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. Author manuscript; available in PMC: 2023 Jul 1.
Published in final edited form as: Heart Fail Clin. 2022 Jul;18(3):479–488. doi: 10.1016/j.hfc.2022.02.005

Cardiac Amyloidosis

Morie Gertz 1
PMCID: PMC9219033  NIHMSID: NIHMS1782408  PMID: 35718420

Introduction

Amyloid deposits are defined by their tinctorial properties. Under the light microscope amyloid deposits are eosinophilic and amorphous when stained with hematoxylin and eosin. With Congo red staining the deposits are positive and under polarized light will exhibit green birefringence. Sixty years later electron microscopy demonstrated that all deposits were fibrillar. All amyloid deposits are protein derived. The clinical characteristics will be driven by the nature of the protein subunit. In Cardiology the two most common subunits accounting for well over 90% of cardiac amyloidosis are either immunoglobulin light chain, AL amyloidosis or transthyretin; TTR amyloidosis. Although 70% of patients with systemic amyloidosis have cardiac involvement the diagnosis is made by cardiologists only 20% of the time (1) suggesting significant gaps in knowledge in how to establish a work flow to arrive at a diagnosis in every day practice. (Figure 1)

Figure 1:

Figure 1:

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Courtesy of Mayo Clinic

One of the problems with early recognition of cardiac amyloidosis is its ability to mimic a host of other disorders. There is no one diagnostic test, except for magnetic resonance imaging with gadolinium that is specific for amyloidosis(2). If stains for amyloid are not requested on biopsy tissue the diagnosis may be overlooked. Bowel amyloidosis has been misdiagnosed as collagenous colitis, glomerular amyloid has been misdiagnosed as hyaline destruction and patients with a history of hereditary cardiomyopathy have been misdiagnosed as hypertrophic cardiomyopathy. (3) The lack of higher reported mortality rates in states with a greater number of black residents suggests under diagnosis of amyloidosis.(4)

Clinical Presentation

The classic presentation of amyloid cardiomyopathy is heart failure with preserved ejection fraction (HFpEF).(5) The symptoms are typical include dyspnea on exertion, lower extremity edema due to high right-sided filling pressures, small pleural effusions with conspicuous absence of ischemic symptomatology. Standard echocardiography will show thickened walls which without Doppler studies can be interpreted as demonstrating hypertrophy either related to hypertension or hypertrophic cardiomyopathy.(6) Since amyloidosis is a disease of diastole the rapid rise of filling pressure leads to a very low end-diastolic volume with a resultant reduction in stroke volume and consequent reduced cardiac output. Compensatory tachycardia is typical and often necessary to sustain cardiac output. Most patients will note the decline in systolic blood pressure over time. Systolic pressures of under 100 mmHg are common at diagnosis. The median age at diagnosis is 66 years. The estimated incidence is 12.1 cases per million person years and the median survival is 2.45 years.(7) In Olmsted county Minnesota however the median age at diagnosis was 76 years with an anticipated 3852 new cases of AL amyloidosis in the United States each year.(8)

Conduction system amyloid is common leading to atrial fibrillation and is a common presentation particularly in TTR cardiac amyloidosis. One of the important clues that leads to the correct diagnosis in practice is the common association of extra cardiac amyloid organ dysfunction. Although 70% of patients with amyloidosis have cardiac involvement, 3/4 of patient with cardiac amyloid will also have evidence of amyloid in other organs. The clinician should be particularly alert to the presence of proteinuria reflecting kidney involvement. Among 1000 patients with AL amyloidosis 318 had combined cardiac and renal involvement. Fifty or 16% of patients required renal replacement therapy the median survival was 18.5 months an independent predictors of death and dialysis were NT proBNP greater than 8500 nanogram/liter and eGFR less than 30 mL/minute.(9)

