Cardiac Sympathetic Denervation in Transthyretin-Related Familial ...

Downloaded from jnm.snmjournals.org by on April 19, 2017. For personal use only.

Cardiac Sympathetic Denervation in Transthyretin-Related Familial Amyloidotic Polyneuropathy: Detection with Iodine-123-MIBG Tomoaki Nakata, Kazuaki Shimamoto, Shuji Yonekura, Naoko Kobayashi, Toshiro Sugiyama, Kohzoh Imai and Osamu limura Second and FürtDepamnent@ oflntemalMedicine,

School ofMedicine, Sapporo Medical Unive,@isy,Sappom, Japan

Infamilialamyloidoticpolyneuropathy (FAP),the peripheralner Vous system is predominantlyimpaired. Cardiac sympathetic functionhas not been directlyassessed. A 65-yr-oldman with severe peripheral neuropathy due to primarysystemic amylol dosis was Studied.Echocardiogramsand ScintigraphiC examine tions with 2011and @rc-pyrophosphate demonstrated highly thickenedbut normallyperfused Ieftventricularwallswithintense diffuse a@old deposits. No definite myocardial activity of Elnallmetaiodobenzylguanidine (MIBG)was detected in any car diac region, indicating leck of sympathetic nerve endings. De

benzylguanidine ([1@I]MIBG)can accumulate specifically in postganglionic sympathetic neurons in the same manner as norepinephrmneand, consequently, the myocardial ac tivity and kinetics of [‘@]I MIBG possibly reflect normal structure and function of the cardiac sympathetic nerves (5). Rapid clearance ofmyocardial [1-123] MIBG has been observed in patients with autonomic neuropathies, such as

Shy-Drager syndrome, idiopathic orthostatic hypotension and diabetes mellitus (6—8).Markedlyreduced MIBG up take has likewise been reported in transplanted human hearts (9).

spite maintainedcardiaccontractility,Ieftventriculardiastolicper WestudiedaFAPpatientwith amethioninesubstitution formance and heart rate variabilityassessed by power spectral analyalswere markedlydepressed. Thus, the myocardialdefect forvaline at position 30 of the transthyretin sequence (TFR of MIBGactivitymayprovkledirecte@denceof impairedcardiac Met 30). The combined use of three myocardial imaging sympathetic nerve endings due to amyloiddeposits in FAP. protocols—@°'11,@Fc-pyrophcaphate and [1-123]MIBG demonstrated the unique characteristics of his myocardial KeyWords:iodine-123-metaiodobenzylguanidine; familialamy tissues, i.e., the left ventricle was normally perfused and loidoticpolyneuropathy;cardiac amyloidosis; cardiac sympa contracting,but it was markedlythickened and totally den thetic nerve function ervated. J NuciMed 1995;36:1040-1042

amilial amyloidotic polyneuropathy (FAP) is a rare sys temic disorder in which the peripheral nervous system becomes markedly impaired, particularly in the extremi ties, due to amyloid deposition. Recent studies have re vealed that a genetic variantof normalprealbumin,namely transthyretin (1TR), causes autosomal dominant heredi tel); systemic

amyloidosis

and is related

to several

clinical

features of this disease, including peripheral neuropathy,

cardiac amyloidosis, amyloid kidney and ocular alterations (1—4).Cardiac amyloidosis causes conduction distur bances, arrhythmias, restrictive cardiomyopathy and low output heartfailure. In a FAP patient, peripheralascending neurons were predominantly

involved; cardiac manifesta

tions were less severe and cardiac sympathetic dysfunction has not been definitely determined. Iodine-123-metaiodo ReceivedJul. 8, 1994;revisIona@pled Sept. 28, 1994. Forcorrespondenonorrepdntsco@ Tomo@dNulMa,MD,SecondDepart ment of InternalMedicine,Schoolof Medicine,Sapporo Medici Unhiersfty,S-i W-16,Chuo-ku, Sapporo 060,Jepan.

