The underlying pathophysiology of amyloidosis is characterized by the abnormal production of misfolded proteins, which aggregate in various organs and tissues and result in deposition, tissue destruction, and ischemia. The three most common forms of amyloidosis in the Western world are amyloid light-chain (AL) – amyloidosis, mutant transthyretin amyloidosis (ATTR) (so-called familial amyloid), and wild-type transthyretin (formerly known as senile systemic or senile cardiac amyloidosis). Rarer forms of amyloid are recognized, including amyloid A (AA) amyloidosis in inflammatory diseases, where cardiac manifestations are rare, and isolated atrial amyloid, a rare amyloidosis caused by atrial natriuretic peptide deposition, of limited functional significance [1▪,2,3]. Appropriate treatment of amyloid disorders requires histologic confirmation of amyloid and the correct identification of the type of amyloid. Currently, mass spectroscopy has provided the highest sensitivity and specificity to allow accurate identification of the amyloid subtypes [1▪]. Preferred diagnostic steps have been outlined well for amyloidosis in other reviews [1▪,4–7].
Identification of cardiac amyloidosis
Electrocardiographic characteristics do not differ significantly between amyloid types: the typical pattern observed is a low voltage or pseudoinfarct pattern on the electrocardiogram [8,9]. Echocardiographic assessment has been the cornerstone in the evaluation of amyloidosis. Two-dimensional and Doppler findings usually include increased wall thickness (often mistaken for hypertrophy), small left ventricle (LV) chamber size, pericardial effusion, and restrictive filling. Analysis of LV and right ventricle (RV) strain may help support the diagnosis and guide prognostic assessment [10–12]. Cardiac magnetic resonance imaging (CMR) has shown efficacy in identifying amyloid by the inability to null the signal, and CMR may be helpful in differentiating AL and ATTR amyloid based on patterns of late gadolinium enhancement, with ATTR being significantly associated with greater late enhancement diffusely [13,14]. Multiple other imaging modalities can be used to diagnose cardiac amyloidosis and identify subclasses of amyloid noninvasively [15,16]. False-positive transthyretin staining can occur on endomyocardial biopsy specimens, and patients can harbor latent transthyretin mutations; thus, assessment for underlying plasma cell dyscrasia should always be performed [17–19]. Ultimately mass spectroscopy of biopsy material has become the gold standard for identifying amyloid subtypes.
General management of cardiac amyloidosis
In general, medical management of congestive heart failure due to cardiac amyloidosis has not been effective and without treatment of the underlying plasma cell or transthyretin disorder, the patients follow a progressive downhill course. Neurohormonal blockade is less effective than in dilated cardiomyopathies, and standard therapy often relies on symptomatic treatment of pulmonary congestion with diuretic therapy . In patients who have progressed to have significant LV systolic dysfunction, afterload reduction remains a reasonable treatment. Cardiac rhythm disturbances are common in amyloidosis and span the spectrum from heart block to atrial and ventricular arrhythmias . Patients with restrictive hemodynamics do not tolerate atrial fibrillation well. Prophylactic implantable cardioverter/defibrillator (ICD) is usually not indicated, as survival benefits have yet to be demonstrated unless the ICD is viewed as a bridge to allow advanced therapies . In workup for transplantation, right heart catheterization will often show increased pulmonary artery systolic pressures and pulmonary vascular resistances with reduction of cardiac output. Elevated right atrial pressures have been shown to be an independently predictor of adverse outcomes .
Among patients with cardiac amyloidosis, factors predicting worse survival include class IV symptoms, increased septal and free wall thickness, restrictive filling, atrial fibrillation, and elevated serum troponin . Because of the dismal prognosis associated with conventional medical management of amyloid heart disease, groups have considered transplantation and mechanical support as potential modalities to provide palliation of symptoms and improve life expectancy. Both transplantation and left ventricular assist device can be a viable option in highly selected patients, although the extent of extracardiac amyloid can limit the benefits [25,26]. Cardiac transplantation in amyloidosis can achieve excellent results , though studies are small, owing to the rarity of the disorder. Five-year survival rates vary between 36% and 83%, depending on amyloid subtype . More recent studies including patients only from the last 5 years have shown a smaller gap between outcomes of cardiac amyloid patients and other cardiomyopathies [29▪▪]. In cardiac amyloidosis, survival in the modern era was characterized by 90% survival at 1 year in one case series [30▪].
Amyloid light-chain disease
AL light chains infiltrate the interstitial space, electrically isolating cardiomyocytes, resulting in the classic low voltage ECG. In the ventricles, amyloid infiltration results in increased wall thickness classically without chamber dilatation. The atria also become infiltrated with light chain deposits but do dilate, consistent with restrictive cardiomyopathy. Abnormal light chain proteins are able to be internalized in unaltered form into the cell . Light chains may result in ischemia through endothelial dysfunction , though more importantly, they may exert a direct cytotoxic effect on the myocardium [33–35].
