Infiltrative and Protein Misfolding Myocardial Diseases

Chapter 43

Infiltrative and Protein Misfolding Myocardial Diseases Hamilton S. Gillespie and Ivor J. Benjamin Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT

INTRODUCTION Both acquired and inherited factors that lead to cardiomyocyte death trigger compensatory pathways which, if insufficient to meet the peripheral metabolic and energetic demands, will progress to heart failure. Separate from common forms of heart disease such as coronary occlusive disease and/or valvular heart disease, protein deposition diseases are infrequent causes of “idiopathic” heart failure. These diseases tend toward an insidious onset and progression, and remain difficult to diagnose with currently few therapeutic options. Imbalances in proteostasis boundaries often give rise to protein aggregates, which produce cellular toxicity, limit cell survival, and trigger end-organ dysfunction. Myofibrillar diseases and infiltrative disorders of the cardiovascular system are associated with intracellular preamyloid preoligomer and extracellular aggregates, respectively (1). In this chapter we first explore these concepts, from basic mechanisms linked to insoluble plaques and toxic aggregates to clinical manifestations, in which protein misfolding and aggregation combine to produce protein aggregation cardiomyopathy (e.g., desmin, αBcrystallin), and infiltrative disorders (e.g., cardiac amyloidosis) of the cardiovascular system.

PROTEIN MISFOLDING IN CARDIAC DISEASE This section provides a brief overview of the protein synthesis, folding, and quality control pathways which play a central role in protein misfolding and infiltrative diseases; it may be supplemented with several recent comprehensive reviews (2,3). Messenger RNA are translated on polyribosomes into nascent polypeptides which then transiently bind to heat shock proteins (Hsps) with chaperone-like properties. Hsps sequester newly synthesized proteins from the harsh intracellular environment and facilitate their maturation into functional tertiary structures, while preventing pathologic protein aggregation. The journey by

Muscle. DOI: http://dx.doi.org/10.1016/B978-0-12-381510-1.00043-0 © 2012 Elsevier Inc. All rights reserved.

which proteins achieve their functional tertiary structures is neither linear nor straight forward. Genetic mutations alter the primary amino acid sequence of a peptide, thereby accelerating protein aggregation, decreasing the cell’s integrity and threatening cell survival (3). Intracellularly, misfolded and aggregated proteins are targeted by the ubiquitin-dependent proteasome pathway, a protein degradation pathway which enhances clearance of misfolded protein aggregates and hence prevents toxicity (4). A similar scenario exists inside the endoplasmic reticulum (ER), the principal site of synthesis, folding, and maturation of peptides before their exit via the secretory apparatus and eventual arrival at their final destination in intracellular membranes (Figure 43.1). Within the ER, molecular chaperones facilitate the folding process in coordination with other enzymes optimized for an oxidizing environment. For example, polydisulfide isomerase (PDI) catalyzes disulfide bond formation and drives protein conformation, through a process termed “oxidative protein folding” (5). Pathophysiological conditions may markedly increase demands upon the folding machinery, outstripping its capacity to crisis levels. Such imbalance triggers ER stress in a compartment-specific manner, activating a cascade of signal transduction events termed the “unfolded protein response” (UPR). In familial amyloid polyneuropathy, which is characterized by extracellular deposits of transthyretin as amyloid fibrils, Teixeira and co-workers have demonstrated the ER stress response occurs with co-activation of the UPR (6). Pathologic conditions may therefore arise from dysregulation of ER homeostasis leading to extracellular aggregates (7).

PATHOPHYSIOLOGY Protein Misfolding Increases Myocardial Dysfunction The human heart utilizes oxidative phosphorylation at sites within the energy-producing mitochondria to generate an

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Normal function

ROS

Desmin α B-crystallin

PH Oligomers

Myofibril

ECM ER

Glycosaminoglycans Serum amyloid P components

Extracellular components

mRNA

AM R120G

Mitochondria

Amyloid fibrils

Aggresome

Misfolded aggregates

FIGURE 43.1 Schematic illustration by which the normal process of protein folding gives rise to two distinct protein misfolding pathways. Extracellular aggregates in the form of amyloid fibrils and intracellular aggresomes best exemplify the pathogenic processes implicated in infiltrative and myofibrillar diseases, respectively. For example, the intermediate filament (IF) protein, desmin, plays key roles in differentiated muscle such as maintaining the stability and integrity of sarcomeres at the Z-disc, and the architecture of cytoskeleton and organelles including mitochondria. Interactions among IF proteins include the chaperone αB-crystallin, which transiently binds to and facilitates proper folding of Z-disc structures under stressful conditions. Inheritable disorders linked to mutations in desmin or CryAB (e.g., R120G) have a propensity for misfolded proteins into discrete structures, termed “aggresomes”. Likewise, genetic or acquired conditions contribute to distinct cellular and molecular events linked to cardiac amyloidosis. When compensatory mechanisms are exhausted then mechanical stress, metabolic perturbations, and imbalances in redox state, termed “oxido-reductive” stress are etiologic factors in cardiomyocyte death, organ dysfunction including heart failure and sudden death.

estimated 3 billion beats in a normal lifespan. Physiological states requiring high metabolic demands are generally matched by physiologic growth and hypertrophy of the myocardium to affect increased cardiac output. These physiologic responses are achieved through dynamic changes in gene expression and increased protein synthesis for force-generation. Such phenotypic adaptation is remarkably achieved often without adverse sequelae to cardiac mechanics, in part due to complementary events in the vasculature, extracellular matrix, and through myofibrillar remodeling. Inherited factors linked to infiltrative and protein misfolding disorders may trigger compensatory pathways, which, if insufficient to meet the peripheral metabolic and energetic demands, transition into the clinical and pathological manifestations termed heart failure.

