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European Journal of Heart Failure 2007 9(6-7):617-624; doi:10.1016/j.ejheart.2007.01.012
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© 2007 European Society of Cardiology

Non-invasive predictors of survival in cardiac amyloidosis

Arnt V. Kristena, Jolanta B. Perzb, Stefan O. Schonlandb, Ute Hegenbartb, Philipp A. Schnabelc, Joern H. Kristend, Hartmut Goldschmidtb, Hugo A. Katusa and Thomas J. Denglera,*

a Department of Cardiology, Angiology, and Respiratory Medicine, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
b Department of Haematology, Oncology, and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
c Department of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany
d Institute of Management in Healthcare and Welfare, Steinbeis University Berlin, Neufeldstr. 6, D-76456 Kuppenheim, Germany

* Corresponding author. Tel: +49 6221 568611; fax: +49 6221 565515. E-mail address: Thomas_Dengler{at}med.uni-heidelberg.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: Patients with cardiac amyloidosis (CA) have increased mortality.

Aims: Clinical, electrocardiographic, and echocardiographic parameters were assessed for risk-stratification of CA.

Methods and results: CA was confirmed by endomyocardial biopsy in 59 patients (54.8±1.2 years) with light-chain (n = 43) or transthyretin amyloidosis (n = 16). Six patients without CA served as controls (NCA). Clinical symptoms, electrocardiographic, and echocardiographic parameters were analyzed for prognostic significance. Of the patients with light-chain amyloidosis, 14 died and 2 underwent heart transplantation. 1-/3-year survival was 68%/63%. Survival depended on left ventricular function (LV-EF), LV mass, radius/wall thickness, septum thickness, low voltage pattern (LVP), conduction delay, NYHA class, and stem cell transplantation. A multivariate model only contained LV-EF and LVP; the beneficial effect of stem cell transplantation was cancelled out as this treatment was withheld in patients with highest cardiac risk. Survival was most limited if both risk factors occurred. Cardiac involvement in transthyretin amyloidosis showed better survival (2 deaths, 1-/3-year survival 91%/83%). Analysis of prognostic risk factor utility in all amyloid patients (light-chain and transthyretin) again revealed LVP and LV-EF, and aetiology of amyloidosis as independent survival parameters.

Conclusion: Prognosis of CA is poor, but aetiology of amyloid, LVP, and LV-EF allows identification of patients at highest risk of death, who may require individual treatment approaches (heart transplantation prior to causative therapy).

Key Words: Cardiac amyloidosis • Echocardiography • Electrocardiography • Endomyocardial biopsy • Risk assessment • Survival

Received September 15, 2006; Revised December 2, 2006; Accepted January 31, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Amyloidosis is a rare disorder of protein conformation and metabolism that results in tissue deposition of insoluble fibrils. Increasing amyloid mass causes organ dysfunction and finally death. Usually, systemic amyloid deposits are formed by immunoglobulin light-chains or mutant proteins, e.g. transthyretin or apolipoprotein AI, and may involve various organs [1]. Heart involvement is observed in about 50% of patients with light-chain amyloidosis [2] and in some specific mutations in transthyretin amyloidosis and is by far the most relevant factor for poor prognosis of these patients [3-6]. Median survival in patients with symptoms of congestive heart failure is about six months [7]. Possible treatment options are high-dose melphalan chemotherapy with autologous stem cell support for light-chain amyloidosis or orthotopic liver transplantation for transthyretin amyloidosis, but the feasibility depends on the extent of cardiac involvement and further organ damage caused by amyloid. To identify patients at highest risk for mortality non-invasive parameters for risk are urgently needed. In the present study clinical data and parameters of electrocardiography and echocardiography at the time of histological diagnosis of CA were assessed for their prognostic utility.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
59 patients (38 males, 21 females, median age 54.8±1.2 years, range 32-78 years, New York Heart Association functional heart failure class (NYHA) 2.3±0.1) with histologically proven CA, ascertained in a university tertiary referral centre between January 1998 and March 2005, were studied. Diagnosis of systemic amyloidosis was based on monoclonal gammopathy by immunoelectrophoresis, immunofixation on serum and urine, or mutant transthyretin gene as potential risk factors for amyloid disease, and confirmed by positive congo red staining of any biopsy (periumbilical fat aspiration, rectum, target organ). Amyloid type was assessed by immunohistology [8] (Fig. 1). CA was caused by immunoglobulin light-chain amyloidosis (n = 43) or transthyretin amyloidosis (transthyretin gene mutation: Asp18Glu (n = 1), Val20Ile (n = 4), Met30Val (n = 4), Phe33Val (n = 1), Ser50Arg (n = 4), Leu58His (n = 1), Ile107Val (n = 1)). In light-chain amyloidosis, high-dose melphalan chemotherapy and autologous stem cell support was performed in patients with age <70 years, NYHA<III, WHO performance score<3 (except for polyneuropathy), and systolic blood pressure >90 mmHg because of the increased risk of treatment-related mortality [9]. Clinical data, electrocardiography, and echocardiography at the time of histological diagnosis of CA were retrospectively reviewed for impact on survival. The patients were divided into survivors (SU) and non-SU; non-SU were defined as patients who died during follow-up due to any cause or who underwent urgent heart transplantation. In 6 further patients with systemic amyloidosis, endomyocardial biopsy was negative for amyloid. This small patient group served as a control for survival curves.


