Review

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Improving strategies for the diagnosis of cardiac amyloidosis Expert Rev. Cardiovasc. Ther. Early online, 1–17 (2015)

Taxiarchis V Kourelis and Morie A Gertz* Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA *Author for correspondence: Tel.: +1 507 284 2511 Fax: +1 507 266 4972 [email protected]

Amyloidosis refers to a group of rare but potentially fatal, protein misfolding diseases. The heart is frequently involved in the most common types, that is, immunoglobulin light chain and transthyretin amyloidosis and is the single most important predictor of patient outcomes. A major limitation in improving patient outcomes, in addition to developing novel therapeutics, is the late diagnosis of the disease. Once suspected, an organ for biopsy should be targeted and the amyloid type should be identified by mass spectrometry. An endomyocardial biopsy should be offered if cardiac involvement is in doubt. Echocardiography, MRI and nuclear imaging can provide valuable diagnostic and prognostic information and can secure the diagnosis if amyloid has been identified in an extracardiac tissue. KEYWORDS: amyloidosis . heart failure . heart failure with preserved ejection fraction . immunoglobulin free light chains . infiltrative cardiomyopathies . transthyretin

The term systemic amyloidosis collectively refers to a group of diseases that cause extracellular deposition of insoluble protein aggregates which are aberrantly folded in a b-pleated sheet configuration [1]. Amyloid deposition leads, through various mechanisms, to the dysfunction of the affected organs. The clinical manifestations of the disease depend on the type of amyloid, the type and extent of organ involvement as well as response to treatment. Diagnosing amyloidosis is challenging because the disease is rare and usually presents with a wide range of non-specific signs and symptoms. At the same time, early diagnosis and timely initiation of treatment are essential to ensure optimal patient outcomes. The most common types of amyloid protein can deposit in cardiac tissue and the extent of cardiac involvement is usually the single most important predictor of patient outcomes [2–4]. In this review, we will discuss the pathogenesis and strategies to improve the diagnosis of cardiac amyloidosis. Pathogenesis of common types of amyloidosis

To date, there are 31 known amyloidogenic proteins in humans [1], 2 of which are iatrogenic

informahealthcare.com

10.1586/14779072.2015.1069181

in nature (enfuvirtide and insulin) and 6 of which can deposit in the heart (TABLE 1). All, except isolated atrial amyloidosis, can involve other organs in addition to the heart. Immunoglobulin light chain amyloidosis

Immunoglobulin light chain (AL) amyloidosis (previously known as primary systemic amyloidosis), is the most common type of amyloidosis with approximately 2000 cases reported each year in the USA but it remains a rare disease when compared with >25,000 cases of multiple myeloma (MM). AL amyloidosis is a result of multiorgan involvement by misfolded AL fragments. The heart is involved in approximately a third to one half of patients [5,6]. It is always preceded by a, diagnosed or undiagnosed, plasma cell dyscrasia [7], most commonly monoclonal gammopathy of undetermined significance (MGUS) followed by smoldering MM and smoldering Waldenstrom’s macroglobulinemia [8]. In approximately 8% of cases, patients fulfill diagnostic criteria for MM at diagnosis of AL amyloidosis, that is, the ‘CRAB’ criteria; hypercalcemia, renal failure, anemia and lytic bone lesions [9]. Although this group of patients tends to have worse overall

 2015 Informa UK Ltd

ISSN 1477-9072

1

Review

Kourelis & Gertz

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Table 1. Amyloidoses affecting the heart. Type/Precursor protein

Pathophysiology

Systemic (S) and/or localized (L)

Acquired (A) or Hereditary (H)

Key clinical characteristics

Immunoglobulin light chain (l:k ratio of 3:1)

Clonal plasma cells produce the monoclonal light chain

S or L

A, H

Virtually all organs can be affected (heart and kidneys most commonly) Carries worst prognosis of all types

Immunoglobulin heavy chain

Clonal plasma cells produce the monoclonal heavy chain

S or L

A

Much rarer than AL. It is more commonly localized

Transthyretin, wild type†

Age-related transthyretin deposition

S

A

Cardiac involvement is predominant. Peripheral neuropathy is less common. Liver and renal function are normal

Transthyretin, mutant variants

Genetic mutations cause misfolding of mainly hepatic-derived transthyretin (transthyretin is also produced in the choroid plexus)

S

H

Multiorgan involvement. Peripheral and autonomic neuropathy. Cardiomyopathy, nephrotic syndrome, liver failure

Serum amyloid A

A liver-derived, acute phase reactant

S

A

Associated with chronic inflammatory conditions and malignancy

Apolipoprotein A I, mutant variants

Genetic mutations cause misfolding of ApoAI

S

H

Most commonly affects heart, liver, kidney and peripheral nerves. Testis, larynx and skin involvement have been reported

Atrial natriuretic factor

Deposition of atrial natriuretic peptide, which increases with aging

L

A

A trial fibrillation is most common characteristic. Affects women more than men



Previously known as ‘senile’ amyloidosis. AA: Serum amyloid A; AANF: Atrial natriuretic factor; ApoAI: Apolipoprotein A I; AH: Immunoglobulin heavy chain; AL: Immunoglobulin light chain.

survival (OS), these patients appear to fare no worse than patients without the classic CRAB criteria but a high plasma cell burden [9]. This observation is important because coexistent multiple myeloma (i.e., CRAB) or a high plasma cell burden in AL amyloidosis are both associated with a higher incidence of cardiac involvement [9] and these patients usually die from complications of end-organ failure (most commonly cardiac complications) rather than complications from MM. In addition to plasma cell burden, other factors that have been associated with cardiac tropism are specific immunoglobulin variable region (IgV) families as well as cytogenetic abnormalities of the malignant plasma cell clone. More specifically, the LV1 IgV family has been associated with a higher risk of cardiac involvement in some studies [10], but this has not been confirmed in more recent, larger cohorts [11]. Abnormal FISH has also been associated with an increased risk of cardiac involvement and worse outcomes, independent of plasma cell burden [12]. The exact mechanism underlying these observations is unclear and so are the factors underlying the increased amyloidogenicity of l light chains compared with k light chains, the restricted repertoire of IgV families encountered in AL amyloidosis [10,13–15] and the variation in response to treatment and amyloid formation kinetics in vivo. Some have hypothesized that in addition to properties intrinsic to the

doi: 10.1586/14779072.2015.1069181

amyloidogenic protein, host factors such as co-deposited chaperone proteins, host immune response and the amyloid nanoenvironment play a crucial role [16]. Once deposited, light chains cause cardiac toxicity by two distinct mechanisms. The first is acute, and relates to the direct toxicity that light chains exert on cardiac myocytes, which is mediated through reactive oxygen species [17–22]. This explains why patients who achieve a hematologic response to therapy derive an immediate benefit with reduction in symptom burden and cardiac biomarkers [6,23]. The second mechanism relates to the subacute impairment of cardiac physiology by the amyloid deposits. This occurs through multiple pathways many of which remain unclear. First, patients with AL amyloid have signs of coronary microvascular dysfunction [24,25], presumably secondary to perivascular amyloid deposition. Autopsies have been reported of patients with ‘clean’ coronaries on cardiac catheterization but widespread small vessel amyloid deposition with associated acute myocardial infarction [24]. This is the reason why angina is sometimes reported in patients with advanced cardiac amyloidosis in the absence of coronary artery disease. Prospective studies have demonstrated that patients with cardiac amyloidosis have lower global left ventricular (LV) myocardial blood flow at rest and during peak hyperemia and higher minimal

Expert Rev. Cardiovasc. Ther.