20% of patients will have simultaneous peripheral neuropathy which is uncommon in other forms of HFpEF. One patient in 6 will have bilateral carpal tunnel syndrome in light chain amyloidosis but almost half of patients with TTR cardiac amyloid will have bilateral carpal tunnel syndrome antedating the diagnosis by as much as a decade.(10) (table 1)Hepatomegaly with elevation of the blood alkaline phosphatase out of proportion to the degree of right-sided filling pressure elevation may reflect simultaneous liver involvement with amyloid. In TTR cardiac amyloidosis lumbar spinal stenosis causing pseudoclaudication and biceps tendon rupture are quite specific findings.(11) when technetium pyrophosphate scanning was performed in patients referred for transaortic valve replacement TTR cardiac amyloidosis was found in 10%. Today all patients referred for (12)TAVR at Mayo clinic are required to have pyrophosphate scanning to ensure amyloid is not contributing to cardiac symptomatology. The association of aortic stenosis with ATTR cardiac amyloidosis is seen in both ATTRwt and ATTRv.(13) Periorbital purpura is seen in approximately 1 patient in 6 with light chain amyloidosis (Figure 2)

Table 1.

Signs and symptoms associated with cardiac amyloidosis

AL ATTR
Carpal Tunnel Syndrome + ++
Purpura +
Pseudoclaudication +
Paresthesia/neuropathy + +
Proteinuria ++
Biceps Rupture +
Glossomeagaly +
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Figure 2:

Figure 2:

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Classic amyloid purpura

Diagnosis

The electrocardiogram can be quite useful in a patient with thickened walls by echocardiography. Patients with prolonged QTc (≥483 msec) had significantly poorer survival. One would anticipate hypertensive cardiomyopathy patients to have increased voltage across the precordium. The finding of low voltage in the limb leads or a pseudo infarction pattern in a patient with no evidence of ischemic symptomatology should raise the suspicion of amyloidosis.(14) Like echocardiography magnetic resonance imaging will demonstrate wall thickening however after gadolinium late enhancement is seen with myocardial nulling and is considered diagnostic for amyloidosis.(15) magnetic resonance imaging also allows assessment of extracellular volume which is significantly increased in cardiac amyloidosis and is prognostic for survival.(16) ECV is independently predictive of prognosis.(16) PET imaging has also been applied for the detection of cardiac amyloidosis. In a meta-analysis the pooled sensitivity of PET for amyloidosis was 0.97 and the specificity was 0.98 the pooled sensitivity of combined amyloid and sodium fluoride PET was 0.88 with specificity of 0.98. Further studies are required to substantiate the diagnostic role of PET imaging for the detection of cardiac amyloidosis.(17) Using florbetapir[18F] PET-CT Retention index in a cohort of patients not felt to have cardiac amyloidosis by conventional methods such as echocardiography, changes consistent with cardiac involvement was seen in 50% of subjects manifest by increased retention. The same “non cardiac” amyloid patients had late gadolinium enhancement in 20% by magnetic resonance imaging and elevated extracellular volume in 20%. This suggests that amyloid infiltration does occur in a pre clinical phase and that these patients are at risk of developing symptomatic cardiac amyloidosis.(18)

When a patient is seen with heart failure and preserved ejection fraction and the echocardiogram demonstrates wall thickening (Figure 3) of any degree the two most important work flow studies are immunoglobulin free light chain assay, immunofixation of serum and urine for kappa and lambda immunoglobulins and a technetium pyrophosphate scan. In a patient with a monoclonal protein and a clinically suspicious ECHO the finding of a monoclonal protein should be considered a high index of suspicion for AL amyloidosis. Abnormalities of the immunoglobulin free light chain assay are not only helpful in pointing to the correct diagnosis, the light chains are part of the staging system and predict outcomes in amyloidosis AL. Serialized measurements of the light chain are used to monitor the impact of therapy and the response depth is a function of the percentage reduction of the involved immunoglobulin light chain. Although endomyocardial biopsy will be the gold standard of diagnosis these invasive biopsies are not required to establish the diagnosis. Since patients with a monoclonal gammopathy will require a bone marrow biopsy to exclude multiple myeloma a Congo red stain can be done on the bone marrow biopsy and will be positive in 50% of patients. The subcutaneous fat aspirate an outpatient procedure done under local where milligrams of fat are removed from the abdominal wall will demonstrate amyloid deposits in 70% of patients. (19) We have also increased the utilization of lip biopsy which is easily accessible in can be done in patients on anticoagulant therapy with a 70% positivity rate for amyloid.