Figure 01
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  		Fig. 1 Flow-chart of diagnostic evaluation in systemic amyloidosis.

 
A review of medical records was performed by a team of physicians blinded to the endomyocardial biopsy findings. Demographic data, NYHA functional class, electrocardiography findings, and echocardiography results performed at the time of biopsy were recorded. Electrocardiography was analyzed for heart rate, PQ interval, ventricular amplitude, corrected QT interval as [QT/(60/heart rate)0.5], primary rhythm, conduction abnormalities, i.e. (in-) complete right or left bundle branch block, (pseudo-) infarction pattern, and low voltage pattern (LVP). Because of abnormal ventricular depolarisation in left bundle branch block these patients were excluded from QT interval analysis (n = 1). Pseudo-infarction pattern was defined as pathologic Q waves (1/4 R amplitude) on the ECG, but no coronary artery disease by angiography. LVP was considered present if no QRS complex amplitude was greater than 0.5 mV in any limb lead or the sum of the S wave amplitude in lead V1 and R wave amplitude in lead V5-6 was less than 1.5 mV [10,11]. Transthoracic echocardiograms were analyzed for enddiastolic left ventricular cavity diameter (LVEDD), endsystolic cavity diameter (LVESD), diastolic interventricular septal thickness (IVS), diastolic posterior wall thickness, left atrial size, pericardial effusion, left ventricular systolic ejection fraction (LV-EF), left ventricular diastolic dysfunction (i.e. E/A-ratio), and granular sparkling of the myocardium by visual inspection. LV-EF was considered impaired at <45% by semi-quantitative assessment. Left ventricular mass was calculated by the modified volume-corrected cube formula of the American Society of Echocardiography [12,13] and indexed to body surface area (left ventricular mass index). Fractional shortening [(LVEDD–LVESD)/LVEDDx100] was used to measure systolic performance.

2.1. Endomyocardial biopsy
Endomyocardial biopsy was obtained in a standard fashion using right femoral venous (n = 29) or arterial (n = 30) approach. A minimum of five biopsies was taken from each patient. Biopsies were immediately fixed in buffered formaldehyde solution (4%) and embedded in paraffin within one day after fixation. Sections of 6 µm were performed. These sections were analyzed with standard hematoxylin-eosin and Congo-red staining for visualization of amyloid deposition. All biopsies were examined by a single, experienced pathologist (P. A. S.) who was blinded to all other study data.

2.2. Statistical analysis
Continuous data were expressed as mean±standard error of mean and compared with the two-tailed Mann Whitney test. Categorical variables were expressed as absolute number and percentages and analyzed using {chi}2 test. p<0.05 was considered statistically significant. Survival was measured from the time of endomyocardial biopsy (and time of diagnosis of amyloid disease). Risk factors for survival were evaluated by both, univariate as well as multivariate analysis using Cox proportional hazards analysis. Survival data were summarized using Kaplan-Meier survival curves. In multivariate analyses, the association between electrocardiography, echocardiography, aetiology of amyloidosis, NYHA, sex, age, and mortality was examined. Analyzing the subgroup of light-chain amyloidosis aetiology of amyloidosis was replaced by autologous stem cell support. The main models were adjusted for variables that were associated with mortality in univariate analyses at the p<0.20 level. The multivariate Cox proportional hazard analyses were performed as stepwise regressions with forward elimination starting with the one expected to have the highest influence. In both analyses the new variable is excluded from the model if not significant (p>0.05). Statistical analyses were performed by J. H. K. using MatLab (Version 7; Release 14; Service Pack 3).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Demographic, clinical, and overall survival data
The baseline characteristics of survivors (SU) and non-survivors (non-SU) are shown in detail in Table 1. Relevant coronary artery disease was excluded in all patients by coronary angiography. No patient had histological signs of lymphatic myocarditis in endomyocardial biopsy. SU and non-SU did not differ in age, body surface area, body mass index, and numbers of involved organs at time of EMB, but non-SU were significantly more symptomatic compared to SU (Table 1). In the overall population (n = 59), 15 patients (25.4%) died and three underwent heart transplantation (5.1%), mean time follow-up of survival was 880±110 days (range 1-3102 days). By Kaplan-Meier analysis starting at time of cardiac biopsy these data are equivalent to transplant-free 1-year survival and 3-year survival rates of 75% and 71%, respectively. Practically all deaths occurred during the first year after diagnosis of CA by endomyocardial biopsy (Fig. 2A). When starting the survival analysis at the time of first amyloid diagnosis in any organ, survival curves were essentially identical (Fig. 2B).


