Skip main navigation

Intracardiac Thrombosis and Anticoagulation Therapy in Cardiac Amyloidosis

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.108.785014Circulation. 2009;119:2490–2497

Abstract

Background— Primary amyloidosis has a poor prognosis as a result of frequent cardiac involvement. We recently reported a high prevalence of intracardiac thrombus in cardiac amyloid patients at autopsy. However, neither the prevalence nor the effect of anticoagulation on intracardiac thrombus has been evaluated antemortem.

Methods and Results— We studied all transthoracic and transesophageal echocardiograms of cardiac amyloid patients at the Mayo Clinic. The prevalence of intracardiac thrombosis, clinical and transthoracic/transesophageal echocardiographic risks for intracardiac thrombosis, and effect of anticoagulation were investigated. We identified 156 patients with cardiac amyloidosis who underwent transesophageal echocardiograms. Amyloidosis was the primary type (AL) in 80; other types occurred in 76 patients, including 56 with the wild transthyretin type, 17 with the mutant transthyretin type, and 3 with the secondary type. Fifth-eight intracardiac thrombi were identified in 42 patients (27%). AL amyloid had more frequent intracardiac thrombus than the other types (35% versus 18%; P=0.02), although the AL patients were younger and had less atrial fibrillation. Multivariate analysis showed that atrial fibrillation, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis, whereas anticoagulation was associated with a significantly decreased risk (odds ratio, 0.09; 95% CI, 0.01 to 0.51; P<0.006).

Conclusions— Intracardiac thrombosis occurs frequently in cardiac amyloid patients, especially in the AL type and in those with atrial fibrillation. Risk for thrombosis increased if left ventricular diastolic dysfunction and atrial mechanical dysfunction were present. Anticoagulation therapy appears protective. Timely screening in high-risk patients may allow early detection of intracardiac thrombus. Anticoagulation should be carefully considered.

Amyloidosis is an uncommon condition. It is estimated that there are 1275 to 3200 new cases annually in the United States on the basis of incidence data from a large ongoing cardiovascular epidemiology study in Olmsted County, Minn.1,2 Amyloidosis is classified by the precursor plasma proteins that form the extracellular fibril deposits. The primary systemic type, AL, is due to monoclonal immunoglobulin free light chains; the hereditary (also known as familial) type is due to mutant transthyretin (or mutant TTR) deposition; the wild-type transthyretin type (wild-type TTR, or “senile” type) is due to normal wild-type transthyretin deposition; and the secondary type (AA type) is related to amyloid A protein, which is an acute reactive protein.2,3 Amyloidosis, especially the AL type, frequently involves the heart and causes arrhythmias, heart failure (HF) with prominent left ventricular (LV) diastolic dysfunction, and sudden cardiac death.4,5 In part because of cardiac involvement, AL amyloidosis has the worst prognosis, with a median survival of 6 months when HF is present.2,5–7

Clinical Perspective on p 2497

We and others have identified a high prevalence of intracardiac thrombosis in these patients at autopsy, especially in AL cardiac amyloidosis.4,8 Furthermore, in our autopsy series, systemic embolism was a significant cause of mortality.8 However, it is possible that autopsy series may overemphasize the frequency of intracardiac thrombosis, and there have been only a few anecdotal reports in the literature on intracardiac thrombosis detected by transesophageal echocardiogram (TEE) or transthoracic echocardiogram (TTE) in live patients.9–15 Thus, the prevalence of intracardiac thrombus and the effects of anticoagulation in living cardiac amyloid patients have not been described. Accordingly, we evaluated both TTE and TEE studies from patients with various types of cardiac amyloidosis to determine how frequently detectable intracardiac thrombi are present, the clinical and echocardiographic characteristics associated with their presence, and the effects of therapeutic anticoagulation.

Methods

Study Groups

We searched the Mayo Clinic Hematology Database for all cases of amyloidosis from 1999 to 2007. There were 1909 cases with either a definite diagnosis of amyloidosis or suspected amyloidosis. This data set was then matched with the TEE database. There were 426 of 1909 patients who underwent TEE studies. Patients were included in the study if they had a positive cardiac biopsy for amyloid regardless of TEE or TTE findings or, for patients who had systemic amyloid as evidenced by positive noncardiac tissue biopsies (such as fat, bone morrow, gastrointestinal tract, liver, and kidney), if they also had a typical cardiac amyloid appearance on echocardiogram or MRI that could not be explained by another comorbidity such as hypertension, LV outflow tract obstruction, or aortic stenosis. Of the 426 patients, 156 met the above criteria and were included in this study. Eighty-seven patients (56%) had positive cardiac amyloid biopsy, and the remaining 69 patients met the second criterion given above.

We excluded 270 patients in whom there was no evidence of amyloidosis (who were included in the initial list because of the term rule out amyloidosis or cerebral amyloid angiopathy in electronic medical record system [215 of 270, 80%] or who had amyloidosis in another organ system but no evidence of cardiac involvement [48 of 270, 18%]). The study was approved by the Mayo Clinic Institutional Review Board.

