Myocardial T1 mapping and extracellular volume quantification in patients with left ventricular non-compaction cardiomyopathy

Myocardial T1 mapping and extracellular volume quantification in patients with left ventricular... Abstract Aims From pathophysiological mechanisms to risk stratification and management, much debate and discussion persist regarding left ventricular non-compaction cardiomyopathy (LVNC). This study aimed to characterize myocardial T1 mapping and extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR), and investigate how these biomarkers relate to left ventricular ejection fraction (LVEF) and ventricular arrhythmias (VA) in LVNC. Methods and results Patients with LVNC (n = 36) and healthy controls (n = 18) were enrolled to perform a CMR with T1 mapping. ECV was quantified in LV segments without late gadolinium enhancement (LGE) areas to investigate diffuse myocardial fibrosis. Patients with LVNC had slightly higher native T1 (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to controls. The ECV was independently associated with LVEF (β = −1.3, P = 0.001). Among patients without LGE, VAs were associated with higher ECV (27.7% with VA vs. 25.8% without VA, P = 0.002). Conclusion In LVNC, tissue characterization by T1 mapping suggests an extracellular expansion by diffuse fibrosis in myocardium without LGE, which was associated with myocardial dysfunction and VA, but not with the amount of non-compacted myocardium. left ventricular non-compaction cardiomyopathy , T1 mapping , extracellular volume , myocardial fibrosis , myocardial dysfunction , ventricular arrhythmias Introduction Three decades after the first imaging1 of the left ventricular non-compaction cardiomyopathy (LVNC), much debate persists in the current literature regarding its classification, over-diagnosis and management.2–4 Recently, the clinical recognition has become more frequent due to the increased awareness, familial screening, and improvements in the cardiovascular imaging.5,6 On the other hand, the low prevalence of LVNC, a rare primary genetic cardiomyopathy, precludes large prospective studies for clarifying its pathogenesis, improving the current diagnosis criteria and finding targeted treatments. The fact is that clinical presentation ranges from asymptomatic to severe clinical settings such as heart failure, embolic events, and ventricular arrhythmias (VA), which are usually associated with poor prognosis.3,7 Cardiovascular magnetic resonance (CMR) imaging has been widely used to diagnose more accurately LVNC, and thereby helping to distinguish true LVNC from the prominent hyper-trabeculation that can occur even in normal individuals.4 CMR is also able to detect myocardial tissue changes, including focal myocardial fibrosis by late gadolinium enhancement (LGE)8 and, recently, diffuse abnormalities in myocardial structure by myocardial T1 mapping and extracellular volume (ECV) fraction, such as oedema and interstitial diffuse fibrosis.9,10 These latter CMR parameters have provided over the last decade new insights into cardiac involvement and pathogenesis of many cardiomyopathies, which have assisted clinical decision making.11 This study was designed to investigate myocardial tissue by T1 mapping and ECV in patients with LVNC and determine how these tissue biomarkers relate to left ventricular function and arrhythmia. Materials and methods In this cross-sectional observational study, 36 patients with LVNC, who are followed at Heart Institute (InCor), were prospectively recruited to perform a CMR study with T1 mapping, before and after contrast injection, from July 2013 to September 2016. Eighteen healthy volunteers, without cardiovascular disease or risk factors, were also enrolled, using age and sex matching (ECV values in normal population are age and gender dependent).12–14 Exclusion criteria included an age under 18, pregnancy, presence of a non-CMR compatible device, contraindications to contrast administration [Glomerular filtration rate (GFR) < 30 mL/s/min] and atrial fibrillation during magnetic resonance scanning (irregular and rapid ventricle rate potentiality cause some inaccurate T1 estimation).15 Any patient with LVNC classified for Stage 2 hypertension was also excluded from this study. This study was approved by the institutional review board for human subject studies, and all participants provided informed written consent prior to enrolment. Of note, the diagnosis of LVNC at our tertiary care hospital is only considered when the clinical pre-test probability is high, which is assessed by the presence of LVNC-related symptoms (e.g. syncope, arrhythmias, and thrombo-embolic events) or impaired LV function with no other cardiac disease cause, coexistent neuro-muscular disorder and/or family history of cardiomyopathy. Patients over age 35, especially in the presence of symptoms/signs of coronary artery disease (CAD) or risk factors, had either additional non-invasive or invasive investigation of CAD.16 Moreover, all patients with suspected LVNC were submitted to CMR to measure the extent of LV trabeculations and to verify whether they meet the imaging criteria.17 Holter monitoring Twenty-four hours ambulatory Holter monitoring in order to investigate VA was performed for all patients. In this study, patients were classified as positive to VA when they presented with either non-sustained ventricular tachycardia (NSVT) or sustained ventricular tachycardia (SVT). NSVT was defined as ≥3 consecutive ventricular premature beats at ≥120 beats per minute, and lasting <30 s. CMR All studies were performed with a 1.5 T CMR scanner (Philips Achieva, Best, The Netherlands). Cine and LGE images were obtained as previously described.18,19 T1 mapping was performed using an ECG-triggered single-shot Modified Look-Locker Inversion recovery (MOLLI) sequence, with the 3(3)3(3)5 sampling pattern, and the following parameters: slice thickness 10 mm, field of view 300 × 300 mm, ACQ matrix (read-out × phase-encodings) 152 × 150, flip angle 40, minimum TI 60 ms, inversion-time increment 150 ms. Three MOLLI short-axis images (basal, mid, and apical slices) were acquired prior, and 15 min after an intravenous bolus of 0.2 mmol per kg of body weight of gadolinium-based contrast (Dotarem®, Guerbet Aulnay-Sous-Bois, France). Basal slice was carefully planned to avoid the LV outflow tract. Similar caution was also exercised for drawing the endocardial contours in order to prevent blood pool contamination especially in thinner myocardial layers (Figure 1). Figure 1 View largeDownload slide T1 Mapping in a patient with LVNC. Mid-ventricular short-axis native T1 (MOLLI) map (a) and manual tracing of the myocardial borders in compacted layer of left ventricle (b). Four-chamber (c) and left ventricular outflow tract cines (d) showing the excellent spatial resolution of cardiac magnetic resonance in characterization of prominent trabeculae and intertrabecular recesses in LVNC. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Figure 1 View largeDownload slide T1 Mapping in a patient with LVNC. Mid-ventricular short-axis native T1 (MOLLI) map (a) and manual tracing of the myocardial borders in compacted layer of left ventricle (b). Four-chamber (c) and left ventricular outflow tract cines (d) showing the excellent spatial resolution of cardiac magnetic resonance in characterization of prominent trabeculae and intertrabecular recesses in LVNC. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Image analysis All CMR images were analysed using cvi42 software (Circle Cardiovascular Imaging Inc., Calgary, Canada) by a trained radiologist with 4 years of cardiovascular imaging experience. End-systolic, end-diastolic LV volumes, LV mass, and LV ejection fraction were measured by standard methods.20 The pattern of LGE was classified as subendocardial, mid-wall, subepicardial, or transmural. For quantification, was adopted a semiautomatic thresholding technique to the LGE images with a signal intensity cut-off value of mean normal myocardium + 5 SD, which had best agreement with visual analysis and also it seems to have the best correlation with histopathology.21 T1 estimation was performed by three-parameter non-linear curve fitting using the signal intensity and time after inversion for each image as previously described.19,22 ECV was then calculated using the partition coefficient (λ) and contemporaneous haematocrit (HCT) as follows:   R1 = 1/T1 (1)  ΔR1 = R1post–R1pre (2)  λ = ΔR1myo/ΔR1blood (3)  ECV = λ·(100−HCT) (4) Native (i.e. pre-contrast) T1 and ECV are reported here only for segments without LGE. Short-axis LGE and myocardial T1 images were segmented as per American Heart Association 16-segment model. As recommended, the apex (segment 17) was excluded from our analysis because it is usually extremely thin in LVNC.17 Compacted myocardial layers located in regions with prominent LV trabeculae and deep intertrabecular recesses were called non-compacted (NC) segments and, conversely, segments when located in regions without any marked trabeculations were classified as compacted. The segments were also classified according to the degree of trabeculations by using the largest non-compacted-to-compacted (NC:C) ratio (maximal NC:C ratio) and the presence of diagnostic CMR criteria (NC:C ratio > 2.3), both in end-diastole17 (Figure 2). Figure 2 View largeDownload slide Boxplots show the differences in native T1 (a) and ECV (b) between patients with LVNC and control subjects. ECV differences (c) between controls and patients with impaired and preserved LV function. ECV, extracellular volume; LVEF, left ventricular ejection fraction. Figure 2 View largeDownload slide Boxplots show the differences in native T1 (a) and ECV (b) between patients with LVNC and control subjects. ECV differences (c) between controls and patients with impaired and preserved LV function. ECV, extracellular volume; LVEF, left ventricular ejection fraction. Statistical analysis Data are expressed as mean ± SD and frequency (percentage). Normality was graphically assessed by QQ-plots and tested using the Shapiro–Wilk test. Comparisons were made using two-sample t-test (or Wilcoxon rank-sum test) and χ2 tests (or Fisher exact test) for continuous and categorical data, respectively. Associations between left ventricular ejection fraction (LVEF) in patients with LVNC and clinical/CMR characteristics were evaluated by the Pearson’s correlation coefficient. Linear regression analysis was used to investigate the relationship between LVEF and the following variables: age, sex, body mass index, cardiovascular risk (Framingham risk score), medications, maximal NC:C ratio, presence of LGE, native T1, and ECV. To avoid overfitting in the multivariate regression model, the Akaike information criterion was assessed and final covariates were included based on clinical knowledge. Effect modification was also investigated using P-values from interaction terms fitted in the multivariate models. Subgroups of patients with LGE-positive and LGE-negative were created to investigate the relationship of myocardial diffuse fibrosis and VA. Differences from these subgroups were examined using one-way analysis of variance (ANOVA) with Bonferroni post hoc tests as needed to correct P-values for multiple comparisons. All statistical analyses were performed with the statistical package R (www.r-project.org) and a P-value <0.05 was considered statistically significant. Results Clinical characteristics Table 1 summarizes the clinical characteristics of patients with LVNC (n = 36) and healthy controls (n = 18). These two groups were well matched by age and sex (41 ± 13 years for control vs. 41 ± 16 years for LVNC; 61% of males for both groups), and near 90% of patients and controls were white. Of 36 patients, 16 (44%) had a family history of LVNC, 11 had VA (31%) during Holter monitoring, and 3 had a prior thrombo-embolic event. The patients had no limiting HF symptoms (72% were NYHA Class I and 28% Class II) and were receiving optimal medical therapy. Table 1 Characteristics of the study population   Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001    Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001  Plus-minus values are means  ±  SD. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ECV, extracellular volume; LGE, late gadolinium enhancement; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; LVNC, left ventricular non-compaction; NC:C non-compacted/compacted; NYHA, New York Heart Association; RVEDVI, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic; RWT, relative wall thickness; VA, ventricular arrhythmia. * P-value for comparison between the three groups. § P-value < 0.05 for LVNC (LVEF ≥ 50%) vs. controls. † P-value < 0.05 for LVNC (LVEF < 50%) vs. controls. ¶ P-value < 0.05 for LVNC (LVEF < 50%) vs. LVNC (LVEF ≥ 50%). Table 1 Characteristics of the study population   Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001    Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001  Plus-minus values are means  ±  SD. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ECV, extracellular volume; LGE, late gadolinium enhancement; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; LVNC, left ventricular non-compaction; NC:C non-compacted/compacted; NYHA, New York Heart Association; RVEDVI, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic; RWT, relative wall thickness; VA, ventricular arrhythmia. * P-value for comparison between the three groups. § P-value < 0.05 for LVNC (LVEF ≥ 50%) vs. controls. † P-value < 0.05 for LVNC (LVEF < 50%) vs. controls. ¶ P-value < 0.05 for LVNC (LVEF < 50%) vs. LVNC (LVEF ≥ 50%). Morpho-functional parameters and LGE (focal myocardial fibrosis) Patients with LVNC had significantly increased LV volumes (P < 0.001) when compared to the control group and mean LVEF of 42 ± 10%, with a total of 24 patients (67%) with impaired LV function (LVEF < 50%). The LV shape in LVNC was more eccentric and dilated than in the control group (low relative wall thickness and LV mass/volume ratio, 0.22 ± 0.07 and 0.58 ± 0.14 g/mL, respectively). The number of LV segments with NC:C ratio > 2.3 and maximal NC:C ratio per patient were 8.8 ± 2.3 and 5.7 ± 1.4, respectively. Twelve patients (33%) had focal myocardial fibrosis (LGE-positive), which was present in 78 of 576 LV segments (14%). The LGE-patterns included mid-wall and subepicardial enhancement in the lateral and inferior walls; and septal mid-wall enhancement at RV–LV junction. T1 mapping (diffuse myocardial fibrosis) Patients with LVNC had slightly higher native T1 values (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to control subjects (Figure 2). Patients with preserved LV function (LVEF ≥ 50%) had significantly lower ECV values than those patients with impaired LVEF (25.3 ± 2.9% vs. 29.4 ± 4.6%, P = 0.008) and marginally higher than controls (P = 0.06). The differences in native T1 and ECV, compared to healthy controls, were mainly found in apical segments, the inferior wall and the septum (Figure 3). A significantly increased ECV was also observed when comparing only NC segments of patients, with matching segment locations in control subjects (26.9% vs. 23.4%, P < 0.001). Of note, neither native T1 nor ECV were significantly different when comparing NC with compacted segments in patients (1021.3 ± 61.8 ms vs. 1020.8 ± 75.5 ms, P = 0.9; 28.2 ± 4.9% vs. 27.8 ± 4.9%, P = 0.39), and also no significant association was observed between the degree of the trabeculations and the T1-derived values (Figure 3). Compared to controls, both LGE-positive and LGE-negative patients had a significantly increased ECV (31.6% ± 5.0 for LGE+ and 26.2% ± 3.0 for LGE, both P < 0.05). Figure 3 View largeDownload slide Bullseye plots show averages for native T1 (a), ECV (b), NC:C ratio (c) and NC:C ratio >2.3 (d) in patients LVNC. The numbers (1–16) inside each bullseye plot represent the left ventricular wall segments according to the American Heart Association classification. For segments 2, 3, and 9, no trabeculations were found. ECV, extracellular volume; NC:C, non-compacted/compacted. Figure 3 View largeDownload slide Bullseye plots show averages for native T1 (a), ECV (b), NC:C ratio (c) and NC:C ratio >2.3 (d) in patients LVNC. The numbers (1–16) inside each bullseye plot represent the left ventricular wall segments according to the American Heart Association classification. For segments 2, 3, and 9, no trabeculations were found. ECV, extracellular volume; NC:C, non-compacted/compacted. Correlations between T1 mapping and functional/clinical characteristics of patients with LVNC Both native T1 and ECV correlated significantly with LVEF (r = −0.38, P = 0.02 and r = −0.67, P < 0.001, respectively) in patients with LVNC. Patients with ECV ≥ 30% (n = 10) had more impaired LV function than those patients with ECV < 30% (LVEF: 30 ± 13% vs. 45 ± 11%, P = 0.001). Beta-blocker and ACE inhibitor or ARB therapy, and LGE (% LV mass) were also associated with LVEF in univariate linear regression models (Table 2). Interestingly, LGE was negative in 50% of patients with ECV ≥ 30%. In the multivariate model, only ECV remained a significant predictor for LVEF in LVNC (β = −1.3, P = 0.001) (Table 2). There was also a trend for beta-blocker therapy to be an effect modifier for the association between ECV and LVEF (β = 4.1, 95% confidence interval, −0.6 to 8.8, P for interaction = 0.08). Table 2 Univariate and multivariate analysis of the determinants of LVEF in patients with LVNC Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease risk (Framingham risk score); ECV, extracellular volume; LGE, late gadolinium enhancement; NC:C, non-compacted/compacted. Table 2 Univariate and multivariate analysis of the determinants of LVEF in patients with LVNC Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease risk (Framingham risk score); ECV, extracellular volume; LGE, late gadolinium enhancement; NC:C, non-compacted/compacted. There were no significant correlations between maximal NC:C ratio and T1-derived indices (r = 0.26 for both ECV and native T1, with P = 0.12). VA, as defined in the methods section, were found in 11 patients (5 with preserved and 6 patients with reduced LVEF). Only 2 patients presented sustained VT and their LVEFs were reduced (34% and 41%). Interestingly, no LGE was detected in five patients (45%) in whom VA was detected and these patients presented the following LVEF: 33%, 51%, 52%, 52%, and 56%. The other six patients presented LGE-positive and mostly had impaired LV function (17%, 31%, 34%, 36%, 41%, and 54%). On the other hand, the mean ECV of LV segments in patients who had VA was significantly higher when compared with those without VA detected, regardless the presence of LGE (27.7% vs. 25.8%, P = 0.002 for