Management of light chain or AL amyloidosis has changed with major advances in recent years. Dr. Ronald Witteles is a Stanford Cardiologist with particular expertise in the treatment of cardiac amyloidosis and shares his expertise with us. He serves as Co-Director of the Stanford Amyloid Center, one of the world's leading amyloid centers.
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Amyloidosis
Description
Amyloidosis
Dr. Oscar M. Westin is a PHd student and a medical doctor at the University Hospital of Copenhagen's Heart Center, Rigshospitalet. In this Podcast Dr. Westin speaks on the Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Cardiac amyloidosis (CA) is linked to a bad prognosis. According to screening studies, CA is often ignored, especially in the elderly. Recent therapy improvements have drawn attention to the condition, although data on CA epidemiology across time is scarce.
Objectives
The goal of this study was to describe all CA patients in Denmark from 1998 to 2017, as well as to look at changes in patient characteristics over time.
Methods
In Danish nationwide registries, all patients with any kind of amyloidosis diagnosed between 1998 and 2017, as well as their comorbidities and medication, were identified. Any diagnosis code for amyloidosis paired with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation, or a procedural code for pacemaker installation, regardless of order, was classified as CA. The index date was established as the date on which those criteria were met. By index date, patients were separated into 5-year segments. We also included control subjects (1:4 ratio) from the general population as a comparison.
Results
619 patients met the CA requirements. The median age at baseline grew from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) in 1998-2002 to 72.3 years in 2013-2017. (IQR: 66.0-79.3 years). Male patients grew from 62.1 percent to 66.2 percent of all patients. In the Danish population aged 65 years, the incidence of CA increased from 0.88 to 3.56 per 100,000 person-years, whereas 2-year mortality reduced from 82.6 percent (IQR: 69.9 percent -90.5 percent) to 50.2 percent (IQR: 43.1 percent -56.9 percent ). CA patients had a considerably greater mortality rate than control participants (log-rank test: P 0.0001).
Conclusions
On a nationwide scale, CA, as defined in this study, was becoming more prevalent. The rising number of male patients and median age indicate that wild-type transthyretin amyloidosis is to blame. The fact that earlier, less advanced illnesses are being recognized more often could explain the lower fatality rate.
Dr. Oscar M. Westin is a PHd student and a medical doctor at the University Hospital of Copenhagen's Heart Center, Rigshospitalet. In this video Dr. Westin speaks on the Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Cardiac amyloidosis (CA) is linked to a bad prognosis. According to screening studies, CA is often ignored, especially in the elderly. Recent therapy improvements have drawn attention to the condition, although data on CA epidemiology across time is scarce.
Objectives
The goal of this study was to describe all CA patients in Denmark from 1998 to 2017, as well as to look at changes in patient characteristics over time.
Methods
In Danish nationwide registries, all patients with any kind of amyloidosis diagnosed between 1998 and 2017, as well as their comorbidities and medication, were identified. Any diagnosis code for amyloidosis paired with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation, or a procedural code for pacemaker installation, regardless of order, was classified as CA. The index date was established as the date on which those criteria were met. By index date, patients were separated into 5-year segments. We also included control subjects (1:4 ratio) from the general population as a comparison.
Results
619 patients met the CA requirements. The median age at baseline grew from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) in 1998-2002 to 72.3 years in 2013-2017. (IQR: 66.0-79.3 years). Male patients grew from 62.1 percent to 66.2 percent of all patients. In the Danish population aged 65 years, the incidence of CA increased from 0.88 to 3.56 per 100,000 person-years, whereas 2-year mortality reduced from 82.6 percent (IQR: 69.9 percent -90.5 percent) to 50.2 percent (IQR: 43.1 percent -56.9 percent ). CA patients had a considerably greater mortality rate than control participants (log-rank test: P 0.0001).
Conclusions
On a nationwide scale, CA, as defined in this study, was becoming more prevalent. The rising number of male patients and median age indicate that wild-type transthyretin amyloidosis is to blame. The fact that earlier, less advanced illnesses are being recognized more often could explain the lower fatality rate.
Dr. Marianna Fontana works as the Director at the Royal Free Hospital in the UCL CMR unit. She is a Honorary Consultant Cardiologist and Professor of Cardiology at the National Amyloidosis Centre at the University College London. In this video Dr. Fontana discusses the Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis.
https://www.jacc.org/doi/10.1016/j.jcmg.2021.06.022
Abstract
The goal of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of ATTR-CM patients; and investigate the relationship between LA pathology and mortality.
