Academic Editor: Peter A. McCullough
Amyloid light-chain (AL) amyloidosis is a multisystemic disease. Among its clinical manifestations, vein and arterial thromboembolic events are included. We report the unusual case of a 57-year-old female patient with AL amyloidosis presenting with an ST segment elevation myocardial infarction due to coronary artery embolization (CE). The patient reported a history of exertional dyspnoea along with episodes of haemoptysis for the last few months. Her coronary angiography demonstrated embolization of the distal segment of the left anterior descending artery. The main findings of her cardiac ultrasound included concentric left ventricular hypertrophy, mildly impaired left ventricular systolic function, left atrium enlargement and a restrictive-like filling pattern, while her chest computed tomography (CT) demonstrated bilateral pleural effusions. Cardiac magnetic resonance imaging that was performed afterwards, indicated areas of microvascular infarction, a small apex infarct and findings compatible with possible amyloidosis, a diagnosis that was confirmed later by fat tissue biopsy. Patient was referred for an oncology consultation, started therapy with direct oral anticoagulants, angiotensin converting enzyme inhibitor, statins and anti-plasma cell therapy. She has been improving since then and has been free of cardiovascular events for a follow-up period of 12 months. Cardiologists ought to be aware of amyloidosis as a rare but possible cause of coronary embolization, while close collaboration with oncologists is required for the establishment of the correct diagnosis.
Coronary embolization (CE) is an important cause of acute myocardial infarction with a reported incidence of 4% to 13% [1, 2]. CE is characterised by the absence of obstructive atherosclerotic disease and normal to near normal coronary arteries, as displayed in coronary angiography (CA) [2, 3]. Definite diagnosis can be difficult to be established and a number of diagnostic criteria have been proposed [1]. CE has been categorized as a potential cause of a type 2 myocardial infarction [4] while the use of imaging modalities such as intravascular ultrasound (IVUS) or optimal coherence tomography (OCT) have been proposed as diagnostic tools for the assessment of intravascular patency and the detection of intracoronary thrombus [5, 6, 7]. Moreover, cardiac magnetic resonance imaging (CMR) provides valuable information regarding late gadolinium enhancement (LGE), fibrosis/scarring and subendocardial or transmural oedema in the distribution area of the affected vessel [7, 8]. Key aspect in understanding the pathophysiology of coronary emboli formation is Virchow’s triad in the context of possible clinical scenarios including: the interaction of blood stasis/slow flow (atrial fibrillation, left ventricular aneurysm, deep vein thrombosis), endothelial injury (vasculitis, arteritis, angioplasty, surgery), predisposing factors (atrial septal defect, ventricular septal defect, endocarditis, mitral stenosis) and hypercoagulability (cancer, thrombophilia, heparin induced thrombophilia, intravascular foreign material) [2, 9, 10]. The differential diagnosis for potential underlying causes in the face of CE can be challenging, requiring a thorough clinical and laboratory workup and the cooperation of many specialties.
A 57-year-old female, with a history of hypertension (treated with angiotensin
II receptor blockers) and cigarette smoking (35 pack-years), presented to the
emergency department, complaining of chest pain with concomitant shortness of
breath that started approximately 2 hours before admission. Moreover, the patient
reported exertional, gradually deteriorating dyspnoea, starting approximately 6
months ago, accompanied by infrequent episodes of haemoptysis. Three months prior
to admission, the patient had undergone a cardiac (clinical examination,
electrocardiogram (ECG), transthoracic echocardiogram (TTE)) and pulmonary
work-up (clinical examination, spirometry, chest radiography) by her family
doctor (as an outpatient), that was reported to be without major pathologic
findings and was also scheduled to undergo bronchoscopy. At admission her ECG
showed ST segment elevation in the anterior and inferior leads and poor R
progression in the precordial leads (Fig. 1). She had a blood pressure of 110/80
mmHg, a heart rate of 97 beats/min and a peripheral oxygen saturation of 93%.
Auscultation of the heart and lungs revealed an S4, grade 1 murmurs in the mitral
and tricuspid valves and bilateral mild attenuation of breath sounds. The
diagnosis of ST segment elevation myocardial infarction was made and treatment
with 180 mg ticagrelor, 325 mg aspirin and 5000 IU of unfractionated heparin was
initiated. She was admitted directly to the catheterization laboratory for
primary coronary intervention. Upon arrival in the cath-lab the pain had
resolved. CA revealed an abrupt occlusion in the distal left anterior descending
artery (LAD) while the rest of the coronary arteries displayed non-significant
atherosclerotic lesions (Fig. 2). A CHOICE PT (Boston Scientific
Admission ECG in sinus rhythm with ST segment elevation in the anterior and inferior leads.
Cranial view of the left coronary artery, revealing abrupt occlusion of the distal LAD.
