Prealbumin – ABC CARDIOL

ABCIC

Editorial

Do Patients with Homozygosity and Compound Heterozygosity for Variants in the Transthyretin Amyloidosis TTR Gene Have More Severe and Earlier Clinical Conditions?

Tonnison de Oliveira Silva et al. Samuel Ulisses Chaves Nogueira do Nascimento

The prevalence of homozygotes for the Val142Ile genetic variant in the transthyretin (TTR) gene is extremely low in the general population (0.72%). This prevalence is slightly higher in endomyocardial biopsy studies (6% to 10%) and in cohorts involving reference centers for TTR cardiac amyloidosis (4% to 14%).^,

Homozygotes represent a distinct subpopulation within the spectrum of cardiac amyloidosis, with clinical characteristics that appear to differ substantially from those of heterozygotes. This genetic variation has been associated with an onset of clinical manifestations in younger patients compared with heterozygotes and also with a higher risk of serious cardiovascular events, such as heart failure and ventricular arrhythmias.³ Besides the earlier onset, observational studies indicate that the disease has a more aggressive phenotypic behavior in homozygous patients, characterized by greater ventricular thickening, worse diastolic function, and a higher load of amyloid fibrils in the heart.³ Thus, homozygotes usually have a higher risk of developing early and more severe heart failure than heterozygotes.^–

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IJCS

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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IJCS

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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IJCS

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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ABCIC

Case Report

Is Wild-type Transthyretin Cardiac Amyloidosis Still Considered a Rare Disease?

Luis Enrique Sanchez Siancas

Introduction

Amyloidosis is a disease characterized by extracellular deposition of insoluble proteins resulting in organ dysfunction. There are more than 30 known proteins capable of aggregating into amyloid fibrils; among these, amyloidosis due to light chain (AL) immunoglobulin and transthyretin amyloidosis (ATTR) represent 98% of cardiac amyloidosis. Transthyretin (TTR) is a tetrameric protein whose function is to transport thyroxine and retinol-binding protein. It is primarily produced in the liver, with smaller quantities found in the choroid plexus and retinal pigment epithelium.

There are two distinct forms of ATTR: hereditary, caused by pathogenic mutations that destabilize the protein, and acquired, also known as wild-type (wtATTR), which results from the accumulation of wtATTR protein. Regarding clinical manifestations of ATTR, in the case of the hereditary type, they depend on the genetic variant involved and can lead to cardiac and extracardiac involvement, including sensory-motor peripheral neuropathies, autonomic neuropathies, gastrointestinal manifestations, among others. In the case of wtATTR, cardiac involvement is the predominant manifestation, characterized by heart failure, conduction disorders, and arrhythmias. The gold standard for diagnosis of cardiac amyloidosis is the demonstration of apple-green birefringence in polarized light microscopy of Congo red-stained tissue. However, confirmatory biopsy is no longer necessary for a diagnosis when the following criteria are met: heart failure with an echocardiogram or cardiac magnetic resonance imaging consistent with amyloidosis, a grade 2 or 3 uptake on radionuclide scintigraphy with 99m-Technetium-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid or pyrophosphate (PYP), and absence of a detectable monoclonal gammopathy. There are currently new disease-modifying therapeutic options available for both hereditary and acquired ATTR. Among the available drugs are selective TTR stabilizers, such as tafamidis, and genetic silencers, such as inotersen or patisiran, which provide the most significant benefit in the early stages of the disease.

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IJCS

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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ABCHF

Viewpoint

Advances in the Diagnosis and Treatment of Cardiac Amyloidosis

Marcus Vinicius Simões et al. Diane Xavier de Ávila Pedro Manoel Marques Garibaldi Evandro Tinoco Mesquita

Introduction

In recent decades, significant advances have led to a complete reformulation of clinical and epidemiological concepts about cardiac transthyretin (ATTR) amyloidosis, summarized in .