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  		Table 1 Baseline characteristics

 


Figure 02
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  		Fig. 2 Comparative analysis of survival of patients with cardiac involvement due to light-chain (AL) and transthyretin, (ATTR) amyloidosis as well as patients with systemic amyloidosis but no cardiac involvement (NCA) after A) diagnosis of cardiac involvement by endomyocardial biopsy (EMB) as well as B) first diagnosis of systemic amyloidosis. | = censored events.

 
3.2. Cardiac light-chain amyloid — survival
Of the 43 patients with light-chain amyloidosis and cardiac involvement 14 (37%) patients died and in two patients (5%) heart transplantation was performed; mean survival time in the non-SU was 257±104 days (range 1-1561 days). In this subgroup 1-year and 3-year survival rates were 68% and 63%, respectively (Fig. 2). In 23 (53%) of the light-chain amyloid patients, high-dose chemotherapy and autologous stem cell support was performed, only 4 of these patients died during follow-up (17%), one patient underwent urgent heart transplantation prior to autologous stem cell transplantation (day 93). In contrast, of the remaining 20 patients deemed ineligible for high-dose chemotherapy and stem cell transplantation 10 patients (50%) died during follow-up, suggesting a marked improvement of long-term survival (37%) by receiving high-dose chemotherapy and stem cell transplantation in patients with light-chain amyloidosis and cardiac involvement (Fig. 3).


Figure 03
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  		Fig. 3 Survival of patients with light-chain amyloidosis after diagnosis of cardiac involvement by endomyocardial biopsy (EMB) dependent on high-dose melphalan chemotherapy and stem cell support (SCT). | = censored events.

 
3.3. Transthyretin cardiac amyloid — survival
Of the 16 patients with transthyretin amyloidosis and cardiac involvement, one (6%) patient died and one (6%) patient underwent urgent heart transplantation. Four patients underwent orthotopic liver transplantation. Prognosis was significantly worse with immunoglobulin light-chain amyloidosis compared to transthyretin amyloidosis in the presence of cardiac involvement (p = 0.045, Fig. 2A and B). For transthyretin amyloidosis 1- and 3-year survival rates were 91% and 83%, respectively.

3.4. Non-invasive cardiac functional parameters
Table 2 summarizes baseline results of electrocardiography in SU and non-SU. Non-SU had significantly increased PQ interval, QRS complex duration, and corrected QT interval as compared to SU. Furthermore, precordial, but not limb lead QRS amplitude was significantly decreased in non-SU. On echocardiography a marked increase of IVS and posterior wall thickness as well as decreased LV-EF was found in non-SU (Table 3). LV myocardial mass did not differ between the groups.


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  		Table 2 Baseline electrocardiography results

 


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  		Table 3 Baseline echocardiography results

 
3.5. Cardiac light-chain amyloid — prognosis
In the larger group of patients with CA due to light-chain amyloid, univariate analysis showed significant associations with prognosis for impaired LV-EF (Fig. 4A), LVP (Fig. 4B), IVS (p = 0.01), NYHA functional class (p = 0.002), intraventricular conduction delay (p = 0.03), left ventricular mass index (p = 0.04), and high-dose chemotherapy with autologous stem cell support (p = 0.007), but not for sex, age, heart rate, PQ interval, corrected QT interval, QRS duration (p = 0.20), pseudo-infarction pattern, left atrial size, LV diameter, fractional shortening, granular sparkling, and diastolic dysfunction. Multivariate analysis identified only LVP (p = 0.043, 95% CI: 0.04-0.87) and LV-EF (p = 0.007, 95% CI: 0.01-0.45) as independent parameters for survival, but not autologous stem cell support (p = 0.865), or NYHA class (p = 0.2) or septal wall thickness (p = 0.16). These two risk factors were present significantly more often in non-SU than in SU (1.1±0.2 risk factors/patient vs. 0.5±0.1 risk factors/patient, p<0.01). When separating the patients into 4 groups based on the presence of risk factors emerging from the multivariate analysis (no risk factor, LVP only, impaired LV-EF only, and both risk factors present), Kaplan-Meier survival analysis showed an excellent risk discrimination parallel to the number of risk factors present with extremely bad prognosis in patients with LVP and LV-EF.