Clinical Data

Clinical information, including demographic data, comorbidities, presence of HF, New York Heart Association (NYHA) functional class, and use of anticoagulants before and at the time of TEE, ECG, TTE, TEE, and MRI, and other laboratory data were abstracted from clinical records. Cardiac rhythm was determined from the patient’s ECG, Holter monitoring data, and medical records. International normalized ratio and activated partial thromboplastin time around the time of TEE were charted. Therapeutic anticoagulation was defined as an international normalized ratio ≥2 at the time of TEE, ≥2 documented consecutive therapeutic international normalized ratios of 2 to 3 before TEE for those with long-term anticoagulation, or at least 48 hours of intravenous heparin therapy or 48 hours of subcutaneous low-molecular-weight heparin therapy before TEE. Other abstracted information included results of tissue biopsies, urine and serum protein electrophoresis, immunofixation, serum free light chain assay, genetic testing, and family history.

Echocardiograms

TTE and TEE studies were reviewed independently by 2 of the authors (D.F. and I.S.S.) who had no knowledge of the clinical and pathological data. Inconsistencies between the reports and reviews were adjudicated by a third cardiologist (K.W.K.). TTE methods have been described in detail elsewhere.8 Briefly, TTE parameters extracted included LV ejection fraction; LV end-diastolic diameter; LV end-systolic diameter; stroke volume; ventricular septum thickness; LV posterior wall thickness; right ventricular free wall thickness; right ventricular systolic pressure; left atrial (LA) volume index; right atrium (RA) enlargement (0=normal, 1=mild, 2=moderate, 3=severe); LV diastolic function grade classified on the basis of mitral inflow pattern, mitral tissue Doppler, and pulmonary venous flow pattern16; mitral inflow E and A velocities; deceleration time; mitral septal annulus tissue Doppler velocity (systolic peak velocity, s′; early peak diastolic velocity, e′; late peak diastolic velocity, a′); and pulmonary venous flow profile (peak systolic velocity [S], peak diastolic velocity [D], D/S, and atrial contractile velocity), E/A, and E/e′.16

The TEE studies were reviewed for the presence or absence of intracardiac thrombus and their location and size.16 LA appendage (LAA) and LA spontaneous contrast and their severity were semiquantified as none, mild, moderate, or severe (0, 1, 2, or 3, respectively).17 LAA emptying velocity was measured by pulse Doppler echocardiography as previously reported.17 The degree of atherosclerosis in aorta was semiquantified as none, mild, moderate, or severe.18,19 Heart rate and blood pressure (BP) at the time of TEE were documented.

Pathology Data

The presence of cardiac or other tissue amyloid deposition was reconfirmed by review of the Congo red– or sulfated Alcian blue–stained specimen. Amyloid subtype was determined immunohistochemically with antibodies against serum amyloid P component, λ, and κ free immunoglobulin light chains, transthyretin (TTR; prealbumin), amyloid A component, and β-2 microglobulin.

Statistical Analysis

Data are expressed as mean±SD for continuous data and percent for ordinal and categorical data. Unpaired Student’s t tests were used to compare continuous variables. χ2 Tests were used to compare categorical data and ordinal variables. Univariate and multivariate analyses were performed to identify factors associated with intracardiac thrombosis. Ordinal variables such as spontaneous contrast in the LAA were treated as categorical variables in these analyses. Multivariate analysis was performed with logistic regression. Variables with a value of P≤0.05 in univariate analysis were considered significant and included in multivariate analyses by the use of several models, including the clinical variables model, TTE variables model, and TEE variables model. Nonsignificant variables were removed. Variables that were statistically significantly associated with intracardiac thrombosis by the above 3 models were then included in a final combined model. Finally, forward stepwise multivariate analyses were also performed, with values of P≤0.05 regarded as statistically significance in each step and included in the model for further analysis. Results for multivariate analyses were reported with the odds ratio, 95% CI, and probability value.

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

Demographic Data and Amyloid Subtypes

Amyloidosis was the AL type in 80, the wild TTR type in 56, the mutant TTR type in 17, and the AA type in 3. Because AA is rare, patients with the AA type were combined into 1 group with the patients with the wild and mutant TTR cases (called other amyloidosis; n=76). Compared with the other amyloid group, the AL group was younger, had fewer male patients, had less atrial fibrillation (AF), were less often receiving anticoagulation therapy, were less often had a history of hypertension, and were more likely to be treated with stem cell transplantation (all P≤0.05; Table 1). There was no significant difference in history of HF, NYHA class, or other variables between the 2 groups listed in Table 1 (all P>0.05).

Table 1. Patient Characteristics in the AL and Other Amyloid Groups

All Patients (n=156)AL (n=80)Other Amyloid (n=76)P
Age, y67±1161±1074±9<0.0001
Male gender, %7765890.0003
Body mass index, kg/m226.1±4.426.4±4.225.6±4.70.35
Heart rate, bpm81±1881±1980±160.51
Systolic BP, mm Hg118±22117±21120±220.29
Diastolic BP, mm Hg70±1471±1369±140.34
AF, %6456720.03
Anticoagulation, %4333540.007
Hypertension, %3930490.02
Diabetes, %5470.43
NYHA class I, %2120220.95
NYHA class II, %353436
NYHA class III, %373934
NYHA class IV, %898
Syncope, %2421260.46
Stem cell transplant, %11210<0.0001
History of thromboembolism, %2224210.69

Indications for TEE

TEE was performed in 57 patients (37%) for AF and/or before direct-current cardioversion in 33 patients (21%) to search for the source for embolism, in 14 patients (9%) to evaluate valvular heart disease, in 12 patients (8%) to rule out endocarditis, and in 6 patients (4%) for other reasons. TEE was performed prospectively in 34 cardiac amyloid patients (22%) after our initial autopsy observations at the discretion of referral hematologists or cardiologists. All TEE studies were performed without major complications or mortality. All patients with TEE except 1 also had TTE studies.