LGE-negative; 33.9% vs. 28.8%, P < 0.001 for LGE-positive) (Figure 4). Figure 4 View largeDownload slide Graph shows the per-segment analysis of ECV in control subjects and patients with LGE-negative and LGE-positive. ECV, extracellular volume; LGE, late gadolinium enhancement; ns, no significant; VA, ventricular arrhythmia. Figure 4 View largeDownload slide Graph shows the per-segment analysis of ECV in control subjects and patients with LGE-negative and LGE-positive. ECV, extracellular volume; LGE, late gadolinium enhancement; ns, no significant; VA, ventricular arrhythmia. Discussion This is the first study to demonstrate diffuse changes in myocardial tissue characteristics by pre- and post-contrast T1 mapping in patients with LVNC, including changes in ECV, in myocardium without focal fibrosis (LGE-negative regions). The main findings include: (i) patients with LVNC showed increased ECV and native T1 compared with controls, but changes in native T1 were relatively small compared with ECV; (ii) for ECV, the observed increase holds true for both LGE-positive and LGE-negative patients; (iii) ECV was associated in LVNC with LV dysfunction and VA, but not with the amount of non-compacted myocardium. Our T1 mapping results in LVNC, of ∼20% higher ECV and ∼3% increased native T1 than in controls, indicate that an expansion of extracellular matrix is more likely than myocardial oedema, in which the native T1 changes are generally greater.10,23 Noteworthy, the mean ECV of our controls was slightly lower than some reported in healthy subjects,13,14 but this may be explained by the fact that majority of our controls was male and relatively young, usually associated to lower ECV values.11,12,24 We have also found a diffuse myocardial involvement in patients with and without focal fibrosis, yet these tissue changes occur particularly in patients with myocardial dysfunction. Indeed, patients with preserved LVEF (≥50%) did not present greater ECV than control subjects, even though all of them were at a high clinical probability. Whether those patients had no disease or simply early stages of LVNC is undetermined, yet the information of a ‘normal’ ECV may be important in clinical practice in terms of prognosis (not diagnosis) at this time point. Similarly, despite the prognostic value, increased ECV in patients with LVEF < 50% can simply reflect the presence of an established cardiomyopathy (not specifically LVNC). Our results are in line with previous pathological studies that documented interstitial diffuse changes in LVNC hearts.25,26 Also, a previous CMR study with T1 mapping in LVNC,27 only evaluating native T1, also found native T1 changes in patients with absence of focal fibrosis (LGE-negative). However, in that study, conclusions regarding diffuse interstitial fibrosis were not provided due to the absence of ECV measurements. Histologically, LGE is usually linked to replacement fibrosis in cardiomyopathies,28,29 which seems to be not modifiable after treatment. On the other hand, T1 mapping plays an important role in recognizing subclinical diffuse myocardial changes,30–32 potentially treatable. Our data describe in more detail the underlying pathophysiology of LVNC and also warrant further studies to investigate this potential role of T1 mapping and ECV in addition to LGE in LVNC, which is usually a marker of irreversible damage and advanced disease. We also demonstrated that ECV in LVNC was strongly associated with LV systolic function and was the only independent predictor LV systolic dysfunction in the multivariate analysis. These findings are in agreement with other cardiomyopathies, in which a strong relationship between abnormal T1-mapping, LV remodelling, and poor outcomes was also demonstrated.33–35 Interestingly, we found a considerable effect of beta-blocker use in positively modifying the relationship between ECV and LVEF, but regrettably this study was not sufficiently powered for this analysis and only a trend was observed (P for interaction = 0.08). Although limited studies are available, this finding parallels the beneficial effect of beta-blocker therapy in LVNC in terms of limiting adverse LV remodelling36 and, recently, modulating the cardiac metabolism.37 Besides the lack of association between trabeculated myocardium and LVEF, we have also found higher levels of ECV and native T1 in basal and mid-LV segments, where low degree or even no trabeculations were found. These findings reinforce previous data that non-compacted segments are not more importantly ‘diseased’,37,38 being likely only an epiphenomenon, rather than a mediator of adversity. ECV changes in our patients with LVNC were also associated with VA over and above LGE. A recent study39 evaluating the electrocardiographic impact of myocardial diffuse fibrosis by T1 mapping and scar (LGE-positive) showed lower QRS voltage in patients with expanded ECV and longer QT interval among those with scar. Likewise, describing electrophysiology features and outcomes of catheter ablation in a small cohort of nine patients with LVNC,40 one patient (with LGE-negative) presented abnormal T1-derived indices (compatible with increased interstitial fibrosis) and that region was found to have a low unipolar voltage. All these electrophysiologic abnormalities have been associated with more adverse outcomes and, hence, we believe these findings support a potential incremental value of ECV over LGE in triggering VA in LVNC. There were limitations in our study. Firstly, although the region of interest was carefully drawn, T1 analysis in apical slices might suffer from some blood contamination due to the limited spatial resolution in thinner layers and, consequently, increase ECV values in those areas. However, the mean thickness of compacted myocardium in those segments was reasonable (3.2 mm) in comparison to the CMR spatial resolution (∼2.0 mm) and, in addition, LV segments with high degree of trabeculations were not significantly associated with high T1-derived values. Secondly, sensitivity by Petersen criteria is lower than Jacquier’s (86% vs. 93.7%), which may have led to a lower proportion of patients correctly classified as having LVNC. Nevertheless, in high pre-test scenarios (such our study population), the post-test