Downloaded from http://heart.bmj.com/ on February 10, 2015 - Published by group.bmj.com
Editorial
Myocardial amyloid infiltration: a less than expected homogeneous process Giuseppe Galati, Claudio Rapezzi Systemic amyloidosis still remains a challenging and probably underdiagnosed disease.1 The three most frequent types of systemic amyloidosis are (i) the acquired monoclonal immunoglobulin light chain amyloidosis (AL), characterised by clonal plasma cells in the bone marrow that produce the immunoglobulin lights chains of the fibrillary deposits; (ii) the hereditary, transthyretin (TTR)-related form (ATTR), which can be caused by 100 mutations of TTR, a transport protein synthesised mainly by the liver; and (iii) the wild-type (non-mutant) TTR-related amyloidosis called systemic ‘senile’ amyloidosis (SSA), which affects mainly the hearts of elderly men.1 2 Pozo et al3 focus on the problem of LV remodelling and on the type of distribution of the ‘hypertrophy’ in patients with cardiac amyloidosis (CA). The concepts of ‘LV remodelling’ and ‘LV geometry’ have been elaborated in the last 20 years mainly related to coronary heart disease, hypertensive heart disease4 and valvular heart disease. Regarding hypertensive heart disease, a spectrum of LVH exists ranging from concentric LV hypertrophy (LVH), characterised by increased LV mass and increased ratio of the LV wall thickness to diastolic diameter (relative wall thickness, RWT), eccentric LVH, characterised by increased LV mass without increase of RWT, and concentric remodelling, characterised by increased RWT without increase of LV mass.4 The variability in the type of cardiac remodelling and pattern of LVH depends on several factors including pressure load (severity, duration and rapidity of onset), volume load, demographic factors (age, race/ethnicity, gender), concomitant medical conditions (coronary artery disease, diabetes mellitus, obesity, valvular heart disease), neurohormonal milieu, alterations of the extracellular matrix and genetic factors.4 These patterns of LVH and cardiac
Cardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum – University of Bologna, Italy Correspondence to Dr Giuseppe Galati, Istituto di Cardiologia, Policlinico S. Orsola-Malpighi, via Massarenti 9, Bologna 40138, Italy; [email protected]
remodelling have also prognostic implications including progression to heart failure, generally with preserved LVEF.4 The paper by Pozo et al3 is the first that focuses on the remodelling pattern— that is, the type of distribution of the increased myocardial thickness within the LV—of the CA. The key finding of this study is the identification, at cardiac MR (CMR), of a spectrum of LVH distribution ranging from normal geometry, eccentric hypertrophy, concentric remodelling and concentric hypertrophy (the authors have used the same terminology and the same criteria previously established for hypertensive heart disease). These new data are potentially relevant from a clinical translational point insofar as they advance our knowledge of the pathophysiology of cardiac amyloidosis and provide some clues for the recognition or at least the suspicion of this underdiagnosed disease. The mechanisms of the variable distribution of LVH in CA remain unclear. In this disease, the increased ventricular parietal thickness can be totally accounted for by amyloid infiltration, in contrast to storage diseases where a cellular hypertrophic reaction is likely triggered by the intracellular storage.5 Notably, the variability in LVH is in line with the variable distribution of amyloidotic myocardial infiltration documented by pathological studies.6 Specifically, the occurrence of segmental distribution of amyloid infiltration—leading to increased thickness—has been demonstrated at the histological level.6 Several factors, including age of the patients, disease duration and type of CA, can affect the type of LVH distribution. Unfortunately the low number of patients in the study of Pozo et al precludes any useful generalisation. As speculated by the authors, aetiology of amyloidosis and disease duration could play a major role. In previous studies, SSA is most frequently associated with concentric LVH,2 whereas AL sometimes shows only mild and asymmetrical increase parietal thickness.1 7 Comorbidities have also to be considered. Previous hypertensive heart disease could explain part of LVH in both SSA and AL patients (less frequently in ATTR).
