Short summary

Aortic valve stenosis is the most common heart valve disease in the western world, but still the pathogenesis is not well established. The disease is based on calcification of the valve and as the calcification progress the valve may be stenotic. As a part of the population-based DANCAVAS trial non-contrast CT scans were performed, and the aortic valve calcification scores were measured on these scans. In this follow-up study we intend to evaluate the prognostic value of the aortic valve calcification scores in terms of aortic valve surgery and mortality.

Rationale

Calcific aortic valve stenosis (AS) is the most common heart valve disease in the western world. The prevalence varies from 2 to 7%, increasing with age. Combined with the rapidly growing elderly population it is likely that the prevalence will increase further in the future. The pathogenesis is divided in two phases: an early initiation phase dominated by valvular lipid deposition, injury, and inflammation, with many similarities to atherosclerosis, and a later propagation phase where procalcific and pro-osteogenic factors dominates and ultimately drive disease progression. Thus aortic stenosis is a progressive disease with calcification or even active bone formation in the valve cusps, compromising valve-opening and causing left ventricular (LV) pressure overload. As aortic stenosis progresses, heart failure symptoms may develop, and when present there is an inexorable deterioration with a poor prognosis. Based on this valve replacement is recommended (Class 1) in symptomatic patients with severe aortic stenosis, but a recent paper has suggested that long-term outcome might be substantially improved by surgery even in asymptomatic patients. Recently, aortic valve calcification (AVC) scores have been developed for non-contrast CT, and have shown to correlate with the grade of aortic stenosis and mortality in patients with established valvular disease. However, the impact of elevated AVC score in the general population is unknown.

Hypothesis

- An increased AVC score is associated with undiagnosed moderate or severe aorta valve stenosis and eventually aortic valve surgery.

Objective

In an asymptomatic general population with no known history of aorta valve disease

- to explore the association between increased AVC score and aortic peak/mean gradient and estimated effective aorta valve area.

- to develop reference values of AVC. 

- to evaluate the prognostic value of the aortic valve calcification scores in terms of aortic valve surgery and mortality.

Design

Case-control prospective observational multicentre study.

Methods

Setting:

In the randomized population-based ongoing DANCAVAS trial 16,000 males and females (aged 65-74 years) are invited to a cardiovascular screening including a non-contrast CT scan. Using these CT scans and established dedicated software, the AVC is measured in all participants.

CT scan: 

Using the Agatston method, calculation of the valve calcification scores are performed off-line by summing-up all spots of calcifications in the aortic- or mitral-valve areas, respectively. These are measured in all DANCAVAS participants. AVC is defined as calcification below the ostium of the coronaries in the aortic sinus Valsalva, within the valve leaflet, or in the aortic annulus.

Echocardiography: 

All individuals with AVC score above 300 Agatston Units (expected 1000) are invited to a supplementary comprehensive echocardiography. In addition, 250 matched controls (matched for age, gender) with no severe valve calcifications are invited. LV volume and ejection fraction (EF) is estimated. LV longitudinal function is assessed using global strain analysis. LV remodelling is assessed by relative wall thickness and LV mass using the Devereaux formula. LV filling pressure is estimated from assessment of mitral inflow and assessment of diastolic motion of the mitral plane using tissue Doppler imaging. Left atrial size is assessed using biplane planimetry, and longitudinal left atrial strain is estimated using 2D speckle tracking. Aortic valve area is estimated by quantitative Doppler ultrasound using the continuity equation. LV outflow tract time-velocity integral is measures with pulsed-wave Doppler by placing the sample volume just below the region of flow convergence. Peak flow velocity across the valve is determined in the window with the highest velocity. Aortic stenosis severity is graded according to current guidelines.

Primary outcome: 

- Severe aortic stenosis, peak flow velocity > 2.5 m/s

- Aortic valve surgery and mortality.

Description of the cohort

Approximately 14,500 males and 750 females from the general population. Mean age 67 years.

Data and biological material

Traditionally cardiovascular risk factors like age, gender, BMI, diabetes mellitus, hypertension, hypercholesterolemia, smoking status, known CVD, family history of CVD and renal function. Additionally the aortic valve calcification score is measured.

Collaborating researchers and departments

Department of Cardiology, Odense University Hospital:

• PhD student Lida Khurrami
• Professor Jacob E Møller, DMSci 
• Professor Axel Diederichsen, PhD

Department of Cardiothoracic and Vascular Surgery, Odense University Hospital:

• Professor Jes Sandal Lindholt, DMSci

Department of Clinical Biochemistry, Odense University Hospital:

• Professor Lars Melholt Rasmussen, DMSci

• Consultant Jess Lambrechtsen, PhD

Department of Cardiology, Little Belt Hospital Vejle: 

• Consultant Flemming Hald Stefensen, PhD

Department of Cardiology, Regional Hospital Central Jutland Silkeborg :

• Consultant Grazina Urbonaviciene, PhD

Publications associated with the project

Lindholt JS, Rasmussen LM, Søgaard R, Lambrechtsen J, Steffensen FH, Frost L, Egstrup K, Urbonaviciene G, Busk M, Olsen MH, Hallas J, Diederichsen AC.  Baseline findings of the population-based, randomized, multifaceted Danish cardiovascular screening trial (DANCAVAS) of men aged 65-74?years. Br J Surg. 2019 Jun;106(7):862-871