Intracardiac Thrombus

Fifty-eight intracardiac thrombi were identified in 42 of 156 patients (27%) by TEE. Most patients with thrombi (30 patients, 71%) had 1 thrombus, whereas 8 patients (19%) had 2 thrombi, and 4 patients (10%) had 3. Most clots occurred in the LAA (n=32) or in the RA appendage (n=19). Of all of these thrombi detected by TEE, only 3 were detected by TTE. There was a significant difference in the frequency of intracardiac thrombosis between patients with AL amyloidosis and the other types (35% versus 18%; P=0.02). The frequencies for intracardiac thrombosis were 18% for the wild TTR type, 17% for the mutant TTR type, and 33% for the AA type.

The frequency of intracardiac thrombi in those receiving therapeutic anticoagulants was only 13%, much lower than in those not on therapeutic anticoagulant therapy at the time of TEE studies (37%; P=0.001). We further analyzed these patients on chronic anticoagulation with therapeutic international normalized ratio at the time of TEE with stratifying findings according to persistent or permanent AF versus non-AF. Chronic anticoagulation was associated with a significantly lower risk for intracardiac thrombosis (prevalence, 18% [6 of 33] versus 50% [13 of 26] in those who were not on anticoagulation; P=0.01). A similar trend was observed for patients who had no AF, with a respective intracardiac thrombosis prevalence of 0% (0 of 12) in the chronic anticoagulation group versus 20% (8 of 40) in the group with no anticoagulation (P=0.09).

Clinical Characteristics and Thrombosis

Compared with the group without thrombosis, the intracardiac thrombosis group was younger, had more AF, but was less apt to be receiving therapeutic anticoagulation (Table 2). They were also more likely to have AL amyloidosis, a lower systolic BP, and a faster heart rate (all P≤0.05). Similar results were obtained after the exclusion of patients who had AF. The prevalence of intracardiac thrombosis was 0% (0 of 21) in other types of cardiac amyloid patients who had no AF, 23% (8 of 35) in those with AL amyloidosis who had no AF, 25% (14 of 55) in those with other types with AF, and 44% (20 of 45) in AL patients with AF (P=0.0002). Other demographic and clinical variables were similar. Interestingly, the group with thrombosis did not have more frequent documented history of embolism. Furthermore, there was no significant difference in the prevalence of intracardiac thrombosis between those patients studied retrospectively and those studied prospectively (31% versus 25%; P=0.25).

Table 2. Characteristics in Patients With and Without Intracardiac Thrombosis

Thrombus StatusAll PatientsPatients Without AF
All (n=156)With (n=42)Without (n=114)PWith (n=8)Without (n=48)P
Age, y67±1164±1269±110.0256±965±120.04
Male gender, %7764820.0650630.23
Body mass index, kg/m226.1±4.425.2±4.726.4±4.30.1824.5±2.925.6±3.90.55
Hypertension, %3926430.0613410.12
Diabetes, %5260.35070.53
Congestive heart failure, %7988750.3688620.46
NYHA class I, %2112250.3612380.46
NYHA class II, %3536342527
NYHA class III, %3743345029
NYHA class IV, %897136
AF, %6481580.00800
Anticoagulation, %4321510.0010290.05
Syncope, %2429220.3927140.18
AL amyloidosis, %5167460.02100560.01
Stem cell transplant, %1112110.9314200.62
History of thromboembolism, %2224220.9232301.00
Nephrotic syndrome, %1724150.2325270.90
Systolic BP, mm Hg118±22110±20122±220.00291±7122±210.0001
Diastolic BP, mm Hg70±1468±1371±140.1857±1071±150.02
Heart rate, bpm81±1886±1679±180.0187±1478±140.13

TTE and Thrombosis

The group with thrombi had a smaller LV end-diastolic dimension, thicker LV posterior wall, larger RA size, smaller stroke volume and cardiac index, lower LV ejection fraction, worse LV diastolic function, shorter deceleration time, poorer LA mechanical activity (lower A and a′ velocity), and higher E/A and E/e′ than the nonthrombotic group. Furthermore, pulmonary vein peak systolic velocity and A velocity were significantly lower and D/S was higher (all P≤0.05). LA volume index was not statistically different. After exclusion of AF patients, the differences in several TTE parameters between the thrombosis group and the nonthrombosis group were no longer statistically different, although the trends were similar (Table 3).