Galati G, et al. Heart November 2014 Vol 100 No 21
As for clinical diagnosis of CA concerns, Pozo et al3 propose a model where RWT, asymmetrical LVH and LVMI (LV mass index) can provide high diagnostic accuracy for detection of CA. We feel that this conclusion should be interpreted with extreme caution as the overall predicting accuracy of the test is strictly dependent upon the prevalence of the disease within population. In the study, the prevalence of CA is 39%, a value not comparable with the real prevalence of the disease in the general population that is less than 0.1%. Furthermore, the predictive accuracy of the proposed model is inevitably influenced by the composition of the control group (in particular, by the prevalence of hypertrophic cardiomyopathy vs hypertensive heart disease). We believe that the criteria suggested by the authors can simply foster a diagnostic suspicion, whereas the final diagnosis of CA should be based on the integrated interpretation of ECG, echocardiography, CMR and ‘bone tracers’ scintigraphy. In particular, 99mTc-3,3-diphosphono1,2-propanodicarboxylic acid (99mTcDPD) scintigraphy is the single most useful tool for the early diagnosis of TTR-related amyloidosis and for the differential diagnosis between TTR-related amyloidosis and the other forms.8 Indeed, it has become increasingly vident that in order to reach a proper diagnosis of infiltrative restrictive cardiomyopathies (amyloidosis and sarcoidosis) it is necessary to use a multimodal imaging approach, integrating echocardiography, CMR and nuclear medicine8 (CMR alone for the diagnosis of CA is insufficient, failing to excellent values for sensitivity and specificity). Since a generic diagnosis of amyloidosis is clinically useless without the identification of the precise aetiology, the search for the type of precursor protein at histological level is mandatory in order to choose the targeted therapeutic strategy. Finally, the author’s hypothesis that amyloid deposition might occur preferentially in the interventricular septum in early disease stages and as disease progresses concentric LVH develops needs to be further investigated. Contributors GG and CR equally contributed to the editorial. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
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Downloaded from http://heart.bmj.com/ on February 10, 2015 - Published by group.bmj.com
Editorial To cite Galati G, Rapezzi C. Heart 2014;100:1659– 1660. Received 23 June 2014 Revised 2 July 2014 Accepted 3 July 2014 Published Online First 22 July 2014
REFERENCES 1
2
3
▸ http://dx.doi.org/10.1136/heartjnl-2014-305710 Heart 2014;100:1659–1660. doi:10.1136/heartjnl-2014-306221
1660
4
Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120: 1203–12. Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretinrelated amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34:520–8. Pozo E, et al. Cardiac Magnetic Resonance evaluation of left ventricular remodeling distribution in cardiac amyloidosis. Heart 2014;100: 1688–95. Drazner MH. The progression of hypertensive heart disease. Circulation 2011;123:327–34.
5
6
7
8
Palecek T, Bultas J, Hajek M, et al. Association between cardiac energy metabolism and gain of left ventricular mass in Fabry disease. Int J Cardiol 2010;144:337–9. Leone O, Longhi S, Quarta CC, et al. New pathological insights into cardiac amyloidosis: implications for non-invasive diagnosis. Amyloid 2012;19:99–105. Lee GY, Kim K, Choi JO, et al. Cardiac amyloidosis without increased left ventricular wall thickness. Mayo Clin Proc 2014;89:781–9. Rapezzi C, Quarta CC, Guidalotti PL, et al. Usefulness and limitations of 99mTc-3,3-diphosphono-1,2propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38:4708.