Background
The clinical importance of LA involvement in ATTR-CM is a hot topic in medicine.
Methods
In 5 explanted ATTR-CM atria, Congo red staining and immunohistochemistry were used to characterize the presence, type, and amount of amyloid and related alterations. In 906 individuals with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other), echo speckle tracking was employed to measure LA reservoir, conduit, contractile function, and stiffness.
Results
The 5 atria had a lot of ATTR amyloid infiltration, which caused loss of normal architecture, vascular remodeling, capillary disruption, and subendocardial fibrosis. After controlling for established predictors, echo speckle tracking in 906 patients with ATTR-CM revealed higher atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]), which remained independently linked with prognosis (lnLA stiff: HR: 1.23; 95 percent CI: 1.03-1.49; P = 0.029). The three phasic functional atrial components were severely harmed (reservoir 8.86 percent [5.94 percent -12.97 percent ]; conduit 6.5 percent [4.53 percent -9.28 percent ]; contraction function 4.0 percent [2.29 percent -6.56 percent ]). Atrial contraction was missing in 22.1 percent of patients with sinus rhythm (SR) "atrial electromechanical dissociation" on electrocardiograms (AEMD). Patients with AEMD had a worse outcome than those with SR and efficient mechanical contraction (P = 0.0018). Patients with atrial fibrillation who received AEMD had a similar prognosis.
Conclusions
ATTR-CM has a phenotype that includes considerable atrial infiltration, gradual loss of atrial function, and increasing stiffness, all of which are strong independent predictors of death. AEMD has developed as a distinct trait that can be used to identify patients in SR who have a bad prognosis.
Dr. Marianna Fontana works as the Director at the Royal Free Hospital in the UCL CMR unit. She is a Honorary Consultant Cardiologist and Professor of Cardiology at the National Amyloidosis Centre at the University College London. In this video Dr. Fontana discusses
https://www.jacc.org/doi/10.1016/j.jcmg.2021.06.022
Abstract
The goal of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of ATTR-CM patients; and investigate the relationship between LA pathology and mortality.
Background
The clinical importance of LA involvement in ATTR-CM is a hot topic in medicine.
Methods
In 5 explanted ATTR-CM atria, Congo red staining and immunohistochemistry were used to characterize the presence, type, and amount of amyloid and related alterations. In 906 individuals with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other), echo speckle tracking was employed to measure LA reservoir, conduit, contractile function, and stiffness.
Results
The 5 atria had a lot of ATTR amyloid infiltration, which caused loss of normal architecture, vascular remodeling, capillary disruption, and subendocardial fibrosis. After controlling for established predictors, echo speckle tracking in 906 patients with ATTR-CM revealed higher atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]), which remained independently linked with prognosis (lnLA stiff: HR: 1.23; 95 percent CI: 1.03-1.49; P = 0.029). The three phasic functional atrial components were severely harmed (reservoir 8.86 percent [5.94 percent -12.97 percent ]; conduit 6.5 percent [4.53 percent -9.28 percent ]; contraction function 4.0 percent [2.29 percent -6.56 percent ]). Atrial contraction was missing in 22.1 percent of patients with sinus rhythm (SR) "atrial electromechanical dissociation" on electrocardiograms (AEMD). Patients with AEMD had a worse outcome than those with SR and efficient mechanical contraction (P = 0.0018). Patients with atrial fibrillation who received AEMD had a similar prognosis.
Conclusions
ATTR-CM has a phenotype that includes considerable atrial infiltration, gradual loss of atrial function, and increasing stiffness, all of which are strong independent predictors of death. AEMD has developed as a distinct trait that can be used to identify patients in SR who have a bad prognosis.