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Improving strategies for the diagnosis of cardiac amyloidosis

coronary vascular resistance compared with controls with hypertensive ventricular hypertrophy [25]. The degree of microvascular function impairment correlates with longitudinal strain (LS) rates, which may offer an additional mechanistic explanation for the prognostic significance of LS rate. An additional mechanism relates to the disruption of the myocardial extracellular matrix by amyloid deposition [26,27]. Serum markers of matrix disruption correlate with structural and functional myocardial changes as well as patient outcomes (i.e., survival) and were found to be more abundant in AL amyloidosis compared with transthyretin (ATTR) amyloidosis, offering an additional mechanism by which light chains cause more severe myocardial dysfunction. Additionally, circulating markers of matrix disruption might have an incremental prognostic value over brain natriuretic peptide (BNP) and troponin. Cardiac arrhythmias are also common in AL and, presumably, are caused either by direct impairment of the conduction system [27–29] or because of autonomic dysfunction in the case of bradyarrhythmias [30]. The exact mechanism by which these patients are more prone to developing conduction abnormalities remains unclear. Finally, progressive amyloid deposition eventually leads to direct impairment of contractility and hemodynamic impairment with development of congestive heart failure with preserved ejection fraction (HFpEF), with a decreased ejection fraction (EF) seen at very late stages of the disease [31]. Transthyretin (ATTR) amyloidoses

ATTR is a hepatic-derived, homotetrameric transporter protein that exists in equilibrium with TTR monomers; however, TTR tetramers are present at 1000x the concentration of the monomers. ATTR amyloidoses represent a very heterogeneous group of amyloidoses. They are further classified into wild-type ATTR (wt-ATTR; previously called senile amyloidosis) and mutated/hereditary ATTR (mt-ATTR). wt-ATTR amyloidosis

wt-ATTR amyloidosis is a disease diagnosed almost exclusively in patients older than 70 years and it is much more common than its mt-ATTR counterpart. Unlike mt-ATTR, which is structurally unstable and more amyloidogenic, the factors that determine wt-ATTR amyloid deposition remain unknown. Some have hypothesized that the age-related increase in the level of protein oxidation increases wt-ATTR amyloidogenicity and could be involved in the onset of the senile forms of the ATTR amyloidoses [32]. Once deposited, ATTR amyloid leads to LV wall thickening, diastolic dysfunction and HFpEF. Similar to AL, direct cardiomyocyte toxicity has been noted with amyloidogenic TTR molecules in vitro and mt-TTR has been shown to be more toxic compared with wt-TTR [33,34]. The exact mechanism by which cell death occurs has not been fully elucidated. It has been hypothesized that, soluble, prefibrillar intermediates rather than their end product, that is, the amyloid fibrils, might be more toxic. These ‘intermediates’ may be formed not only prior to mature amyloid fibrils but they informahealthcare.com

Review

might also be a result of amyloid fibril breakdown mediated by neutrophil extracellular traps formed by adjacent neutrophils [35]. In this way, ATTR might not be much different to AL in terms of cardiomyocyte toxicity. What makes AL ‘deadlier’ is the rate of accumulation of pre-fibrillary intermediates (TTR and light chains, respectively), which is much more rapid in the case of AL. Extracellular matrix disruption is seen in ATTR as well as in AL amyloidosis [27]. Emerging evidence suggests that cell damage in ATTR amyloid starts much earlier and might be a result of deposition of lower molecular weight non-amyloid ATTR species that precede detectable ATTR amyloid fibril deposition [34,36,37]. The causal association between wt-ATTR and diastolic heart failure is also dynamic and likely bidirectional: on the one hand, wt-ATTR amyloid and pre-amyloid fibrils can lead to diastolic heart failure but at the same time both advanced age and heart failure are associated with increased oxidative stress, as are several of the comorbidities (chronic kidney disease, hypertension and vascular disease) commonly coexisting in these patients [38]. Therefore, the pathogenesis of wt-ATTR is a complex interplay between the amyloid protein and host-dependent factors. In vivo data suggest that hepatic-derived chaperones might be important for regulating TTR deposition and toxicity. In a mouse model of wt-TTR, livers of mice with cardiac TTR deposition had increase in the number of transcripts encoding both cytoplasmic and endoplasmic reticulum chaperones and genes involved in proteasome function and ubiquitination compared with controls [39]. The authors hypothesized that the chaperone activity of the liver determines the presence or absence of extracellular cardiac TTR deposition. The incidence of this disease is underestimated since, not infrequently, it remains undiagnosed. In autopsy series and among patients with HFpEF, moderate or severe interstitial wtATTR deposition was present in 5% of patients (mostly men), with mild interstitial or intramural coronary vascular deposition present in 12% of patients [38]. Others have identified amyloid deposition in up to 25% of autopsy specimens in patients older than 80 years of age [40], suggesting that wt-ATTR is much more common in the general elderly population than previously thought. Inherent limitations of autopsy series make them more susceptible to bias and therefore interpretation of these results should be done with caution. First, they are susceptible to ascertainment bias, since patients with an antemortem clinical suspicion of amyloid might be more likely to get an autopsy. Second, details about the cause of death were not always available. Finally, the severity of amyloid deposition was not specifically considered (i.e., significant vs minor amyloid deposition in autopsy specimens). Nonetheless, these studies underline that cardiac ATTR might be more common than previously thought. More recently, with the advent of novel therapeutics the diagnosis of cardiac ATTR should be excluded more aggressively since these patients might benefit from disease-specific treatment in addition to medical management for their heart failure. doi: 10.1586/14779072.2015.1069181