Definitions and Classifications The protein misfolding disorders which produce myocardial dysfunction in humans are subdivided according to the precipitation of the misfolded protein or protein aggregates within the intracellular or extracellular space. Those disorders in which the protein aggregates accumulate within the extracellular space are termed infiltrative disorders, of which amyloidosis serves as a prototype. Here toxic protein aggregates interact with and disrupt the extracellular matrix, leading to mechanical dysfunction as well as direct cellular toxicity. Intracellular aggregation of misfolded protein, localized at Z-disc structures, produces the myofibrillar myopathies (MFM). Direct intracellular toxicity and dysfunction result in cell death and the eventual pathologic state.

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Infiltrative and Protein Misfolding Myocardial Diseases

Amyloidosis Amyloidosis refers to a specific pathologic state wherein soluble protein precursors aggregate within the extracellular space to produce insoluble amyloid fibrils (8). The term amyloid was first introduced by the German botanist Matthias Schleiden and later adopted by the pathologist Rudolph Virchow to describe waxy proteinaceous deposits in human tissues, which he mistakenly identified as carbohydrate (“amyloid” from the Greek amulon 5 starch) (9,10). This descriptive term has carried forward to the present day, despite starches playing only a minor role in amyloid deposits. Amyloid fibrils are, by definition, comprised of misfolded precursor proteins arranged in beta-pleated sheets, aligned with the N and C-terminal ends oriented in opposing directions. Several sheets aggregate, dependent upon the precursor protein, secondary components, and the local environment, to form an ultrastructure known as the amyloid fibril. These fibrils deposit within the extracellular space commonly associated with the extracellular matrix (11). These amyloid deposits are associated with many disease states, including Alzheimer’s disease, familial polyneuropthy, and diseases of the myocardium as discussed here. Accurate identification of the precursor protein is paramount in determining both therapy and prognosis. At least 27 separately identified soluble amyloid precursor proteins have been identified, which under specific conditions in vivo produce disease in humans (Table 43.1) (11,12). AL amyloidosis, often referred to as primary amyloidosis, occurs as a result of monoclonal light chain immunoglobulin aggregation and deposition. These light TABLE 43.1 Amyloid Fibril Nomenclature, and Associated Disease States in Humans Amyloid Precursor Protein Affected Tissue and/ Nomenclature or Disease State AL

Immunoglobulin light chain

AH

Immunoglobulin heavy chain

Aβ2M

β2-microglobulin

Hemodialysis-associated amyloidosis Joint involvement

ATTR

Transthyretin

Familial, senile systemic Tenosynovium

AA

(Apo)serum AA

Secondary, reactive

AANF

Atrial natriuretic factor

Cardiac atria

Adapted from Sipe et al., 2010 (12).

Primary amyloidosis Multiple myeloma associated

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chains are often born of a small clonal population of plasma cells and/or may occur as a secondary complication of multiple myeloma or other B-cell dyscrasia in 20% of cases (13,14). Although AL amyloidosis is the most likely to produce cardiac disease among the known amyloid variants, isolated cardiac involvement is quite rare, and occurs in less than 5% of patients (14 16). Transthyretin (TTR) is a plasma protein produced by the liver which normally serves as a major retinol (vitamin A) binding protein and as a transporter for circulating thyroxine (17). ATTR amyloidosis occurs when either wild-type or a mutant transthyretin serves as the amyloid precursor protein (18). Transthyretin-related amyloidoses arising from more than 70 described mutations in the ATTR gene fall into the category of hereditary amyloidosis, along with other less common amyloid variants including apolipoprotein A-I, lysozyme, and fibrinogen α-chain (8). Transmission occurs in a late autosomal dominant fashion with each mutation manifesting a unique clinical phenotype, with variable cardiac involvement (17). ATTR amyloidosis may also result from wildtype transthyretin deposition, often referred to as “senile” amyloidosis due to its propensity to affect the elderly population. While small amounts of wild-type transthyretin deposits are therefore not uncommon in the elderly, increased deposition may become significant enough to produce diastolic dysfunction and restrictive physiology in certain individuals. AA amyloidosis, formerly described as secondary amyloidosis, results from a chronically high level of acute phase reactant expression, specifically serum amyloid A protein (SAA). Cardiac involvement significant enough to produce clinical sequelae is rare (19).