Dr. Alexander is a cardiologist with advanced training in heart failure. He also works at Stanford University School of Medicine as an Assistant Professor of Cardiovascular Medicine. Dr. Alexander sees a wide range of patients and specializes in the care of severe heart failure and transplant situations. He also runs a research center that studies various types of heart failure. In this video Dr. Alexander discusses Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.06.002
Abstract-
Introduction
When amyloid fibrils invade the myocardial interstitium, causing a stiffened myocardium and restrictive cardiomyopathy, cardiac amyloidosis (CA) develops. CA is caused by systemic light chain amyloidosis (AL) or transthyretin amyloidosis in more than 95% of cases (ATTR). A clonal plasma cell dyscrasia that produces amyloidogenic monoclonal immunoglobulins causes AL amyloidosis. These immunoglobulins then misfold and deposit in the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, among other organs (1). Transthyretin (2), a liver-derived thyroid hormone and retinol protein transporter, experiences tetramer dissociation, misfolds, and produces amyloid fibrils in various distant organs, resulting in ATTR amyloidosis (3).
It's critical to distinguish between AL and ATTR amyloidosis since their clinical outcomes and therapies are vastly different. Continued amyloid accumulation promotes greater organ damage, hence delays in diagnosis result in poorer results. Furthermore, diagnostic ambiguity may cause a delay in the start of amyloid-directed treatment.
As a result, a high index of clinical suspicion combined with adequate diagnostic sequencing can lead to an accurate and rapid diagnosis of CA. We provide a patient case that demonstrates the difficulties that can arise when 99mtechnetium pyrophosphate scintigraphy (99mTc-PYP) scanning is used inappropriately to identify ATTR-CA in a patient with suspected CA and a plasma cell dyscrasia.
Description of the Situation
A 63-year-old man with bilateral carpal tunnel syndrome reported with dyspnea on exertion, positional lightheadedness, and chest pain to an outpatient facility. He had a mildly increased troponin I level of 0.23 ng/mL during his first episode of chest pain (reference range: 0-0.09 ng/mL). He had 510 pg/mL of N-terminal pro–B-type natriuretic peptide (reference range: 100 pg/mL). In leads II, III, and aVF, an electrocardiogram indicated sinus rhythm, a right bundle branch block, and Q waves. A left ventricular ejection fraction of 55%, bi-atrial enlargement, concentric left ventricular hypertrophy, and grade II diastolic dysfunction were discovered on an echocardiography. Coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient was prescribed furosemide, metoprolol, lisinopril, and spironolactone after being diagnosed with heart failure with preserved ejection fraction due to hypertension. However, due to hypotension, metoprolol was quickly withdrawn, and he was switched to midodrine. Despite medical treatment, the patient had many outpatient visits and was admitted to the hospital for dyspnea and chest pain on multiple occasions.
The patient was evaluated for ischemia again two years later. During exercise, an exercise treadmill test revealed no inducible ischemia but did reveal paroxysmal supraventricular tachycardia and infrequent premature ventricular contractions. In a second Zio Patch (iRhythm Technologies, Inc) investigation, nonsustained ventricular tachycardia was discovered, with the longest episode lasting 39 beats. A second coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient's nonischemic cardiomyopathy was subsequently investigated further using cardiac magnetic resonance imaging (CMR). A left ventricular ejection fraction of 39%, modest concentric left ventricular hypertrophy, and diffuse late gadolinium enhancement with an inability to null the blood pool were all found on CMR imaging, all of which were problematic for CA.
Following these findings, the CMR report indicated that hematologic testing for monoclonal gammopathy and a 99mTc-PYP scan be conducted in parallel. An aberrant immunoglobulin G lambda monoclonal protein was discovered by serum electrophoresis with immunofixation. A serum free lambda of 152.03 mg/L (reference range: 5.71-26.30 mg/L), a serum free kappa of 8.91 mg/L (reference range: 3.30-19.40 mg/L), and a kappa:lambda ratio of 0.06 were found in serum free light chains (reference range: 0.26-1.65). When taken together, these findings point to a lambda monoclonal gammopathy. The patient also had a 99mTc-PYP scan during this time, which exhibited a heart/contralateral lung ratio of 1.47 and was read as grade 2 myocardial uptake (myocardial tracer uptake equals rib uptake) (Figure 1). However, single-photon emission computed tomography (SPECT) imaging with obvious myocardial uptake was inconclusive. His team identified him with wild-type ATTR amyloidosis based on the 99mTc-PYP scan and TTR genetic testing that came out negative for a variation.
