Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure

NCT ID: NCT05167799

Last Updated: 2021-12-22

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 25 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-05-13
• Study Completion Date: 2024-06-01

Brief Summary

The primary aim of this observational registry is to evaluate the efficacy of CCM in patients with heart failure with mid-range or reduced EF and diagnosis of TTR amyloidosis. The efficacy will be evaluated in terms of composite of occurrence of heart failure-related hospitalizations and/or acute intravenous interventions (IVI) at 12-month follow up compared to those reported 12 months before CCM implantation. Among the secondary endpoints, clinical functional status, quality of life, drug changes and Echocardiographic parameters will be evaluated and compared from baseline to follow up.

Detailed Description

Amyloidosis represents a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Cardiac amyloidosis is primarily associated with the systemic production and release of a number of amyloidogenic proteins, notably immunoglobulin light chain proteins (also known as amyloid light chain or AL) or transthyretin proteins (TTR). Notably, although myocardial dysfunction is generally understood as a result of infiltration by extracellular amyloid deposits, there is experimental evidence of direct cytotoxic effect, possibly due to oxidative stress.

Since neither HF optimal medical therapy nor HF devices seems to have a clear benefit in amyloid cardiomyopathy, this clinical setting needs to test other therapeutic options.

Randomized clinical trials have shown that Cardiac contractility modulation (CCM) may be considered as a concrete therapeutic option in patients with symptomatic Heart Failure (HF) despite optimal medical therapy (OMT), with Left Ventricular Ejection Fraction (LVEF) between 25% and 45%, with narrow QRS complex (<130ms).

CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2+ cycling and stretch response genes. Specifically, 3-month on CCM therapy resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase (MAPK) and p21 Ras and increased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors. Notably, pre-clinical data suggest that triggering p38α MAPK autophosphorylation plays a crucial role in amyloidogenic light-chain mediated cellular oxidative stress, dysfunction and ultimately cell death in cardiomyocytes. Therefore CCM mechanism of action could be beneficial in cardiac amyloidosis but there are no data in this specific clinical setting.

Conditions

Amyloidosis Cardiac; Heart Failure

Keywords

Cardiac Amyloidosis; Heart Failure; Cardiac Contractility Modulation; CCM

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

Cardiac Amyloidosis patients

Patients with established diagnosis of amyloid TTR Cardiomyopathy, baseline ejection fraction ≥25% and ≤45%, at least one hospitalization due to worsening heart failure over the year before entry into the registry.

Already implanted with ICD or PM if needed, fullfilling the indication for CCM implantation.

Cardiac Contractility Modulation (CCM)

Intervention Type: DEVICE

Patients will be implanted with CCM device according to indications, to improve Heart Failure symptoms and then enrolled in the Registry if they fullfil Inclusion and Exclusion Criteria (First of all if they are diagnosed with TTR Amyloidosis)

Interventions

Cardiac Contractility Modulation (CCM)

Patients will be implanted with CCM device according to indications, to improve Heart Failure symptoms and then enrolled in the Registry if they fullfil Inclusion and Exclusion Criteria (First of all if they are diagnosed with TTR Amyloidosis)

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Age 18 years or older
• Male or a nonpregnant female
• All of the following: Established diagnosis of amyloid TTR Cardiomyopathy; baseline ejection fraction ≥25% and ≤45%; at least one hospitalization due to worsening heart failure over the year before entry into the registry.
• ICD if indicated
• PM if indicated
• Willing and able to return for all follow-up visits

Exclusion Criteria

• AL amyloid cardiomyopathy
• Subjects who have a potentially correctible cause of heart failure (eg, Ischemic or valvular or congenital heart disease).
• Scheduled for CABG or PCI or has undergone a CABG within 90 d or PCI within 30 d.
• Myocardial infarction within 90 days
• Mechanical tricuspid valve
• Prior heart transplant
• Chronic haemodialysis
• Familial TTR amyloidotic cardiomyopathy with significant polyneuropathy potentially eligible for Patirisan or Inotersen17
• Unable to provide informed consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ospedale C & G Mazzoni

OTHER

Sponsor Role: lead

Responsible Party

Procolo Marchese

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Procolo Marchese, MD

Role: PRINCIPAL_INVESTIGATOR

Ospedale Mazzoni (Ascoli Piceno)

Locations

Ospedale Mazzoni

Ascoli Piceno, Marche (AP), Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Procolo Marchese, MD

Role: CONTACT

Phone: +393921133283

Email: procolo.marchese@gmail.com

Facility Contacts

Procolo Marchese

Role: primary

References

Shi J, Guan J, Jiang B, Brenner DA, Del Monte F, Ward JE, Connors LH, Sawyer DB, Semigran MJ, Macgillivray TE, Seldin DC, Falk R, Liao R. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4188-93. doi: 10.1073/pnas.0912263107. Epub 2010 Feb 11.

Reference Type: RESULT

PMID: 20150510 (View on PubMed)

Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res. 2004 Apr 30;94(8):1008-10. doi: 10.1161/01.RES.0000126569.75419.74. Epub 2004 Mar 25.

Reference Type: RESULT

PMID: 15044325 (View on PubMed)

Kristen AV, Dengler TJ, Hegenbart U, Schonland SO, Goldschmidt H, Sack FU, Voss F, Becker R, Katus HA, Bauer A. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm. 2008 Feb;5(2):235-40. doi: 10.1016/j.hrthm.2007.10.016. Epub 2007 Oct 9.

Reference Type: RESULT

PMID: 18242546 (View on PubMed)

Abraham WT, Kuck KH, Goldsmith RL, Lindenfeld J, Reddy VY, Carson PE, Mann DL, Saville B, Parise H, Chan R, Wiegn P, Hastings JL, Kaplan AJ, Edelmann F, Luthje L, Kahwash R, Tomassoni GF, Gutterman DD, Stagg A, Burkhoff D, Hasenfuss G. A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation. JACC Heart Fail. 2018 Oct;6(10):874-883. doi: 10.1016/j.jchf.2018.04.010. Epub 2018 May 10.

Reference Type: RESULT

PMID: 29754812 (View on PubMed)

Anker SD, Borggrefe M, Neuser H, Ohlow MA, Roger S, Goette A, Remppis BA, Kuck KH, Najarian KB, Gutterman DD, Rousso B, Burkhoff D, Hasenfuss G. Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur J Heart Fail. 2019 Sep;21(9):1103-1113. doi: 10.1002/ejhf.1374. Epub 2019 Jan 16.

Reference Type: RESULT

PMID: 30652394 (View on PubMed)

Other Identifiers

AMYCCM190421

Identifier Type: -

Identifier Source: org_study_id