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Home , Pulmonary heart disease

Clinics and Practice 2018; volume 8:1054

Revisiting transthyretin related our hospital with worsening shortness of cardiac : breath (SOB) of 1-week duration. Her SOB Correspondence: Munish Sharma, Department was worse even on walking less than 50 of Internal , Easton Hospital, Easton, Case report and review meters on a flat surface. Her primary cardi- PA, USA. E-mail: [email protected] of literature ologist at a different health facility had Key words: ; endomy- diagnosed her with CHF a year prior to this ocardial biopsy; cardiac magnetic resonance Munish Sharma,1 Eduard Koman,2 presentation. She was compliant with her imaging; ECG findings in cardiac amyloido- Gary S. Ledley,2 Sung-Hae Cho2 home dose of furosemide 40 mg daily. She sis. was primarily treated with intravenous 1 Department of , furosemide 40 mg daily and her home med- Conflict of interest: the authors declare no 2 Easton Hospital, Easton; Department of ications including atenolol 50 mg daily and conflict of interest. Medicine-Division of , Drexel lisinopril 5 mg daily were continued. University College of Medicine- Patient did not have history of myocardial Received for publication: 16 December 2017. Revision received: 30 April 2018. Hahnemann University Hospital, infarction in the past and did not have prior Accepted for publication: 2 May 2018. Philadelphia, PA, USA exercise/nuclear stress test or cardiac catheterization. On examination, her blood This work is licensed under a Creative pressure was 110/70 mm Hg, rate was Commons Attribution NonCommercial 4.0 62 bpm and regular, respiratory rate was 12 License (CC BY-NC 4.0). Abstract per minute, temperature 98.6 F and SaO2 of more than 92% at room air. Her neck was ©Copyright M. Sharma et al., 2018 Licensee PAGEPress, Italy Amyloidosis is a complex group of dis- supple and cardiovascular examination Clinics and Practice 2018; 8:1054 orders that can involve many organs and revealed muffled , normal doi:10.4081/cp.2018.1054 cause their dysfunction. Cardiac involve- S1S2 with no appreciable murmur. ment indicates worse prognosis and influ- Her ECG showed normal sinus rhythm, ences treatment strategies. Cardiac amyloi- ventricular rate of 64 bpm, left axis devia- only dosis is an under-diagnosed entity and high tion, low voltage QRS complexes with Q was detected with a special stain (Figure 4). index of clinical suspicion and careful inter- waves in inferior and antero-septal leads Urine protein electrophoresis and serum pretation of basic diagnostic tools such as (Figure 1). Her echocardiogram was signif- protein electrophoresis results were not sig- electrocardiogram and echocardiography is icant for moderate concentric left ventricu- nificant. Liquid chromatography tandem needed for early detection. Congestive heart lar hypertrophy (LVH), mild globaluse hypoki- mass spectrometry detected a peptide pro- failure due to restrictive pattern and/or con- nesis of left (LV), EF of 40-45%, file consistent with ATTR (transthyretin/ duction system abnormality, in absence of grade III diastolic dysfunction, trace mitral prealbumin)-type amyloid deposition. should raise suspi- regurgitation (MR) and severe tricuspid Patient wished to follow up with her cion. We present a case of transthyretin regurgitation (TR). Pulmonary arterial sys- primary specialist .She was related cardiac amyloidosis and discuss the tolic pressure was 45-50 mm Hg and esti- discharged on her previous home regimen key clinical and diagnostic findings along mated right atrial (RA) pressure of 3 and new diagnosis of ATTR-type cardiac with review of existing literature regarding mmHg. Interventricular septum was thick- amyloidosis was conveyed to the primary its management and outcomes. ened and showed granular sparkling cardiologist. appearance (Figure 2). In contrast, her echocardiogram done on 10/2016 had shown an EF of 50-55%, grade I diastolic Introduction dysfunction with evidence of trace TR. Her Discussion left heart catheterization revealed no signif- Amyloidosis is a unique group of disor- icant coronary artery disease while right Majority of cardiac amyloidosis is ders caused by accumulation of insoluble heart catheterization showed; RA pressure caused by one of the two different types of protein fibers, known as amyloid fibrils in 12 mm hg, right ventricle pressure = 55/10 protein; light chains or transthyretin. Light the extracellular spaces of Non-commercial tissues and mmhg, PA pressure = 55/25 (mean of 30 chain (AL) amyloidosis occurs due to clon- organs. Involvement of different organs and mmhg), pulmonary capillary wedge pres- al proliferation of plasma cells in bone mar- tissues in amyloidosis is often responsible sure (PCWP) = 20 mmhg, Aortic pressure row producing large amount of light chains, for missed or delayed diagnosis, and amy- (Ao)=134/64 (mean=97) mm hg, left ven- which are mis-folded into beta-pleated loidosis remains a considerable clinical tricular end diastolic pressure (LVEDP) = sheets and get deposited in various tissues. challenge as it is implicated in 1/1000 death 15 mm hg, cardiac output = 4.83 L/min, car- AL amyloidosis is the most common type of in developed countries.1 Cardiac involve- diac index (CI) = 2.71 L/min/m2. A cardiac cardiac amyloidosis. About 2000 to 3000 ment can be primary, a part of systemic magnetic resonance imaging (MRI) showed new cases of AL amyloidosis occur each amyloidosis, or a result of chronic systemic global hypokinesis of the LV with diffuse year in the United States, two thirds of these diseases. myocardial delayed enhancement and patients are male, and almost all of them are hypertrophy of interventricular septum over the age of 50. Transthyretin-related without any evidence of perfusion defect. (TTR) amyloidosis is derived from Case Report This constellation of symptoms was consis- transthyretin, which is produced by the tent with cardiac amyloidosis (Figure 3). liver. There are 2 types of TTR-related amy- On 3/2017, a 72-year-old female with Right ventricular endomyocardial biopsy loidosis: a genetic form known as heredi- history of CHF with preserved ejection obtained during right heart catheterization tary transthyretin-related amyloidosis fraction (EF) of 50-55 %, hypertension and showed deposits of amorphous material (ATTR) and a nonhereditary form known as Rheumatoid Arthritis (RA) was admitted to consistent with amyloid. No stainable iron wild-type ATTR amyloidosis. In ATTR,

