolic BP in individuals with CKD stage G1-5. Results were consistent when stratifying by dose of sodium bicarbonate or duration of intervention. Similarly, there was no significant increase in the use of antihypertensive medication or diuretics in individuals taking sodium bicarbonate, whereas there was a greater decrease in antihypertensive medication use in individuals taking sodium bicarbonate compared with controls. CONCLUSIONS: Our results suggest, with moderate certainty, that sodium bicarbonate supplementation does not adversely affect systolic BP in CKD or negatively influence antihypertensive medication requirements.

A genomic deep field view of hypertension.

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing.

Cardiovascular precision medicine - A pharmacogenomic perspective.

Precision medicine envisages the integration of an individual's clinical and biological features obtained from laboratory tests, imaging, high-throughput omics and health records, to drive a personalised approach to diagnosis and treatment with a higher chance of success. As only up to half of patients respond to medication prescribed following the current one-size-fits-all treatment strategy, the need for a more personalised approach is evident. One of the routes to transforming healthcare through precision medicine is pharmacogenomics (PGx). Around 95% of the population is estimated to carry one or more actionable pharmacogenetic variants and over 75% of adults over 50 years old are on a prescription with a known PGx association. Whilst there are compelling examples of pharmacogenomic implementation in clinical practice, the case for cardiovascular PGx is still evolving. In this review, we shall summarise the current status of PGx in cardiovascular diseases and look at the key enablers and barriers to PGx implementation in clinical practice.

Role of Uromodulin in Salt-Sensitive Hypertension.

The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality. More recently, Mendelian randomization studies have shown that genetically driven levels of uromodulin have a causal and adverse effect on kidney function. On a mechanistic level, salt sensitivity is an important factor in the pathophysiology of hypertension, and uromodulin is involved in salt reabsorption via the NKCC2 (Na+-K+-2Cl- cotransporter) on epithelial cells of the ascending limb of loop of Henle. In this review, we provide an overview of the multifaceted physiology and pathophysiology of uromodulin including recent advances in its genetics; cellular trafficking; and mechanistic and clinical studies undertaken to understand the complex relationship between uromodulin, blood pressure, and kidney function. We focus on tubular sodium reabsorption as one of the best understood and pathophysiologically and clinically most important roles of uromodulin, which can lead to therapeutic interventions.

Machine learning integration of multimodal data identifies key features of blood pressure regulation.

BACKGROUND: Association studies have identified several biomarkers for blood pressure and hypertension, but a thorough understanding of their mutual dependencies is lacking. By integrating two different high-throughput datasets, biochemical and dietary data, we aim to understand the multifactorial contributors of blood pressure (BP). METHODS: We included 4,863 participants from TwinsUK with concurrent BP, metabolomics, genomics, biochemical measures, and dietary data. We used 5-fold cross-validation with the machine learning XGBoost algorithm to identify features of importance in context of one another in TwinsUK (80% training, 20% test). The features tested in TwinsUK were then probed using the same algorithm in an independent dataset of 2,807 individuals from the Qatari Biobank (QBB). FINDINGS: Our model explained 39·2% [4·5%, MAE:11·32 mmHg (95%CI, +/- 0·65)] of the variance in systolic BP (SBP) in TwinsUK. Of the top 50 features, the most influential non-demographic variables were dihomo-linolenate, cis-4-decenoyl carnitine, lactate, chloride, urate, and creatinine along with dietary intakes of total, trans and saturated fat. We also highlight the incremental value of each included dimension. Furthermore, we replicated our model in the QBB [SBP variance explained = 45·2% (13·39%)] cohort and 30 of the top 50 features overlapped between cohorts. INTERPRETATION: We show that an integrated analysis of omics, biochemical and dietary data improves our understanding of their in-between relationships and expands the range of potential biomarkers for blood pressure. Our results point to potentially key biological pathways to be prioritised for mechanistic studies. FUNDING: Chronic Disease Research Foundation, Medical Research Council, Wellcome Trust, Qatar Foundation.

Underrepresentation of ethnic minorities in hypertension research-a survey of enablers and barriers among South Asian and African communities in Glasgow.

