Late-onset restrictive cardiomyopathy is the cardinal feature of ATTR-CMP, irrespective of the underlying genotype. In patients suffering from wild-type ATTR-CMP or ATTR-CMP due to TTR variant p.V142I, restrictive cardiomyopathy may even be the only symptom [1]. It should be noted, though, that isolated ATTR-CMP is a rather rare phenotype of TTR amyloidosis. The disease is more commonly associated with polyneuropathy - and the interested reader is referred to the respective entry on this platform -, but mixed phenotypes have also been described. Patients may show symptoms and signs of ATTR-CMP and polyneuropathy, and they may have impaired renal function or suffer from vision loss [1] [2]. Patients with wild-type ATTR-CMP frequently develop carpal tunnel syndrome before showing any symptoms of cardiac disease [3].

Initial symptoms of cardiac involvement may comprise reduced tolerance to exercise, dyspnea on exertion, and progressive fatigue [4]. These symptoms are related to an increased left ventricular wall thickness, as revealed by sonography. The cardiac septum may also be thickened, and patients may erroneously be diagnosed with hypertrophic cardiomyopathy. Electrocardiography may confirm conduction blocks and arrhythmia, with ATTR-CMP-related arrhythmia often proving resistant to therapy [2] [5]. Electrocardiographic voltage seems to depend on the underlying genotype: Certain types of ATTR-CMP are related to low voltage in the limb leads, but normal or increased voltage have also been observed [2].

Advanced amyloidotic cardiomyopathy is accompanied by symptoms of congestive heart disease, including right heart failure with jugular vein distention, hepatomegaly, abdominal fullness, and peripheral edema [6]. Patients tend to lose weight and eventually succumb to their disease.

Patients should be queried for a possible family history of cardiac disease, death due to cardiac failure, or even diagnoses of ATTR-CMP. Certain mutations are predominantly found in high-risk kindreds, suggesting founder effects. Nevertheless, about half of ATTR-CMP patients have no family history at all of cardiac disease [2] [4]. The late onset of symptoms, limited penetrance, and a non-hereditary etiology of the disease may all contribute to an inconspicuous family anamnesis.

With regard to the patient's own medical history, particular attention should be paid to such disorders known to precede or accompany ATTR-CMP. Patients may not relate carpal tunnel syndrome, nephritic syndrome, or visual impairment to their heart condition, but the treating physician should be able to do so and voice a suspicion of cardiac amyloidosis [6].

The identification of the amyloid type is a prerequisite for treatment planning. In this context, the differentiation between light chain amyloidosis and TTR amyloidosis is particularly challenging. Neither sonography nor electrocardiography allow for the distinction of amyloid types, and patients should be referred for gadolinium-enhanced magnetic resonance imaging and/or bone scintigraphy with 99mTc-DPD. Characteristic findings are global or patchy subendocardial late gadolinium enhancement and myocardial uptake of 99mTc-DPD, respectively [5]. These imaging techniques increasingly replace the current gold standard of diagnosis, which is endomyocardial biopsy, an invasive procedure that may be difficult to carry out in the elderly [7]. Congo red staining of biopsy specimens may corroborate the presence of amyloid deposits, and positive results should entail immunohistochemical analyses with antibodies selective for transthyretin amyloid to confirm the type of amyloid protein involved in the disease [5] [6].

Both diagnostic imaging and histological analyses should be complemented by genetic studies to clarify whether amyloid deposits comprise wild-type or variant transthyretin. While homozygosity for wild-type TTR can be shown by means of gel electrophoresis, the identification of gene variants requires the TTR gene to be sequenced [6].