Staging the disease is crucial for prognosticating in AL-amyloidosis and considering advanced therapies. A newer staging system not only incorporates troponin-t (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), but also plasma cell-related characteristics free light chain difference (FLC-diff) difference between malignant light chain clones, and other light chains). Median survival ranges from 6 to 94 months based on these criteria . Longitudinal strain and global longitudinal strain have been shown to be highly predictive of survival in patients with AL amyloidosis in addition to typical clinical data including age, New York Heart Association (NYHA) class, Karnofsky index, NT-proBNP, and TnT [37–40]. Complications in AL-amyloid cardiomyopathy are not limited to the myocardium. Intracardiac thrombosis is common, with 51% in one autopsy study versus 16% in non-AL and 35% versus 18% on echocardiography (26% of patients experienced fatal thromboembolic events) [41,42]. Additionally, ischemia and myocardial infarction, probably related to perivascular amyloid, may occur in AL-amyloidosis .
Evolving medical therapy
Various chemotherapy regimens have been utilized for AL amyloidosis. Early studies suggested that melphalan-based therapy was superior to other chemotherapy regimens, regardless of extent of cardiomyopathy [44,45], although other regimens have been used with success . Large studies have reported that cardiac response of up to 40%–50% can be obtained with high-dose melphalan therapy and autologous stem cell transplant (ASCT), regardless of stage of cardiac involvement [47,48▪,49]. The effect can persist long-term . More recently, bortezomib-based induction therapy has been associated with improved survival, and notably, cardiac response rates between 40 and 100% [51–54]. In relapsed patients, pomalidomide and dexamethasone may be an option for refractory patients, although cardiac recovery was less predictable than the hematologic response . Recent studies have indicated a possible beneficial effect of green tea or green tea extract with decreased progression of disease, but conclusions must be tempered by small sample size .
Solid organ transplant: heart transplant
Screening before transplantation is crucial to assess for multiorgan involvement that may preclude transplantation . The degree of end-organ dysfunction by extracardiac amyloid needs to be carefully assessed. Virtually every report demonstrating favorable outcomes for heart transplantation with amyloid represents a highly selected population. Some consider that severe peripheral neuropathy or hepatic portal tract amyloidosis should be considered absolute contraindications to heart transplant (HTx), and significant gastrointestinal involvement should be considered a relative contraindication . In addition, our own experience has demonstrated that the presence of recurrent pleural effusions is often indicative of pulmonary amyloid and portends a poor outcome (data unpublished).
Heart transplantation without addressing the underlying plasma cell disorder may have limited long-term utility. Complications such as recurrence of amyloid in the graft or progressive extracardiac amyloid impact outcomes [58,59,60▪,61]. After heart transplantation without adjunctive chemotherapy, 5-year survival has been shown to be as low as 20%, whereas survival was 37% in patients receiving chemotherapy. These outcomes were worse than non-AL amyloid controls . A United Kingdom registry study reported a median survival of 3.4 years from HTx without adjunctive therapy . Studies of restrictive cardiomyopathy as a group have shown comparable outcomes to nonrestrictive indications, although amyloidosis continued to be in a subgroup with higher mortality, with estimated 5-year mortality of 47% , which has caused some to question the premise of isolated cardiac transplantation in AL-amyloid . Rarely, even in patients ineligible for ASCT, good outcomes after isolated cardiac transplantation have been observed . In HTx-only patients, recurrent or de-novo amyloidosis should be considered in the differential diagnosis of graft failure [67,68].
Combined solid organ transplant: heart and bone marrow transplant
More recently, combined transplantation with HTx along with chemotherapy/ASCT has been performed for AL amyloid. Early studies observed improved outcomes compared to HTx alone, with a 5-year survival of 65% and post-ASCT median survival of 57 months . Excellent survival and response to treatment can occur only in the context of patients who are able to complete the staged stem cell transplant, usually done sometime after the HTx [70,71]. In the United Kingdom experience, improved outcomes were noted for patients who underwent cardiac transplantation followed by ASCT with 5-year survival of 64% . After HTx, in those patients who would receive ASCT, median survival has been shown to be comparable with HTx for other indications at 9.7 years, compared with 3.4 years without ASCT . Other experiences have also achieved similar outcomes for HTx-ASCT in AL amyloid compared with other HTx indications [72▪▪]. Interest in combined Tx must be tempered by high-waiting list mortality and has led our group and others to develop strategies involving pretreatment of the plasma cell disorder with chemotherapy in an attempt to produce a remission in the disease as patients await organ transplantation. Timing of ASCT after HTx is uncertain. One experience has shown excellent outcomes when ASCT has been delayed for 1 year compared with 6–9 months at other centers . In our experience, relapse is not uncommon and we have repeated a second ASCT in one case.
Mayo Clinic experience
Our center recently conducted an analysis of patients with AL amyloid undergoing HTx for primarily cardiac manifestation of AL amyloid (unpublished data, Grogan and Dispenzieri). These patients all had biopsy-confirmed AL amyloidosis by Congo red staining with cardiac involvement (NYHA IV symptoms, ventricular thickness >15 mm, or ejection fraction <40%). Additional criteria for transplantation included an age less than 60 years, no evidence of malignancy and a positive serum monoclonal protein. Bone marrow was consistent with amyloidosis and not multiple myeloma, with a low bone marrow plasma cell labeling index. Patients were excluded if they exhibited nephrotic range proteinuria.