[Clinics and Practice 2018; 8:1054] [page 59] Case Report genetic mutation is present from the birth bone scintigraphy can be used reliable diag- ally seen in the late stages. EF is preserved but the abnormal deposition into tissues nosis without the need for histology espe- until end stage but strain is impaired very starts from age 30 to 60 years. It is a slowly cially in patients without monoclonal gam- early. In the late stages of the disease, a sys- progressive disease that usually affects the mopathy.9 Low voltage in the limb leads is tolic dysfunction of the left ventricle is heart of men, almost always in the sixth or one of the most common ECG manifesta- seen. Impairment of left ventricle diastolic seventh decade of life.2 tions, mainly in AL cardiac amyloidosis function is the first functional sign of car- Cardiac amyloidosis most commonly (50% cases) compared to lesser frequency diac involvement. At first, a reduced E manifests as heart failure. Dyspnea and in familial disease (25%) and senile cardiac wave with an increased deceleration time signs of right heart failure including periph- amyloidosis (40%).10 and a reduced early diastolic velocity of the eral edema, and are Echocardiographic findings generally left ventricular wall (E’) are noted. In the common presentation. Pulmonary edema is appear in the latter stages of the disease. advanced stage of the disease, an overt rare, although the left sided heart pressures Typically, granular appearance of the restrictive pattern can be found with are elevated. Rarely, due to disproportionate myocardium is seen in conventional 2-D increased E wave and decreased A wave, amyloid deposition in the inter-ventricular echocardiography. This finding is nonspe- shortened mitral inflow deceleration time septum, cardiac amyloidosis may be misdi- cific and is highly dependent on the and severely reduced E’ wave velocity.12 11 agnosed as hypertrophic .3 machine settings. A normally sized ventri- With the advent of new echocardiographic Presence of purpura, leg or jaw claudication cle with increased wall thickness in both techniques related to deformation imaging, or suggests involvement of small ventricles is generally seen. Bi-atrial dila- promising results have been seen in diag- 13 vessel. Typically, small and intramyocardial tion and inter-atrial septal thickening are nosing subclinical cases. vessel involvement gives rise to normal typically seen in the advanced stages. Cardiovascular magnetic resonance coronary angiography. Syncope or pre-syn- Ventricular dilation is also a feature gener- (CMR) is more sensitive than echocardiog- cope are common and are associated with a high mortality in the 3 months following the event.4 Ventricular have not been found to be frequently associated with only syncopal episodes in cardiac amyloidosis. It is more likely multifactorial; postural or exertional hypotension due to excessive diuresis and autonomic neuropathy are the possible mechanisms. The conduction sys- use tem is very frequently affected. High-grade and symptomatic are uncommon. Infra-His conduction times have been found to have prolonged. But, this prolongation may not be suspected clinically if the QRS is narrow on the ECG. Prolongation of His- ventricular interval has been found in few studies to be the sole independent predictor of subsequent sudden death. In spite of this, the routine screening for such conduction system abnormalities have not been recom- Figure 1. ECG revealing , low voltage QRS complexes with Q waves in mended as the benefit of pacemaker or inferior and anteroseptal leads (Pseudo-infarct pattern). implantable cardioverter defibrillator (ICD) in prevention of sudden cardiac death has not been established in cases of Non-commercial cardiac amyloidosis.5,6 Patients are also at risk for cardiac thromboembolism, especially those with AL amyloidosis or atrial .7 The etiology of is more commonly CHF rather than direct amyloid deposition. There has to be high degree of suspicion of in a patient with moderate to large pericardial effusion because the classic echocardiographic signs of cardiac tamponade, such as right atrial and right ventricular compression may be absent. Endomyocardial biopsy has a nearly 100% sensitivity/specificity and allows for definitive subtyping.8 Immunofluorescence can be performed for subtyping but in case of any doubt about the diagnosis, mass Figure 2. Granular sparkling pattern of thickened inter ventricular wall seen in echocar- spectrometry should be performed. In diogram. patients with cardiac ATTR amyloidosis,