Transthyretin is mainly produced in the liver, and orthotopic liver transplantation eliminates more than 95% of abnormal, amyloidogenic transthyretin from the circulation of patients with hereditary TTR amyloidosis [8]. For a long time, liver transplantation has been considered the only curative treatment of TTR amyloidosis, and it has usually been carried out in patients with early-onset disease. ATTR-CMP, however, is generally diagnosed beyond the age of 70 years, and advanced cardiac involvement may require additional heart transplantation. What's more, liver transplantation has been described to provoke a paradoxical acceleration of cardiac amyloid deposition [8]. The risks of the procedure thus outweigh the potential benefits of liver transplantation in these patients, and other treatment options must be explored. Similarly, liver transplantation is not a viable approach to wild-type ATTR-CMP [5].

Recent advances in the treatment of TTR amyloidosis give some hope to those suffering from ATTR-CMP [2] [5]:

• Small interfering RNAs like Revusiran may suppress the expression of the TTR gene. Revusiran has been shown to lower serum levels of wild-type and variant transthyretin by >85% in ATTR-CMP patients.
• Antisense oligonucleotides like ISIS-TTRrx may be administered to inhibit the translation of transthyretin, thereby decreasing the overall amyloid load and delaying disease progression.
• Other drugs are developed that aim at the stabilization of the tetrameric transthyretin molecule and the reduction of amyloid deposition, or the dissolution of the amyloid matrix. Tafamidis meglumine and diflunisal, as well as doxycycline plus tauroursodeoxycholic acid and the anthracycline 4'-iodo-4'-deoxy-doxorubicin shall be mentioned in this context.

These treatment strategies are currently tested in clinical trials, many of which have yielded promising results. Nevertheless, controlled trials in ATTR-CMP patients are still pending, and none of the aforementioned compounds has yet been approved for the therapy of ATTR-CMP.

Additionally, patients should be provided conventional treatment for heart failure while respecting their specific needs. Because ATTR-CMP patients tend to be hypotensive and may have impaired renal function, medication limiting the heart's ability to adjust myocardial contractility and beat rate according to activity or demand should be avoided [6]. Conditions like atrial fibrillation are accompanied by increased risks of thrombus formation and warrant the administration of anticoagulants, and arrhythmic patients may require a pacemaker [2].

ATTR-CMP follows a progressive course and is universally fatal, and there are little differences in the prognoses of patients diagnosed with non-hereditary or hereditary ATTR-CMP. With regard to the former, median survival times of five years have been reported, and death occurs at a median age of 81 years. For hereditary ATTR-CMP due to TTR variant p.V142I, the median survival time from diagnosis has been reported to be 33 months, with patients dying at a median age of 78 years [1].

ATTR-CMP may refer to non-hereditary and hereditary types of TTR amyloidosis:

• Non-hereditary ATTR-CMP has formerly been designated as senile systemic amyloidosis and is related to the deposition of native or wild-type transthyretin [2]. It is currently considered an age-related disorder whose causes remain unknown.
• Hereditary ATTR-CMP, by contrast, is caused by mutations in the TTR gene that result in the synthesis and deposition of variant transthyretin. About 140 variants of TTR have been described, 130 of which are amyloidogenic. The underlying mutation strongly affects the phenotype of the patient: The most common phenotype associated with variant TTR is familial amyloid polyneuropathy, while isolated familial amyloid cardiomyopathy is a rare disease [1]. Still, the understanding of genotype-phenotype correlations remains incomplete, and an exhaustive list of mutations leading to ATTR-CMP cannot be provided. Variant p.V142I has been related to ATTR-CMP, as have variants p.V40I, p.E62D, and p.S43N, among others [1]. Hereditary ATTR-CMP is generally considered an autosomal dominant disorder, but asymptomatic carriers of amyloidogenic TTR variants have occasionally been described [1] [6].

The majority of patients with wild-type ATTR-CMP are Caucasian males, who are most commonly diagnosed during their eighth decade of live [1]. Females may be affected, too, but only account for about 2% of the patients [2]. Even though autopsy studies confirmed the presence of wild-type transthyretin deposits in about 25% of people aged 85 years and older, this type of ATTR-CMP is rarely confirmed, supporting the hypothesis that it is highly underdiagnosed [9].

