Biomarkers of Inflammation and Fibrosis in Conduction Disorders After TAVI

Official title

The Role of Inflammation and Fibrosis in the Development of Conduction Disorders After Transcatheter Aortic Valve Implantation

Overview

Prediction of conduction disorders (CDs) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) is an important and complex process with a significant impact on patient outcomes. The goal of this observational prospective trial is to investigate the role of pre-procedural values of systemic biomarkers of inflammation and fibrosis in the prediction of new-onset CDs and permanent pacemaker implantation (PPI) in patients undergoing the TAVI procedure.

Detailed description

Transcatheter aortic valve implantation (TAVI) has become an established therapeutic option for the management of severe aortic stenosis (AS) in patients at all levels of surgical risk. Significant improvements in procedural safety and efficacy, along with growing operator experience, have led to a reduction of periprocedural complications. However, the incidence of new-onset conduction disorders (CDs) remains relatively high. This represents a cause for concern, especially regarding the trend of expanding TAVI indication towards younger and lower-risk patients.

Since certain CDs and PPI after TAVI are associated with poorer outcomes, identifying patients at high risk for new-onset CDs is paramount. With careful pre-procedural planning and modification of procedural steps, it is possible to avoid the occurrence of CDs in some patients. After the procedure, more intensive and prolonged electrocardiographic (ECG) monitoring should be applied in patients at high risk. A substantial number of TAVI-related CD predictors have been identified and should be evaluated in every patient, including clinical, electrocardiographic, anatomic, and procedural-related factors.

The process of inflammation and fibrosis plays a significant role in the pathogenesis of degenerative AS, causing not only valvular changes, but also myocardial and conduction system remodeling, with limited research addressing the latter. Circulating biomarkers of inflammation and fibrosis, reflecting the underlying pathological changes of the conduction system, could potentially be correlated with the risk of TAVI-related CDs. Those biomarkers have not been investigated as predictors of the aforementioned disorders so far. Routinely and widely available inflammatory biomarkers could be used in everyday clinical practice as additional predictors for the development of TAVI-related CDs and consequently contribute to an individualized approach in planning the procedure. In accordance with certain more specific and complex biomarkers, analysis of this correlation could also contribute to understanding and clarifying the role of inflammation and fibrosis in the pathogenesis of new-onset CDs in patients undergoing the TAVI procedure.

Trial objective: To investigate the role of pre-procedural values of systemic biomarkers of inflammation and fibrosis in the prediction of new-onset CDs and permanent pacemaker implantation (PPI) in patients with severe AS undergoing TAVI procedure.

Methodology: This is an observational prospective trial that will include a minimum of 102 consecutive patients with severe AS hospitalized in Clinical Hospital Center Rijeka for a planned TAVI procedure, according to the previous Heart Team decision. In all patients, peripheral venous blood samples will be collected before the procedure for analysis and calculation of inflammatory and fibrosis biomarkers (C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), calprotectin, lactate-dehydrogenase (LD), ferritin, CRP/albumin ratio (CAR), index of systemic immuno-inflammation (SII), and transforming growth factor-β1 (TGF- β1). In a patient subpopulation of 40 individuals, four specific microRNAs (miR-21, miR-29b, miR-155, and miR-146b) involved in the regulation of fibrosis and inflammation, will be additionally analyzed. Pre-procedural echocardiographic parameters to assess the extent of extravalvular cardiac damage related to AS and myocardial deformation analysis as a non-invasive marker of fibrosis will be evaluated and correlated with rates of new-onset TAVI-related CDs. The electrocardiogram (ECG) will be analysed before and consecutively after the procedure, during hospitalization, and at a 3-month follow-up. Patients will be assigned to a group with or without new-onset CD, whether a previously defined CD or PPI was recorded during the index hospitalization and follow-up period.

Interventions

• Diagnostic test Biomarkers of inflammation and fibrosis in pre-procedural serum blood samples
  In all patients, peripheral venous blood samples will be collected before the TAVI procedure for analysis and calculation of prespecified inflammatory and fibrosis biomarkers. In a subpopulation of 40 individuals, four specific microRNAs (miR-21, miR-29b, miR-155, and miR-146b) will be additionally analysed. The level of each biomarker will be correlated with rates of new-onset TAVI-related CDs and compared between patients with detected and patients without detected new-onset CDs.
• Diagnostic test Transthoracic echocardiography with myocardial deformation analysis and staging according to the extent of cardiac damage related to AS
  The echocardiographic stage of extravalvular cardiac damage related to AS and myocardial deformation parameters will be analysed in each patient before TAVI procedure and compared between the group with detected new-onset CDs and the group without new-onset CDs with a goal to examine their predictive value for the development of TAVI-related CDs.

