Analysis of Calcium Score of Severe Aortic Stenosis in Patients With and Without Cardiac Amyloidosis (CAUSATIVE Study) (CAUSATIVE)

Analysis of Calcium Score Values of Severe Aortic Stenosis in Patients With and Without Cardiac Amyloidosis (CAUSATIVE Study)

The concomitant presence of cardiac amyloidosis (CA) in patients with aortic stenosis (AS) may challenge the estimation of stenosis degree. In patients with dual pathology (AS + CA) the most frequent AS hemodynamic profile is paradoxical low-flow, low-gradient AS.

In this setting, estimating stenosis degree with cardiac ultrasound may be challenging and aortic valve calcium score estimation by cardiac CT is a valuable exam.

Preliminary findings from small case series showed that patients with severe AS and CA presented less valvular calcium deposition compared to patients with severe AS alone. On this basis, confirmation of these findings would have a huge clinical impact on diagnosis, choice of treatment strategy and understanding of the pathophysiology of these patients.

The aim of the study is to study the correlation between valvular calcium score (assessed by EKG-gated CT) and effective orifice area (assessed through echocardiogram) according to cardiac amyloidosis presence (in the overall population and among hemodynamic phenotypes of cardiac amyloidosis).

As secondary endpoints the study will sought to assess TAVI/SAVR efficacy, procedural complications, in-hospital mortality, all-cause death and heart failure hospitalization at 1 year, according to absence or presence of CA.

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis, Severe; Amyloidosis Cardiac

Detailed Description

Aortic stenosis (AS) is the most common valvular pathology in the elderly population, and there is an anticipated increase in prevalence and associated costs for treating this condition in the future. In a non-negligible percentage of cases (approximately 15%), another pathology is associated, namely cardiac amyloidosis, especially in the wild-type ATTR form. Patients with both pathologies (AS+ATTR) have a worse prognosis compared to those with AS alone. Based on the available data up to now, ATTR-associated amyloidotic cardiomyopathy does not appear to significantly influence the immediate outcome of TAVI or short-term outcomes. However, among patients with amyloidosis, there is an increased frequency of heart failure in subsequent follow-ups. The mechanism behind this dual pathology remains unclear. Epidemiological similarities (advanced age) alone do not explain the association. It is possible that there is a direct causal link between amyloidosis and aortic stenosis (amyloidosis as a co-cause or contributing factor to valvular stenosis), or that the elevated intramyocardial strain due to degenerative valvular stenosis promotes amyloidogenesis and myocardial infiltration. Understanding the extent of valvular calcifications in individual cases would provide better insights into the pathogenesis of this dual pathology. There are also diagnostic implications. Amyloidosis could potentially complicate the accurate classification of the severity of aortic pathology. For example, patients with AS+ATTR often exhibit a "low-flow low-gradient" paradoxical hemodynamic profile. In these cases, estimating the valve area with an echocardiogram is challenging, and evaluating the valvular calcium score through CT assumes an important diagnostic role. Preliminary studies suggest that, for the same degree of stenosis severity, there may be a lower quantity of calcium in the valves of patients with AS+ATTR compared to those with AS alone. Preliminary studies suggest that, for the same degree of stenosis severity, there may be a lower quantity of calcium in the valves of patients with AS+ATTR compared to those with AS alone. In a 1:1 propensity matching of over 300 patients (mostly without aortic stenosis), those with amyloidosis had lower aortic valvular calcium scores (p<0.01). In a small series of 13 cases with AS+ATTR, 12 had aortic valvular calcium scores below the severity cut-offs recommended by the guidelines. If confirmed, traditionally used calcium score cut-offs may be inadequate, with significant implications for treatment selection and therefore prognosis.

• Study Type: Observational
• Enrollment (Estimated): 480

Contacts and Locations

• Study Contact: Name: Matteo Serenelli, Doctor; Phone Number: 0532236269; Email: m.serenelli@ospfe.it
• Study Contact Backup: Name: Paolo Cimaglia, Doctor; Phone Number: 0532236269; Email: p.cimaglia@ospfe.it

Study Locations

• Italy
  • Ferrara, Italy, 44124
    • Recruiting
    • University Hospital Of Ferrara
    • Contact: Matteo Serenelli, Doctor; Phone Number: 0532236269; Email: m.serenelli@ospfe.it
    • Contact: Paolo Cimaglia, Doctor; Phone Number: 0532236269; Email: paolo.cimaglia@ospfe.it

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Group 1 "DUAL PATHOLOGY"

• Age >65 years
• Severe aortic stenosis at echocardiographic examination
• TAVI o SAVR planned or already undergone TAVI/SAVR
• ECG-gated cardiac CT and echocardiographic examinations available before TAVI/SAVR
• Cardiac uptake at bone tracer scintigraphy with a Perugini score of 2 or 3.