1040

CASE REPORT A 65-yr-oldmanwas admittedwithnumbnessanddisabilityin his extremities. He had no past history of cerebrovascularor cardiacaccident,drugabuse, alcoholism,or endocrinologic,met abolic,inflammatory or othersystemicdisorders.Onadmission, he hadnormalsinus rhythmwith a rateof 76/mmand a blood pressureof 160/80mmHgin the supinepositionand 140178mmHg intheuprightposition.Neurologicalexaminationdisclosedmark edly reduced light and tendon reflexes and highly impaired sen

sory and motor systemsin his extremities;by contrast, there was no evidenceof animpairedcentralnervoussystemexceptforthe light-reflexabnormality. No other physical abnormalitieswere detected.Conductancevelocities of peripheralsensory nerves were not measurable in the lower extremities;velocities were markedly reduced in the upper limbs, and the amplitudes were quite low. Therewere no abnormalitiesin hematology, renalfunc

tion and serologic, metabolic and hormonal tests. Urinalysis showedneitherproteinurianorBence-Jonesprotein,anda bone marrow test showed no evidenceof plasma cell dyscrasia. His tologyof gastricbiopsyspecimensstainedby hematoxylineosin andCongored clearlydemonstrateddepositionofamyloidprotein in the muscularismucosaeand smallvessel walls. Myocardial biopsy was not performed because of disability due to severely symptomatic peripheral neuropathy T1'R Met 30 was detected in

Thejoumal of NuclearMedicine• Vol 36• No. 6•June1995

Downloaded from jnm.snmjournals.org by on April 19, 2017. For personal use only.

(A)

@ @

(B)

I

FIGURE 1. Mterior planarscan (upperpanels) and shod-axial — tomogramsQowerpanals)with2OFfl(,@) @rC-pyrOphOSphate (B).Theleftventricularwallsaresymmetrically thickenedbutnor FIGURE 2. Iodlne-123-MIBG scans ofthe anteriorchest and ab mallyperfused,and Intenseand diffuseposltMlyof pyrophosphate domen30 mk@ (upperleftpanel)and 4 hr (upperlightpanel)postin _Isobserved over the heart, particularlyin the leftventricle, as much jectionshow no definiternyocardlaluptake In any cardiac region as inadjacentbone. despitethe activitiesnormallyobservedinthe liverand lungs.Note thatthe serialtransversetomogramson the earlyscan (lowerpan els)dearly supportthe lackof positivernyocardialMIBG. plasma,however,by radioimmunoassay usingmonoclonalanti bodies establishedby Arald et al. (10—11). Family investigation showedno possibilityof peripheralneuropathyor cardiacamy performancewas reducedduringthis 3-yrfollow-upperiod,in loidosis. From these findings, the diagnosis of a sporadic case of which LVEF fell from 70%to 55%and fractionalshorteningfell iTh-related familialamyloidoticpolyneuropathytype 1 (lower from40%to 32%,the patientsurviveswithadvancedperipheral limbtype) (3,4)was established. neuropathybut no cardiac symptoms. The electrocardiogram (ECO)revealedfirstdegreeatrioven tricular block and bifascicular block. Abnormal Q waves were DISCUSSION found in leads II, Ill, and aVF, and the T wave was invertedin In addition to intense and diffuse positivity of@'Fc-PYP leadsV4-6.A chestradiographshoweda cardiothoracic ratioof scanning, markedly impaired sympathetic innervation was 54% and no pulmonary venous congestion. Holter monitoring clearly demonstrated by ‘@I MIBG scanning with TFR revealed no serious ventricular complexes. Two-dimensional Met30. echocardiogramsrevealedsymmetricallyincreasedwallthickness Despite its limited diagnostic value, a positive @Tc of the left ventricle with a characteristic granularsparklingap PYP scan has been demonstrated in cardiac amyloidosis pearancebut a normallymaintainedleft ventricular(LV)cavity size as well as normalsystolicfunction.LV fractionalshortening (13—14).Although myocardial tissue diagnosis of amyloi was 40%,andthe end-diastolicthicknessesof the LV posterior dosis was not made in this patient, massive myocardial wall and the interventricular septum were 18 mm and 16 mm, uptake of pyrophosphate, a characteristic granular spar respectively.Althoughneitherasynergicwallmotionnorvalvular kling appearance on echocardiograms, and amyloid depos disease were detected, Doppler ultrasound showed highly re

its in the 01 tract strongly support amyloid infiltration into

duced early velocity(E) and increasedlate velocity(A)of trans mitralflow.A/E increasedto 1.6. Radionudideventriculography showeda normalLVEF(70%), noasynergy,buthighlyreducedLVdiastolicfunction;peakfilling ratewas 2.08(EDC/sec)andtheratioof peakfillingrateto peak ejectionratewas0.62(12).Myocardialthalliumscintigraphy dem

the heart. Pyrophosphate interacts specifically with amy bid fibers because of their calcium affinity (14). Amyloid proteins accumulated extraceliularly can be attributed to myocardial cell atrophy and to the loss of membrane integ nty leading to necrosis and replacement of myocytes. LV

