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systemic immunoglobulin light - chain ( al ) amyloidosis is a disorder of plasma cells characterized by the deposition of amyloid fibrils in various organs , eventually leading to organ dysfunction and death .
once a diagnosis of cardiac amyloidosis has been established , survival time is limited . of late ,
novel agents such as bortezomib have apparently become established as important drugs for the treatment of systemic al amyloidosis . here
we present a case of systemic al amyloidosis with severe cardiac involvement in a 64-year - old woman .
we expected bortezomib to be efficacious but could not avoid the complication of fatal ventricular fibrillation ( vf ) . in this case report , we evaluated the possibility of cardiac toxicity induced by bortezomib by investigating the clinical course of the patient and reviewing the relevant literature .
a 64-year - old female suffering from general fatigue , appetite loss , and weight loss was referred to our institute for the investigation of m - protein and hypercalcemia . upon hospital admission ,
her eastern cooperative oncology group performance status was 2 and her karnofsky performance status ( kps ) was approximately 50% .
she was also found to suffer from class ii heart failure according to the functional classification system of new york heart association ( nyha ) .
physical examination revealed a palpable liver edge 15 cm below the costal margin and bilateral pretibial pitting edema .
results of her blood test revealed the following : aspartate aminotransferase , 81 ( normal , 13 - 33 ) u / l ; alkaline phosphatase , 534 ( 115 - 359 )
u / l ; -glutamyl transpeptidase , 311 ( 10 - 47 ) u / l ; lactate dehydrogenase , 343 ( 119 - 229 ) u / l ; calcium , 11.7 ( 8.7 - 10.3 ) mg / dl ; creatinine , 1.18 ( 0.4 - 0.7 ) mg / dl ; brain natriuretic peptide ( bnp ) , 1630.5 ( 0 - 8.4 ) pg / ml ; n - terminal prohormone of bnp ( nt - probnp ) , 8290 ( 0 - 125 ) pg / ml ; and troponin t , 0.242 ( 0 - 0.014 ) ng / ml . her serum beta-2 microglobulin level was 5.5 ( 0 - 2.5 ) mg / l and free light chain difference ( flc - diff ) was 33.46 mg / dl .
a bone marrow aspirate revealed 10% plasma cells with cd38 , cd138 , and cytoplasmic + phenotypes .
diffuse osteoporosis was revealed by radiography , and magnetic resonance imaging showed the absence of focal lesions .
electrocardiography ( ecg ) revealed left - axis deviation , low - voltage qrs complexes , and first degree atrioventricular block ( figure 1a ) .
a 24-h holter ecg demonstrated 129 beats of ventricular premature contractions ( vpcs ) and 1268 beats of atrial premature contractions ( apcs ) , including 5 vpc short runs ( maximum , 5 runs ) and apc short runs ( maximum , 8 runs ; figure 1b ) .
transthoracic echocardiography revealed a left ventricular ejection fraction of 64% , diffuse thickening of the left and right ventricular walls with granular sparkling , and pericardial effusion .
she was diagnosed with systemic al amyloidosis associated with bence jones protein type multiple myeloma ( mm ) .
after written informed consent was obtained from the patient , administration of dexamethasone and bortezomib ( oral dexamethasone , 20 mg / day , days 1 - 4 ; bortezomib , 1.3 mg / m / day , subcutaneous injection on day 4 ) was initiated under 24-h ecg monitoring ( figure 1c ) .
serum calcium levels were corrected by intravenous infusions of normal ( 0.9% ) saline with elcatonin , leading to increased body weight .
after adjustment of infusions and diuretic treatment , her body weight returned to that at baseline .
the day before the onset of vf , her serum mineral levels were within normal limits as follows : calcium , 9.2 mg / dl ; magnesium , 1.8 ( 1.8 - 2.7 ) mg / dl ; and potassium , 3.9 ( 3.6 - 4.9 ) mmol / l .
the patient no longer complained of insomnia , constipation , or the stress of hospital admission .
however , approximately 84 h after bortezomib administration , in the middle of the night , the patient conversed with nursing staff and walked to the rest room for urination . a few minutes later , her cardiac monitor alarm sounded and showed vf pattern .
she was found lying down at her bedside . cardiopulmonary resuscitation ( cpr ) using direct current shocks with epinephrine and amiodarone
her serum mineral levels were as follows : sodium , 138.1 ( 138 - 146 ) mmol / l ; potassium , 3.56 mmol / l ; ionized calcium , 1.11 ( 1.1 - 1.4 ) mmol / l ; and bicarbonate , 29.9 ( 22 - 30 )
continuous cpr for approximately 30 min failed to recover the cardiac features required to sustain the general circulation , but just after the injection of vasopressin , her arterial pulsations recovered .
autopsy revealed congested , hemorrhagic lungs and right and left ventricular hypertrophy ( heart weight , 400 g ) .
gross examination revealed round - to - web - like yellow waxy deposits in the myocardium .
histopathological examination revealed cardiac amyloid deposition , even in the atrioventricular node , and no ischemic lesion was complicated ( figure 1d , e ) .
