Characterization of Myocardial Interstitial Fibrosis and Cardiomyocyte Hypertrophy by Cardiac MRI in Heart Failure

Characterization of Myocardial Interstitial Fibrosis and Cardiomyocyte Hypertrophy by Cardiac MRI in Heart Failure

Characterization of Myocardial Interstitial Fibrosis and Cardiomyocyte Hypertrophy by Cardiac MRI In Heart Failure: Implication on Early Remodeling and on the Transition to Heart Failure

The investigators hypothesised that novel MRI metrics derived from myocardium post-gadolinium T1 mapping analysis will improve the current knowledge about the role interstitial fibrosis and cardiomyocyte hypertrophy in the development of left ventricular (LV) remodelling and clinical Heart Failure (HF). The investigators believe that these recently described variables will be associated with prognostically important indices in HF development.

Cardiac hypertrophy is one of the earliest manifestations of myocardial disease, representing a modifiable, prognostic response to hemodynamic stimuli across physiologic (e.g., exercise) and pathologic states (e.g., hypertension, aortic stenosis). The extent of myocardial hypertrophy is determined by a combination of cardiomyocyte size and extracellular volume (ECV) expansion/interstitial fibrosis: while physiologic (exercise-induced) hypertrophy reflects mostly reversible cardiomyocyte hypertrophy, pathologic hypertrophy (e.g., in heart failure) is a combination of both interstitial fibrosis (potentially irreversible) and cardiomyocyte hypertrophy (reversible). Current methods to delineate the potential for LV reverse remodeling (e.g., natriuretic peptides and echocardiographic or clinical markers) detect primarily advanced disease, missing a critical opportunity to intervene and follow patients at an early disease phase where myocardial pathology may be reversible. Therefore, establishing novel, quantitative metrics of myocardial tissue phenotype that define a transition from hypertrophy to fibrosis, and then to irreversible LV remodeling/dysfunction may facilitate targeting therapies at a modifiable stage of disease in HF. The investigator's group has recently extended cardiac T1 mapping MRI techniques to quantify the intracellular lifetime of water (τic) serially as an index of cardiomyocyte diameter, validating this technique histologically in mouse models of pressure overload.

Heart Failure patients with preserved ejection fraction (HFpEF) randomized to this arm will keep receiving their conventional clinical care, being instructed to continue and maintain their usual daily activities.

Heart Failure patients with preserved ejection fraction (HFpEF) randomized to this arm will keep receiving their conventional clinical care and participate in a supervised, facility based training program consisting of stretching exercises and aerobic exercise in treadmill.

Heart Failure patients with reduced ejection fraction (HFrEF) randomized to this arm will keep receiving their conventional clinical care, being instructed to continue and maintain their usual daily activities.

Heart Failure patients with reduced ejection fraction (HFrEF) randomized to this arm will keep receiving their conventional clinical care and participate in a supervised, facility based training program consisting of stretching exercises and aerobic exercise in treadmill.

30-40min of aerobic exercise in treadmill. The aerobic intensity will be established by heart rate levels that corresponded to anaerobic threshold up to 10% below the respiratory compensation point obtained in the cardiopulmonary exercise test. This intensity corresponded to 60-72% peak V̇o2. During the exercise sessions, when a training effect will be observed, as indicated by a decrease by 8 to 10% in heart rate, the treadmill velocity or inclination will be increased to return to the target heart rate levels.

15 min of local strengthening exercises will be performed in major muscle groups (legs, arms and trunk muscles): three series of each exercise, 12-15 repetitions.

Investigate whether rehabilitation compared to usual care is associated with significant favorable myocardial remodeling assessed by CMR determination of ECV.

Left Ventricular ejection fraction (%) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Right Ventricular ejection fraction (%) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Left ventricular mass absolute (g) and index (g/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Left ventricular diastolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Right ventricular diastolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Left ventricular systolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Right ventricular systolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Left ventricular stroke volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Right ventricular stroke volume (absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

Late gadolinium enhancement (LGE) will be determined by cardiac magnetic resonance using a previously describe inversion recovery sequence after 10-15 minutes of a cumulative dose of 0,2 mmol/kg of gadolinium diethylenetriamine pentaacetic acid. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

LV mass/volume ratio (g/mL) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

VO2max will be evaluated by cardiopulmonary test. Patients will performed the cardiopulmonary test at baseline and after 4 months of the intervention.

Quality of life will be evaluated by numerical score of Minnesota Questionnaire. Patients will performed the Minnesota Questionnaire at baseline and after 4 months of the intervention.

Change in cardiac sympathetic function assessed by cardiac uptake of metaiodobenzylguanidine (MIBG) labeled with I-123. Patients will performed the MIBG study at baseline and after 4 months of the intervention.

τic will be determined by cardiac magnetic resonance T1 measurements acquired before and after administration of gadolinium diethylenetriamine pentaacetic acid (0,2mmol/kg), at 2 different time points (baseline and 4-moths after the intervention)

Inclusion Criteria: Age> 18 years Functional limitation (New York Heart Association Class II or worse) No contraindication to exercise (American College of Cardiology / American Heart Association criteria) Eligibility to take MRI (absence of metallic devices, and glomerular filtration rate > 40ml / min / 1.73m2, etc.) Prior diagnosis of Heart Failure (by the Framingham criterion) Therapy with diuretic and euvolemia state (evaluated by cardiologist and cardiopulmonary exercise testing) Transthoracic echocardiogram Exclusion Criteria: Severe ischemia in any stress test Hypertrophic cardiomyopathy or any infiltrative heart disease Chronic obstructive pulmonary disease , pulmonary hypertension (Pulmonary artery pressure> 60mmHg) Severe left or right valve disease. Pacemaker or implantable cardioverter defibrillator Myocardial infarction or revascularization in 3 months Anemia (hemoglobin <10 grams / dl) until 1 month before cardiopulmonary exercise testing

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