Introduction Aortic Stenosis (AS) is characterised by pressure overload left ventricular hypertrophy (LVH) and associated diastolic dysfunction. Important determinants of exercise capacity in AS may include the presence of LVH, diastolic dysfunction and microvascular dysfunction. There are no medical therapies in AS of proven value. Ranolazine is licenced for the treatment of angina. It inhibits late sodium channel activation and has been shown to improve diastolic dysfunction in isolated myocytes.
Methods In this prospective, open label pilot study with blinded endpoint analysis, we recruited patients with asymptomatic moderate/severe AS and diastolic dysfunction or LVH. They underwent trans-thoracic echocardiography, exercise testing and adenosine stress cardiac magnetic resonance imaging at baseline, 6 weeks after commencing Ranolazine (maximum dose 750 mg BD) and again at 10 weeks (4 weeks after discontinuation). Tagged images were acquired at three short-axis slices on a 3T platform (Siemens Skyra). Myocardial perfusion reserve was calculated from stress and resting blood flow. The primary hypothesis was that Ranolazine would improve peak early diastolic strain rate (PEDSR) on tagged MRI.
Results Fifteen patients (PPG 48.8 ± 12.4 mmHg, MPG 27.1 ± 7.5 mmHg, AVA 1.26 ± 0.31 cm2, LV mass index 66.72 ± 15.35 g/m2) completed the week-6 visit and 13 completed the final visit. There was a trend for the global PEDSR to increase from the baseline to week-6 (0.79 ± 0.15 to 0.86 ± 0.18, p = 0.198, n = 15). For those who completed the final visit (n = 13), PEDSR increased from baseline to week-6 and then returned close to the baseline value at week-10 (Table 1). There was no significant change in MPR or echocardiographic measures of diastolic dysfunction. The total exercise duration increased from 10.47 ± 3.68 min to 11.60 ± 3.25 min (n = 15, p = 0.06), with a trend for the maximal HR and SBP to be lower at week-6, resulting in a reduction in exercise LV rate-pressure product (LVRPP), suggesting improved myocardial efficiency. On splitting the patients into low and high-MPR subgroups based on the median MPR, the trend for the improvement in PEDSR (0.88 ± 0.80, 1.03 ± 0. 30, 0.86 ± 0.15) and reduction in exercise LVRPP was maintained in the low-MPR subgroup only.
Conclusions This pilot hypothesis-generating study has shown some signals towards Ranolazine improving diastolic function and exercise myocardial efficiency in patients with AS, particularly in those with a lower MPR. The current results would support a larger study in patients with diastolic dysfunction.
Funding This study was funded and sponsored by Menarini International Operation, Luxembourg with support from the NIHR Leicester Cardiovascular Biomedical Research Unit (CVBRU).
- Aortic stenosis
- Diastolic dysfunction
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