CLINICAL MANIFESTATIONS Myofibrillar Disorders Both infiltrative and myofibrillar conditions can produce cardiac manifestations and adverse outcomes from cardiac arrhythmia, disorders of thrombostasis, vascular disturbances, heart failure and sudden death. Impairment of left ventricular filling, decreased and/or normal size of both ventricular cavities, and preserved systolic function are pathognomonic hallmarks. Syncope, dizziness, and palpitations are presenting signs and symptoms in patients who experience conduction abnormalities. Shortness of breath and dyspnea on exertion are symptoms of involvement and weakness of the respiratory muscles. Proximal and distal muscle weakness may be initial manifestations with progression into the axial, facial, truncal, and neck flexor muscles. In a report of infantile onset MFM associated with autosomal recessive αB-crystallin (CryAB) mutation, Forrest and colleagues described a 4-month-old

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infant whose initial feeding difficulties and muscle stiffness progressed into respiratory support on a ventilator and feeding by gastrostomy tube at 19 months of age (20). The clinical course is notable for recovery punctuated with relapses. Genetic mutations linked to dilated and hypertrophic cardiomyopathy (HCM) exhibit signs and symptoms of variable penetrance, late-onset, and exacerbations by environmental stimuli. Sudden death in young adults with hypertrophic cardiomyopathy is often associated with strenuous exercise and physical activity. In contrast, MFM has a peak incidence in the 40s whereas infiltrate diseases often have an insidious onset in later adult life.

Infiltrative Disease Cardiac amyloidosis (or amyloid cardiomyopathy) serves as the archetypal restrictive cardiomyopathy, as amyloid deposition within the myocardium begets a loss of elasticity. This leads to restrictive physiology with impaired ventricular filling (typically with preserved systolic function), increased end-diastolic pressure, and hence congestive physiology often occurring both in the left and right heart simultaneously. Any tissue may be affected, and multiple-organ system dysfunction is common at the time of diagnosis. Ventricular arrhythmias, atrial arrhythmias, and conduction blocks (including sinus, AV nodal, fascicular, and bundle branch disease) are common complications of amyloid disease, and are a frequent cause of

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death in such patients (21). Though an unusual diagnosis, amyloidosis may be involved in as many as 1 out of every 1000 deaths in developed countries, with an incidence between 6.1 to 10 cases per million person-years in the United States (1200 3200 new cases each year) (14,16,22). Prognosis remains grim, particularly in AL amyloidosis, where untreated median survival is just 6 months when clinical heart failure is present, and 5-year survival is less than 10% (23). Cardiac amyloid infiltration is associated with a high incidence of both intra-cardiac thrombus formation and embolic phenomena, carrying significant morbidity and mortality (24 28). When compared to other types of amyloid disease, AL amyloidosis is associated with a much higher rate of both (25,28). Thromboembolism may be the cause of death in as many as 25% of patients with AL amyloidosis, compared to 16% in other forms, and intra-cardiac thrombi are present at autopsy in 50% of patients (24,25). The thrombogenic properties of an amyloid-laden myocardium are potentiated by significant electromechanical dissociation, leading to stagnant blood with the atria. Thrombi manifest in many cases despite an electrical rhythm that includes atrial systole (Figure 43.2) (25,28,29). Grade II or III diastolic dysfunction on echocardiogram, atrial size, and a reduction in the atrial ejection velocity (A wave less than 19 23 cm/s) are all independently associated with an increased risk of intracardiac thrombus formation (28). Some experts suggest anticoagulation for those patients, without other FIGURE 43.2 Pulsed wave spectral Doppler echocardiography in an apical four-chamber view in a patient with AL amyloidosis, with sample volume place at the coaptation of the mitral valve leaflet tips to capture mitral inflow velocities. Note that the rhythm on the ECG demonstrates sinus rhythm with clearly defined p-waves. There is a prominent E wave, representing mitral inflow during early diastole. There is not, however, a clearly defined A wave evident on spectral Doppler, reflecting little to no atrial mechanical activity despite an electrical p-wave on ECG.

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Infiltrative and Protein Misfolding Myocardial Diseases

contraindication, who demonstrate a peak transmitral inflow velocity of less than 20 cm/s on echocardiographic evaluation using spectral Doppler during early diastole (E-wave) (23). Confounding attempts to predict and prevent thrombotic complications of amyloid disease, hemorrhagic complications are likewise common. Deposition of amyloid fibrils in small vessel walls with subsequent vascular injury can lead to fragility, producing the pathognomonic finding of periorbital ecchymosis (“raccoon eyes”) in patients with AL amyloidosis (30). Further, patients with amyloidosis may manifest bleeding dyscrasias often with, though not necessitated by, evidence of prolonged laboratory measures of thrombosis. Factor X may adsorb onto the surface of amyloid fibrils producing clinically remarkable factor X deficiency (31 33). Factor II, V, IX, and XIII deficiencies, as well as acquired von Willebrand syndrome, have also been described, particularly for AL amyloidosis (34). There have, however, been no prospective trials to establish guidelines for anticoagulation in patients with amyloidosis, and data on bleeding risk particularly in the setting of anticoagulant therapy is sparse. The risk of thrombotic complication, particularly cardioembolic phenomenon, must be weighed against the risk of hemorrhage in individual cases.

