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

Validation of Cardiovascular Magnetic Resonance Against Invasive Haemodynamics in Patients With Heart Failure With Preserved Ejection Fraction (DECIPHER HFpEF)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Normal Ejection Fraction
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Actual): 185

Contacts and Locations

Study Locations

• Germany
  • Bad Nauheim, Germany
    • Kerckhoff Klinik
  • Berlin, Germany
    • Charite Centrum Herz-, Kreislauf- und Gefäßmedizin
  • Göttingen, Germany
    • University Hospital Göttingen
  • Heidelberg, Germany
    • University Hospital
  • Leipzig, Germany
    • Herzzentrum Leipzig
  • Mainz, Germany
    • Uniersity Hospital Mainz
  • Hesse
    • Frankfurt, Hesse, Germany, 60590
      • University Hospital Frankfurt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Goethe University
• Collaborators: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
• Investigators: Principal Investigator: Eike C Nagel, MD, PhD, Goethe University Frankfurt

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2018
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: May 14, 2017
• First Submitted That Met QC Criteria: August 12, 2017
• First Posted (Actual): August 16, 2017

Study Record Updates

• Last Update Posted (Estimate): March 10, 2023
• Last Update Submitted That Met QC Criteria: March 8, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: Protocol_ Version 1 20170225

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be shared with other researchers within the German Centre for Cardiovascular Research (DZHK) via the Use and Access Rules
• IPD Sharing Time Frame: 1 year after finalization of primary analysis
• IPD Sharing Access Criteria: Via Use and Access Policy of DZHK
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No