Review

Kourelis & Gertz

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

mt-ATTR amyloidosis

mt-ATTR is the most common hereditary amyloidosis and very commonly affects the heart. More than 100 different amyloidogenic mutations have been described in mt-ATTR, each of which is encoded on chromosome 18. A valine-to-isoleucine substitution (V122I) in the ATTR protein is the most common variant and is seen in approximately 4% of African Americans [41]. It is associated with late-onset restrictive amyloid cardiomyopathy and heart failure, although its prior association with increased mortality has not been confirmed in a recent large cohort with long-term follow-up [42]. The mechanisms of toxicity by mt-ATTR are similar to those described above for wt-ATTR, but because the rate of amyloid deposition is much higher in mt-ATTR, patient outcomes are significantly worse. Molecular chaperones that are frequently co-deposited in the microenvironment of the amyloid plaque have been shown to both promote and inhibit ATTR amyloid formation and toxicity [43–46]. Female sex hormones might play a protective role in mt-ATTR, since onset of cardiomyopathy occurs earlier and the incidence and the severity of cardiac involvement was higher in men or postmenopausal women compared with premenopausal women [47]. In vivo data are conflicting since, although testosterone increases transcription of ATTR, so does estrogen [48]. Atrial natriuretic factor amyloidosis

Atrial natriuretic factor amyloidosis or isolated atrial amyloidosis is a localized form of amyloidosis that is caused by infiltration of the atrial myocardium by amyloidogenic atrial natriuretic peptide, a hormone normally produced by atrial cardiomyocytes. Similar to wt-ATTR, the incidence of this disease increases with age, with prevalence estimates as high as 90% in the ninth decade [49]. However, unlike ATTR, amyloid deposition is more pronounced in females [49]. The anterior parts and the left atrium tend to be more heavily infiltrated than the posterior parts or the right atrium [49]. The presence of atrial natriuretic factor amyloidosis is associated with atrial fibrillation [50] and other atrial tachyarrhythmias [51] as well as with congestive heart failure [52,53], although the causal nature of this association is not entirely clear. It has been hypothesized that ANF amyloid formation is ‘kick-started’ by early changes related to cardiac dysfunction caused by early preamyloid intermediates. These early fibrils are unstable but as congestive heart failure progresses the formation of more stable amyloid fibrils is favored [53]. At later stages, ANF likely directly impairs cardiac contractility and evidence for that is provided by studies showing direct association of amyloid fibrils with atrial myofibrils [49]. Serum amyloid A

Serum amyloid A (AA) amyloidosis was previously known as secondary amyloidosis and is associated with a number of systemic inflammatory conditions that subsequently lead to deposition of fibrils derived from the acute-phase reactant serum AA. Cardiac involvement is quite rare [27] and the kidneys are doi: 10.1586/14779072.2015.1069181

almost always affected [28]. Even when cardiac involvement is present, it is usually much milder compared with extracardiac involvement [29]. The natural history of the disease is unique, in that, only a small minority of patients with chronic inflammation develop clinically overt AA amyloidosis and the disease is typically preceded by many years of active inflammation, and the clinical presentation is then relatively acute. What eventually triggers rapid amyloid deposition or causes emergence of amyloid toxicity is unknown [30]. Apolipoprotein A1

Apolipoprotein A1 amyloidosis commonly affects the kidneys and sometimes the liver [46]. Cardiac involvement has been reported but is thought to be rare [47,48]. Mechanisms of toxicity have not been fully elucidated but are thought to be mediated by attenuating the anti-apoptotic activity of angiogenin [49] and promoting inflammation in situ [50,51]. Clinical manifestations

Successful diagnosis of amyloidosis is challenging because the disease is rare and it usually manifests with non-specific signs and symptoms. Late diagnosis is not uncommon and it is a major limitation in achieving optimal patient outcomes [54]. In AL amyloidosis for instance up to a third of patients die within the first 18 months of diagnosis, most because of advanced cardiac involvement [3,55]. Even in patients who have an established diagnosis of a plasma cell dyscrasia not requiring treatment, such as MGUS or smoldering myeloma, where one would expect clinicians to have a higher index of suspicion, diagnosis is delayed by about a year from the time of symptom development [8]. Prior comorbidities that might confound the diagnosis are present in approximately 20% of AL patients and 40% of ATTR patients [8,56,57]. During this period precious organ function is lost. Delayed diagnosis is also common, probably being the rule rather than the exception, in non-AL amyloidosis [58,59], but patient outcomes are not as severely affected due to its more indolent nature. Symptoms due to cardiac involvement

Cardiac involvement by amyloidosis usually presents with signs and symptoms of HFpEF. A drop in the EF is usually seen in advanced disease. Because of its more aggressive nature, AL patients typically present with more advanced heart failure symptomatology when compared with ATTR patients [56]. Dyspnea at rest or exertion is the most common symptom of cardiac involvement in both AL and ATTR amyloidosis [8,56] and it develops at a median of 6 months prior to diagnosis in patients with AL [8]. Hypotension or syncope at presentation are seen in 5–10% of patients at diagnosis and are associated with worse outcomes [60]. Peripheral edema and hepatic congestion can often be present; the former can be present in patients with renal involvement and the latter can mimic hepatic involvement by amyloid. Angina-like chest pain can be a sign of intracardiac small vessel involvement [24,25]. Expert Rev. Cardiovasc. Ther.

Improving strategies for the diagnosis of cardiac amyloidosis

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Unusual manifestations such as constrictive pericarditis have been reported but these are exceptionally rare [61]. Amyloid deposition can be found in surgically removed heart valves, more commonly in aortic stenosis [62], but valvulopathies are not a common manifestation of most amyloidoses.