BACKGROUND: Hypertension is the biggest contributor to the global cardiovascular burden with evidence for ethnic differences in treatment response and outcomes. Under-representation of ethnic minorities in clinical research is well known, and despite wide-ranging public engagement events by the Glasgow Blood Pressure Clinic team, there was a lack of participation of ethnic minorities in both engagement activities and clinical trials conducted by them. This study aims to explore the awareness and knowledge of hypertension and the facilitators and barriers to participation in hypertension clinical research among South Asian (SA) and African (AFR) communities in Glasgow. METHODS: A survey questionnaire was co-developed with representatives from South Asian (SA) and African (AFR) patients and community members in Glasgow to understand awareness and knowledge of hypertension and enablers and barriers to participation in clinical research. The survey was distributed to adults (aged > 18) years of SA or AFR ancestry at public engagement events at venues that were frequently visited by these two communities in Glasgow. RESULTS: The survey response rate was 337 (67.4%) consisting of 242 (71.8%) South Asian (SA) and 56 (16.9%) African (AFR) respondents. Thirty-nine questionnaires were excluded because of incompletion. Most of the respondents were not born in the UK and were in the 35-53-year group (AFR 29 (51%), SA 113 (47%)). The proportion living in the most deprived (SIMD 1) and least deprived (SIMD 5) was respectively 26 (12.4%) and 34 (16.2%) for SA and 20 (42.6%) and 2 (4.3%) for AFR. There was a considerable recognition that treatment needs to be ethnicity-specific (SA/AFR = 107 (48%)/23 (45.1%)) and that current cardiovascular disease treatment guidelines were not tailored for different ethnicities 84 (38.5%)/23 (45.1%). The key enablers encouraging research participation are enhanced health information, conducting aspects of their clinical research visits/appointments at a location they frequently visited and allowing a family member to accompany them. Barriers included concerns about the use of personal information and side effects of the new treatment. CONCLUSION: Our survey confirmed enablers and barriers to ethnic minority participation in research. We find improving and evolving awareness and beliefs among the ethnic minority population including community leaders. Thus, continual review of researchers' beliefs and attitudes is also essential to ensure engagement activities keep up with these changing perceptions.

Unravelling the Distinct Effects of Systolic and Diastolic Blood Pressure Using Mendelian Randomisation.

A true discrepancy between the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cardiovascular (CV) outcomes remains unclear. This study performed two-sample Mendelian randomization (MR) using genetic instruments that exclusively predict SBP, DBP or both to dissect the independent effect of SBP and DBP on a range of CV outcomes. Genetic predisposition to higher SBP and DBP was associated with increased risk of coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Genetically proxied SBP exclusively was associated with CAD (OR 1.18, 95% CI: 1.03-1.36, per 10 mmHg), stroke (1.44[1.28-1.62]), ischemic stroke (1.49[1.30-1.69]), HF (1.41[1.20-1.65]), AF (1.28[1.15-1.43]), and T2DM (1.2[1.13-1.46]). Genetically proxied DBP exclusively was associated with stroke (1.21[1.06-1.37], per 5 mmHg), ischemic stroke (1.24[1.09-1.41]), stroke small-vessel (1.35[1.10-1.65]) and CAD (1.19[1.00-1.41]). Multivariable MR using exclusive SBP and DBP instruments showed the predominant effect of SBP on CAD (1.23[1.05-1.44], per 10 mmHg), stroke (1.39[1.20-1.60]), ischemic stroke (1.44[1.25-1.67]), HF (1.42[1.18-1.71]), AF (1.26[1.10-1.43]) and T2DM (1.31[1.14-1.52]). The discrepancy between effects of SBP and DBP on outcomes warrants further studies on underpinning mechanisms which may be amenable to therapeutic targeting.

Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study.

INTRODUCTION: COVID-19 may lead to long-term endothelial consequences including hypertension, stroke and myocardial infarction. A pilot study 'COVID-19 blood pressure endothelium interaction study', which found that patients with normal blood pressure (BP) at the time of hospital admission with COVID-19 showed an 8.6 mm Hg higher BP ≥12 weeks after recovery, compared with a group without COVID-19. The 'LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure'(LOCHINVAR) study is designed to provide definitive evidence of the long-term impact of COVID-19 on BP. METHODS AND ANALYSIS: The LOCHINVAR study is an observational clinical phenotyping study comparing longitudinal BP change between individuals with and without COVID-19 infection. 150 participants (30-60 years) with no history of hypertension and not on BP lowering medications will be recruited to the study to attend three visits (baseline, 12 months, 18 months). Cases will be patients who were admitted to the Queen Elizabeth University Hospital (QEUH), Glasgow, UK, with suspected/confirmed COVID-19 until 31 December 2021 and who were alive at discharge. Controls will be those who have never had confirmed COVID-19 infection. All participants will undergo clinical and vascular phenotyping studies which will include 24-hour ambulatory BP monitoring systolic BP (ABPM SBP), brachial flow-mediated dilatation urine and blood samples to assess the renin-angiotensin system, vascular inflammation and immune status. The primary outcome is the change in systolic 24-hour ABPM (ABPM SBP) between the cases and controls. Sample size was calculated to detect a mean difference of 5 mm Hg ABPM SBP at 80% power. ETHICS AND DISSEMINATION: The protocol of this study has been approved by the West of Scotland Research Ethics Committee 5 (21/WS/0075), Scotland, UK. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed hypertension journals and will be presented at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05087290.

Vascular dysfunction and increased cardiovascular risk in hypospadias.

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.