PACIFIC-PRESERVED : PhenomApping, ClassIFication, and Innovation for Cardiac Dysfunction – HF With PRESERVED LVEF Study

Overview

This is a prospective multicenter study to decipher phenotypic variability within patients with heart failure and preserved left ventricular ejection fraction (HFpEF). From a registry of heart failure patients (2500 anticipated) hospitalized in the participating centers in the last 3 years, 300 HFpEF patients, 100 patients with heart failure and reduced ejection fraction (HFrEF) and 100 matched subjects without heart failure will be enrolled for an extensive phenotyping with physical evaluation, biomarkers and omics, cardiac and vascular imaging and telemonitoring of cardiovascular parameters. Cluster analysis with machine learning methods will be performed to define phenogroups unique to the HFpEF patient population.

Full Title of Study: “Redefining the Phenotypic Spectrum of Heart Failure With Preserved Ejection Fraction (HFpEF) by Deep Phenotyping and Machine Learning Methods: The PACIFIC-PRESERVED Study (PhenomApping, ClassIFication, and Innovation for Cardiac Dysfunction – HF With PRESERVED LVEF Study)”

Study Type

  • Study Type: Observational [Patient Registry]
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: December 2021

Detailed Description

Heart failure with preserved ejection fraction (HFpEF) is a complex and prevalent syndrome with currently no efficient therapy. This syndrome is likely explained by different pathophysiological inputs leading to common symptoms of heart failure. These pathophysiological abnormalities can primarily involve the heart but also other organs with secondary impact on the myocardium. There is however no clear understanding and diagnostic algorithms of the different HFpEF subpopulations. Novel mathematical methods (such as machine learning) can help identifying clusters within an heterogeneous population such as HFpEF patients.

A registry (2500 anticipated) will be constituted with patients hospitalized for congestive heart failure in the participating centers during the last 3 years. From this registry, 500 patients will be invited to visit in the hospital for 8-10 hours for physical examination, ECG, performance-based tests, blood draw, cMRI, echocardiography (rest and low-level exercise), Ultrafast echo (for non-invasive measurement of myocardial stiffness), low radiation cardiac CT (for calcium scoring), non-invasive measurement of arterial stiffness. They will be asked to fill out questionnaires about dyspnea, depression and about general health and quality of life. They will then be equipped with a smart connected garment (with cardiovascular & hemodynamic sensors), a connected weight balance and a blood pressure monitoring device for telemonitoring collection of cardiovascular hemodynamic parameters in real-life conditions (for 14 days).

Patients included in the registry will be followed-up for 3 years using medico-administrative databases and vital status, cardiovascular and heart failure outcomes will be collected.

Interventions

  • Other: Extensive phenotyping
    • Prospective assessment of physical evaluation, biomarkers and omics, cardiac and vascular imaging and telemonitoring of cardiovascular parameters for 14 days.

Arms, Groups and Cohorts

  • HFpEF patients
    • Heart failure patients (NYHA II-IV) with left ventricular ejection fraction ≥ 50%, 1000 patients anticipated among which 300 with extensive phenotyping
  • HFrEF patients
    • Heart failure patients (NYHA II-IV) with left ventricular ejection fraction ≤ 40%, 1000 patients anticipated among which 100 with extensive phenotyping (age- and gender-matched on participating HFpEF patients)
  • Subjects apparently without heart failure
    • Subjects without history or signs of heart failure, 100 subjects anticipated with extensive phenotyping (age- and gender-matched on participating HFpEF patients)

Clinical Trial Outcome Measures

Primary Measures

  • Machine learning algorithm to identify distinct phenotypic subgroups among HFpEF patients
    • Time Frame: 14 days
    • Machine learning-based cluster analysis using extensive phenotyping data from HFpEF, HFrEF and subjects without apparent HF