Figure 3:

Figure 3:

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2D echo demonstrating marked thickening of the left ventricular septum and free wall

The presence of a positive pyrophosphate scan (Figure 4) is highly sensitive for the diagnosis of TTR amyloidosis. (20)In the absence of a monoclonal protein a scan that is graded 2 or 3 in uptake is considered diagnostic of ATTR amyloidosis without biopsy.(21) However, if a monoclonal protein is present and a technetium pyrophosphate scan is positive, tissue biopsy is required to establish a diagnosis. Approximately 25% of patients with TTR cardiac amyloidosis have a detectable abnormality of immunoglobulins. The presence of both make it difficult to distinguish ATTR from AL amyloidosis and the distinction is important given the differences in therapies for the two forms of amyloidosis. All patients with suspect ATTR amyloidosis based on a pyrophosphate scan should have the TTR gene sequenced. Once considered rare, mutations in the ATTR gene are seen in 3.5 % of African Americans (V142I) and this inherited form of amyloid cardiomyopathy is almost certainly under diagnosis because the median age at recognition is over 70 years and the etiology of the heart failure can be misattributed to other more common forms of heart disease. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure.(22) Recent artificial intelligence algorithms have been developed that can analyze the echocardiogram and the EKG for wild-type TTR cardiac amyloidosis providing a positive predictive value of 3 to 4%. This automated strategy would increase the detection of cardiac amyloidosis.(23)

Figure 4:

Figure 4:

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Technetium pyrophosphate scan showing 3+ uptake in the myocardium with a SPECT image demonstrating the radionucleotide localizes to the ventricle

Classification of type

When a pathologist reports out a tissue positive biopsy demonstrating Congo red uptake with green birefringence the task remains incomplete. All positive amyloid biopsies require classification of type because the similarities between AL and ATTR do not allow discrimination of the 2 types based on clinical features alone. Historically immunohistochemistry was used to classify the various types of amyloid. This technique has fallen out of favor for several reasons. There are more than 20 proteins reported to form amyloid fibrils. These include Apolipoproteins, fibrinogen, lysozyme and insulin among others. This would require a very large panel of antisera and multiple tissue sections for classification which is beyond the scope of most routine immunohistochemistry laboratories. Commercial anti sera used in immunohistochemistry are generally directed to the constant portion of the immunoglobulin light chain when trying to diagnose AL amyloidosis. Amyloid deposits raise two major barriers. Most light chain amyloid deposits represent only fragments of the intact immunoglobulin light chain with the constant portion deleted and is not present in the amyloid deposit and therefore will not be recognized by commercial anti serua. Secondly amyloid fibrils are characterized by misfolding of the protein which often hides the epitope from antibody recognition. In prospective studies immunohistochemistry will fail to definitively diagnose the amyloid protein subunit in upwards of 20% of specimens.(24) Mass spectrometry can be performed on tissue while still on the glass slide and does not require paraffin blocks or frozen tissue samples. A sample stained with Congo red can be directly excised from the glass slide placed into a cuvette and the individual peptides can be separated by molecular weight in a mass spectrometer and sequenced. Peptides are compared to a library of sequenced proteins. Samples will demonstrate positive control seen in all amyloid deposits such as serum amyloid P protein. (25) The failure rate with this technique the is less than 5% and is usually because the amyloid deposits are present in trace amounts. This has become the new gold standard for identification of the amyloid type.(26) this technique has been reported in the diagnosis of 21 different established forms of amyloidosis. Amino acid substitutions in cases of hereditary amyloidosis were diagnosed with 100% specificity. The median age of A TTR amyloidosis was 74.4 years. AL amyloidosis represented 59% of patients and ATTR amyloidosis represented 28% of patients(27)

