The Importance of Correct Diagnosis of Transthyretin Amyloid Cardiomyopathy

Cardiac amyloidosis is a serious and progressive infiltrative disease caused by the deposition of amyloid fibrils in the heart. It can result from rare genetic variants in hereditary forms or as a consequence of acquired conditions. It is now known that cardiac amyloidosis is more frequent than traditionally considered [1]. In total, nine amyloidogenic proteins can accumulate in the myocardium, causing significant cardiac disease. More than 98% of diagnosed cardiac amyloidosis cases result from fibrils composed of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR), either in its hereditary (ATTRv) or acquired (ATTRwt) form [2].The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) is difficult to estimate due to underdiagnosis and evolving diagnostic modalities. However, it is estimated that more than 120,000 US adults have ATTR-CM, with 5,000–7,000 new cases diagnosed each year. The median age at diagnosis falls in the eighth or ninth decades of life, with most affected patients being men [3].The pathophysiology of cardiac amyloidosis is multifactorial and includes increased oxidative stress, mitochondrial damage, apoptosis, impaired metabolism, and modifications in intracellular calcium balance [4]. The amyloid fibrils affecting the heart include immunoglobulin light chains (AL) and transthyretin protein (ATTR). ATTRwt has the highest prevalence, ranging from 155 to 191 cases per million, whereas ATTRv has an estimated prevalence of 5.2 cases per million. The incidence of ATTR cardiac amyloidosis is approximately one case per 5,800 individuals [5].Cardiac amyloidosis often results in heart failure with preserved left ventricular ejection fraction (HFpEF) and may exhibit echocardiographic features of restrictive cardiomyopathy associated with left ventricular hypertrophy. However, left ventricular systolic dysfunction and normal wall thickness can also be observed [6]. ATTRwt-CA predominantly affects males over 60 years of age and typically presents as HFpEF, with dyspnea, fatigue, and weakness being common symptoms [7].Transthyretin (TTR), synthesized mainly by the liver, transports thyroxine (thyroid hormone) and retinol (vitamin A). When misfolded, it can form amyloid fibrils that deposit in the heart, causing heart failure, conduction block, or arrhythmias such as atrial fibrillation [8]. In a study by Bergmann et al. [9] all patients presented with the wild-type-form of the disease. Their age distribution was consistent with previous studies, as was the predominance of male patients and heart failure with preserved ejection fraction. The estimated prevalence for Iceland, with 393,600 inhabitants, would be around 68 cases, making this sample significant for the country [9].Invasive diagnostic criteria apply to all forms of cardiac amyloidosis, whereas non-invasive criteria are accepted only for ATTR. ATTR amyloidosis can be diagnosed without histology if imaging exams, such as echocardiography and cardiac MRI, reveal characteristic findings, and scintigraphy with 99mTc-pyrophosphate (PYP), 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), or 99mTc-hydroxymethylene diphosphonate (HMDP) shows grade 2 or 3 myocardial uptake [1]. To exclude clonal dyscrasia, tests such as serum free light chain (FLC) assay, serum protein electrophoresis (SPIE), and urine protein electrophoresis (UPIE) with immunofixation should be performed. Noninvasive diagnostic tools, such as electrocardiography, echocardiography, and cardiac magnetic resonance imaging, can raise suspicion for cardiac amyloidosis. Bone scintigraphy can confirm ATTR noninvasively, while AL requires histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging [10].Recently, the efficacy of various disease-modifying agents targeting the amyloidogenic process has been demonstrated, transforming ATTR-CA from an incurable to a treatable disease [7]. Emerging therapeutic agents under development for AL and ATTR cardiac amyloidosis have shown potent and rapid effects with a favorable safety profile [11]. Notably, tafamidis has demonstrated potential to improve the condition of these patients [12].In recent years, the diagnosis of ATTR amyloidosis has gained importance due to the therapeutic potential of tafamidis, which has demonstrated reductions in mortality and hospitalizations due to cardiovascular causes. Additional therapies are emerging, including transthyretin gene (TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization, and inhibition of oligomer aggregation to prevent fibril formation. Anti-TTR fibril antibodies and amyloid degradation therapies are also under investigation. Once a pathology with no therapeutic options, ATTR amyloidosis now has multiple emerging treatment possibilities.The author has no conflicts of interest to declare.This study received no subsidy or sponsorship.Carlos Scherr: personal and individual work.