Project 9: Mechanisms underlying low flow, low gradient aortic stenosis
PI Göttingen: G. Hasenfuß; PI London: A.M. Shah, M. Mayr; PhD student: M. El Kenani - finished PhD, Double degree
Scientific background and preliminary results
Low flow-low gradient aortic stenosis is a rather new disease entity. It combines reduced stroke volume with reduced aortic valve area resulting in transaortic valve gradients lower than seen in conventional aortic stenosis. Low flow-low gradient aortic stenosis is frequently accounting for up to 30% of all patients with aortic valve stenosis. Diagnosis of low flow-low gradient aortic stenosis is difficult. Because transvalvular gradient is proportional to the square of transvalvular flow, already small changes in flow result in large changes of pressure gradients. Two forms of low flow-low gradient aortic stenosis can be identified: 1. classical low flow-low gradient aortic stenosis, and 2. paradoxical low flow-low gradient aortic stenosis. Classical low flow-low gradient aortic stenosis is seen in patients with reduced systolic function (ejection fraction), often in patients with coronary aortic disease or cardiomyopathy. Paradoxical low flow-low gradient aortic stenosis occurs in patients with normal ejection fraction and reduced stroke volume. Reduced stroke volume despite normal ejection fraction results from structural heart disease with diastolic dysfunction and often reduced longitudinal shortening. Most patients suffer from arterial hypertension. A number of reports concluded particular poor prognosis of patients with paradoxical low flow-low gradient compared to conventional aortic stenosis. The molecular mechanisms underlying paradoxical low flow-low gradient aortic stenosis are poorly understood. This partly results from the fact that no animal model to study the disease is available. It is therefore a goal of the present project, to develop a mouse model of paradoxical low flow-low gradient aortic stenosis and to study biopsy samples from patients undergoing transcatheter aortic valve replacement procedures (TAVR).
Preliminary results were obtained in patients with conventional aortic stenosis with preserved ejection fraction and in patients with aortic stenosis and reduced ejection fraction. While normal ejection fraction in severe aortic stenosis was associated with mild fibrosis and absence of apoptosis, severe fibrosis accompanying apoptosis was seen in the transition from normal to here reduced ejection fraction. This was accompanied with dramatic changes of gene expression as detected by next generation sequencing. Human data were compared with studies in mice with pTAC exhibiting normal function (one week after surgery) and reduced function (eight weeks after surgery). Comparing human and mouse myocardium conserved genes across species with expression changes during the transition steps have been identified.
We are now aiming to include samples from patients with both types of low flow-low gradient aortic stenosis in our analysis. This and in addition, analysis of myocardial function and proteome analysis will further allow to understand the mechanism of paradoxical low flow-low gradient aortic stenosis, and will help to identify potential treatment strategies despite or in addition to valve replacement. We previously showed that functional myocytes can be isolated from biopsy samples and studied regarding contractile function and excitation-contraction coupling processes. Overall, these data demonstrate that biopsy samples from patients undergoing catheter-based aortic valve procedures can be used to understand molecular and functional mechanisms underlying the disease, and comparison of human and mouse model allows for identifying genes with conserved regulation during different stages of the disease process.
Hypotheses of the PhD project
It is a goal to identify functional and molecular alterations underlying low flow-low gradient aortic stenosis in general and paradoxical low flow-low gradient stenosis in particular. In the project the doctoral researcher will work on the following hypotheses:
1. In myocytes from patients with paradoxical low flow-low gradient aortic stenosis, calcium cycling is impaired with prolonged calcium transients and increase spark frequency, but with normal calcium transient amplitude.
2. In myocytes from patients with classical low flow-low gradient aortic stenosis, calcium transients are reduced.
3. In myocardium from patients with classical low flow-low gradient aortic stenosis, apoptosis and fibrosis are increased compared to myocardial from patients with paradoxical low flow-low gradient aortic stenosis.
4. Differences exist in transcriptome profile between classical low flow-low gradient aortic stenosis and paradoxical low flow-low gradient aortic stenosis explaining functional alterations.
5. A mouse model with transversal aortic constriction and diastolic dysfunction mimics findings in human myocardium.
Research interests: Cardiac response to mechanical load, signalling in heart failure
Speaker British Heart Foundation Centre of Research Excellence
Research interests: Cardiovascular proteomics, miRNA, stem cells
PhD student 2nd IRTG 1816 cohort (MD/PhD), Double Degree
Current Position: Postdoctoral Researcher, University Medical Center Göttingen, Germany