Group 2 "CONTROL GROUP"

• Age >65 years
• Severe aortic stenosis at echocardiographic examination
• TAVI o SAVR planned or already undergone TAVI/SAVR
• ECG-gated cardiac CT and echocardiographic examinations available before TAVI/SAVR
• patients with no cardiac uptake at scintigraphy with bone tracer.

Description

Inclusion Criteria:

• signed informed consent
• age ≥65 years old
• severe AS
• planned or performed TAVI/SAVR
• at least one red-flag suggestive of CA
• availability of EKG-gated CT
• availability of echocardiogram performed before TAVI/SAVR
• availability of bone scintigraphy performed within 1 year from CT

Exclusion Criteria:

• suboptimal acoustic window that may undermine the assessment of AS severity and phenotype profiling

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Group 1 - "Dual Pathology"; Age >65 years; Severe aortic stenosis at echocardiographic examination; TAVI o SAVR planned or already undergone TAVI/SAVR; ECG-gated cardiac CT and echocardiographic examinations available before TAVI/SAVR; Cardiac uptake at bone tracer scintigraphy with a Perugini score of 2 or 3.
Group 2- "Control Group"; Age >65 years; Severe aortic stenosis at echocardiographic examination; TAVI o SAVR planned or already undergone TAVI/SAVR; ECG-gated cardiac CT and echocardiographic examinations available before TAVI/SAVR; Patients with no cardiac uptake at scintigraphy with bone tracer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between valvular calcium score and effective orifice area.	Correlation between valvular calcium score (assessed by EKG-gated CT) and effective orifice area (assessed through echocardiogram) according to cardiac amyloidosis presence (in the overall population and among hemodynamic phenotypes of cardiac amyloidosis).	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TAVI/SAVR efficacy	Echocardiographic mean and maximal aortic gradient (mmHg) will be assessed.	At time of post-procedural echocardiographic assessment (through study completion, an average of 1 month)
TAVI/SAVR efficacy	Echocardiographic effective orifice valvular area (EROA) will be assessed and reported in cm2.	At time of post-procedural echocardiographic assessment (through study completion, an average of 1 month)
Procedural Complications	Procedural complications will be assessed as per VARC definitions	At an average of 12 months
In-hospital Mortality	In-hospital Mortality will be assessed from hospital records	At an average of 12 months
All-cause Mortality and Heart Failure Hospitalization	The composite of all-cause Mortality and Heart Failure Hospitalization will be assessed through clinical follow-up, hospital records, and telephone follow-up.	At an average of 12 months

Collaborators and Investigators

• Sponsor: University Hospital of Ferrara
• Investigators: Principal Investigator: Matteo Serenelli, Doctor, Azienda Ospedaliero Universitaria di Ferrara

Publications and helpful links

General Publications

• Hussan et al. Aortic Valve Calcium Score Cut-Offs Used To Identify Hemodynamically Severe Aortic Stenosis May Not Apply In Patients With Cardiac Amyloidosis. ACC.20 World Congress of Cardiology (https://www.jacc.org/doi/abs/10.1016/S0735-1097%2820%2932791-1)
• Hussain M, Hanna M, Griffin BP, Conic J, Patel J, Fava AM, Watson C, Phelan DM, Jellis C, Grimm RA, Rodriguez LL, Schoenhagen P, Hachamovitch R, Jaber WA, Cremer PC, Collier P. Aortic Valve Calcium in Patients With Transthyretin Cardiac Amyloidosis: A Propensity-Matched Analysis. Circ Cardiovasc Imaging. 2020 Oct;13(10):e011433. doi: 10.1161/CIRCIMAGING.120.011433. Epub 2020 Sep 23. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: September 15, 2023
• First Submitted That Met QC Criteria: September 27, 2023
• First Posted (Actual): October 4, 2023

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Amyloidosis; Aortic stenosis; Calcium Score; Low-flow low-gradient
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Proteostasis Deficiencies; Aortic Valve Stenosis; Amyloidosis; Constriction, Pathologic
• Other Study ID Numbers: 72/2022/Oss/AOUFe

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The data will be available from the principal investigator on reasonable request.

Drug and device information, study documents

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