**3. Symptoms and diagnosis**

Early diagnosis of cardiac amyloidosis is not easy since its symptoms are polymorphous and do not clearly lead clinicians to think about a rare diagnosis. The dominant pathophysiology is restrictive cardiomyopathy resulting in a diastolic failure. Frequent are arrhythmias, conductions disorders and syncopes. Angina may be present from obstructive intraluminal coronary microangiopathy (Narang, Chopra et al. 1993; Whitaker, Tungekar et al. 2004; Neben-Wittich, Wittich et al. 2005; Tsai, Seldin et al. 2011) which, in usual absence of epicardial coronary stenoses, can be classified as syndrome X – (Yagishita, Tanimoto et al. 2009). Low-voltage QRS amplitudes on ECG (≤ 10 mV in all precordial leads or ≤ 5 mV in all limb leads) is a relatively constant finding but not very specific since it may be present also in obesity, emphysema, effusion, hypothyroidism and other clinical conditions (Shah, Inoue et al. 2006). Atrial fibrillation is common.

Besides some indicative information from patient´s history (hematological disorders, chronic inflammatory processes, polyneuropathy) echocardiography, in current clinical practice, has the potential to raise suspicion on cardiac amyloidosis in a given patient. Echocardiography diagnosis of cardiac amyloidosis is based on combination of two dimensional (2D) a Doppler image. In 2D both left and right ventricular wall thickness is

intractable low cardiac output or fatal arrhytmia. Sudden cardiac death may be preceded by

Secondary amyloidosis (AA) is caused by the accumulation of amyloid A fibrils formed from an acute-phase reactant, serum amyloid A protein, in chronic inflammatory diseases like rheumatoid arthritis, familial Mediterranean fever, chronic infections, chronic lung diseases, tuberculosis, and inflammatory bowel disease. The heart seems to be affected less frequently whereas the kidney involvement leads to proteinuria and renal failure. The treatment of the underlying inflammatory process can reverse the disease (Gillmore, Lovat

Senile systemic amyloidosis is related to liver production of a wild-type transthyretin transport protein (TTR). Amyloid deposits can be found in the heart, aorta, brain, pancreas, lung, liver, kidneys, and other organs. Senile systemic amyloidosis seems to be an age related disease, affecting predominantly men above the age of 70, with age-increasing incidence. Median survival of 75 months indicates less aggressive course of the disease

Hereditary (familial) amyloidosis is an autosomal dominant disease in which genetically mutated proteins, namely TTR, form the insoluble deposits. More than 80 transthyretin mutation have been identified as well as mutations in other proteins (fibrinogen Aa, lysozyme, apolipoprotein A-I, and gelsolin) have also been reported (Connors, Richardson et al. 2000). Besides cardiac involvement the other manifestations are peripheral and autonomic polyneuropathy with mainly gastrointestinal symptoms, renal impairment. Isolated atrial amyloidosis (AANF) is caused by atrial natriuretic peptide secretion in response to atrial dilation in valvular disease and chronic atrial fibrillation as well as in correlation to increasing age. Thin atrial amyloid deposits however do not affect significantly the cardiac performance. Cardiac amyloidosis may also develop in patients receiving long-term dialysis due to accumulation of beta2-microglobulin from chronic uremia (Gorevic, Casey et al. 1985). Amyloid deposits may be found in myocardium,

pericardium and valves with minimal clinical impact (Noel, Zingraff et al. 1987).

Early diagnosis of cardiac amyloidosis is not easy since its symptoms are polymorphous and do not clearly lead clinicians to think about a rare diagnosis. The dominant pathophysiology is restrictive cardiomyopathy resulting in a diastolic failure. Frequent are arrhythmias, conductions disorders and syncopes. Angina may be present from obstructive intraluminal coronary microangiopathy (Narang, Chopra et al. 1993; Whitaker, Tungekar et al. 2004; Neben-Wittich, Wittich et al. 2005; Tsai, Seldin et al. 2011) which, in usual absence of epicardial coronary stenoses, can be classified as syndrome X – (Yagishita, Tanimoto et al. 2009). Low-voltage QRS amplitudes on ECG (≤ 10 mV in all precordial leads or ≤ 5 mV in all limb leads) is a relatively constant finding but not very specific since it may be present also in obesity, emphysema, effusion, hypothyroidism and other clinical conditions (Shah,

Besides some indicative information from patient´s history (hematological disorders, chronic inflammatory processes, polyneuropathy) echocardiography, in current clinical practice, has the potential to raise suspicion on cardiac amyloidosis in a given patient. Echocardiography diagnosis of cardiac amyloidosis is based on combination of two dimensional (2D) a Doppler image. In 2D both left and right ventricular wall thickness is

syncope (Chamarthi, Dubrey et al. 1997).

(Cohen 1967; Ng, Connors et al. 2005).

**3. Symptoms and diagnosis** 

Inoue et al. 2006). Atrial fibrillation is common.

et al. 2001).

increased. Size of the ventricles remains unchanged while the atria are dilated. Myocardium displays highly abnormal texture described as "granular and sparkling" appearance due to acoustic mismatch between highly reflective amyloid deposits and normal myocardial tissue (Siqueira-Filho, Cunha et al. 1981). Pericardial effusion and signs of pulmonary hypertension are common. Pulsed wave Doppler parameters show diastolic left ventricular dysfunction, typically restrictive pattern, i.e. increased velocity of passive LV filling transmitral E wave and shortening of its deceleration time, shortening of isovolumic relaxation time and inversion of systolic and diastolic pulmonary vein velocity ratio.

Cardiac catheterization can confirm the nonspecific pathophysiology of restrictive cardiomyopathy (elevation of diastolic pressure in both ventricles and right-sided pressure curve with a dip and plateau or square root sign). Normal coronarography despite angina complaints fits the diagnosis of cardiac amyloidosis. Cardiac magnetic resonance imaging enables to visualize in 3D and high-resolution morphologic dimensions of the heart and regional wall motion. Decreased tissue signal intensity along with late subendocardial tissue enhancement by gadolinium can be helpful in differentiating amyloid cardiomyopathy (Maceira, Joshi et al. 2005; Bucciarelli-Ducci, Locca et al. 2007).

Ultimate diagnostic tool, though employed at advanced stage of diagnosis workup, is the biopsy specimen with positive Congo red staining for amyloid. Endomyocardial biopsy, if positive in four samples, gives almost 100% diagnostic sensitivity for amyloidosis. Tissue specimen can also be obtained from rectal submucosa or by abdominal fat aspiration (with sensitivity ranging between 75 – 85%, and 84 – 88%, respectively (Shah, Inoue et al. 2006).

Diagnostic difficulties are obvious: before enough clinical findings are gathered to justify the use of sophisticated and invasive diagnostic tools, the pathway to correct diagnosis may be tedious. Incorporating the possibility of cardiac amyloidosis into clinician´s thinking and careful consideration of all available data and findings is mandatory for obtaining the proper diagnosis fast.