Over a 20-year period, greater than 3000 patients were evaluated for AL amyloid at Mayo Clinic. Twenty one percent were found to have overt heart failure (668 patients) and a highly selected group of 23 patients ultimately underwent cardiac transplantation for AL amyloid cardiomyopathy. Overall median survival was 3.5 years (CI 1.2–8.2 years). One year survival was 77%, 2-year survival was 65%, and 5-year was 43%. Causes of death were attributed to progressive amyloidosis (12), complications from ASCT (3), and others (5). Median survival for patients able to complete ASCT was 6.3 years (CI 1.2–8.6 years), and for those achieving a complete remission (n = 7), median survival was 10.8 years.
Mutant transthyretin amyloidosis (familial amyloid)
Mutant transthyretin amyloidosis (ATTRm) or familial amyloidosis, also referred to as familial amyloid polyneuropathy (FAP), is a hereditary disorder characterized by abnormal amyloid accumulation secondary to mutations in the transthyretin gene accounting for protein instability and heterotopic deposition. Transthyretin is hepatically produced.
ATTRm is a heterogeneous disease . The most common mutation is Val30Met. The most common manifestation is a combination of cardiac and neurologic involvement, although mutations in ATTRm can be thought of as a spectrum from predominantly cardiotropic through mixed presentations, to mutations that predominantly affect the peripheral and autonomic nervous systems or the gastrointestinal (GI) tract . Males may be affected more . Aggressive TTR mutations are noted to be Gly47Glu and Leu12Pro, whereas Val30Met is associated with a less aggressive course . Other mutations have been identified as most common, including Glu89Gln, Ile68Leu, Phe64Leu, Thr49Ala, Arg34Thr, Ala36Pro, and among others [75,78]. Ile68Leu is most frequently associated with a cardiac-only phenotype . However, Thr60Ala genotype is associated with frequent cardiac involvement (93%) . Prognosis is, in general, better in ATTRm than in AL-amyloid as ATTRm has a long latency period before clinical signs and symptoms develop [80,81].
Hereditary TTR has an association with various ethnicities ; most notably, in general African American populations, TTR Val122Ile is frequently isolated (23%), and disease associated with this mutation carries a better prognosis than AL amyloid (27 month median survival from diagnosis) [83,84], although slightly worse than other ATTRm mutations . Overall prevalence of Val122Ile TTR mutation is roughly 3%, although cardiac penetrance (∼54%) is higher in homozygous patients and patients over the age of 70 years [86,87].
Diagnosis of ATTRm can be challenging. Echocardiographic patterns differ only slightly between familial amyloid and AL-amyloid. Notably, longitudinal strain is more evident in the latter, but other parameters vary according to degree of involvement and cardiac dysfunction [88▪]. Endomyocardial biopsy can be utilized to diagnose ATTRm. Specifically, TTR amyloid subtype can be suggested by examination of amyloid fragments from endomyocardial biopsy with amino acid sequencing  or mass spectroscopy. Yield of biopsy from noncardiac involved organ sites for TTR cardiac amyloid is 73% for FAC overall, while fat aspiration was 67% . Other sites including bone marrow and rectal or sural nerve had lower yield at 41% and 28%, respectively .
Single solid organ transplant
Although unusual, isolated HTx has been utilized for Val122Ile with good outcomes. Two case reports highlight success of isolated heart transplantation among patients with ATTRm with the Val122Ile mutation [91,92]. However, in general, based on larger experiences, isolated HTx is not used in ATTRm, as adjunctive therapy is usually required .
Typically, liver transplant (LTx) is performed for primary neuropathic phenotype, Val30Met. Survival in one experience was excellent with 75% survival at 5 years. Nevertheless, given potential complications of LTx, focus for transplantation should be on young patients with early manifestations [60▪]. The efficacy of LTx in other genotypes varies. For example, there is relatively little experience with LTx in Val122Ile . Additionally, isolated LTx is associated with poor outcomes in some genotypes, such as Thr60Ala. Given the latency of amyloid manifestations with TTR, domino LTx has been utilized as a means to enhance donor organ supply [60▪]. Recent analysis suggested a 5-year survival of 69% with rare occurrence of amyloidosis, even at 10 years posttransplant . In our experience with HTx–LTx for TTR amyloid, the majority of the time the liver can be used for a domino transplant (usually to a recipient over the age of 60 years) and can help ameliorate concerns regarding organ allocation [94▪].
Combined heart–liver transplant
In general, combined HTx–LTx can be utilized in familial amyloidosis with significant cardiac involvement with good results . One experience suggested an estimated survival after combined HTx–LTx of 75% at 1 year and 64% at 5 years , although our experiences have shown 100% survival at 1 year and 75% 5-year and 60% 10 year survival with lower rejection rates than HTx alone [96,97]. In addition, combined heart–liver transplantation demonstrates attenuated development of transplant vasculopathy compared with HTx alone .
