Amyloidosis – ABC CARDIOL

IJCS

Editorial

Cardiac Amyloidosis TTR: The Hidden Culprit Behind Aortic Stenosis in the Elderly

Sandrigo Mangini et al. Lígia Lopes Balsalobre Trevizan

Calcific aortic stenosis (AS), a condition marked by leaflet fibrosis and calcification, is driven by mechanical stress and biological stimuli that activate pro-inflammatory pathways. It results from a complex, progressive process that occurs over many years, and becomes increasingly prevalent with age. Aging itself is associated with a “low-grade inflammatory state”, which promotes and sustains various pathological conditions, including cardiac amyloidosis (CA)^, that is mostly related to wild-type transthyretin (TTR) and less commonly to variant TTR and light chain amyloidosis (AL). CA is phenotypically associated with heart failure with preserved ejection fraction (HFPEF), and wild type TTR is estimated to be prevalent in approximately 13% of elderly over 60. However, different from calcific AS that has a similar gender distribution, the wild-type TTR is more prevalent in men.

In a study with elderly patients, Conte et al. reported amyloid deposition in 37% of stenotic aortic valves, 10% of sclerotic valves, and no findings of amyloid in controls. Amyloid deposition was linked to greater fibrosis and calcification. Imunohistochemistry suggested involvement of serum amyloid A1 (SAA1) and TTR. These findings indicate that amyloid deposition in aortic valves may be more common and is related to aging and degenerative changes.

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Original Article

Prevalence of Cardiac Amyloidosis in Elderly Patients With Aortic Stenosis

Ng Kin Key et al. Adelina Sanches de Melo Joberto Pinheiro Sena Adriano Dias Dourado … Julia Micheli Perez Jose Carlos Raimundo Brito Gilson Feitosa Gilson Soares Feitosa-Filho

Abstract

Background:

Aortic Stenosis (AS) is one of the most common valvular heart diseases in adults, especially the elderly. The persistence of heart failure symptoms and worse outcomes despite valve replacement treatment may be associated with the coexistence of Cardiac Amyloidosis (CA).

Objective:

To determine the prevalence of CA in patients with calcific AS.

Methods:

This was a cross-sectional study. Elderly patients with moderate to severe AS underwent cardiac scintigraphy with bone radiotracer for diagnosis of CA. Patients diagnosed with Transthyretin (TTR) amyloidosis by scintigraphy underwent genetic studies. Groups with altered and unaltered scintigraphy results for continuous variables were compared using an independent t-test for normally distributed variables and a Mann-Whitney test for those with asymmetric distribution. Statistical significance was set at p-value < 0.05

Results:

Forty-one patients with AS underwent pyrophosphate scintigraphy. The mean age of the cases was 79 ± 6 years, 23 (56%) were female, 23 (56%) had classic severe AS pattern, and 8 (19.5%) had low-flow low-gradient AS with reduced Ejection Fraction (EF). Carpal tunnel syndrome was present in 2 (4%) patients, 8 (19%) had polyneuropathy. A RAISE score ≥ 2 was found in 4 patients (9%). Four patients were diagnosed with TTR amyloidosis, one of whom had a Val122I genetic mutation. Three (75%) of the patients diagnosed with AE/AI were male. There were no statistically significant differences between the isolated AS and AS/CA groups.

Conclusion:

The prevalence of CA in patients with moderate to severe AS of probable calcified etiology in our sample was 10%.