DIAGNOSIS Diagnosis of MFM A high index of suspicion is required for prompt and correct diagnosis of MFM, and sporadic cases linked to genetic causes are likely to be the most challenging. A chief complaint for clinical evaluation of muscle weakness will be evaluated by a medical team of pediatricians, neurologists, and cardiologists, beginning with a comprehensive physical examination and a battery of diagnostic tests. Serial examinations will assess for muscle power, rigidity, percussion myotonia, deep tendon, and plantar reflexes. Slit lamp ophthalmologic examinations are required to assess for cataracts. In affected cases, the clinical laboratory tests will be positive for excessive elevated muscle-specific creatine kinase or cardiac troponin. Electrocardiographic abnormalities include right or left bundle branch block, first-degree atrioventricular (AV) block, high grade AV block, left-ventricular hypertrophy, low voltage, and nonspecific ST-T wave changes. An echocardiogram will noninvasively assess if overall cardiac ventricular function and wall motion abnormalities support cardiac involvement. Complementary studies for multi-system disorders include brain, spinal, muscle, and cardiac magnetic resonance imaging (MRI). Abnormal cardiac findings can be nonspecific for MFM or protein aggregation cardiomyopathy even if there is decreased

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overall left ventricular systolic function. Both sensory and motor nerve conduction studies are performed as well as electromyography of major muscle groups to assess for abnormal spontaneous electrical activity. Muscle biopsy provides tissue for immunohistologic staining, assessment of fiber size and integrity, evidence of vacuolation, necrosis, phagocytosis and intermyofibrillar architecture (20). Complementary studies using electron microscopy afford the definitive opportunity to diagnose myofibrillar disruption at the Z-disc structures, along with granular deposits and aggregates. For either desmin or CryAB mutations, immunolohistologic staining will be positive for desmin, CryAB, p62, and myotilin. Routine genetic tests covering known inheritable factors are commercially available, and genomic studies from the Mayo Clinic’s cohort of MFM patients have successfully identified new candidates (35).

Cardiac Amyloidosis Suspicion of cardiac amyloidosis is most often based upon direct identification of pathologic amyloid deposition in other tissue beds, in association with evidence of congestive heart failure and findings typical of cardiac amyloidosis on non-invasive cardiac imaging. Such findings are substantial enough in the appropriate clinical context to establish a diagnosis. However, evidence of amyloid deposition on endomyocardial biopsy remains the diagnostic gold standard, and identification of the precise amyloid precursor is paramount in determining therapy and prognosis. Under standard histopathologic staining techniques, such as hematoxylin eosin, amyloid deposits appear as amorphous, hyaline-like material, resistant to proteolytic digestion. Congo-red stain is able to intercalate within the anisotropic structure of the amyloid fibrils, thereby producing the characteristic apple-green birefringence under polarized light, which is characteristic of all amyloid. Electron microscopy reveals rigid, non-branching, 7.5 10 nm diameter fibrils. In general, different types of amyloid fibrils are indistinguishable by light microscopy (short of the use of immunofluorescence) and only rarely distinguishable on electron microscopy (11). The precise form of amyloid, determined by its precursor protein, may be ascertained by immunohistochemical staining techniques. In certain instances, the presence of pathologic concentrations of a suspicious precursor in the peripheral blood may be used to infer the source of amyloid deposition. Echocardiography is a mainstay in the non-invasive diagnosis of amyloid cardiomyopathy. Unfortunately, echocardiographic findings considered characteristic of amyloidosis are often seen only in advanced disease (23). Cardiac amyloid involvement classically produces bi-ventricular thickening, retained ventricular internal dimensions, and bi-atrial enlargement (Figure 43.3) the

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FIGURE 43.3 Two examples of transthoracic echocardiograms in two separate patients with AL amyloidosis. Note the biventricular hypertrophy and biatrial enlargement. The image on the left is a non-standard subcostal view with the left ventricle and left atrium to the left of the image. The patient on the left (a) also has a small to moderate pericardial effusion. The image on the right (b) is an apical four-chamber view, also with a moderate pericardial effusion, and a small pleural effusion just anterior to the right atrium.

“snow cone” appearance in the four-chamber apical echocardiographic window (36). Other echocardiographic findings may include increased myocardial reflectivity with a highly speckled or granular appearance to the myocardium (though this may be less specific when modern harmonic tissue image processing is utilized), thickening of the inter-atrial septum and atrioventricular valves with some degree of regurgitation, as well as a small to moderate pericardial effusion (37). Spectral Doppler often reveals evidence of elevated filling pressures, and may demonstrate diminutive or absent flow across the AV valves during atrial systole, despite sinus rhythm indicative of electromechanical dissociation and poor atrial contractility due to amyloid infiltration (Figure 43.2). These findings are not, however, specific for amyloid or restrictive cardiomyopathy, as longstanding hypertension can produce similar findings. Yet, ventricular hypertrophy in the context of low voltage on surface electrocardiogram is highly suspicious for cardiac amyloidosis. Nuclear medicine studies utilizing specific radiolabeled moieties are successful in identifying amyloid deposition, but tend to be insensitive and relatively nonspecific. The most commonly used radio-tracers are 99mtechnetiumpyrophosphate and labeled serum amyloid P protein (SAP) labeled with 123iodine. SAP is a component all amyloid fibrils, and measurement of plasma clearance of injected 123 iodine labeled SAP, whole body uptake (utilizing a gamma camera), and urinary clearance of the radiolabeled protein correlates to total body amyloid deposition and can be used to diagnose systemic amyloidosis and follow progression or response to therapy via serial examination

