Background and Aim. A hypertensive response to exercise (HRE) considered relative-to-fitness is associated with adverse cardiovascular (CV) outcomes. However, risk may differ by sex, which would have important ramifications for CV risk stratification. This study aimed to determine if an HRE defined relative-to-fitness confers sex-specific CV risk amongst a large clinical population referred for exercise stress testing.

Methods. Data from 22,750 individuals (mean age 54.4±13.1 years; 58.3% male) referred for exercise stress testing at six Australian hospitals were extracted and linked to fatal and nonfatal CV events ascertained through hospital admission, emergency presentation, and death registry datasets. An HRE relative-to-fitness was defined as the ratio of peak exercise systolic blood pressure (SBP) and peak metabolic equivalents (SBP/METPeak) ≥90th sex-specific percentile. Cox proportional hazard models were used to assess associations with CV events, including a sex interaction analysis adjusting for age, pre-exercise SBP and history of CV disease.

Results. During a mean follow-up of 53.7±33.3 months, 2,150 CV events occurred. Peak exercise SBP was higher in males than females; however, when considered relative-to-fitness (SBP/METPeak) was consistently higher in females across all age groups. In sex-stratified analyses, an HRE considered relative-to-fitness was associated with a 29% higher risk of CV events in females (HR:1.76, 95%CI:1.45,2.13) compared with males (HR:1.38, 95%CI:1.21,1.57) (interaction HR:1.29, 95%CI:1.01,1.64). Similar findings were observed using a fixed SBP/METPeak threshold (>18 mmHg/MET), with females demonstrating a higher risk of CV events than males (interaction HR:1.24, 95%CI:1.01,1.54). Conversely, an HRE without consideration of fitness (peak SBP ≥90th percentile) yielded inconsistent associations with CV events.

Conclusions. When an HRE is considered relative-to-fitness, females are at greater risk of fatal and nonfatal CV events compared with males. These findings highlight the importance of incorporating fitness into the interpretation of exercise BP responses to improve risk stratification, particularly in females.

Introduction: Monotherapy remains the most common treatment for hypertension in Australia. Contemporary international guidelines recommend dual therapy, preferably as a single-pill combination (SPC), for most patients. We evaluated the prognostic value of monotherapy versus dual and triple therapies, delivered as SPCs or multiple-pill combinations (MPCs), for all-cause, cardiovascular and stroke mortality.

Methods: Using the Australian Person-Level Integrated Data Asset, we identified adult patients persistent with an unchanged antihypertensive regimen for at least 12 months during 2016–2017, and assessed mortality outcomes up to eight years of follow-up.

Results: We included 2,383,824 adults (mean age 66±13 years; 51% female) prescribed monotherapy (52%), 2-drug MPCs (12%), 2-drug SPCs (25%), 3-drug MPCs (2%), 3-drug MPCs (2-drug SPC + 1 drug) (7%), and 3-drug SPCs (2%). Participants using MPCs were older and had a higher burden of multimorbidity. Compared with monotherapy, 2-drug SPCs (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.79–0.81, p <0.001), 3-drug MPCs (2-drug SPC + 1 drug) (HR 0.82, 95% CI 0.81–0.83, p <0.001) and 3-drug SPCs (HR 0.79, 95% CI 0.76–0.82, p<0.001) were associated with lower risk of all-cause mortality, whereas 2-drug MPCs (HR 1.06, 95% CI 1.05–1.07, p <0.001) and 3-drug MPCs (HR 1.05, 95% CI 1.03–1.07, p <0.001) were associated with higher risk, with all analyses adjusted for age, sex, entitlement class (concessional or general beneficiary), socioeconomic status, and multimorbidity. Similar patterns were observed for cardiovascular, stroke, and cardiac mortality. Sensitivity analyses excluding patients prescribed beta-blockers demonstrated findings consistent with the main analysis, with SPCs associated with lower all-cause, cardiovascular, stroke, and cardiac mortality outcomes compared with monotherapy.

Conclusion: Patients persistently prescribed monotherapy had a 10–36% higher risk for all-cause, cardiovascular and stroke mortality compared with those prescribed SPCs. These findings support the urgent need to update Australian hypertension guidelines to adopt SPCs as first-line therapy, and encourage broader adoption and global implementation efforts to significantly increase SPC use to reduce preventable deaths.