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ABC

Original Article

Clinical, Laboratory, and Imaging Profile in Patients with Systemic Amyloidosis in a Brazilian Cardiology Referral Center

Fábio Fernandes et al. Aristóteles Comte de Alencar Neto Bruno Vaz Kerges Bueno Caio Rebouças Fonseca Cafezeiro … João Henrique Rissato Roberta Shcolnik Szor Mariana Lombardi Peres de Carvalho Wilson Mathias Júnior Angelina Maria Martins Lino Jussara Bianchi Castelli Evandro de Oliveira Souza Félix José Alvarez Ramires Viviane Tiemi Hotta José Soares Júnior Caio de Assis Moura Tavares José Eduardo Krieger Carlos Eduardo Rochitte André Dabarian Ludhmila Abrahão Hajjar Roberto Kalil Filho Charles Mady

Abstract

Background

Systemic amyloidosis is a disease with heterogeneous clinical manifestations. Diagnosis depends on clinical suspicion combined with specific complementary methods.

Objective

To describe the clinical, laboratory, electrocardiographic, and imaging profile in patients with systemic amyloidosis with cardiac involvement.

Methods

This study was conducted with a convenience sample, analyzing clinical, laboratory, electrocardiographic, echocardiographic, nuclear medicine, and magnetic resonance data. Statistical significance was set at p < 0.05.

Results

A total of 105 patients were evaluated (median age of 66 years), 62 of whom were male. Of all patients, 83 had transthyretin (ATTR) amyloidosis, and 22 had light chain (AL) amyloidosis. With respect to ATTR cases, 68.7% were the hereditary form (ATTRh), and 31.3% were wild type (ATTRw). The most prevalent mutations were Val142Ile (45.6%) and Val50Met (40.3%). Time from onset of symptoms to diagnosis was 0.54 and 2.15 years, in the AL and ATTR forms, respectively (p < 0.001). Cardiac involvement was observed in 77.9% of patients with ATTR and in 90.9% of those with AL. Alterations were observed in atrioventricular and intraventricular conduction in 20% and 27.6% of patients, respectively, with 33.7% in ATTR and 4.5% in AL (p = 0.006). In the ATTRw form, there were more atrial arrhythmias than in ATTRh (61.5% versus 22.8%; p = 0.001). On echocardiogram, median septum thickness in ATTRw, ATTRh, and AL was 15 mm, 12 mm, and 11 mm, respectively (p = 0.193). Elevated BNP was observed in 89.5% of patients (median 249, ICR 597.7), and elevated troponin was observed in 43.2%.

Conclusion

In this setting, it was possible to characterize cardiac involvement in systemic amyloidosis in its different subtypes by means of clinical history and the diagnostic methods described.

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ABCHF

Viewpoint

New Paradigms in Cardiac Amyloidosis: The Current Experience of the Northeast Region of Brazil

Tonnison Silva et al. Carlos Eduardo Lucena Montenegro Marcelo Dantas Tavares de Melo Luiz Ritt André Luiz Cerqueira Almeida

Cardiac amyloidosis (CA) is a severe and progressive infiltrative disease caused by the deposition of amyloid fibrils, with poor prognosis and limited therapeutic options. It can occur due to rare genetic variants or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of obtaining non-invasive diagnosis, we now know that CA would perhaps be better classified as an underdiagnosed disease rather than as a rare one.^–

González-Lopez et al. demonstrated that, in a series of 120 patients with preserved ejection fraction heart failure, 13.3% had a diagnosis of transthyretin-associated amyloid cardiomyopathy (ATTR-CM). In patients with aortic stenosis, we found a prevalence of around 15% of ATTR-CM, and, in necropsy studies, amyloid protein deposition was found in 25% of patients over 85 years old, which shows the importance of this diagnosis in the spectrum of myocardial diseases.

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ABCHF

Viewpoint

Genetic Testing in Amyloidosis: For Whom?

Paulo Vinicius Ramos Souza et al. Fabio Fernandes Felix José Alvarez Ramires

Over the past years, the recognition of cardiac involvement due to deposition of amyloid substances has received greater emphasis. Cardiac amyloidosis (CA), as it is known, has been shown to be a more prevalent cause of heart failure with preserved ejection fraction than in previous decades, although diagnosis remains a constant challenge.