onstrated markedlythickened LV walls but no definite hypoper

systolic

performance

and myocardial

perfusion

in this

case, however, indicate that viable myocytes are function vealedintensediffuseuptakesinbothventricularwalls(Fig.1B). ing sufficiently, althoughmassive amyloid deposits restrict Iodine-123-MIBG (111 MBq) was injected intravenously during LV diastolic filling and disturb conduction systems. restingandfastingconditions.Planarandtomographic scanswere It is of great interest that neither early nor late scans obtained30 mm and 4 hr after injection.No definitemyocardial demonstrated definite MIBG uptake in any cardiac region. uptake was detected. In contrast, the activitiesin the liver and Several mechanisms might account for the markedly and lungswere normal(Fig.2). In addition,powerspectralanalysisof heart rate variabilityshowedno detectablehigh-frequencyspec globally reduced MIBO uptake. Myocardial ischemia or fused area (Fig. 1A). PIP scanning with 555 MBq of

@Tcre

coronary artery disease is unlikely because there is no nent,suggestinghiglilydamagedvagalandsympatheticactivities evidence of chest pain, asynergic wall motion, or reduced tral component,

but a markedly reduced low-frequency

compo

of theheart.Thesefindingsindicatethatneurologicalabnormali thaffium perfusion. Accelerated clearance of MIBG from ties were present not only in the peripheralnervous system but the heartas seen in autonomicneuropathy(5,7) and dilated alsoin the cardiacautonomicnervoussystems.Althoughsystolic cardiomyopathy (15) appears even less possible. Scanning

Detectionof Cardiac SympatheticDenervationwith 1@l-MIBG • Nakatalat al.

1041

Downloaded from jnm.snmjournals.org by on April 19, 2017. For personal use only.

during the first 30 min postinjection mainly reflects the greater influx of MIBG into extraneuronal spaces in myo

cardial tissue rather than into the neuronal component. Therefore, myocardial MIBG uptake was assessed 30 min and 4 hr postinjection in our patient. The latter scan dis plays neural uptake of MIBG more specifically. The lack of MIBG positivity, even in the early image, suggests loss or destruction of cardiac sympathetic nerve endings rather than functional abnormalities such as an increase in re lease, metabolism, turnover of norepinephrine(MIBG) or alterations in the storage mechanism (16). The findings of pyrophosphate deposits and lack of MIBG positivity may indicate amyloid infiltrationinto cardiac sympathetic nerve endings, such as that occurringin peripheralneurons of the extremities. In view of the findings of Sisson et al. (7) and our experience (unpublished observation) with the Shy Drager syndrome, the possibility that total cardiac dener vation derives from injury to preganglionic fibers of the sympathetic nervous system cannot be ruled out com pletely. The markedly depressed cardiac autonomic func tion revealed by the depressed low- and high-frequency components of heart rate variability suggests cardiac sym pathetic denervation. These characteristics appear quite similar to those of transplantedhearts (9). Several implications follow from the lack of MIBO pos itivity in a FAP patient. First, the finding indicates cardiac sympathetic nerve involvement in TFR Met 30-related FAP. Like peripheral nerves, cardiac sympathetic nerve endings may also be susceptible to amyloid protein-related nerve damage. Second, amyloid deposits and sympathetic nerve dysfunction may possibly exacerbate arrhythmias and conduction disturbances leading to sudden cardiac death. Third, impairedcardiac sympathetic regulationmay further impair diastolic performance due to massive amy bid deposition or it may blunt the compensatory mecha nism for exercise intolerance and heart failure. Fourth, cardiac sympathetic nerve involvement may define the de gree of progression of the disease and determine the prog nosis in a FAP patient. The clinical features of LV diastolic dysfunction but normally maintained thallium perfusion and systolic function in this case may be an early conse quence of myocardial amyloid deposition priorto a deteri orative clinical outcome. Further experience is necessary, however, to establish the clinical implications of impaired cardiac sympathetic nerves related to ‘fFR Met 30 FAP. Markedly reduced MIBG uptake on early and delayed images appears to be associated with functional and ana

scintigraphy may be an effective tool for direct and visual assessment of cardiac sympathetic innervation and to ex ploring the mechanisms of impairment by the combined use of other noninvasive methods. ACKNOWLEDGMENTS The authorsthankDr. Yukio Andoh ofthe First Departmentof

InternalMedicine,KumamotoUniversity,for measuringa variant form of transthyretinin the patientsera with his monoclonal antibody.We are also gratefulto Naomi M. Anderson, PhD for excellenteditorialassistance. REFERENCES 1. Sanchez-RamosJA, Redondo-SanchezR, Garcia-CrespoP, Superby. Jeldres A, Schuller-Perez A. Cardiac amyloidosis. Cardiov&cc Rev Rep 19845:524-529.