Secondary Measures

  • Prognosis
    • Time Frame: 3 years
    • Identify phenotypic subgroup(s) with higher risk of cardiovascular and HF outcomes
  • Myocardial stiffness
    • Time Frame: 3 years
    • Assess the diagnostic and prognostic value of myocardial stiffness measured with ultrafast cardiac echography
  • Sarcopenia and muscular capacity
    • Time Frame: 3 years
    • Prevalence and importance of muscle loss, weakness measured with hand grip strength test (Kg) and with the short physical performance battery (SPPB, combining the results of gait speed, chair stand and balance tests) in HFpEF patients
  • Exercise tolerance
    • Time Frame: 3 years
    • Measure exercise tolerance with 6-minute walk test
  • Cardiac fibrosis
    • Time Frame: 3 years
    • Prevalence, diagnostic and prognostic importance of cardiac fibrosis (as estimated by cMRI and specific biological markers) in HFpEF patients
  • Arterial Stiffness
    • Time Frame: 3 years
    • Assess the diagnostic and prognostic value of arterial stiffness measured by pulse wave velocity
  • Right heart and pulmonary circulation
    • Time Frame: 3 years
    • Assess the diagnostic and prognostic value of novel markers to quantify right heart function and pulmonary circulation measured with cMRI
  • Ventricular-arterial coupling
    • Time Frame: 3 years
    • Machine learning-based analysis on 4D MRI recordings to estimate ventricular-arterial coupling
  • Omics signature
    • Time Frame: 3 years
    • Apply multi-omics techniques (including measurements of miRNA, lNcRNA, inflammation markers, and DNA methylation level) to define specific biological signatures to HF and HFpEF patients
  • Quality of life evaluation
    • Time Frame: 3 years
    • General and HF QOL questionnaires: Kansas city cardiomyopathy questionnaire – the sum of responses from all 12 items, Range for subscale is 0-100 and the range for the summary score is 0-100 with lower scores indicating more significant disease impact; Global quality of life score with SF36 (Short form 36 health survey): The norm data is 0-100, the health related quality of life is increased as the scores are increased.
  • Telemonitoring of weight
    • Time Frame: 3 years
    • Remote measurement of body weight
  • Telemonitoring of cardiac rythm
    • Time Frame: 3 years
    • Remote measurement of cardiac arrhythmias
  • Telemonitoring of ECG
    • Time Frame: 3 years
    • Remote measurement of heart rate variability
  • Telemonitoring of physical activity
    • Time Frame: 3 years
    • Remote measurement of physical activity with an actimeter
  • Telemonitoring of blood pressure
    • Time Frame: 3 years
    • Remote measurements of blood pressure in mmHg
  • Telemonitoring of pulmonary function
    • Time Frame: 3 years
    • Remote measurement of respiratory rate
  • Telemonitoring of oxygen saturation
    • Time Frame: 3 years
    • Remote measurement of oxygen saturation (%)
  • Telemonitoring of pulmonary congestion
    • Time Frame: 3 years
    • Remote evaluation of pulmonary congestion with measurement of thoracic impedance
  • Digitalized ECG
    • Time Frame: 3 years
    • Develop novel machine learning based markers of HF, of HFpEF and HFrEF
  • Cardiac echography
    • Time Frame: 3 years
    • Rest and low-effort evaluation of cardiac parameters
  • Cardiac calcium scoring
    • Time Frame: 3 years
    • Evaluation of calcium scoring among participants
  • Cardiac MRI
    • Time Frame: 3 years
    • Novel biomarkers of cardiac fibrosis, extra-cellular volume, matrix remodeling
  • Left atria
    • Time Frame: 3 years
    • Evaluation of LA remodeling (volumes) and function (strain)

Participating in This Clinical Trial

Inclusion Criteria

All subjects

  • Affiliation to a social security scheme, universal medical coverage (CMU) or any equivalent scheme
  • Physical state compatible with the carrying out of the investigations according to the judgment of the investigator

For HFpEF patients:

  • Hospitalization in one of the partner hospitals in the last 30 months
  • With a diagnosis of symptomatic congestive heart failure (NYHA II to IV)
  • With a plasma concentration of BNP ≥ 100 μg / ml or NT-proBNP ≥ 300 μg / ml or having had an administration of a dose of intravenous diuretics during hospitalization for congestive heart failure
  • Left ventricular ejection fraction ≥ 50%
  • Hospital discharge for at least 3 months

For HFrEF patients:

  • Hospitalization in one of the partner hospitals in the last 30 months
  • With a diagnosis of symptomatic congestive heart failure (NYHA II to IV)
  • Plasma concentration of BNP ≥ 100 μg / ml or NT-proBNP ≥ 300 μg / ml or administered a dose of intravenous diuretics during hospitalization for congestive heart failure
  • Hospital discharge for at least 3 months
  • Left ventricular ejection fraction ≤ 40%
  • Matched age and sex to HFpEF patients (for participants to extensive phenotyping)

For subjects apparently without heart failure :

  • Subject without a notable medical history or medical history
  • Normotensive or who may have an essential hypertension of grade 1 (≤159 / 99 mmHg), treated or not
  • Can present a dyslipidemia, treated by hygieno-dietetic measures alone
  • Sinus heart rate
  • Estimated glomerular filtration rate ≥ 60 ml / min (CKD epi)
  • Matched age and sex to HFpEF patients (for participants to extensive phenotyping)

Exclusion Criteria

All subjects

  • Pregnancy or breastfeeding
  • Participation in another interventional study
  • Person placed under the safeguard of justice
  • Subject that can not understand the procedures related to the protocol
  • Severe obesity (BMI > 40 Kg / m2)
  • Patient who has already had a severe allergy to gadolinium MRI contrast agents
  • MRI usual contraindications: Pace-maker, defibrillator, metallic objects

For both HFpEF and HFrEF patients:

  • History of right ventricular infarction
  • History of cardiac transplantation or circulatory assistance
  • Major surgery scheduled for less than 6 months, coronary revascularization of less than 3 months
  • Pacemaker or any implanted device (or foreign body) not compatible with MRI
  • Presence of very severe co-morbidity: end-stage renal failure (GFR <15ml / min), severe chronic obstructive pulmonary disease (COPD), severe valve disease (including severe aortic stenosis),
  • Hypertrophic cardiomyopathy of known genetic cause
  • Known amyloidosis with apparent extracardiac manifestations
  • Other antecedent of known congenital heart disease type, Post-embolic chronic pulmonary heart, Restrictive Cardiopathy, Diagnosed Fabry Disease

For HFpEF patients:

  • History of systolic dysfunction with proven LVEF reduction (≤ 40%)

For subjects apparently without heart failure :

  • Medication use other than pure systemic or local estrogen / progestin and progestin contraceptives and paracetamol
  • Acute pathology within 8 days prior to inclusion
  • Cardiac or vascular organic impairment or apparent chronic diseases
  • Chronic treatment outside a treatment for high blood pressure
  • Having already had ≥3 MRI with injection of gadolinium contrast agents

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 90 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Collaborator
    • BPIfrance
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Jean-Sébastien HULOT, MD PhD, Principal Investigator, AP – HP, Hôpital Européen Georges-Pompidou, Paris, France
  • Overall Contact(s)
    • Jean-Sébastien HULOT, MD PhD, 0033156092017, jean-sebastien.hulot@aphp.fr

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