Background
Hypothesis
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The presence and extent of myocardial fibrosis are associated with markers of LV decompensation.
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The presence and extent of myocardial fibrosis have a negative effect on LV reverse remodeling and patient functional recovery following AVR.
Study objectives
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To evaluate the prognostic significance of myocardial fibrosis in patients with severe AS undergoing AVR.
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To identify parameters of multimodality imaging [two-dimensional (2D) echocardiography with an extended myocardial deformation analysis, 1.5 T contrast-enhanced CMR with T1 parametric mapping] predictive of LV decompensation.
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To quantify LV reverse remodeling 12 months following AVR through CMR and echocardiographic measurements.
Methods
Study design
Study population
Inclusion Criteria: | |
• Severe AS (defined as AVA ≤1 cm2 or AVA index (iAVA) ≤0.6 cm2/m2 as determined by ultrasound examination) | |
• Males and females of any ethnic group ≥18 years of age | |
• Signed an informed patient consent form | |
Exclusion Criteria: | |
• Unable to provide informed consent | |
• Severe valvular heart disease other than AS | |
• Coronary artery disease requiring revascularization | |
• History of myocardial infarction | |
• Prior cardiac surgery | |
• Severe renal impairment - eGFR < 30 ml/min/1.73 m2 | |
• Any absolute contraindication to CMR | |
• Permanent atrial fibrillation | |
• Patient with implanted cardiac devices (pacemaker, ICD) | |
• Inherited or acquired cardiomyopathy | |
• Other medical conditions that limit life expectancy or preclude AVR | |
• Pregnant or nursing women | |
• Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study or to follow the protocol |
Aortic valve replacement
Data collection
Blood testing
Echocardiography
2D speckle tracking echocardiography (STE)
CMR protocol
Basic description
LGE imaging
T1 mapping
Measurement of the ECV and native T1 values
Histological analysis
Demographic data and comorbidities | |
STS risk score | |
EuroSCORE II | |
Serum biomarkers: | |
▸ Brain natriuretic peptide | |
▸ Troponin I | |
Cardiovascular imaging biomarkers: | |
▸ Transthoracic 2D echocardiogram with strain analysis (GLS) | |
▸ 1.5 T contrast-enhanced CMR with T1 mapping (Native T1, ECV) | |
Myocardial histological analysis: | |
▸Quantitative myocardial fibrosis assessment (CVF) | |
Functional status and quality of life assessment: | |
▸New York Heart Association functional class | |
▸Minnesota Living with Heart Failure Questionnaire | |
▸6-min walking test |
Outcome measures
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In-hospital and 30-day all-cause mortality (time frame: 30 days)
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Length of hospital stay
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Time to the event (death or MACE) (time frame: 24 months)
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Cardiovascular mortality (from 30 days up to 24 months following AVR)
Clinical follow-up
Statistical analysis
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Linear regression analysis to model the relationship between the extent of myocardial fibrosis and patient outcomes.
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Univariate and multivariate regression analysis of CMR-derived predictors of adverse clinical events.
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Comparison of clinical, serum, and imaging (CMR and echocardiography) biomarker data between patients with different extents of fibrosis.
Sample size justification
Study timetable
Dissemination of results
Discussion
Strengths
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The present prospective multicenter study is designed to explore associations between left ventricular myocardial fibrosis and clinical outcomes in severe AS patients undergoing AVR. It has clearly established aims, inclusion and exclusion criteria, as well as defined methods and endpoints.
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The non-invasive measurement of myocardial fibrosis by CMR with T1 mapping is validated against invasive histological assessment.
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The trial is restricted to isolated AS, excluding cardiac pathologies which could possibly contribute to myocardial fibrosis burden, such as obstructive coronary heart disease and other significant valvular heart diseases.
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Inclusion of both surgical and TAVR cohorts will allow the investigation of patients with different risk profiles.
Limitations
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The selected sample size may be inadequate to allow a subgroup analysis.
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Limitations of CMR to establish diffuse and focal fibrosis: no reference regions of normal myocardium due to diffuse fibrosis, arbitrary selection of threshold of signal intensity, overlap of T1 values between normal and diseased myocardium.
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The FIB-AS study excludes patients with comorbidities, such as obstructive coronary artery disease, a history of myocardial infarction, renal failure, and persistent atrial arrhythmias; therefore, our results should not be overgeneralized to a broader AS patient population.