Background and Aim: Renin-independent aldosterone production exists along a continuum preceding overt primary aldosteronism and may contribute to cardiovascular injury before the onset of hypertension. Whether changes in aldosterone and renin during the transition from adolescence to young adulthood identify this phenotype and influence vascular health is unknown. This study investigated how changes in aldosterone and renin from adolescence to young adulthood relate to vascular function, and whether blood pressure mediates this relationship.

Methods: Participants from the Raine Study were included if they had plasma aldosterone and direct renin measured at ages 17 and 27, and vascular assessments (aortic augmentation index [Aix] and aortic distensibility) at age 27. Multivariable linear regression models were employed to investigate associations between changes in aldosterone and renin from age 17 to 27 and vascular parameters at age 27. Mediation analysis was used to test whether blood pressure at age 27 mediated these associations.

Results: Among 610 participants (388 men, 222 women; 6% and 20% with blood pressure ≥130/80 mmHg at 17 and 27 years, respectively), aldosterone and renin significantly decreased from age 17 to 27 (median aldosterone 351 to 239 pmol/L, p<0.001; renin 24.3 to 13.8 mU/L, p<0.001). In men, a smaller decrease in aldosterone, but not in renin, was independently associated with higher AIx (β 1.23% [95%CI 0.23−2.23] per 100 pmol/L, p=0.016) and lower aortic distensibility (β -0.27 ×10-³ mmHg-¹ [95%CI -0.50−-0.046] per 100 pmol/L, p=0.019). The association with AIx was more pronounced in men with a greater-than-median reduction in renin (<-10.6 mU/L) (β 2.61% [95%CI 0.97−4.26] per 100 pmol/L, p=0.002). Mediation analysis indicated these associations were largely attributable to direct effects, rather than indirect effects mediated by blood pressure at age 27. There were no associations observed in women.

Conclusions: In the transition to early adulthood, a blunted decline in aldosterone combined with a pronounced drop in renin may signal the emergence of renin-independent aldosterone production, with an adverse effect on vascular health largely independent of blood pressure. These findings were limited to men and suggest that early aldosterone dysregulation may contribute to cardiovascular risk before the development of overt hypertension.

Background and Aim: Influenza A virus (IAV) is primarily considered a respiratory pathogen, yet severe infection is accompanied by systemic inflammation and cardiovascular complications. Pregnancy markedly increases susceptibility to severe influenza, but how pulmonary infection translates into maternal systemic and foetal pathology remains incompletely understood. Over a series of studies, we investigated the host mechanisms that amplify IAV-induced inflammation and subsequently defined how these responses extend beyond the lung to disrupt maternal vascular and placental function during pregnancy.

Methods: Using experimental IAV infection in mice, we combined genetic and pharmacological manipulation of reactive oxygen species-generating and innate immune pathways with assessment of pulmonary and systemic inflammation, maternal haemodynamics, vascular reactivity, vascular immune-cell recruitment, placental pathology and foetal outcomes.

Results: Our initial studies identified NOX2 oxidase-derived reactive oxygen species as important amplifiers of IAV-induced inflammation, establishing a pathogenic role for host redox signalling during infection. Subsequent studies in pregnancy revealed that IAV pathology extends beyond the respiratory tract. Viral RNA was detected in the maternal aorta and accompanied by vascular oxidative stress, immune-cell recruitment and profound endothelial dysfunction, together comprising a systemic vascular inflammatory phenotype. Maternal vascular dysfunction coincided with placental injury, impaired foetal growth and placental and foetal-brain hypoxia. Pharmacological suppression of vascular inflammation with low-dose aspirin preserved endothelial function and improved foetal outcomes, demonstrating a causal and modifiable contribution of the maternal vascular response. More recently, genetic deletion of TLR7 markedly attenuated IAV-induced maternal haemodynamic and vascular dysfunction and reduced downstream placental and foetal pathology, identifying viral RNA sensing as an upstream regulator of this response.

Conclusions: Collectively, these studies define a biological continuum in which pulmonary viral infection engages host redox and innate immune pathways that propagate inflammation into the maternal systemic circulation. During pregnancy, this response manifests as a distinct vascular syndrome linking maternal infection to placental dysfunction and foetal hypoxia. These findings broaden the pathophysiology of influenza beyond the lung and identify the maternal vasculature as an integral component of the host response to respiratory viral infection.