(38). This technique does not, however, distinguish one type of amyloid from another. Cardiac magnetic resonance (CMR) imaging is beginning to play a significant role in both diagnosis and prognosis of patients with amyloid cardiac disease and other infiltrative disorders of the myocardium. CMR imaging techniques for detection of amyloid deposition are in development, and recent studies have demonstrated good sensitivity and specificity (80 90% and 90 95%, respectively) at experienced centers (39,40). Anatomic abnormalities, easily visualized and measured on cardiac MR, include an increase in cardiac mass, thickening of the right ventricle, and particularly thickening of the right atrial wall and interatrial septum. Diffuse sub-endocardial late gadolinium enhancement, with patchy infiltration into the myocardium, is also a common finding (41). Amyloid protein aggregates, and the resulting tissue fibrosis and reaction within the extracellular matrix, seem to exhibit a unique pharmacodynamic interaction with gadolinium, thus requiring specific protocols in order to image adequately. Early studies of CMR in amyloid noted a significant decrease in T1 spin relaxation times, being quite different between fibrosed and healthy myocardium, though this finding is not specific to amyloid deposition. When present in non-amyloid cardiomyopathies, the degree of difference in signal may be useful in distinguishing amyloid from other causes of myocardial infiltration (40,41).

MYOFIBRILLAR CARDIOMYOPATHIES Recent years have witnessed substantial progress in establishing genetically heterogeneous etiologies for over

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TABLE 43.2 Human Myofibrillar Diseases Involving Z-disc Structures Gene

Mutation (inheritance pattern)

Associated Pathology

References

α-actinin

AD, missense mutation,

Hypertrophic cardiomyopathy

93,94

BAG3

AD

Childhood onset, severe myopathy, cardiomyopathy, polyneuropathy

35

CryAB, HSPB5

AD, AR

Hypertrophic cardiomyopathy, respiratory disturbances, and lens opacities

45,95

Desmin

Autosomal dominant, autosomal recessive, X-linked

Cardiomyopathy, muscle atrophy, respiratory insufficiency

42,49,96

Filamin-C

AD

Myopathy, cardiomyopathy, respiratory muscle weakness

97

Myotilin,

AD

Proximal muscle weakness, cardiac involvement, peripheral neuropathy, limb-girdle muscular dystrophy 1A

98,99

Hypertrophic cardiomyopathy

100

Muscle weakness

99

MLP ZASP, Cypher

AD

Others Zyxin Myopalladin Telethonin AD, autosomal dominant; AR, autosomal recessive.

20 myofibrillar myopathy (MFM) disorders (42). Several disease-causing mutations of the small heat shock protein αB-crystallin (CryAB) have been identified (43,44) but the R120G mutation of hCryAB causes an autosomal dominant, multisystem disorder that includes cardiomyopathy in humans (45 47). Adding to the growing list of myofibrillar diseases are mutations in myotilin, filamin-C, Z-band alternatively spliced PDZ-containing protein ZASP, the antiapoptotic BAG3 (Bcl-2 associated anthanogen-3), and plectin, all of which localize to or are closely related to the Z-disc. It is therefore likely that additional non-lethal mutations of components of the Z-disc will be identified (Table 43.2). In this section, we discuss the myofibrillar myopathies that represent a subset of muscular dystrophies associated with morphological and ultrastructural abnormalities of the Z-disc structures (47). The Z-disc complex of the cytoskeletal network traverses the cell from the plasmalemma to the nuclear envelope and consists of the overlapping thin filament actin, intermediate filament desmin, muscle LIM Protein (MLP), titin, α-actinin, and the titinbinding protein telothonin. As a result, the Z-disc network not only transmits mechanical strain but is well-adapted to modulate the dynamic stress conditions and signal transduction pathways essential for maintaining myofibrillar integrity (47,48). MFM exhibits early histological

and ultrastructural evidence of Z-disc disintegration, which is followed by dense granulomatous deposits of other Z-disc proteins sequestered within protein aggregates (49). “Desmin-related myopathy” and desminopathy are commonly used terms for MFM associated with immunohistochemical staining positive for desmin and when either desmin or CryAB alone is mutated (42,50 52). Because similar clinical manifestations were found to be genetically linked to mutations in either desmin or CryAB, these terms have historical relevance and limitations that might be overcome with a new classification scheme. For example, we have used the term protein aggregation cardiomyopathy (PAC) to selectively describe a human mutation in αB-crystallin (R120GCryAB) characterized by protein misfolding and large cytoplasmic aggregates in mice (53).