Prognosis

Over the past 2 decades multiple parameters have been identified that predict outcomes in patients with cardiac amyloidosis. Initially the echocardiogram was used and the ejection fraction, deceleration time, wall thickness, granular sparkling appearance and atrial failure had all been associated with survival. (28) Global longitudinal strain is particularly useful in the diagnosis of amyloid based on the presence of apical sparing but has been prognostic as well and should be regularly measured in these patients. (29) The use of echocardiography to predict outcomes however has been crit a size due to inter observer variability and the fact that echocardiographic parameters do not retain their significance in multi variable models. Cardiac magnetic resonance imaging has also provided predictors of survival particularly by measurements of extracellular volume. Extracellular volume measurements have a greater diagnostic sensitivity compared with late gadolinium enhancement and native T1. Extracellular volume provides high diagnostic and prognostic utility for the assessment of cardiac amyloidosis. (30)Several staging systems have been proposed in light chain amyloidosis. All of them have validity and some are better at predicting early mortality the others long-term survival. The most common in use today is the Mayo 2018 staging system which measures the N terminal fragment of brain naturetic peptide, high sensitivity troponin T and the difference between the involved and uninvolved immunoglobulin free light chain levels. For ATTR cardiac amyloidosis the most common staging system use combines the BNP with eGFR. These systems are listed in table 2.

Table 2.

Staging systems cardiac amyloidosis

AL Points Stage Median Survival, mo.
0 I >120
1 II 69
2 III 16
3 IV 6
ATTR 0 I 69.2
1 II 46.7
2 III 24.1
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AL 1 point each for dFLC >180mg/L; NTproBNP >1800 pg./mL; HS TroponinT ≥40ng/L(61)

ATTR 1 point each for NTproBNP>300ng/L; eGFR<45 mL/min(62)

Supportive management of amyloidosis

The mainstay of therapy is reduction of preload with the use of loop diuretics. Because of superior absorption torsemide is preferred to furosemide in our practice. For patients that have refractory edema metolazone can be quite useful but aggressive use can lead to profound hypokalemia and hypotension leading to syncope. Patients with significant amyloid cardiomyopathy require higher intravascular fluid volumes and higher filling pressures to fill the noncompliant ventricle.

Most patients have significant tachycardia required to maintain cardiac output. For most patient’s beta blockade to reduce the cardiac rate will result in exacerbation of symptoms. Even in patients that have significant supraventricular tachyarrhythmias digoxin is to be preferred to metoprolol or carvedilol. Contrary to earlier reports digoxin use for rate control in atrial fibrillation is safe. No deaths were attributed to digoxin use or toxicity.(31) Afterload reduction plays little role in patients with diastolic heart failure and the use of angiotensin-converting enzymes inhibitors or angiotensin receptor blocker inhibitors will result in hypotension with no improvement in cardiac output.

Atrial arrhythmias occur commonly, among 25 patients with cardiac amyloidosis that underwent cardioversion for atrial arrhythmias, sinus rhythm was restored in 96% of patients but 36% of patients experience procedural complications an 80% had recurrence of atrial a rhythm is at 1 year. This suggests that cardioversion in cardiac amyloidosis is not efficient for achieving long-term rate control.(32) The placement of a pacemaker can be useful in patients that have significant bradycardia but the value of implantable cardiac defibrillators remains controversial.(33) Multiple case series have been published with mixed results and no clear demonstrable survival prolongation. Many patients die with electrical mechanical dissociation, and it is unclear whether the defibrillator impulse can capture in an amyloid involved ventricle. Among 472 patients with cardiac amyloidosis with implantable cardiac defibrillators the 1-year mortality was 27% more than double patients receiving an ICD for non amyloid heart disease. The most powerful predictor of death was syncope.(34) In a report of 15 patients undergoing autologous stem cell transplantation with cardiac defibrillators, 5 had detectable arrhythmias and 2 had defibrillator discharges.(35) Transplant related mortality was 6.7% Intraventricular assist devices have also been used but most patients with amyloidosis have very small left ventricular chambers due to the massive infiltration of the ventricular wall and major technical difficulties exist in the safe placement of an assist device in amyloid laden myocardium.(36). One case report in a patient with AL lambda amyloidosis underwent left ventricular assist device implantation and 90 days after hospital discharge had not had complications or hospital readmission. Implanting the inflow cannula into the left atrium via a conduit may reduce the risks of complications.(37)