2. HesseA, AitlandK, LinkeRP,AlmeidaMR.etaLCardiacamyloidosis: a reviewand report of a new transthyretin(prealbumin)variant. Br Hew@J 1993;70:111—115.

3. &nson MD.Inheritedamyloidosis. MedGenet1991;28:73-78. 4. StauntonH. Familialamyloidpolyneuropathies. In:VinkenPJ,ed.Hand. book ofclinical neumlogy. Amsterdam: Elsevier,1991:89-115.

5. KlineRC, Swanson DP,WielandDM, Ctal. Myocardial imaging in man

with1-123metaiodobenzylguanidine.JNuclMed 1981;22129-132. 6. NakajoM, ShimabukuroK, Miyaji N, et al: Rapidclearanceof iodine-131. MIBG from the heart and liver of patients with adrenergic dysfunction and

pheochrnmocytoma.INuciMed 1985;26:357-365. 7. Sisson JC, Shapiro B, Meyers L, Ct al. Metaiodobenzylguanidine to map scintigraphically the adrenergic nervous system in man. INuciMed 1987;

28:1625-1636. 8. MantysaariM, KuikkaJ, MustonenJ, et al. Noninvasivedetectionof cardiacsympatheticnervousdysfunctionin diabeticpatientsusing[1@I]me. taiodobenzylguanidine. Diabetes 1992;41:1069-1075.

9. DaeMW,DemarcoT, BotvinickEH, et al. SCintigraphiC assessmentof MIBG uptake in glObally denervated human and canine hearts—implica tions for clinical studies. INUC! Med 199233:1444-1450. 10. MitaS,MaedaS,IdeM,TsuzuioT,ShimadaK,ArakiS.Familialamy

loidoticpolyneuropathy diagnosedby clonedhumanprealbumincDNA. Neurology 1986;36:298-301. 11. NakazatoM,KangawaK,MinandnoN,TawaraS,MatsuoH,ArahS. Radioimmunoassay for detecting prealbumin in the serum for diagnosis of

familialainyloidoticpolyneurnpathy(Japanesetype).BioChemBiOphyRer Cominun 1984;122:719—725.

12.NakataT, NotoT, UnoK, etal.Normalized leftventricular fillingindexes to detect diastolic dysfunction in hypertension and hypertrophic cardiomy

opathy. Can I Cwdiol 1991;7:350—356. 13. WizenbergT, Muz J, Sohn YH, SamIOWSki W, WeisslerA. Value of @tivemyocardial technetium-99m-pyrophosphate Scintigraphy in the noninvasive diagnosis of cardiac aInyIOidOSiS.Am Heart I 1982;103:468-

47314. Kula RW, EngelWK, Line BR. Scanningfor soft-tissueamyloid.Lancet

1977;1:92-93.

15.Henderson EB,KahnJK,CorbettJR,etal.Abnormal 1-123 metaiodoben

to amyloid deposits in TFR-related FAP type 1. MIBG

zylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Cir@ cidation 1988;78:1192—1199. 16. Ganguly piçBeamish RE, Dhalla KS, Innes IR, Dhalla NS. Norepineph tine storage, distribution and release in diabetic cardiomyopathy. Am I Fkysiol 1987;252:E734-739.

1042

The Journalof NuclearMedicine• Vol.36 • No. 6 • June 1995

tomical abnormalities

of cardiac sympathetic

neurons due

Downloaded from jnm.snmjournals.org by on April 19, 2017. For personal use only.

Cardiac Sympathetic Denervation in Transthyretin-Related Familial Amyloidotic Polyneuropathy: Detection with Iodine-123-MIBG Tomoaki Nakata, Kazuaki Shimamoto, Shuji Yonekura, Naoko Kobayashi, Toshiro Sugiyama, Kohzoh Imai and Osamu Iimura J Nucl Med. 1995;36:1040-1042.

This article and updated information are available at: http://jnm.snmjournals.org/content/36/6/1040

Information about reproducing figures, tables, or other portions of this article can be found online at: http://jnm.snmjournals.org/site/misc/permission.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml

The Journal of Nuclear Medicine is published monthly. SNMMI | Society of Nuclear Medicine and Molecular Imaging 1850 Samuel Morse Drive, Reston, VA 20190. (Print ISSN: 0161-5505, Online ISSN: 2159-662X) © Copyright 1995 SNMMI; all rights reserved.