Molecular Pathogenesis Several adaptive mechanisms are envisioned to affect mutant desmin or CryAB expression within the protein synthesis machinery, protein degradation pathways, or both. Because the defective chaperone R120GCryAB is itself prone to misfolding and self-aggregation, several lines of evidence suggest that the mechanisms for delayed

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onset, severity, and tissue specificity of these disorders involve intracellular folding, secretion, and degradation pathways. The ubiquitin proteasome and autophagy lysosome pathways are the two main routes of protein degradation in eukaryotic cells. Proteins with short halflives are mostly degraded by the ubiquitin-proteasome system (UPS) whereas cytosolic proteins with long halflives are degraded by autophagic pathways (54,55). The UPS degrades short-lived nuclear or cytosolic proteins and misfolded proteins of the endoplasmic reticulum-assisted degradation (ERAD) system (56). Also, production or accumulation of intracellular protein aggregates has been reported to overwhelm and impair the UPS (57,58). There is, however, limited knowledge about the molecular events that determine whether the majority of aggregation-prone Z-disc mutations trigger UPS dysfunction. Autophagy is another process capable of clearing the aggregate-prone protein. Autophagy can relieve proteasome inhibition by removing aggregates too large for efficient proteasome-mediated clearance through bulk degradation of cytoplasmic proteins in lysosomes (59). While impairment of the proteasomal pathway triggers activation of autophagy, allowing cells to reduce the burden of unattended UPS substrates (60 62), Tannous et al. have shown recently that R120G CryAB increased the abundance of autophagosomes or autophagic activity in cardiomycytes and blunted macroautophagy increased the accumulation of R120G aggregates (60). Pathological manifestations of the R120GCryAB mutation are often age-dependent and tissue-restricted with variable penetrance (46). Besides large cytoplasmic protein aggregates, most genotypes are also characterized histologically with mitochondrial dysfunction, or apoptosis (63). Biochemical studies of mutant CryAB proteins have suggested a loss-of-function mechanism based on decreased chaperone-like properties when assessed in vitro with client protein. Our laboratory has challenged this paradigm by demonstrating that mouse hearts exhibiting R120G CryAB protein-misfolding cardiomyopathy found in humans are under “reductive stress” from an overactive antioxidative system. Decreasing the function of glucose-6-phosphate dehydrogenase (G6PD), which generates the reductant NADPH, “cures” the disease in mice by ameliorating reductive stress, aggresome formation, hypertrophy, heart failure and death (53). A plausible alternative hypothesis is that “gain-of-toxic” function mutations lead to excess reducing equivalents. Such findings further suggest a “gain of toxic” function mechanism might be more common than previously envisioned although direct evidence is presently lacking and represents a future line of investigations in humans.

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AMYLOID CARDIOMYOPATHIES Molecular Pathogenesis The process of amyloid formation, from precursor protein synthesis to final deposition, is highly complex. It begins with intracellular synthesis of the amyloid precursor peptide followed by transport of the precursor peptide out of the cell and into the extracellular space, where extracellular chaperones provide escort. Here the amyloid precursor is exposed to a myriad of interactions with both organic and inorganic molecules including proteases, metals ions, pH, temperature, and components of the extracellular matrix. In the pathogenesis of amyloid formation, these interactions encourage conformational change in the precursor to allow formation of oligomer precursors to the amyloid fibril. Interaction and aggregation of these oligimers to form amyloid fibrils then leads to deposition of the insoluble amyloid aggregates. This last step is precipitated by binding of serum amyloid protein (SAP), as well as via interactions with components of the extracellular matrix, commonly glycosaminoglycans. Amyloid fibril formation is potentiated by several factors, including the disposition of the wild-type amyloid precursor toward amyloid formation, mutation of the precursor protein toward a more amyloidogenic state, concentration of the precursor protein at the target tissue, extracellular factors that can modify or chaperone the precursor protein toward amyloid formation, and extracellular factors that promote amyloid deposition within the target tissue. Any or all of these mechanisms may be implicated in each type of amyloidosis. These pathways also may provide potential for therapeutic intervention already available, or direction toward the development of future therapies. As outlined elsewhere in this chapter and in this book, protein folding is a chaotic process, governed by subtle manipulation of statistical mechanics and is thereby continuously subject to random perturbation. In many cases, the functional wild-type protein represents a transient state among many that is entropically encouraged by chaperones, a specific biochemical milieu, and/or the primary, secondary, tertiary, and quaternary structures of the peptide itself. The folding energy landscape theory elegantly describes this process (64). Fundamental to amyloid precursor proteins is their ability to exist in more than one conformational state in vivo (11). In general, proteins that demonstrate rapid folding kinetics and high stability in their native, non-pathologic, folded state will minimize the threat of toxicity. Alteration to the underlying peptide sequence, as resulting from a genetic mutation, may have only a subtle effect on its final conformational state. The secondary

