Microvascular Dysfunction Assessment to Predict Left Ventricular Reverse Remodeling (MICROREV)

Microvascular Dysfunction Assessment to Predict Left Ventricular Reverse Remodeling in Idiopathic Dilated Cardiomyopathy

Patients presenting with idiopathic dilated cardiomyopathy and left ventricle dysfunction (LVEF <40%), naive of anti-remodeling cardiac medical therapy, will undergo invasive coronary microvascular assessment based on thermodilution. The primary endpoint, namely the left ventricle reverse remodeling, will be assessed after 12 months of optimal medical therapy based on transthoracic echocardiography. The primary endpoint will be evaluated by an independent central core lab. Patients enrolled in the study will be followed for a period of 5 years to monitor their clinical status. During the study period participants may undergo multimodality diagnostic tests including ECG telemetry monitoring, cardiopulmonary exercise testing, cardiovascular cardiac magnetic resonance.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Left Ventricular Dysfunction; Idiopathic Dilated Cardiomyopathy
• Intervention / Treatment: Diagnostic test: Thermodilution based assessment of coronary microcirculation

Detailed Description

This is a prospective, multicentric, single-arm explorative clinical study in patients presenting with heart failure and idiopathic dilated cardiomyopathy with LVEF ≤ 40%. Patients identified as eligible for the protocol will be asked for written informed consent to participate in the study.

After appropriate treatment of the acute heart failure phase, participants will undergo coronary angiography to rule out obstructive coronary disease.

Fractional flow reserve (FFR) will be assessed as per standard clinical practice and a value ≤ 0.80 will be considered abnormal. Microvascular assessment will be performed using the same pressure/thermodilution guidewire used for FFR assessment with the derivation of coronary flow reserve (CFR), index of microcirculatory resistance (IMR) and the microvascular resistance reserve (MRR).

Steady-state hyperemia will be obtained using an intravenous adenosine infusion or intracoronary papaverine as per routine clinical practice.

The primary endpoint will be assessed based on the variation of echocardiographic indices from the baseline to 12-month follow up. Transthoracic echocardiography will be performed to confirm the diagnosis and obtain information about adverse cardiac remodeling and after 12 months of optimal medical therapy to evaluate reverse remodeling.

Patients will be clinically managed by a dedicated heart failure team to optimize medical therapy and organize the follow-up.

Patients enrolled in the study will be clinically followed for a period of 5 years to monitor the clinical status and report major adverse cardiac events.

During the study period participants may undergo multimodality diagnostic tests according to the recent international guidelines. Data from these tests will be collected if the test will be performed per clinical practice:

1. 3-leads ECG telemetry monitoring (or 24 hours Holter ECG) to detect or quantify atrial and/or ventricular arrhythmias during the hospitalization.
2. N-terminal pro-B-type natriuretic peptide (NT - proBNP).
3. Cardiopulmonary exercise testing (CPET) to assess functional capacity.
4. Contrast enhanced cardiac magnetic resonance. CMR assessment may be repeated at 12 months follow-up.
5. Genetic counseling and genetic testing, performed by an appropriately trained healthcare professional is recommended in patients with idiopathic DCM by the latest international guidelines to enable diagnosis, prognostication, therapeutic stratification.

• Study Type: Interventional
• Enrollment (Estimated): 190
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Natascia Antonioli; Phone Number: 0039 0458122320; Email: studi.clinici.cardiologia@aovr.veneto.it

Study Locations

• Italy
  • Ferrara, Italy
    • Not yet recruiting
    • Azienda Ospedaliera Universitaria di Ferrara
    • Contact: Elisabetta Tonet
    • Contact: Gianluca Campo
  • Genova, Italy
    • Not yet recruiting
    • Cardiothoracic and Vascular Department (DICATOV) IRCCS, Ospedale Policlinico San Martino
    • Contact: Italo Porto
  • Milan, Italy
    • Not yet recruiting
    • Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) dell'Ospedale San Raffaele
    • Contact: Matteo Montorfano
    • Contact: Marco Ancona
  • Milan, Italy
    • Not yet recruiting
    • Ospedale Galeazzi di Sant'Ambrogio IRCCS
    • Contact: Giovanni Monizzi
  • Naples, Italy
    • Not yet recruiting
    • University of Naples Federico II
    • Contact: Giovanni Esposito
    • Contact: Luigi Di Serafino
  • Roma, Italy
    • Not yet recruiting
    • Fondazione Policlinico Universitario A. Gemelli IRCCS
    • Contact: Cristina Aurigemma
    • Contact: Francesco Burzotta
    • Sub-Investigator: Antonio M Leone
  • Rome, Italy
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria Sant'Andrea
    • Contact: Emanuele Barbato
  • Torino, Italy
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
    • Contact: Fabrizio D'Ascenzo
  • Verona, Italy, 37126
    • Recruiting
    • Azienda Ospedaliera Universitaria di Verona
    • Contact: Flavio Ribichini; Phone Number: 0039 0458122320; Email: flavio.ribichini@univr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female, aged >18 years
• First diagnosis of idiopathic DCM (defined according to the most recent ESC Guidelines) with LVEF ≤ 40% and clinical indication to diagnostic coronary angiography
• Willing and able to give informed consent for participation in the study

Exclusion Criteria:

