Accepted Manuscript Cardiovascular Magnetic Resonance Determinants of Left Ventricular NonCompaction Dana K. Dawson , MD David J. McLernon , PhD Vimal J. Raj , MD Alicia M. Maceira , MD Sanjay Prasad , MD Michael P. Frenneaux , MD Dudley J. Pennell , MD Philip J. Kilner , MD PII:
S0002-9149(14)01128-X
DOI:
10.1016/j.amjcard.2014.05.017
Reference:
AJC 20474
To appear in:
The American Journal of Cardiology
Received Date: 1 April 2014 Revised Date:
2 May 2014
Accepted Date: 6 May 2014
Please cite this article as: Dawson DK, McLernon DJ, Raj VJ, Maceira AM, Prasad S, Frenneaux MP, Pennell DJ, Kilner PJ, Cardiovascular Magnetic Resonance Determinants of Left Ventricular NonCompaction, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.05.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Cardiovascular Magnetic Resonance Determinants of Left Ventricular NonCompaction
RI PT
Dana K. Dawson1 MD, David J. McLernon1 PhD, Vimal J. Raj2 MD, Alicia M. Maceira3 MD, Sanjay Prasad4 MD, Michael P. Frenneaux1 MD, Dudley J. Pennell4 MD, Philip J. Kilner4 MD
SC
From: 1- University of Aberdeen, Aberdeen, UK, 2 - Leicester Royal Infirmary, UK, 3 - ERESA-Cardiac Imaging Unit, Valencia, Spain, 4 - NIHR Cardiovascular
M AN U
Biomedical Research Unit, Royal Brompton Hospital and Imperial College London
Running title: Dawson, Refining the Criteria for Noncompaction
TE D
Correspondence: Dr. Dana Dawson
EP
School of Medicine and Dentistry University of Aberdeen
AC C
Aberdeen AB25 2ZD, UK
Tel: + 44 224 437965
Fax: + 44 224 437971
E-mail: [email protected] Clinical Trial Registration Information: The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735, http://www.clinicaltrials.gov/ct2/show/NCT00930735
1
ACCEPTED MANUSCRIPT Abstract: Insufficient precision remains in accurately identifying LVNC from the healthy normal morphological spectrum. We aim to provide a better distinction between normal left
RI PT
ventricular (LV) trabeculations and LV non-compaction (LVNC). We used a previously well defined cohort of 120 healthy volunteers as normal reference values for the trabecular/compacted (T/C) ratio derived from a consistent selection of short axis cardiovascular magnetic resonance (CMR) images. We performed forward
SC
selection of logistic regression models, selecting the best model which was
M AN U
subsequently assessed for discrimination and calibration, validated, and converted into a clinical diagnostic chart to benchmark the boundaries of detection from a cohort of 30 patients considered to have LVNC. We showed that 3 combinations of a maximal end-diastolic T/C ratio [≥1 (apex), >1.8 mid-cavity] or [>2 (apex), ≥0.6 midcavity] or [>0.5 (base), >1.8 (mid-cavity)] separate the cohorts with the highest
TE D
accuracy [C-statistic (95% CI) of 0.9749 (0.9748 to 0.9751) for the diagnostic chart]. Quantitative CMR also shows that patients considered to have LVNC have a
EP
significantly reduced EF compared to normal volunteers. At mid-cavity and apical level it is difficult to identify papillary muscles which are replaced by a dense
AC C
trabecular meshwork. In conclusion, we developed a new, refined diagnostic tool for identifying LVNC, based on an a priori assessment of the trabecular architecture in healthy volunteers.
Key words: trabeculations, left ventricular non-compaction, cardiomyopathy
2
ACCEPTED MANUSCRIPT The diagnostic criteria for Left ventricular noncompaction (LVNC) proposed by Chin1 have been comprehensively redefined by Jenni2 with 2D-Echocardiography and Petersen3 with cardiovascular magnetic resonance (CMR). However, considerable uncertainty remains because on the one hand some normal subjects
RI PT
appear to fulfil the current LVNC definition4,5,6 yet on the other hand, patients with clear evidence of hypertrabeculation may be excluded. Furthermore, significant
differences exist between Echocardiography and CMR in the orientation of the short
SC
axis images and criteria derived from one imaging modality are not applicable to the other. In the current study, we used our previously published segmental
M AN U
Trabecular/Compacted (T/C) ratios in the left ventricles (LV) of healthy volunteers as the benchmark for separation from a cohort of patients considered to have LVNC. We applied multivariable logistic regression analysis to derive clinical prediction models to estimate the probability of LVNC. The models were assessed for their
TE D
predictive ability using methods of discrimination and calibration. The best model was subsequently internally validated to test for over-fitting. From this model a
detection of LVNC.
