Introduction: Challenging the Ejection Fraction Paradigm
For decades, cardiac amyloidosis (CA) was taught as the quintessential model of restrictive cardiomyopathy—a disease characterized by rigid ventricles, impaired filling, and a paradoxically preserved left ventricular ejection fraction (LVEF). However, as our diagnostic capabilities have evolved from post-mortem findings to sophisticated imaging and biochemical screening, this monolithic view has been challenged. Clinicians frequently encounter CA patients with varying degrees of systolic impairment or, conversely, those who maintain near-normal diastolic function in the early stages of the disease.
A recent landmark study by Zampieri et al., published in Circulation: Heart Failure, provides a rigorous re-evaluation of these phenotypes. By analyzing a massive real-world cohort of patients with both Transthyretin (TTR-CA) and Light Chain (AL-CA) amyloidosis, the researchers have clarified the prevalence of these states and, more importantly, their prognostic trajectories. Their findings suggest that while restriction is indeed the most common presentation, the transition between states is a dynamic process that clinicians must navigate with precision.
Highlights
Predominance of Restriction
Restrictive physiology (LVEF >40% with Grade II/III diastolic dysfunction) is the most frequent presentation at diagnosis, occurring in approximately 56% of TTR-CA and 59% of AL-CA cases.
Preserved Function as a Window of Opportunity
Roughly one-third of patients present with preserved LV function. However, this state is often transient, particularly in TTR-CA, where more than 16% of patients progress to restrictive physiology within the follow-up period.
Prognostic Hierarchy
Survival is highest in patients with preserved LV function and lowest in those with systolic dysfunction (LVEF ≤40%). However, these phenotypes may not be independent predictors of mortality when adjusted for other clinical variables, suggesting they serve as markers of disease burden.
Disease Burden and the Clinical Challenge
Cardiac amyloidosis represents an increasingly recognized cause of heart failure with preserved ejection fraction (HFpEF). The disease is driven by the extracellular deposition of misfolded proteins—either monoclonal light chains in AL-CA or transthyretin in TTR-CA—within the myocardial interstitium. This deposition leads to progressive wall thickening, increased myocardial stiffness, and eventual microvascular ischemia.
The clinical challenge lies in the fact that LVEF often remains within the ‘normal’ range until the very late stages of the disease. Relying solely on LVEF can lead to a false sense of security, masking the severe diastolic impairment and reduced stroke volume that characterize the restrictive phenotype. Understanding the distribution of these phenotypes at the time of diagnosis is critical for risk stratification and the initiation of disease-modifying therapies.
Study Design and Phenotypic Definitions
The study retrospectively analyzed 540 patients with TTR-CA and 280 patients with AL-CA. To ensure clinical relevance, the cohort was divided into three distinct LV phenotypes based on echocardiographic parameters at the time of diagnosis:
1. Preserved LV Function
Defined as an LVEF >40% associated with Grade I (mild) diastolic dysfunction. This represents the earliest detectable stage of cardiac involvement.
2. Restrictive Phenotype
Defined as an LVEF >40% associated with Grade II or III (moderate to severe) diastolic dysfunction. This is the classic presentation of amyloid heart disease.
3. Systolic Dysfunction
Defined as an LVEF ≤40%, regardless of the degree of diastolic impairment. This represents advanced myocardial infiltration and damage.
The primary endpoint was a composite of all-cause mortality and heart transplantation. The researchers also tracked the ‘phenotypic drift’—how patients moved from preserved function to more advanced stages over time.
Key Findings: The Landscape of CA at Diagnosis
The results confirm that cardiac amyloidosis is rarely a ‘mild’ disease at the time of clinical presentation. In the TTR-CA cohort, only 32.0% of patients had preserved LV function, while 56.1% already exhibited restrictive physiology. Systolic dysfunction was present in 11.9% of cases.