Galati G, et al. Heart November 2014 Vol 100 No 21
Downloaded from http://heart.bmj.com/ on February 10, 2015 - Published by group.bmj.com
Myocardial amyloid infiltration: a less than expected homogeneous process Giuseppe Galati and Claudio Rapezzi Heart 2014 100: 1659-1660 originally published online July 22, 2014
doi: 10.1136/heartjnl-2014-306221 Updated information and services can be found at: http://heart.bmj.com/content/100/21/1659
These include:
References Email alerting service
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This article cites 7 articles, 3 of which you can access for free at: http://heart.bmj.com/content/100/21/1659#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Metabolic disorders (946) Drugs: cardiovascular system (8087) Hypertension (2742) Diabetes (797)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Editorial
Myocardial amyloid infiltration: a less than expected homogeneous process Giuseppe Galati, Claudio Rapezzi Systemic amyloidosis still remains a challenging and probably underdiagnosed disease.1 The three most frequent types of systemic amyloidosis are (i) the acquired monoclonal immunoglobulin light chain amyloidosis (AL), characterised by clonal plasma cells in the bone marrow that produce the immunoglobulin lights chains of the fibrillary deposits; (ii) the hereditary, transthyretin (TTR)-related form (ATTR), which can be caused by 100 mutations of TTR, a transport protein synthesised mainly by the liver; and (iii) the wild-type (non-mutant) TTR-related amyloidosis called systemic ‘senile’ amyloidosis (SSA), which affects mainly the hearts of elderly men.1 2 Pozo et al3 focus on the problem of LV remodelling and on the type of distribution of the ‘hypertrophy’ in patients with cardiac amyloidosis (CA). The concepts of ‘LV remodelling’ and ‘LV geometry’ have been elaborated in the last 20 years mainly related to coronary heart disease, hypertensive heart disease4 and valvular heart disease. Regarding hypertensive heart disease, a spectrum of LVH exists ranging from concentric LV hypertrophy (LVH), characterised by increased LV mass and increased ratio of the LV wall thickness to diastolic diameter (relative wall thickness, RWT), eccentric LVH, characterised by increased LV mass without increase of RWT, and concentric remodelling, characterised by increased RWT without increase of LV mass.4 The variability in the type of cardiac remodelling and pattern of LVH depends on several factors including pressure load (severity, duration and rapidity of onset), volume load, demographic factors (age, race/ethnicity, gender), concomitant medical conditions (coronary artery disease, diabetes mellitus, obesity, valvular heart disease), neurohormonal milieu, alterations of the extracellular matrix and genetic factors.4 These patterns of LVH and cardiac
Cardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum – University of Bologna, Italy Correspondence to Dr Giuseppe Galati, Istituto di Cardiologia, Policlinico S. Orsola-Malpighi, via Massarenti 9, Bologna 40138, Italy; [email protected]
remodelling have also prognostic implications including progression to heart failure, generally with preserved LVEF.4 The paper by Pozo et al3 is the first that focuses on the remodelling pattern— that is, the type of distribution of the increased myocardial thickness within the LV—of the CA. The key finding of this study is the identification, at cardiac MR (CMR), of a spectrum of LVH distribution ranging from normal geometry, eccentric hypertrophy, concentric remodelling and concentric hypertrophy (the authors have used the same terminology and the same criteria previously established for hypertensive heart disease). These new data are potentially relevant from a clinical translational point insofar as they advance our knowledge of the pathophysiology of cardiac amyloidosis and provide some clues for the recognition or at least the suspicion of this underdiagnosed disease. The mechanisms of the variable distribution of LVH in CA remain unclear. In this disease, the increased ventricular parietal thickness can be totally accounted for by amyloid infiltration, in contrast to storage diseases where a cellular hypertrophic reaction is likely triggered by the intracellular storage.5 Notably, the variability in LVH is in line with the variable distribution of amyloidotic myocardial infiltration documented by pathological studies.6 Specifically, the occurrence of segmental distribution of amyloid infiltration—leading to increased thickness—has been demonstrated at the histological level.6 Several factors, including age of the patients, disease duration and type of CA, can affect the type of LVH distribution. Unfortunately the low number of patients in the study of Pozo et al precludes any useful generalisation. As speculated by the authors, aetiology of amyloidosis and disease duration could play a major role. In previous studies, SSA is most frequently associated with concentric LVH,2 whereas AL sometimes shows only mild and asymmetrical increase parietal thickness.1 7 Comorbidities have also to be considered. Previous hypertensive heart disease could explain part of LVH in both SSA and AL patients (less frequently in ATTR).