AC C
Methods
EP
simple clinical diagnostic chart was developed to determine the boundaries of
We previously recruited 120 healthy volunteers (10 males and10 females each in six deciles of age, 20-80 years old) in whom we characterised the LV trabeculations7. Subsequently, we selected a reference LVNC group (n=30) as cases in which either Echocardiography or CMR diagnosed LVNC by the respective Jenni and Petersen criteria and further, agreed between two independent expert readers after consideration of clinical presentation [abnormal ECG (68%) , arrhythmias (23%), systemic embolization (7%), heart failure (70%), family history of another 3
ACCEPTED MANUSCRIPT cardiomyopathy (20%)]. These were empirically divided in two subgroups: those with ‘normal ‘ LV Ejection fraction (EF) (LV EF>55%) and those with abnormal LV EF (LV EF2.3 on CMR has been chosen by Petersen and colleagues for its high specificity in their study3, when this cutoff was applied to the Multi-Ethnic Study of Atherosclerosis participants, over 43% of subjects fulfilled this LVNC diagnostic criterion on CMR6. In this study, we present the largest series reported so far, of unrelated patients, investigated with CMR and benchmarked against a well characterised healthy volunteer population, in whom we have already shown that the T/C ratio does not vary with gender or age only when measured at ED7,8. The best 9
ACCEPTED MANUSCRIPT performance model identified that a combination of a basal, mid-cavity and apical segments at ED is the best selector of LVNC cases from the normal population. We included patients considered to have LVNC with both “normal” and reduced EF. It is less clear if the two LVNC groups represent different stages of progression of the
RI PT
condition or whether they are phenotypic expressions of different spectra of disease and a longitudinal study would be required to clarify this. In a condition with such a varied phenotypic expression it is perhaps not surprising that a single defining cut-off
SC
(convenient in clinical practice) may be either too sensitive4 or too specific3 for
reliable diagnosis. The diagnostic tool resulting from our integrated analysis of a
M AN U
large cohort of LVNC cases and a representative selection of healthy volunteers represents a robust refinement of the current diagnostic criteria. This was developed from the standard method of acquisition of a full coverage of the entire LV as a stack of short axis cines that can be easily implemented to any routine CMR study. Such a
TE D
diagnostic chart can be integrated in a set of diagnostic criteria for LVNC, similar to those used by the Task Force for ARVC15 of Duke criteria for Infective Endocarditis16. An interpretation of the imaging findings based on probabilities, as
EP
proposed here, in conjunction with other clinical variables would be a more robust
AC C
diagnostic strategy and is likely to provide better sensitivity and specificity compared to an isolated T/C cut-off from imaging alone. Larger prospectively conducted studies will be necessary to test the performance of this new proposed diagnostic tool in clinical practice and integrated it with other clinical variables, as suggested above, but this is beyond the scope of the current work. As the ethnic origin of both our patients and healthy volunteers was predominantly white Caucasian, our conclusions cannot be extrapolated to other ethnic populations without prospective validation. The debate continues on whether 10
ACCEPTED MANUSCRIPT short or long axis slices should be used for diagnosis, as each of them have advantages and disadvantages (short axis slices in CMR are more oblique towards the apex, whereas long axis ones are less suited for AHA segmental analysis and it is technically more difficult to reproduce the slice location). Finally, the proposed
RI PT
diagnostic chart includes an area of intermediate probability, which in the authors’ view needs to be recognised as a necessary limitation. A gold standard for the
diagnosis of LVNC continues to be lacking as no imaging or pathology signature has
M AN U
SC
yet been agreed and this also pertains to our “LVNC reference group”.
Funding sources:
This study was supported by the UK NIHR Cardiovascular Biomedical Research Unit
TE D
of Royal Brompton & Harefield NHS Foundation Trust and the van Geest Advanced Imaging Fellowship to Dr Dawson.