The patient continued to complain of shortness of breath while her chest X-ray
revealed pulmonary congestion along with bilateral pleural effusions. A brain
natriuretic peptide (BNP) of 1520 pg/mL [Quidel Triage BNP Test
The transthoracic echo of the patient displayed concentric hypertrophy of the walls of the left ventricle (A), with hypokinesia of the apical intraseptum and the apex, slightly to mildly impaired systolic function, left atrium enlargement and a restrictive-like filling pattern (B,C).
A computed tomography of the thorax and abdomen performed the following day displayed significant bilateral pleural effusions and hypertrophy of the cardiac walls with no evidence of pericardial effusion or thickening and no evidence suggestive of acute or chronic pulmonary thromboembolic disease (Fig. 4). Due to suspected diagnosis of an infiltrative cardiac disease, CMR was performed. Results included hyperintense signals in the areas of the apex of the LV and the apical interventricular septum in the T2 weighted scan. During the LGE phase, hyperintense signals in the apical areas of the LV and surrounding spots of low signal intensity were noticed, findings compatible with microvascular infarction, whilst the rest of the myocardium of the LV, especially the hypertrophic interventricular septum, displayed dispersed increased signals. Similar findings were noted in areas of the right ventricle and both of the atria. No intracardiac thrombus was detected. The demonstrated evidence advocated for a small infarct at the apex of the LV along with concomitant microvascular infarction and evidence of infiltrative myocardial disease, indicative of heart amyloidosis [12, 13, 14] (Fig. 5).
Thorax-abdomen CT of the patient displaying significant bilateral pleural effusions and left ventricular hypertrophy.
During late gadolinium enhancement phase, hyperintense signals in the apical areas of the left ventricle and surrounding spots of low signal intensity were noticed (A,B), findings compatible with microvascular infarction, the rest of the hypertrophic myocardium of the left ventricle (C,D), especially the hypertrophic intraventricular septum, displayed dispersed increased signals, findings also noted in areas of the right ventricle and both of the atria (A,B).
A serum protein electrophoresis revealed only hypogammaglobulinemia but
immunofixation revealed a small
Therapy with a direct oral anticoagulant (DOAC), angiotensin converting enzyme
inhibitor and statin along with bortezomib was commenced and the patient was
discharged a few days later, clinically stable with a recommendation for frequent
clinical follow-ups and to continue her oncology treatment as an outpatient. She
received therapy with bortezomib, lenalidomide and dexamethasone, achieved a very
good partial response within 2 months, followed by daratumumab and finally
achieving a complete hematologic response. A follow-up TTE at 3 months
demonstrated a LV with mildly impaired systolic function (LV ejection fraction =
50% assessed by the biplane Simpson’s method), concentric hypertrophy, grade 2
diastolic dysfunction, mild mitral regurgitation, mild dilatation of the atria
with no other major findings. The follow-up CMR at 3 months recorded abnormal
gadolinium kinetics and diffuse circumferential mesomyocardial LGE of the LV,
transmural infarction of the apical inferior wall and LV apex with increased
references at T1 mapping and marked increase of the extracellular volume (ECV =
45%). Her NTproBNP levels reduced from 14053 pg/mL to 3431 pg/mL (PATHFAST
Amyloidosis is a multiorgan disease characterised by the extracellular
aggregation of fibrillar proteins [14, 16]. Light chain AL, variant transthyretin
and wild-type transthyretin amyloidosis are the most commonly described types
affecting the heart [13, 15, 17]. Cardinal pathophysiologic features of systemic
and/or localized amyloidosis include an overload of amyloid production,
accumulated fractions of muted misfolding proteins and an increased propensity of
amyloid formation by normal proteins [15]. Clinical symptoms are mainly dependant
on the herald emerging accumulating protein type in the affected organs while
kidneys, liver, heart, gastrointestinal tract and nervous system are the most
common frequently reported targets of amyloid deposits [13, 15, 17, 18]. Early
diagnosis, progressive multiorgan dysfunction and cardiac involvement have been
proposed as some of the most crucial factors that determine survival [15, 19, 20]. In cases of lone cardiac involvement prognostic factors comprise free light
chains-difference
A recent position statement of the European Association of Cardiology (ESC) proposes a diagnostic algorithm for the diagnosis of cardiac amyloidosis [13]. In our case, the patient presented suggestive features on both TTE and CMR, whereas fat tissue biopsy documented amyloid infiltration.
