BACKGROUND
Aortic stenosis affects not only the valve but also the myocardium. In
response to the increased afterload, left ventricular hypertrophy initially
occurs as a compensatory response to maintain wall stress and cardiac
output but ultimately, decompensation and heart failure ensues. The
transition from adaptation to decompensation is driven by myocyte death
and myocardial fibrosis. The aims of the thesis are to investigate
cardiovascular magnetic resonance assessment of disease severity and
myocardial fibrosis, and explore its relationship with other biomarkers of
disease activity and clinical outcome in patients with aortic stenosis.
METHODS AND RESULTS
The conventional assessment of aortic stenosis relies heavily on two-dimensional
and Doppler echocardiography but there are inherent
limitations in echocardiography that can affect the severity classification. I
demonstrated that cardiovascular magnetic resonance offered a more
accurate estimation of left ventricular volumes and mass, and excellent
myocardial characterization. Indeed, inaccurate stroke volume estimation by
Doppler echocardiography and inconsistent thresholds in current guidelines
accounted for more than 40% of patients with discordant small-area, lowgradient
aortic stenosis. These data may explain the variable prognosis
reported in this unique group of patients, and argue for more accurate
assessment of borderline cases with cardiovascular magnetic resonance.
Late gadolinium enhancement imaging detects focal areas of established
myocardial fibrosis. In many conditions, including aortic stenosis, a more
diffuse form of fibrosis predominates, which is potentially reversible and not
readily identified by late gadolinium enhancement. Recently several
myocardial T1 mapping approaches have been developed to quantify diffuse
fibrosis. Using a standardized and systematic approach, I compared several
commonly used T1 mapping techniques and identified that extracellular
volume had the best profile (reproducibility and discriminatory potential) for
the identification of diffuse fibrosis in patients with aortic stenosis.
Cardiac troponin is a structural protein present in the cardiac myocytes.
Recent advances in assay technology have substantially improved
sensitivity, allowing quantification of troponin concentrations with a high
degree of precision in everyone. In more than 250 patients with aortic
stenosis, I demonstrated that cardiac troponin I concentrations were
independently associated with markers of left ventricular decompensation
(hypertrophy and fibrosis) and predicted clinical outcome in patients with
aortic stenosis. This suggests that myocardial fibrosis detected by
cardiovascular magnetic resonance is consequent on myocardial injury
secondary to left ventricular decompensation.
Left ventricular hypertrophy with strain pattern on a 12-lead
electrocardiogram is associated with poor outcome in patients with aortic
stenosis, but the mechanism of this electrocardiographic pattern has not been
described. In more than 300 patients with aortic stenosis, I demonstrated
that these characteristic repolarization abnormalities were a highly specific
marker of focal mid-wall myocardial fibrosis (specificity of 99% and
sensitivity of 54%). Moreover, the prognostic value of this
electrocardiographic pattern was again confirmed with markedly worse
long-term outcomes in these patients.
CONCLUSION
I have demonstrated that cardiovascular magnetic resonance can assist in the
assessment of disease severity in patients with aortic stenosis and discordant
echocardiographic findings. Moreover, I have validated the assessment of
diffuse myocardial fibrosis, as well as, demonstrated the close association
between myocardial fibrosis and biomarkers of myocardial injury and
electrocardiographic strain pattern that predicted an adverse outcome in
patients with aortic stenosis