AC C
none
EP
Disclosures:
11
ACCEPTED MANUSCRIPT 1. Chin,TK, Perloff,JK, Williams,RG, Jue,K, and Mohrmann,R,Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990;82:507-513.
2. Jenni,R, Oechslin,E, Schneider,J, Attenhofer,JC, and Kaufmann,PA,Echocardiographic
RI PT
and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666-671.
3. Petersen,SE, Selvanayagam,JB, Wiesmann,F, Robson,MD, Francis,JM, Anderson,RH,
SC
Watkins,H, and Neubauer,S,Left Ventricular Non-Compaction: Insights From
M AN U
Cardiovascular Magnetic Resonance Imaging. J Am Coll Cardiol 2005;46:101-105.
4. Kohli,SK, Pantazis,AA, Shah,JS, Adeyemi,B, Jackson,G, McKenna,WJ, Sharma,S, and Elliott,PM,Diagnosis of left-ventricular non-compaction in patients with leftventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J
TE D
2008;29:89-95.
5. Gati,S, Chandra,N, Bennett,RL, Reed,M, Kervio,G, Panoulas,VF, Ghani,S, Sheikh,N, Zaidi,A, Wilson,M, Papadakis,M, Carre,F, and Sharma,S,Increased left ventricular
EP
trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart 2013;99:401-408.
AC C
6. Kawel,N, Nacif,M, Arai,AE, Gomes,AS, Hundley,WG, Johnson,WC, Prince,MR, Stacey,RB, Lima,JA, and Bluemke,DA,Trabeculated (noncompacted) and compact myocardium in adults: the multi-ethnic study of atherosclerosis. Circ Cardiovasc Imaging 2012;5:357-366.
7. Dawson,DK, Maceira,AM, Raj,VJ, Graham,C, Pennell,DJ, and Kilner,PJ,Regional Thicknesses and Thickening of Compacted and Trabeculated Myocardial Layers of the
12
ACCEPTED MANUSCRIPT Normal Left Ventricle Studied by Cardiovascular Magnetic Resonance / Clinical Perspective. Circ Cardiovasc Imaging 2011;4:139-146.
8. Maceira,AM, Prasad,SK, Khan,M, and Pennell,DJ,Normalized left ventricular systolic
resonance. J Cardiovasc Magn Reson. 2006;8:417-426.
RI PT
and diastolic function by steady state free precession cardiovascular magnetic
9. Harrell,FE, Jr., Lee,KL, Califf,RM, Pryor,DB, and Rosati,RA,Regression modelling
SC
strategies for improved prognostic prediction. Stat Med 1984;3:143-152.
M AN U
10. Peduzzi,P, Concato,J, Kemper,E, Holford,TR, and Feinstein,AR,A simulation study of the number of events per variable in logistic regression analysis. Journal of Clinical Epidemiology 1996;49:1373-1379.
11. Steyerberg EW,Clinical prediction models: a practical approach to development,
TE D
validation, and updating. 2009; New York, Springer.
12. Harrell FE,LKMD,Tutorial in biostatistics: multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and
EP
reducing errors. Stat Med 1996;15:361-387.
AC C
13. Jacquier,A, Thuny,F, Jop,B, Giorgi,R, Cohen,F, Gaubert,JY, Vidal,V, Bartoli,JM, Habib,G, and Moulin,G,Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular noncompaction. Eur Heart J 2010;31:1098-1104.
14. Captur,G, Muthurangu,V, Cook,C, Flett,AS, Wilson,R, Barison,A, Sado,DM, Anderson,S, McKenna,WJ, Mohun,TJ, Elliott,PM, and Moon,JC,Quantification of left ventricular trabeculae using fractal analysis. J Cardiovasc Magn Reson. 2013;15:3646 13
ACCEPTED MANUSCRIPT 15. Marcus,FI, McKenna,WJ, Sherrill,D, Basso,C, Bauce,B, Bluemke,DA, Calkins,H, Corrado,D, Cox,MGPJ, Daubert,JP, Fontaine,G, Gear,K, Hauer,R, Nava,A, Picard,MH, Protonotarios,N, Saffitz,JE, Sanborn,DMY, Steinberg,JS, Tandri,H, Thiene,G, Towbin,JA, Tsatsopoulou,A, Wichter,T, and Zareba,W,Diagnosis of Arrhythmogenic
RI PT
Right Ventricular Cardiomyopathy/Dysplasia: Proposed Modification of the Task Force Criteria. Circulation 2010;121:1533-1541.
