Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design

Abstract

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild–moderate CAVS will be included in the study, and baseline 18F-sodiumfluoride (18F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT).

Cardiovascular 18F-fluoride positron emission tomography-magnetic resonance imaging: A comparison study

“…Study subjects from two ongoing 18 F-fluoride PET/CT trials were approached regarding participation in the current study and having a PET/MR scan immediately following their PET/CT. The SALTIRE 2 trial (Bisphosphonates and RANKL Inhibition in Aortic Stenosis, NCT02132026) recruited patients aged over 50 years with a peak aortic jet velocity of [2.5 m/s and grade 2-4 calcification of the aortic valve on echocardiography.…”

“…The SALTIRE 2 trial (Bisphosphonates and RANKL Inhibition in Aortic Stenosis, NCT02132026) recruited patients aged over 50 years with a peak aortic jet velocity of [2.5 m/s and grade 2-4 calcification of the aortic valve on echocardiography. The PRE 18 FFIR trial (Prediction of recurrent events with 18 F-fluoride to identify ruptured and high-risk coronary artery plaques in patients with myocardial infarction, NCT02278211) recruited patients with recent myocardial infarction and multi-vessel coronary artery disease on invasive angiography. Exclusion criteria for both trials include inability to receive iodinated contrast, renal impairment (estimated glomerular filtration rate B30 mL/min/1.73 m 2 ) or women of child-bearing potential.…”

“…Calcification is a key pathological process in both aortic stenosis and coronary atherosclerosis. The development of 18 F-fluoride imaging now allows calcification activity to be imaged directly, providing a marker of disease activity in aortic stenosis and coronary atherosclerosis with potential to improve patient risk stratification.…”

“…To date, cardiac studies investigating the uptake of 18 F-fluoride have predominantly employed hybrid PET/ CT, but interest has recently developed in Positron Emission Tomography/Magnetic Resonance (PET/MR) platforms. PET/MR provides several potential advantages compared to PET/CT including reduced radiation exposure, integrated functional assessment, improved soft tissue characterisation and motion correction.…”

“…We aimed to validate PET/MR (using both the Dixon and radial GRE attenuation correction approaches) against PET/CT in patients undergoing the two paired scans. In particular, we sought to compare the pattern of aortic valve and coronary 18 F-fluoride uptake on PET/MR and PET/CT and to investigate whether quantification of tracer uptake in these regions differs between the two imaging approaches.…”