Galati G, et al. Heart November 2014 Vol 100 No 21
As for clinical diagnosis of CA concerns, Pozo et al3 propose a model where RWT, asymmetrical LVH and LVMI (LV mass index) can provide high diagnostic accuracy for detection of CA. We feel that this conclusion should be interpreted with extreme caution as the overall predicting accuracy of the test is strictly dependent upon the prevalence of the disease within population. In the study, the prevalence of CA is 39%, a value not comparable with the real prevalence of the disease in the general population that is less than 0.1%. Furthermore, the predictive accuracy of the proposed model is inevitably influenced by the composition of the control group (in particular, by the prevalence of hypertrophic cardiomyopathy vs hypertensive heart disease). We believe that the criteria suggested by the authors can simply foster a diagnostic suspicion, whereas the final diagnosis of CA should be based on the integrated interpretation of ECG, echocardiography, CMR and ‘bone tracers’ scintigraphy. In particular, 99mTc-3,3-diphosphono1,2-propanodicarboxylic acid (99mTcDPD) scintigraphy is the single most useful tool for the early diagnosis of TTR-related amyloidosis and for the differential diagnosis between TTR-related amyloidosis and the other forms.8 Indeed, it has become increasingly vident that in order to reach a proper diagnosis of infiltrative restrictive cardiomyopathies (amyloidosis and sarcoidosis) it is necessary to use a multimodal imaging approach, integrating echocardiography, CMR and nuclear medicine8 (CMR alone for the diagnosis of CA is insufficient, failing to excellent values for sensitivity and specificity). Since a generic diagnosis of amyloidosis is clinically useless without the identification of the precise aetiology, the search for the type of precursor protein at histological level is mandatory in order to choose the targeted therapeutic strategy. Finally, the author’s hypothesis that amyloid deposition might occur preferentially in the interventricular septum in early disease stages and as disease progresses concentric LVH develops needs to be further investigated. Contributors GG and CR equally contributed to the editorial. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
1659
Downloaded from http://heart.bmj.com/ on February 10, 2015 - Published by group.bmj.com
Editorial To cite Galati G, Rapezzi C. Heart 2014;100:1659– 1660. Received 23 June 2014 Revised 2 July 2014 Accepted 3 July 2014 Published Online First 22 July 2014
REFERENCES 1
2
3
▸ http://dx.doi.org/10.1136/heartjnl-2014-305710 Heart 2014;100:1659–1660. doi:10.1136/heartjnl-2014-306221
1660
4
Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120: 1203–12. Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretinrelated amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34:520–8. Pozo E, et al. Cardiac Magnetic Resonance evaluation of left ventricular remodeling distribution in cardiac amyloidosis. Heart 2014;100: 1688–95. Drazner MH. The progression of hypertensive heart disease. Circulation 2011;123:327–34.
5
6
7
8
Palecek T, Bultas J, Hajek M, et al. Association between cardiac energy metabolism and gain of left ventricular mass in Fabry disease. Int J Cardiol 2010;144:337–9. Leone O, Longhi S, Quarta CC, et al. New pathological insights into cardiac amyloidosis: implications for non-invasive diagnosis. Amyloid 2012;19:99–105. Lee GY, Kim K, Choi JO, et al. Cardiac amyloidosis without increased left ventricular wall thickness. Mayo Clin Proc 2014;89:781–9. Rapezzi C, Quarta CC, Guidalotti PL, et al. Usefulness and limitations of 99mTc-3,3-diphosphono-1,2propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38:4708.
Galati G, et al. Heart November 2014 Vol 100 No 21
Downloaded from http://heart.bmj.com/ on February 10, 2015 - Published by group.bmj.com
Myocardial amyloid infiltration: a less than expected homogeneous process Giuseppe Galati and Claudio Rapezzi Heart 2014 100: 1659-1660 originally published online July 22, 2014
doi: 10.1136/heartjnl-2014-306221 Updated information and services can be found at: http://heart.bmj.com/content/100/21/1659
These include:
References Email alerting service
Topic Collections
This article cites 7 articles, 3 of which you can access for free at: http://heart.bmj.com/content/100/21/1659#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Metabolic disorders (946) Drugs: cardiovascular system (8087) Hypertension (2742) Diabetes (797)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
