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Patterns of cardiac involvement in type i familial amyloidotic polyneuropathy
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PREMORTEM RE,COGNITION OF SYSTEMIC SENILE AMYLOIDOSIS WITH CARDIAC INVOLVEMENT Robert A. Kyle and Morie A. Gertz, Mayo Clinic, Rochester, Minnesota All patients with the d i a g n o s i s of amyloidosis at the Mayo Clinic from J a n u a r y 1, 1984, through May 1, 1992, were reviewed. Amyloid was confirmed histologically by alcian blue and alkaline Congo red staining. The labeled streptavidin-biotin immunoperoxidase method was used with antisera against A t A~.,, AA, transthyretin, and ~2-microglobulin. Anti-Pcomponent and antisera to albumi~a were used as controls. Chest radiographs, electrocardiograms, transthoracic eehocardiograms, and cardiac catheterization data of all patients were reviewed. Serum and urine were examined with immunoelectrophoresis and immunofLxation for the presence of a monoelonal protein. Lymphocyte DNA was examined for transthyretin mutations associated with familial amyloidosis. We identified 18 patients with myocardial tissue that stained positive for amyloid with alcian blue and Congo red. All tissue stained with transthyretin antiser~. Congestive heart failure was present at diagnosis in 17 of the 18 patients. Atrial fibrillation was found in 11 patients. No monoclonal protein was found in the serum or urine. The echocardiographic findings were consistent with infdtrative cardiomyopathy due to amyloidosis in 15 patients. Right heart pressures were elevated in all seven patients who had right heart catheterization. No transthyretin mutations were found in the leukocyte DNA from 12 patients. The actuarial median survival was 5 years; in contrast, the median survival was 4 months in 63 patients with primary amyloidosis (AL) who presented with congestive heart failure. We conclude that patients with cardiac amyloid and no monoelonal protein in the serum or urine must have immunohistochemical staining for Jcand ~.light chains and transthyretin to distinguish between senile cardiac amyloidosis, familial amyloidosis, and primary amyloidosis. Patients with senile cardiac amyloidosis should not be treated with alkylating agents. Their survival is much longer than that of patients with primary amy1o i dos i s.
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PATTERNS OF CARDIAC INVOLVEMENT IN TYPE I FAMILIAL AMYLOIDOTIC POLYb~UROPATHY A. Carvalho j, C. Fonseca I, J. Sfi-Noguairal, H.Morais I, M. Minhoto I, M. Carvalho2, M. Alves 2, M.L. Sales-Luis2, F. Ceia I, A, Sales-Luis l Serviqo de Medicina],H.S.Francisco Xavier,Lisbua,Portugal Centro de Estudos Egas Moniz e Servic¢ode Neurologia2, H.Sante Maria, Lisboa Portugal Infiltration by amyloid is a feature of Familial Amyloidotic Polyaenropathy Portuguese type(FAP), responsible for various systemic manifestations. Cardiac involvement is now well documented, but its timing and pattern are heterogeneous. It interferes with enesthesy and operative procedures, inanely those of liver transplent(LT), the only eventually curative therapy for FAP. Aim of the Study:To evaluate severity and pattern of cardiac manifestations in FAP in order to select adequate therapeutic procedures. Methodology:We studied prospectively 110 patients(P) with FAP. .All P had characteristic clinical and electromyographic fentutes of the disease and were TI'Rmet30+.Physical examination, 24-hour Holter ECO(Holter) and M+2D+colour/Doppler Echocardiography(Echo)were recorded in all P, Holter were classified as 0-normal, l-nonmodulated sinus rhythin/lst degree AV block,2-2nd degree AV block/SA block/wondering pacemaker,3-Advancod SA or AV block.Echo were classified as 0-normal,l-Abnormal brightness/diastolic impairment,2-1+Increased ventricoler wall thickness,3-2+eularged left atria. Population:56 women and 54 men) aged 19-78, in Stages 0-VI(Sales'classification), time of evolution 0-18 y,55P had 3,5+9,6 years of follow-up. Most P were in stages 11to IV(88,7%).Althoug Holter and Echo abnormalities could be found since earlier stage L their severity increased according to stage and time of evolution, as does