Table 3. TTE Characteristics in Patients With and Without Intracardiac Thrombosis

Thrombus StatusAll PatientsPatients Without AF
AllWith (n=42)Without (n=114)PWith (n=8)Without (n=48)P
RV indicates right ventricular; RAE, RA enlargement; CI, cardiac index; LVEF, LV ejection fraction; and PV, pulmonary vein.
LV end-diastolic diameter, mm45±843±846±70.0244±945±80.77
LV end-systolic diameter, mm32±833±1032±80.5537±1030±90.09
LV septal thickness, mm15.7±3.916.3±3.615.3±3.90.2015±3.714.9±3.60.95
LV posterior wall thickness, mm14.8±3.315.8±3.214.4±3.20.0214.4±3.113.9±3.10.67
RV free wall thickness, mm8.8±2.59.5±2.98.5±2.30.089.8±2.38.6±2.50.33
LA volume index, mL/m248±2251±1747±230.3843±741±290.90
Normal RA, %155190.040400.20
Mild RAE, %147162918
Moderate RAE, %2629252912
Severe RAE, %4559404230
Stroke volume, mL65±2351±1871±230.000940±1173±260.001
CI, L · m−2 · min−12.6±0.82.3±0.62.8±0.90.00021.9±0.52.9±1.00.008
LVEF, %50.9±14.943.2±13.753.8±14.40.000137.8±1556±150.002
Normal LV diastolic function, %1010.0001020.0001
LV diastolic function 1, %14018035
LV diastolic function 2, %31839035
LV diastolic function 3, %4359384326
LV diastolic function 4, %11334572
Mitral deceleration time, ms181±54159±39188±560.004144±24195±650.09
Mitral E velocity, m/s0.94±0.290.93±0.260.94±0.310.850.90±0.240.96±0.330.70
Mitral A velocity, m/s0.44±0.330.21±0.180.52±0.330.00010.28±0.100.64±0.350.0003
E/A2.7±1.93.9±2.22.3±1.60.0015.0±3.02.1±1.90.004
Mitral annulus s′ velocity, cm/s4.6±1.83.7±1.84.9±1.70.0083.0±1.05.3±1.60.01
Mitral annulus e′ velocity, cm/s4.5±1.83.6±1.44.8±1.90.0023.5±1.05.0±2.00.09
Mitral annulus a′ velocity, cm/s3.0±2.61.8±2.13.6±2.90.012.0±1.04.6±3.10.11
E/e′23±1229±1521±100.00227±1321±110.21
PV systolic velocity, m/s0.35±0.180.28±0.180.38±0.180.0090.22±0.110.46±0.180.007
PV diastolic velocity, m/s0.62±0.200.64±0.180.61±0.200.450.67±0.230.55±0.220.23
PV A velocity, m/s0.21±0.140.13±0.110.23±0.140.0040.10±0.120.27±0.160.03
PV diastolic/systolic ratio2.4±1.83.0±1.72.2±1.80.053.1±0.71.5±1.20.008
RV systolic pressure, mm Hg42.7±12.344.4±11.642.1±12.60.3340±941±140.89

No significant differences existed in intracardiac thrombosis between LV diastolic function grade 2 and grade 1 (0% [0 of 21] versus 7% [3 of 46]; P=0.49). The prevalence of intracardiac thrombosis was 44% for grade 3 or 4. Comparing restrictive filling pattern (grade 3 or 4 diastolic function) with nonrestrictive filling pattern (grade 1 or 2) gave an odds ratio for intracardiac thrombosis of 17.1 (95% CI, 5.9 to 73.8; P<0.0001) by univariate analysis.

TEE and Thrombosis

Those with intracardiac thrombi more frequently had spontaneous echo contrast in the LA, more severe spontaneous echo contrast in both the LA and LAA, and lower LAA emptying velocity compared with the nonthrombotic group. Similar results were obtained after the exclusion of patients who had AF. There was no difference in the degree of atherosclerosis in aorta (Table 4).

Table 4. TEE Characteristics in Subjects With and Without Intracardiac Thrombosis

Thrombus StatusAll PatientsPatients Without AF
All (n=156)With (n=42)Without (n=114)PWith (n=8)Without (n=48)P
LAA emptying velocity, cm/s23±1413±527±150.000111±235±170.03
No LAA spontaneous contrast, %398500.00010710.0001
LAA spontaneous contrast 1, %8011011
LAA spontaneous contrast 2, %17141809
LAA spontaneous contrast 3, %3678221009
No LA spontaneous contrast, %398500.00010730.001
LA spontaneous contrast 1, %901309
LA spontaneous contrast 2, %2946234011
LA spontaneous contrast 3, %234614607
No atherosclerosis, %2619280.6919180.58
Mild atherosclerosis, %4248404542
Moderate atherosclerosis, %2122212826
Severe atherosclerosis, %111112814

Multivariate Analysis and ROC

By multivariate analysis, AF, therapeutic anticoagulation, and lower systolic BP were independently associated with intracardiac thrombosis, whereas there was a borderline trend for AL type in the model when only clinical variables were used (Table 5). For TTE variables, LV diastolic function was the only variable independently associated with intracardiac thrombosis. Comparing restrictive filling with nonrestrictive filling LV diastolic function, we obtained an odds ratio of 10.6 (95% CI, 1.5 to 220.3; P=0.04). For TEE variables, the only independent variable associated with intracardiac thrombosis was LAA emptying velocity. When clinical, TTE, and TEE variables that were statistically significant by the above 3 models were included in the final model, AF, anticoagulation therapy, LV diastolic function, and LAA emptying velocity were independently associated with intracardiac thrombosis. Forward stepwise multivariate analysis was performed, with the inclusion of age, gender, amyloid type, AF, anticoagulation therapy, heart rate, systolic BP, LAA spontaneous contrast, LAA emptying velocity, LV ejection fraction, LV diastolic function, A velocity, and stroke volume as dependent variables. LAA emptying velocity, LV diastology, and AF were independently associated with increased risk for intracardiac thrombosis (P<0.0001, P=0.002, and P=0.04, respectively), whereas systolic BP showed a trend (P=0.12) but anticoagulation therapy was no longer statistically significant (P=0.18).

