The Deep Phenotype of Lamin A/C Cardiomyopathy

The Deep Phenotype of Lamin A/C Cardiomyopathy - A Proof-of-principle Relax-omic Pipeline

This study seeks to discover clinically useful tests to improve the diagnosis of a rare and serious heart muscle disease caused by mutations in a gene called 'Lamin'.

Patients born with lamin gene mutations have apparently healthy hearts initially, they begin experiencing symptoms in their twenties or thirties, and by age 45 the majority have undergone a heart transplant, experienced a major cardiac complication, or have died. Sudden heart rhythm abnormalities are a major cause of sudden death so earlier diagnosis can save lives by enabling timely treatment or implantation of specialised pacemakers (defibrillators). In clinical practice, diagnosis of lamin heart disease currently relies on the genetic test. Very little is known about the detailed imaging features of the hearts of patients with lamin heart disease although advanced echocardiography and cardiac MRI now offer the opportunity to study the health of the heart without the need for radiation.

Study Overview

• Status: Recruiting
• Conditions: Lamin A/C Gene Mutation; Dilated Cardiomyopathy, Familial

Detailed Description

• Research participants will undergo resting 12-lead ECG, 24-hour ambulatory ECG, baseline echocardiography, exercise echocardiography, cardiac MRI scan.
• Blood samples will be collected in all participants from both centers for immediate laboratory testing.
• Blood and urine samples will be collected in all participants and used for metabolomic, proteomic and lipidomic profiling and for targeted metabolite and enzyme analysis.
• Blood samples will be collected in all participants for future gene code analysis (DNA / RNA).

• Study Type: Observational
• Enrollment (Anticipated): 150

Contacts and Locations

• Study Contact: Name: Prof. James C Moon, Professor of Cardiology; Phone Number: +44 (0)2034566020; Email: j.moon@ucl.ac.uk
• Study Contact Backup: Name: Mashael Alfarih, Research Fellow; Email: m.alfarih.17@ucl.ac.uk

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Recruiting
    • University Hospital Birmingham (UHB)
    • Principal Investigator: Dr Rick Steeds, Consultant Cardiologist
  • London, United Kingdom
    • Recruiting
    • Barts Heart Center, St Bartholomew's Hospital NHS Trust
    • Contact: James C Moon, Professor of Cardiology; Phone Number: +44 (0)2034566020; Email: j.moon@ucl.ac.uk
    • Principal Investigator: Dr Saidi Mohiddin, Consultant Cardiologist
  • London, United Kingdom
    • Recruiting
    • Royal Brompton Hospital NHS Trust (RBHT)
    • Principal Investigator: Dr Sanjay Prasad, Consultant Cardiologist
  • London, United Kingdom
    • Recruiting
    • Royal Free Hospital NHS Trust (RFH)
    • Principal Investigator: Dr Gabriella Captur, Consultant Cardiologist
  • London, United Kingdom
    • Recruiting
    • University College London Hospital NHS Trust (UCLH)
    • Principal Investigator: Dr Simon J Woldman, Consultant Cardiologist
  • Papworth Everard, United Kingdom
    • Recruiting
    • Papworth Hopsital NHS Trust
    • Principal Investigator: Dr Stephen Pettit, Consultant Cardiologist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adults with known pathogenic lamin (LMNA+) gene mutations, adults with heart muscle failure but normal (wild-type) LMNA gene (DCMWT) and matched healthy volunteers (HV).

Description

Inclusion Criteria:

• LMNA+ cases with pathogenic LMNA mutations for LMNA+ and heart myocardial samples from the explanted hearts of LMNA+ patients who are scheduled to undergo clinically indicated heart transplantation at the Papworth Hospital NHS Trust.
• DCMWT cases: patients with heart muscle failure but with wild-type lamin gene. Heart myocardial samples from the explanted hearts of DCMWT patients who are scheduled to undergo clinically indicated heart transplantation at the Papworth Hospital NHS Trust.
• HV (controls): matched to cases.

Exclusion Criteria:

• Needle-phobia that would preclude blood-letting
• Participants unwilling to consent
• Patients that have a conventional contraindication for cardiac magnetic resonance imaging (MRI).
• Patients that have had a blood transfusion within the last month and patients having haemodialysis will be excluded.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Lamin DCM (LMNA+); Adults with known pathogenic lamin (LMNA+) gene mutation.
Wild types DCM (DCMwt); Adults with heart muscle failure but normal (wild-type) LMNA gene (DCMwt).
Healthy Volunteers (HV); Matched healthy volunteers (HV).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Positive and negative predictive value of imaging-omics test for diagnosing LMNA-related heart muscle disease.	3-4 years

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: NIHR Rare Diseases Translational Research Collaboration; Barts Cardiovascular registry

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2019
• Primary Completion (Anticipated): February 1, 2025
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: January 15, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): October 16, 2019
• Last Update Submitted That Met QC Criteria: October 15, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Heart failure; Dilated Cardiomyopathy; Lamin A/C Cardiomyopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: 16/0661; 17/LO/0167 (Other Identifier: REC reference)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: no sharing of individual patient data is planned.

Drug and device information, study documents

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