Figure 04
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  		Fig. 4 Association of clinical parameters with survival in patients with light-chain cardiac amyloidosis after diagnosis of cardiac involvement by endomyocardial biopsy (EMB). A) Normal (≥ 45%) vs. impaired (<45%) LV function (LV-EF), and B) presence vs. absence of low voltage pattern (LVP). | = censored events.

 
3.6. All cardiac amyloid patients — prognosis
When extending the analysis to patients with cardiac involvement of transthyretin amyloidosis, a significant association with prognosis was shown for LV-EF (Fig. 5A), presence of LVP (Fig. 5B), aetiology of amyloid (p = 0.0484), IVS (p = 0.0018), NYHA (p = 0.0060), intraventricular conduction delay (p = 0.0378), and left ventricular mass index (p = 0.0051) by univariate analysis. Multivariate analysis again showed only LV-EF (p = 0.0083, 95% CI: 0.02-0.53), LVP (p = 0.0328, 95% CI: 0.04-0.87), and in addition aetiology of amyloidosis (p = 0.0484, 95% CI: 0.02-0.97) as independent variables. Again, NYHA symptom class (p = 0.25) or septal wall thickness (p = 0.22) was not a significant risk predictor. Due to the small number of patients and deaths in the transthyretin amyloid group, a separate subgroup analysis was not performed.


Figure 05
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  		Fig. 5 Association of clinical parameters with survival in patients with cardiac amyloidosis (light-chain and transthyretin forms) after diagnosis of cardiac involvement by endomyocardial biopsy (EMB). A) Normal (≥45%) vs. impaired (<45%) LV function (LV-EF), and B) presence vs. absence of low voltage pattern (LVP). | = censored events.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Cardiac involvement is common in patients with systemic amyloidosis and is characterized by poor prognosis and limited treatment modalities. New treatment strategies including heart transplantation prior to high-dose chemotherapy and autologous stem cell support require identification of patients at highest risk for death [14].

The aim of the present study was to evaluate parameters for non-invasive risk assessment of patients with CA based on electrocardiography and echocardiography. The current data demonstrate that in patients with biopsy-proven CA 1) survival is worse in light-chain than in transthyretin amyloidosis, but not as dismal as previously reported, 2) practically all deaths from light-chain amyloid occurred within the first year after diagnosis of cardiac involvement, deaths from transthyretin amyloidosis occurred later in progression, 3) despite superior prognosis in transthyretin than light-chain amyloid the identical set of non-invasive parameters (impaired LV-EF and LVP) predict prognosis, and 4) eligibility for high-dose chemotherapy and stem cell transplantation in light-chain amyloid confers an increase in the likelihood of long-term survival.

4.1. Survival in cardiac light-chain amyloidosis
In the present study, 1- and 3-year survival of the light-chain amyloid patients (68% and 63%) was worse than in heart failure of usual aetiology with comparable symptomatic severity (mean NYHA class of all amyloid patients 2.2±0.1). Reported survival rates in the placebo groups of the COPERNICUS [15] study were 81.5% and in the CIBIS II [16] study 82.7%. However, survival rates in our study were markedly better than in the study by Kyle and Greipp [17], who reported a 1-year survival of approximately 30%. Interestingly, in our study almost all deaths occurred within the first 12 months after diagnosis, with a plateau of survival in the following years. Deaths were mostly in patients not eligible for high-dose chemotherapy and autologous stem cell transplantation indicating a marked beneficial effect of this potentially curative treatment approach on survival. Patients succumbing rapidly to cardiac amyloid disease may also represent a subgroup at high risk for death based on the amyloid distribution [18] or velocity of protein deposition in the heart [19]. High-dose melphalan chemotherapy and autologous stem cell transplantation is generally accepted as a therapeutic approach to improve survival [5,20,21] and quality of life [22] in light-chain amyloidosis. Patients with advanced cardiac involvement, as indicated by impaired left ventricular systolic function, have so far generally been considered ineligible for autologous stem cell transplantation [5,6,23], explaining to a large extent the particularly impaired survival in this subgroup of patients. In the present study, high-dose chemotherapy and stem cell transplantation was not of prognostic impact by the multivariate analysis, most likely due to the cancellation of an independent effect by substantial overlap with high cardiac risk. The velocity of increased therapy-related mortality of high-dose chemotherapy and stem cell transplantation with cardiac failure underscored the early therapy-related death of one of the patients (50%) with impaired LV function in the high-dose chemotherapy group. Consequently, identification of such patients at high risk of early death becomes a major goal to implement advanced individual treatment strategies including heart transplantation to enable subsequent curative high-dose chemotherapy [14].