probability of Petersen criteria is much higher, enhancing the role of CMR as a rule-in test.41 Thirdly, our relative small sample size is a real limitation. Despite the large confidence interval of the interaction term of beta-blocker use suggests that the effect may be substantial, the evidence of this study is limited and it was penalized by the sample size. Similarly, we recognize that results of the multivariate analysis should be interpreted as an exploratory analysis and hypothesis-generating. Prospective properly designed studies with larger patient cohorts are needed to further validate the prognostic implications of our findings. Conclusion In conclusion, tissue characterization by T1 mapping provided new insights into the pathophysiology of LVNC, suggesting a myocardial extracellular expansion by diffuse fibrosis. This expansion was strongly associated with LV function and VA, over and above LGE, but not with the amount of non-compacted myocardium. These findings lend support for the role of this technique in refining the risk stratification of LVNC patients. Conflict of interest: None declared. References 1 Engberding R, Bender F. Identification of a rare congenital anomaly of the myocardium by two-dimensional echocardiography: persistence of isolated myocardial sinusoids. Am J Cardiol  1984; 53: 1733– 4. Google Scholar CrossRef Search ADS PubMed  2 Arbustini E, Weidemann F, Hall JL. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? J Am Coll Cardiol  2014; 64: 1840– 50. Google Scholar CrossRef Search ADS PubMed  3 Oechslin E, Jenni R. Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? Eur Heart J  2011; 32: 1446– 56. 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Google Scholar CrossRef Search ADS PubMed  40 Muser D, Liang JJ, Witschey WR, Pathak RK, Castro S, Magnani S et al.   Ventricular arrhythmias associated with left ventricular noncompaction: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm  2017; 14: 166– 75. Google Scholar CrossRef Search ADS PubMed  41 Petersen SE. CMR and LV noncompaction: does it matter how we measure trabeculations? JACC Cardiovasc Imaging  2013; 6: 941– 3. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Myocardial T1 mapping and extracellular volume quantification in patients with left ventricular non-compaction cardiomyopathy

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Oxford University Press
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2047-2404
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10.1093/ehjci/jey022
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Abstract

Abstract Aims From pathophysiological mechanisms to risk stratification and management, much debate and discussion persist regarding left ventricular non-compaction cardiomyopathy (LVNC). This study aimed to characterize myocardial T1 mapping and extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR), and investigate how these biomarkers relate to left ventricular ejection fraction (LVEF) and ventricular arrhythmias (VA) in LVNC. Methods and results Patients with LVNC (n = 36) and healthy controls (n = 18) were enrolled to perform a CMR with T1 mapping. ECV was quantified in LV segments without late gadolinium enhancement (LGE) areas to investigate diffuse myocardial fibrosis. Patients with LVNC had slightly higher native T1 (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to controls. The ECV was independently associated with LVEF (β = −1.3, P = 0.001). Among patients without LGE, VAs were associated with higher ECV (27.7% with VA vs. 25.8% without VA, P = 0.002). Conclusion In LVNC, tissue characterization by T1 mapping suggests an extracellular expansion by diffuse fibrosis in myocardium without LGE, which was associated with myocardial dysfunction and VA, but not with the amount of non-compacted myocardium. left ventricular non-compaction cardiomyopathy , T1 mapping , extracellular volume , myocardial fibrosis , myocardial dysfunction , ventricular arrhythmias Introduction Three decades after the first imaging1 of the left ventricular non-compaction cardiomyopathy (LVNC), much debate persists in the current literature regarding its classification, over-diagnosis and management.2–4 Recently, the clinical recognition has become more frequent due to the increased awareness, familial screening, and improvements in the cardiovascular imaging.5,6 On the other hand, the low prevalence of LVNC, a rare primary genetic cardiomyopathy, precludes large prospective studies for clarifying its pathogenesis, improving the current diagnosis criteria and finding targeted treatments. The fact is that clinical presentation ranges from asymptomatic to severe clinical settings such as heart failure, embolic events, and ventricular arrhythmias (VA), which are usually associated with poor prognosis.3,7 Cardiovascular magnetic resonance (CMR) imaging has been widely used to diagnose more accurately LVNC, and thereby helping to distinguish true LVNC from the prominent hyper-trabeculation that can occur even in normal individuals.4 CMR is also able to detect myocardial tissue changes, including focal myocardial fibrosis by late gadolinium enhancement (LGE)8 and, recently, diffuse abnormalities in myocardial structure by myocardial T1 mapping and extracellular volume (ECV) fraction, such as oedema and interstitial diffuse fibrosis.9,10 These latter CMR parameters have provided over the last decade new insights into cardiac involvement and pathogenesis of many cardiomyopathies, which have assisted clinical decision making.11 This study was designed to investigate myocardial tissue by T1 mapping and ECV in patients with LVNC and determine how these tissue biomarkers relate to left ventricular function and arrhythmia. Materials and methods In this cross-sectional observational study, 36 patients with LVNC, who are followed at Heart Institute (InCor), were prospectively recruited to perform a CMR study with T1 mapping, before and after contrast injection, from July 2013 to September 2016. Eighteen healthy volunteers, without cardiovascular disease or risk factors, were also enrolled, using age and sex matching (ECV values in normal population are age and gender dependent).12–14 Exclusion criteria included an age under 18, pregnancy, presence