Orthostatic hypotension is common in patients with amyloidosis and may reflect autonomic failure or moderate to severe cardiac involvement with aggressive diuretic therapy. Standard therapies for orthostatic hypotension include fludrocortisone and midodrine. Recently droxidopa a norepinephrine precursor was reported to be self and well tolerated with improvement in presyncope symptoms in 80% of patients.(38)

Specific treatment directed against the amyloidosis

ATTR

Currently available therapies for the management of ATTR amyloidosis fall into 2 categories gene silencing and tetramer stabilizers. Transthyretin is a protein found in all mammals. It is responsible for transportation of thyroxine and retinol binding protein. In the native state it circulates as a tetramer with a central pocket that binds to thyroxine much in the same way as four globin chains form a tetramer and bind to oxygen in the central pocket. When there is a mutation in transthyretin the tetrameric form of the protein becomes unstable and will dissociate under physiologic conditions. The monomers which are not present in normal adults will miss fold into amyloid Proto fibrils and subsequently fully formed amyloid fibrils capable of depositing in heart peripheral and autonomic nerves and the vitreous chamber of the eye. The 1st stabilizer diflunisal is a nonsteroidal agent that prevents the tetramer from dissociating. It was shown in a double-blind placebo-controlled trial to reduce the neurological impairment in patients with mutant TTR amyloid polyneuropathy.

Tafamidis is a stabilizer that was tested both in wild-type and mutant TTR amyloid cardiomyopathy. Eligibility required a minimum NT proBNP of 600 pg. per mL. This trial that had a composite endpoint of all cause survival and cardiac hospitalization showed significant benefit for the treated arm leading to its approval. This is an oral medication administered once daily with a very favorable toxicity profile.(39). AG-10 is an investigational stabilizing agent that is currently in clinical trial.(40)AG10 is also a ATTR stabilizer. In a randomized double-blind placebo controlled study of orally administered Ag 10 in healthy adults, the drug was well tolerated with no safety signals. The drug half life is 25 hours. Over 90% stabilization of TTR was observed at steady state at the highest dose. Stabilization resulted in an increase in TTR levels. It would be predicted to be potentially beneficial for both mutant and wild-type ATTR.(41)

Gene silencing medications are either small interfering RNAs or anti sense oligo nucleotides. Both have tested their value in mutant TTR peripheral neuropathy and have demonstrated improvement in neurologic impairment and quality of life when compared with a 15 to 18-month placebo arm in phase 3 trials. Both agents patisiran (42, 43)and inotersin are undergoing testing in amyloid cardiomyopathy of both mutant and wild-type. In the analysis of a randomized double-blind placebo-controlled trial of patisiran, the drug improved absolute global longitudinal strain compared with placebo at 18 months with the greatest differential increase observed in the basal region. The agent appears to prevent deterioration of global longitudinal strain by attenuating disease progression in the basal region.(44) Vutrisiran which can silence the TTR gene is administered subcutaneously once every 3 months has completed accrual in a placebo-controlled trial in patients with amyloid cardiomyopathy (Helios B). In vitro studies have demonstrated that doxycycline also can act as a stabilizer of the transthyretin tetramer. Retrospective case control studies have suggested that the use of doxycycline improves outcome in patients with cardiac amyloidosis but the evidence is weak and no prospective studies demonstrating benefit have been published to date.(45)