A

Review

B

Symptoms due to extracardiac involvement

Virtually every organ can be involved by AL amyloidosis. A comprehensive review of these symptoms is beyond the scope of this review. Signs and symptoms that are relatively specific for AL are worth keeping in mind. For instance, macroglossia Figure 1. Soft tissue involvement in amyloidosis. Macroglossia (A) and periorbital and periorbital involvement (FIGURE 1) are purpura (B) in light chain amyloidosis. usually present in only approximately 10 and 33% of AL patients at diagnosis, respectively [5], but when present AL amyloidosis should always Hypogammaglobulinemia is frequently seen as a result of excluded. Both of these symptoms are not a feature of nephrotic range proteinuria or simply because of immunosuppression related to the malignant plasma cell clone and can be ATTR [56]. Renal involvement is common in AL and presents with an early clue for the diagnosis of AL amyloidosis. A circulating nephrotic range proteinuria but it is uncommon in ATTR, monoclonal protein is common in the general population and although a subset of patients with ATTR V30M develop when present in combination with a CR-positive organ biopsy, nephrotic range proteinuria [63]. Peripheral and autonomic neu- does not always secure the diagnosis of AL amyloidosis. Amyropathy are seen in approximately 10% of patients with AL loid typing should always be performed in these cases since we but more than half of patients with cardiac ATTR and are have encountered non-AL amyloidosis with an associated more common in mt-ATTR compared with wt-ATTR [64]. In MGUS [66] or even localized AL with a different clonality than AL, peripheral neuropathy is associated with autonomic neu- that of a circulating monoclonal protein. Cardiac biomarkers (troponin, BNP or N-terminal pro-BNP ropathy in approximately 80% of cases [65]. Electroneuromyography usually reveals axonal sensorimotor polyneuropathies. It [NT-proBNP]) should be tested in patients with AL and nonhas an ascending pattern in ATTR. A history of carpal tunnel AL amyloidosis. There are very sensitive (>90%) for cardiac syndrome is seen in approximately half of the patients with involvement in AL [67] but less sensitive in non-AL [68,69], ATTR [56] and is worth eliciting during the patient examina- although their specificity is low since they can be elevated in a number of other conditions. In addition, they have prognostic tion, although it is non-specific. significance in AL [3,55] and possibly in non-AL, although they have not been validated as prognostic markers in the latter [69]. Diagnostic evaluation Obtaining an endomyocardial biopsy (EMB) is not always In AL, the 2004-Mayo AL amyloidosis staging system stratifies practically feasible and the diagnosis is frequently established patients by cardiac troponin T and NT-proBNP thresholds on the basis of a combination of non-invasive tests and docu- (0.035 ng/ml and 332 pg/ml, respectively) as follows: stage I, mentation of Congo red (CR) amyloid deposits in tissues such both below threshold, stage II, either above threshold and stage III, both above threshold. The 2012-Mayo AL amyloidosis as bone marrow, abdominal fat, rectum or lip. staging system found that adding difference in concentration between involved and uninvolved free light chains as a marker Initial testing Simple peripheral blood tests can offer valuable information. of plasma cell burden has an incremental prognostic value over Cytopenias can sometimes be seen in the 5–10% of AL amy- the old stage system. The newer system stratifies patients by loidosis patients who present with concomitant MM and are cardiac troponin T, NT-proBNP and difference between the associated with worse prognosis [9]. Cytopenias should not be involved and uninvolved free light chain thresholds (0.05 ng/ attributed to non-AL amyloidosis. Since AL amyloidosis is a ml, 1800 pg/ml and 18 mg/dl, respectively): stage I, all below low plasma cell burden disease, a monoclonal spike might not threshold, stage II, two below threshold, stage III, one below be seen on serum protein electrophoresis. It is therefore impor- threshold and stage IV, none below threshold. Finally, cardiac tant to always check a serum immunofixation and free light biomarkers are used to follow cardiac organ response to treatchain levels, which also have prognostic value [3]. ment [70] so establishing a baseline is critical. informahealthcare.com

doi: 10.1586/14779072.2015.1069181

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Review

Kourelis & Gertz

Figure 2. Low voltages and pseudo-infarct pattern in cardiac amyloidosis.

A cholestatic liver pattern with an increased alkaline phosphatase is also suggestive of liver infiltration. Increase in bilirubin or liver transaminases is less common. This and absence of jugular venous distention on exam can help differentiate between liver infiltration and congestive hepatopathy because of heart failure. Proteinuria can be suggestive of renal involvement and can help with the differential diagnosis of peripheral edema in these patients. Howell–Jolly bodies can be observed in the rare patient with splenic infiltration and resulting hyposplenism. Coagulation parameters can be abnormal in patients with liver involvement (low factor V), malabsorption (vitamin K-dependent factors) or because of direct binding of circulating AL fibrils with factor X. Classic electrocardiographic findings include low voltages or QS waves (FIGURE 2), which, when found together, have a low sensitivity (28%) but a relatively high sensitivity (98%) for diagnosing cardiac involvement in one study [71] and are found more commonly in more advanced cardiac infiltration. For this reason, they tend to be more common in AL and less common in non-AL amyloidosis [72]. Some authors have suggested that electrocardiographic data can be used to quickly differentiate cardiac amyloid from hypertrophic cardiomyopathy [73], but this claim requires validation in an independent cohort. Cardiac arrhythmias and atrial fibrillation in particular are seen in approximately 10% of patients with ATTR [56]. Not surprisingly, atrial fibrillation was encountered in approximately half of patients with isolated atrial amyloidosis [51] in pre-mortem ECGs. On the other hand, supraventricular arrhythmias appear to be less common in patients with AL amyloidosis. In AL amyloidosis, non-sustained ventricular tachycardias were noted in 100% of patients with cardiac involvement undergoing autologous stem cell transplant while on continuous telemetry doi: 10.1586/14779072.2015.1069181

monitoring [29]. The exact incidence of ventricular arrhythmias or sudden cardiac death is not precisely known since these events are difficult to capture in practice; older reports estimate them to be approximately 50 and 10%, respectively [74]. A 6-min walk test is another non-invasive test that can be considered as ‘baseline’, particularly in non-AL amyloidosis It is cheap, simple and has been used and validated in multiple recent clinical trials as a surrogate of clinical outcomes [75]. Targeting an organ for biopsy

The gold standard for diagnosis of all cardiac amyloidoses is an EMB followed by amyloid typing to determine the amyloidogenic protein. Since EMB might not always be practical to obtain, extracardiac tissues are commonly targeted for biopsy. However, this procedure is indicated if the diagnosis continues to be equivocal after an extensive workup, or if an unequivocal diagnosis before heart transplantation is needed, posttransplantation (FIGURE 3) rejection is suspected, or amyloid deposition is primarily confined to the heart. Guidelines from the American College of Cardiology/American Heart Association state that EMB should not be performed routinely in patients with heart failure, unless the definitive diagnosis is required to specifically direct therapy [75]. Therefore, in suspected cardiac amyloidosis in experienced centers significant complications were rare (12 months to approximately 4 years. Treatment options for non-AL are still limited to liver transplantation and supportive care with a number of promising experimental agents still in development.

Delayed diagnosis is likely to remain a problem in the near future. Some experts have recommended an annual urine analysis for proteinuria and testing of cardiac biomarkers in all patients with MGUS as screening for AL amyloidosis but it is unknown whether this practice is effective or cost-effective. Different cardiac biomarkers (e.g., soluble ST2) are likely to enter clinical practice in non-AL cardiac amyloidosis. Soluble ST2 correlates with cardiac ‘stiffness’ and fibrosis better than NT-proBNP and troponin and might be a better marker of cardiac dysfunction in non-AL. Advances in proteomics are likely to advance our understanding of the pathogenesis of AL and non-AL amyloidosis and to increase diagnostic sensitivity. Identification of unique amyloid proteomic markers in organ biopsies may soon replace CR as the first step in diagnosis and may identify the presence of amyloid or pre-amyloid fibrils much earlier and more objectively. Furthermore, study of the amyloid proteome might provide answers to what defines inter-patient variability in organ tropism, amyloid formation and breakdown dynamics in vivo and response to treatment. Finally, advances in therapeutics are still desperately needed. AL is more fortunate in that regard since it benefits from rapid advances in MM, although all of these approaches only address plasma cell burden and ignore the already deposited amyloid core. Monoclonal antibodies that will selectively target misfolded proteins and small interfering RNAs have the potential

informahealthcare.com

doi: 10.1586/14779072.2015.1069181

Review

Kourelis & Gertz

Clinical and echocardiographic suspicion of cardiac amyloidosis

Check serum and urine IFE and free light chains Negative

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Positive

Fat aspirate biopsy and MS typing

Hematology referral. Bone marrow and fat pad biopsy

Positive by CR AL likely. Perform MS typing, chemistries 24 h urine protein

Negative by CR but high index of suspicion remains Endomyocardial biopsy. Advanced imaging (MRI, nuclear) if patient declines