16. Durack,DT, Lukes,AS, and Bright,DK,New criteria for diagnosis of infective
SC
endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis
AC C
EP
TE D
M AN U
Service. Am. J Med 1994;96:200-209.
14
ACCEPTED MANUSCRIPT FIGURE LEGENDS:
Figure 1: Receiver operator characteristic curves of the final two models: diastolic (A) and systolic (B).
RI PT
Figure 2: A – Diagnostic chart to predict LVNC from T/C ratios measured at ED: the high, medium and low probabilities of diagnosing LVNC are shown in red, yellow and green respectively, with the corresponding cut-offs of detection for the maximal T/C
SC
ratio measured in basal, mid-cavity and apical segments; B - Bar graph showing the proportion of patients actually diagnosed with LVNC within each of the predicted
M AN U
probability of LVNC categories used in the chart in A; C - Prospective validation of the new diagnostic model versus the T:C>2.3 criteria: The red dots show where both agree on a positive LVNC diagnosis, the green dots show where they both agree on a negative diagnosis, the yellow dots show where the probability from our model is
TE D
between 0.15 and 0.5 (notice for these points the Petersen cut-off is below 2.3 for all), and the black dots show where they do not agree.
EP
Figure 3: An example of a patient where the ED T/C ratio at the base (A), mid-cavity (B) and apex (C) are: 1.4 (T=8 mm, C=5.6 mm), 1.9 (T=14 mm, C=7.2 mm) and 2
AC C
(T=12 mm, C=6 mm). This patient would not be diagnosed with LVNC by the 2.3 cutoff but is reclassified as LVNC by the diagnostic tool proposed. C=compacted, white arrows, T=trabecular, black arrows Figure 4: Examples of LV mid-cavity ED frames of a normal volunteer (A), a patient with dilated cardiomyopathy (B) for comparison, a patient with LVNC and reduced EF (C) and a patient with LVNC and normal EF (D) – note that a trabecular meshwork replaces the distinct papillary muscle heads in the LVNC patients at midcavity level. 15
ACCEPTED MANUSCRIPT
Left ventricular noncompaction
RI PT
Normal volunteers
Ejection fraction
S0002-9149(14)01128-X
DOI:
10.1016/j.amjcard.2014.05.017
Reference:
AJC 20474
To appear in:
The American Journal of Cardiology
Received Date: 1 April 2014 Revised Date:
2 May 2014
Accepted Date: 6 May 2014
Please cite this article as: Dawson DK, McLernon DJ, Raj VJ, Maceira AM, Prasad S, Frenneaux MP, Pennell DJ, Kilner PJ, Cardiovascular Magnetic Resonance Determinants of Left Ventricular NonCompaction, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.05.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Cardiovascular Magnetic Resonance Determinants of Left Ventricular NonCompaction
RI PT
Dana K. Dawson1 MD, David J. McLernon1 PhD, Vimal J. Raj2 MD, Alicia M. Maceira3 MD, Sanjay Prasad4 MD, Michael P. Frenneaux1 MD, Dudley J. Pennell4 MD, Philip J. Kilner4 MD
SC
From: 1- University of Aberdeen, Aberdeen, UK, 2 - Leicester Royal Infirmary, UK, 3 - ERESA-Cardiac Imaging Unit, Valencia, Spain, 4 - NIHR Cardiovascular
M AN U
Biomedical Research Unit, Royal Brompton Hospital and Imperial College London
Running title: Dawson, Refining the Criteria for Noncompaction
TE D
Correspondence: Dr. Dana Dawson
EP
School of Medicine and Dentistry University of Aberdeen
AC C
Aberdeen AB25 2ZD, UK
Tel: + 44 224 437965
Fax: + 44 224 437971
E-mail: [email protected] Clinical Trial Registration Information: The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735, http://www.clinicaltrials.gov/ct2/show/NCT00930735
1
ACCEPTED MANUSCRIPT Abstract: Insufficient precision remains in accurately identifying LVNC from the healthy normal morphological spectrum. We aim to provide a better distinction between normal left
RI PT
ventricular (LV) trabeculations and LV non-compaction (LVNC). We used a previously well defined cohort of 120 healthy volunteers as normal reference values for the trabecular/compacted (T/C) ratio derived from a consistent selection of short axis cardiovascular magnetic resonance (CMR) images. We performed forward
SC
selection of logistic regression models, selecting the best model which was
M AN U
subsequently assessed for discrimination and calibration, validated, and converted into a clinical diagnostic chart to benchmark the boundaries of detection from a cohort of 30 patients considered to have LVNC. We showed that 3 combinations of a maximal end-diastolic T/C ratio [≥1 (apex), >1.8 mid-cavity] or [>2 (apex), ≥0.6 midcavity] or [>0.5 (base), >1.8 (mid-cavity)] separate the cohorts with the highest
TE D
accuracy [C-statistic (95% CI) of 0.9749 (0.9748 to 0.9751) for the diagnostic chart]. Quantitative CMR also shows that patients considered to have LVNC have a
EP
significantly reduced EF compared to normal volunteers. At mid-cavity and apical level it is difficult to identify papillary muscles which are replaced by a dense
AC C
trabecular meshwork. In conclusion, we developed a new, refined diagnostic tool for identifying LVNC, based on an a priori assessment of the trabecular architecture in healthy volunteers.