Our center was referred to the patient for further treatment. The patient underwent an endomyocardial biopsy two months following the 99mTc-PYP scan due to the existence of a monoclonal gammopathy, which proved CA. When mass spectrometry was used to subtype amyloid, it discovered a peptide profile that was compatible with AL (lambda)-type amyloid deposition rather than ATTR amyloidosis. A later bone marrow biopsy indicated a lambda-restricted plasma cell population of 10% to 20%. As a result, the patient was diagnosed with AL-CA. The initial misdiagnosis of ATTR-CA was due to the incorrect use and interpretation of 99mTc-PYP imaging. As a result, there was a three-month gap between the initial identification of a monoclonal gammopathy and the start of AL-CA treatment.
Bortezomib, cyclophosphamide, and dexamethasone were given to the patient as an anti-plasma cell therapy. Daratumumab was later added to the mix. Hematologic remission was achieved for the patient. Despite his hematologic remission, he nevertheless had considerable limitations as a result of his cardiac condition (New York Heart Association functional class III heart failure symptoms and orthostasis, requiring midodrine).
Discussion
This instance illustrates the dangers of using and interpreting 99mTc-PYP scans incorrectly during a CA examination. It also underlines the significance of early detection and therapy in AL-CA in order to reverse the myocardium's consequences of light chain toxicity and fibril deposition. For detecting ATTR amyloidosis, bone scintigraphy has emerged as a viable noninvasive alternative to endomyocardial biopsy. Endomyocardial biopsy has long been the gold standard for confirming ATTR amyloidosis histologically. This treatment, however, can result in problems like as tamponade and valvular injury, and should only be performed by experienced clinicians. Bone scintigraphy, on the other hand, is simpler to perform and more widely available in most clinical settings. As a result, bone scintigraphy may make it easier to diagnose ATTR amyloidosis, a previously underdiagnosed but curable cause of heart failure (2).
Expert guidelines and consensus recommendations underline the need of excluding AL amyloidosis when scheduling a bone scintigraphy scan because >20 percent of patients with AL-CA will have grade 2 or 3 radiotracer uptake (4,5). If a monoclonal gammopathy is ruled out via serum and urine testing, grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy provides a 100 percent specificity and positive predictive value for ATTR-CA (6). It's crucial to get SPECT pictures for bone scintigraphy scans in addition to ruling out AL amyloidosis. Planar scintigraphy can result in false-positive scan results if radiotracer blood pooling occurs and is mistaken for myocardial uptake (7). According to follow-up SPECT imaging, the false-positive rate in individuals with grade 2 uptake on planar images is 64 percent due to blood pooling or a lack of myocardial uptake (8).
In situations of monoclonal gammopathy, a biopsy (e.g., endomyocardial) should be used instead of a 99mTc-PYP scan to confirm the presence of CA and correctly characterize the amyloid subtype. Because many older individuals with ATTR-CA can also have an unrelated monoclonal gammopathy, biopsy is still required in many cases in lieu of a 99mTc-PYP scan to confirm an ATTR-CA diagnosis (9).
It's critical to follow diagnostic standards to guarantee a thorough and accurate assessment of CA (10). Understanding the appropriate usage and caveats of interpreting bone scintigraphy will be critical to avoid misdiagnosis as ATTR-CA becomes more widely recognized and 99mTc-PYP scans become more extensively used. When there is a clinical suspicion of CA based on history, electrocardiography, echocardiography, CMR imaging, or biomarkers, consensus recommendations call for CA screening. Many clinical indicators were present in our patient, including intolerance to heart failure medicines and orthostatic hypotension needing midodrine. He also experienced bilateral carpal tunnel syndrome and a low-level positive troponin reading for a long time. Although ATTR was suspected, the initial step was to rule out the presence of a monoclonal gammopathy, as finding a monoclonal protein would necessitate an endomyocardial biopsy to rule for AL amyloidosis. A positive 99mTc-PYP scan must be evaluated in the context of ruling out AL amyloid while screening for a monoclonal gammopathy and undergoing 99mTc-PYP. Furthermore, whereas 99mTc-PYP planar pictures demonstrated grade 2 tracer uptake in our patient, SPECT imaging revealed no obvious myocardial uptake, increasing the possibility of a false-positive finding due to blood pool uptake. Despite the existence of a gammopathy, the patient was wrongly diagnosed with ATTR-CA because the 99mTc-PYP scan indicated radiotracer uptake. After a later endomyocardial biopsy and amyloid subtyping using mass spectrometry, the actual diagnosis of AL amyloidosis was made.