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Review Article

Evolving Therapies for Transthyretin Cardiac Amyloidosis: New Clinical Trials with Amyloid Fibrils Depleter

Marcus Vinícius Simões et al. Fábio Fernandes André Dabarian Flavio Henrique Valicelli Claudio Tinoco Mesquita

Abstract

Amyloidosis is caused by the extracellular deposition of insoluble protein arrangements, formed from structural changes in different precursor proteins. The prominent clinical and epidemiological relevance of transthyretin amyloid cardiomyopathy (ATTR-CM), whose increased incidence is associated with the aging of the global population, given its high prevalence in the elderly population, has motivated the intensification of the search for specific therapeutic targets capable of altering the natural course of the disease. The past few years have been especially prolific with the emergence of significant new therapies for ATTR-CM, with important trials demonstrating positive results and changing the natural history of an inexorable and deadly disease. Up to now, the available drugs mainly promote stabilization of disease progression in patients with no advanced heart disease but grant no reversal of the structural cardiac disease in most cases. The transthyretin (TTR)-depleters based on monoclonal antibodies directed against the deposited amyloid fibers hold promise to fulfill these expectations. The DepleTTR-CM will test the safety and efficacy of a monoclonal antibody directed against TTR fibrils deposited in the myocardium of patients with ATTR-CM. This will be the first multicenter randomized controlled trial to test this new class of anti-amyloid treatment, the “amyloid fibril depleters”. This is a strategy designed to revert the amyloid accumulation in the cardiac interstitium, which is expected to translate into relevant clinical benefits, with the potential to close a gap in the ATTR-CM treatment strategies, mainly in patients with more severe disease.

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Original Article

Prognostic Value of the 6-Minute Walk Test and Clinical Characteristics of Patients With Transthyretin Amyloid Cardiomyopathy

Cristhian Espinoza Romero et al. Natalia Melo Pereira Georgina Del Cisne Jadán Luzuriaga Bruno Vaz Kerges Bueno … Suenia Carvalhal Thais Borges Barbara Reis Fábio Fernandes

Abstract

Background:

In transthyretin amyloid cardiomyopathy (ATTR-CM), the assessment of functional capacity is of great importance. A distance < 300m covered in the 6-minute walk test (6MWT) is linked to a poorer prognosis in heart failure (HF) patients. However, in ATTR-CM, this association is not well-established, particularly among its various presentations and variants.

Objectives:

To evaluate functional capacity and, the prognostic value of the 6MWT in patients with ATTR-CM and to identify their clinical characteristics according to the type of ATTR-CM.

Methods:

This was a retrospective, single-center study that included patients with a confirmed diagnosis of ATTR-CM who performed the 6MWT. Median follow-up was 19 months (8 – 29). The significance level was set at P < 0.05.

Results:

A total of 32 patients were analyzed; 59.4% had the hereditary form (ATTRh), of which 63.2% were Val142Ile. Mean left ventricular ejection fraction (LVEF) was lower in the ATTRh group when compared to the wild-type form (ATTRwt) [42 ±11 versus 52± 9 %; p = 0.029]. Median distance walked in the 6MWT was 328 m (269 – 397; IQR) in ATTRwt and 304 m (246 – 387; IQR) in ATTRh, with no difference between groups (p = 0.833). In patients with a distance <300 m in the 6MWT, survival was lower (28.8 vs 36.3 months; p = 0.041).

Conclusions:

A distance <300 m walked in the 6MWT was linked to shorter event-free survival in patients with ATTR-CM. Functional capacity of most patients was very low, and no differences were observed in the distance covered between the wild-type form and the hereditary form of ATTR.

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Review Article

Cardiac Amyloidosis in Women: An Underappreciated Diagnosis

Larissa Neto Espíndola et al. Gláucia Maria Moraes de Oliveira Cláudia Maria Vilas Freire Marildes Luiza de Castro Maria Cristina Costa de Almeida

Abstract

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy that affects the heart mostly in two forms: immunoglobulin light chain amyloidosis (AL-CM) and transthyretin amyloidosis.

Transthyretin amyloid cardiomyopathy (ATTR-CM) predominantly affects the elderly population, mainly men (about 70-80%), and usually manifests with symptoms of heart failure (HF).

Despite technological advances in medicine, CA is still an underdiagnosed condition, especially in women, partly due to the known male predominance and high level of suspicion required for diagnosis. It is important to remember that amyloidosis is a systemic disease with a heterogeneous and non-specific presentation. It’s worth paying attention to the patient’s medical history and red flags in clinical and diagnostic tests (electrocardiogram [ECG], echocardiogram [ECHO], cardiac magnetic resonance [CMR]).