Positive by CR

Negative by CR but high index of suspicion remains

If TTR identify underlying mutation

Endomyocardial biopsy. Advanced imaging (MRI, nuclear) if patient declines

Figure 8. Suggested diagnostic evaluation of patients who present with clinical suspicion of cardiac amyloidosis. AL: Immunoglobulin light chain amyloidosis; CR: Congo red; IFE: Immunofixation; TTR: Transthyretin amyloidosis.

to be first-in-class disease-modifying agents for both AL and non-AL amyloidosis. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial

conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues .

Amyloidoses are a highly heterogeneous group of rare diseases caused by deposition of misfolded proteins in various organs. The heart is commonly affected in many cases and is a major determinant of patient outcomes.

.

The two most common amyloidoses affecting the heart are immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis.

.

The disease presents with very non-specific signs and symptoms and a high index of suspicion should be maintained. A major ‘bottleneck’ in improving patient outcomes is late diagnosis, during which precious organ function is lost.

.

Once suspected, the first step in diagnosis includes testing of cardiac biomarkers and targeting an organ for biopsy. Fat pad and/or a bone marrow biopsy are easily obtainable and can have a high yield in identifying Congo red amyloid deposits.

.

If in doubt, an endomyocardial biopsy should always be pursued.

.

Amyloid typing by mass spectrometry is the gold standard for identifying the amyloidogenic protein.

.

Modern echocardiography has increased the sensitivity and specificity for identifying early cardiac involvement and is an essential part of the diagnostic work-up.

.

More advanced imaging (MRI and nuclear based) should be considered on a case-by-case basis, but is usually not necessary to diagnose the disease. The incremental prognostic value that these methods have over echocardiography and cardiac biomarkers is also unclear.

doi: 10.1586/14779072.2015.1069181

Expert Rev. Cardiovasc. Ther.

Improving strategies for the diagnosis of cardiac amyloidosis

high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013;31:4319-24

References

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

Papers of special note have been highlighted as: . of interest .. of considerable interest 1.

Sipe JD, Benson MD, Buxbaum JN, et al. Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 2014;21:221-4

..

This paper describes the modern nomenclature used to classify amyloidogenic proteins.

2.

3.

..

4.

5.

6.

7.

8.

9.

Bellavia D, Pellikka PA, Dispenzieri A, et al. Comparison of right ventricular longitudinal strain imaging, tricuspid annular plane systolic excursion, and cardiac biomarkers for early diagnosis of cardiac involvement and risk stratification in primary systematic (AL) amyloidosis: a 5-year cohort study. Eur Heart J Cardiovasc Imaging 2012;13:680-9 Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30: 989-95 This is the revised staging system for immunoglobulin light chain (AL) amyloidosis that adds difference in concentration between involved and uninvolved free light chains to cardiac biomarkers and refines prognostic statification of patinets.

10.

11.

12.

13.

14.

15.

Kristen AV, Scherer K, Buss S, et al. Noninvasive risk stratification of patients with transthyretin amyloidosis. JACC Cardiovasc Imaging 2014;7:502-10 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32: 45-59 Kaufman GP, Dispenzieri A, Gertz MA, et al. Kinetics of organ response and survival following normalization of the serum free light chain ratio in AL amyloidosis. Am J Hematol 2015;90:181-6 Peled Y, Gramlich M, Yoskovitz G, et al. Titin mutation in familial restrictive cardiomyopathy. Int J Cardiol 2014;171: 24-30 Kourelis TV, Kumar SK, Go RS, et al. Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias. Am J Hematol 2014;89:1051-4 Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally

informahealthcare.com

Perfetti V, Palladini G, Casarini S, et al. The repertoire of lambda light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44. Blood 2012;119:144-50 Taxiarchis V, Kourelis DS, Jason D. Theis, marina ramirez-alvarado, paul kurtin, morie gertz, stephen zeldenrust, ahmet dogan and angela dispenzieri. clarifying immunoglobulin gene family usage. In AL amyloidosis by mass spectrometry of amyloid. ISA annual meeting. Indianapolis, IN; 2014 Warsame R, Kumar SK, Gertz MA, et al. Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death. Blood Cancer J 2015;5:e310 Comenzo RL, Zhang Y, Martinez C, et al. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood 2001;98:714-20 Abraham RS, Geyer SM, Price-Troska TL, et al. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood 2003;101:3801-8 Perfetti V, Casarini S, Palladini G, et al. Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood 2002;100:948-53

Review

20.

Brenner DA, Jain M, Pimentel DR, et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 2004;94:1008-10

21.

Shi J, Guan J, Jiang B, et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci USA 2010;107:4188-93

22.

Dubrey S, Mendes L, Skinner M, et al. Resolution of heart failure in patients with AL amyloidosis. Ann Intern Med 1996;125: 481-4

23.

Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 2006;107:3854-8

24.

Tsai SB, Seldin DC, Wu H, et al. Myocardial infarction with “clean coronaries” caused by amyloid light-chain AL amyloidosis: a case report and literature review. Amyloid 2011;18:160-4

25.

Dorbala S, Vangala D, Bruyere J Jr, et al. Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis. JACC Heart Fail 2014;2: 358-67

26.

Tanaka K, Essick EE, Doros G, et al. Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases in cardiac amyloidosis. J Am Heart Assoc 2013;2:e005868

27.

Biolo A, Ramamurthy S, Connors LH, et al. Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail 2008;1: 249-57

16.

Wilson MR, Yerbury JJ, Poon S. Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity. Mol Biosyst 2008;4:42-52

28.

17.

Shin JT, Ward JE, Collins PA, et al. Overexpression of human amyloidogenic light chains causes heart failure in embryonic zebrafish: a preliminary report. Amyloid 2012;19:191-6

Boldrini M, Salinaro F, Mussinelli R, et al. Prevalence and prognostic value of conduction disturbances at the time of diagnosis of cardiac AL amyloidosis. Ann Noninvasive Electrocardiol 2013;18:327-35

29.

18.

Diomede L, Rognoni P, Lavatelli F, et al. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis. Blood 2014;123: 3543-52

19.

Liao R, Jain M, Teller P, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 2001;104:1594-7

Goldsmith YB, Liu J, Chou J, et al. Frequencies and types of arrhythmias in patients with systemic light-chain amyloidosis with cardiac involvement undergoing stem cell transplantation on telemetry monitoring. Am J Cardiol 2009;104:990-4

.