the % of abnormal Holter and Echo.However, sorae heterogeneity was found. So, we analysed 5 subpopulations~-ll symptomatic P with normal Holter and Echo(5,16%).B-7 P(3,3%) with normal or nearly normal Holter(Holter 1) and severe Echo abnormalities(Echo 2 ).C- 24 P with mild Holtar and Echo almormalities(l 1,3%).D-23 P with severe Holler abncn'nmlities(Holter 3) and normal Echo(10,g%).E-17 P(7,9%) with severe Holter and Echo almormalities(3). Results: A-These P in stages I(1), 11(7) and I11(3) were younger than D and E(40,9%i-8,13, p=O,028);they had shorter evolution time than C,D and E(3,27+~,28, p=0,O35,p=0,0001), however ranging between I and 8 years.B-Included 3 old P(60.64), one P with mild arterial hypertension, that could explain Echo findings and 3 P(30.47y),in stages H,IH and IV, with evolution time of 7 years.C-Mean age similar to A(40,75:[~6,56, p=0,9), lower Rum D and E(p-~0,002,p--0,01);stages I(I), 1I(3),I~13) and IV(5), with longer evolution time(6,35£-4), ran~ng from 1 to 20 ymrs.D-23 P, mean age 47,17:t:7,09, with the longest evolution time, higher than C, similar to E(9,24:k3,74, ranging 5 to 18 years, p---'0,015), in stages I~4),~(9),lV(7),V(2) and VI(l).E-These P were slightly older(47,65i-9,7), in meae advanced steges(l~-5, IV- 10, V-2, VI-1)and also had lenger time of evolmion(8,5-+.2,83, ran~tzinS from 4 to ! 5 years,), althoug not significantly different from C (p=O,06). Conclusions:In FAP, non-modulation of henrt rate and conduction and rhythm disturbances usuaUy precede Echo abnormalities;the longer is the evolution time, the higher is the incidence and severity of cardiac involvement.However, cardiac involvement can occur either earlier or later than expected in a significant % of P; this fact remains to be explained. Cardiac abnormalities can occur and proge~ in an beterc~eneous pattern. Knowledge of these discrepancies between time of evolution, stage and cardiac involvement must be considered as in the selection of patients for LT as for their adequate management.
75
PREMORTEM RE,COGNITION OF SYSTEMIC SENILE AMYLOIDOSIS WITH CARDIAC INVOLVEMENT Robert A. Kyle and Morie A. Gertz, Mayo Clinic, Rochester, Minnesota All patients with the d i a g n o s i s of amyloidosis at the Mayo Clinic from J a n u a r y 1, 1984, through May 1, 1992, were reviewed. Amyloid was confirmed histologically by alcian blue and alkaline Congo red staining. The labeled streptavidin-biotin immunoperoxidase method was used with antisera against A t A~.,, AA, transthyretin, and ~2-microglobulin. Anti-Pcomponent and antisera to albumi~a were used as controls. Chest radiographs, electrocardiograms, transthoracic eehocardiograms, and cardiac catheterization data of all patients were reviewed. Serum and urine were examined with immunoelectrophoresis and immunofLxation for the presence of a monoelonal protein. Lymphocyte DNA was examined for transthyretin mutations associated with familial amyloidosis. We identified 18 patients with myocardial tissue that stained positive for amyloid with alcian blue and Congo red. All tissue stained with transthyretin antiser~. Congestive heart failure was present at diagnosis in 17 of the 18 patients. Atrial fibrillation was found in 11 patients. No monoclonal protein was found in the serum or urine. The echocardiographic findings were consistent with infdtrative cardiomyopathy due to amyloidosis in 15 patients. Right heart pressures were elevated in all seven patients who had right heart catheterization. No transthyretin mutations were found in the leukocyte DNA from 12 patients. The actuarial median survival was 5 years; in contrast, the median survival was 4 months in 63 patients with primary amyloidosis (AL) who presented with congestive heart failure. We conclude that patients with cardiac amyloid and no monoelonal protein in the serum or urine must have immunohistochemical staining for Jcand ~.light chains and transthyretin to distinguish between senile cardiac amyloidosis, familial amyloidosis, and primary amyloidosis. Patients with senile cardiac amyloidosis should not be treated with alkylating agents. Their survival is much longer than that of patients with primary amy1o i dos i s.
