Hypertension is a major risk factor for mortality with ageing. In previous studies, we found an association of allelic variants of 11 genes with longevity. We provided evidence that for 7 of the genes their effect on longevity involves protecting against the risk of mortality from major chronic diseases of aging, particularly hypertension. We determined that of 1,733 proteins that increased with age (p ≤ 0.05), 872 were found to increase mortality (p ≤ 0.05), and 105 demonstrated interaction with the longevity genotypes that mitigated the otherwise expected increase in aging and mortality (i.e., conferred resilience) (p ≤ 0.05). In the present study, we provide data showing the overlap between the biological pathways involving each of these genes and known aging pathways. We report that the proteins modified by the longevity genotypes participate in: (1) extracellular matrix transition, (2) TGF-β/BMP signaling, (3) secretion programs (including SASP), (4) cytokine/TNF responses, (5) glycosaminoglycan interactions, and (6) growth control. The proteomic pathways involved in protection involve: (1) regulation of epithelial to mesenchymal transition (EMT) and mesenchymal cell differentiation, (2) regulation of cellular secretion, (3) TGF-β receptor signaling and response, (4) regulation of cell growth, (5) SMAD binding, and (6) cytokine receptor binding. These pathways shed light on the causes of chronic disease, including hypertension, stroke, stem cell maintenance, sarcopenia, wound healing and cancer. Together, our findings provide a comprehensive compendium of the pathways and mechanisms influenced by these longevity genes, thus providing targets for precision medicine to help counter aging and ageing-related diseases such as hypertension. Longevity variants of FLT1 and GHR increases lifespan by reducing mortality risk posed by hypertension. In hypertension, abnormal VEGFR signalling alters vascular structure resulting in endothelial dysfunction.

Background: Individuals with long QT syndrome (LQTS) have an increased susceptibility to seizures. Seizures themselves can produce profound autonomic and cardiovascular disturbances, including QT prolongation and cardiac arrhythmias. The interaction between prolonged QT interval and seizure-induced cardiovascular dysfunction may contribute to fatal arrhythmias and sudden unexpected death in epilepsy (SUDEP). However, clinically relevant large animal models that reproduce this combination are lacking, limiting the development and testing of targeted therapies.

Aim: To establish and characterise a clinically relevant sheep model combining prolonged QT interval with convulsive seizures to investigate seizure-associated cardiovascular dysfunction.

Methods: Four anaesthetised adult female Merino sheep were surgically instrumented for continuous measurement of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), electrocardiogram (ECG) and electroencephalogram (EEG). An acquired prolonged QT phenotype was induced using intravenous haloperidol (1.5 mg/kg over 30 min), followed by seizure induction with intravenous pentylenetetrazol (PTZ; 10 mg/kg/min for 4 min). Cardiovascular and electrophysiological responses were assessed before and following induction of prolonged QT and during the postictal period.

Results: Haloperidol significantly prolonged corrected QT interval (QTc) from 403.5 ± 12.4 to 521.3 ± 28.3 ms (P = 0.012), establishing a prolonged QT phenotype. Subsequent PTZ-induced seizures produced further QTc prolongation (to 530.0 ± 17.3 ms) and marked cardiac electrical instability within 10 min of seizure onset. All animals developed cardiac arrhythmias, including ventricular trigeminy, premature atrial and ventricular beats and sinus arrhythmia consistent with transient sinus node dysfunction. Arrhythmias persisted for up to 60 min postictally. One animal developed pulseless ventricular tachycardia progressing to ventricular fibrillation and death.

Conclusion: We established a new sheep model combining prolonged QT interval and convulsive seizures that reproduces key cardiovascular abnormalities associated with seizure-related cardiac risk. This large mammalian model provides a clinically relevant platform to investigate the mechanisms linking seizures, QT prolongation and malignant arrhythmias, and to evaluate novel therapeutic strategies to prevent cardiovascular complications and SUDEP.

Background: High-dose intravenous ascorbic acid (vitamin C) has failed to improve health outcomes in septic shock, whereas megadose sodium ascorbate rapidly reverses vasoplegia in ovine sepsis. Whether these divergent effects reflect formulation-specific cardiovascular pharmacology remains unknown.

Aim: To determine whether equimolar megadoses of sodium ascorbate and ascorbic acid differ in their effects on vasopressor responsiveness and strong-ion and acid–base balance.