Table 5. Predictors for Thromboembolism by Multivariate Analyses

Model*PredictorsOR95 % CIP
OR indicates odds ratio.
*Model 1: clinical variables included are amyloid type, AF, anticoagulation, heart rate, and systolic BP (with 10-mm Hg increase). Model 2: TTE variables included are LV diastolic function
(†grade 3 or 4 versus grade 2 or less), LV ejection fraction, stroke volume, and mitral A velocity. Model 3: TEE variables included are LAA emptying velocity
(‡10-cm/s increase in velocity) and spontaneous echo contrast in LA and LAA (semiquantification as 0 to 3 as categorical variables). Model 4: combined model included amyloid type, AF, anticoagulation, systolic BP, LV diastolic function (grade 3 or 4 versus grade 2 or less), and LAA emptying velocity.
1AL type2.30.96–5.60.06
AF6.82.5–20.70.0001
Anticoagulation0.20.07–0.470.0003
Systolic BP0.70.55–0.870.0008
2LV diastolic function10.61.5–220.30.04
3LAA emptying velocity0.230.06–0.640.003
4AF11.81.0–395.20.05
Anticoagulation0.090.01–0.510.006
LV diastolic function15.27.5–>999.90.008
LAA emptying velocity0.10.01–0.320.0001

A receiver-operating characteristics analysis for LAA emptying velocity to predict intracardiac thrombosis was performed. With 15 cm/s as the cutoff, LAA emptying velocity had a sensitivity of 70% and a specificity of 73%. With 23 cm/s as the cutoff, which is comparable to that reported previously,17 the sensitivity increased to 100%, but the specificity decreased to 53%. The area under the curve was 0.81. Using grade 3 as a cutoff value for LV diastolic function had a sensitivity of 92% and a specificity of 59%. The area under the curve was 0.82. Multivariate analysis with AF, LAA emptying velocity, and LV diastolic function as dependent variables increased the area under the curve to 0.85. When further stratifying thrombosis risk on the basis of LAA emptying velocity and LV diastolic function, we found 0% intracardiac thrombosis in patients with LAA emptying velocity >15 cm/s and LV diastolic function grade ≤2, 26% in patients with either LAA emptying velocity ≤15 cm/s or LV diastolic grade 3 or 4, and 67% in patients who had both (P<0.0001). Similar results were obtained after further stratification by AF. The respective prevalence of intracardiac thrombosis was 0%, 15%, and 50% for non-AF patients (P=0.02) and 0%, 32%, and 72% for AF patients (P=0.002), respectively.

Twenty-three patients underwent TEE-guided cardioversion. Four patients failed cardioversion after multiple trials; 19 patients were initially successfully converted to sinus rhythm. Seven patients did not have follow-up. For the remaining 12 patients, the median time to recurrent AF was 2 months (25% to 75% in the quartile of 0.5 to 11 months). Only 3 patients remained in sinus rhythm for >12 months. Symptomatic improvement was noted in 5 patients after cardioversion.

Discussion

Our data from a large TEE study of patients with different types of cardiac amyloidosis confirm our previous autopsy study describing a high frequency of intracardiac thrombosis. We were able to identify that AF, poor LV diastolic function, and LA mechanical dysfunction as indicated by a low LAA emptying velocity were independent predictors of intracardiac thrombosis. Furthermore, it appears from our data that therapeutic anticoagulation therapy protects against intracardiac thrombosis. Low systolic BP also was independently associated with increased risk for intracardiac thrombosis, whereas the AL type of cardiac amyloidosis had a borderline trend when only clinical variables were considered for multivariates analyses.

Intracardiac Thrombosis in Cardiac Amyloidosis

Our TEE study confirms the observations of Roberts and Waller4 and our prior autopsy study that showed a high prevalence of intracardiac thrombosis in cardiac amyloidosis. AL type was associated with a 35% prevalence of intracardiac thrombosis compared with 18% in the other amyloid groups despite the fact that the other amyloid groups were older and more frequently had AF. The prevalence of intracardiac thrombosis in TTR-related amyloid (either wild or mutant TTR) is comparable to that reported in the AF population without anticoagulation.20–22 In comparison, AL patients have a higher prevalence of intracardiac thrombosis than that reported in the general nonamyloid AF population.20–22 In fact, the prevalence of intracardiac thrombosis is comparable to that reported in patients with severe mitral valve stenosis with AF, which had the highest prevalence of intracardiac thrombosis (33%).23

Clinical Variables and Intracardiac Thrombosis

Several studies have shown that advanced age, HF, diabetes, and hypertension are risk factors for thromboembolism and thus presumably increased risk for intracardiac thrombi in nonamyloid AF patients.24,25 In our present study, AF and low systolic BP were independently associated with thrombosis. A low systolic BP may reflect a low cardiac output status and severe amyloid heart disease with cardiac decompensation. Most important, we identified that therapeutic anticoagulation was significantly associated with a decreased risk for intracardiac thrombosis by both univariate and multivariate analyses.