76
PATTERNS OF CARDIAC INVOLVEMENT IN TYPE I FAMILIAL AMYLOIDOTIC POLYb~UROPATHY A. Carvalho j, C. Fonseca I, J. Sfi-Noguairal, H.Morais I, M. Minhoto I, M. Carvalho2, M. Alves 2, M.L. Sales-Luis2, F. Ceia I, A, Sales-Luis l Serviqo de Medicina],H.S.Francisco Xavier,Lisbua,Portugal Centro de Estudos Egas Moniz e Servic¢ode Neurologia2, H.Sante Maria, Lisboa Portugal Infiltration by amyloid is a feature of Familial Amyloidotic Polyaenropathy Portuguese type(FAP), responsible for various systemic manifestations. Cardiac involvement is now well documented, but its timing and pattern are heterogeneous. It interferes with enesthesy and operative procedures, inanely those of liver transplent(LT), the only eventually curative therapy for FAP. Aim of the Study:To evaluate severity and pattern of cardiac manifestations in FAP in order to select adequate therapeutic procedures. Methodology:We studied prospectively 110 patients(P) with FAP. .All P had characteristic clinical and electromyographic fentutes of the disease and were TI'Rmet30+.Physical examination, 24-hour Holter ECO(Holter) and M+2D+colour/Doppler Echocardiography(Echo)were recorded in all P, Holter were classified as 0-normal, l-nonmodulated sinus rhythin/lst degree AV block,2-2nd degree AV block/SA block/wondering pacemaker,3-Advancod SA or AV block.Echo were classified as 0-normal,l-Abnormal brightness/diastolic impairment,2-1+Increased ventricoler wall thickness,3-2+eularged left atria. Population:56 women and 54 men) aged 19-78, in Stages 0-VI(Sales'classification), time of evolution 0-18 y,55P had 3,5+9,6 years of follow-up. Most P were in stages 11to IV(88,7%).Althoug Holter and Echo abnormalities could be found since earlier stage L their severity increased according to stage and time of evolution, as does the % of abnormal Holter and Echo.However, sorae heterogeneity was found. So, we analysed 5 subpopulations~-ll symptomatic P with normal Holter and Echo(5,16%).B-7 P(3,3%) with normal or nearly normal Holter(Holter 1) and severe Echo abnormalities(Echo 2 ).C- 24 P with mild Holtar and Echo almormalities(l 1,3%).D-23 P with severe Holler abncn'nmlities(Holter 3) and normal Echo(10,g%).E-17 P(7,9%) with severe Holter and Echo almormalities(3). Results: A-These P in stages I(1), 11(7) and I11(3) were younger than D and E(40,9%i-8,13, p=O,028);they had shorter evolution time than C,D and E(3,27+~,28, p=0,O35,p=0,0001), however ranging between I and 8 years.B-Included 3 old P(60.64), one P with mild arterial hypertension, that could explain Echo findings and 3 P(30.47y),in stages H,IH and IV, with evolution time of 7 years.C-Mean age similar to A(40,75:[~6,56, p=0,9), lower Rum D and E(p-~0,002,p--0,01);stages I(I), 1I(3),I~13) and IV(5), with longer evolution time(6,35£-4), ran~ng from 1 to 20 ymrs.D-23 P, mean age 47,17:t:7,09, with the longest evolution time, higher than C, similar to E(9,24:k3,74, ranging 5 to 18 years, p---'0,015), in stages I~4),~(9),lV(7),V(2) and VI(l).E-These P were slightly older(47,65i-9,7), in meae advanced steges(l~-5, IV- 10, V-2, VI-1)and also had lenger time of evolmion(8,5-+.2,83, ran~tzinS from 4 to ! 5 years,), althoug not significantly different from C (p=O,06). Conclusions:In FAP, non-modulation of henrt rate and conduction and rhythm disturbances usuaUy precede Echo abnormalities;the longer is the evolution time, the higher is the incidence and severity of cardiac involvement.However, cardiac involvement can occur either earlier or later than expected in a significant % of P; this fact remains to be explained. Cardiac abnormalities can occur and proge~ in an beterc~eneous pattern. Knowledge of these discrepancies between time of evolution, stage and cardiac involvement must be considered as in the selection of patients for LT as for their adequate management.