The Effect of Allopurinol on Left Ventricular Mass in Patients with Treated Essential Hypertension

Abstract

Left ventricular hypertrophy (LVH) confers a high cardiovascular risk independent of blood pressure. It is prevalent in hypertensive patients even when the blood pressure is controlled, and LVH regression has prognostic benefit. Residual risk remains in well controlled hypertension and therefore novel non-blood pressure lowering therapies are required to regress LVH with the aim of improving cardiovascular morbidity and mortality. Increased activation of redox signalling by oxidative stress (OS) leads to myocyte hypertrophy and fibrosis and is a major non-haemodynamic contributor to LVH. Allopurinol can act as a potent anti-oxidant by inhibiting xanthine oxidase generated reactive oxygen species and has been shown to improve vascular OS and reduce LVH in other conditions such as chronic kidney disease, diabetes mellitus and ischaemic heart disease. The main aim of this thesis is to investigate whether allopurinol regresses LVH in patients with optimally treated, well-controlled hypertension.

The trial design was a double-blind placebo-controlled study of 66 patients with hypertension and echocardiographic LVH. Patients were randomly allocated to allopurinol 600mg daily or placebo for 12 months. The primary outcome was the change in left ventricular mass detected by cardiac magnetic resonance imaging (CMRI) from baseline to the final visit. Secondary end-points assessed change in flow mediated dilation, augmentation index, pulse wave velocity, blood pressure control, biomarkers (Urate, High sensitivity C-Reactive Protein (HsCRP), Thiobarbituric acid reactive substances (TBARs), N-terminal prohormone B-Type Natriuretic Peptide (NTproBNP), Procollagen type I carboxy-terminal Propeptide (PICP) and soluble ST2 (sST2) and other CMRI parameters.

The two groups were well matched at baseline, importantly there were no statistically significant differences in gender, BMI, blood pressure, number of antihypertensive medications, urate (allopurinol 374.31 ± 85.63 µmol/L, placebo 347.28 ± 108.33µmol/L) and LV mass. Allopurinol failed to regress left ventricular mass (LVM) compared to placebo (indexed LVM -0.18 ± 2.39 g/m1.7 vs -1.60 ± 1.60g/m1.7; p = 0.009). OS markers (TBARs) increased from baseline in the cohort taking allopurinol compared to placebo (0.26 ± 0.85uM vs -0.34 ± 0.83uM; 0.007). No significant change was seen in FMD, AIx, PWV, BP, other biomarkers or the other CMRI parameters. Uric acid (UA) is a major antioxidant in human plasma but can become a pro-oxidant in certain conditions. By lowering uric acid with allopurinol, we have increased oxidative stress, altered the redox balance unfavourably and attenuating LVM regression compared to placebo.

In conclusion, allopurinol prevented LVM regression in normo-uricaemic subjects with well controlled hypertension and LVH, potentially from increased oxidative stress secondary to the reduction of urate, an antioxidant. This trial demonstrates that LVM regression with allopurinol is not universal and future trials should carefully select cohorts who are most likely to benefit.

Date of Award	2019
Original language	English
Awarding Institution	University of Dundee
Sponsors	British Heart Foundation
Supervisor	Jacob George (Supervisor) & Allan Struthers (Supervisor)