[page 60] [Clinics and Practice 2018; 8:1054] Case Report raphy. A distinctive pattern of global left standard recommendation in patients with bortezomib, cyclophosphamide, and dex- ventricular late gadolinium enhancement diastolic or systolic heart failure. Salt and amethasone. (LGE), which is rarely seen in other car- fluid restriction along with loop is ATTR amyloidosis is not a malignant diomyopathies, provides strong clue to the the mainstay of treatment of cardiac amy- process and chemotherapy has no role. In diagnosis. Preliminary studies of the pre- loidosis. Due to autonomic dysfunction and ATTR amyloidosis, for specific mutations dicted value of LGE in patients with sus- inability to augment stroke volume in the source of the amyloidogenic protein is pected cardiac amyloidosis have shown response to in the presence of a the liver and thus the evaluation for liver sensitivities of 86 and 88% and specificities small left ventricular cavity, angiotensin transplantation should be immediately initi- of 86 and 90%. Supportive laboratory tests converting enzyme inhibitors and ated. Transplantation of the liver can be cur- for AL amyloidosis like proteinuria, alka- angiotensin receptor blockers are not suit- ative in selected patients with familial line phosphatase and free light chain assays able. Beta-blockers tend to exacerbate ATTR amyloidosis but not in wild-type can be helpful in evaluating the likelihood brady-arrhythmias while digoxin binds to ATTR. Unfortunately, there have been of the disease prior to biopsy and monitor- amyloid fibrils and can lead to potential reports of cardiac disease progression even ing diseases response to chemotherapy. digoxin toxicity. Anticoagulation is recom- after liver transplantation in familial ATTR Genetic testing for transthyretin gene in mended in patients with concomitant atrial amyloidosis.17 If significant heart failure is ATTR amyloidosis has relevance for family fibrillation, systemic thromboembolism, concomitantly present, isolated liver trans- members and predicts sites of organ and intra-cardiac thrombi or with atrial con- plantation is contraindicated and considera- involvement as well as treatment options. tractile dysfunction in presence of normal tion should be given to a combined liver- 15 Prognosis depends mainly on the extent sinus rhythm. The role of ICD in heart transplant or just heart alone. of cardiac involvement. It is generally better preventing sudden cardiac death (SCD) in in ATTR amyloidosis compared to AL amy- cardiac amyloidosis is not clear. Since the loidosis. A revised staging system for the electromechanical dissociation is the likely disease published in 2012, includes circulat- cause of SCD in these patients, efficacy of Conclusions ing free light chain levels besides troponin ICD therapy is doubted and safety has also 16 (T or I) and N-terminal pro-B-type natri- not been well established. onlyWith the advent of newer diagnostic uretic peptide. It divides the disease into 4 The main treatment option in patients tools, more cases of cardiac amyloidosis stages with median survival of 94.1, 40.3, with AL amyloidosis is chemotherapy. have been diagnosed over the last decade. 14, and 5.8 months for Stages 1, 2, 3, and 4, Administration of chemotherapy and/or Early diagnosis and timely intervention respectively.14 autologous stem cell transplantationuse after sub typing of amyloidosis is crucial in The treatment of cardiac amyloidosis (ASCT) is done with an aim to eradicate the determining the outcome of the disease. mainly encompasses therapy of heart failure underlying plasma cell clone responsible Thus, high index of clinical suspicion for and the treatment of the underlying disease. for AL amyloid formation and to achieve a cardiac amyloidosis is required in patients The treatment of heart failure differs from 90 percent or greater reduction in serum presenting with established disease or with free light chain levels. The most common diagnostic clues such as unexplained ven- initial chemotherapy regimens used current- tricular hypertrophy with inappropriately ly are bortezomib-based regimens such as low ECG voltages and unexplained heart

