Reliability of Cardiac Troponins for the Diagnosis of Myocardial Infarction in the Presence of Skeletal Muscle Disease (H&M)

Heart&Muscle Study

Visits to the emergency department (ED) for chest pain are extremely common and require a safe, rapid and efficacious treatment algorithm to exclude a possible AMI. These diagnostic algorithms are partly based on an important laboratory value, which showed growing utility in the diagnostic and prognostic of many cardiovascular diseases in the last years : cardiac troponin.

However, some patients with muscle disease often present with unexplained elevated high-sensitive cardiac Troponin T (hs-cTnT) levels in the absence of cardiac disease. The investigators aim at the characterization of the behaviour of this biomarker and its alternative (high-sensitive cardiac Troponin I), which will have important clinical implications on patients management.

Study Overview

• Status: Recruiting
• Conditions: Muscle Weakness; Muscle Atrophy; Muscle Spasticity; Muscle Cramp; Muscle Soreness; Muscle Damage; Myopathy; Muscle Injury

Detailed Description

Introduction: The detection of cardiomyocyte injury as quantified by blood concentrations of cardiac troponin T (cTnT) or I (cTnI) is central in the diagnosis of acute myocardial infarction (AMI). While multiple cardiac disorders other than AMI may also lead to cardiomyocyte injury and therefore elevations in cTnT and cTnI, latest generations of cTnT and cTnI assays are considered to have near exclusive cardiac-specificity. Overall, both analytes (cTnT and cTnI) seem to have comparable diagnostic accuracy among patients presenting with suspected AMI to the emergency department (ED). However, their use in the diagnosis of AMI in patients with a skeletal muscle disease is questioned, as especially cTnT was found to be elevated in this setting. These increased cTnT levels have been successively attributed to a possible re-expression of cTnT isoforms in the diseased muscle, to a primary cardiac involvement associated with the muscle disease or to a cross-reaction of the hs-cTnT assay with TnT of muscle origin.

Aim: To characterize cTn levels in patients with a skeletal muscle disease to assess their utility in the field of cardiology (through their implication in AMI diagnosis and their diagnostic and prognostic accuracy regarding a possible cardiac involvement) and in the field of neurology (for the detection and risk-stratification of the muscle disorder itself).

Methodology: This study will be conducted at the University Hospital of Basel, at the Kantonsspital Aarau, both in Switzerland, and at the University Hospital of Innsbruck, Austria. A prospective cohort patient will be recruited through the neurology, rheumatology and cardiology clinics of these three hospitals. This prospective cohort of patients presenting with skeletal muscle disease will allow us to systematically screen patients for cTn increases, to investigate the prevalence and characteristics of a possible primary cardiac involvement (as documented by electrocardiogram, echocardiography, magnetic resonance imaging, cTnI, NT-proBNP (N-terminal pro-B-type Natriuretic Peptide) and any available further cardiac testing) and to explore the origins of the elevated cTn levels using muscle biopsies. Furthermore, this prospective cohort will document the role of these biomarkers in the diagnosis, prognosis and risk-stratification of the muscle disease. Patients will receive a 1- and 3-year follow-up visit with blood draw in order to measure cTn and other biomarkers and record the impact of the evolution and treatment of the muscle disease on these levels. Major adverse cardiac events including cardiovascular death, AMI, hospitalization for heart failure, and the development of clinical or subclinical heart failure as quantified by elevated blood concentrations of NT-proBNP will be recorded during follow-up.

Potential significance: Elevated cTnT levels do not only have consequences regarding the diagnosis of AMI but also raise many questions regarding their possible use as a diagnostic, prognostic and risk-stratification marker regarding the different muscle injuries and their possible primary cardiac involvement.

• Study Type: Observational
• Enrollment (Anticipated): 800

Contacts and Locations

• Study Contact: Name: Jeanne du Fay de Lavallaz, MD; Phone Number: +41 61 2652525 (Zentrale); Email: jeanne.dufaydelavallaz@usb.ch
• Study Contact Backup: Name: Christian Mueller, MD; Phone Number: +41 61 328 6549; Email: christian.mueller@usb.ch

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Recruiting
    • Medical University Innsbruck
    • Contact: Julia Wanschitz, MD; Phone Number: +43 512 9003 - 0; Email: Julia.Wanschitz@i-med.ac.at
• Switzerland
  • Basel, Switzerland, 4056
    • Recruiting
    • University Hospital Basel
    • Contact: Jeanne du Fay de Lavallaz, MD; Email: jeanne.dufaydelavallaz@usb.ch
    • Contact: Christian Mueller, MD; Email: christian.mueller@usb.ch
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital Bern
    • Contact: Britta Maurer
  • Zürich, Switzerland
    • Recruiting
    • University Hospital Zurich
  • Aargau
    • Aarau, Aargau, Switzerland, 5001
      • Recruiting
      • Canton Hospital of Aarau
      • Contact: Angelika Hammerer, MD; Phone Number: +41 62 838 53 01; Email: angelika.hammerer@ksa.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Consecutive participants which have been or currently are in treatment for a muscle disease at the University hospital of Basel, at the Canton Hospital of Aarau, University Hospital of Zürich or Bern or at the Medical University of Innsbruck, or who received a new diagnosis/suspicion of such a disease will be included.