Primary outcome measures

• Pre-procedural levels of C-reactive protein (mg/L) and calprotectin (mg/L) [Time frame: At hospital admission, before TAVI procedure]
• Pre-procedural level of interleukin-6 (ng/L) [Time frame: At hospital admission, before TAVI procedure]
• Pre-procedural levels of procalcitonin (µg/L) and ferritin (µg/L) [Time frame: At hospital admission, before TAVI procedure]
• Pre-procedural level of transforming growth factor-β1(pg/ml) [Time frame: At hospital admission, before TAVI procedure]
• Pre-procedural level of lactate-dehydrogenase (U/I) [Time frame: At hospital admission, before TAVI procedure]
• Pre-procedural C-reactive protein to albumin ratio and index of systemic immuno-inflammation values [Time frame: At hospital admission, before TAVI procedure]

Secondary outcome measures (5)

• Pre-procedural levels of microRNAs (miR-21, miR-29b, miR-155, and miR-146b) in a subpopulation of 40 patients [Time frame: At hospital admission, before TAVI procedure]
• Myocardial deformation parameters [Time frame: At hospital admission, before TAVI procedure]
• Left ventricle apical to basal strain ratio [Time frame: At hospital admission, before TAVI procedure]
• Myocardial work index (mmHg%) [Time frame: At hospital admission, before TAVI procedure]
• Stage of extravalvular cardiac damage (0-4) [Time frame: At hospital admission, before TAVI procedure]

Eligibility criteria

Inclusion criteria

• Written consent to participate in the trial
• Diagnosis of severe AS according to current European Society of Cardiology (ESC) guidelines for valvular heart disease

Exclusion criteria

• Acute infectious disease
• Chronic inflammatory or autoimmune disease
• Corticosteroid or other immunosuppressive therapy
• Active malignant disease
• Liver disease accompanied by dysfunction
• Permanent pacemaker implanted previously
• An acute myocardial infarction within three months before the procedure
• A surgical procedure within three months before the procedure
• Previous surgical or transcatheter aortic valve replacement/implantation
• End-stage chronic kidney disease (eGFR <15 ml/min)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Croatia · 1 center

• Clinical Hospital Center Rijeka — Rijeka

Publications

• Damas F, Nguyen Trung ML, Postolache A, Petitjean H, Lempereur M, Viva T, Oury C, Dulgheru R, Lancellotti P. Cardiac Damage and Conduction Disorders after Transcatheter Aortic Valve Implantation. J Clin Med. 2024 Jan 11;13(2):409. doi: 10.3390/jcm13020409. PMID 38256543
• Ramos-Mondragon R, Galindo CA, Avila G. Role of TGF-beta on cardiac structural and electrical remodeling. Vasc Health Risk Manag. 2008;4(6):1289-300. doi: 10.2147/vhrm.s3985. PMID 19337543
• Friedman HS, Zaman Q, Haft JI, Melendez S. Assessment of atrioventricular conduction in aortic valve disease. Br Heart J. 1978 Aug;40(8):911-7. doi: 10.1136/hrt.40.8.911. PMID 687491
• Verheule S, Schotten U. Electrophysiological Consequences of Cardiac Fibrosis. Cells. 2021 Nov 18;10(11):3220. doi: 10.3390/cells10113220. PMID 34831442
• Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003 Feb 25;107(7):984-91. doi: 10.1161/01.cir.0000051865.66123.b7. PMID 12600911
• Conte M, Petraglia L, Campana P, Gerundo G, Caruso A, Grimaldi MG, Russo V, Attena E, Leosco D, Parisi V. The role of inflammation and metabolic risk factors in the pathogenesis of calcific aortic valve stenosis. Aging Clin Exp Res. 2021 Jul;33(7):1765-1770. doi: 10.1007/s40520-020-01681-2. Epub 2020 Sep 25. PMID 32978752
• Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, Capodanno D, Conradi L, De Bonis M, De Paulis R, Delgado V, Freemantle N, Gilard M, Haugaa KH, Jeppsson A, Juni P, Pierard L, Prendergast BD, Sadaba JR, Tribouilloy C, Wojakowski W; ESC/EACTS Scientific Document Group. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022 Feb 12;43(7):561-632 PMID 34453165
• Auffret V, Puri R, Urena M, Chamandi C, Rodriguez-Gabella T, Philippon F, Rodes-Cabau J. Conduction Disturbances After Transcatheter Aortic Valve Replacement: Current Status and Future Perspectives. Circulation. 2017 Sep 12;136(11):1049-1069. doi: 10.1161/CIRCULATIONAHA.117.028352. PMID 28893961

Identifiers

NCT: NCT07201363 · 003052401131

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