Accurate and timely diagnosis is crucial for appropriate management and prognosis.

So far, the under-representation of women in clinical trials may have also limited the evidence on sex-specific diagnosis, and outcomes.

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Review Article

Pyrophosphate Scintigraphy: Use in the Diagnosis and Monitoring of Cardiac Amyloidosis

Claudio Tinoco Mesquita et al. Davi Shunji Yahiro José Felipe Ramos dos Santos Luís Eduardo Machado … Jose Gregorio Valero Rodriguez Giovane Leal de Azevedo Junior Marcus Simões

Abstract

Cardiac amyloidosis (CA) is a progressive condition marked by the accumulation of amyloid fibrils in cardiac tissue, resulting in cardiac dysfunction and, ultimately, heart failure. Pyrophosphate scintigraphy has emerged as a promising tool for the early detection and monitoring of CA, providing valuable insights into the disease’s extent and severity. This review examines the current use of pyrophosphate scintigraphy in distinguishing between different types of amyloidosis, assessing risk levels, and monitoring patients with CA. It underscores the clinical significance and prospects of this imaging technique.

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Viewpoint

Heart Rate Control or Rhythm Control in Patients With Atrial Fibrillation and Cardiac Amyloidosis

Lígia Lopes Balsalobre Trevizan et al. Sandrigo Mangini

Introduction

Cardiac amyloidosis (CA) manifests as a gradually progressive infiltrative condition characterized by the accumulation of insoluble protein aggregates within the myocardium and cardiac conduction system. The majority of CA cases are associated with precursor proteins, particularly immunoglobulin light chains (AL-CA) and transthyretin (ATTR-CA), which represent over 95% of cases. ATTR precursor substances may originate from a broad spectrum, encompassing both wild-type (ATTRwt) and variant (ATTRv) genes.

Arrhythmias in CA result from a combination of factors. The deposition of amyloid fibrils and infiltration into the myocardium cause thickening of the atrial and ventricular walls, leading to compromised relaxation. Consequently, this cascade results in increased filling pressures and atrial dilation, making individuals more susceptible to atrial fibrillation (AF) and other atrial arrhythmias. While left atrial (LA) enlargement has historically been linked with AF, new-onset AF can occur even without LA enlargement, suggesting a complex pathophysiology of AF in CA, where various processes affect LA structure, function, and mechanics in different ways, thereby heightening the AF risk. The usual manifestation of LA remodeling involves substantial infiltration of the atrial walls, leading to gradual impairment of atrial function and heightened stiffness, often observed without significant LA dilation.

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Review Article

A Critical Review of Echocardiographic Findings for Diagnosing Cardiac Amyloidosis

Silvio Henrique Barberato et al. Adenalva Lima de Souza Beck Viviane Tiemi Hotta Daniela do Carmo Rassi

Abstract

This article provides a critical review of the diagnostic value of several echocardiographic findings in cardiac amyloidosis (CA). The importance of early and accurate detection of CA is emphasized, considering its challenging diagnosis and the need for a high index of suspicion by clinicians. Echocardiography is often the first choice for imaging assessment of cardiac structure and function when CA is suspected. The article encompasses several conventional echocardiographic features and speckle-tracking echocardiography-derived deformation parameters. Some of these indexes are grouped together to form scores, which can improve the accuracy of diagnosing CA. However, particularly in earlier stages, echocardiography has low specificity to distinguish amyloid from other hypertrophic phenotypes, highlighting the need for correlation with clinical red flags, laboratory tests, and additional cardiac imaging modalities.