Description

Inclusion Criteria:

• Diagnostic or suspicion of muscle disease as presence of specified keyword in patient's file or as screened by colleagues of the rheumatology, neuromuscular or other medical clinics.
• Patient consent available

Exclusion Criteria:

• Patient's refusal
• Age <18 years old
• Terminal kidney insufficiency with need for dialysis.
• Temporary exclusion criteria : Acute health condition such as myocardial infarction, patients presenting with a major trauma, a sepsis, patients shortly after cardiac surgery, and patients in shock (>100 bpm, <90 systolic BP, evidence of organ dysfunction).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Comparison of cTnT and cTnI levels as measured by different hs-cTn assays in patients with skeletal muscle disease.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of levels of cTnT and cTnI as measured by hs-assays in matched patients with and without skeletal muscle disease.		1 year
Regression model of diverse patients' characteristics on levels of hs-cTnI and hs-cTnT in the context of skeletal muscle disease versus no skeletal muscle disease.		1 year
Prognostic value of hs-cTn levels in patients with and without skeletal muscle disease.		3 years
Characterization of cTnT and cTnI on skeletal muscle biopsies from myopathic patients.		1 year
Characterization of the impact of cTnT and cTnI on the diagnosis and prognosis of muscle diseases	Prognosis defined as the incidence of Major Cardiovascular Events (MACE is defined as a composite of death, acute myocardial infarction, life-threatening arrhythmia (cardiac arrest, sustained ventricular tachycardia, atrioventricular (AV) -block III), cardiac arrest/reanimation, acute heart failure (requiring admission to a hospital or intra-hospital transfer to the intensive care unit), stroke/transient ischemic attack, pulmonary embolism)	3 years

Other Outcome Measures

Outcome Measure	Time Frame
Research on the development of a new cTnT-assay	3 years
Protein characterization	3 years
Cardiac troponin as predictors or screening tools for a cardiac involvement	3 years
Cardiac troponin as predictor of evolution and therapeutic response of the muscle disease or muscle regeneration.	3 years
Characterisation of cardiac troponin in diseases of various etiologies involving muscles	3 years
Impact of muscle symptoms on cardiac troponin	3 years
Cardiac troponin versus other markers (e.g. CK) of inflammation/necrosis of peripheral muscles.	3 years

Collaborators and Investigators

• Sponsor: Christian Müller, MD
• Collaborators: University Hospital Inselspital, Berne; Medical University Innsbruck; University Hospital, Zürich; Cantonal Hospital of Aarau, Switzerland
• Investigators: Principal Investigator: Christian Mueller, MD, University Hospital, Basel, Switzerland; Principal Investigator: Angelika Hammerer, MD, Canton Hospital Aarau; Principal Investigator: Julia Wanschitz, MD, Medical University Innsbruck

Publications and helpful links

General Publications

• Schmid J, Liesinger L, Birner-Gruenberger R, Stojakovic T, Scharnagl H, Dieplinger B, Asslaber M, Radl R, Beer M, Polacin M, Mair J, Szolar D, Berghold A, Quasthoff S, Binder JS, Rainer PP. Elevated Cardiac Troponin T in Patients With Skeletal Myopathies. J Am Coll Cardiol. 2018 Apr 10;71(14):1540-1549. doi: 10.1016/j.jacc.2018.01.070.
• Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol. 2011 Oct 18;58(17):1819-24. doi: 10.1016/j.jacc.2011.08.026. Epub 2011 Sep 29.
• du Fay de Lavallaz J, Prepoudis A, Wendebourg MJ, Kesenheimer E, Kyburz D, Daikeler T, Haaf P, Wanschitz J, Loscher WN, Schreiner B, Katan M, Jung HH, Maurer B, Hammerer-Lercher A, Mayr A, Gualandro DM, Acket A, Puelacher C, Boeddinghaus J, Nestelberger T, Lopez-Ayala P, Glarner N, Shrestha S, Manka R, Gawinecka J, Piscuoglio S, Gallon J, Wiedemann S, Sinnreich M, Mueller C; BASEL XII Investigators. Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T. Circulation. 2022 Jun 14;145(24):1764-1779. doi: 10.1161/CIRCULATIONAHA.121.058489. Epub 2022 Apr 7.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Anticipated): January 1, 2025
• Study Completion (Anticipated): January 1, 2027

Study Registration Dates

• First Submitted: September 4, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Actual): December 12, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: troponin
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Pain; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Musculoskeletal Pain; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Atrophy; Muscle Hypertonia; Myalgia; Muscle Weakness; Muscular Atrophy; Muscle Spasticity; Spasm; Muscle Cramp
• Other Study ID Numbers: BASEL XII; RESEARCH GRANT (Other Grant/Funding Number: BELGIAN STUDY GROUP FOR PEDIATRIC ENDOCRINOLOGY VZW/ASBL)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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