Tesi etd-03252026-003022
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Tipo di tesi
Dottorato
Autore
CASTIGLIONE, VINCENZO
URN
etd-03252026-003022
Titolo
Role of Biomarkers for Pathophysiological Characterization, Diagnosis, and Outcome Prediction in Cardiac Amyloidosis
Settore scientifico disciplinare
MED/11
Corso di studi
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
Relatori
relatore Prof. EMDIN, MICHELE
Parole chiave
- amiloidosi cardiaca
- biomarcatori
- peptide natriuretico
- transtiretina
- troponina
Data inizio appello
26/05/2026;
Disponibilità
parziale
Riassunto analitico
Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by the extracellular deposition of misfolded proteins within the myocardium, leading to progressive structural remodelling, heart failure, and adverse prognosis. Although historically considered a rare disease, CA is now increasingly recognized and diagnosed, owing to greater awareness, improved non-invasive imaging strategies, and the availability of disease-modifying therapies. Nonetheless, important unmet needs remain in early detection, diagnostic refinement, prognostic stratification, and in the understanding of the mechanisms underlying heart failure in this setting. Against this background, circulating biomarkers may offer an integrated clinical and pathophysiological perspective on the disease.
This PhD thesis investigates the role of biomarkers in CA across the whole disease continuum, from characterization of heart failure pathophysiology to population-based screening, diagnostic work-up, and prognostic assessment. The present work integrates different original studies conducted in patients with both light chain (AL) and transthyretin (ATTR) amyloidosis, with a predominant focus on ATTR-CA.
A first line of investigation addressed the feasibility of a community-based screening strategy for ATTR-CA. In the CATCH study, a 2-step screening program was applied in elderly subjects from the general population, integrating clinical red flags, including circulating biomarkers, with confirmatory imaging based on bone scintigraphy and monoclonal protein assessment. Four individuals fulfilled criteria for a non-invasive diagnosis of wild-type ATTR-CA, corresponding to an estimated prevalence of 0.46% among subjects aged 65 to 90 years. These findings indicate that ATTR-CA is not rare in elderly individuals and support the feasibility of structured screening strategies for earlier disease recognition.
A second line of work focused on the diagnostic role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) in patients with suspected CA. These biomarkers showed a robust diagnostic value and enabled clinically meaningful rule-out and rule-in strategies. In particular, NT-proBNP <180 ng/L and hs-TnT <14 ng/L identified effective rule-out thresholds, while hs-TnT ≥86 ng/L emerged as the optimal rule-in cut-off. These findings support the integration of cardiac biomarkers into current diagnostic flowchart for CA, improving selection of patients for advanced imaging or invasive evaluation.
The thesis also explored the prognostic role of circulating transthyretin (TTR) as a disease-specific biomarker in patients with ATTR-CA treated with tafamidis. Baseline TTR levels and early changes at 30 days after tafamidis initiation were both associated with clinical outcomes. Lower baseline TTR and a blunted early increase at 30 days identified patients at higher risk of adverse events, including all-cause mortality and heart failure hospitalization, whereas higher baseline levels and a greater early increase were associated with a more favourable prognosis. The relevant thresholds for clinical stratification were 18 mg/dL for baseline TTR and 7.5 mg/dL for 30-day TTR change. Complementary analyses on the biological variability of TTR in patients with ATTR-CA provided a framework for interpreting longitudinal changes in clinical practice.
Finally, the thesis addressed the pathophysiology of heart failure in CA through the study of neurohormonal activation and transcardiac biomarker gradients. Compared with matched patients with non-amyloid heart failure, patients with CA exhibited a distinct neurohormonal profile, supporting the concept that heart failure in amyloidosis is characterized not only by infiltrative and restrictive abnormalities, but also by relevant neurohormonal activation. In parallel, direct transcardiac measurements demonstrated net myocardial release of natriuretic peptides, cardiac troponins, and norepinephrine, providing in vivo evidence of ongoing myocardial stress, injury, and sympathetic activation. Altogether, these findings contribute to defining the pathophysiological basis of heart failure in CA and may also provide the rationale for neurohormonal antagonist strategies in these patients.
In conclusion, this thesis demonstrates the clinical and pathophysiological relevance of circulating biomarkers in CA across the entire disease continuum. Future integration of biomarker-based strategies into clinical pathways may support earlier disease recognition, improved risk stratification, and therapeutic monitoring.
This PhD thesis investigates the role of biomarkers in CA across the whole disease continuum, from characterization of heart failure pathophysiology to population-based screening, diagnostic work-up, and prognostic assessment. The present work integrates different original studies conducted in patients with both light chain (AL) and transthyretin (ATTR) amyloidosis, with a predominant focus on ATTR-CA.
A first line of investigation addressed the feasibility of a community-based screening strategy for ATTR-CA. In the CATCH study, a 2-step screening program was applied in elderly subjects from the general population, integrating clinical red flags, including circulating biomarkers, with confirmatory imaging based on bone scintigraphy and monoclonal protein assessment. Four individuals fulfilled criteria for a non-invasive diagnosis of wild-type ATTR-CA, corresponding to an estimated prevalence of 0.46% among subjects aged 65 to 90 years. These findings indicate that ATTR-CA is not rare in elderly individuals and support the feasibility of structured screening strategies for earlier disease recognition.
A second line of work focused on the diagnostic role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) in patients with suspected CA. These biomarkers showed a robust diagnostic value and enabled clinically meaningful rule-out and rule-in strategies. In particular, NT-proBNP <180 ng/L and hs-TnT <14 ng/L identified effective rule-out thresholds, while hs-TnT ≥86 ng/L emerged as the optimal rule-in cut-off. These findings support the integration of cardiac biomarkers into current diagnostic flowchart for CA, improving selection of patients for advanced imaging or invasive evaluation.
The thesis also explored the prognostic role of circulating transthyretin (TTR) as a disease-specific biomarker in patients with ATTR-CA treated with tafamidis. Baseline TTR levels and early changes at 30 days after tafamidis initiation were both associated with clinical outcomes. Lower baseline TTR and a blunted early increase at 30 days identified patients at higher risk of adverse events, including all-cause mortality and heart failure hospitalization, whereas higher baseline levels and a greater early increase were associated with a more favourable prognosis. The relevant thresholds for clinical stratification were 18 mg/dL for baseline TTR and 7.5 mg/dL for 30-day TTR change. Complementary analyses on the biological variability of TTR in patients with ATTR-CA provided a framework for interpreting longitudinal changes in clinical practice.
Finally, the thesis addressed the pathophysiology of heart failure in CA through the study of neurohormonal activation and transcardiac biomarker gradients. Compared with matched patients with non-amyloid heart failure, patients with CA exhibited a distinct neurohormonal profile, supporting the concept that heart failure in amyloidosis is characterized not only by infiltrative and restrictive abnormalities, but also by relevant neurohormonal activation. In parallel, direct transcardiac measurements demonstrated net myocardial release of natriuretic peptides, cardiac troponins, and norepinephrine, providing in vivo evidence of ongoing myocardial stress, injury, and sympathetic activation. Altogether, these findings contribute to defining the pathophysiological basis of heart failure in CA and may also provide the rationale for neurohormonal antagonist strategies in these patients.
In conclusion, this thesis demonstrates the clinical and pathophysiological relevance of circulating biomarkers in CA across the entire disease continuum. Future integration of biomarker-based strategies into clinical pathways may support earlier disease recognition, improved risk stratification, and therapeutic monitoring.
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