Highlights
At the time of diagnosis, approximately one-third of patients with cardiac amyloidosis (CA) present with preserved left ventricular function, challenging the traditional view that the disease is synonymous with restrictive physiology.
Restrictive ventricular physiology remains the most prevalent phenotype (approximately 56-59%), while systolic dysfunction (LVEF ≤40%) is relatively uncommon at presentation, occurring in only 8-12% of cases.
Patients with transthyretin cardiac amyloidosis (TTR-CA) show a higher rate of progression from preserved function to restriction compared to those with light chain cardiac amyloidosis (AL-CA), though progression to overt systolic dysfunction is rare in both groups.
While preserved LV function is associated with better event-free survival, these specific echocardiographic phenotypes are not independent predictors of mortality when adjusted for other clinical variables.
The Evolving Landscape of Cardiac Amyloidosis
For decades, cardiac amyloidosis (CA) has been clinically characterized as the quintessential restrictive cardiomyopathy. The textbook description typically involves a small, stiff left ventricle (LV) with thickened walls, impaired diastolic filling, and a paradoxically preserved ejection fraction (LVEF) until the terminal stages of the disease. However, as diagnostic techniques—particularly technetium-labeled bone scintigraphy and advanced cardiac MRI—have become more widely utilized, clinicians are identifying CA earlier in its natural history and in a more heterogeneous population.
The traditional tenet of CA as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has recently come under scrutiny. Understanding the true prevalence of different LV phenotypes and how they evolve is critical for risk stratification and the timing of therapeutic interventions, especially with the emergence of highly effective TTR-stabilizing agents and modern plasma cell-directed therapies.
Study Design and Phenotypic Classification
In a comprehensive retrospective analysis recently published in Circ Heart Fail, researchers evaluated a large real-world cohort of 820 patients diagnosed with CA (540 with TTR-CA and 280 with AL-CA). The study aimed to map the prevalence and clinical significance of systolic dysfunction versus restrictive physiology at the time of diagnosis and track their progression over time.
To provide a clear clinical framework, the researchers divided the patients into three distinct LV phenotypes based on echocardiographic findings:
1. Preserved LV Function
Defined as an LVEF >40% associated with mild (Grade I) diastolic dysfunction. This represents an earlier or less aggressive stage of myocardial infiltration.
2. Restriction
Defined as an LVEF >40% but associated with more advanced (Grade II or III) diastolic dysfunction. This aligns with the classic restrictive cardiomyopathy model.
3. Systolic Dysfunction
Defined as an LVEF ≤40%, regardless of the degree of diastolic impairment.
The primary endpoint of the study was a composite of all-cause mortality and heart transplantation. The median follow-up period allowed researchers to observe not just survival, but the transition of patients from the “preserved” state into more advanced phenotypic categories.
Key Findings: Prevalence at Diagnosis
The study revealed a remarkably consistent distribution of phenotypes across both the TTR and AL subtypes of the disease. Despite the different pathophysiologies—where AL-CA is driven by the proteotoxicity of light chains and TTR-CA by the gradual infiltration of misfolded transthyretin—the structural impact on the heart followed a similar pattern.
In the TTR-CA cohort, 32.0% of patients presented with preserved LV function, 56.1% with restriction, and 11.9% with systolic dysfunction. In the AL-CA cohort, the numbers were nearly identical: 32.9% with preserved function, 58.6% with restriction, and 8.5% with systolic dysfunction. These findings confirm that while restriction is indeed the most common presentation, nearly one out of every three patients is being diagnosed at a stage where diastolic function is only mildly impaired and LVEF remains robust.
Phenotypic Progression and Longitudinal Stability
One of the most valuable aspects of this research is the longitudinal data regarding how these phenotypes evolve. Among patients who started with preserved LV function, the rate of conversion to a restrictive phenotype was notable. In TTR-CA, 16.3% of those with preserved function progressed to restriction by their last evaluation. In AL-CA, this conversion rate was slightly lower at 12.9%.
Interestingly, progression to overt systolic dysfunction (LVEF ≤40%) was rare. Only 1.8% of TTR-CA patients with initially preserved function moved into the systolic dysfunction category, and notably, no patients in the AL-CA “preserved” group made this transition during the study period. This suggests that for many patients, the disease pathway primarily involves a progressive stiffening of the myocardium rather than a loss of contractility, at least as measured by LVEF.
Prognostic Significance and Survival Outcomes
The survival data highlighted the high stakes of a CA diagnosis, particularly for those with AL-CA. The 3-year freedom from the composite end point (death or transplant) showed a clear gradient based on phenotype:
TTR-CA Survival:
Preserved LV function: 75%
Restriction: 61%
Systolic dysfunction: 44%
AL-CA Survival:
Preserved LV function: 46%
Restriction: 32%
Systolic dysfunction: 21%
While these numbers show that patients with preserved function fare better than those with restriction or systolic dysfunction, the study reached a critical statistical conclusion: these phenotypes were not independent predictors of the composite end point. This indicates that while the echocardiographic phenotype is a useful marker of disease severity, it likely reflects underlying factors such as the total amyloid burden, duration of disease, and biomarkers (like NT-proBNP and Troponin) which are more direct drivers of mortality.
Expert Commentary: Clinical Implications
This study provides a necessary “reality check” for the clinical community. The finding that one-third of patients have preserved LV function at diagnosis is a testament to improved awareness and earlier detection. However, it also serves as a warning: clinicians cannot rule out cardiac amyloidosis simply because a patient does not exhibit classic restrictive physiology on an echocardiogram.
The lack of independent prognostic value for the LV phenotypes suggests that we should not rely solely on LVEF or diastolic grading to determine a patient’s risk. Instead, a multi-parametric approach—incorporating strain imaging, cardiac biomarkers, and extracardiac involvement—remains the gold standard for staging. Furthermore, the high rate of progression to restriction in TTR-CA underscores the importance of early initiation of TTR-stabilizing therapies to potentially halt this transition.
One limitation of the study is its retrospective nature, which may introduce selection bias. Additionally, the cohort was assessed at the time of diagnosis; as screening programs for populations with HFpEF or aortic stenosis expand, we may see an even higher prevalence of the “preserved” phenotype in the future.
Conclusion
Cardiac amyloidosis is a dynamic disease that spans a spectrum of mechanical and physiological states. While the restrictive phenotype is the most frequent manifestation, a significant portion of patients present with preserved ventricular function. Understanding that these patients are at high risk for progression to restriction—but less likely to develop primary systolic failure—allows for more tailored counseling and monitoring. Ultimately, while LV phenotypes provide a snapshot of the heart’s structural state, they must be integrated into a broader clinical context to accurately predict outcomes and guide therapy in this complex patient population.
References
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. Circ Heart Fail. 2026 Feb 24:e012337. doi: 10.1161/CIRCHEARTFAILURE.125.012337. Epub ahead of print. PMID: 41732853.
