Validation of CMR Against Invasive Haemodynamics in Patients With HFpEF (DECIPHER-HFpEF)

• ClinicalTrials.gov Identifier: NCT03251183
• Recruitment Status: Completed
• First Posted: August 16, 2017
• Last Update Posted: March 10, 2023
• Sponsor: Goethe University
• Collaborator: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
• Information provided by (Responsible Party): Prof. Eike Nagel, Goethe University

Study Description

Brief Summary:

Heart failure (HF) currently affects app. 2% of the western population and app. 10% of people >75 years. In about 50% of patients with symptomatic HF ejection fraction (EF) is preserved (HF-PEF). Once patients develop symptoms, the prognosis is poor with 25% mortality at 1 year and 50% mortality at 5 years. HFpEF is one of the major unresolved areas in clinical cardiology. The diagnosis of HFpEF remains a diagnosis of exclusion and currently no non-invasive measure provides a clear diagnosis.

Cardiovascular magnetic resonance (CMR) provides non invasive and radiation free evaluation of heart structure and function. New CMR parameters offer the possibility to describe the underlying pathological and physiological changes associated with HFpEF.

The investigators propose to undertake the first systematic comparison between a CMR protocol and invasive haemodynamics as the best possible gold standard, as well as define the histopathological drivers in myocardial biopsies. The investigators will also examine the relations with tissue and serological biomarkers implicated in HFpEF and the role with standard and novel parameters by echocardiography. If successful, this study will provide tools for a reliable and accurate non-invasive characterization of patients with HFpEF, supporting the diagnosis and grading the severity of disease. This study will provide a reference basis for future diagnostic algorithms in HFpEF, both, for CMR and echocardiography, but also for their relative value in comparison to blood markers or invasive testing. In addition to a new pathway to acess the effects of current and novel therapeutic interventions, the investigators see the greatest potential in identifying a disease stage where the myocardial injury may be reversible.

Condition or disease	Intervention/treatment
Heart Failure With Normal Ejection Fraction	Diagnostic Test: Comprehensive Cardiovascular magnetic resonance (CMR); Diagnostic Test: Blood sampling; Diagnostic Test: TTE (EchoErgo); Diagnostic Test: Invasive pressure-volume (PV) Loops; Diagnostic Test: Left ventricular (LV) biopsy

Study Design

• Study Type: Observational
• Actual Enrollment: 185 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Validation of Cardiovascular Magnetic Resonance Against Invasive Haemodynamics in Patients With Heart Failure With Preserved Ejection Fraction (DECIPHER HFpEF)
• Actual Study Start Date: January 14, 2018
• Actual Primary Completion Date: December 31, 2022
• Actual Study Completion Date: December 31, 2022

