**4. Clinical manifestations and physical examination**

As previously mentioned, amyloidosis is a systemic disease. Therefore, patients with cardiac amyloidosis have amyloid fibril affecting the cardiovascular system and involvement of the musculoskeletal system, peripheral nervous system, and autonomic nervous system. Since the systemic manifestation commonly precedes the cardiac manifestation, it often results in delayed diagnosis. Non-cardiac clinical manifestations are diverse and includes lumbar spinal stenosis, GI symptoms such as constipation or diarrhea, nausea or vomiting, unexplained nephrotic syndrome with some degrees of renal insufficiency, sensorimotor peripheral neuropathy, arrhythmias, autonomic and peripheral neuropathies, and bilateral carpal tunnel syndrome. The latter can be diagnosed up to 10 years before confirmation and diagnosis of ATTR amyloidosis [13, 14, 18, 19]. Therefore, by the time patient starts to develop cardiovascular symptoms, usually there is extensive systemic and myocardial infiltration. A survey of 533 people, including patients with ATTR and their family members, by Lousada et al. found that the correct diagnosis in patients with wild-type ATTR, was made within 6 months in up to 46% of patients and at times the correct diagnosis required >5 different physicians [29].

Cardiovascular manifestations can be four-fold, including congestive heart failure due to restrictive cardiomyopathy, vascular abnormalities, autonomic dysfunction, and conduction abnormalities. Dyspnea is the most common complaint associated with elevated right heart side pressure. Physical examination in advanced disease is noteworthy for prominent jugular venous distention associated with evident "x" and "y" descent, peripheral edema, hepatic congestion, and ascites [30]. The lower extremity edema is usually disproportionate to the degree of heart failure and is related to the degree of nephrotic syndrome. A right ventricular S3 is usually present and correlates with the degree of right ventricular dilatation and dysfunction. The S4 is always absent despite a decrease in left ventricular compliance due to atrial dysfunction secondary to amyloid infiltration. Lung field can reveal bilateral pleural effusion that tends to be diuretics resistant requiring in many cases frequent thoracentesis for fluid removal with high degree of recurrence [31].

Vascular involvement can be seen due to amyloid deposition leading to increase in vessel wall thickness or endothelial functional abnormalities (**Figure 1**). Autopsy studies have demonstrated amyloid infiltration of the small intramural coronary arteries in up to 88–90% of AL patients. Furthermore, the arterial abnormalities do not appear to be related to echocardiographic evidence of cardiac involvement [32]. Patients may present with atypical and typical angina pectoris due to small vessels involvement [33]. Persistent increase in troponin level may be present leading with misdiagnosis of non-ST elevation myocardial infarction [34]. Despite the presence or absence of at true ischemic event, this elevation of cardiac markers is a negative prognostic factor [35, 36].

A hallmark of CA is autonomic dysfunction and can be interpreted as an early symptom, thus patients should be carefully evaluated for dizziness, near syncope
