Prevalence and Prognostic Significance of Restriction Versus Systolic Dysfunction in Patients With Transthyretin and Light Chain Cardiac Amyloidosis

Patient Information

Cardiac amyloidosis (CA) is traditionally viewed as a prototype of heart failure with restrictive ventricular physiology and preserved systolic function. However, the real-world prevalence of different left ventricular (LV) phenotypes and their clinical impact have remained under-explored. This study analyzed a large cohort of 820 patients diagnosed with CA, consisting of 540 patients with transthyretin cardiac amyloidosis (TTR-CA) and 280 patients with light chain cardiac amyloidosis (AL-CA).

Patients were assessed at the time of diagnosis and categorized into three distinct LV phenotypes based on echocardiographic and clinical parameters. The cohort represented a real-world clinical population presenting with symptoms ranging from mild exertional dyspnea to advanced heart failure.

Diagnosis

The diagnosis of cardiac amyloidosis was established using standard clinical guidelines, including tissue biopsy, scintigraphy (for TTR-CA), and assessment of free light chains (for AL-CA). Patients were further stratified into three LV phenotypes:

• Preserved LV Function: Defined as an LV ejection fraction (LVEF) >40% associated with grade I diastolic dysfunction.
• Restriction: Defined as an LVEF >40% associated with grade II or III diastolic dysfunction (restrictive filling patterns).
• Systolic Dysfunction: Defined as an LVEF ≤40%, regardless of the grade of diastolic dysfunction.

Results showed that at the time of diagnosis, restriction was the most common phenotype in both groups. In TTR-CA, 32.0% had preserved function, 56.1% showed restriction, and 11.9% presented with systolic dysfunction. Similarly, in AL-CA, 32.9% had preserved function, 58.6% showed restriction, and 8.5% presented with systolic dysfunction.

Differential Diagnosis

When evaluating patients for cardiac amyloidosis, several other conditions must be considered and ruled out, including:

• Hypertrophic Cardiomyopathy (HCM): Often confused with CA due to wall thickening; however, CA typically presents with lower ECG voltage and specific scintigraphy patterns.
• Hypertensive Heart Disease: May cause significant LV hypertrophy but lacks the multisystem involvement often seen in AL-CA.
• Storage Diseases (e.g., Fabry Disease): These can mimic the infiltrative nature of CA but are identified through genetic testing and specific enzyme assays.
• Aortic Stenosis: Severe stenosis can lead to secondary hypertrophy; however, co-occurrence with TTR-CA is increasingly recognized in elderly populations.

Treatment and Management

While the study focused on phenotypic prevalence and progression, standard management for these patients involved a multi-disciplinary approach. For AL-CA, treatment focused on hematologic response using chemotherapy regimens (e.g., daratumumab, cyclophosphamide, bortezomib, and dexamethasone). For TTR-CA, management included TTR stabilizers such as Tafamidis, or in hereditary cases, TTR silencers.

Supportive care focused on volume management. Diuretics (loop diuretics and mineralocorticoid receptor antagonists) were utilized to maintain euvolemia, though clinicians remained cautious of the narrow therapeutic window in restrictive phenotypes where cardiac output is highly dependent on heart rate and preload.

Outcome and Prognosis

The study evaluated survival free from a composite end point of all-cause mortality and heart transplantation over a 3-year period. The outcomes varied significantly by phenotype at diagnosis:

• TTR-CA: 3-year event-free survival was 75% for preserved function, 61% for restriction, and 44% for systolic dysfunction.
• AL-CA: 3-year event-free survival was 46% for preserved function, 32% for restriction, and 21% for systolic dysfunction.

Notably, progression from preserved LV function toward restriction was common (16.3% in TTR-CA and 12.9% in AL-CA), whereas progression to systolic dysfunction was rare. Although preserved function predicted better survival, these phenotypes were not independent predictors of the composite end point when adjusted for other clinical variables.

Discussion

This comprehensive analysis challenges some traditional views of cardiac amyloidosis. While the ‘typical’ patient is often described as having preserved LVEF, this study confirms that a majority of patients (over 50%) already exhibit restrictive physiology at the time of diagnosis. This suggests that the window for ‘preserved’ function is relatively short and that the disease is often detected late in its physiological progression.

The high rate of conversion from preserved function to restriction emphasizes the importance of frequent monitoring and early intervention. The rarity of progression to systolic dysfunction suggests that the primary driver of heart failure in CA remains diastolic impairment and infiltrative restriction rather than a primary loss of contractility, even though systolic markers (like global longitudinal strain) may decline early.

Ultimately, while phenotype provides a snapshot of the patient’s hemodynamic state and prognostic risk, the underlying etiology (AL vs. TTR) and the severity of systemic involvement remain the primary drivers of long-term mortality.

References

1. Zampieri M, Biagioni G, Del Franco A, et al. Prevalence and Prognostic Significance of Restriction Versus Systolic Dysfunction in Patients With Transthyretin and Light Chain Cardiac Amyloidosis. Circulation. Heart failure. 2026;e012337. PMID: 41732853.
2. Gertz MA, Dispenzieri A. Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review. JAMA. 2020.
3. Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021.