Groups and Cohorts

Group/Cohort	Intervention/treatment
Main group; Blood sampling Comprehensive Cardiovascular magnetic resonance (CMR) Transthoracic echocardiography (TTE) (EchoErgo) Invasive pressure-volume (PV) Loops Left ventricular (LV) biopsy	Diagnostic Test: Comprehensive Cardiovascular magnetic resonance (CMR); Cardiovascular magnetic resonance (CMR) provides non-invasive, radiation-free and in-depth evaluation of myocardial structure and function. In addition to established tools for assessment of cardiac volume, mass, function and regional myocardial scar with late Gadolinium enhancement (LGE), several novel quantitative CMR parameters will be assessed including T1-mapping or fully quantitative perfusion Imaging.; Diagnostic Test: Blood sampling; Blood samples will eventually be analysed for markers related to heart failure (BNP/NT)-pro-BNP, myocardial inflammation and fibrosis (cytokine profiling, Galectin-3, Procollagen Type I and III, hsCRP). Whole blood will be frozen for DNA isolation and genome analysis. Peripheral blood mononuclear cells will be isolated by Ficoll in a subset of patients and will be used for RNA isolation allowing RNA-seq or reverse transcription (RT) - polymerase chain reaction (PCR) analysis.; Diagnostic Test: TTE (EchoErgo); Measurements will include cavity dimensions, flow velocities, myocardial motion velocity and strain as well as for change of parameters during ergometric stress.; Diagnostic Test: Invasive pressure-volume (PV) Loops; Multiple parameters (including EDPVR, ESPVR, dp/dt min, Tau, Ea) will be derived from the various PV loop assessments and additional relevant parameters will be calculated. Right ventricular and pulmonary pressures including pulmonary vascular resistance will be measured with Swan-Ganz catheters using right venous femoral approach.; Diagnostic Test: Left ventricular (LV) biopsy; A set of myocardial biopsies for each patient will be stained with Masson Trichrome for qualitative and quantitative assessment of the collagen volume fraction; fat droplets will be identified by red oil staining, Congo Red for amyloid immunohistology will be used to determine total leukocytes (CD45), T-cells (CD3) and monocytes/macrophages (CD68). A second set of biopsies will be frozen immediately and stored at -80°. Western blot analysis will be performed to determine alterations at the myofilament level including titin isoform composition and phosphorylation status.
Reproducibility group; Stress-perfusion Cardiovascular magnetic resonance (CMR)	Diagnostic Test: Comprehensive Cardiovascular magnetic resonance (CMR); Cardiovascular magnetic resonance (CMR) provides non-invasive, radiation-free and in-depth evaluation of myocardial structure and function. In addition to established tools for assessment of cardiac volume, mass, function and regional myocardial scar with late Gadolinium enhancement (LGE), several novel quantitative CMR parameters will be assessed including T1-mapping or fully quantitative perfusion Imaging.; Diagnostic Test: Blood sampling; Blood samples will eventually be analysed for markers related to heart failure (BNP/NT)-pro-BNP, myocardial inflammation and fibrosis (cytokine profiling, Galectin-3, Procollagen Type I and III, hsCRP). Whole blood will be frozen for DNA isolation and genome analysis. Peripheral blood mononuclear cells will be isolated by Ficoll in a subset of patients and will be used for RNA isolation allowing RNA-seq or reverse transcription (RT) - polymerase chain reaction (PCR) analysis.
Age/gender matched control group; Blood sampling Stress-perfusion Cardiovascular magnetic resonance (CMR) TTE (EchoErgo)	Diagnostic Test: Comprehensive Cardiovascular magnetic resonance (CMR); Cardiovascular magnetic resonance (CMR) provides non-invasive, radiation-free and in-depth evaluation of myocardial structure and function. In addition to established tools for assessment of cardiac volume, mass, function and regional myocardial scar with late Gadolinium enhancement (LGE), several novel quantitative CMR parameters will be assessed including T1-mapping or fully quantitative perfusion Imaging.; Diagnostic Test: Blood sampling; Blood samples will eventually be analysed for markers related to heart failure (BNP/NT)-pro-BNP, myocardial inflammation and fibrosis (cytokine profiling, Galectin-3, Procollagen Type I and III, hsCRP). Whole blood will be frozen for DNA isolation and genome analysis. Peripheral blood mononuclear cells will be isolated by Ficoll in a subset of patients and will be used for RNA isolation allowing RNA-seq or reverse transcription (RT) - polymerase chain reaction (PCR) analysis.; Diagnostic Test: TTE (EchoErgo); Measurements will include cavity dimensions, flow velocities, myocardial motion velocity and strain as well as for change of parameters during ergometric stress.
Healthy volunteers; Blood sampling Stress-perfusion Cardiovascular magnetic resonance (CMR) TTE (EchoErgo)	Diagnostic Test: Comprehensive Cardiovascular magnetic resonance (CMR); Cardiovascular magnetic resonance (CMR) provides non-invasive, radiation-free and in-depth evaluation of myocardial structure and function. In addition to established tools for assessment of cardiac volume, mass, function and regional myocardial scar with late Gadolinium enhancement (LGE), several novel quantitative CMR parameters will be assessed including T1-mapping or fully quantitative perfusion Imaging.; Diagnostic Test: Blood sampling; Blood samples will eventually be analysed for markers related to heart failure (BNP/NT)-pro-BNP, myocardial inflammation and fibrosis (cytokine profiling, Galectin-3, Procollagen Type I and III, hsCRP). Whole blood will be frozen for DNA isolation and genome analysis. Peripheral blood mononuclear cells will be isolated by Ficoll in a subset of patients and will be used for RNA isolation allowing RNA-seq or reverse transcription (RT) - polymerase chain reaction (PCR) analysis.; Diagnostic Test: TTE (EchoErgo); Measurements will include cavity dimensions, flow velocities, myocardial motion velocity and strain as well as for change of parameters during ergometric stress.

Outcome Measures

Primary Outcome Measures :

1. Significant influence of MR Imaging Parameters on a multivariate model to describe the invasive pressure volume relations (EDPVR). [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using a multivariable regression analysis and a respective F test.