Clinical HF and NYHA class were not significantly different in patients with or without thrombosis as observed in prior study.8 Because many patients were elderly with multiple comorbidities, the clinical diagnosis of HF or NYHA class is a subjective indicator of overall well-being and may not always be accurate for grading the severity of HF. Moreover, other traditional risk factors for thromboembolism such as age, diabetes, and hypertension were not significantly associated with intracardiac thrombosis. We speculated that risk factors with only modest effect could not be detected in this special study population in which overwhelming effects from AL type, AF, and anticoagulation therapy are likely to have masked their modest effects.

TTE, TEE Characteristics, and Intracardiac Thrombosis

Univariate analysis showed that the group with thrombi had evidence of more advanced cardiac amyloid deposition as indicated by a smaller LV end-diastolic dimension, thicker LV wall, poorer LV systolic and diastolic function, higher LV filling pressure estimated by E/e′, and less LA mechanical activity than the group without thrombi. Furthermore, LA and LAA spontaneous contrast were present more often and were more pronounced in those with intracardiac thrombi. Similar TTE and TEE results were obtained after exclusion of AF patients. Therefore, AF plays only a partial role for intracardiac thrombosis. Multivariate analyses showed that only 2 echocardiography variables, LV diastolic dysfunction and low LAA emptying velocity, were, in addition to AF, independently associated with intracardiac thrombosis. The observation was not surprising because LV diastolic function is graded on the basis of several TTE features, including mitral inflow profile and mitral annulus tissue Doppler, whereas LAA emptying velocity directly reflects LAA mechanical function.

Our present and prior studies support the hypothesis that the combination of systolic and diastolic ventricular dysfunction and chronic amyloid infiltrate in the atria leads to atrial mechanical dysfunction,15,26 atrial enlargement, and blood stasis.27,28 Such atrial electrical-mechanical dissociation at least partially explains why some cardiac amyloid patients developed atrial thrombosis while in sinus rhythm.15,26,29 It is possible that endomyocardial damage and endothelial dysfunction from amyloid depositions and hypercoagulability may also contribute, although the data to support these hypotheses have been limited.7,30–32

Anticoagulation and Intracardiac Thrombosis

We identified that therapeutic anticoagulation therapy at the time of TEE was associated with a significantly lower risk for intracardiac thrombosis. Thus, effective anticoagulation might reduce thromboembolism, which is a significant contributor to mortality in cardiac amyloid patients.8 However, anticoagulation may exacerbate the hemorrhagic tendency, which is a well-known complication of amyloidosis, because of fragile blood vessel walls secondary to amyloid deposition and the coexisting coagulopathy in such patients.2,32 In our prior autopsy series, 3 cardiac amyloid patients died of massive gastrointestinal bleeding.8 Therefore, the potential benefits of anticoagulation must be carefully weighed against possible hemorrhagic complications before anticoagulation is initiated.

Further Directions

A recent study suggests that chemotherapy in AL patients with cardiac involvement results in a clinical improvement despite an unchanged TTE appearance.33 Improvement may be due to the abolition of the production of new light chains, which are toxic to myocardium by increasing oxidant stress and causing diastolic dysfunction.34,35 Furthermore, there has been report of echocardiographic improvement and decreased amyloid accumulation by 99mTc-PYP scintigram after chemotherapy and stem cell transplantation.36 Therefore, it is possible that early detection of amyloidosis, vigilant screening for intracardiac thrombosis with early anticoagulation, and more aggressive treatment of the underlying plasma dyscrasia might improve the prognosis.3,28,37,38 However, a prospective study to specifically address the issue of intracardiac thrombosis and anticoagulation is needed before a definite recommendation can be made.

Study Strengths and Limitations

We evaluated a large series of cardiac amyloidosis in which the majority had cardiac biopsy. Furthermore, all patients except 1 had both TEE and TTE studies performed. We routinely evaluate diastolic function in all TTE studies performed in our laboratory. However, this study has several limitations. First, the high frequency of intracardiac thrombosis could be partially related to referral bias because most TEE studies were performed as a result of the presence of AF or in an attempt to discern a source for embolization. It has been reported that the prevalence of AF in AL and familial amyloidosis was 19% to 45%.8,39–41 Thus, our patients had more prevalent AF and may have had more advanced cardiac amyloid involvement as indicated by TTE. Our observation may not apply to early-stage amyloidosis or the general cardiac amyloidosis population. Most likely, the prevalence of intracardiac thrombosis would be much lower in early-stage cardiac amyloidosis because of better cardiac diastolic function, preserved LA/LAA contractility, and less AF. Interestingly, however, there was no significant difference in the prevalence of thrombosis between the groups evaluated retrospectively and those evaluated prospectively, although the prospective group was of modest size (n=34). Second, the frequency of thrombosis and embolism could have been underestimated because small emboli may be clinically silent and may have been overlooked, especially in the RA appendage. Finally, although our study is the only large series study on intracardiac thrombosis in living cardiac amyloid patients, our sample size of 156 subjects may have lacked the power to detect factors that have only modest effects on intracardiac thrombosis.