of a non-CMR compatible device, contraindications to contrast administration [Glomerular filtration rate (GFR) < 30 mL/s/min] and atrial fibrillation during magnetic resonance scanning (irregular and rapid ventricle rate potentiality cause some inaccurate T1 estimation).15 Any patient with LVNC classified for Stage 2 hypertension was also excluded from this study. This study was approved by the institutional review board for human subject studies, and all participants provided informed written consent prior to enrolment. Of note, the diagnosis of LVNC at our tertiary care hospital is only considered when the clinical pre-test probability is high, which is assessed by the presence of LVNC-related symptoms (e.g. syncope, arrhythmias, and thrombo-embolic events) or impaired LV function with no other cardiac disease cause, coexistent neuro-muscular disorder and/or family history of cardiomyopathy. Patients over age 35, especially in the presence of symptoms/signs of coronary artery disease (CAD) or risk factors, had either additional non-invasive or invasive investigation of CAD.16 Moreover, all patients with suspected LVNC were submitted to CMR to measure the extent of LV trabeculations and to verify whether they meet the imaging criteria.17 Holter monitoring Twenty-four hours ambulatory Holter monitoring in order to investigate VA was performed for all patients. In this study, patients were classified as positive to VA when they presented with either non-sustained ventricular tachycardia (NSVT) or sustained ventricular tachycardia (SVT). NSVT was defined as ≥3 consecutive ventricular premature beats at ≥120 beats per minute, and lasting <30 s. CMR All studies were performed with a 1.5 T CMR scanner (Philips Achieva, Best, The Netherlands). Cine and LGE images were obtained as previously described.18,19 T1 mapping was performed using an ECG-triggered single-shot Modified Look-Locker Inversion recovery (MOLLI) sequence, with the 3(3)3(3)5 sampling pattern, and the following parameters: slice thickness 10 mm, field of view 300 × 300 mm, ACQ matrix (read-out × phase-encodings) 152 × 150, flip angle 40, minimum TI 60 ms, inversion-time increment 150 ms. Three MOLLI short-axis images (basal, mid, and apical slices) were acquired prior, and 15 min after an intravenous bolus of 0.2 mmol per kg of body weight of gadolinium-based contrast (Dotarem®, Guerbet Aulnay-Sous-Bois, France). Basal slice was carefully planned to avoid the LV outflow tract. Similar caution was also exercised for drawing the endocardial contours in order to prevent blood pool contamination especially in thinner myocardial layers (Figure 1). Figure 1 View largeDownload slide T1 Mapping in a patient with LVNC. Mid-ventricular short-axis native T1 (MOLLI) map (a) and manual tracing of the myocardial borders in compacted layer of left ventricle (b). Four-chamber (c) and left ventricular outflow tract cines (d) showing the excellent spatial resolution of cardiac magnetic resonance in characterization of prominent trabeculae and intertrabecular recesses in LVNC. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Figure 1 View largeDownload slide T1 Mapping in a patient with LVNC. Mid-ventricular short-axis native T1 (MOLLI) map (a) and manual tracing of the myocardial borders in compacted layer of left ventricle (b). Four-chamber (c) and left ventricular outflow tract cines (d) showing the excellent spatial resolution of cardiac magnetic resonance in characterization of prominent trabeculae and intertrabecular recesses in LVNC. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Image analysis All CMR images were analysed using cvi42 software (Circle Cardiovascular Imaging Inc., Calgary, Canada) by a trained radiologist with 4 years of cardiovascular imaging experience. End-systolic, end-diastolic LV volumes, LV mass, and LV ejection fraction were measured by standard methods.20 The pattern of LGE was classified as subendocardial, mid-wall, subepicardial, or transmural. For quantification, was adopted a semiautomatic thresholding technique to the LGE images with a signal intensity cut-off value of mean normal myocardium + 5 SD, which had best agreement with visual analysis and also it seems to have the best correlation with histopathology.21 T1 estimation was performed by three-parameter non-linear curve fitting using the signal intensity and time after inversion for each image as previously described.19,22 ECV was then calculated using the partition coefficient (λ) and contemporaneous haematocrit (HCT) as follows:   R1 = 1/T1 (1)  ΔR1 = R1post–R1pre (2)  λ = ΔR1myo/ΔR1blood (3)  ECV = λ·(100−HCT) (4) Native (i.e. pre-contrast) T1 and ECV are reported here only for segments without LGE. Short-axis LGE and myocardial T1 images were segmented as per American Heart Association 16-segment model. As recommended, the apex (segment 17) was excluded from our analysis because it is usually extremely thin in LVNC.17 Compacted myocardial layers located in regions with prominent LV trabeculae and deep intertrabecular recesses were called non-compacted (NC) segments and, conversely, segments when located in regions without any marked trabeculations were classified as compacted. The segments were also classified according to the degree of trabeculations by using the largest non-compacted-to-compacted (NC:C) ratio (maximal NC:C ratio) and the presence of diagnostic CMR criteria (NC:C ratio > 2.3), both in end-diastole17 (Figure 2). Figure 2 View largeDownload slide Boxplots show the differences in native T1 (a) and ECV (b) between patients with LVNC and control subjects. ECV differences (c) between controls and patients with impaired and preserved LV function. ECV, extracellular volume; LVEF, left ventricular ejection fraction. Figure 2 View largeDownload slide Boxplots show the differences in native T1 (a) and ECV (b) between patients with LVNC and control subjects. ECV differences (c) between controls and patients with impaired and preserved LV function. ECV, extracellular volume; LVEF, left ventricular ejection fraction. Statistical analysis Data are expressed as mean ± SD and frequency (percentage). Normality was graphically assessed by QQ-plots and tested using the Shapiro–Wilk test. Comparisons were made using two-sample t-test (or Wilcoxon rank-sum test) and χ2 tests (or Fisher exact test) for continuous and categorical data, respectively. Associations between left ventricular ejection fraction (LVEF) in patients with LVNC and clinical/CMR characteristics were evaluated by the Pearson’s correlation coefficient. Linear regression analysis was used to investigate the relationship between LVEF and the following variables: age, sex, body mass index, cardiovascular risk (Framingham risk score), medications, maximal NC:C ratio, presence of LGE, native T1, and ECV. To avoid overfitting in the multivariate regression model, the Akaike information criterion was assessed and final covariates were included based on clinical knowledge. Effect modification was also investigated using P-values from interaction terms fitted in the multivariate models. Subgroups of patients with LGE-positive and LGE-negative were created to investigate the relationship of myocardial diffuse fibrosis and VA. Differences from these subgroups were examined using one-way analysis of variance (ANOVA) with Bonferroni post hoc tests as needed to correct P-values for multiple comparisons. All statistical analyses were performed with the statistical package R (www.r-project.org) and a P-value <0.05 was considered statistically significant. Results Clinical characteristics Table 1 summarizes the clinical characteristics of patients with LVNC (n = 36) and healthy controls (n = 18). These two groups were well matched by age and sex (41 ± 13 years for control vs. 41 ± 16 years for LVNC; 61% of males for both groups), and near 90% of patients and controls were white. Of 36 patients, 16 (44%) had a family history of LVNC, 11 had VA (31%) during Holter monitoring, and 3 had a prior thrombo-embolic event. The patients had no limiting HF symptoms (72% were NYHA Class I and 28% Class II) and were receiving optimal medical therapy. Table 1 Characteristics of the study population   Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001    Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001  Plus-minus values are means  ±  SD. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ECV, extracellular volume; LGE, late gadolinium enhancement; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; LVNC, left ventricular non-compaction; NC:C non-compacted/compacted; NYHA, New York Heart Association; RVEDVI, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic; RWT, relative wall thickness; VA, ventricular arrhythmia. * P-value for comparison between the three groups. § P-value < 0.05 for LVNC (LVEF ≥ 50%) vs. controls. † P-value < 0.05 for LVNC (LVEF < 50%) vs. controls. ¶ P-value < 0.05 for LVNC (LVEF < 50%) vs. LVNC (LVEF ≥ 50%). Table 1 Characteristics of the study population   Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001    Control subjects (n = 18)  LVNC (LVEF ≥ 50%) (n = 12)  LVNC (LVEF < 50%) (n = 24)  P-value*  Age (years)  41 ± 13  39 ± 17  43 ± 15  0.62  Male sex, n (%)  11 (61)  8 (67)  14 (59)  0.89  White race, n (%)  16 (89)  11 (92)  22 (92)  0.74  Body mass index (kg/m2)  25 ± 3  26 ± 5  27 ± 5  0.22  Serum creatinine (mg/dL)  0.9 ± 0.3  1.0 ± 0.3  1.0 ± 0.2  0.92  Hypertension, n (%)    4 (33)  13 (54)    Diabetes, n (%)    1 (8)  3 (13)    Family history of LVNC, n (%)    9 (75)  7 (29)    Thrombo-embolic event, n (%)    0 (0)  3 (13)    NYHA Class > I, n (%)    0 (0)  10 (42)    VA, n (%)    5 (42)  6 (25)    Medical therapy           Beta-blocker, n (%)    6 (50)  21 (88)     ACE inhibitor or ARB, n (%)    9 (75)  23 (96)     Diuretic, n (%)    3 (25)  13 (54)     Oral anticoagulant, n (%)    3 (25)  17 (71)    CMR findings           LVEDVI (mL/m2)  71 ± 11  91 ± 16  127 ± 45†¶  <0.001   LVESVI (mL/m2)  26 ± 5  41 ± 11  76 ± 31†¶  <0.001   LVEF (%)  63 ± 5  54 ± 4§  36 ± 8†¶  <0.001   LV mass index (g/m2)  56 ± 10  57 ± 15  69 ± 24  0.05   LV mass/LVEDV (g/mL)  0.79 ± 0.13  0.62 ± 0.1§  0.56 ± 0.15†  <0.001   RWT  0.33 ± 0.07  0.24 ± 0.07§  0.22 ± 0.08†  <0.001   RVEDVI (mL/m2)  78 ± 13  84 ± 25  84 ± 29  0.68   RVESVI (mL/m2)  32 ± 8  37 ± 13  48 ± 25†  0.02   RVEF (%)  60 ± 4  57 ± 4§  45 ± 12†¶  <0.001   Maximal NC:C ratio    5.2 ± 1.2  6 ± 1.4     Segments with NC:C > 2.3, n (%)    8.1 ± 2  9.1 ± 2.4     LGE-positive, n (%)    2 (17)  10 (42)     LGE (% LV mass)    0.2 ± 0.5  2.5 ± 4.3     Native T1 (ms)  995 ± 22  1007 ± 31  1032 ± 46†  0.008   ECV (%)  23.5 ± 2.2  25 ± 3  29.4 ± 4.6†¶  <0.001  Plus-minus values are means  ±  SD. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ECV, extracellular volume; LGE, late gadolinium enhancement; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; LVNC, left ventricular non-compaction; NC:C non-compacted/compacted; NYHA, New York Heart Association; RVEDVI, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic; RWT, relative wall thickness; VA, ventricular arrhythmia. * P-value for comparison between the three groups. § P-value < 0.05 for LVNC (LVEF ≥ 50%) vs. controls. † P-value < 0.05 for LVNC (LVEF < 50%) vs. controls. ¶ P-value < 0.05 for LVNC (LVEF < 50%) vs. LVNC (LVEF ≥ 50%). Morpho-functional parameters and LGE (focal myocardial fibrosis) Patients with LVNC had significantly increased LV volumes (P < 0.001) when compared to the control group and mean LVEF of 42 ± 10%, with a total of 24 patients (67%) with impaired LV function (LVEF < 50%). The LV shape in LVNC was more eccentric and dilated than in the control group (low relative wall thickness and LV mass/volume ratio, 0.22 ± 0.07 and 0.58 ± 0.14 g/mL, respectively). The number of LV segments with NC:C ratio > 2.3 and maximal NC:C ratio per patient were 8.8 ± 2.3 and 5.7 ± 1.4, respectively. Twelve patients (33%) had focal myocardial fibrosis (LGE-positive), which was present in 78 of 576 LV segments (14%). The LGE-patterns included mid-wall and subepicardial enhancement in the lateral and inferior walls; and septal mid-wall enhancement at RV–LV junction. T1 mapping (diffuse myocardial fibrosis) Patients with LVNC had slightly higher native T1 values (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to control subjects (Figure 2). Patients with preserved LV function (LVEF ≥ 50%) had significantly lower ECV values than those patients with impaired LVEF (25.3 ± 2.9% vs. 29.4 ± 4.6%, P = 0.008) and marginally