• Obstructive CAD (defined as angiographically intermediate disease [50%-70%] with impaired FFR or as angiographically severe disease [>70%] in 1 or more epicardial vessels)
• History of previous myocardial infarction, percutaneous revascularization or coronary-aortic bypass graft (CABG) surgery
• Valvular heart disease (rheumatic heart disease, severe aortic stenosis, severe aortic regurgitation, severe primary mitral regurgitation)
• Infective endocarditis
• Congenital heart disease
• Peripartum cardiomyopathy
• Acute myocarditis (detected by endomyocardial biopsy - histological criteria - or by CMR - Lake Louis criteria) and pericarditis
• Persistent tachyarrhythmias (documented persistent high-rate supraventricular arrhythmias)
• Excessive alcohol intake (>80 g/die for at least five years)
• History of chemotherapy (anthracycline therapy, cumulative dosages >250 mg/m2)
• History of uncontrolled arterial hypertension (blood pressure >160/100 mmHg)
• Stage IV and V of chronic kidney disease (eGFR < 30 ml/min, estimated through CKD - EPI Creatinine Equation)
• Allergy or other contraindication to iodinated contrast and/or adenosine
• Chronic resting O2 saturation <85%
• Pregnancy or suspected pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Microvascular assessment; Coronary microvascular assessment	Diagnostic test: Thermodilution based assessment of coronary microcirculation; Coronary microvascular assessment with the derivation of CFR, IMR and MRR will be performed using a standard pressure/thermodilution guidewire.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Left ventricular reverse remodeling (LVRR)	LVRR, defined as LVEF increase ≥ 10% and LVEDDi decrease ≥ 10%, will be assessed with transthoracic echocardiography and analyzed off-line by an independent central corelab.	After 12 months of guidelines directed optimal medical therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse clinical events	Composite of cardiovascular death, new hospitalization for HF, ICD implantation, heart transplantation or ventricular mechanical assistance implantation during follow-up in patients with and without coronary microvascular dysfunction	Up to 5 years
Rate of LVRR at cardiac magnetic resonance	LVRR, defined as LVEF increase ≥ 10% and LVEDDi decrease ≥ 10%, in patients who will undergo CMR at baseline and at 12 months follow up.	After 12 months of guidelines directed OMT
Changes in functional capacity at cardiopulmonary exercise test	Variations of VO2 max at CPET after 12 months of guidelines-defined OMT	After 12 months of guidelines-defined OMT
Prevalence of different CMD endotypes and their correlation with the severity of adverse cardiac remodeling.	CMD endotypes (defined as IMR >25 units and/or CFR <2)	At baseline
Left ventricle adverse cardiac remodeling at cardiovascular magnetic resonance.	Measures of LV adverse remodeling at CMR	At baseline

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Collaborators: Abbott Medical Devices
• Investigators: Principal Investigator: Roberto Scarsini, MD PhD, Azienda Ospedaliera Universitaria di Verona

Publications and helpful links

General Publications

• McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available. Erratum In: Eur Heart J. 2021 Oct 14;:
• Del Buono MG, Montone RA, Camilli M, Carbone S, Narula J, Lavie CJ, Niccoli G, Crea F. Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Sep 28;78(13):1352-1371. doi: 10.1016/j.jacc.2021.07.042.
• Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, De Winter T, Elliott PM, Flather M, Garcia-Pavia P, Haugaa KH, Ingles J, Jurcut RO, Klaassen S, Limongelli G, Loeys B, Mogensen J, Olivotto I, Pantazis A, Sharma S, Van Tintelen JP, Ware JS, Kaski JP; ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023 Oct 1;44(37):3503-3626. doi: 10.1093/eurheartj/ehad194. No abstract available.
• Merlo M, Pyxaras SA, Pinamonti B, Barbati G, Di Lenarda A, Sinagra G. Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol. 2011 Mar 29;57(13):1468-76. doi: 10.1016/j.jacc.2010.11.030.
• Rosano GMC, Moura B, Metra M, Bohm M, Bauersachs J, Ben Gal T, Adamopoulos S, Abdelhamid M, Bistola V, Celutkiene J, Chioncel O, Farmakis D, Ferrari R, Filippatos G, Hill L, Jankowska EA, Jaarsma T, Jhund P, Lainscak M, Lopatin Y, Lund LH, Milicic D, Mullens W, Pinto F, Ponikowski P, Savarese G, Thum T, Volterrani M, Anker SD, Seferovic PM, Coats AJS. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2021 Jun;23(6):872-881. doi: 10.1002/ejhf.2206. Epub 2021 May 20.
• Gulati A, Ismail TF, Ali A, Hsu LY, Goncalves C, Ismail NA, Krishnathasan K, Davendralingam N, Ferreira P, Halliday BP, Jones DA, Wage R, Newsome S, Gatehouse P, Firmin D, Jabbour A, Assomull RG, Mathur A, Pennell DJ, Arai AE, Prasad SK. Microvascular Dysfunction in Dilated Cardiomyopathy: A Quantitative Stress Perfusion Cardiovascular Magnetic Resonance Study. JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 2):1699-1708. doi: 10.1016/j.jcmg.2018.10.032. Epub 2019 Jan 16.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2024
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: March 30, 2024
• First Submitted That Met QC Criteria: April 9, 2024
• First Posted (Actual): April 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: heart failure; left ventricular reverse remodeling; coronary microvascular dysfunction; optimal medical therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated; Ventricular Dysfunction; Ventricular Dysfunction, Left
• Other Study ID Numbers: 121CET-MICROREV-DCM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Yes.

IPD Sharing Time Frame

The present study is powered for assessing left ventricular reverse remodeling in patients with and without coronary microvascular dysfunction. However, the study is not powered for clinical adverse events. In order to obtain compelling evidence on this latter endpoint, the data of the present study will be merged with those of clinical studies sharing the same inclusion and exclusion criteria and study interventions.

Data will be available for individual patient level analysis in order to merge our data with other studies sharing inclusion and exclusion criteria. Data will be available after the completion of the primary endpoint.

• IPD Sharing Access Criteria: Direct request to study Principal Investigator.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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