Evolving medical therapy
Several medical therapies are being investigated for TTR cardiomyopathy [60▪]. For example, diflunisal, a nonsteroidal antiinflammatory medication has been shown, in vitro, to stabilize TTR tetramer. Initial phase I trials suggested adequate safety , and prospectively, diflunisal reduced the rate of progression of neurologic impairment . Tafamidis, a thyroxine analog binding TTR, blocks the dissociation of TTR mutant multimers into monomers, which is required for the pathogenesis. It has been studied in prospective fashion in Val30Met-mutated TTR  and non-Val30Met-mutated TTR and has shown efficacy in improving neuropathy and stabilizing TTR . Several antisense therapies have been in clinical trial for neuropathy and appear to hold promise for broader indications. Green tea or green tea extract, specifically epigallocatechin-3-gallate, as in AL-amyloid, has been associated with inhibition of amyloid deposition in ATTRm . Lastly, doxycycline has shown promise in translational studies and is being assessed as an adjunctive agent in ATTRm . Long-term effects of these novel therapies and others remain to be investigated .
Wild-type transthyretin amyloid (senile amyloid)
Senile amyloidosis is more closely related to the familial amyloid, with wild-type transthyretin identified on myocardial biopsy. Although the presence of wild-type transthyretin-associated cardiac amyloid is discovered occasionally incidentally, a large deposition of amyloid with this molecular phenotype signals senile systemic amyloidosis (SSA or ATTRwt) . The diagnosis requires the exclusion of underlying plasma cell dyscrasias that predispose to amyloidosis . Presentation of SSA typically involves male patients with a more slowly progressive course characterized by heart failure predominantly with diastolic dysfunction. Because of the age group, coexistent coronary artery disease often exists and may confuse the picture, resulting a delay in diagnosis. This disorder is underappreciated in the differential diagnosis of heart failure with preserved ejection fraction (HFpEF) in elderly males [106▪] and decreased recognition may relate to the age at presentation [75,107]. Echocardiographically, increased ventricular wall thickness is more evident than in AL amyloid [74,88▪,104,105,108], and ejection fraction may be slightly lower . Notably absent are the findings typical of AL amyloid, including macroglossia and proteinuria [104,108]. Additionally, NT-proBNP is often less elevated in SSA than AL amyloid, and 99mTc pyrophosphate scans can be used to differentiate transthyretin amyloidoses from AL amyloidoses [108,109]. Poorer prognosis is associated with higher NYHA class on presentation, a positive troponin, and prior requirement for pacemaker .
Although thought to be primarily a disease of the heart, extracardiac manifestations are present in some patients with SSA. For example, in one study, peripheral neuropathy was present at a comparable rate to AL amyloid patients, whereas carpal tunnel syndrome was more common . Additionally, deposition in the gastrointestinal tract, bladder, and fat aspirates has been identified . Further deposition has been seen in the aorta, brain, liver, lungs, and kidneys, although this is not thought to be pathologically involved . Biopsies of extracardiac sites are occasionally utilized for transthyretin amyloid diagnosis, including tissue sampling of involved organs and fat aspiration, although with lower yield in SSA .
Systemic senile amyloidosis may have significantly improved survival compared to AL amyloid from time of recognition [104,105]. Similarly, compared to ATTRm, SSA has an improved prognosis , with median survival estimates from 24 to 75 months [84,88▪,104,108]. Cardiac transplantation has been utilized in relatively few patients with SSA given the typical advanced age at presentation; however, presence of SSA alone is not an exclusionary criterion, and HTx has been used with some success [59,62]. We have, however, observed late findings of extracardiac amyloid manifestations, suggesting that cardiac transplantation prolongs life in these patents, allowing them to live long enough to develop extracardiac complications.
Sarcoidosis is a systemic disease, affecting nearly every organ system. Cardiac sarcoidosis is a relatively frequent manifestation, as 10%–20% of patients with sarcoidosis may have identifiable granulomas in cardiac tissue [112▪]. Additionally, because of the infiltrative nature of sarcoidosis, manifestations such as arrhythmias are common. When ventricular dysfunction develops as a result of sarcoidosis, its management is similar to other causes of cardiomyopathy . However, immunosuppressants are added to treat the granulomatous myocarditis . Overall, prognosis is closer to idiopathic cardiomyopathy than amyloidosis .
There exists hesitancy to transplant patients with sarcoid cardiomyopathy as a result of the possibility of re-emergence of cardiac sarcoid [116,117]; however, outcomes have supported the notion of transplantation [118,119]. Among United Network of Organ Sharing database HTx recipients, neither the frequency of rejection episodes nor the overall mortality was worse in patients transplanted for sarcoidosis than other etiologies of cardiomyopathy . A separate study showed a nonsignificant difference in long-term outcomes between sarcoid and other causes of cardiomyopathy . Nevertheless, a trend towards poorer outcomes in the latter study and prior concerns regarding recurrence of sarcoidosis, both intracardiac and extracardiac, limits the utility of transplantation [119,120]. Recent data in lung transplantation demonstrated a high rate of recurrence of histologic sarcoidosis (7 of 30 patients) without negatively impacting long-term survival . Similar data have not been reported for a large group of HTx recipients.