Key words: trabeculations, left ventricular non-compaction, cardiomyopathy
2
ACCEPTED MANUSCRIPT The diagnostic criteria for Left ventricular noncompaction (LVNC) proposed by Chin1 have been comprehensively redefined by Jenni2 with 2D-Echocardiography and Petersen3 with cardiovascular magnetic resonance (CMR). However, considerable uncertainty remains because on the one hand some normal subjects
RI PT
appear to fulfil the current LVNC definition4,5,6 yet on the other hand, patients with clear evidence of hypertrabeculation may be excluded. Furthermore, significant
differences exist between Echocardiography and CMR in the orientation of the short
SC
axis images and criteria derived from one imaging modality are not applicable to the other. In the current study, we used our previously published segmental
M AN U
Trabecular/Compacted (T/C) ratios in the left ventricles (LV) of healthy volunteers as the benchmark for separation from a cohort of patients considered to have LVNC. We applied multivariable logistic regression analysis to derive clinical prediction models to estimate the probability of LVNC. The models were assessed for their
TE D
predictive ability using methods of discrimination and calibration. The best model was subsequently internally validated to test for over-fitting. From this model a
detection of LVNC.
AC C
Methods
EP
simple clinical diagnostic chart was developed to determine the boundaries of
We previously recruited 120 healthy volunteers (10 males and10 females each in six deciles of age, 20-80 years old) in whom we characterised the LV trabeculations7. Subsequently, we selected a reference LVNC group (n=30) as cases in which either Echocardiography or CMR diagnosed LVNC by the respective Jenni and Petersen criteria and further, agreed between two independent expert readers after consideration of clinical presentation [abnormal ECG (68%) , arrhythmias (23%), systemic embolization (7%), heart failure (70%), family history of another 3
ACCEPTED MANUSCRIPT cardiomyopathy (20%)]. These were empirically divided in two subgroups: those with ‘normal ‘ LV Ejection fraction (EF) (LV EF>55%) and those with abnormal LV EF (LV EF2.3 on CMR has been chosen by Petersen and colleagues for its high specificity in their study3, when this cutoff was applied to the Multi-Ethnic Study of Atherosclerosis participants, over 43% of subjects fulfilled this LVNC diagnostic criterion on CMR6. In this study, we present the largest series reported so far, of unrelated patients, investigated with CMR and benchmarked against a well characterised healthy volunteer population, in whom we have already shown that the T/C ratio does not vary with gender or age only when measured at ED7,8. The best 9
ACCEPTED MANUSCRIPT performance model identified that a combination of a basal, mid-cavity and apical segments at ED is the best selector of LVNC cases from the normal population. We included patients considered to have LVNC with both “normal” and reduced EF. It is less clear if the two LVNC groups represent different stages of progression of the
RI PT
condition or whether they are phenotypic expressions of different spectra of disease and a longitudinal study would be required to clarify this. In a condition with such a varied phenotypic expression it is perhaps not surprising that a single defining cut-off
SC
(convenient in clinical practice) may be either too sensitive4 or too specific3 for
reliable diagnosis. The diagnostic tool resulting from our integrated analysis of a
M AN U
large cohort of LVNC cases and a representative selection of healthy volunteers represents a robust refinement of the current diagnostic criteria. This was developed from the standard method of acquisition of a full coverage of the entire LV as a stack of short axis cines that can be easily implemented to any routine CMR study. Such a