The distribution in the AL-CA cohort was remarkably similar, despite the different underlying biology of the disease. Preserved LV function was seen in 32.9%, restriction in 58.6%, and systolic dysfunction in 8.5%. This similarity suggests that the mechanical impact of amyloid infiltration on the myocardium follows a common physiological pathway, regardless of whether the protein is transthyretin or light chains.
Phenotypic Progression
One of the study’s most illuminating findings concerns the stability of these phenotypes. Among patients who initially presented with preserved LV function, the conversion rate to the restrictive phenotype was significant: 16.3% in TTR-CA and 12.9% in AL-CA. Interestingly, the progression to overt systolic dysfunction (LVEF ≤40%) was rare in those who started with preserved function (1.8% in TTR and 0% in AL), suggesting that the decline in LVEF is a late-stage event that usually follows a period of restrictive physiology.
Survival Outcomes and Prognostic Significance
As expected, the phenotypic classification correlated strongly with survival. The 3-year freedom from the composite endpoint (mortality/transplant) showed a clear gradient:
In TTR-CA:
Preserved: 75%
Restriction: 61%
Systolic Dysfunction: 44%
In AL-CA:
Preserved: 46%
Restriction: 32%
Systolic Dysfunction: 21%
The markedly lower survival rates in AL-CA across all phenotypes highlight the added burden of light-chain proteotoxicity, which causes direct cardiomyocyte damage independent of the physical infiltration. However, the study’s multivariate analysis revealed a crucial nuance: while these phenotypes are associated with different outcomes, they were not independent predictors of the composite endpoint. This suggests that the phenotypic category is a surrogate for the total volume of amyloid deposition and the duration of the disease process rather than an independent biological driver of risk.
Expert Commentary: Mechanistic Insights
The transition from preserved function to restriction is the hallmark of amyloid progression. Mechanistically, this represents the point where the expansion of the extracellular matrix overcomes the compensatory mechanisms of the myocardium. In the restrictive stage, the left atrium becomes the primary driver of ventricular filling, and the loss of atrial kick (often due to concomitant atrial fibrillation) can lead to rapid clinical decompensation.
The relative rarity of the systolic dysfunction phenotype (under 12% in both groups) is also noteworthy. It suggests that most CA patients succumb to complications of low cardiac output or arrhythmias while their LVEF is still technically ‘mid-range’ or ‘preserved.’ This reinforces the argument that LVEF is a poor marker of myocardial health in infiltrative diseases. Global Longitudinal Strain (GLS) and stroke volume index are likely more sensitive measures of the actual contractile work being performed by the heart.
Clinical Implications and Future Directions
The high rate of progression from preserved to restrictive states underscores the need for aggressive early intervention. For TTR-CA, the availability of TTR stabilizers like tafamidis has changed the therapeutic landscape. This study suggests that identifying patients in the ‘Preserved’ stage—before the onset of restrictive filling—may be the key to maximizing the benefits of these expensive therapies.
Furthermore, the data suggest that clinicians should not wait for a drop in LVEF to escalate care or consider advanced heart failure therapies. A patient with an LVEF of 45% and Grade III diastolic dysfunction is at significantly higher risk than a patient with an LVEF of 45% and Grade I dysfunction, despite having the same ‘preserved’ ejection fraction status.
Summary and Conclusion
The study by Zampieri et al. provides a definitive look at the phenotypic architecture of cardiac amyloidosis. It confirms that restrictive physiology is the dominant clinical state and that ‘preserved’ function is a precarious and often temporary phase. While the specific phenotype is a powerful marker of a patient’s current risk, it is ultimately the underlying amyloid burden and the specific protein type (AL vs. TTR) that dictate the long-term prognosis. For the modern cardiologist, these findings serve as a reminder: look past the ejection fraction and focus on the physiology of the rigid heart.
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. Circ Heart Fail. 2026;e012337. doi:10.1161/CIRCHEARTFAILURE.125.012337.
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.
3. Garcia-Pavia P, Rapezzi C, Adler Y, 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;42(16):1554-1568.