With advances in pathophysiological knowledge of this disease, as well as relevant advances in diagnostic methods, particularly in the field of cardiovascular imaging, there has been a significant contribution to earlier identification of CA, as well as a consistent change in the natural course of the disease, given that we are witnessing the emergence of therapies that are capable of prolonging these patients’ survival.

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ABCHF

Case Report

Heart Failure Due to Cardiac Transthyretin Amyloidosis

Humberto Butzke da Motta et al. Guilherme Oliveira Magalhães Costa Andreia Biolo

Abstract

A 90-year-old male patient presented with complaints and physical examination compatible with decompensated heart failure. Electrocardiogram showed atrial fibrillation and low voltage in limb leads, and echocardiogram identified biatrial dilatation, in addition to mild increases in ventricular wall thickness and diameter. Magnetic resonance imaging confirmed suspicion of cardiac amyloidosis. With negative serum and urinary protein electrophoresis and positive pyrophosphate cardiac scintigraphy, diagnosis of transthyretin cardiac amyloidosis was confirmed. Transthyretin gene mutations were not identified on sequencing, characterizing wild-type transthyretin cardiac amyloidosis.

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ABC

Case Report

Transthyretin Amyloidosis (ATTR) – The Role of Multimodality in the Definitive Diagnosis

Tonnison de Oliveira Silva et al. Eduardo Sahade Darze Luiz Eduardo Fonteles Ritt André Luiz Cerqueira Almeida Antônio Ximenes

Introduction

Transthyretin amyloidosis (ATTR) is a rare cause of restrictive cardiomyopathy and/or peripheral polyneuropathy, of a progressive, irreversible and fatal nature, underdiagnosed and with its definitive diagnosis performed late. Early diagnosis, characterization of the type of amyloidosis and subsequent establishment of specific therapy are fundamental for a better prognosis of this disease. We present a case of ATTR where clinical suspicion associated with multimodality diagnosis — nuclear medicine — was able to safely deliver diagnosis, without the need for biopsy.

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ABC

Original Article

Frequency of Cardiovascular Involvement in Familial Amyloidotic Polyneuropathy in Brazilian Patients

Márcia Cavalcanti de Campos Queiroz et al. Roberto Coury Pedrosa Amanda Cardoso Berensztejn Basílio de Bragança Pereira … Emília Matos do Nascimento Martha Maria Turano Duarte Pedro Paulo Pereira-Junior Marcia Waddington Cruz

Background:

Familial amyloidotic polyneuropathy (FAP) is a rare disease diagnosed in Brazil and worldwide. The frequency of cardiovascular involvement in Brazilian FAP patients is unknown.

Objective:

Detect the frequency of cardiovascular involvement and correlate the cardiovascular findings with the modified polyneuropathy disability (PND) score.

Methods:

In a national reference center, 51 patients were evaluated with clinical examination, electrocardiography (ECG), echocardiography (ECHO), and 24-hour Holter. Patients were classified according to the modified PND score and divided into groups: PND 0, PND I, PND II, and PND > II (which included PND IIIa, IIIb, and IV). We chose the classification tree as the statistical method to analyze the association between findings in cardiac tests with the neurological classification (PND).

Results:

ECG abnormalities were present in almost 2/3 of the FAP patients, whereas ECHO abnormalities occurred in around 1/3 of them. All patients with abnormal ECHO also had abnormal ECG, but the opposite did not apply. The classification tree identified ECG and ECHO as relevant variables (p < 0.001 and p = 0.08, respectively). The probability of a patient to be allocated to the PND 0 group when having a normal ECG was over 80%. When both ECG and ECHO were abnormal, this probability was null.

Conclusions:

Brazilian patients with FAP have frequent ECG abnormalities. ECG is an appropriate test to discriminate asymptomatic carriers of the mutation from those who develop the disease, whereas ECHO contributes to this discrimination.

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