In conclusion, cardiac amyloidosis is a heterogeneous disease characterized by separate pathophysiologies, and as a result prognosis improves substantially when appropriate steps are undertaken to ensure adequate screening and workup prior to advanced therapies. Selection of treatment modality significantly depends on subclassification of amyloidosis. Although transplantation in sarcoidosis is infrequent, owing to concerns about recurrence, transplantation outcomes are comparable to nonrestrictive cardiomyopathies. Medical therapy for amyloid disorders and inflammatory states such as sarcoidosis are evolving such that the need for organ replacement may become less important in the years ahead.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1▪. Gertz MA, Dispenzieri A, Sher T. Pathophysiology and treatment of cardiac amyloidosis
. Nat Rev Cardiol 2014; 12:91–102.
An excellent review of contemporary management of cardiac amyloidosis with particular focus on novel chemotherapeutics.
2. Louros NN, Iconomidou VA, Tsiolaki PL, et al. An N-terminal pro-atrial natriuretic peptide (NT-proANP) ‘aggregation-prone’ segment involved in isolated atrial amyloidosis
. FEBS Lett 2014; 588:52–57.
3. Millucci L, Ghezzi L, Bernardini G, et al. Prevalence of isolated atrial amyloidosis
in young patients affected by congestive heart failure. Sci World J 2012; 1–8.
4. Chee CE, Lacy MQ, Dogan A, et al. Pitfalls in the diagnosis of primary amyloidosis
. Clin Lymphoma Myeloma Leuk 2010; 10:177–180.
5. Kapoor P, Thenappan T, Singh E, et al. Cardiac amyloidosis
: a practical approach to diagnosis and management. Am J Med 2011; 124:1006–1015.
6. Mollee P, Renaut P, Gottlieb D, Goodman H. How to diagnose amyloidosis
. Intern Med J 2014; 44:7–17.
7. Maleszewski JJ, Murray DL, Dispenzieri A, et al. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc Pathol 2013; 22:189–194.
8. Murtagh B, Hammill SC, Gertz M, et al. Electrocardiographic findings in primary systemic amyloidosis
and biopsy-proven cardiac involvement. Am J Cardiol 2005; 95:535–537.
9. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis
. Am J Cardiol 2014; 114:1089–1093.
10. 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; 20:1194–1202.
11. 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 stud. Eur Hear J - Cardiovasc Imaging 2012; 13:680–689.
12. 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; 101:1039–1045.
13. Dungu JN, Valencia O, Pinney JH, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis
. JACC Cardiovasc Imaging 2014; 7:133–142.
14. Takeda M, Amano Y, Tachi M, et al. MRI differentiation of cardiomyopathy showing left ventricular hypertrophy and heart failure: differentiation between cardiac amyloidosis
, hypertrophic cardiomyopathy, and hypertensive heart disease. Jpn J Radiol 2013; 31:693–700.
15. Aljaroudi WA, Desai MY, Tang WHW, et al. Role of imaging in the diagnosis and management of patients with cardiac amyloidosis
: state of the art review and focus on emerging nuclear techniques. J Nucl Cardiol 2014; 21:271–283.
16. 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; 54:213–220.
17. Satoskar A, Efebera Y, Hasan A, et al. Strong transthyretin immunostaining, potential pitfall in cardiac amyloid typing. Am J Surg Pathol 2012; 29:997–1003.
18. Wechalekar AD, Offer M, Gillmore JD, et al. Cardiac amyloidosis
, a monoclonal gammopathy and a potentially misleading mutation. Nat Clin Pract Cardiovasc Med 2009; 6:128–133.
19. Leone O, Longhi S, Quarta CC, et al. New pathological insights into cardiac amyloidosis
: implications for noninvasive diagnosis. Amyloid 2012; 19:99–105.
20. Nash N, Brij S, Clesham G. Cardiac amyloidosis
and the use of diuretic and ace inhibitor therapy in severe heart failure. Int J Clin Pract 1997; 51:384–385.
21. Singla A, Hogan W, Ansell S, et al. Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transpl 2014; 19:1233–1237.Epub ahead of print.
22. Lin G, Dispenzieri A, Kyle R, et al. Implantable cardioverter defibrillators in patients with cardiac amyloidosis
. J Cardiovasc Electrophysiol 2013; 24:793–798.
23. Russo C, Green P, Maurer M. The prognostic significance of central hemodynamics in patients with cardiac amyloidosis
. Amyloid 2013; 1–5.
24. 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; 22:647–654.
25. Topilsky Y, Pereira NL, Shah DK, et al. Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. Circ Hear Fail 2011; 4:266–275.
26. Swiecicki PL, Edwards BS, Kushwaha SS, et al. Left ventricular device implantation for advanced cardiac amyloidosis
. J Hear Lung Transplant 2013; 32:563–568.
27. Bograd AJ, Mital S, Schwarzenberger JC, et al. Twenty-year experience with heart transplantation for infants and children with restrictive cardiomyopathy: 1986-2006. Am J Transplant 2008; 8:201–207.
28. Bradshaw SH, Veinot JP. Cardiac amyloidosis
. Curr Opin Cardiol 2012; 1.