This paper suggest that arrhthmias are universally present in this patient population.

doi: 10.1586/14779072.2015.1069181

Review 30.

.

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

31.

Kourelis & Gertz

Sayed RH, Rogers D, Khan F, et al. A study of implanted cardiac rhythm recorders in advanced cardiac AL amyloidosis. Eur Heart J 2015;36:1098-105 This study demonstrates that bradyarrhtmias are freqently recognized prior to sudden cardiac death in patients with advanced cardiac involvement in AL amyloidosis. Al-Zahrani GB, Bellavia D, Pellikka PA, et al. Doppler myocardial imaging compared to standard two-dimensional and Doppler echocardiography for assessment of diastolic function in patients with systemic amyloidosis. J Am Soc Echocardiogr 2009;22:290-8

32.

Zhao L, Buxbaum JN, Reixach N. Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry 2013;52:1913-26

33.

Reixach N, Deechongkit S, Jiang X, et al. Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci USA 2004;101:2817-22

34.

35.

36.

37.

38.

39.

Bourgault S, Choi S, Buxbaum JN, et al. Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs. Biochem Biophys Res Commun 2011;410: 707-13

human senile systemic (transthyretin) amyloidosis? Faseb J 2012;26:2283-93 .

Interesting data supporting that hepatic-derived chaperones might influence amyloidogenicity.

40.

Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40:232-9

53.

Millucci L, Ghezzi L, Bernardini G, et al. Prevalence of isolated atrial amyloidosis in young patients affected by congestive heart failure. ScientificWorldJournal 2012;2012:293863

54.

Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med 2015;372:21-9

Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating physicians. Blood 2013;121: 5124-30

55.

Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22:3751-7

56.

Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013;2:e000098

57.

Gutierrez PS, Fernandes F, Mady C, et al. Clinical, electrocardiographic and echocardiographic findings in significant cardiac amyloidosis detected only at necropsy: comparison with cases diagnosed in life. Arq Bras Cardiol 2008;90:191-6

58.

Koivuniemi R, Paimela L, Suomalainen R, et al. Amyloidosis is frequently undetected in patients with rheumatoid arthritis. Amyloid 2008;15:262-8

59.

Takigawa M, Hashimura K, Ishibashi-Ueda H, et al. Annual electrocardiograms consistent with silent progression of cardiac involvement in sporadic familial amyloid polyneuropathy: a case report. Intern Med 2010;49:139-44

60.

Finocchiaro G, Merlo M, Pinamonti B, et al. Long term survival in patients with cardiac amyloidosis. Prevalence and characterisation during follow-up. Heart Lung Circ 2013;22:647-54

61.

Singh V, Fishman JE, Alfonso CE. Primary systemic amyloidosis presenting as constrictive pericarditis. Cardiology 2011;118:251-5

62.

Kristen AV, Schnabel PA, Winter B, et al. High prevalence of amyloid in 150 surgically removed heart valves–a comparison of histological and clinical data reveals a correlation to atheroinflammatory

.

This paper demonstrated that the V122I variant was associated with a highr risk of heart failure but not death in African American patients.

43.

Magalhaes J, Saraiva MJ. Clusterin overexpression and its possible protective role in transthyretin deposition in familial amyloidotic polyneuropathy. J Neuropathol Exp Neurol 2011;70:1097-106

45.

Sidorova TN, Mace LC, Wells KS, et al. Quantitative Imaging of Preamyloid Oligomers, a Novel Structural Abnormality, in Human Atrial Samples. J Histochem Cytochem 2014;62:479-87

Greene MJ, Sam F, Soo Hoo PT, et al. Evidence for a functional role of the molecular chaperone clusterin in amyloidotic cardiomyopathy. Am J Pathol 2011;178:61-8

46.

Sorgjerd K, Ghafouri B, Jonsson BH, et al. Retention of misfolded mutant transthyretin by the chaperone BiP/GRP78 mitigates amyloidogenesis. J Mol Biol 2006;356: 469-82

47.

Rapezzi C, Riva L, Quarta CC, et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 2008;15:40-8

48.

Goncalves I, Alves CH, Quintela T, et al. Transthyretin is up-regulated by sex hormones in mice liver. Mol Cell Biochem 2008;317:137-42

doi: 10.1586/14779072.2015.1069181

Millucci L, Paccagnini E, Ghezzi L, et al. Different factors affecting human ANP amyloid aggregation and their implications in congestive heart failure. PLoS ONE 2011;6:e21870

42.

Azevedo EP, Guimaraes-Costa AB, Torezani GS, et al. Amyloid fibrils trigger the release of neutrophil extracellular traps (NETs), causing fibril fragmentation by NET-associated elastase. J Biol Chem 2012;287:37206-18

Buxbaum JN, Tagoe C, Gallo G, et al. Why are some amyloidoses systemic? Does hepatic “chaperoning at a distance” prevent cardiac deposition in a transgenic model of

52.

Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-73

Greene MJ, Klimtchuk ES, Seldin DC, et al. Cooperative stabilization of transthyretin by clusterin and diflunisal. Biochemistry 2015;54:268-78

Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113-22

Ariyarajah V, Steiner I, Hajkova P, et al. The association of atrial tachyarrhythmias with isolated atrial amyloid disease: preliminary observations in autopsied heart specimens. Cardiology 2009;113:132-7

41.

44.

Sousa MM, Cardoso I, Fernandes R, et al. Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am J Pathol 2001;159: 1993-2000

51.

49.

50.

Steiner I, Hajkova P. Patterns of isolated atrial amyloid: a study of 100 hearts on autopsy. Cardiovasc Pathol 2006;15:287-90 Rocken C, Peters B, Juenemann G, et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002;106:2091-7

Expert Rev. Cardiovasc. Ther.

Improving strategies for the diagnosis of cardiac amyloidosis

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

conditions. Cardiovasc Pathol 2010;19: 228-35 63.

Lobato L, Beirao I, Silva M, et al. End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation, survival and prognostic factors. Amyloid 2004;11:27-37

64.

Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34: 520-8

73.

74.

Tomas MT, Santa-Clara MH, Monteiro E, et al. Body composition, muscle strength, functional capacity, and physical disability risk in liver transplanted familial amyloidotic polyneuropathy patients. Clin Transplant 2011;25:E406-14

76.

Parrillo JE, Aretz HT, Palacios I, et al. The results of transvenous endomyocardial biopsy can frequently be used to diagnose myocardial diseases in patients with idiopathic heart failure. Endomyocardial biopsies in 100 consecutive patients revealed a substantial incidence of myocarditis. Circulation 1984;69:93-101

Wang AK, Fealey RD, Gehrking TL, et al. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc 2008;83:1226-30

66.

Maleszewski JJ, Murray DL, Dispenzieri A, et al. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc Pathol 2013;22:189-94

67.

