Cardiac Amyloidosis (CA) is a progressive, potentially fatal and infiltrative cardiomyopathy caused by extracellular deposition of transthyretin-derived insoluble amyloid fibrils in the myocardium [1-4].

The infiltrative process results in biventricular wall thickening with concentric ventricular remodeling and low cardiac output. The subsequent elevation of pressure in the atria is associated with atrial dilatation. The conduction system is also frequently disrupted, with atrial arrhythmias and atrioventricular conduction delays being common [5].

The two most prevalent forms of CA are: light chain immunoglobulin (AL) and transthyretin (ATTR) amyloidosis [5, 6]. ATTR includes the wild-type (>90% of cases) and the hereditary or variant type (<10% of cases) [6].

Wild-type ATTR-CA is almost exclusively a disease of older adults with male preponderance [7]. 16% of patients with severe aortic stenosis undergoing aortic valve replacement have transthyretin cardiac amyloidosis [8,9].

Age >65 years and heart failure along with a left ventricular wall thickness 12mm at echocardiography are major criteria for the suspicion of CA [6].

Cardiac amyloidosis typically appears within a constellation of extracardiac signs and symptoms: involvement of soft tissues leads to an increased incidence of bilateral carpal tunnel syndrome, spinal stenosis or spontaneous biceps tendon rupture [7], as well as proteinuria, peripheral polyneuropathy, dysautonomia, macroglossia, deafness and skin discoloration and bruising [1].

Cardiac involvement in amyloidosis typically presents with heart failure symptoms and signs with prominent features of right ventricular failure (peripheral congestion) including lower extremity edema, jugular vein distention, hepatic congestion, ascites and dyspnea [4]. Possible family history may also raise suspicion [1].

In addition, NT-proBNP may be disproportionately high (> 3000 pg/mL) due to direct compression of cardiomyocytes and stress caused by raised filling pressures and troponin elevation (> 0.05 ng/mL) may be persistent. On ECG, the findings are a decreased QRS voltage to mass ratio, pseudo-Q waves and AV conduction disease. On echocardiogram, granular sparkling texture of the myocardium, atrial dilatation, pericardial effusion, aortic stenosis, increased wall and valve thickness, preserved ejection fraction, reduced global longitudinal left ventricular strain (< -15%), Doppler E/e’ ratio >11 and TAPSE ≤19mm can be found. On CMR, there is a subendocardial/transmural late gadolinium enhancement or increased extracellular volume [1, 5].

Early recognition remains essential to afford the best treatment efficacy [7]. A timely definitive diagnosis should be obtained as patient outcomes depend largely on early initiation of therapy [1].

Invasive diagnostic criteria apply to all forms of cardiac amyloidosis whereas non-invasive criteria are accepted only for ATTR [1]. Cardiac ATTR amyloidosis can be diagnosed in the absence of histology in the setting of typical echocardiographic/CMR findings when radionuclide bone scintigraphy shows Grade 2 or 3 myocardial uptake of radiotracer (Grade 2: similar myocardial and bone uptake. Grade 3: myocardial uptake greater than bone with reduced/absent bone uptake) and clonal dyscrasia is excluded (by all the following tests: serum free light chain assay, serum and urine protein electrophoresis with immunofixation) [1].

Scintigraphy has a specificity and positive predictive value for TTR-CA of up to 100% (able to identify pre- symptomatic disease) [5,6]. In contrast, CMR has a sensitivity and specificity of 85% and 92%, respectively [6].

Treatment of CA involves two areas: treatment and prevention of complications and comorbidities, the most common are aortic stenosis, heart failure, thromboembolism, atrial fibrillation, conduction disorders and ventricular arrhythmias. and stopping or delaying amyloid deposition by specific treatment [1]. Tafamidis should be generally considered the agent of choice in wtTTR-CA patients because it reduced all- cause mortality and cardiovascular hospitalizations, mainly in those patients with NYHA class I and II at baseline. [1, 6]. Functional improvement occurred within 6 months, whereas the decrease in mortality took nearly 2 years to occur [6].

Advances in cardiac imaging and improved awareness among physicians have facilitated the diagnosis of cardiac amyloidosis over the last decade. Involvement of the heart in the setting of amyloidosis carries an adverse prognosis. Timely diagnosis is of the greatest importance for appropriate treatment modalities that may crucially modify the natural history of the disease [4].

In this case, the patient (>65-year-old male) showed multiple signs and symptoms during the last year with negative serum free light chains, negative serum and urine immunofixation and negative ATTR mutation in association with laboratorial, electrocardiographic, echocardiographic, cardiac magnetic resonance with gadolinium contrast and scintigraphy findings in favor of wild-type transthyretin cardiac amyloidosis. After the diagnosis the patient started tafamidis and he was referred to a cardiac amyloidosis center.