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Review Article

Heart Failure Management of Patients with Amyloid Cardiomyopathy

Vanessa Simioni Faria et al. Ciro Mancilha Murad Fabiana G. Marcondes-Braga

Abstract

Cardiac amyloidosis (CA) can lead to progressive heart failure (HF) by depositing insoluble amyloid fibrils within the myocardial extracellular space, resulting in an infiltrative and restrictive cardiomyopathy. Although CA was previously perceived as rare and incurable, recent advances in diagnostics and emerging therapies have been changing this outlook. It is crucial to spread awareness about CA to facilitate earlier diagnosis and proper therapeutic interventions, enhancing patient prognosis and survival. Currently, there is an estimated delay of 2 years from symptom onset to diagnosis, typically involving consultation with an average of 5 different professionals. Advances in cardiovascular imaging have facilitated earlier and more accurate diagnosis, reducing the necessity for invasive procedures, such as endomyocardial biopsy. Presently, tafamidis is the only drug that has been shown to offer prognostic benefits in ATTR-CA. Tafamidis is a highly specific medication targeting the circulating TTR protein, stabilizing the TTR tetramer to prevent its dissociation into amyloidogenic monomers that deposit in the myocardium. Alongside specific amyloidosis therapy, supportive HF treatment may be required; however, managing CA with medications typically used for HF with reduced ejection fraction (HFrEF) can be challenging due to potential intolerance. The effectiveness of guideline-directed medical therapy (GDMT) remains undetermined and still requires evaluation through randomized controlled clinical trials (RCCTs). Thus, the treatment cornerstone remains the judicious use of loop diuretics and mineralocorticoid receptor antagonists to control volume overload. Due to the safety profile, not adversely affecting hemodynamics or renal function, sodium-glucose transport protein 2 (SGLT2) inhibitors may be an effective treatment for CA, but they also still require evaluation through RCCTs.

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Review Article

Gene Silencing Therapeutics in Cardiology: A Review Article

Patrick Y. Jay et al. Martin A. Maier Laura Saltonstall Lisa Duarte … Ilia Antonino John Vest

Abstract

Therapeutics that inhibit enzymes, receptors, ion channels, and cotransporters have long been the mainstay of cardiovascular medicine. Now, oligonucleotide therapeutics offer a modern variation on this paradigm of protein inhibition. Rather than target a protein, however, small interfering ribonucleic acids and antisense oligonucleotides target the messenger RNA (mRNA) from which a protein is translated. Endogenous, cellular mechanisms enable the oligonucleotides to bind a selected sequence on a target mRNA, leading to its degradation. The catalytic nature of the process confers an advantage over the stoichiometric binding of traditional small molecule therapeutics to their respective protein targets. Advances in nucleic acid chemistry and delivery have enabled development of oligonucleotide therapeutics against a wide range of diseases, including hyperlipidemias and hereditary transthyretin-mediated amyloidosis with polyneuropathy. While most of these therapeutics were initially designed for rare diseases, recent clinical trials highlight the potential impact of oligonucleotides on more common forms of cardiovascular disease.

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Review Article

Cardiac Magnetic Resonance and amyloidosis: Review

Vaneza Ferreira Ribeiro et al. Diogo Costa Leandro de Oliveira Daniel Gama das Neves Nágela Simão Vinhosa Nunes … Humberto Villacorta Junior Marcelo Souto Nacif

Abstract

Amyloidosis is a disease caused by extracellular deposition of insoluble protein fibrils, that results in changes in tissue architecture and consequently modification of the organ structure. Cardiac involvement is common in amyloidosis. Two major types of systemic amyloidosis affect the myocardium – immunoglobulin light chain and transthyretin amyloidosis – each leading to different prognosis. Early detection and diagnosis of cardiac amyloidosis are the main objectives in the assessment of the disease. New techniques of magnetic resonance imaging have minimized the need for biopsies for the diagnosis. Late gadolinium enhancement technique, and more recently T1 mapping, have allowed a simplified evaluation of amyloid deposits and extracellular volume. The aim of this review was to describe basic concepts and updates of the use of magnetic resonance imaging for the diagnosis amyloidosis and evaluation of its severity.

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