There is active research into the use of monoclonal antibodies in the treatment of ATTR cardiac amyloidosis. A selective anti ATTR antibody has been developed having been cloned following comprehensive analysis of B-cells derived from healthy elderly subjects. This antibody binds selectively to disease associated ATTR aggregates both wild-type and mutant ATTR but does not bind to physiologic transthyretin. This antibody binds and activates macrophages which will remove ATTR deposits from patient derived myocardium by macrophages. The activity of ATTR removal has led to the development of an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.(46) CRISPR-Cas9–based in vivo gene editing has been used in the management of variant TTR amyloidosis. Six patients were treated with a lipid nanoparticle encapsulated messenger RNA for Cas9 protein. At the higher dose level reduction in serum TTR protein concentration was 87% adverse events were mild. This targeted knock out of TTR may translate into slowing of disease progression or potential improvement in neuropathy.(47)

AL

Since the source of the amyloid fibril subunit in light chain amyloidosis is a clonal population of plasma cells in the bone marrow all therapies to date are directed to eradication of the plasma cell clone thereby disrupting light chain synthesis. Response to therapy in light chain amyloidosis is assessed by the difference between the involved and uninvolved immunoglobulin free light chain (dFLC). The use of the immunoglobulin free light chain ratio can be misleading and is discouraged. (48) The best reported responses occur in those patients who achieve a complete response as measured by normalization of the difference between involved and uninvolved free light chain with immunofixation negativity of the serum and urine. Further refinement of the response criteria has demonstrated even better outcomes when the dFLC falls below 10 milligrams per liter. At this level of response increased organ response and an extended survival has been demonstrated in 2 independent cohorts.(49)

The Backbone of therapy for light chain amyloidosis is the use of weekly subcutaneous bortezomib. In an observational study of 915 patients the median overall survival with bortezomib was 72 months. Cardiac responses were 61% in those that achieve stringent dFLC response.(50) A prospective randomized trial adding daratumumab in anti-CD 38 monoclonal antibody to 3 chemotherapy agents bortezomib cyclophosphamide and dexamethasone showed a 3 fold increase in the hematologic complete response rate and a doubling of the cardiac response rate as defined by 30% reduction in the NT proBNP level. (51) The method of grading response of the heart in AL amyloidosis is defined as a 30 to 59% reduction in NT proBNP (partial response, PR); a greater than or equal to 60% reduction in NT proBNP (very good partial response, VGPR); and a complete response defined as an NT proBNP less than 450 micrograms per milliliter. Cardiac progression or relapse is (52)finding a 30% increase in the NT proBNP. Currently a widely accepted chemotherapy approach would be the use of daratumumab combined with bortezomib cyclophosphamide dexamethasone for 6 months followed by monthly daratumumab for a total of 24 months of therapy. Survival outcome has not been reported.

For over 25 years autologous stem cell transplantation has been used to achieve hematologic an organ response is in the management of light chain amyloidosis. (53)Myeloablative chemotherapy must be undertaken with extreme caution in patients with cardiac amyloidosis. Patients who undergo autologous stem cell transplantation have a period of severe neutropenia ranging from 6 to 10 days. During this period the development of bacteremia and sepsis is common. When patients with cardiac amyloidosis develop sepsis induced hypotension their cardiac reserve is insufficient to compensate for the fall in vascular resistance. Patients can develop hypotension, lactic acidosis and ultimately death. In early studies of autologous stem cell transplantation patients with cardiac amyloidosis had mortality rates in excess of 20%. (54) Current selection criteria require new York Heart Association class 2 or better, a systolic blood pressure above 90 and a high sensitivity troponin level generally less than 75 nanogram per liter. With current techniques mortality associated with stem cell transplantation is approximately 3%. Reported response rates for renal, cardiac and liver were 54%, 62% and 56% respectively. Organ response was strongly associated with prolonged survival.(55)