the amyloidosis had also spread to the tongue , lung , liver , colon , kidney , bone marrow , adrenal gland , thyroid gland , and ovaries .
the present patient possessed one of two risk factors ( systolic blood pressure < 100 mmhg ) in stage iii cardiac amyloidosis . according to the revised prognostic staging system for al amyloidosis
, the present patient is categorized to stage 3 ( nt - probnp 1800 pg / ml , and flc - diff 18 mg / dl ) .
both studies indicated that the survival curves of these most advanced stage iii patients had dropped steeply at first 6 months after diagnosis .
therefore , the risk of developing lethal arrhythmia due to cardiac amyloidosis is estimated to be extremely high in the present patient .
in addition , if we exclude the other possible causes of kps values , vital signs , blood examination results , and documented infections , the direct trigger of vf seemed to be ascribed to vasovagal syncope after urination .
it is true that the largest study conducted with bortezomib in multiple myeloma showed minimum adverse effect of bortezomib on the incidence of heart failure .
however , concerning about al myloidosis , the adverse cardiac events at grade 3 occurred more frequently in the 1.3 mg / m twice - weekly group ( 29% ) than the 1.6 mg / m once - weekly group ( 6% ) .
accordingly , we could not overlook the time - course between the injection of bortezomib and the occurrence of vf in the present patient . in the literatures ,
seven patients suffered congestive heart failure 3 - 5 days after bortezomib administration and recovered within 2 weeks ( table 1 ) . like our patient
, a patient has been complicated with cardiac dysfunction after the first administration of bortezomib .
a rat model revealed that reversible cardiac damages occurred within 1 week of bortezomib treatment .
taken together , some adverse effects involving cardiomy - ocytes may occur at some interval after bortezomib administration .
the efficacy of bortezomib for al amyloidosis has been also proposed . however , there are some notable events that took place during these trials
. one of the 67 patients in the former trial was complicated with acute heart failure during cycle 2 of botezomib , resulting in death 2 days after the last dose of the drug .
this patient had a history of coronary artery disease and heart failure . in the latter trial , after 3 cycles of cyclophosphamide , bortezomib , and dexamethasone , 1 patient was complicated with fluid overload while another patient developed decompensated heart failure .
although the authors did not mention the possibility of accidental cardiac event independent of bortezomib nor the association between bortezomib and heart failure , we can not deny the cardiac arrest induced by bortezomib . according to the data in vitro , the ubiquitin - proteasome system ( ups )
is activated in hypertrophic cardiomyocytes , and it protects blood vessels from the formation and rupture of plaques , and maintains protein quality in cardiaomyocytes . with regard to dilated cardiomyopathy , the genes for ups are highly expressed in a rat model and human heart specimens .
age - related activation of the ups has been proposed to maintain essential cardiac stroke . once proteasome activity is inhibited , atherosclerotic plaques become unstable , smooth muscle cells become apoptotic , and expression of the adrenergic sensitizer grk2 increases , which can harm cardiaomy - ocytes .
the inhibition of nuclear factor - kappa b by bortezomib is responsible for higher incidence of cardiac damage in al amyloidosis compared to multiple myeloma . in the future , we should determine the mechanism that could have been associated with lethal vf in our patient .
our patient did not have a history of syncope , and then no indication for preventive implantation of a pacemaker . according to a trial , 19 patients associated with
syncope and/or 2 consecutive vpc beats received an implantable cardioverter - defibrillator ( icd ) , and 6 of them died from electromechanical dissociation . in our patient
, immediate direct - current shocks were not effective for recovery from cardiac arrest . accordingly , whether we could have avoided the occurrence of lethal vf in our patient by icd implantation remains unclear . with regard to cpr , vasopressin has been considered to be a promising alternative to epinephrine and proposed as an initial vasopressor for cardiac arrest .
our patient required frequent injections of epinephrine , one shot of vasopressin could have maintained her blood pressure for a long period , and then this may have been effective in maintaining the systemic circulation .
we described a form of systemic al amyloidosis with cardiac involvement that resulted in sudden cardiac death induced by vf following bortezomib therapy .
we should not ignore the potential risk of lethal arrythmia associated with advanced cardiac amyloidosis during bortezomib treatment .
futhermore , vasopressin may be useful for cpr in patients with cardiac amyloidosis requiring frequent injection of epinephrine .
a 64-year - old female was diagnosed with systemic amyloidosis associated with multiple myeloma . 
 bortezomib and dexamethasone - therapy was initiated ; however , she developed lethal ventricular fibrillation ( vf ) and cardiac arrest after 84 hours of therapy . 
 cardiopulmonary resuscitation using direct current shocks with epinephrine and amiodarone was initiated but failed to receive cardiac function . 
 although her arterial pulsations recovered immediately after the injection of vasopressin , she died of heart failure 8 hours after the onset of vf . 
 cardiac amyloidosis was verified by autopsy . 
 although the direct association of bortezomib with lethal vf remained to be clarified in our patient , the current report emphasizes on bortezomib as a substantial risk factor for cardiomyocyte damage . 
 the potential risk of lethal events associated with cardiac amyloidosis should be carefully considered during bortezomib treatment for patients with al amyloidosis .