Abnormal cardiac formation in hypertrophic cardiomyopathy: fractal analysis of trabeculae and preclinical gene expression.
BACKGROUND
Mutations in genes coding for sarcomeric proteins cause hypertrophic cardiomyopathy. Subtle abnormalities of the myocardium may be present in mutation carriers without left ventricular hypertrophy (G+LVH-) but are difficult to quantify. Fractal analysis has been used to define trabeculae in left ventricular noncompaction and to identify normal racial variations. We hypothesized that trabeculae measured by fractal analysis of cardiovascular magnetic resonance images are abnormal in G+LVH- patients, providing a preclinical marker of disease in hypertrophic cardiomyopathy.


RESULTS
Cardiovascular magnetic resonance was performed on 40 G+LVH- patients (33±15 years, 38% men), 67 patients with a clinical diagnosis of hypertrophic cardiomyopathy (53±15 years, 76% men; 31 with a pathogenic mutation [G+LVH+]), and 69 matched healthy volunteers (44±15 years, 57% men). Trabeculae were quantified by fractal analysis of cine slices to calculate the fractal dimension, a unitless index of endocardial complexity calculated from endocardial contours after segmentation. In G+LVH- patients, apical left ventricular trabeculation was increased compared with controls (maximal apical fractal dimension, 1.249±0.07 versus 1.199±0.05; P=0.001). In G+LVH+ and G-LVH+ cohorts, maximal apical fractal dimension was greater than in controls (P<0.0001) irrespective of gene status (G+LVH+: 1.370±0.08; G-LVH+: 1.380±0.09). Compared with controls, G+LVH- patients also had a higher frequency of clefts (28% versus 8%; P=0.02), longer anterior mitral valve leaflets (23.5±3.0 versus 19.7±3.1 mm; P<0.0001), greater septal systolic wall thickness (12.6±3.2 versus 11.2±2.1 mm; P=0.03), higher ejection fraction (71±4% versus 69±4%; P=0.03), and smaller end-systolic volumes (38±9 versus 43±12 mL; P=0.03).


CONCLUSIONS
Increased myocardial trabecular complexity is one of several preclinical abnormalities in hypertrophic cardiomyopathy sarcomere gene mutation carriers without LVH.
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Gabriella
G
Captur
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Luis R
LR
Lopes
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Vimal
V
Patel
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Chunming
C
Li
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Paul
P
Bassett
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Petros
P
Syrris
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Daniel M
DM
Sado
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Viviana
V
Maestrini
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Timothy J
TJ
Mohun
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
William J
WJ
McKenna
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Vivek
V
Muthurangu
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu).
Perry M
PM
Elliott
From Division of Cardiovascular Imaging and Inherited Cardiovascular Disease Unit, The Heart Hospital, part of University College London NHS Foundation Trust, London, United Kingdom (G.C., L.L., V.P., P.S., D.M.S., V. Maestrini, W.J.M., P.M.E., J.C.M.); UCL Institute of Cardiovascular Science (G.C., L.L., V.P., P.B., P.S., D.M.S., V. Maestrini, W.J.M., V. Muthurangu, P.M.E., J.C.M.) and Biostatistics Joint Research Office (P.B.), University College London, London, United Kingdom; Department of Radiology, University of Pennsylvania, Philadelphia (C.L.); Developmental Biology Division, MRC National Institute for Medical Research, London, United Kingdom (T.J.M.); and UCL Centre for Cardiovascular Imaging and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom (V. Muthurangu). james.moon@uclh.nhs.uk.
James C
JC
Moon
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D017709:Fractals; D015870:Gene Expression; D006352:Heart Ventricles / Q000002:abnormalities* / Q000000981:diagnostic imaging; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D011859:Radiography; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
cardiomyopathy, hypertrophic; genetics; magnetic resonance imaging