Conclusions
In patients with signs of monoclonal gammopathy, an endomyocardial biopsy is required for a proper diagnosis of CA. Bone scintigraphy imaging is a potentially noninvasive technology that has the potential to improve ATTR-CA diagnosis, a previously unknown but now curable cause of heart failure. A clear framework for CA evaluations, on the other hand, is critical for avoiding diagnostic delays and increasing outcomes. This is especially important for AL-CA, which has a median survival time of 6 months if left untreated (11). Our example highlights the dangers of using and interpreting bone scintigraphy imaging for CA incorrectly, as well as the significance of checking for an underlying plasma cell dyscrasia. Providers will need to follow a systematic diagnostic strategy as knowledge of CA and novel therapeutics rises, in order to minimize undue financial hardship and diagnostic delay.
Dr. Alexander is a cardiologist with advanced training in heart failure. He also works at Stanford University School of Medicine as an Assistant Professor of Cardiovascular Medicine. Dr. Alexander sees a wide range of patients and specializes in the care of severe heart failure and transplant situations. He also runs a research center that studies various types of heart failure. In this video Dr. Alexander discusses Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.06.002
Abstract-
Introduction
When amyloid fibrils invade the myocardial interstitium, causing a stiffened myocardium and restrictive cardiomyopathy, cardiac amyloidosis (CA) develops. CA is caused by systemic light chain amyloidosis (AL) or transthyretin amyloidosis in more than 95% of cases (ATTR). A clonal plasma cell dyscrasia that produces amyloidogenic monoclonal immunoglobulins causes AL amyloidosis. These immunoglobulins then misfold and deposit in the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, among other organs (1). Transthyretin (2), a liver-derived thyroid hormone and retinol protein transporter, experiences tetramer dissociation, misfolds, and produces amyloid fibrils in various distant organs, resulting in ATTR amyloidosis (3).
It's critical to distinguish between AL and ATTR amyloidosis since their clinical outcomes and therapies are vastly different. Continued amyloid accumulation promotes greater organ damage, hence delays in diagnosis result in poorer results. Furthermore, diagnostic ambiguity may cause a delay in the start of amyloid-directed treatment.
As a result, a high index of clinical suspicion combined with adequate diagnostic sequencing can lead to an accurate and rapid diagnosis of CA. We provide a patient case that demonstrates the difficulties that can arise when 99mtechnetium pyrophosphate scintigraphy (99mTc-PYP) scanning is used inappropriately to identify ATTR-CA in a patient with suspected CA and a plasma cell dyscrasia.
Description of the Situation
A 63-year-old man with bilateral carpal tunnel syndrome reported with dyspnea on exertion, positional lightheadedness, and chest pain to an outpatient facility. He had a mildly increased troponin I level of 0.23 ng/mL during his first episode of chest pain (reference range: 0-0.09 ng/mL). He had 510 pg/mL of N-terminal pro–B-type natriuretic peptide (reference range: 100 pg/mL). In leads II, III, and aVF, an electrocardiogram indicated sinus rhythm, a right bundle branch block, and Q waves. A left ventricular ejection fraction of 55%, bi-atrial enlargement, concentric left ventricular hypertrophy, and grade II diastolic dysfunction were discovered on an echocardiography. Coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient was prescribed furosemide, metoprolol, lisinopril, and spironolactone after being diagnosed with heart failure with preserved ejection fraction due to hypertension. However, due to hypotension, metoprolol was quickly withdrawn, and he was switched to midodrine. Despite medical treatment, the patient had many outpatient visits and was admitted to the hospital for dyspnea and chest pain on multiple occasions.
The patient was evaluated for ischemia again two years later. During exercise, an exercise treadmill test revealed no inducible ischemia but did reveal paroxysmal supraventricular tachycardia and infrequent premature ventricular contractions. In a second Zio Patch (iRhythm Technologies, Inc) investigation, nonsustained ventricular tachycardia was discovered, with the longest episode lasting 39 beats. A second coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient's nonischemic cardiomyopathy was subsequently investigated further using cardiac magnetic resonance imaging (CMR). A left ventricular ejection fraction of 39%, modest concentric left ventricular hypertrophy, and diffuse late gadolinium enhancement with an inability to null the blood pool were all found on CMR imaging, all of which were problematic for CA.
Following these findings, the CMR report indicated that hematologic testing for monoclonal gammopathy and a 99mTc-PYP scan be conducted in parallel. An aberrant immunoglobulin G lambda monoclonal protein was discovered by serum electrophoresis with immunofixation. A serum free lambda of 152.03 mg/L (reference range: 5.71-26.30 mg/L), a serum free kappa of 8.91 mg/L (reference range: 3.30-19.40 mg/L), and a kappa:lambda ratio of 0.06 were found in serum free light chains (reference range: 0.26-1.65). When taken together, these findings point to a lambda monoclonal gammopathy. The patient also had a 99mTc-PYP scan during this time, which exhibited a heart/contralateral lung ratio of 1.47 and was read as grade 2 myocardial uptake (myocardial tracer uptake equals rib uptake) (Figure 1). However, single-photon emission computed tomography (SPECT) imaging with obvious myocardial uptake was inconclusive. His team identified him with wild-type ATTR amyloidosis based on the 99mTc-PYP scan and TTR genetic testing that came out negative for a variation.
Our center was referred to the patient for further treatment. The patient underwent an endomyocardial biopsy two months following the 99mTc-PYP scan due to the existence of a monoclonal gammopathy, which proved CA. When mass spectrometry was used to subtype amyloid, it discovered a peptide profile that was compatible with AL (lambda)-type amyloid deposition rather than ATTR amyloidosis. A later bone marrow biopsy indicated a lambda-restricted plasma cell population of 10% to 20%. As a result, the patient was diagnosed with AL-CA. The initial misdiagnosis of ATTR-CA was due to the incorrect use and interpretation of 99mTc-PYP imaging. As a result, there was a three-month gap between the initial identification of a monoclonal gammopathy and the start of AL-CA treatment.
Bortezomib, cyclophosphamide, and dexamethasone were given to the patient as an anti-plasma cell therapy. Daratumumab was later added to the mix. Hematologic remission was achieved for the patient. Despite his hematologic remission, he nevertheless had considerable limitations as a result of his cardiac condition (New York Heart Association functional class III heart failure symptoms and orthostasis, requiring midodrine).
Discussion
This instance illustrates the dangers of using and interpreting 99mTc-PYP scans incorrectly during a CA examination. It also underlines the significance of early detection and therapy in AL-CA in order to reverse the myocardium's consequences of light chain toxicity and fibril deposition. For detecting ATTR amyloidosis, bone scintigraphy has emerged as a viable noninvasive alternative to endomyocardial biopsy. Endomyocardial biopsy has long been the gold standard for confirming ATTR amyloidosis histologically. This treatment, however, can result in problems like as tamponade and valvular injury, and should only be performed by experienced clinicians. Bone scintigraphy, on the other hand, is simpler to perform and more widely available in most clinical settings. As a result, bone scintigraphy may make it easier to diagnose ATTR amyloidosis, a previously underdiagnosed but curable cause of heart failure (2).
Expert guidelines and consensus recommendations underline the need of excluding AL amyloidosis when scheduling a bone scintigraphy scan because >20 percent of patients with AL-CA will have grade 2 or 3 radiotracer uptake (4,5). If a monoclonal gammopathy is ruled out via serum and urine testing, grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy provides a 100 percent specificity and positive predictive value for ATTR-CA (6). It's crucial to get SPECT pictures for bone scintigraphy scans in addition to ruling out AL amyloidosis. Planar scintigraphy can result in false-positive scan results if radiotracer blood pooling occurs and is mistaken for myocardial uptake (7). According to follow-up SPECT imaging, the false-positive rate in individuals with grade 2 uptake on planar images is 64 percent due to blood pooling or a lack of myocardial uptake (8).
In situations of monoclonal gammopathy, a biopsy (e.g., endomyocardial) should be used instead of a 99mTc-PYP scan to confirm the presence of CA and correctly characterize the amyloid subtype. Because many older individuals with ATTR-CA can also have an unrelated monoclonal gammopathy, biopsy is still required in many cases in lieu of a 99mTc-PYP scan to confirm an ATTR-CA diagnosis (9).
It's critical to follow diagnostic standards to guarantee a thorough and accurate assessment of CA (10). Understanding the appropriate usage and caveats of interpreting bone scintigraphy will be critical to avoid misdiagnosis as ATTR-CA becomes more widely recognized and 99mTc-PYP scans become more extensively used. When there is a clinical suspicion of CA based on history, electrocardiography, echocardiography, CMR imaging, or biomarkers, consensus recommendations call for CA screening. Many clinical indicators were present in our patient, including intolerance to heart failure medicines and orthostatic hypotension needing midodrine. He also experienced bilateral carpal tunnel syndrome and a low-level positive troponin reading for a long time. Although ATTR was suspected, the initial step was to rule out the presence of a monoclonal gammopathy, as finding a monoclonal protein would necessitate an endomyocardial biopsy to rule for AL amyloidosis. A positive 99mTc-PYP scan must be evaluated in the context of ruling out AL amyloid while screening for a monoclonal gammopathy and undergoing 99mTc-PYP. Furthermore, whereas 99mTc-PYP planar pictures demonstrated grade 2 tracer uptake in our patient, SPECT imaging revealed no obvious myocardial uptake, increasing the possibility of a false-positive finding due to blood pool uptake. Despite the existence of a gammopathy, the patient was wrongly diagnosed with ATTR-CA because the 99mTc-PYP scan indicated radiotracer uptake. After a later endomyocardial biopsy and amyloid subtyping using mass spectrometry, the actual diagnosis of AL amyloidosis was made.
Conclusions
In patients with signs of monoclonal gammopathy, an endomyocardial biopsy is required for a proper diagnosis of CA. Bone scintigraphy imaging is a potentially noninvasive technology that has the potential to improve ATTR-CA diagnosis, a previously unknown but now curable cause of heart failure. A clear framework for CA evaluations, on the other hand, is critical for avoiding diagnostic delays and increasing outcomes. This is especially important for AL-CA, which has a median survival time of 6 months if left untreated (11). Our example highlights the dangers of using and interpreting bone scintigraphy imaging for CA incorrectly, as well as the significance of checking for an underlying plasma cell dyscrasia. Providers will need to follow a systematic diagnostic strategy as knowledge of CA and novel therapeutics rises, in order to minimize undue financial hardship and diagnostic delay.
Dr. Jan Griffin is a cardiologist at New York-Presbyterian/Columbia University Irving Medical Center in New York, NY. She graduated from the Royal College of Surgeons of Ireland with a medical degree. In this video Dr. Griffin discusses ATTR Amyloidosis: Current and Emerging Management Strategies.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Because of noninvasive imaging and increased awareness, transthyretin cardiac amyloidosis (ATTR-CA) is becoming more common. Because pathogenic alleles do not have complete clinical penetrance, there is a substantial population of asymptomatic transthyretin variant carriers. More research is needed into screening techniques, monitoring, and therapy of subclinical ATTR-CA. The development of effective medicines based on a scientific understanding of ATTR-CA pathogenesis is perhaps the most significant translational success. These include recently established transthyretin protein stabilization and transthyretin production suppression methods. Data on neurohormonal blocking in ATTR-CA is scarce, with medical treatment focusing primarily on fluid management. Atrial fibrillation is a frequent condition that necessitates anticoagulation due to the risk of thrombus formation. Although conduction disorders and ventricular arrhythmias are common, little is known about the best ways to treat them. Finally, because aortic stenosis and ATTR-CA are usually seen together, transcatheter valve replacement is the chosen treatment option.
Highlights
• ATTR-CA is becoming more well-known as a result of increased awareness and the development of noninvasive diagnostic approaches.
• Clinical penetrance of harmful alleles is incomplete, with inadequate data for asymptomatic carriers' screening or care.
• Biological understanding of ATTR-CA pathophysiology has led to effective TTR stabilizers and silencers as targeted therapeutics.
• Future treatments could involve CRISPR, amyloid extraction/degradation, and amyloid seeding inhibition.