TTR variant p.V142I, presumably the most common cause of hereditary ATTR-CMP, is mostly carried by patients of African ancestry. Indeed, the prevalence of TTR variant p.V142I has been estimated at >3 % in people of African descent [10]. The patients' median age at the time of diagnosis is 76 years, although homozygosity may provoke an earlier onset of cardiac dysfunction [1].

In general, reported incidence and prevalence rates are increasing. This fact is generally attributed to improvements in the diagnosis of ATTR-CMP and does most likely not reflect any change in disease demographics.

ATTR-CMP may or may not be related to mutations in the TTR gene and the synthesis of abnormal transthyretin. Changes in the conformational structure of the protein result in the dissociation of the native tetramer, misfolding, misassembly, and the aggregation of insoluble amyloid fibrils [5]. These amyloid fibrils are deposited extracellularly and interfere with organ function mainly due to their physical presence; they compress, obstruct, and hinder local blood circulation. However, intermediates such as protofibrils and soluble oligomers may also mediate cytotoxic effects. The latter depend on the underlying genotype and are of different severity [2].

The causes of wild-type ATTR-CMP are poorly understood, so no recommendations can be given to prevent late-onset cardiac disease due to transthyretin depositions. With regard to hereditary ATTR-CMP, families known to harbor amyloidogenic variants of the TTR gene may benefit from genetic counseling. This particularly applies to those kindreds suffering from early-onset disease with devastating and widespread amyloidosis and reduced life expectancy, which account for a small minority of ATTR-CMP patients.

Amyloidoses are a group of disorders characterized by the aggregation and extracellular deposition of a specific protein. More than two dozen different amyloid fibril proteins have been identified in humans, and the nature of the amyloid precursor protein is pivotal for the classification of the disease. Transthyretin is one of those proteins, and its accumulation in different organ systems provokes distinct types of transthyretin amyloidosis [5].

Transthyretin amyloidoses may predominantly affect the heart, causing ATTR-CMP or familial amyloid cardiomyopathy, the nervous system, as observed in patients with familial amyloid polyneuropathy, or other organs. All these types of the disease are associated with diminished stability of transthyretin tetramers, which may or may not be caused by mutations in the TTR gene. Patients may carry amyloidogenic variants of the gene, or they may experience the consequences of age-related modifications of transthyretin. Accordingly, they are diagnosed with hereditary ATTR-CMP or wild-type ATTR-CMP.

Transthyretin is mainly produced in the liver and fulfills a variety of functions in the human body, e.g., assisting in the transport of thyroid hormones and vitamin A, which is essential for vision. Transthyretin may undergo conformational changes, either due to inherited mutations in the TTR gene or age-related modifications, and may form insoluble amyloid fibrils that accumulate in the extracellular compartment. This is a space-occupying process associated with the compression and obstruction of adjacent structures, whose function may be limited in the course of the disease. Transthyretin amyloid is preferentially deposited in the heart, nervous system, and eyes, and patients who present with cardiac disease due to transthyretin amyloidosis are diagnosed with TTR amyloidosis with cardiomyopathy (ATTR-CMP). It should be noted that multiple organ systems may be affected, and patients may develop neuropathies, such as carpal tunnel syndrome, before manifesting signs and symptoms of heart disease.

The cardinal symptom of ATTR-CMP is heart failure. In early stages of the disease, patients may claim reduced tolerance to exercise, premature fatigue, and dyspnea. Advanced ATTR-CMP is associated with abdominal fullness, leg edema, and jugular vein distention. Affected individuals may also suffer from arrhythmia. Within years, ATTR-CMP causes congestive heart failure and leads to death. Despite intense research efforts, curative treatment is not yet available. Patients are provided symptomatic treatment to maintain life quality, and, if at all possible, may be enrolled in clinical trials on drugs that limit the synthesis of transthyretin, stabilize its native conformation, or favor the dissolution of abnormal amyloid fibrils.

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