Short summary

Aortic Stenosis (AS) is the most common valvular disease in the Western world. Increased afterload leads to hypertrophy and myocardial fibrosis (MF) of the left ventricle (LV). Standard of treatment is an operation, which is usually delayed until patients develop symptoms such as dyspnea, chest pain or exertional fainting. However, some patients show little symptom improvement after the operation. This may be due to severe MF of the LV. We hypothesize that patients with AS and severe MF have reduced symptom improvement after the operation, and that MF can be detected by a computerized tomography (CT) scan.

Rationale

Aortic stenosis is the most common valvular disease in the Western World. It is a slow evolving degenerative disease caused by gradual accumulation of calcium in the valve. Untreated it is fatal. Reduced opening area of the valve causes obstruction of the blood in the left cardiac ventricle, which leads to raised pressure in the left ventricle. In turn, the left ventricle produces "fibrosis", a form of scar tissue, as a result of the raised pressure.

The standard of treatment for aortic stenosis is an operation, aortic valve repair (AVR), where a mechanical or biological valve replaces the old one. The operation involves a substantial risk of postoperative mortality, and is therefore delayed until the patient starts to develop symptoms in form of shortness of breath, chest pains or fainting. For most patients AVR causes significant symptom reduction and reduced mortality. For about one third of the patients undergoing AVR, there is no symptom improvement and an increased mortality. Recent studies have indicated that patient with severe fibrosis in their left ventricle have little or no symptom improvement and an increased mortality, leading to suspect that their ventricle is so stiff from fibrosis that it is beyond repair. These patients may not benefit from an operation, or should possibly have had AVR performed at an earlier stage of the disease.

Today cardiac fibrosis can be detected by a biopsy which is invasive. Cardiac MRI has recently been evaluated as a new method to detect fibrosis, but this method is costly and contraindicated for some patients. Cardiac computerized tomography (CCT) has been proposed as a method to evaluate cardiac fibrosis, but has not been properly validated yet.

In this study we will compare different methods (biopsy, MRI, CCT, ultrasound and different biomarkers) to evaluate the extent of myocardial fibrosis in 130 patients with severe aortic stenosis who are scheduled for AVR. We will focus on their symptom improvement and survival rate one year after the operation. Our main thesis is that patients with severe fibrosis before the operation have little or no symptom improvement and reduced survival after the operation. If this thesis is correct, it will question which patients to offer AVR. Some patients we operate today may have no benefit from the operation because the left ventricle is damaged from severe fibrosis and some patients, from who we withhold the operation today, may benefit from AVR before they develop severe fibrosis.

Description of the cohort

We aim to include 130 consecutive adult patients with severe aortic stenosis, defined as an aortic valve area under or equal to 1 cm², who are referred to aortic valve replacement at Odense University Hospital. Recruitment started March 1^st 2014 and is expected to continue until January 1^st 2016.

Patients with significant concomitant valvular disease, chronic kidney disease (eGFR<40 ml/min/1,73 m²), atrial fibrillation, pacemaker or implanted cardioverter defibrillator (ICD) are excluded.

Data and biological material

Basic demographic data including medical history, medicine status, smoking, NYHA- and CCS-classification and DUKE activity status index are obtained at baseline and repeated after 6 and 12 months.

Height, weight, blood pressure and 6 minutes walking test at baseline. Repeated after 6 and 12 months.

Echocardiography with 2D- and 3D-data, Doppler and  tissue Doppler and strain and speckle tracking at baseline. Repeated after 6 and 12 months.

MRi of the heart, volumes of left and right ventricle and left atrium, left ventricular mass, flow in aorta and pulmonary artery, late gadolinium enhancement and in some patients also T1-mapping. Measured at baseline and after 12 months.

CT of the heart with contrast. ECV fraction is measured at baseline and after 12 months.

Myocardial biopsy and aortic valve are excised during aortic operation. The biopsy is divided in two; one aliquot is used for histology and one is saved for possible proteomic analyses. The aortic valve is saved for possible proteomic analyses.

In a subgroup of 40 patients, a symptom-limited supine cycle ergometer exercise test with simultaneous right-sided catheterization and echocardiography is performed one year after the operation. Pulmonary artery, capillary wedge and central venous pressures are measured along with blood pressure, pulse and oxygen saturation at rest and at increasing intervals until exhaustion. At rest and at peak exercise, a central venous blood sample is analyzed for lactate concentration, oxygen saturation and pH. In the same subgroup, a VO2-max test on a cycle ergometer is performed one year after surgery.

Collaborating researchers and departments

Department of Cardiology, Odense University Hospital

• Professor Jacob E. Møller, MD, PhD, DMSc
• Jordi S. Dahl, MD, PhD
• Kristian A. øvrehus, MD, PhD
• Eva Søndergaard, MD, PhD

Department of Biochemistry, Odense University Hospital

• Professor Lars M. Rasmussen, MD, PhD, DMSc
• Akhmadjon Irkhumadenov, MD

Department of Pathology, Odense University Hospital

• Professor Niels Marcussen, MD, PhD