Background and aim: Preeclampsia, defined by new onset maternal hypertension and organ dysfunction during pregnancy, was previously thought to be a disorder of the placenta that resolves after delivery. However, emerging evidence shows life-long cardiovascular disease risk increases after an affected pregnancy. The human placenta is an abundant source of extracellular vesicles, as the syncytiotrophoblast continuously extrudes trophoblast-derived extracellular vesicles (T-EVs) directly into the maternal blood throughout pregnancy. We hypothesised that T-EVs can induce long-term changes in the maternal cardiovascular system and in the case of preeclampsia this may drive adverse cardiovascular outcomes postpartum.

Methods: T-EVs were isolated from human placenta, obtained from mothers who had experienced either normotensive, early-onset or late-onset preeclamptic pregnancies. The T-EVs were then injected into pregnant normotensive Wistar or Spontaneously Hypertensive rats (SHR) over 10 days. Arterial pressure was measured intensely during pregnancy and up to 2-weeks postpartum, and intermittently to 12-months postpartum. Post-mortem vascular function of mesenteric arteries was assessed via wire myography at two time points: 2-weeks and 12-months postpartum.

Results: During pregnancy and the early postpartum period preeclamptic T-EVs did not have a major effect on arterial pressure. However, at two weeks postpartum the mesenteric arteries from the rats exposed to T-EVs obtained from early-onset preeclamptic pregnancies showed greater vasoconstriction to the thromboxane A2 agonist U46619 in both Wistar (n=8, P<0.0002) and SHR (n=5, P<0.0001). Additionally, vessels from rats exposed T-EVs from both early-onset (Wistar, P=0.0338 and SHR, P=0.0112) and late-onset (Wistar n=8, P<0.001) preeclamptic placenta showed less vasodilation to acetylcholine. By twelve months post-partum both the Wistar and SHR rats exposed to the preeclamptic T-EVs had elevated systolic pressures, relative to the animals that received either T-EVs from normotensive pregnancies or vehicle (P<0.01). Vascular responses showed preeclamptic T-EVs elevated vasoconstriction, with increased responses to phenylephrine and endothelin-1 in vessels that had been exposed to T-EVs from early-onset and late-onset preeclamptic placenta (P<0.001) versus those from normotensive pregnancies or vehicle.

Conclusions: Together our results suggest that T-EVs are key in mediating vascular dysfunction associated with preeclampsia, and this effect is sustained well beyond pregnancy, contributing to cardiovascular dysfunction later in life.

Background and Aim: Increased arterial stiffness frequently coexists with aortic stenosis in older patients, imposing an additional vascular load on the left ventricle beyond valvular outflow obstruction. Transcatheter aortic valve implantation (TAVI) relieves valvular obstruction in aortic stenosis, but downstream vascular effects are less well defined. We aimed to compare short-term and medium/late post-TAVI changes in central haemodynamics using pulse wave analysis (PWA), with a focus on the subendocardial viability ratio (SEVR, or Buckberg index), defined from the ratio of diastolic to systolic pressure-time area, as an indirect measure of myocardial supply-demand balance since coronary perfusion occurs predominantly during diastole.

Methods: Two cohorts were analysed: a short-term group with paired baseline and day-1 post-TAVI measurements, and a medium/late group with paired baseline and 6-8 weeks follow-up post-TAVI. Haemodynamic assessment included blood pressure, heart rate, and PWA using radial tonometry calibrated to brachial cuff pressures. Within-cohort changes used paired t-tests; between-cohort changes used Welch tests. Medium/late follow-up occurred a median 60 days post-TAVI (IQR 40-119; range 28-812).

Results: The short-term group (n=56; 81.6±7.7 years; 31 male) and medium/late group (n=20; 80.4±6.5 years; 12 male) were similar by age and sex. In the short-term group, SEVR increased from 123.4±26.8% to 139.3±29.4% (+15.9 points; p<0.001), central systolic blood pressure fell from 133.6±14.7 to 117.2±16.3 mmHg (-16.5 mmHg; p<0.001). Augmentation index corrected to heart rate at 75 beats per minute (AIx@75) fell from 38.2±13.2% to 25.2±13.2% (-13.0 points; p<0.001), and heart rate was unchanged (p=0.579). In the medium/late group, SEVR increased from 126.6±28.7% to 143.5±29.5% (+16.9 points; p=0.023) and AIx@75 fell from 36.3±7.6% to 30.0±7.5% (-6.3 points; p=0.001), while central systolic blood pressure was unchanged.

Conclusions: TAVI was associated with improved vascular efficiency based on PWA-derived haemodynamic indices, including higher SEVR and lower AIx@75 in both the short-term and medium/late groups. Post-TAVI vascular remodelling may support improved myocardial supply-demand balance and coronary perfusion improvement, as suggested indirectly by SEVR; however, correlation with direct coronary perfusion measurements would strengthen this claim.