TE D
diagnostic chart can be integrated in a set of diagnostic criteria for LVNC, similar to those used by the Task Force for ARVC15 of Duke criteria for Infective Endocarditis16. An interpretation of the imaging findings based on probabilities, as
EP
proposed here, in conjunction with other clinical variables would be a more robust
AC C
diagnostic strategy and is likely to provide better sensitivity and specificity compared to an isolated T/C cut-off from imaging alone. Larger prospectively conducted studies will be necessary to test the performance of this new proposed diagnostic tool in clinical practice and integrated it with other clinical variables, as suggested above, but this is beyond the scope of the current work. As the ethnic origin of both our patients and healthy volunteers was predominantly white Caucasian, our conclusions cannot be extrapolated to other ethnic populations without prospective validation. The debate continues on whether 10
ACCEPTED MANUSCRIPT short or long axis slices should be used for diagnosis, as each of them have advantages and disadvantages (short axis slices in CMR are more oblique towards the apex, whereas long axis ones are less suited for AHA segmental analysis and it is technically more difficult to reproduce the slice location). Finally, the proposed
RI PT
diagnostic chart includes an area of intermediate probability, which in the authors’ view needs to be recognised as a necessary limitation. A gold standard for the
diagnosis of LVNC continues to be lacking as no imaging or pathology signature has
M AN U
SC
yet been agreed and this also pertains to our “LVNC reference group”.
Funding sources:
This study was supported by the UK NIHR Cardiovascular Biomedical Research Unit
TE D
of Royal Brompton & Harefield NHS Foundation Trust and the van Geest Advanced Imaging Fellowship to Dr Dawson.
AC C
none
EP
Disclosures:
11
ACCEPTED MANUSCRIPT 1. Chin,TK, Perloff,JK, Williams,RG, Jue,K, and Mohrmann,R,Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990;82:507-513.
2. Jenni,R, Oechslin,E, Schneider,J, Attenhofer,JC, and Kaufmann,PA,Echocardiographic
RI PT
and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666-671.
3. Petersen,SE, Selvanayagam,JB, Wiesmann,F, Robson,MD, Francis,JM, Anderson,RH,
SC
Watkins,H, and Neubauer,S,Left Ventricular Non-Compaction: Insights From
M AN U
Cardiovascular Magnetic Resonance Imaging. J Am Coll Cardiol 2005;46:101-105.
4. Kohli,SK, Pantazis,AA, Shah,JS, Adeyemi,B, Jackson,G, McKenna,WJ, Sharma,S, and Elliott,PM,Diagnosis of left-ventricular non-compaction in patients with leftventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J
TE D
2008;29:89-95.
5. Gati,S, Chandra,N, Bennett,RL, Reed,M, Kervio,G, Panoulas,VF, Ghani,S, Sheikh,N, Zaidi,A, Wilson,M, Papadakis,M, Carre,F, and Sharma,S,Increased left ventricular
EP
trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart 2013;99:401-408.
AC C
6. Kawel,N, Nacif,M, Arai,AE, Gomes,AS, Hundley,WG, Johnson,WC, Prince,MR, Stacey,RB, Lima,JA, and Bluemke,DA,Trabeculated (noncompacted) and compact myocardium in adults: the multi-ethnic study of atherosclerosis. Circ Cardiovasc Imaging 2012;5:357-366.
7. Dawson,DK, Maceira,AM, Raj,VJ, Graham,C, Pennell,DJ, and Kilner,PJ,Regional Thicknesses and Thickening of Compacted and Trabeculated Myocardial Layers of the
12
ACCEPTED MANUSCRIPT Normal Left Ventricle Studied by Cardiovascular Magnetic Resonance / Clinical Perspective. Circ Cardiovasc Imaging 2011;4:139-146.
8. Maceira,AM, Prasad,SK, Khan,M, and Pennell,DJ,Normalized left ventricular systolic
resonance. J Cardiovasc Magn Reson. 2006;8:417-426.