4.2. Risk prediction in light-chain amyloidosis with cardiac involvement
In the present study, for the first time a high risk group of patients with cardiac amyloidosis was identified by a small set of non-invasive functional cardiac parameters (LVP, LV-EF) with excellent stepwise risk discrimination, culminating in an extremely poor prognosis in patients presenting with both, markedly impaired LV-EF and LVP. An association between decreased LV-EF in patients with CA and diminished survival has been reported by several authors [3,24]. Probably, even better prediction of prognosis may be possible by quantitative assessment of LV-EF using cardiac magnetic resonance imaging. Although LVP had a weaker association with survival compared to impaired LV-EF it was present in more patients. This is an important finding and of clinical relevance, since both parameters are easy to perform, of low cost, and widely available. However, no data have previously been reported on prognostic efficacy of electrocardiography, even though LVP is a common finding in CA [11] and, in the presence of echocardiographic left ventricular hypertrophy, characteristic of amyloid heart disease [25].

Clinical classification of congestive heart failure according to NYHA functional class is a well established integrative parameter for limitation of exercise capacity. Almost all patients in the present study (38/43) had cardiac symptoms (NYHA 2.4±0.1), but only 14 of them died. In our prognostic model heart failure NYHA symptom class as a risk factor is superseded by quantitative and objective parameters such as LV-EF. Due to the long period of follow-up, NT-proBNP and cTNT, both established predictive parameters in cardiac amyloid disease [26,27], were not available at the time of diagnosis for all patients (about 50%) and were therefore excluded from the present analysis because the limited data did not add substantially to the predictive model.

4.3. Survival and risk prediction in patients with transthyretin amyloidosis and cardiac involvement
Patients with transthyretin amyloidosis and cardiac involvement had a markedly better prognosis in the present study than comparable light-chain amyloid patients; only 1 (7%) patient of Vietnamese origin died during follow-up period, this patient carried a mutation uncommon in Caucasians (Ser50Arg). All patients presented with clinical symptoms at the time of diagnosis, therefore a bias by inclusion of asymptomatic gene carriers identified by genetic analysis might not arise. 1- and 3-year survival of patients with transthyretin amyloidosis was 91% and 83% (p<0.05 vs. light-chain amyloid) suggesting superior prognosis in patients with transthyretin amyloidosis.

Due to the smaller number of patients (n = 16) and deaths (n = 1) with transthyretin amyloidosis and cardiac involvement, a separate risk analysis was not performed. When, however, performing multivariate risk analysis of all patients with amyloidosis and cardiac involvement (i.e. patients with light-chain amyloid and transthyretin forms combined), the identical set of non-invasive parameters (LV-EF, LVP) was identified for prediction of survival, although prognosis itself is demonstrably different. Consequently, multivariate analysis of the combined cohorts, showed aetiology of amyloid cardiac disease as an additional independent risk factor for survival, a finding that has - to our knowledge - not been reported to date.

4.4. Conclusions
Prognosis of advanced CA is worse in light-chain than in transthyretin amyloidosis, but it is not as dire as assumed previously, with most deaths occurring within the first year after diagnosis. The combination of non-invasive parameters of electrocardiography (LVP), echocardiography (LV-EF), and aetiology of amyloid disease identified patients at highest risk that are potential candidates for advanced therapeutic approaches at specialized centres including heart transplantation prior to causative therapy regimens.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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 Eur J Heart FailHome page
A. V. Kristen, F.-U. Sack, S. O. Schonland, U. Hegenbart, B. M. Helmke, A. Koch, P. A. Schnabel, C. Rocken, S. Hardt, A. Remppis, et al.
Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light-chain amyloidosis
Eur J Heart Fail, October 1, 2009; 11(10): 1014 - 1020.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
C. Rapezzi, G. Merlini, C. C. Quarta, L. Riva, S. Longhi, O. Leone, F. Salvi, P. Ciliberti, F. Pastorelli, E. Biagini, et al.
Systemic Cardiac Amyloidoses: Disease Profiles and Clinical Courses of the 3 Main Types
Circulation, September 29, 2009; 120(13): 1203 - 1212.
[Abstract] [Full Text] [PDF]

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