**6. Cardiac amyloidosis**

Along with the kidneys, the heart is one of the most commonly affected organs in cases of amyloidosis, as amyloid fibrils deposit in its parenchyma and impair it from functioning optimally. The deposition of either light chain amyloid (AL) or transthyretin (TTR) in the cardiac myocardium is responsible for the vast majority (>95%) of cases of amyloid cardiomyopathy [57]. This infiltration of the myocardial tissue essentially results in a clinical presentation of heart failure with preserved ejection fraction; therefore, the treatment is twofold and is targeted at both the primary, underlying disease process and at the secondary heart failure.

### **6.1 AL amyloid**

In regards to the primary disease, treatment varies substantially based on the nature of the abnormal protein that is deposited in the cardiac tissue. AL amyloid, or primary amyloid, affects the heart by depositing abnormally-folded proteins into the myocardium, rendering the ventricles concentrically thickened, thus impairing their ability to accommodate adequate filling volumes. Some studies suggest that the amyloidogenic proteins also have direct cytotoxic effects on the myocardial cells. The pathogenic proteins in AL amyloid are misfolded immunoglobulin light chains produced by a number of clonal plasma cells in the bone marrow; therefore, cytotoxic therapies against these cells have been proven to be effective. A combination of oral melphalan, dexamethasone, autologous stem cell transplantation and/ or bortezomib is often utilized and tailored to each individual case based on various factors such as age, stage of disease, and patient's desire for treatment. These drug regimens are further discussed in the section on renal amyloidosis treatment.

#### **6.2 TTR amyloid**

In transthyretin amyloidosis, the protein transthyretin (TTR) loses stability, misfolds, and deposits in organs throughout the body, including the cardiac myocardium. In contrast to other types of amyloidosis, which may or may not involve the heart, TTR almost always features cardiac involvement and myocardial protein deposition. The consequences of protein deposition in the heart are essentially the same across all types of amyloidosis as the ventricles thicken and result in a restrictive type of cardiomyopathy that prevents the heart from properly filling with blood during the diastolic phase of the cardiac cycle. The restrictive cardiomyopathy leads to a clinical picture of heart failure, with symptoms that often significantly decrease the patient's quality of life. The most definitive treatment for TTR amyloidosis is liver transplantation. This is because the TTR protein is produced in the liver and eliminating the source of the protein would eliminate the pathogenic process altogether. Liver transplantation, however, may not be an option for patients who are not candidates for the procedure. This is where a recently studied drug, Tafamidis, plays a key role. Tafamidis is an agent that exhibits its therapeutic effect by stabilizing the TTR protein, thus preventing its misfolding and subsequent deposition in organs of the body. In a randomized, placebo-controlled, double blind study performed in September 2018, Tafamidis was found to improve the quality of life of amyloidosis patients by slowing the progression of the disease and reducing the functional impairment of affected nerves and systems throughout the body [58, 59]. Other drugs that also may be beneficial in TTR amyloidosis cases include an NSAID called Diflunisal, doxycycline, and an antisense therapy called ISIS-TTRrx. Both Diflunisal and doxycycline are thought to have the same mechanism of action as Tafamidis, as they stabilize the TTR protein and prevent amyloidogenesis. ISIS-TTRrx's mechanism of action differs and works by directly

**31**

*Amyloidosis: Systems-Based Therapies*

**6.3 Heart failure**

*DOI: http://dx.doi.org/10.5772/intechopen.85201*

**7. Amyloidosis of the respiratory tract**

**7.1 Nodular pulmonary amyloidosis**

suppressing the gene that expresses the TTR protein. These agents are still being

Heart failure secondary to cardiac amyloidosis is treated rather differently than heart failure that is organic or secondary to other causes. Agents that typically play key roles in heart failure management, such as beta blockers, ace inhibitors, and calcium channel blockers, are avoided and, sometimes, even contraindicated. These drugs are ineffective in cases of amyloid cardiomyopathy due to the pathophysiology of protein deposition rather than intrinsic cellular dysfunction of the cardiac cells. Utilization of calcium channel blockers, for example, results in an apparent amplification of the drugs' negative inotropic effects and a resultant decompensation of the amyloid cardiomyopathy [60, 61]. One class of drugs- the loop diuretics- remains the cornerstone medication utilized even in cases of heart failure due to amyloid cardiomyopathy. A loop diuretic combined with an aldosterone antagonist has been found to be the most efficacious combination of treatment for amyloid-associated heart failure [57, 62]. Along with drug therapy, other vital lifestyle changes include salt and fluid restriction, as well as regular weight measurements to monitor volume status.

Amyloidosis is characterized by pathological misfolding of the amyloid protein and its deposition as fibrils leading to organ dysfunction. Amyloidosis of the respiratory tract can be localized or a part of a systemic picture of dysfunction. Pulmonary amyloidosis is only symptomatic if amyloid deposits are present on the alveoli, causing impaired gas exchange. Amyloid deposition in the lung parenchyma

Tissue deposits of misfolded amyloid protein in the form of fibrils characterize systemic amyloidosis. There are 15 different kinds of systemic amyloidoses, defined based on the characteristics of the deposited amyloid protein [63]. The primary kinds of amyloidosis that impact the lungs are systemic AL and localized AL consisting of monoclonal light chains, AA amyloid consisting of apolipoprotein serum amyloid A, and ATTRwt consisting of wild-type transthyretin [64]. Regardless of the type of amyloid fibril that is deposited, all fibrils have the same backbone structure that the Congo red stain binds in order to reveal an apple-green birefringence under polarized light [65]. Tissue biopsy is central to diagnosis of amyloidosis as treatment modalities vary based on the type of amyloid protein that is deposited. Less invasive procedures like abdominal fat biopsy and fine needle biopsy are indicated over more invasive procedures like transbronchial biopsy [66, 67]. Once a biopsy is obtained, it is evaluated using immunohistochemistry. The lungs are a common site of amyloid deposition, although not always symptomatic. There are three main kinds of pulmonary amyloidosis: nodular, diffuse, and tracheobronchial. Systemic amyloidosis is symptomatic, and often as a result of chronic inflammation.

Nodular amyloid deposits involving the lung are usually an incidentaloma on chest imaging and usually consist of AL light chain or mixed AL-AH light chainheavy chain [68, 69]. Nodular amyloidosis has been associated with mucosa associated lymphoid tissue (MALT) and Sjogren disease [68]. In a study of 49 individuals with nodular AL amyloidosis, surgical resection and systemic chemotherapy

may manifest as nodular deposits or lead to localized lymphomas.

investigated for efficacy in experiments and clinical trials [59].

suppressing the gene that expresses the TTR protein. These agents are still being investigated for efficacy in experiments and clinical trials [59].