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and tertiary structures of the beta pleated sheet within the precursor amyloid oligomer as well as the quaternary structure of the amyloid fibril itself are dominated by hydrogren bonding between the terminal carbonyl and amide ends of the peptide, and less by interactions between amino acid side-chains as is often the case within the wild-type globular protein. Genetic alterations resulting in altered translation of the final peptide primary sequence can disrupt these side chain interactions and hence protein folding. In AL amyloidosis, the genetic, and hence amino acid, sequence of the immunoglobulin light chain determines its likelihood of participation in amyloid fibril formation. This amino acid sequence is further implicated in identifying the target organ in which deposition will occur (65,66). In other forms of amyloidosis, it is a wild-type protein which aggregates in the final amyloid deposit, dependent upon specific extracellular conditions to do so. The physiologic function of a wild-type protein necessitates a conformation that is remarkably unstable in some instances. This is the case in several transport proteins implicated in amyloid disease, such as apolipoprotein-A1 and transthyretin. These proteins require a high degree of plasticity in their final state in order to complex with their target molecules thyroxine in the case of transthyretin and cholesterol in the case of apoplipoprotein-A1 (as a component of high-density lipoprotein). This need for plasticity is a molecular gamble, wherein a misfolded state may become manifest and if conditions are right provide a near inescapable energy nadir, resulting in eventual aggregation and precipitation. The story of amyloid might thus be patterned after Robert Louis Stevenson’s story of Dr Jekyll and Mr Hyde, wherein the protein has been trapped in its misanthropic state, unable to readily undergo a conformational change back to what would be its functional wild-type, or perhaps another non-toxic intermediate state. Deposition of pre-amyloid oligomers within a specific tissue requires a number of factors which drive the stoichiometry toward precipitation. Local pH, temperature, and moieties within the extracellular matrix may all play a role. Availability of glycosaminoglycan and other components of the extracellular matrix serve both as scaffolding and structural components of the amyloid fibril (11,67). Presence of amyloid fibrils themselves may accelerate deposition of new amyloid fibrils. This phenomenon is clearly manifest in the ongoing amyloid fibril formation in cardiac tissue following liver transplantation for ATTR amyloidosis (68). Here the mutant-ATTR laden amyloid serves to seed ongoing deposition of new amyloid fibrils from wild-type transthyretin, which would not ordinarily occur under pristine conditions. Injection of

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mice with an amyloid aggregate of AA amyloid fibrils has been demonstrated to accelerate deposition of amyloid fibrils in a murine model of AA amyloidosis, though this same finding is not universal to all forms of amyloid (69,70).

Cellular Toxicity The mechanisms of tissue toxicity in the systemic amyloidoses are varied, and often specific to the amyloid precursor proteins. Amyloid fibrils cause mechanical disruption of the extracellular matrix and trigger oxidative stress in afflicted tissues, either interacting with or disrupting cell membranes thereby resulting in an influx of calcium, eventually leading to cell death (64,71). Toxicity ascribed to the final amyloid deposits tells only a fraction of the story, however. Mounting evidence suggests that amyloid precursor proteins or pre-fibril oligomers are also responsible for a significant, if not dominant portion of direct cellular toxicity in certain forms of amyloidosis (72,73). This phenomenon can be demonstrated by infusion of light-chain immunoglobulins from humans with AL amyloidosis into mice (74). Intense oxidative stress also underlies this effect, leading to eventual activation of an apoptotic pathway due to severe cell stress (74 76). Such direct cardiomyocyte toxicity often manifests as both systolic and diastolic dysfunction. However, as amyloid deposition progresses, mechanical disruption of the extracellular matrix will lead to dominantly diastolic pathophysiology. Further compensation within the myocardium via hypertrophic mechanisms will serve to worsen this dysfunction.

THERAPY AND MANAGEMENT Cardiac Amyloidosis The management of amyloidosis has three primary aims: to reduce exposure to the amyloid precursor protein, provide general supportive care, and, if possible, repair the affected tissues. Accurate identification of the amyloid precursor protein is crucial in providing faithful prognosis and management of the disease. As patients with amyloid cardiomyopathy advance in their disease, scrupulous management of cardiac filling pressures, most often with diuretics, becomes the mainstay of therapy. The clinician must be vigilant not only toward cardiac dysfunction, but toward dysfunction present in other organ systems particularly the kidneys which may be subclinical at presentation. Digoxin, as well as nifedipine, have been demonstrated to bind to amyloid fibrils in vitro, with the potential to produce local toxicity not reflected in serum drug levels (77,78).