Common cardiac and extracardiac clinical manifestations of AL amyloidosis, among others, include heart failure, arrhythmias, autonomic dysfunction, peripheral polyneuropathy, proteinuria, bilateral carpal syndrome and skin bruising [13]. Even though amyloidosis is known to predispose in thromboembolic events [18], there are relatively few cases in the literature of patients with cardiac AL amyloidosis and without atrial fibrillation, developing arterial thrombosis (peripheral artery emboli, mesenteric ischemia and stroke) [18, 22, 23, 24]. Intracardiac emboli have been described as manifestations of AL amyloidosis with cardiac involvement [18, 25, 26] as also cases of AL mimicking coronary syndromes (but with non-occluding coronary arteries lesions) [27]. The hypercoagulable state that characterises AL amyloidosis is considered to play a critical role in the manifestation of venous and arterial thromboembolic events [28]. Park et al. [22] reported that patients with AL amyloidosis and high disease burden, as expressed in high serum concentrations of free light chains and b2 microglobulin, are prone to venous and arterial thromboembolism, due to the inflammatory cytokines (tumor necrosis a-factor, interleukin-6) cascade activation that in turn dysregulates endothelium function, platelets and coagulation factors. Additionally, Cho et al. [29] indicated that fibrils of amyloid penetrate into the intima of large epicardial coronary arteries as also the smaller microvascular arterioles and thus leading to embolic events, ischemia and mural thrombosis.
Antithrombotic treatment of patients with blood malignancies and arterial thrombosis can be challenging in daily clinical practice, while few reports in literature describe similar cases [30, 31, 32, 33]. Clinical management of chronic anticoagulation treatment should carefully assess the ischemic risk and haemorrhagic danger of each patient individually. Contemporary literature supports the notion of DOAC’s safe profile in the prevention of systemic embolism, even in cases with concomitant LV thrombus [34] in the present case the decision for chronic treatment with a DOAC was amenable to existent literature data displaying antithrombotic management in patients with systematic/arterial thromboembolic events [30, 31, 32, 33]. Regarding cancer patients, the use of DOAC’s has been described mainly in the context of deep vein thrombosis and pulmonary embolism [35].
A small number of cases report haemoptysis as the first clinical manifestation of cardiac AL amyloidosis. Frail microvascular pulmonary capillaries and/or parenchymal disease, characterised by the infiltration of amyloid fibrils, are considered as underlying causes, in addition to a non-compliant diseased myocardium with elevated LV filling pressures and left atrial myopathy, that in cases of increased workload or high systemic resistance can lead to episodes of flash pulmonary oedema [24, 36].
Careful screening is mandatory in order to exclude other causes of cardiomyopathy, including hypertensive heart disease, hypertrophic cardiomyopathy, high output heart failure, mitochondrial myopathies, mucchopolyscharidosis or Anderson-Fabry disease. Despite that all of the prementioned pathologies can ultimately lead to restrictive cardiomyopathy and heart failure, they can also share a common imaging phenotype (LV hypertrophy) at least in their early stages [17]. Prompt detection of concomitant clinical and laboratory/imaging evidence suggesting amyloidosis is required for the accurate differential diagnosis and treatment. Specifically for the cases of AL amyloidosis, a number of diagnostic “red flags” indicative of the disease have been proposed [13, 14, 15, 37, 38]. These key diagnostic signs and symptoms include polyneuropathy, dysautonomia, macroglossia, impaired kidney function-proteinuria for the extracardiac manifestations and hypotension, abnormal ECG findings (e.g., low voltage QRS), elevated NTProBNP and troponin levels along with echocardiographic (e.g., granular sparkling of myocardium, reduced longitudinal strain with apical sparing pattern, increased right ventricular wall thickness) as also CMR evidence (e.g., subendocardial LGE, increased extracellular volume, abnormal gadolinium kinetics) for the cardiac findings respectively [12, 13, 17].
A number of limitations must be acknowledged regarding the present case report. Firstly, no intravascular imaging (IVUS, OCT) or follow-up CA data are available for further diagnostic information regarding the embolization of the LAD. Secondly, data on LA mechanics (such as LA strain) as well as on hypercoagulability screening tests were not available.
Amyloidosis can cause embolization of the coronary arteries and lead to acute coronary syndrome and heart failure. Careful clinical work up is required, whereas imaging techniques such as echocardiography and CMR, in conjunction with analytical and histological data, can be of great relevance to overall patient management. This case report highlights some of the potential manifestations of amyloidosis, showcasing the importance of an integrative approach and of the close collaboration between cardiologists and oncologists, in this challenging clinical entity.
CP, ET, EK, MAD designed the case report study and contributed to the manuscript conceptualization, preparation and draft of the manuscript and writing of the case report. IB, KT contributed to library searches and assembling relevant literature, data acquisition, data interpretation, writing of the case report and were the main contributors to the design of the figures. All authors contributed to the critical review and final approval of the manuscript.
The study fulfills the ethical requirements of the Declaration of Helsinki, with regards to human subjects’ research (ethical and scientific committee of Alexandra Hospital protocol number 457). Written consent was obtained from the patient.
The authors would like to express their gratitude to all those who helped them during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.
All relevant data are included in the manuscript.