29▪▪. Davis MK, Lee PHU, Witteles RM. Changing outcomes after heart transplantation in patients with amyloid cardiomyopathy. J Hear Lung Transplant 2014; 1–9.
Newer analysis of the UNOS database suggesting improved survival in amyloid cardiomyopathy with cardiac transplantation compared with historical controls in relation to nonamyloid cardiomyopathy.
30▪. Davis MK, Kale P, Liedtke M, et al. Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. Am J Transplant 2015; 15:650–658.
Large experience of transplantation in AL amyloid showing acceptable survival after combined heart transplant-chemotherapy.
31. Levinson RT, Olatoye OO, Randles EG, et al. Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes. Sci Rep 2013; 3:1278.
32. Ramirez-Alvarado M. Amyloid formation in light chain amyloidosis
. Curr Top Med Chem 2012; 12:2523–2533.
33. Sikkink LA, Ramirez-Alvarado M. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell Death Dis 2010; 1:e98.
34. Shi J, Guan J, Jiang B, et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a noncanonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A 2010; 107:4188–4193.
35. Guan J, Mishra S, Shi J, et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol 2013; 487:109–113.
36. 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; 30:989–995.
37. Buss SJ, Emami M, Mereles D, et al. Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis
: incremental value compared with clinical and biochemical markers. J Am Coll Cardiol 2012; 60:1067–1076.
38. Dispenzieri A, Gertz MA, Kumar SK, et al. High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis
. Heart 2014; 100:383–388.
39. Dispenzieri A, Dingli D, Kumar SK, et al. Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis
treated with immune modulatory drugs. Am J Hematol 2013; 85:757–759.
40. Suresh R, Grogan M, Maleszewski JJ, et al. Advanced cardiac amyloidosis
associated with normal interventricular septal thickness: an uncommon presentation of infiltrative cardiomyopathy. J Am Soc Echocardiogr 2014; 27:440–447.
41. Feng D, Edwards WD, Oh JK, et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis
. Circulation 2007; 116:2420–2426.
42. Feng D, Syed IS, Martinez M, et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis
. Circulation 2009; 119:2490–2497.
43. 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; 18:160–164.
44. Hoshino J, Ubara Y, Sawa N, et al. How to treat patients with systemic amyloid light chain amyloidosis
? Comparison of high-dose melphalan, low-dose chemotherapy and no chemotherapy in patients with or without cardiac amyloidosis
. Clin Exp Nephrol 2011; 486–492.
45. Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis
. N Engl J Med 2008; 357:1083–1093.
46. Kumar SK, Lacy MQ, Hayman SR, et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 2011; 86:640–645.
47. Girnius S, Seldin D. Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis
and cardiac involvement. Bone Marrow 2013; 49:1–6.
48▪. Jimenez-Zepeda VH, Franke N, Reece DE, et al. Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis
: experience of a single institution. Br J Haematol 2014; 164:722–728.
Contemporary experience with ASCT in AL amyloid, describing use of biomarkers to improve patient selection.
49. Madan S, Kumar S, Dispenzieri A, et al. High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis
with cardiac involvement. Blood 2012; 119:1117–1122.
50. Mejhert M, Hast R, Sandstedt B, Janczewska I. Ten-year follow-up after autologous stem cell transplantation of a patient with immunoglobulin light-chain (AL) amyloidosis
with deposits in the heart, liver and gastrointestinal tract. BMJ Case Rep 2011; 1–5.
51. Kikukawa Y, Yuki H, Hirata S, et al. Combined use of bortezomib, cyclophosphamide, and dexamethasone induces favorable hematological and organ responses in Japanese patients with amyloid light-chain amyloidosis
: a single-institution retrospective study. Int J Hematol 2014; 133–139.
52. Lee JY, Lim SH, Kim SJ, et al. Bortezomib, melphalan, and prednisolone combination chemotherapy for newly diagnosed light chain (AL) amyloidosis
. Amyloid 2014; 21:261–266.
53. Scott EC, Heitner SB, Dibb W, et al. Induction bortezomib in AL amyloidosis
followed by high dose melphalan and autologous stem cell transplantation: a single institution retrospective study. Clin Lymphoma, Myeloma Leuk 2014; 14:424–430.e1.
54. Nelson MR, Lanza LA, Reeder CB, et al. Histologic remission of cardiac amyloidosis
: a case report. Amyloid 2012; 19:106–109.
55. Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis
. Blood 2012; 119:5397–5404.
56. Kristen AV, Lehrke S, Buss S, et al. Green tea halts progression of cardiac transthyretin amyloidosis
: an observational report. Clin Res Cardiol 2012; 101:805–813.
57. Varr BC, Liedtke M, Arai S, et al. Heart transplantation and cardiac amyloidosis
: approach to screening and novel management strategies. J Hear Lung Transplant 2012; 31:325–331.
58. Kpodonu J, Massad MG, Caines A, Geha AS. Outcome of heart transplantation in patients with amyloid cardiomyopathy. J Hear Lung Transplant 2005; 24:1763–1765.
59. Dubrey SW, Comenzo RL. Amyloid diseases of the heart: current and future therapies. Qjm 2012; 105:617–631.
60▪. Castaño A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis
: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 2014; 20:163–178.