Palladini G, Campana C, Klersy C, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation 2003;107:2440-5

77.

Suhr OB, Anan I, Backman C, et al. Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis? J Intern Med 2008;263: 294-301

78.

69.

70.

..

71.

72.

Damy T, Deux JF, Moutereau S, et al. Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis. Amyloid 2013;20: 212-20 Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541-9 This paper presents updated criteria for hematologic and organ response to treatment. Changes in septum diameter or ejection fraction are no longer important when assessing cardiac response to treatment in AL amyloidosis. Cheng Z, Zhu K, Tian Z, et al. The findings of electrocardiography in patients with cardiac amyloidosis. Ann Noninvasive Electrocardiol 2013;18:157-62 Cyrille NB, Goldsmith J, Alvarez J, et al. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol 2014;114:1089-93

informahealthcare.com

Falk RH, Rubinow A, Cohen AS. Cardiac arrhythmias in systemic amyloidosis: correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984;3(1): 107-13

75.

65.

68.

Namdar M, Steffel J, Jetzer S, et al. Value of electrocardiogram in the differentiation of hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, amyloidosis, and Fabry disease. Am J Cardiol 2012;109: 587-93

79.

Pellikka PA, Holmes DR Jr, Edwards WD, et al. Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement. Arch Intern Med 1988;148:662-6 Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens. J Clin Oncol 2015;33:1371-8 Bochtler T, Hegenbart U, Kunz C, et al. Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone. Amyloid 2014;21:9-17

80.

Fine NM, Arruda-Olson AM, Dispenzieri A, et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis. Am J Cardiol 2014;113:1723-7

81.

Clement CG, Truong LD. An evaluation of Congo red fluorescence for the diagnosis of amyloidosis. Hum Pathol 2014;45:1766-72

82.

Vrana JA, Theis JD, Dasari S, et al. Clinical diagnosis and typing of systemic amyloidosis in subcutaneous fat aspirates by mass spectrometry-based proteomics. Haematologica 2014;99:1239-47

.

Novel mass spetrometry-based method to type fat pad biopsy specimens.

83.

Pomerance A, Slavin G, McWatt J. Experience with the sodium sulphate-Alcian

Review

Blue stain for amyloid in cardiac pathology. J Clin Pathol 1976;29:22-6 84.

Gilbertson JA, Theis JD, Vrana JA, et al. A comparison of immunohistochemistry and mass spectrometry for determining the amyloid fibril protein from formalin-fixed biopsy tissue. J Clin Pathol 2015;68:314-17

85.

Satoskar AA, Efebera Y, Hasan A, et al. Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing. Am J Surg Pathol 2011;35:1685-90

86.

Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009;114: 4957-9

..

Seminal paper describing a mass spectrometry methodology for amyloid typing in clinical tissue specimens.

87.

Theis JD, Dasari S, Vrana JA, et al. Shotgun-proteomics-based clinical testing for diagnosis and classification of amyloidosis. J Mass Spectrom 2013;48: 1067-77

88.

Jason DT, Julie AV, Oana MM, et al. Proteome of amyloidosis: Mayo Clinic Experience In 4139 Cases. Blood 2013; 122(21)

89.

Casadonte R, Kriegsmann M, Deininger SO, et al. Imaging mass spectrometry analysis of renal amyloidosis biopsies reveals protein co-localization with amyloid deposits. Anal Bioanal Chem 2015;407(18):5323-31

90.

Dasari S, Theis JD, Vrana JA, et al. Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies. J Proteome Res 2015;14:1957-67

91.

D’Souza A, Theis J, Quint P, et al. Exploring the amyloid proteome in immunoglobulin-derived lymph node amyloidosis using laser microdissection/ tandem mass spectrometry. Am J Hematol 2013;88:577-80

92.

Linke RP. On typing amyloidosis using immunohistochemistry. Detailed illustrations, review and a note on mass spectrometry. Prog Histochem Cytochem 2012;47:61-132

.

Interesting paper describing the diagnostic accuracy of immunohistochemistry when using novel antibodies against amyloidogenic proteins.

93.

Fernandez de Larrea C, Verga L, Morbini P, et al. A practical approach to the diagnosis of

doi: 10.1586/14779072.2015.1069181

Review

Kourelis & Gertz

amyloidosis. Am J Cardiol 2009;103: 1429-33

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

systemic amyloidoses. Blood 2015;125: 2239-44 94.

Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckletracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 2012;98:1442-8

95.

Baccouche H, Maunz M, Beck T, et al. Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three-dimensional speckle tracking echocardiography. Echocardiography 2012;29:668-77

96.

97.

98.

99.

100.

101.

102.

103.

Sun JP, Stewart WJ, Yang XS, et al. Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography. Am J Cardiol 2009;103:411-15 Porciani MC, Lilli A, Perfetto F, et al. Tissue Doppler and strain imaging: a new tool for early detection of cardiac amyloidosis. Amyloid 2009;16:63-70 Bellavia D, Abraham TP, Pellikka PA, et al. Detection of left ventricular systolic dysfunction in cardiac amyloidosis with strain rate echocardiography. J Am Soc Echocardiogr 2007;20:1194-202 Lindqvist P, Olofsson BO, Backman C, et al. Pulsed tissue Doppler and strain imaging discloses early signs of infiltrative cardiac disease: a study on patients with familial amyloidotic polyneuropathy. Eur J Echocardiogr 2006;7:22-30 Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am J Cardiol 2008;101: 1039-45 Migrino RQ, Mareedu RK, Eastwood D, et al. Left ventricular ejection time on echocardiography predicts long-term mortality in light chain amyloidosis. J Am Soc Echocardiogr 2009;22:1396-402 Kristen AV, Perz JB, Schonland SO, et al. Non-invasive predictors of survival in cardiac amyloidosis. Eur J Heart Fail 2007;9:617-24 Austin BA, Duffy B, Tan C, et al. Comparison of functional status, electrocardiographic, and echocardiographic parameters to mortality in endomyocardial-biopsy proven cardiac

doi: 10.1586/14779072.2015.1069181

104.

Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 2014;129: 1840-9

.

This paper underlines how patterns of LV function and structure differ between AL and ATTR.

105.

106.

107.

108.

109.

110.

111.

112.

113.

subtype. Rev Esp Cardiol (Engl) 2012;65: 440-6 114.

Rapezzi C, Quarta CC, Guidalotti PL, et al. Usefulness and limitations of 99mTc-3,3diphosphono-1,2-propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38:470-8

115.

Bokhari S, Shahzad R, Castano A, et al. Nuclear imaging modalities for cardiac amyloidosis. J Nucl Cardiol 2014;21:175-84

116.

Tanaka M, Hongo M, Kinoshita O, et al. Iodine-123 metaiodobenzylguanidine scintigraphic assessment of myocardial sympathetic innervation in patients with familial amyloid polyneuropathy. J Am Coll Cardiol 1997;29:168-74

117.