Conclusions

This study demonstrated a high frequency of intracardiac thrombosis in patients with cardiac amyloidosis, especially in the AL type. AF, poor LV diastolic function, and poor atrial mechanical function were independently associated with increased risk for intracardiac thrombosis. Importantly, therapeutic anticoagulation therapy appeared protective against intracardiac thrombosis. Early screening for intracardiac thrombosis by TEE, especially in the high-risk patient as identified in our study, may be indicated. If intracardiac thrombosis or severe LAA mechanical dysfunction (especially with coexisting restrictive LV filling) is detected, anticoagulation should be carefully considered.

We greatly appreciate the Division of Biomedical Statistics and Informatics at Mayo Clinic for the assistance on statistical analysis.

Disclosures

None.

Footnotes

Correspondence to DaLi Feng, MD, or Kyle W. Klarich, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail or [email protected]

References

  • 1 Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O'Fallon WM, Kurland LT. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992; 79: 1817–1822.CrossrefMedlineGoogle Scholar
  • 2 Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997; 337: 898–909.CrossrefMedlineGoogle Scholar
  • 3 Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005; 112: 2047–2060.LinkGoogle Scholar
  • 4 Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac dysfunction: analysis of 54 necropsy patients. Am J Cardiol. 1983; 52: 137–146.CrossrefMedlineGoogle Scholar
  • 5 Skinner M, Anderson J, Simms R, Falk R, Wang M, Libbey C, Jones LA, Cohen AS. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 1996; 100: 290–298.CrossrefMedlineGoogle Scholar
  • 6 Kyle RA, Greipp PR. Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc. 1983; 58: 665–683.MedlineGoogle Scholar
  • 7 Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine. 2003; 82: 291–298.CrossrefMedlineGoogle Scholar
  • 8 Feng D, Edwards WD, Oh JK, Chandrasekaran K, Grogan M, Martinez MW, Syed II, Hughes DA, Lust JA, Jaffe AS, Gertz MA, Klarich KW. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation. 2007; 116: 2420–2426.LinkGoogle Scholar
  • 9 Botker HE, Rasmussen OB. Recurrent cerebral embolism in cardiac amyloidosis. Int J Cardiol. 1986; 13: 81–83.CrossrefMedlineGoogle Scholar
  • 10 Browne RS, Schneiderman H, Kayani N, Radford MJ, Hager WD. Amyloid heart disease manifested by systemic arterial thromboemboli. Chest. 1992; 102: 304–307.CrossrefMedlineGoogle Scholar
  • 11 Cools FJ, Kockx MM, Boeckxstaens GE, Heuvel PV, Cuykens JJ. Primary systemic amyloidosis complicated by massive thrombosis. Chest. 1996; 110: 282–284.CrossrefMedlineGoogle Scholar
  • 12 Santarone M, Corrado G, Tagliagambe LM. Images in cardiology: biatrial thrombosis in cardiac amyloidosis. Heart. 1999; 81: 302.CrossrefMedlineGoogle Scholar
  • 13 Santarone M, Corrado G, Tagliagambe LM, Manzillo GF, Tadeo G, Spata M, Longhi M. Atrial thrombosis in cardiac amyloidosis: diagnostic contribution of transesophageal echocardiography. J Am Soc Echocardiogr. 1999; 12: 533–536.CrossrefMedlineGoogle Scholar
  • 14 Willens HJ, Levy R, Kessler KM. Thromboembolic complications in cardiac amyloidosis detected by transesophageal echocardiography. Am Heart J. 1995; 129: 405–406.CrossrefMedlineGoogle Scholar
  • 15 Dubrey S, Pollak A, Skinner M, Falk RH. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J. 1995; 74: 541–544.CrossrefMedlineGoogle Scholar
  • 16 Oh JK. The Echo Manual. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999.Google Scholar
  • 17 Mugge A, Kuhn H, Nikutta P, Grote J, Lopez JA, Daniel WG. Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: identification of a subgroup of patients at increased embolic risk. J Am Coll Cardiol. 1994; 23: 599–607.CrossrefMedlineGoogle Scholar
  • 18 Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke: the French Study of Aortic Plaques in Stroke Group. N Engl J Med. 1996; 334: 1216–1221.CrossrefMedlineGoogle Scholar
  • 19 Amarenco P, Duyckaerts C, Tzourio C, Henin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992; 326: 221–225.CrossrefMedlineGoogle Scholar
  • 20 Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol. 1995; 25: 1354–1361.CrossrefMedlineGoogle Scholar
  • 21 Weigner MJ, Thomas LR, Patel U, Schwartz JG, Burger AJ, Douglas PS, Silverman DI, Manning WJ. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med. 2001; 110: 694–702.CrossrefMedlineGoogle Scholar
  • 22 Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001; 344: 1411–1420.CrossrefMedlineGoogle Scholar
  • 23 Srimannarayana J, Varma RS, Satheesh S, Anilkumar R, Balachander J. Prevalence of left atrial thrombus in rheumatic mitral stenosis with atrial fibrillation and its response to anticoagulation: a transesophageal echocardiographic study. Indian Heart J. 2003; 55: 358–361.MedlineGoogle Scholar
  • 24 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154: 1449–1457.CrossrefMedlineGoogle Scholar
  • 25 Predictors of thromboembolism in atrial fibrillation, I: clinical features of patients at risk: the Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med. 1992; 116: 1–5.CrossrefMedlineGoogle Scholar
  • 26 Plehn JF, Southworth J, Cornwell GG 3rd. Brief report: atrial systolic failure in primary amyloidosis. N Engl J Med. 1992; 327: 1570–1573.CrossrefMedlineGoogle Scholar
  • 27 Murphy L, Falk RH. Left atrial kinetic energy in AL amyloidosis: can it detect early dysfunction? Am J Cardiol. 2000; 86: 244–246.CrossrefMedlineGoogle Scholar
  • 28 Modesto KM, Dispenzieri A, Cauduro SA, Lacy M, Khandheria BK, Pellikka PA, Belohlavek M, Seward JB, Kyle R, Tajik AJ, Gertz M, Abraham TP. Left atrial myopathy in cardiac amyloidosis: implications of novel echocardiographic techniques. Eur Heart J. 2005; 26: 173–179.CrossrefMedlineGoogle Scholar
  • 29 Stables RH, Ormerod OJ. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Heart. 1996; 75: 426.Google Scholar
  • 30 Berghoff M, Kathpal M, Khan F, Skinner M, Falk R, Freeman R. Endothelial dysfunction precedes C-fiber abnormalities in primary (AL) amyloidosis. Ann Neurol. 2003; 53: 725–730.CrossrefMedlineGoogle Scholar
  • 31 Inoue H, Saito I, Nakazawa R, Mukaida N, Matsushima K, Azuma N, Suzuki M, Miyasaka N. Expression of inflammatory cytokines and adhesion molecules in haemodialysis-associated amyloidosis. Nephrol Dial Transplant. 1995; 10: 2077–2082.MedlineGoogle Scholar
  • 32 Yood RA, Skinner M, Rubinow A, Talarico L, Cohen AS. Bleeding manifestations in 100 patients with amyloidosis. JAMA. 1983; 249: 1322–1324.CrossrefMedlineGoogle Scholar
  • 33 Dubrey S, Mendes L, Skinner M, Falk RH. Resolution of heart failure in patients with AL amyloidosis. Ann Intern Med. 1996; 125: 481–484.CrossrefMedlineGoogle Scholar
  • 34 Liao R, Jain M, Teller P, Connors LH, Ngoy S, Skinner M, Falk RH, Apstein CS. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. 2001; 104: 1594–1597.LinkGoogle Scholar
  • 35 Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res. 2004; 94: 1008–1010.LinkGoogle Scholar
  • 36 Yagi S, Akaike M, Ozaki S, Moriya C, Takeuchi K, Hara T, Fujimura M, Sumitomo Y, Iwase T, Ikeda Y, Aihara K, Kimura T, Nishiuchi T, Abe M, Matsumoto T. Improvement of cardiac diastolic function and prognosis after autologous peripheral blood stem cell transplantation in AL cardiac amyloidosis. Intern Med. 2007; 46: 1705–1710.CrossrefMedlineGoogle Scholar
  • 37 Dubrey SW, Burke MM, Hawkins PN, Banner NR. Cardiac transplantation for amyloid heart disease: the United Kingdom experience. J Heart Lung Transplant. 2004; 23: 1142–1153.CrossrefMedlineGoogle Scholar
  • 38 Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003; 349: 583–596.CrossrefMedlineGoogle Scholar
  • 39 Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol. 2005; 95: 535–537.CrossrefMedlineGoogle Scholar
  • 40 Rahman JE, Helou EF, Gelzer-Bell R, Thompson RE, Kuo C, Rodriguez ER, Hare JM, Baughman KL, Kasper EK. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004; 43: 410–415.CrossrefMedlineGoogle Scholar
  • 41 Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997; 336: 466–473.CrossrefMedlineGoogle Scholar
circulationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & Wilkins
CLINICAL PERSPECTIVE12052009