Excellent review of therapies for cardiac amyloidosis, with particular focus on novel, targeted medications.
61. Luo J-M, Chou N-K, Chi N-H, et al. Heart transplantation in patients with amyloidosis
. Transplant Proc 2010; 42:927–929.
62. Dubrey SW, Burke MM, Hawkins PN, Banner NR. Cardiac transplantation
for amyloid heart disease: the United Kingdom experience. J Hear Lung Transplant 2004; 23:1142–1153.
63. Sattianayagam PT, Gibbs SDJ, Pinney JH, et al. Solid organ transplantation in AL amyloidosis
. Am J Transplant 2010; 10:2124–2131.
64. DePasquale EC, Nasir K, Jacoby DL. Outcomes of adults with restrictive cardiomyopathy after heart transplantation. J Hear Lung Transplant 2012; 31:1269–1275.
65. Nohria A. Should we avoid heart transplantation in cardiomyopathy due to radiotherapy/chemotherapy or amyloidosis
? the devil is in the details. J Hear Lung Transplant 2012; 31:1253–1256.
66. Audard V, Matignon M, Weiss L, et al. Successful long-term outcome of the first combined heart and kidney transplant in a patient with systemic Al amyloidosis
. Am J Transplant 2009; 9:236–240.
67. Luk A, Ahn E, Lee A, et al. Recurrent cardiac amyloidosis
following previous heart transplantation. Cardiovasc Pathol 2010; 19:e129–e133.
68. Kintsler S, Jäkel J, Brandenburg V, et al. Case report cardiac amyloidosis
in a heart transplant patient – a case report and retrospective analysis of amyloidosis
evolution. Intractable Rare Dis Res 2015; 4:60–64.
69. Lacy MQ, Dispenzieri A, Hayman SR, et al. Autologous stem cell transplant after heart transplant for light chain (AL) amyloid cardiomyopathy. J Hear Lung Transplant 2008; 27:823–829.
70. Kristen AV, Sack FU, Schonland SO, et al. Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light-chain amyloidosis
. Eur J Heart Fail 2009; 11:1014–1020.
71. Dey B, Chung S, Spitzer T, et al. Cardiac transplantation
followed by dose-intensive melphalan and autologous stem cell transplantation for AL amyloidosis
and heart failure. Transplantation 2012; 127:358–366.
72▪▪. Gilstrap L, Niehaus E, Malhorta R, et al. End stage cardiac amyloidosis
: predictors of survival to cardiac transplantation
and long term outcomes. J Hear Lung Transpl 2015; 33:149–156.
Recent analysis of factors predicting survival in amyloid cardiomyopathy patients undergoing transplantation. Findings indicated the importance of cardiac cachexia as a negative prognostic marker.
73. Estep JD, Bhimaraj A, Cordero-Reyes a M, et al. Heart transplantation and end-stage cardiac amyloidosis
: a review and approach to evaluation and management. Methodist Debakey Cardiovasc J 2012; 8:8–16.
74. Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 2010; 7:398–408.
75. 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; 34:520–528.
76. Rapezzi C, Riva L, Quarta CC, et al. Gender-related risk of myocardial involvement in systemic amyloidosis
. Amyloid 2008; 15:40–48.
77. Barreiros AP, Post F, Hoppe-Lotichius M, et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transplant 2007; 13:465–466.
78. Kristen AV, Ehlermann P, Helmke B, et al. Transthyretin valine-94-alanine, a novel variant associated with late-onset systemic amyloidosis
with cardiac involvement. Amyloid 2007; 14:283–287.
79. Sattianayagam PT, Hahn AF, Whelan CJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J 2012; 33:1120–1127.
80. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009; 120:1203–1212.
81. Roig E, Almenar L, González-Vílchez F, et al. Outcomes of heart transplantation for cardiac amyloidosis
: subanalysis of the Spanish registry for heart transplantation. Am J Transplant 2009; 9:1414–1419.
82. Mohty D, Damy T, Cosnay P, et al. Cardiac amyloidosis
: updates in diagnosis and management. Arch Cardiovasc Dis 2013; 106:528–540.
83. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis
in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis
and immunoglobulin light chain amyloidosis
. Am Heart J 2009; 158:607–614.
84. Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis
Cardiac Study (TRACS). Am Heart J 2012; 164:222–228.e1.
85. Ruberg F, Berk J. Transthyretin (TTR) cardiac amyloidosis
. Circulation 2012; 126:1286–1300.
86. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J 2010; 159:864–870.
87. Reddi HV, Jenkins S, Theis J, et al. Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis
in the african american population in the seventh decade of life. J Mol Diagnostics 2014; 16:68–74.
88▪. Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis
. Circulation 2014; 129:1840–1849.
Contemporary description of echocardiographic differences between transthyretin and AL amyloid cardiomyopathy, highlighting that the mechanism of cardiomyopathy in AL amyloid in not solely related to structural changes.
89. Benson MD, Breall J, Cummings OW, Liepnieks JJ. Biochemical characterisation of amyloid by endomyocardial biopsy. Amyloid 2009; 16:9–14.