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Deleterious effects and clinical deterioration have been demonstrated in small groups of patients treated with these medications (79). Autonomic instability as a result of direct amyloid neuropathy, as well as cardiac dysfunction, renders response to vasodilator therapy difficult to predict and often poorly tolerated. In providing therapy for cardiac rhythm disturbances, response to cardiac pacing is unclear. As noted, many patients with amyloid disease will develop electrical-mechanical dissociation, which may confound attempts at pacing, raise defibrillation thresholds, and undermine the benefit of implantable cardiac defibrillators in this population (80,81). Due to the high rate of intraventricular conduction abnormality in the setting of amyloid, bi-ventricular pacing might be proposed as a potential therapeutic option; however, data have not been presented in support of this concept. In AA amyloidosis, therapy directed at the underlying source of inflammation with immunomodulatory agents, anti-inflammatory medications, or direct tissue resection as the case indicates, have demonstrated benefit (14,82). More aggressive chemotherapeutic regimens have been tried and are under development; however many chemotherapeutic agents carry cardiotoxic effects themselves, and thus their utility is limited once cardiac involvement has become clinically significant. Liver transplantation may be successful in arresting amyloid deposition in hereditary ATTR amyloidosis, however the damaged organs are not generally repaired in this manner and may require subsequent transplant if disease has progressed far enough. Myocardial amyloid deposition in certain forms of hereditary (ATTR) amyloidosis may worsen following liver transplantation as well, requiring combined heart and liver transplant (83). AL amyloidosis presents a unique clinical problem in that the cardiac myocytes are disturbed both by the deposited amyloid fibrils as well as a direct toxicity from the circulating immunoglobulin light chains. Suppression of the plasma cell clone producing the offending immunoglobulin light chain amyloid precursors in AL amyloidosis, most commonly with melphelan and corticosteroids in combination, may arrest amyloid formation and even lead to a regression of tissue amyloid deposits and secondary toxicities (31). Such therapy can preserve organ function and diminish the direct toxicity of the light chains themselves, and demonstrates improved survival in prospective studies (82). High dose chemotherapy followed by peripheral autologous stem cell rescue (stem cell transplantation) may be an option to reduce or eliminate the offending clonal B-cell population, however higher degrees of cardiac dysfunction often make this procedure poorly tolerated, with treatment-related mortality as high as 10 25% (14,84). Cardiac transplantation, either with adjuvant chemotherapy or sequenced with stem-cell transplantation, has emerged as a therapeutic

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option and clearly improves survival among well selected patients with amyloid (85 88). Sequential cardiac and stem-cell transplant in AL amyloidosis may provide a roughly four-fold increase in survival (80% vs. 17% at 1 year in well selected individuals). Survival of cardiac transplant patients with amyloid may be near one-half that of non-amyloid transplant recipients (85,88). Mechanical support may offer improved quality and perhaps extension of life in latter stages of cardiac disease. Left ventricular assist devices have been successfully implanted in patients with amyloid cardiomyopathy, with positive results as either destination or bridging therapy (89).

FUTURE DIRECTIONS Pharmaceuticals aimed at disruption of amyloid formation and interaction with other serum proteins are in development. As understanding of the pathogenic mechanisms of amyloidosis has advanced the potential points for therapeutic intervention have broadened immensely. Beyond supportive care, therapy has focused on the initial step in the pathogenesis of amyloid: reduction or elimination of the precursor protein. However, the remainder of the amyloid pathway may provide low-hanging fruit for future intervention by preventing amyloid formation even once an amyloidogenic precursor has been synthesized. Drugs that deplete serum amyloid protein (SAP), or interfere with its interactions either with other amyloid precursors or specific tissue factors have demonstrated positive results (1,14). Ligands that stabilize the amyloid precursor proteins, thereby preventing a conformational change toward a true amyloidogenic state, are also being explored. For example, patients consuming large amounts of green tea polyphenols have demonstrated a reduction in ventricular mass in the case of ATTR amyloidosis, and both a reduction in LV mass and an improvement in LV systolic function in AL amyloidosis (90,91). It is important to consider that, though insoluble, deposited amyloid fibrils do exhibit equilibrium with their soluble precursors. This has important implications in therapy for amyloidosis, as elimination or reduction of the amyloid precursors can lead to a shift in this equilibrium toward solubilizing deposited amyloid fibrils out of affected tissues (90). New paradigms in medicine and science that subsequently overturn the prevailing dogma are initially confronted with skepticism and a reluctance to forego deeply entrenched beliefs. Diabetes, coronary artery disease, and inheritable cardiomyopathies are widely recognized risk factors for cardiovascular diseases but their underlying pathogenic mechanisms remain poorly understood. Recent insights of the etiologic factors underscore the challenges and opportunities for diagnosis, prognosis, and possible therapies. Pharmacological treatment with β-adrenergic blockade, now the mainstay of heart failure

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management, ranks among the most stunning reversals in evidence-based medicine in recent times. Few proven therapies have been developed for MFM beyond the implantation of pacemakers or defibrillators if clinically indicated for conduction abnormalities or the prevention of sudden death, respectively. The mechanisms of such protein misfolding diseases, which are characterized by aberrant oligomerization and aggregation, remain poorly understood but defining the pathogenesis of MFM might uncover new pathways as potential targets for therapeutic interventions against heart failure (92).

ACKNOWLEDGMENTS This work was supported, in part, by the NIH Director’s Pioneer Award Program (DP1OD006438-02) and ARRA (5R01HL063834-06) to IJB. We thank Jamila Roehrig for her excellent editorial and technical assistance with the graphic artwork.

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