Currently there are no validated techniques for removing amyloid fibrils in tissue. Two monoclonal antibodies are about to be tested in patients who are therapy I with Mayo stage IV cardiac amyloidosis. In both trials the monoclonal antibody developed to remove the amyloid deposits will be combined with bortezomib cyclophosphamide dexamethasone and compared with placebo bortezomib cyclophosphamide dexamethasone. The antibodies CAEL-101(56) and birtamimab (57)are currently activated and accruing patients. Both antibodies have demonstrated in vitro activity by leading to macrophage activation following binding to the amyloid deposits and subsequent proteolysis. It is hypothesized that by combining anti amyloid antibodies with anti-plasma cell chemotherapy deeper response a longer survival will be achieved.

Organ transplantation

Before the development of highly effective anti-plasma cell chemotherapy the outcomes of cardiac transplantation for AL amyloidosis were poor often due to recurrence of amyloid both in the transplanted heart as well as the gastrointestinal tract and kidney. With the introduction of highly effective chemotherapy, outcomes have improved substantially. A recent report of 46 patients were reported of whom seven were bridged to cardiac transplantation with a ventricular assist device. The 1-year survival for the entire cohort was 91%, 83% with AL amyloidosis and 94% with TTR amyloidosis. In the group with AL amyloidosis all received chemotherapy before heart transplant, 5 of 8 patients subsequently received autologous stem cell transplant an average of 1 year after the cardiac allograft.(58) A 2nd series of 31 patients, 13 light chain amyloid 18, ATTR reported no significant difference in mortality between amyloid cardiomyopathy and heart transplantation for other indications. Extra cardiac amyloidosis was not considered a contraindication to transplantation. Posttransplant chemotherapy included both bortezomib based chemotherapy as well as autologous stem cell transplantation. Sixteen patients underwent heart transplantation for AL amyloidosis with stem cell transplantation performed in 9 patients at a median of 13.5 months following heart transplantation. One-year survival was 87.5%- and 5-year survival was 76.6%. The strategy of stem cell transplant 1 year after heart transplant was feasible, safe and resulted in excellent outcomes.(59) Survival at 8 years was over 80%.(60) Patients with wild-type TTR amyloidosis can be transplanted, the anticipated time to recurrence is quite long. The primary limitation is the advanced age of most patients with symptomatic cardiac failure and wild-type TTR amyloidosis.

Conclusion

The major gap in the management of patients with amyloidosis revolves around early diagnosis. All patients with thickened ventricular walls without a history of hypertension and those with heart failure with preserved ejection fraction should include immunoglobulin free light chain measurements and technetium pyrophosphate scanning as part of the initial evaluation. The former should raise the suspicion of light chain amyloidosis and lead to subcutaneous fat aspiration and a bone marrow for Congo red staining. Endomyocardial biopsy is generally not required to establish the diagnosis. Patients with strong uptake in the myocardium on pyrophosphate scanning that lack a monoclonal protein can be considered as having TTR amyloidosis. Genetic testing should be performed to ensure that the amyloidosis is not a mutation. Early diagnosis is important because all forms of amyloidosis have FDA approved therapies that have been shown to improve outcomes.

Key points.

  • Amyloidosis is a common cause of heart failure with preserved ejection fraction and a high index of suspicion is required to confirm this diagnosis

  • The major types of cardiac amyloidosis are AL or light chain amyloidosis and TTR or transthyretin amyloidosis (senile cardiac amyloidosis)

  • The diagnosis can be suspected by simple screening blood tests and simple imaging studies

  • Endomyocardial biopsy is not required to make the diagnosis

  • All forms of cardiac amyloidosis have FDA approved therapies that result in improved outcomes

Clinics Care Points.

  • If the echocardiogram shows wall thickening consistent with hypertension amyloidosis should be considered

  • The most important blood test when amyloidosis is being considered is the immunoglobulin free light chain assay

  • Prognosis is determined by troponin or (NT-pro) BNP

  • The most valuable imaging study is the PYP scan which is sensitive but not specific since both AL and TTTR amyloidosis can be positive

Footnotes

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