90. Fine NM, Arruda-Olson AM, Dispenzieri A, et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis
. Am J Cardiol 2014; 113:1723–1727.
91. Ammirati E, Marziliano N, Vittori C, et al. The first Caucasian patient with p.Val122Ile mutated-transthyretin cardiac amyloidosis
treated with isolated heart transplantation. Amyloid 2012; 19:113–117.
92. Hamour IM, Lachmann HJ, Goodman HJB, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis
. Am J Transplant 2008; 8:1056–1059.
93. Bolte FJ, Schmidt HH-J, Becker T, et al. Evaluation of domino liver transplantations in Germany. Transpl Int 2013; 26:715–723.
94▪. Barbara DW, Rehfeldt KH, Heimbach JK, et al. The perioperative management of patients undergoing combined heart-liver transplantation. Transplantation 2015; 99:139–144.
Excellent retrospective analysis of the perioperative management of combined cardiac-liver transplantation.
95. Nagpal a D, Chamogeorgakis T, Shafii AE, et al. Combined heart and liver transplantation: the Cleveland Clinic experience. Ann Thorac Surg 2013; 95:179–182.
96. Raichlin E, Daly RC, Rosen CB, et al. Combined heart and liver transplantation: a single-center experience. Transplantation 2009; 88:219–225.
97. Nelson LM, Penninga L, Sander K, et al. Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy. Clin Transplant 2013; 27:203–209.
98. Topilsky Y, Raichlin E, Hasin T. Combined heart and liver transplant attenuates cardiac allograft vasculopathy compared with isolated heart transplantation. Transplantation 2013; 95:859–865.
99. Castano A, Helmke S, Alvarez J, et al. Diflunisal for ATTR cardiac amyloidosis
. Congest Hear Fail 2012; 29:997–1003.
100. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013; 310:2658–2667.
101. Coelho T, Maia LF, Da Silva a M, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012; 79:785–792.
102. Merlini G, Planté-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis
. J Cardiovasc Transl Res 2013; 6:1011–1020.
103. Ueda M, Ando Y. Recent advances in transthyretin amyloidosis
therapy. Transl Neurodegener 2014; 3:19.
104. Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis
presenting with heart failure. Arch Intern Med 2005; 165:1425–1429.
105. Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis
with cardiac involvement. Am J Med 1996; 101:395–400.
106▪. 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; 2:113–122.
Multicenter autopsy study of patients with diagnosis of HFpEF, revealing a possibly clinical underestimation of wild-type transthyretin amyloid cardiomyopathy.
107. Shah S, Dungu J, Dubrey SW. Senile cardiac amyloidosis
: an underappreciated cause of heart failure. BMJ Case Rep 2013; 2013:2012–2014.
108. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis
: clinical features at presentation and outcome. J Am Heart Assoc 2013; 2:1–11.
109. Bokhari S, Castano A, Pozniakoff T, et al. 99MTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis
from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2012; 29:997–1003.
110. Dharmarajan K, Maurer M. Transthyretin cardiac amyloidoses in older North Americans. J Am Geriatr Soc 2012; 29:997–1003.
111. Givens RC, Russo C, Green P, Maurer MS. Comparison of cardiac amyloidosis
due to wild-type and V122I transthyretin in older adults referred to an academic medical center. Aging health 2013; 9:229–235.
112▪. Hamzeh N, Steckman DA, Sauer WH, et al. Pathophysiology and clinical management of cardiac sarcoidosis
. Nat Rev Cardiol 2015; 1–11.
Thorough and broad review of the contemporary management of cardiac sarcoidosis.
113. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American college of cardiology foundation/american heart association task force on practice guidelines. JACC 2013; 62:e147–e239.
114. Hamzeh NY, Wamboldt FS, Weinberger HD. Management of cardiac sarcoidosis
in the United States: A Delphi study. Chest 2012; 141:154–162.
115. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077–1084.
116. Bartram U, Thul J, Bauer J, et al. Systemic sarcoidosis
after cardiac transplantation
in a 9-year-old child. J Hear Lung Transplant 2006; 25:1263–1267.
117. Yager JEE, Hernandez AF, Steenbergen C, et al. Recurrence of cardiac sarcoidosis
in a heart transplant recipient. J Hear Lung Transplant 2005; 24:1988–1990.
118. Zaidi AR, Zaidi A, Vaitkus PT. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Hear Lung Transplant 2007; 26:714–717.
119. Akashi H, Kato TS, Takayama H, et al. Outcome of patients with cardiac sarcoidosis
undergoing cardiac transplantation
-single-center retrospective analysis. J Cardiol 2012; 60:407–410.
120. Roberts WC, Vowels TJ, Ko JM, et al. Cardiac transplantation
for cardiac sarcoidosis
with initial diagnosis by examination of the left ventricular apical ‘core’ excised for insertion of a left ventricular assist device for severe chronic heart failure. Am J Cardiol 2009; 103:110–114.
121. Banga A, Sahoo D, Lane CR, et al. Disease recurrence and acute cellular rejection episodes during the first year after lung transplantation among patients with sarcoidosis
. Transplantation 2015; [Epub ahead of print].