Delahaye N, Dinanian S, Slama MS, et al. Cardiac sympathetic denervation in familial amyloid polyneuropathy assessed by iodine-123 metaiodobenzylguanidine scintigraphy and heart rate variability. Eur J Nucl Med 1999;26:416-24

118.

Antoni G, Lubberink M, Estrada S, et al. In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET. J Nucl Med 2013;54:213-20

119.

Dorbala S, Vangala D, Semer J, et al. Imaging cardiac amyloidosis: a pilot study using (1)(8)F-florbetapir positron emission tomography. Eur J Nucl Med Mol Imaging 2014;41:1652-62

120.

Ruberg FL. T1 mapping in cardiac amyloidosis: can we get there from here? JACC Cardiovascular Imaging 2013;6: 498-500

121.

Kristen AV, Haufe S, Schonland SO, et al. Skeletal scintigraphy indicates disease severity of cardiac involvement in patients with senile systemic amyloidosis. Int J Cardiol 2013;164:179-84

Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111: 186-93

122.

Rapezzi C, Quarta CC, Guidalotti PL, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovascular Imaging 2011;4: 659-70

Perugini E, Rapezzi C, Piva T, et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart 2006;92:343-9

123.

Vogelsberg H, Mahrholdt H, Deluigi CC, et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol 2008;51:1022-30

..

Interesting paper underscoring how late gadolinium enchanchement patterns can help in the diagnosis of cardiac amyloidosis.

124.

Austin BA, Tang WH, Rodriguez ER, et al. Delayed hyper-enhancement magnetic resonance imaging provides incremental

Ogiwara F, Koyama J, Ikeda S, et al. Comparison of the strain Doppler echocardiographic features of familial amyloid polyneuropathy (FAP) and light-chain amyloidosis. Am J Cardiol 2005;95:538-40 Liu D, Hu K, Niemann M, et al. Effect of combined systolic and diastolic functional parameter assessment for differentiation of cardiac amyloidosis from other causes of concentric left ventricular hypertrophy. Circ Cardiovasc Imaging 2013;6:1066-72 Han S, Chong V, Murray T, et al. Preliminary experience of 99mTc-Aprotinin scintigraphy in amyloidosis. Eur J Haematol 2007;79:494-500 Janssen S, van Rijswijk MH, Piers DA, et al. Soft-tissue uptake of 99mTc-diphosphonate in systemic AL amyloidosis. Eur J Nucl Med 1984;9: 538-41 Glaudemans AW, van Rheenen RW, van den Berg MP, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid 2014;21:35-44

Bokhari S, Castano A, Pozniakoff T, et al. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6:195-201 de Haro-del Moral FJ, Sanchez-Lajusticia A, Gomez-Bueno M, et al. Role of cardiac scintigraphy with (9)(9)mTc-DPD in the differentiation of cardiac amyloidosis

Expert Rev. Cardiovasc. Ther.

Improving strategies for the diagnosis of cardiac amyloidosis

method for the diagnosis of cardiac amyloidosis. Int J Cardiovasc Imaging 2014;30:1105-15

diagnostic and prognostic utility in suspected cardiac amyloidosis. JACC Cardiovascular Imaging 2009;2:1369-77 125.

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/17/15 For personal use only.

126.

127.

128.

129.

130.

131.

Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovascular Imaging 2010;3:155-64 Di Bella G, Minutoli F, Mazzeo A, et al. MRI of cardiac involvement in transthyretin familial amyloid polyneuropathy. AJR Am J Roentgenol 2010;195:W394-9 Dungu JN, Valencia O, Pinney JH, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovascular Imaging 2014;7:133-42 Brooks J, Kramer CM, Salerno M. Markedly increased volume of distribution of gadolinium in cardiac amyloidosis demonstrated by T1 mapping. J Magn Res Imaging 2013;38:1591-5 Karamitsos TD, Piechnik SK, Banypersad SM, et al. Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovascular Imaging 2013;6:488-97 White JA, Kim HW, Shah D, et al. CMR imaging with rapid visual T1 assessment predicts mortality in patients suspected of cardiac amyloidosis. JACC Cardiovascular Imaging 2014;7:143-56 Aquaro GD, Pugliese NR, Perfetto F, et al. Myocardial signal intensity decay after gadolinium injection: a fast and effective

informahealthcare.com

132.

133.

APOLLO: the study of an investigational drug, patisiran (ALN-TTR02), for the treatment of transthyretin (TTR)-mediated amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT01960348 A extension study to evaluate revusiran (ALN-TTRSC) in patients with transthyretin (TTR) cardiac amyloidosis. Available from: www.clinicaltrials.gov/ct2/ show/NCT02292186

Review

139.

The vital amyloidosis study, a Phase III, multicenter efficacy and safety study of NEOD001. Available from: www. clinicaltrials.gov/ct2/show/NCT02312206

140.

A study to evaluate the safety of GSK2398852 when co-administered with GSK2315698 in patients with systemic amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT01777243

141.

Study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT02245867

134.

Efficacy and safety of ISIS-TTR Rx in familial amyloid polyneuropathy. Available from: www.clinicaltrials.gov/ct2/show/ NCT01737398

142.

Oral doxycycline administered as an adjunct to plasma cell directed therapy in light chain amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT02207556

135.

Safety and efficacy evaluation of Fx-1006A in subjects with transthyretin amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT00925002

143.

Epigallocatechin gallate (EGCG) in cardiac AL amyloidosis (EpiCardiAL). Available from: www.clinicaltrials.gov/ct2/show/ NCT01511263

136.

Safety and efficacy of tafamidis in patients with transthyretin cardiomyopathy (ATTRACT). Available from: www.clinicaltrials. gov/ct2/show/NCT01994889

144.

137.

The effect of diflunisal on familial transthyretin amyloidosis (DFNS01). Available from: www.clinicaltrials.gov/ct2/ show/NCT01432587

A trial for the treatment of cardiac ALamyloidosis with the green tea compound epigallocatechin-3-gallate (TAME-AL). Available from: www.clinicaltrials.gov/ct2/ show/NCT02015312

145.

Gertz MA, Dispenzieri A, Sher T. Pathophysiology and treatment of cardiac amyloidosis. Nat Rev Cardiol 2015;12(2): 91-102

138.

Phase I/2, open label, dose escalation study of NEOD001 in subjects with light chain (AL) amyloidosis. Available from: www. clinicaltrials.gov/ct2/show/NCT01707264

doi: 10.1586/14779072.2015.1069181

Improving strategies for the diagnosis of cardiac amyloidosis.

Amyloidosis refers to a group of rare but potentially fatal, protein misfolding diseases. The heart is frequently involved in the most common types, t...
1MB Sizes 0 Downloads 15 Views