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Figure 3. Diffuse delayed LV myocardial contrast enhancement seen in cardiac MRI (blue arrows) in two different views. Figure 4. Congo red staining of myocardial tissue suggestive of cardiac amyloidosis.

[Clinics and Practice 2018; 8:1054] [page 61] Case Report failure occurring with characteristic dys- ease in cardiac amyloidosis. Am J al. Noninvasive diagnosis of biopsy- function of other organs. and Cardiol 1997;80:1491. proven cardiac amyloidosis. J Am Coll rhythm management is the mainstay of 6. Reisinger J, Dubrey SW, Lavalley M, et Cardiol 2004;43:410-5. medical management for cardiac involve- al. Electrophysiologic abnormalities in 13. Otto MC. , hyperten- ment, along with anticoagulation when indi- AL (primary) amyloidosis with cardiac sive and pulmonary heart disease. cated. Chemotherapy and/or stem cell trans- involvement. J Am Coll Cardiol Textbook of Clinical Echocardiography. plantation is reserved for AL amyloidosis. 1997;30: 1046. Third ed. Elsevier Saunders; 2004. p. 7. Zubkov AY, Rabinstein AA, Dispenzieri Liver and/or heart transplantation should be 227-59. considered in familial ATTR amyloidosis. A, et al. Primary systemic amyloidosis 14. Koyama J, Ray-Sequin PA, Falk RH. There are investigational drugs currently with ischemic stroke as a presenting Longitudinal myocardial function underway but not yet established for use. complication. 2007;69:1136. 8. Pellikka PA, Holmes DR Jr, Edwards assessed by tissue velocity, strain, and WD, et al. Endomyocardial biopsy in 30 strain rate tissue Doppler echocardiog- patients with primary amyloidosis and raphy in patients with AL (primary) car- References suspected cardiac involvement. Arch diac amyloidosis. Circulation 2003;107: Intern Med 1988;148:662. 2446-52. 1. Pepys MB. Amyloidosis. Annu Rev 9. Vrana JA, Gamez JD, Madden BJ, et al. 15. Kumar S, Dispenzieri A, Lacy MQ, et Med 2006;57:223-41. Classification of amyloidosis by laser al. Revised prognostic staging system 2. Quarta CC, Kruger JL, Falk RH. microdissection and mass spectrome- for light chain amyloidosis incorporat- Cardiac amyloidosis. Circulation try-based proteomic analysis in clinical ing cardiac biomarkers and serum free 2012;126:12. biopsy specimens. Blood 2009;114: light chain measurements. J Clin Oncol 3. Sedlis SP, Saffitz JE, Schwob VS, et al. 4957. 2012;30:989-95. Cardiac amyloidosis simulating hyper- 10. Gillmore JD, Maurer MS, Falk RH, et 16. Feng D, Syed IS, Martinez M, et al. trophic cardiomyopathy. Am J Cardiol al. Nonbiopsy diagnosis of cardiac Intracardiac and anticoagu- 1984;53:969. transthyretin amyloidosis. Circulation only 4. Chamarthi B, Dubrey SW, Cha K, et al. 2016;133:2404-12. lation therapy in cardiac amyloidosis. Features and prognosis of exertional 11. Murtagh B, Hammill SC, Gertz MA, et Circulation 2009;119:2490. syncope in light-chain associated AL al. Electrocardiographic findings in pri- 17. Dubrey SW, Davidoff R, Skinner M, et cardiac amyloidosis. Am J Cardiol mary systemic amyloidosis and biopsy- al. Progression of ventricular wall 1997;80:1242. proven cardiac involvement. Amuse J thickening after liver transplantation for 5. Mathew V , Olson LJ, Gertz MA, et al. Cardiol 2005;95:535. familial amyloidosis. Transplantation Symptomatic conduction system dis- 12. Rahman JE, Helou EF, Gelzer-Bell R, et 1997;64:74.

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