Methods: Adult Merino ewes with established Gram-negative sepsis were randomised to intravenous sodium ascorbate (3.0 g/kg; n=6) or an equimolar dose of vitamin C (2.67 g/kg; n=7), administered as a loading dose followed by a 7-h infusion. Noradrenaline was titrated to maintain mean arterial pressure at ~80 mmHg. Serial arterial blood chemistry was assessed, with acid–base effects characterised using Stewart strong-ion difference and partitioned standard base-excess analyses.

Results: Before treatment, MAP fell similarly in the sodium-ascorbate (86.0 to 70.0 mmHg) and ascorbic-acid groups (85.2 to 69.0 mmHg; pooled P<0.0001). Noradrenaline requirements to restore mean arterial pressure to ~80 mmHg progressively increased with ascorbic acid (0.3 ± 0.1 to 0.7 ± 0.2 µg/kg/min) but decreased with sodium ascorbate (0.3 ± 0.1 to 0.2 ± 0.1 µg/kg/min; PGroupxTime=0.0001). Neither formulation altered arterial pH. Compared with ascorbic acid, sodium ascorbate produced greater increases in bicarbonate (29.5 ± 1.1 vs 26.0 ± 0.9 mmol/L; PGroupxTime=0.006) and base excess (5.9 ± 1.0 vs 1.7 ± 1.3 mmol/L; PGroupxTime=0.01). Sodium ascorbate produced a greater increase in apparent strong-ion difference (52.7 ± 2.0 vs 37.4 ± 3.3 mEq/L at 31 h; PGroup×Time = 0.009). Plasma sodium was also higher with sodium ascorbate (160.0 ± 1.7 vs 148.3 ± 2.6 mmol/L; treatment PGroupxTime=0.0002).

Conclusions: Equimolar megadose sodium ascorbate, but not ascorbic acid, restored vasopressor responsiveness in established sepsis. Distinct strong-ion and acid–base effects, despite unchanged arterial pH suggest formulation-specific pharmacology, underlies this haemodynamic divergence. Sodium ascorbate and ascorbic acid are therefore not therapeutically interchangeable at pharmacological doses.

Background: Up to 55% of patients who undergo cardiac surgery requiring cardiopulmonary bypass (CPB) suffer postoperative delirium, with almost 40% developing long-term postoperative cognitive dysfunction. Although the underlying mechanisms are not well understood, blood-brain barrier (BBB) disruption is thought to play a significant role. Clinical studies have typically examined blood and cerebrospinal fluid biomarkers to determine BBB disruption, with a limited number of MRI studies. Direct, non-invasive measures of BBB permeability in patients remains technically challenging.

Aim: To investigate the severity and time course of CPB-induced frontal lobe BBB disruption in a clinically relevant ovine model. Importantly, disruption of different components of the BBB, such as tight junctions (occludin) and astrocytic end feet (aquaporin-4), were characterised.

Methods: Female Merino sheep were anaesthetised and underwent CPB for approximately two hours before termination at the end of CPB (n = 7) or following a 48-hour recovery period with (n = 7) or without (n = 10) pre-existing heart failure (HF), induced by progressive coronary ligation. Naïve controls did not undergo any surgical procedures (n = 6). Brains were perfused with 4% paraformaldehyde, dehydrated in 20% sucrose, and frontal lobe samples were cryosectioned. Immunohistochemistry was then performed to measure occludin and aquaporin-4 expression.

Results: There was a significant decrease in vessel coverage of occludin between the naïve sheep and sheep with HF 48 hours after the end of CPB (p = 0.03 for percentage area), indicating increased breakdown of the BBB. There was a trend towards less occludin expression in healthy sheep 48 hours after CPB compared with naïve controls (p = 0.07). This is in line with previous findings in microglia, with exaggerated neuroinflammation after CPB with pre-existing HF.

Conclusions: These findings suggest an increased severity of BBB disruption in the frontal lobe with pre-existing HF 48 hours after the end of CPB. These results provide evidence of the impact of CPB on BBB integrity continuing beyond surgery which may contribute to cognitive dysfunction seen in patients. Future studies should further investigate the time course of CPB-induced BBB disruption and impacts on the wider neurovascular unit.