Background and Aim: Postmenopausal females experience a greater cardiovascular disease (CVD) burden than age-matched males. However, the underlying mechanisms remain poorly understood, limiting the development of targeted, female-specific CVD therapies.

Methods: To identify female-specific transcriptomic drivers of hypertension during ageing, we utilised multi-tissue RNA-sequencing data from 193 CVD-free participants aged > 55 years in the Genotype-Tissue Expression (GTEx) database. We extracted the first three principal components (PCs) to capture major sources of variation in whole-blood transcriptome data. The sex-specific differences in hypertension coexpression signatures were assessed using the hypertension–sex interaction term. We then validated the findings in age-matched Framingham Heart Study (FHS) participants (n=1,605). We also analysed gene coexpression in the kidney, heart, and artery in males and females in the GTEx cohort (n=123).

Results: PC1 was more strongly negatively associated with hypertension in females than in males in both cohorts, as indicated by significant negative hypertension–sex interaction terms, and thus named as a female hypertension coexpression signature. The top 500 genes all contributed positively to PC1 and were enriched for post-transcriptional modification and insulin signalling. ETS family transcription factors (TFs) regulated these genes. Notably, 10 ETS TFs showed significant negative hypertension–sex interactions (FDR<0.05) and accurately predicted the female hypertension coexpression signature (R = 0.94, namely, the “ETS expression score”). In female, but not male, GTEx donors, the blood PC1 score was associated with a pro-inflammatory transcriptome in the artery and kidneys, especially in CD4+ and CD8+ T cells, a well-known mechanism that regulates blood pressure. Moreover, the interaction terms between uncontrolled hypertension and sex on both the female hypertension coexpression signature and ETS expression score were significant in the FHS cohort.

Conclusion: We identified the ETS-transcriptomic axis as a potential mechanism explaining sex differences in human hypertension during ageing. This signature is associated with a multi-organ pro-inflammatory transcriptome, suggesting the ETS family may be a druggable mediator for females with hypertension.

Background and Aim: High-fibre dietary interventions are well established in the prevention and management of hypertension, yet their interactions with oral therapeutics remain poorly understood. Fibre fermentation lowers intestinal pH via production of acidic microbial metabolites, which may alter drug ionisation and absorption. This study aims to identify oral therapeutics whose absorption is modulated by lower intestinal pH using machine learning and in silico modelling.

Methods: From 3022 DrugBank-approved compounds, 1099 oral human-targeted drugs were selected. Structural and clinical parameters were retrieved from DrugBank, PubChem, and the WHO Essential Medicines list. Baseline pharmacokinetic profiles generated via JChem and pkCSM were validated against experimental values. Schrödinger’s Maestro tools (Epik, Jaguar, LigPrep, QikProp) were used to simulate pH-dependent profiles. A scoring system integrating drug class, Biopharmaceutics Classification System (BCS) class, lipophilicity, solubility, and predicted absorption parameters categorised drugs as positively, negatively, or unaffected by reduced intestinal pH.

Results: Of 1099 drugs, 631 had no changes in ionisation state within the physiological pH range and were therefore unaffected by diet-derived pH changes. Among the remaining 468 drugs, 52.4% (n=245) were unaffected/minorly affected, 10.3% (n=48) were negatively affected, and 37.4% (n=175) were positively affected (enhanced absorption). Out of these 468 drugs, 16.5% (n=77) belong to cardiovascular and haematological drugs. Within this subset, 42.9% (n=33) were unaffected, 11.7% (n=9) were negatively affected, and 45.4% (n=35) benefited from lower pH. Response varied by therapeutic subclass: 90% of diuretics and ~50% of renin-angiotensin system agents benefited from lower pH, whereas 69.2% of cardiac therapy drugs were unaffected or negatively affected.

Conclusions: This in silico modelling suggests that a lowering in intestinal pH, such as that induced by high fibre diets, can have significant effects on the absorption of antihypertensive and cardiovascular drugs. These drug- and class-specific interactions support further in vitro and ex vivo validation to optimise combined dietary and oral pharmacological therapies to improve blood pressure control.