RI PT
and diastolic function by steady state free precession cardiovascular magnetic
9. Harrell,FE, Jr., Lee,KL, Califf,RM, Pryor,DB, and Rosati,RA,Regression modelling
SC
strategies for improved prognostic prediction. Stat Med 1984;3:143-152.
M AN U
10. Peduzzi,P, Concato,J, Kemper,E, Holford,TR, and Feinstein,AR,A simulation study of the number of events per variable in logistic regression analysis. Journal of Clinical Epidemiology 1996;49:1373-1379.
11. Steyerberg EW,Clinical prediction models: a practical approach to development,
TE D
validation, and updating. 2009; New York, Springer.
12. Harrell FE,LKMD,Tutorial in biostatistics: multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and
EP
reducing errors. Stat Med 1996;15:361-387.
AC C
13. Jacquier,A, Thuny,F, Jop,B, Giorgi,R, Cohen,F, Gaubert,JY, Vidal,V, Bartoli,JM, Habib,G, and Moulin,G,Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular noncompaction. Eur Heart J 2010;31:1098-1104.
14. Captur,G, Muthurangu,V, Cook,C, Flett,AS, Wilson,R, Barison,A, Sado,DM, Anderson,S, McKenna,WJ, Mohun,TJ, Elliott,PM, and Moon,JC,Quantification of left ventricular trabeculae using fractal analysis. J Cardiovasc Magn Reson. 2013;15:3646 13
ACCEPTED MANUSCRIPT 15. Marcus,FI, McKenna,WJ, Sherrill,D, Basso,C, Bauce,B, Bluemke,DA, Calkins,H, Corrado,D, Cox,MGPJ, Daubert,JP, Fontaine,G, Gear,K, Hauer,R, Nava,A, Picard,MH, Protonotarios,N, Saffitz,JE, Sanborn,DMY, Steinberg,JS, Tandri,H, Thiene,G, Towbin,JA, Tsatsopoulou,A, Wichter,T, and Zareba,W,Diagnosis of Arrhythmogenic
RI PT
Right Ventricular Cardiomyopathy/Dysplasia: Proposed Modification of the Task Force Criteria. Circulation 2010;121:1533-1541.
16. Durack,DT, Lukes,AS, and Bright,DK,New criteria for diagnosis of infective
SC
endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis
AC C
EP
TE D
M AN U
Service. Am. J Med 1994;96:200-209.
14
ACCEPTED MANUSCRIPT FIGURE LEGENDS:
Figure 1: Receiver operator characteristic curves of the final two models: diastolic (A) and systolic (B).
RI PT
Figure 2: A – Diagnostic chart to predict LVNC from T/C ratios measured at ED: the high, medium and low probabilities of diagnosing LVNC are shown in red, yellow and green respectively, with the corresponding cut-offs of detection for the maximal T/C
SC
ratio measured in basal, mid-cavity and apical segments; B - Bar graph showing the proportion of patients actually diagnosed with LVNC within each of the predicted
M AN U
probability of LVNC categories used in the chart in A; C - Prospective validation of the new diagnostic model versus the T:C>2.3 criteria: The red dots show where both agree on a positive LVNC diagnosis, the green dots show where they both agree on a negative diagnosis, the yellow dots show where the probability from our model is
TE D
between 0.15 and 0.5 (notice for these points the Petersen cut-off is below 2.3 for all), and the black dots show where they do not agree.
EP
Figure 3: An example of a patient where the ED T/C ratio at the base (A), mid-cavity (B) and apex (C) are: 1.4 (T=8 mm, C=5.6 mm), 1.9 (T=14 mm, C=7.2 mm) and 2
AC C
(T=12 mm, C=6 mm). This patient would not be diagnosed with LVNC by the 2.3 cutoff but is reclassified as LVNC by the diagnostic tool proposed. C=compacted, white arrows, T=trabecular, black arrows Figure 4: Examples of LV mid-cavity ED frames of a normal volunteer (A), a patient with dilated cardiomyopathy (B) for comparison, a patient with LVNC and reduced EF (C) and a patient with LVNC and normal EF (D) – note that a trabecular meshwork replaces the distinct papillary muscle heads in the LVNC patients at midcavity level. 15
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Left ventricular noncompaction
RI PT
Normal volunteers
Ejection fraction
