Histological and functional effects of aortic valve disease on left ventricular function prior to and after surgical intervention

This research project aims to apply, modify and validate cardiac magnetic resonance imaging (cMRI) as a diagnostic tool for identification of fibrotic changes in the heart muscle due to pressure and volume overload caused by aortic valve disease. Furthermore, we hypothesize that these tissue changes (the amount and the location of the fibrotic tissue) can be connected to the impairment of the left ventricular function (LVF) in the advanced natural history of aortic valve disease. By using cMRI we hope to gain further information by non-invasive means on whether this impairment is reversible following surgical therapy. In addition to histological and functional studies at rest we plan to survey the anaerobe (physical) capacity of the study persons by performing cardiopulmonary exercise testing pre- and postoperatively and study the relationship between physical performance capacity and left ventricular function (LVF).

• Staff:

Jan Engvall , Assoc Prof		Researcher		CMIV, IMH
Johan Kihlberg , PhD-student		Researcher		CMIV, IMH
Henrik Haraldsson , PhD		Researcher		CMIV, IMH
Marcel Warntjes , PhD, Clinical scientist		Researcher		CMIV, IMH
Tino Ebbers , Prof		Researcher		CMIV, IMH
Eva Nylander , Prof		Researcher		CMIV, IMH

• Former Staff:

• Project Description:

Study population
Within the frames of this study 30 patients with aortic valve disease (AS and AR) referred to surgery are to be included. Exclusion criteria are concomitant heart valve disease (mitral, tricuspid or pulmonalis), congenital heart disease (except bicuspid aortic valve), hemodynamic instability (emergency operation), previous cardiac surgery, history of myocardial infarction and coronary artery disease.
Baseline
Prior to surgery in addition to the routine cardiac echocardiographic even a cMRI and a CPET study are to be performed. During surgery, under direct vision endo-myocardial biopsy of the heart is to be taken. Images are recorded and stored digitally and to be analysed off-line.
CPET
Testing is to be carried out with patients in a sitting position, using an electrically braked bicycle ergometer and with continuous electrocardiographic monitoring. The patients breathe through an open, low resistance mouthpiece with their nostrils clamped. Exhaled air flow is measured indirectly by pressure gradients using a linear pneumotachometer and O2 and CO2 content are analysed on a breath-by-breath basis by gas analyser. The pneumotachograph and gas analysers are calibrated prior to each test. Exercise protocol is to be chosen individually at the time of the preoperative CPET with an initial workload of 30 to 100 Watts for five to six minutes, followed by a continual increment in workload of 10 to 20 Watts per minute. Patients are instructed to pedal at a constant speed maintaining 60 revolutions per minute until exhaustion. Systolic blood pressure is recorded non-invasively every third minute during the test, while perceived exertion, dyspnoea and chest pain are to be assessed using the Borg scales. Physical fitness of each patient is classified taking age, gender and body mass into consideration according to their achieved peakVO2.
Echocardiography
Transthoracic ultrasound (TTE) scan at rest is to be performed according to current guidelines. Severity of stenosis and regurgitation are to be graded. Left ventricular diameters in end-diastole, end-systole (LVED, LVES) and LV wall thickness in end-diastole are to be measured by M-mode and LV mass calculated according to Devereaux’s formula. The velocity of E and A waves, E/A ratio and pulmonary venous systolic and diastolic velocity are to be analysed and used for an integrated description of diastolic function. Left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV) and ejection fraction (EF) according to Simpson’s rule are to be calculated.



cMRI
cMRI scan is to be performed for T1 and T2 mapping of the left ventricle to assess the extracellular volume and possible diffuse fibrosis. In addition, functional analysis with DENSE and visualization of macrofibrosis with late gadolinium enhancement will be performed.
Left ventricular volumes, EF and left ventricular mass are to be calculated from the cine images. Flow images are generated by 2D phase contrast recording of through-plane flow times the flow area produces an estimate of stroke volume and cardiac output.
Left ventricular biopsy
During surgery are 3-5 biopsies to be taken of the free wall of the left ventricle in 10 patients under visual control. Samples are to be dyed by hematoxylin-eosin and analyzed
Blood samples will be taken for the analysis of NP-proBNP.

3-month follow-up
TTE and cMRI are performed and blood samples are taken in the same fashion as baseline.

2-year follow-up
In addition to TTE, cMRI and blood samples even CPET is performed.
Significance

According to our hypothesis cMRI has the potential to image the amount and the distribution of fibrotic tissue resulting in a ‘fibrosis-map’ on the left ventricle. This map is compared with the histological samples can validate the method for further clinical use.
Adding CPET to the study makes it possible to connect histological and physiological changes in the left ventricle to physical capacity. Positive results of this study would mean that changes at tissue level and their effect on the left ventricle can be studied relatively easy by a non-invasive imaging modality providing information on how histological changes resulting from aortic valve disease affect left ventricular function and the result of surgical intervention. Thus preoperative screening as well as timing and indication of surgery may be optimized further. This can lead to lower morbidity and improved quality of life after surgery.

Staff involved in the project are Jan Engvall (echo, exercise, MRI), Johan Kihlberg (MRI), Henrik Haraldsson (DENSE MRI, mapping), Marcel Warntjes (Mapping MRI), Tino Ebbers (DENSE MRI), Eva Nylander (Echo, exercise)