We recently reported a high prevalence of intracardiac thrombi at autopsy in patients with cardiac amyloid. We also found that intracardiac thrombi resulted in embolism and significant mortality, which was often unappreciated clinically. Thus far, neither the prevalence nor the effect of anticoagulation on intracardiac thrombi has been evaluated antemortem. We therefore studied transesophageal echocardiograms of cardiac amyloid patients at the Mayo Clinic. The prevalence of intracardiac thrombosis, clinical and transthoracic/transesophageal echocardiographic risks for intracardiac thrombosis, and effect of anticoagulation were investigated in 156 patients with cardiac amyloidosis who underwent transesophageal echocardiograms. Primary amyloid (AL) was present in 80 patients, and other types of amyloid were present in 76 patients, including 56 with the wild transthyretin type, 17 with the mutant transthyretin type, and 3 with a secondary type. There was a high prevalence of intracardiac thrombi (42 of 156 patients, 27%). Patients with AL amyloid had thrombi more often than the other types (35% versus 18%; P=0.02). Multivariate analysis showed that atrial fibrillation, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis; anticoagulation was associated with a significantly decreased risk. We suggest that clinicians consider evaluation of intracardiac thrombosis in patients with cardiac amyloid, especially in patients with high-risk features such as atrial fibrillation, left ventricular diastolic dysfunction, and atrial mechanical dysfunction. Timely screening may allow earlier detection. The risks and benefits of anticoagulation can then be carefully considered.

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.