Secondary Outcome Measures :

1. Association between CMR T1-mapping and biopsy results. [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using suitable regression and correlation Analysis.
2. Association between CMR flow echocardiographic flow [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using suitable regression and correlation Analysis.
3. Association between a model for diastolic function based on CMR with a model of diastolic function based on echocardiography [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using suitable regression and correlation Analysis.
4. Association between CMR function and echocardiographic function [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using suitable regression and correlation Analysis.
5. Discriminatory capacity of a multivariate model of invasive and a multivariate model of non-invasive variables. [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using the patient and control groups with comparative ROC analysis and DeLong tests.
6. Reproducibility at one site. [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using respective intra-class correlations in the groups with multiple measurements.
7. Variability between the different sites. [ Time Frame: up to 4 weeks. No follow up is planned. ]
   Using respective intra-class correlations in the groups with multiple measurements.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Patients with diagnostic criteria for HFpEF, age/gender matched controls and healty volunteers

Criteria

Main/reproducibility group:

Inclusion Criteria:

1. Ability to provide informed consent
2. Typical HF symptoms (NYHA stage II-III) within the last 6 months
3. EF > 45 % with absence of structural heart disease on echocardiography (except left ventricular hypertrophy or left atrial enlargement)

4. Echocardiographic evidence of increased left ventricular filling pressures

   1. E/E'sep >15 OR E/E'lat >12 OR Av E/E' >13 OR
   2. E/E' >9 AND left atrial (LA) volume >34 ml/m2 OR systolic pulmonary artery pressure (PAsys): >35 mmHg;
5. Indication for invasive hemodynamic work-up
6. Unclear aetiology of heart failure
7. Adults: age >18 years

Exclusion Criteria:

1. Patients unable or unwilling to provide informed consent
2. High likelihood of non-diagnostic PV loops of MR imaging (e.g. atrial fibrillation or high rate of premature ventricular contraction (PVC) (> 10 ventricular Extrasystole (VES)/minute), > 150 kg body weight, inability to lie flat or still)
3. Contraindication for invasive work-up (allergy to contrast agent, severe renal insufficiency with estimated glomerular filtration rate (eGRF) <30 ml/min)
4. Contraindications for a contrast enhanced CMR study (allergy to contrast agent, incompatible devices or implants (e.g. non-MR conditional pacemaker), severe claustrophobia)
5. Previous medical history of EF <45%
6. Imaging findings confirming a specific diagnosis of myocardial impairment (e.g. amyloid, ischaemic heart disease, valvular disease)

Age-gender matched controls:

Inclusion Criteria:

1. Ability to provide informed consent
2. No current or history of symptoms, signs or therapy for heart disease
3. EF > 45 % with absence of structural heart disease on echocardiography (except left ventricular hypertrophy or left atrial enlargement)
4. Adults: age >18 years

Exclusion Criteria:

1. Patients unable or unwilling to provide informed consent
2. High likelihood of non-diagnostic MR imaging (e.g. atrial fibrillation or high rate of PVC (> 10 VES/minute), > 150 kg body weight, inability to lie flat or still)
3. Contraindications for a contrast enhanced CMR study (allergy to contrast agent, incompatible devices or implants (e.g. non-MR conditional pacemaker), severe claustrophobia, severe renal insufficiency with eGRF <30 ml/min))
4. Previous medical history of EF <45%
5. Imaging findings confirming a specific diagnosis of myocardial impairment (e.g. amyloid, ischaemic heart disease, valvular disease)

Healthy volunteers:

Inclusion Criteria:

1. Ability to provide informed consent
2. No current or history of symptoms, signs or therapy for heart disease
3. EF ≥ 50 % with absence of structural heart disease on echocardiography

Exclusion Criteria:

1. Contraindications for an MR study
2. High likelihood of non-diagnostic MR imaging (e.g. atrial fibrillation or high rate of PVC (> 10 VES/minute), > 150 kg body weight, inability to lie flat or still)
3. Subjects unable or unwilling to provide informed consent
4. EF <50% in patient history
5. Imaging findings confirming a specific diagnosis of myocardial impairment (e.g. amyloid, ischaemic heart disease, valvular disease)

Contacts and Locations

Locations

Germany

University Hospital Frankfurt

Frankfurt, Hesse, Germany, 60590

Kerckhoff Klinik

Bad Nauheim, Germany

Charite Centrum Herz-, Kreislauf- und Gefäßmedizin

Berlin, Germany

University Hospital Göttingen

Göttingen, Germany

University Hospital

Heidelberg, Germany

Herzzentrum Leipzig

Leipzig, Germany

Uniersity Hospital Mainz

Mainz, Germany

Sponsors and Collaborators

Goethe University

Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

Investigators

• Principal Investigator: Eike C Nagel, MD, PhD; Goethe University Frankfurt

More Information

• Responsible Party: Prof. Eike Nagel, Univ. Prof. Dr. med., Goethe University
• ClinicalTrials.gov Identifier: NCT03251183
• Other Study ID Numbers: Protocol_ Version 1 20170225
• First Posted: August 16, 2017
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All data will be shared with other researchers within the German Centre for Cardiovascular Research (DZHK) via the Use and Access Rules
• Supporting Materials: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: 1 year after finalization of primary analysis
• Access Criteria: Via Use and Access Policy of DZHK
• URL: https://www.dzhk.de

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases