Cardiac Amyloidosis

Abstract

Cardiac amyloidosis is a protein-folding disorder mostly caused by abnormal deposition of either transthyretin proteins or light chain (AL) proteins, into one or more organs, including the heart. The main cardiac manifestations are right ventricular heart failure and arrhythmias. Extracardiac symptoms usually precede cardiac symptoms and are evident several years before the development of symptomatic cardiac problems. The prognosis is poor without appropriate management. Non-invasive evaluation with multi-imaging modalities has allowed earlier diagnosis, particularly when used in combination with monoclonal gammopathy evaluation. Management will vary depending on the subtype of amyloidosis. It consists of supportive treatment of cardiac-related symptoms, pharmacological treatment that targets amyloid fibrils formation and deposition, thus attacking the underlying disease, and addressing the management of extracardiac symptoms to improve the patients’ quality of life.

1. Introduction

Amyloidosis is an infiltrative disorder primarily caused by extracellular tissue deposition of amyloid fibrils. It occurs when the misfolded protein assembles with similar proteins to form oligomers, which circulate in the blood and deposit as highly ordered fibrils, in the interstitial space of target organs [1]. These deposits are comprised of insoluble low molecular weight protein subunits ranging from 5 to 25 kD leading to the outlined systemic disease [2]. Up to date there are at least 25 different human and 8 different animal amyloidogenic proteins identified [1]. Tissue infiltration occurs in many organs such as kidney, liver, autonomic nervous system, and heart. However, >95% of cardiac amyloidosis is secondary to immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) [3].

It was previously understood that cardiac amyloidosis was a rare and fatal disease. Nevertheless, with the emergence of advanced cardiac imaging studies as well as the availability of new pharmacological treatment for transthyretin amyloidosis and increased awareness of the disease among physicians, and better guidance for accurate diagnosis there has been a marked increase in diagnosis of this previously underrecognized medical condition. Nevertheless, despite increased awareness of the disease, sociodemographic disparities in diagnosis and management of cardiac amyloidosis exist, thus leading to a delay in treatment and increased disease severity at time of diagnosis within certain sociodemographic groups [4, 5].

In this chapter, we will discuss in detail the clinical presentation, identification process, and implications for early detection of cardiac amyloidosis to improve patient outcomes. Additionally, we will discuss new emerging therapeutic approaches and the importance of socioeconomic disparities within the disease.

2. Pathophysiology

Cardiac amyloidosis (CA) is also known as “stiff heart syndrome” because the amyloid protein infiltration leads to increased cardiac wall thickness and ventricular stiffness (Figure 1) [1]. The natural progression of amyloidosis includes involvement of other organs prior to its cardiac manifestation.

Figure 1.

Cardiac amyloidosis Pathophysiology. (A) Gross specimen inspection reveals a rubbery consistency of the myocardium. On some occasions, there can be evidence of intracardiac thrombi. The lighter-tan colored material is amyloid (green arrowhead) and the darker tissue represents normal myocardium (blue arrowhead). (B) Hematoxylin and eosin-stained (inset) microscopic sections with characteristic ring-like encircling of myofibers and the lack of the wavy fibrillar character of collagen. (C) 400× magnification and (D) is 400× magnification of the eosin-stained section with Congo Red staining microscopic sections, amyloid is red-orange, the protein is birefringent so that when Congo Red-stained tissue is viewed under polarized light it transmits an apple-green color.

2.1 AL amyloidosis

In AL amyloidosis, the deposits are formed by accumulation of kappa or lambda light chain proteins. These proteins in normal conditions are produced by plasma cells. However, when the cells overproduce light chains, they become amyloidogenic and deposit in the autonomic and peripheral sensory nervous system, spleen, lungs, and heart. This process can happen spontaneously or because of certain blood or immune system cancers. The major conditions associated with AL amyloidosis are multiple myeloma, Waldenström’s macroglobulinemia, and B-cell lymphomas [6].

In addition to mechanical and architectural damage mediated by cardiac AL-fibril deposition, the soluble AL protein has been proven to have directly toxic effects on myocardial tissue. In experimental mouse models, it was shown that the rapid progression of heart failure and left ventricular dysfunction seen in AL amyloidosis is caused by toxic effect of circulating light chains on the already diseased myocardium by the amyloid protein deposition [7]. Later another group demonstrated that this toxic effect was mediated by p38α mitogen-activated protein kinases (MAPK) signaling which can upregulate pro-BNP. In fact, increased pro-BNP can be indicative of both amyloid disease activity and the degree of cardiac injury [8, 9].

2.2 ATTR cardiomyopathy

ATTR cardiomyopathy is caused by a transthyretin protein (TTP), previously known as prealbumin. It is a 55 kD protein whose main function is to transport both thyroxine (T4) and retinol-binding protein. About 85% of the TTP protein is produced in the liver, with the rest being synthesized in the choroid plexus, the retinal and ciliary pigment epithelia of the eye, and the pancreas [10, 11, 12]. TTP normally circulates as a homotetramer, with a small amount of transthyretin circulating in monomeric form. The monomeric form of transthyretin is prone to misfolding leading to a gradual formation of amyloid deposits. There are two types of transthyretin amyloidosis, hereditary or variant (ATTRv) and wild or senile (ATTRwt), both of which are caused by a misfolding of TTR protein.

2.2.1 Hereditary ATTR (ATTRv)

The hereditary type is caused by a TTR gene missense mutation the patient is born with, that causes a decrease in the stability of the tetramer conformation of the protein, promoting its dissociation into monomers and consequent leading to misfolding. Following the dissociation and misfolding events, the aggregation and deposition of insoluble TTR and nonbranching amyloid fibers, typically with a diameter of 10 nm, occur in the extracellular spaces of many tissues and organs [11]. Currently, there are over 130 identified point mutations in the gene that encodes TTR synthesis, which is located on the long arm of chromosome 18 [10, 11]. Most of these point mutations can cause amyloidosis disease. In the US, the most common mutation is the V122I, found in 3–3.5% of individuals of African descent. Despite the prevalence of the mutation within the African American population, cardiac amyloidosis still represents a severely underdiagnosed form of heart failure within this population [13]. ATTRv phenotypic expression will vary depending on the type of transthyretin protein mutation with symptoms ranging from severe peripheral neuropathy (familial amyloidotic polyneuropathy) to cardiac amyloid cardiomyopathy and conduction abnormalities (familial amyloid cardiomyopathy) [9, 10, 11].

2.2.2 Wild-type or senile ATTR (ATTRwt)

In ATTRwt, it is believed the phenomenon occurs as part of an unknown aging-related mechanism, where TTR molecules misfold and deposit within the heart and other organs as amyloid fibrils. The most common clinical manifestations are motor and sensory neuropathy, gastrointestinal disturbances, and cardiomyopathy [14]. Both amyloid deposition and its effects on surrounding organs establish the phenotype of the disease [1]. Amyloid fibers can cause direct compression or obstruction in neighboring structures, which manifests as conditions such as carpal tunnel syndrome and vitreous opacities [14]. As amyloid fibers accumulate, patients experience progressive dysfunction with symptoms that may not start until years after the initial amyloid formation and deposition [11].

3. Epidemiology

About >95% of cases of cardiac amyloidosis are caused or related to light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis.

3.1 AL-amyloidosis

AL amyloidosis has an incidence of approximately 4000 new cases of amyloidosis annually in the United States. However, the actual incidence may be higher due to the disease under diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are males [15]. However, only half of these patients present cardiac manifestations of systemic (AL) amyloidosis. Once heart failure symptoms ensue, prognosis is poor with a median survival of <6 months if plasma cell dyscrasia is left untreated [16]. In AL-cardiac amyloidosis, poor prognosis is associated with increased LV relative wall thickness, older age, NYHA class, elevated pro-BNP, and increased C-reactive proteins [16, 17].

3.2 ATTR amyloidosis

On the other hand, ATTR amyloidosis, which was thought to be a rare cause for CA, has recently been more frequently diagnosed. This is a result of the use of new cardiac imaging techniques and increased availability of imaging and diagnostic tools clinical practices, that have revolutionized the diagnosis of cardiac diseases. However, despite advances and availability in imaging techniques, this condition is still frequently underdiagnosed due its myriad of signs and symptoms, which are often associated with other diseases, leading to a poorly delineated prevalence of the disease. Earlier reports of patients undergoing noninvasive diagnosis with patients older than 60 years, Gonzalez et al. found a staggering 13% prevalence of CA in patients admitted with clinical diagnosis of decompensated heart failure with preserved ejection fraction [13]. Meanwhile, AbouEzzeddine et al. performed a community based-setting cohort study in which ATTR-CM was found in a substantial number of older male patients with heart failure with preserved ejection fraction (HFpEF) (2.5% with 95% CI, 1.4–4.0%). This study highlights the importance of systemic screening for CA in male patients with HFpEF and LV wall thickening [14].

3.2.1 ATTRwt

ATTRwt almost exclusively occurs in male patients 70 years or older with a median survival after the onset of heart failure of 7.5 years [18]. The average worldwide prevalence is estimated to be 1/6000 [19]. Interestingly autopsy studies on from patients with antemortem diagnosis of HFpEF demonstrated presence of fibrillar deposits within the heart in 25% of the patients older than 80 years of age [20]. Moreover several studies have shown that one in seven elderly patient with aortic stenosis also suffer from cardiac amyloidosis [5]. While the exact mechanism or reason behind the frequent coexistence of both diseases in such patients is not fully understood, several hypotheses have been drawn in aims to provide a plausible explanation. The coexistence of severe aortic stenosis with ATTRwt has been shown to not have a significant impact in patient survival; special considerations should be taken with these patients at the time of treatment and will be addressed in greater detail later in the chapter. In comparison to ATTRv, ATTRwt almost exclusively affects the heart with involvement of both atrial and ventricular chambers and frequent incidence of conduction disorder and arrhythmias [20]. However, patients with ATTRwt have been shown to have some extracardiac manifestations of the disease such as musculoskeletal involvement like carpal tunnel syndrome in up to 33–49%, traumatic bicep rupture 33%, and lumbar stenosis 37% [21, 22, 23]. Extracardiac symptoms can precede cardiac ones up 5–7 years before cardiac amyloidosis diagnosis [24].

3.2.2 ATTRv

ATTRv onset has been shown to occur earlier in males than in females. Interestingly, the age of onset is progressively earlier in successive generations [11]. From the hereditary subtypes, the mutations known to have cardiac effects are TTR V30M, t TTR V122I, and TTR T60A. Most of these mutations are found clustered into distinct ethnicity groups and/or within certain geographical areas. Its inheritance has an autosomal dominant pattern [25]. The V30M mutation is the most common mutation worldwide, especially in parts of Portugal, Japan, and northern Sweden. Nevertheless, it has also been identified in Spain, France, South America, and some nonendemic areas of Africa. It has a slight female predominance with a bimodal presentation with earlier onset of V30M ATTR symptoms being mostly neurological and late-onset symptoms that present with both cardiomyopathic and polyneuropathic involvement [26].

On the other hand, the most common mutation in the US associated with late-onset cardiomyopathy is V122I. It is frequently diagnosed among African Americans with an incidence of 3–4% compared to 0.44% among white individuals. Moreover, within African American population this mutation can be found in up to 10% of the patients over 65 years of age who have developed severe HF [27]. The T60A variant is the second-most-common TTR variant in the US and the most common in the UK and Ireland, affecting approximately 1% of the population of north-western Ireland. It has an unknown gender distribution which occurs in patients >60 years of age with cardiac involvement as well as autonomic and peripheral neuropathies [10, 11, 27]. However, even though there are no set gender distribution male patients tend to have a mean age of presentation of 60–65 years of age, while female patients tend to have a latter onset. ATTRv is an important cause of heart failure that disproportionately affects people of African descent. Despite the high burden of ATTRv among black individuals, just a few studies include African American patients and most of the clinical data, we have for ATTRv come from North America and Europe. Moreover, despite the known and well-established predisposition to cardiovascular diseases within other minority groups such as Hispanic/Latino population, the only minority group to be included and studied in clinical trials so far has been African American patients [28]. There is no known clinical data to describe epidemiological characteristics of ATTRv in the Hispanic/Latino population. Nevertheless, efforts to promote earlier identification of ATTRv in general practice will improve clinical outcomes for all groups.

4. Clinical manifestations and physical examination

As previously mentioned, amyloidosis is a systemic disease. Therefore, patients with cardiac amyloidosis have amyloid fibril affecting the cardiovascular system and involvement of the musculoskeletal system, peripheral nervous system, and autonomic nervous system. Since the systemic manifestation commonly precedes the cardiac manifestation, it often results in delayed diagnosis. Non-cardiac clinical manifestations are diverse and includes lumbar spinal stenosis, GI symptoms such as constipation or diarrhea, nausea or vomiting, unexplained nephrotic syndrome with some degrees of renal insufficiency, sensorimotor peripheral neuropathy, arrhythmias, autonomic and peripheral neuropathies, and bilateral carpal tunnel syndrome. The latter can be diagnosed up to 10 years before confirmation and diagnosis of ATTR amyloidosis [13, 14, 18, 19]. Therefore, by the time patient starts to develop cardiovascular symptoms, usually there is extensive systemic and myocardial infiltration. A survey of 533 people, including patients with ATTR and their family members, by Lousada et al. found that the correct diagnosis in patients with wild-type ATTR, was made within 6 months in up to 46% of patients and at times the correct diagnosis required >5 different physicians [29].

Cardiovascular manifestations can be four-fold, including congestive heart failure due to restrictive cardiomyopathy, vascular abnormalities, autonomic dysfunction, and conduction abnormalities. Dyspnea is the most common complaint associated with elevated right heart side pressure. Physical examination in advanced disease is noteworthy for prominent jugular venous distention associated with evident “x” and “y” descent, peripheral edema, hepatic congestion, and ascites [30]. The lower extremity edema is usually disproportionate to the degree of heart failure and is related to the degree of nephrotic syndrome. A right ventricular S3 is usually present and correlates with the degree of right ventricular dilatation and dysfunction. The S4 is always absent despite a decrease in left ventricular compliance due to atrial dysfunction secondary to amyloid infiltration. Lung field can reveal bilateral pleural effusion that tends to be diuretics resistant requiring in many cases frequent thoracentesis for fluid removal with high degree of recurrence [31].

Vascular involvement can be seen due to amyloid deposition leading to increase in vessel wall thickness or endothelial functional abnormalities (Figure 1). Autopsy studies have demonstrated amyloid infiltration of the small intramural coronary arteries in up to 88–90% of AL patients. Furthermore, the arterial abnormalities do not appear to be related to echocardiographic evidence of cardiac involvement [32]. Patients may present with atypical and typical angina pectoris due to small vessels involvement [33]. Persistent increase in troponin level may be present leading with misdiagnosis of non-ST elevation myocardial infarction [34]. Despite the presence or absence of at true ischemic event, this elevation of cardiac markers is a negative prognostic factor [35, 36].

A hallmark of CA is autonomic dysfunction and can be interpreted as an early symptom, thus patients should be carefully evaluated for dizziness, near syncope and syncopal events. However, many factors may contribute to syncope such as postural hypotension due to excessive diuresis or autonomic neuropathy and small ventricular cavities. Low blood pressure is a common finding and not necessarily accompanied by orthostatic hypotension. It has long been known that syncope is common in AL amyloid heart disease and mostly precipitated by physiologic stress. Stress-precipitated syncope is associated with a poor prognosis in such patients, both in terms of their median survival (2 months) and as a common precursor of sudden cardiac death [32]. Additionally, autonomic dysfunction in these patients is associated with decreased cardiac output. However, there is no evident association between syncopal events and mortality in ATTR patients despite frequent events and poor quality of life [37, 38].

5. Diagnostic evaluation

The diagnostic evaluation begins with a complete history and physical examination, mainly considering both cardiac and non-cardiac signs and symptoms or “red flags” that suggest high suspicion for the condition to delineate a diagnostic approach using a combination of serum biomarkers as well as imaging studies (Table 1).

Clinical findings	Imaging studies	Biomarkers
Cardiac symptoms; Heart Failure Intolerance to standard HF treatment Cardiac arrhythmias (CAVB, slow AF Low flow low gradient or paradoxical Low flow low gradient AS Non-cardiac Symptoms; Musculoskeletal-> bilateral carpal tunnel, lumbar spinal stenosis, biceps tendon rupture Symptoms of peripheral or sensorimotor neuropathy and dysautonomia Gastrointestinal manifestations such as diarrhea, constipation, or unintentional weight loss Renal impairment or cardiorenal syndrome	Transthoracic echocardiogram; Increase left ventricular wall width >1.2 cm in the absence of underlying cause Phenotypical echocardiographic finding of infiltrative characteristics such as atrioventricular wall thickening, interatrial septum thickening, and thickening of the left ventricular free wall CMR; Global subendocardial late gadolinium enhancement Elevated native T1 value Expanded ECV	Persistent elevation of troponin in the absence of acute coronary events Persistent elevation of N-Pro-BNP

Table 1.

Red flags for cardiac amyloidosis.

HF, heart failure; CAVB, complete atrioventricular block; AF, atrial fibrillation; AS, aortic stenosis; CMR, cardiac magnetic resonance; ECV, extracellular volume; N-Pro-BNP, N-terminal-pro hormone-brain natriuretic peptide.

5.1 Serum biomarkers

5.1.1 ATTR

Witteles et al. propose considering evaluation of ATTR cardiomyopathy in patients older than 65 years (females >75 years) with a diagnosis of heart failure and ≥ 1 clinical finding indicative of ATTR such as suggestive imaging tests results, and/or chronic elevation in biomarkers (troponins, BNP, pro-BNP) [39, 40, 41]. Appropriate assessment include evaluation of absence of monoclonal gammopathy using serum free light chains (FLC), serum, and urine immunofixation electrophoresis as serum protein electrophoresis is insensitive leasing to false negative results.

5.1.2 AL cardiac amyloidosis

Pro-BNP concentration is found to be increased in patients with heart failure and in patients with AL amyloidosis before the onset of clinical heart failure. This peptide is considered a marker for cardiac involvement. A report where pro-BNP was measured in patients with AL amyloidosis, found that its concentration was elevated despite the presence of clinical heart failure. Moreover, the diagnostic utility of pro-BNP study in 152 patients identified with amyloidosis where a plasma N-terminal pro-BNP concentration of 152 pmol/L detected cardiac involvement with a sensitivity of 93% and specificity of 90% [42].

5.2 Electrocardiogram (ECG)

Low voltage electrocardiogram QRS (<0.5 mV on limb leads, <1 mV on precordial leads, and Sokolow index defined as the sum of amplitudes of the S-wave in V1 and the R-wave in V_5-6 < 1.5 mV) has always been thought to be pathognomonic of cardiac amyloidosis (Figure 2). Nevertheless, this finding has been shown to have low sensitivity and its prevalence varies markedly according to the etiology of cardiomyopathy. Low voltage QRS is found in around 60% of AL-type amyloidosis and in close to 20% of ATTR type amyloidosis [43]. However, when present it has been associated with poor survival regardless the type of cardiac amyloidosis [43]. Moreover, a Sokolow index <1.5 mV was shown to be predictive of a combined outcome of time to hospitalization, heart transplant, or death in both AL and ATTR cardiomyopathies [44]. On the other hand, some studies have suggested that an increase in LV mass to EKG voltage relationship (mass-voltage ratio) might be more specific to CA than low voltage alone perse [45, 46]. Left ventricular hypertrophy changes have been described in precordial leads in small group of patients with very uncommon hypertrophy changes noted in limb leads [43].

Figure 2.

Low voltage ECG 12-lead electrocardiography depicting the typical changes observed in cardiac amyloidosis. Low voltage limb leads (orange arrowhead) and poor precordial leads “R” wave progression with pseudo infarct pattern (green arrowhead) secondary to amyloid infiltration at the level of the left ventricular myocardium. Also, there is evidence of sinoatrial and atrioventricular conduction defects in this case there is a 1st degree AV block secondary to amyloid infiltration into the conduction system.

Other electrocardiographic evaluation using signal-averaged ECG (SAECG) shows that late potentials were significantly more frequents on patients with echocardiographic evidence of cardiac amyloidosis (31% vs. 9% in those with normal echocardiograms) and was independently predictive of an increased risk of sudden cardiac death [47].

5.3 Transthoracic echocardiography

Transthoracic echocardiography is cornerstone in the diagnostic evaluation of patients with heart disease and is considered the standard of care in cases in which CA is suspected. Cardiac amyloidosis has very distinctive echocardiographic features such as small LV cavity with associated increased left ventricular thickening (>12 mm) (Figures 1 and 3), biatrial enlargement, increased thickness of right ventricle, interatrial septum, and atrioventricular valves (Figure 3) with near normal LV systolic performance. The often-described increased echogenicity characterized as granular or sparkling texture pathognomonic of cardiac amyloidosis is not very sensitive and only present in a minority of patients especially when disease is advanced (Figure 3) [48, 49]. However, this changes which are often referred to as hypertrophy are inaccurate since it is caused by a progressive infiltrative process rather than myocyte hypertrophy as it occurs in other forms of cardiomyopathy. AL and ATTR have overlapping echocardiographic features, although in general ATTR is characterized by thicker walls, owing to the more insidious nature of deposition and late diagnosis versus the toxic aspect of light chains in AL facilitating apoptosis and earlier recognition. However, asymmetric left ventricular thickness, mimicking hypertrophic cardiomyopathy, has been described in patients with familial amyloidosis [50]. Studies have demonstrated that there is a correlation between severity of LV thickness, a higher frequency of associated echocardiographic abnormalities such as left atrial enlargement or granular sparkling appearance and more common reduced systolic function with a decrease survival (median of 1.1 years) in these patients [51]. RV involvement assessed with TAPSE <14 mm is associated with events such as worsening of heart failure, increased mortality and heart transplant (Figure 3) [48, 52]. Diastolic dysfunction to different degrees is common and is present in all patients. In advanced CA, doppler mitral flow evaluation shows restrictive pattern characterized with short deceleration time of E wave with decreased A wave velocity (Figure 3). Diminished A wave velocity is due to progression of restrictive disease and intrinsic atrial dysfunction.

Figure 3.

Transthoracic echocardiogram with characteristic findings of cardiac amyloidosis (A) PLAX & SAX Markedly thickened myocardium with severe concentric hypertrophy and abnormal texture described as ground glass appearance. Prominent and thickened MV leaflets and severe LA enlargement. Associated posterior pericardiac effusion (B) mitral valve inflow velocities with shortened deceleration time of the “E” wave (98 ms) and absent “A” wave with an E/A > 2 consistent with severe diastolic impairment also known as restrictive pattern. MVI TDI with lateral velocities with 5-5-5 pattern (s’—systolic, e’—early diastolic, and a’—late-atrial-diastolic) with TDI velocities <5 cm/s. (C) Echocardiogram with evidence of increased RV thickening (88 mm) and dilated cavity, reduced RVs’ TDI and TAPSE suggestive of RV dysfunction. (D) Left ventricular showing a decrease in global longitudinal deformation (absolute value <−15. Cherry-on-top sign (yellow arrow) on the STE “Bulls” map due to a relative reduction of the middle and basal segments of the left ventricle compared to the apical segments. There is an Apical to Basal/mid segments >2.1.

Tissue Doppler, strain, and strain rate imaging allows early diagnosis of diastolic dysfunction in patients with cardiac amyloid and helps distinguish cardiac amyloidosis from other restrictive cardiomyopathies etiologies such as constrictive pericarditis. Usually, a mitral annular diastolic velocity (E’) <8 cm/s is a good discriminator for restrictive physiology [51, 52]. In patient with more advanced presentation of CA, the “5-5-5” sign with TDI velocities are <5 cm/s (Figure 3). Other signs of advanced CA besides tissue velocities include increased isovolumetric contraction time (IVCT) and isovolumetric relaxation time (IVRT) and decreased ejection time. However, regional strain has shown long-axis dysfunction in early cardiac amyloidosis and impairment of longitudinal contraction despite preserved fractional shortening. Reduction in global measures of systolic function, such as left ventricular (LV) ejection fraction, are late manifestations and characteristics of advanced disease. In CA, overall global longitudinal strain (GLS) is < −15 with a characteristically depressed longitudinal strain of the basal and mid-ventricular segment while preserved apical segments, better known as apical sparing or “Cherry-on-top” is common (Figure 3). Moreover, reduced GLS have been suggested to be an independent predictor of survival in both AL and ATTR [51]. Left atrial strain analysis by stress echocardiogram (STE) (normal −40%) shows severely decreased LA function with elevated LA volumes and can be helpful for monitoring and prediction of thromboembolic risk (Figure 3) [48].

5.4 Cardiac magnetic resonance imaging (MRI)

Cardiac MRI has been used for identification of cardiac amyloidosis in patients with unexplained heart failure and arrhythmias in which echocardiographic findings are suspicious yet inconclusive [52]. It is a highly specific tool for the diagnosis of CA because of its intrinsic capacity to characterized tissue by using late gadolinium enhancement and parametric mapping techniques (T1) and its ability to assess extracellular Volume [ECV]) (Figure 4) [53]. In CA, late gadolinium enhancement (LGE) distributes in the extracellular space not following a specific coronary distribution. Different patterns have been observed such as diffuse patterns that can progress from subendocardial to transmural. The circumferential subendocardial LGE has been more frequently seen in patients with AL-CM whereas the diffuse transmural LGE pattern has been more frequently associated with ATTR-CM [54]. The degree and severity of LGE is associated with increased mortality. Native (noncontrast) T1 or T1 time is measured without contrasts and may reflect changes in tissue composition such as in intracellular or extracellular compartments affected by collagen, protein, edema, lipids, and iron content [54]. Whereas postcontrast T1 is used to calculate ECV a which is a surrogate parameter for the extracellular matrix. Both, native T1 and ECV have demonstrated their usefulness as biomarkers for CA diagnosis [54]. A series from National Amyloidosis Centre in the United Kingdom followed hematologic-measured treatment response and correlated them with ECV findings. They concluded that cardiac MRI-detected change in ECV at 6 months to be prognostic for long-term outcomes, even after controlling for the hematologic response. Suggesting that cardiac involvement in AL amyloidosis does not walk so tightly together with hematologic involvement and that serial analysis of the presumed cardiac amyloid burden with cardiac MRI during treatment may be important to comprehensively assess treatment response [55].

Figure 4.

Common cardiac MRI findings found in cardiac amyloidosis using state-of-the art cardiac MRI approach. The rights of this figure were obtained. Permission for the reproduction of the image was obtained by the authors. Magnetic Resonance Imaging, First published: 30 June 2022, DOI: 10.1002/jmri.28314.

5.5 Bone radiotracers

99mTc-PYP/DPD/HMDP cardiac scans have become a chief diagnostic tool used in the diagnosis and differentiation of cardiac amyloidosis. In 1980, it was observed for the first time the uptake of ^99mTc-phosohate in cardiac material from patients undergoing bone scan for evaluation of bone metastasis [56]. Later in 2005, Perugini et al. demonstrated the usefulness of ^99mTc-DPD scintigraphy in diagnosis and successful differentiation of TTR versus AL etiology in patients with documented cardiac amyloidosis [56]. Radiotracer uptake was attributed to possible higher calcium content un ATTR amyloid deposits [57, 58].

There are two approaches for pyrophosphate image interpretation: quantitative vs. semiquantitative evaluation (Figure 5). In the quantitative PYP evaluation, a circular target region of interest (ROI) is drawn over the heart on the planar images and are mirrored on the contralateral chest to account for the background of the ribs (H/CL) [52]. Total and absolute counts are measured in each ROI and a ratio of heart-to-contralateral lung determined. When myocardial uptake is visually present in 1 hour, it is considered positive for ATTR if H/CL >1.5. On the other hand, the Perugini grading scale is a semi-quantitative method of scoring cardiac uptake following injection of 99mTc-DPD, 99mTc-Pyrophosphate or 99mTc-HMDP scintigraphy in the investigation of cardiac amyloidosis (particularly ATTR amyloidosis). The grading scale visually compares tracer uptake in the myocardium and ribs and will grade it from 0 to 3 depending on the cardiac uptake compared to the rib with 0 as no cardiac uptake and 3 as cardiac uptake greater than rib uptake. Visual scores greater than 2 on planar ± SPECT/CT imaging without evidence for monoclonal proteins in blood and urine, renders a diagnosis of ATTR cardiac amyloidosis with specificity and positive predictive value >98% (Figure 5) [52, 59]. Substantial uptake (Grade 2 or 3) has been reported in more than 20% of patients with AL cardiac amyloidosis.

Figure 5.

Cardiac scintigraphy in cardiac amyloidosis. (A) Qualitative assessment with evident Perugini Grade 3. The Perugini visual grading rule as follows: grade 0 = cardiac uptake not visible, grade 1 = mild cardiac uptake visible but inferior to skeletal uptake, grade 2 = moderate cardiac uptake visible equal to or greater than skeletal uptake, and grade 3 = strong cardiac uptake with little or no skeletal uptake. In the (B) semi-quantitative analysis of planar images, the counts per pixel of the heart to contralateral chest have a value of 1.7 (red circle with the H denotes heart or cardiac uptake and green circle with CL denotes contralateral uptake). Semi-quantitative analysis of planar images with both anterior and lateral views planar images are evaluated, by drawing a patient-specific circular ROI on the heart and mirroring it to the contralateral chest to calculate the heart-to-contralateral (H/CL).

5.6 Tissue biopsy

Tissue diagnosis with endomyocardial biopsy remains the goal standard for diagnosis CA. However, since it is invasive, it is usually reserved for those patients in which noninvasive assessment has been equivocal such as in the case of patients where plasma cell dyscrasia cannot be entirely ruled out or those with presence of low-grade uptake [55]. Diagnosis is evident with confirmation of amyloid deposition throughout with evidence of apple-green birefringence using Congo Red staining (Figure 1). The type of cardiac amyloidosis can also be determined using mass spectrometry and immunohistochemistry approaches. Another approach that is less invasive is the use of fat pad biopsy, however, its sensitivity is less than that of tissue biopsy (20% vs. 60–80%) [1].

5.7 Genetic testing

All the approaches described above can be used to distinguish between AL amyloidosis and ATTR amyloidosis. However, as it was discussed in Section 3.2 there are two distinct kinds of ATTR, one hereditary and one senile. Therefore, to distinguish between both and to further identify the kind of mutation that exists in the case of ATTRv, genetic testing is granted.

A summarized flowchart for ease and aid of cardiac amyloidosis diagnosis can be found in Figure 6.

Figure 6.

Cardiac amyloidosis diagnosis flowchart.

6. Natural history and prognosis

The overall prognosis of cardiac amyloidosis depends on the type of amyloidogenic protein accumulating in the heart. For instance, AL-CM has the worst prognosis and is considered a hematologic emergency. It has a median survival of 6 months without disease-specific treatment. Therefore, it is imperative to differentiate between AL and ATTR-CM. On the other hand, ATTR is frequently misdiagnosed, leading to delayed diagnosis and treatment. Disease causes significant impairment in physical health, productivity, and lower quality of life. Once ATTR is diagnosed, untreated patients have a median survival of 2–3.5 years. There are multiple staging systems based on clinical as NYHA class, and laboratories such as NT-pro-BNP, troponin, and renal parameters which help delineate treatment strategist (Table 2).

Transthyretin-CA

AL-CA

Mayo Clinic Model; Based on cohort of ATTRwt patients using trop T (>0.05 ng/ml) and NT-pBNP (>3000 levels pg/ml); Stage I-> No elevated biomarkers. Median survival 66 months Stage 2-> One elevated biomarker. Median survival 40 months Stage 3-> Both elevated biomarkers. Median survival 20 months UK Risk Model; Based on cohort of wt and hATTR patients with prognostic stages based on renal dysfunction (eGFR threshold <45 ml/min/1.73 m^2 and NT-pBNP (>3000 levels pg/ml); Stage I-> Both above threshold. Median survival 69.2 months Stage 2-> One marker above threshold. Median survival 46.7 months Stage 3-> Both markers above threshold. Median survival 20 months Chen et al. incremental value of diuretic dose and NYHA functional to UK and Mayo Clinic Risk Models; Based on cohort of wtATTR patients. Addition of NYHA status and diuretic dose to UK model and Mayo Clinic staging; Diuretic dose -> 0 points for 0 mg/kg, 1 point >0–0.5 mg/mg, 2 points >0.5–1 m g/kg, 3 points >1 mg/kg NYHA functional class -> 1 point NYHA 1, 2 points NYHA 2, 3 points NYHA 3, 4 points NYHA 4

Revised MAYO (2012) Staging System; Incorporated biomarkers with cut off NT- NT-pro-BNP ≥1800 ng/L, cardiac troponin T ≥ 0.025 mcg/L, and the difference between involved and uninvolved serum free light chains (dFLC) ≥18 mg/dL as risk factors.; Stage 1-> No elevation in any of the parameters-> Median Survival 55 months Stage 2 with elevation of one of the parameters-> Median survival 19 months, Stage 3 at least two parameters abnormally elevated-> Median survival 12 months Stage 4 three or more parameters abnormally elevated-> Median survival 5 months Mayo Staging; Incorporates biomarkers with cut-off of troponin <0.035 mcg/L and NT-pro-BNP <332 ng/L; Stage 1-> No elevation in any of the parameters-> Median Survival 26 months Stage 2 with elevation of one of the parameters-> Median survival 11 months Stage 3 at least two parameters abnormally elevated-> Median survival 4 months

Table 2.

Prognostic staging system for cardiac amyloidosis.

ATTR, transthyretin amyloidosis; wtATTR, wild type-transthyretin amyloidosis; h or v ATTR, hereditary or variant type-transthyretin amyloidosis; eGFR, estimated glomerular filtration rate; N-Pro-BNP, N-terminal-pro hormone-brain natriuretic peptide; NYHA, New York Heart Association; dFLC, lambda to kappa free light chain ratio difference.

7. Treatment options

Management of cardiac amyloidosis consists of treatment and management to stabilize heart failure symptoms while providing medications to stabilize amyloidogenic protein (Figures 7 and 8 and Table 2). An interdisciplinary treatment approach is paramount in lieu of patients’ limited physical capacity and quality of life due to the extensive extracardiac symptom involvement. Diuretics tend to be the first line of management for the control of congestive symptoms. These may be prescribed in combination with mineralocorticoid receptor antagonists. Usually, these patients have higher rate of third spacing with associated right heart failure, thus frequently require diuretics with better bioavailability such as bumetanide and torsemide and addition of mineralocorticoid agents. One of the main challenges patients with CA face is recurrent congestion requiring high dose of diuretics as well as frequent hospitalization. However not all traditional drugs used for the treatment of HF are adequate or have been proven to exert any benefit in patients with cardiac amyloidosis.

Figure 7.

AL-cardiomyopathy pharmacological therapeutic treatment flowchart. IMiDs, immunomodulator drugs; Afib, atrial fibrillation; DOA, direct oral anticoagulants; VKA, vitamin K antagonist; PPM, permanent pacemaker; ICD, internal cardiac defibrillator; CRT, cardiac resynchronization therapy; VT, ventricular tachycardia; SCD, sudden cardiac death; ARNI, angiotensin receptor-neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitor; BB, betablocker; OTH, orthotropic heart transplant.

Figure 8.

ATTR-amyloidosis pharmacological therapeutic treatment flowchart. Afib, atrial fibrillation; DOA, direct oral anticoagulants; VKA, vitamin K antagonist; PPM, permanent pacemaker; ICD, internal cardiac defibrillator; CRT, cardiac resynchronization therapy; VT, ventricular tachycardia; SCD, sudden cardiac death; ARNI, angiotensin receptor-neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitor; BB, betablocker; OTH, orthotropic heart transplant.

On the other hand, neurohormonal antagonists which are typically used in HF treatment are often poorly tolerated and might be counterproductive in some patients. Angiotensin-converting enzyme inhibitors (ACEI), aldosterone receptor blockers (ARB), and aldosterone receptor/Neprilysin inhibitors (ARNI) often lead to hypotension. Moreover, beta-blockers are known to exacerbate bradyarrhythmias in this population. Digoxin binds to amyloid fibrils, leading to potential drug toxicity even when circulating levels are within normal range, and should be avoided unless there is difficulty controlling atrial fibrillation. Similarly, calcium blockers should be avoided as well since they tend to bind irreversibly to amyloid fibers, thus causing bradycardia.

Orthostatic hypotension is a common debilitating symptom in patients with cardiac amyloidosis, often leading to significant deterioration and poor quality of life. Its management include pharmacological interventions such as the use of sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine, or the norepinephrine transporter inhibitor atomoxetine along with use of compressions stockings. A retrospective study of patients with AL-CM showed droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine. Slow titration may be important to minimize rapid changes in blood pressure [60].

Cardiac arrhythmias are commonly secondary to infiltration of amyloid proteins to cardiac conduction system as well as fibrosis at the sinoatrial node and atrioventricular nodes which disrupts the transmission of electrical impulses along the conduction fibers, additional direct cytotoxic effects of amyloid fibers have been described in AL-CA [61]. Atrial fibrillation (AF) is the most common rhythm disturbance seen among patients, with a prevalence ranging between 10 and 69% [41, 62]. When it comes to treatment and rhythm control options, patients with cardiac amyloidosis have limited strategies due to intolerance to most of the rate control medications, leading to low output states and hemodynamic deterioration. Nevertheless, AF does not significantly affect the overall survival of patients with ATTR cardiomyopathy. Rhythm control strategies including antiarrhythmic treatment, synchronized cardioversion, and AF ablation are more effective when performed earlier during the disease course [63]. Amiodarone can be used to safely restore heart rhythm and can be considered the agent of choice in those patients with beta blocker intolerance requiring both rhythm and rate control. Anticoagulation is highly recommended in these patients because of higher rates if thrombi and thromboembolic events when compared to aged-matched population without the disease [64]. A retrospective study showed no difference on thrombotic events or major bleeding events between both groups [65]. Hence anticoagulation prescription is indicated to all patient with CA and atrial fibrillation unless prohibitive risk of bleeding. In a comparative study in patients who underwent Left atrial appendage devise placement, it was demonstrated that devise reduce the risk of bleeding complications and ischemic cerebrovascular events in a similar fashion than patients without CA [66]. Sinus bradycardia and bifasicular block are common and progression to complete AV block is not infrequent requiring permanent pacemaker implantation [67]. Biventricular pacing is recommended over regular permanent pacemaker due to risk of induced desynchrony by the last one. It has been found that CRT response was associated with lower rates of cardiac events in this population especially in younger patients [68]. Although sudden cardiac death is common in AL amyloidosis, most of the times it has been the result of electromechanical dissociation rather than ventricular arrhythmias. Therefore, defibrillator implantation is recommended in cases in which a sudden death event has been aborted and it is understood that the patient has a survival of ≥12 months.

7.1 Cardiac amyloidosis disease specific treatment

7.1.1 AL-cardiomyopathy

Patients with amyloid cardiomyopathy due to AL amyloidosis need identification and management with chemotherapeutic regimens that will control production of light chain gammopathy and/or autologous cell transplantation (ASCT) [7]. The goal of treatment in patients with cardiac involvement is to achieve complete resolution or normalization of serum kappa and lambda free light chain (FLC) and FLC ratio. Staging is paramount as the risk of treatment-related mortality associated with ASCT in AL amyloidosis restricts the use of this procedure to a small group of selected patients. Multiple prognostic models have been proposed for patients with amyloidosis, most simple staging models incorporate NT-proBNP and cardiac troponin that can be easily used in clinical settings (Table 2) [69]. There are several different choices of anti-plasma cell medications (alkylating agents, immunomodulatory drugs (IMiDs) and proteosomes inhibitors) approved for treatment of myeloma multiple and can be used off-label for the treatment of AL amyloidosis. Daratumumab is the first monoclonal Ab that has been demonstrated to be highly effective in the treatment of AL-CA [70]. The intensity and type of therapy chosen is affected by the number and extent of organ involvement. Patients with AL cardiomyopathy with New York Heart Association (NYHA) functional class 3 and above are not considered for autologous stem cell transplant (ASCT). The treatment goal is to achieve a complete hematological response or extremely low levels of serum FLCs. For those patients who are candidates for stem cell transplantation, ASCT involves administration of high-dose melphalan followed by stem cell rescue (Figure 7).

7.1.2 Transthyretin cardiomyopathy

ATTR amyloidosis which was previously managed only by treating symptomatology and volume congestion, is now treated with disease modifying therapies targeted at the level of synthesis, stabilization and/or elimination of the TTR protein. Thus, avoiding overproduction of abnormal TTR protein. Strategies for management are divided in transthyretin tetramer stabilizers, synthesis inhibitors and clearance of amyloid deposits (Figure 8).

7.1.2.1 Transthyretin stabilizers

Tafamidis is a transthyretin stabilizer which works by binding to the thyroxine site of TTR with high affinity, thus slowing dissociation of TTR tetramers into monomers and preventing aggregation in amyloid fibrils. It is indicated in ATTR-CM and heart failure with functional class 1–3 (NYHA). The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled 441 patients allocated in a 2:1:2 to Tafamidis 80 mg, Tafamidis 20 mg, or placebo [71]. Tafamidis improved survival, reduced cardiovascular (CV)-related hospitalizations, as well as measures of functionality and health-related quality of life (HRQoL) in patients with ATTR-CM. The study was not designed to assess the relative efficacy between study drug dosages, but it showed a significant reduction in the increased NT-pro BNP and troponin I over time in patients with the 80 mg dose over the ones using 20 mg, with higher number of patients with stable or reduced NT-proBNP levels at 30-months. This was better analyzed in the ATTR-ACT long term study treated for additional 60 months using the 80 mg dose. Demonstrating a 30% relative risk reduction of death when compared to the 20 mg dose [72].

In a similar fashion, Diflunisal, a nonsteroidal anti-inflammatory, is known to have capability to stabilize TTR protein by increasing its dissociation barrier by binding to the thyroxine site. It could be used off-label for the treatment of ATTR. Diflunisal has been shown to reduce neurologic deterioration in patients with familial amyloid polyneuropathy due to hereditary transthyretin amyloidosis [73, 74, 75]. Additionally, in patients with cardiac involvement, diflunisal treatment resulted in measurable differences in cardiac troponins as well as pro-BNP and echocardiographic parameters of cardiac structure and function after only 1 year of administration [73, 74]. Nevertheless, the medication has been associated the usual side effects seen with NSAIDS such as gastric disturbances, nephrotoxicity as well as cardiac toxicity.

There are other medications in development with ATTR stabilization capabilities, Acoramidis (AG10) and mds84. Acoramidis (AG10) appeared to be safe and well tolerated during phase 2 clinical trial and completely stabilized TTR [76]. The ATTRibute-CM Study is an undergoing phase 3 study with main aim to demonstrate Acoramidis usefulness in improvement of exercise capacity, survival, and secondary end point of improvement of health-related quality of life, all-cause mortality, and rate of cardiovascular-related hospital events when compared to placebo [73]. Lastly, mds84 is bivalent ligand TTR that can bind to the binding groove as well as central protein channel pockets. In vitro studies have demonstrated higher potency capabilities when compared to other TTR stabilizers [73, 74]. So far, there is no evidence of undergoing available clinical trials.

7.1.2.2 Transthyretin gene silencers

Patisiran is a double-stranded small interfering RNA which decreases the production of abnormal TTR by binding to the RNA-induced silencing complex mediating cleavage of the protein’s mRNA to prevent TTR synthesis by the liver. It has FDA approval for treatment of ATTRv polyneuropathy. The APOLLO trial demonstrated improvement in the biomarker NT-proBNP as well as echocardiographic parameters such as LV-wall thickness, end-diastolic volume, cardiac output, and global longitudinal strain in those patients with cardiac involvement. Further sub analysis demonstrated improvement in functional capacity, decreased hospitalizations and mortality when compared to placebo [77]. These findings provided off-label alternative use for hereditary (variant) ATTR-CM.

The APOLLO-B, a randomized placebo control trial for treating both types of ATTR-CM designed to determine usefulness of siRNA to improve functional capacity and decrease hospital admissions and MACE. Inotersen, an antisense oligonucleoside inhibitor that causes degradation of TRR mRNA through binding to the TTR mRNA produced by the liver. The medication is administered by subcutaneous injection weekly. Similarly, to Patisiran, it is indicated for treatment of ATTRv polyneuropathy. Dasgupta et al., presented data from a single center which demonstrated long-term treatment in ATTR CM was safe and effective at inhibiting progression and potentially reverting amyloid burden accompanied by increased exercise tolerance and decrease in mean LV mass measured by CMR [78].

There are two ongoing investigational drugs that target gene silencing of TTR undergoing evaluation with phase 3 trials. Eplontersen CARDIO-TTRansform and Vutrisiran (HELIOS-A and HELIOS-B) [73]. In the HELIOS-A, Vutrisiran, preliminary results showed improvement on the exploratory cardiac biomarkers, NT-pro-BNP endpoints when compared to placebo (P < 0.05).

7.1.2.3 Transthyretin degraders

Doxycycline is a tetracycline derivative which poses anti-amyloidogenic properties, disrupting pre-formed TTR fibrils in vitro [79, 80]. Tauroursodeoxycholic acid (TUDCA), a biliary acid has similar effect in reducing non−/pre-fibrillary TTR deposits. This was demonstrated in transgenic mice where the combination of both drugs had a synergistic effect and have shown disease stabilization, good tolerability, and low toxicity profile with 1-year of treatment [80].

Monoclonal anti-serum amyloid protein is an antibody targeting normal non fibrillar glycoprotein SAP promoting a giant cell reaction that will remove visceral amyloid deposits. Medication is administered intravenously. This drug is still undergoing evaluation and a clear utility in amyloid cardiomyopathy has not been demonstrated [73, 74].

7.2 Advanced heart failure therapies

Cardiac amyloidosis is a progressive disease with significant risk of progression of heart failure and mortality associated to a restrictive physiology along with characteristically small, hypertrophied LV ventricle. This leads to a significant anatomic concern as a small LV cavity could lead to suction events by obstructing the inflow cannula thereby predisposing the patient to low flow, hypotension, pump thrombosis as well as arrhythmias and worsening RV dysfunction. Furthermore, this population has frequent RV involvement with associated pulmonary hypertension and right heart failure which would further limit ventricular assistant devise use feasibility. There are only a few small studies with overall conflicting results to draw conclusions. Hence consideration of treatment should be done on a patient-to-patient basis. One small study suggest left ventricular assist device (LVAD) implantation is technically feasible for patients with severe heart failure due to advanced cardiac amyloidosis [81]. Another single-center case series highlighted the feasibility of supporting highly selected CA patients with continuous flow-left ventricular assist devise (CF-LVAD) as bridge to transplant (BTT) or destination therapy (DT including the HeartMate 3 pump) with reasonable outcomes, principally for those with a reduced LVEF and an absence of significant pre-implant RV dysfunction or pulmonary artery pulsatile index (PAPI) ≤ 1.5 [81, 82].

Improvement in treatment options in patients with cardiac amyloidosis has opened the possibility for heart transplant in carefully selected patients with advanced heart failure including those that require combined heart-liver or heart-kidney. Barrette et al. analyzed 31 patients who underwent heart transplants for cardiac amyloidosis (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) that were carefully selected for the procedure. His findings disclosed there was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications [83].

7.3 Transthyretin cardiomyopathy in aortic stenosis

Aortic stenosis (AS) is the most prevalent valvular disease seen in over 4% of octogenarian patients. Multiple studies have described a prevalence of cardiac amyloidosis in patients with aortic stenosis which range from 4% up to 29% [84]. Hence, AS-CA frequently coexists in this population. Aortic stenosis should be graded according to guidelines but taking into consideration that in these settings the patient will present with low flow/low gradient patterns (i.e., AVA <1.0 cm², mean gradients <40 mm Hg and stroke volume index <35 ml/m²). A multicenter prospective of close to 400 patients referred for aortic valve replacement mostly through transcatheter aortic valve replacement (TAVR) showed that even though dual pathology of severe AS-CA conferred overall worse disease by functional capacity, cardiac remodeling and biomarkers, the patients had improved outcome when procedure was performed. Furthermore, their data confirmed AS-CA was common and affected 1 in 8 patients referred for TAVR [85].

8. Conclusions

Cardiac amyloidosis, previously believed to be a rare condition, is often underdiagnosed. Multisystemic presentations cause delays in diagnosis, which reduces the opportunity of treatment at initial stages. The advent of disease advanced multi-imaging modalities has improved identification and diagnosis of disease, with non-invasive diagnosis becoming cornerstone in treatment decision making process. Patient stratification is key for treatment decision and prognosis. Early diagnosis is key for prognosis, course of action, successful response to therapy, and a better treatment outcome.

Conflicts of interest

The contents of this publication do not represent the views of the VA Caribbean Healthcare System, the Department of Veterans Affairs, or the United States Government. Dr. Sonia I. Vicenty is the Director of The Heart Failure Clinic and Associate Director of the Cardiovascular Disease Fellowship Program at the VA Caribbean HealthCare System, San Juan, PR. She is a sponsored speaker for Pfizer, and investigator for IONIS involved CARDIO-TTRansform trial. Dr. Ingrid Bonilla has no conflict of interest to disclose.