Introduction
Over the last decade, the field of transthyretin cardiac amyloidosis (ATTR-CA) has undergone a transformation, with an increasing recognition that many ATTR-CA patients were previously undiagnosed and instead assumed to have hypertension, heart failure with preserved ejection fraction (HFpEF), or hypertrophic cardiomyopathy (1). Delays in diagnosis were almost prevalent, and they still exist today, sadly (2). However, with increased awareness of clinical clues and the ability to diagnose ATTR-CA without a biopsy (3), reports have shown ATTR-CA in patients hospitalized with HFpEF (13%) (4), patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) (16%) (5), and up to 40% of high-risk populations, such as Afro-Caribbeans with heart failure and increased ventricular wall thickness undergoing TAVR (6). As a result, every cardiologist has come across patients with ATTR-CA, whether they are aware of it or not. Despite the exponential increase in the use of cardiac bone scintigraphy and multisocietal guidelines supporting nonbiopsy diagnosis (7,8), there are certain major traps to avoid. Failure to check for monoclonal proteins or an over-reliance on planar imaging are two examples (9). The development of effective medicines based on a biological understanding of the underlying pathophysiology has been the most significant "translational victory" (10). These treatments have a significant impact on the quality and quantity of life for those who are afflicted. This article focuses on the treatment of ATTR-CA patients and the evolving therapy landscape (Central Illustration).
Dr. Jan Griffin is a cardiologist at New York-Presbyterian/Columbia University Irving Medical Center in New York, NY. She graduated from the Royal College of Surgeons of Ireland with a medical degree. In this video Dr. Griffin discusses ATTR Amyloidosis: Current and Emerging Management Strategies.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Because of noninvasive imaging and increased awareness, transthyretin cardiac amyloidosis (ATTR-CA) is becoming more common. Because pathogenic alleles do not have complete clinical penetrance, there is a substantial population of asymptomatic transthyretin variant carriers. More research is needed into screening techniques, monitoring, and therapy of subclinical ATTR-CA. The development of effective medicines based on a scientific understanding of ATTR-CA pathogenesis is perhaps the most significant translational success. These include recently established transthyretin protein stabilization and transthyretin production suppression methods. Data on neurohormonal blocking in ATTR-CA is scarce, with medical treatment focusing primarily on fluid management. Atrial fibrillation is a frequent condition that necessitates anticoagulation due to the risk of thrombus formation. Although conduction disorders and ventricular arrhythmias are common, little is known about the best ways to treat them. Finally, because aortic stenosis and ATTR-CA are usually seen together, transcatheter valve replacement is the chosen treatment option.
Highlights
• ATTR-CA is becoming more well-known as a result of increased awareness and the development of noninvasive diagnostic approaches.
• Clinical penetrance of harmful alleles is incomplete, with inadequate data for asymptomatic carriers' screening or care.
• Biological understanding of ATTR-CA pathophysiology has led to effective TTR stabilizers and silencers as targeted therapeutics.
• Future treatments could involve CRISPR, amyloid extraction/degradation, and amyloid seeding inhibition.
Introduction
Over the last decade, the field of transthyretin cardiac amyloidosis (ATTR-CA) has undergone a transformation, with an increasing recognition that many ATTR-CA patients were previously undiagnosed and instead assumed to have hypertension, heart failure with preserved ejection fraction (HFpEF), or hypertrophic cardiomyopathy (1). Delays in diagnosis were almost prevalent, and they still exist today, sadly (2). However, with increased awareness of clinical clues and the ability to diagnose ATTR-CA without a biopsy (3), reports have shown ATTR-CA in patients hospitalized with HFpEF (13%) (4), patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) (16%) (5), and up to 40% of high-risk populations, such as Afro-Caribbeans with heart failure and increased ventricular wall thickness undergoing TAVR (6). As a result, every cardiologist has come across patients with ATTR-CA, whether they are aware of it or not. Despite the exponential increase in the use of cardiac bone scintigraphy and multisocietal guidelines supporting nonbiopsy diagnosis (7,8), there are certain major traps to avoid. Failure to check for monoclonal proteins or an over-reliance on planar imaging are two examples (9). The development of effective medicines based on a biological understanding of the underlying pathophysiology has been the most significant "translational victory" (10). These treatments have a significant impact on the quality and quantity of life for those who are afflicted. This article focuses on the treatment of ATTR-CA patients and the evolving therapy landscape (Central Illustration).
We discuss transthyretin (aTTR) cardiac amyloidosis, symptoms, appropriate diagnostic testing and different treatment options available. Dr. Matt Maurer from NewYork-Presbyterian Hospital/Columbia University shares his expertise with us.
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Management of light chain or AL amyloidosis has changed with major advances in recent years. Dr. Ronald Witteles is a Stanford Cardiologist with particular expertise in the treatment of cardiac amyloidosis and shares his expertise with us. He serves as Co-Director of the Stanford Amyloid Center, one of the world's leading amyloid centers.
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