higher than controls (P = 0.06). The differences in native T1 and ECV, compared to healthy controls, were mainly found in apical segments, the inferior wall and the septum (Figure 3). A significantly increased ECV was also observed when comparing only NC segments of patients, with matching segment locations in control subjects (26.9% vs. 23.4%, P < 0.001). Of note, neither native T1 nor ECV were significantly different when comparing NC with compacted segments in patients (1021.3 ± 61.8 ms vs. 1020.8 ± 75.5 ms, P = 0.9; 28.2 ± 4.9% vs. 27.8 ± 4.9%, P = 0.39), and also no significant association was observed between the degree of the trabeculations and the T1-derived values (Figure 3). Compared to controls, both LGE-positive and LGE-negative patients had a significantly increased ECV (31.6% ± 5.0 for LGE+ and 26.2% ± 3.0 for LGE, both P < 0.05). Figure 3 View largeDownload slide Bullseye plots show averages for native T1 (a), ECV (b), NC:C ratio (c) and NC:C ratio >2.3 (d) in patients LVNC. The numbers (1–16) inside each bullseye plot represent the left ventricular wall segments according to the American Heart Association classification. For segments 2, 3, and 9, no trabeculations were found. ECV, extracellular volume; NC:C, non-compacted/compacted. Figure 3 View largeDownload slide Bullseye plots show averages for native T1 (a), ECV (b), NC:C ratio (c) and NC:C ratio >2.3 (d) in patients LVNC. The numbers (1–16) inside each bullseye plot represent the left ventricular wall segments according to the American Heart Association classification. For segments 2, 3, and 9, no trabeculations were found. ECV, extracellular volume; NC:C, non-compacted/compacted. Correlations between T1 mapping and functional/clinical characteristics of patients with LVNC Both native T1 and ECV correlated significantly with LVEF (r = −0.38, P = 0.02 and r = −0.67, P < 0.001, respectively) in patients with LVNC. Patients with ECV ≥ 30% (n = 10) had more impaired LV function than those patients with ECV < 30% (LVEF: 30 ± 13% vs. 45 ± 11%, P = 0.001). Beta-blocker and ACE inhibitor or ARB therapy, and LGE (% LV mass) were also associated with LVEF in univariate linear regression models (Table 2). Interestingly, LGE was negative in 50% of patients with ECV ≥ 30%. In the multivariate model, only ECV remained a significant predictor for LVEF in LVNC (β = −1.3, P = 0.001) (Table 2). There was also a trend for beta-blocker therapy to be an effect modifier for the association between ECV and LVEF (β = 4.1, 95% confidence interval, −0.6 to 8.8, P for interaction = 0.08). Table 2 Univariate and multivariate analysis of the determinants of LVEF in patients with LVNC Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease risk (Framingham risk score); ECV, extracellular volume; LGE, late gadolinium enhancement; NC:C, non-compacted/compacted. Table 2 Univariate and multivariate analysis of the determinants of LVEF in patients with LVNC Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  Variables  Univariate analysis   β-coefficient  P-value  Age (years)  −0.2  0.13  Male sex  2.4  0.51  BMI (kg/m2)  0.2  0.58  CVD risk  −0.2  0.13  Beta-blocker  −12.1  0.002  ACE inhibitor or ARB  −14.4  0.009  Maximal NC:C ratio  −2.2  0.09  LGE (% LV mass)  −0.9  0.04  Native T1  −0.08  0.09  ECV  −1.8  <0.001    Multivariate analysis  Beta-blocker  −1.9  0.66  ACE inhibitor or ARB  −5.8  0.28  LGE (% LV mass)  −0.4  0.43  ECV  −1.3  0.001  ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease risk (Framingham risk score); ECV, extracellular volume; LGE, late gadolinium enhancement; NC:C, non-compacted/compacted. There were no significant correlations between maximal NC:C ratio and T1-derived indices (r = 0.26 for both ECV and native T1, with P = 0.12). VA, as defined in the methods section, were found in 11 patients (5 with preserved and 6 patients with reduced LVEF). Only 2 patients presented sustained VT and their LVEFs were reduced (34% and 41%). Interestingly, no LGE was detected in five patients (45%) in whom VA was detected and these patients presented the following LVEF: 33%, 51%, 52%, 52%, and 56%. The other six patients presented LGE-positive and mostly had impaired LV function (17%, 31%, 34%, 36%, 41%, and 54%). On the other hand, the mean ECV of LV segments in patients who had VA was significantly higher when compared with those without VA detected, regardless the presence of LGE (27.7% vs. 25.8%, P = 0.002 for LGE-negative; 33.9% vs. 28.8%, P < 0.001 for LGE-positive) (Figure 4). Figure 4 View largeDownload slide Graph shows the per-segment analysis of ECV in control subjects and patients with LGE-negative and LGE-positive. ECV, extracellular volume; LGE, late gadolinium enhancement; ns, no significant; VA, ventricular arrhythmia. Figure 4 View largeDownload slide Graph shows the per-segment analysis of ECV in control subjects and patients with LGE-negative and LGE-positive. ECV, extracellular volume; LGE, late gadolinium enhancement; ns, no significant; VA, ventricular arrhythmia. Discussion This is the first study to demonstrate diffuse changes in myocardial tissue characteristics by pre- and post-contrast T1 mapping in patients with LVNC, including changes in ECV, in myocardium without focal fibrosis (LGE-negative regions). The main findings include: (i) patients with LVNC showed increased ECV and native T1 compared with controls, but changes in native T1 were relatively small compared with ECV; (ii) for ECV, the observed increase holds true for both LGE-positive and LGE-negative patients; (iii) ECV was associated in LVNC with LV dysfunction and VA, but not with the amount of non-compacted myocardium. Our T1 mapping results in LVNC, of ∼20% higher ECV and ∼3% increased native T1 than in controls, indicate that an expansion of extracellular matrix is more likely than myocardial oedema, in which the native T1 changes are generally greater.10,23 Noteworthy, the mean ECV of our controls was slightly lower than some reported in healthy subjects,13,14 but this may be explained by the fact that majority of our controls was male and relatively young, usually associated to lower ECV values.11,12,24 We have also found a diffuse myocardial involvement in patients with and without focal fibrosis, yet these tissue changes occur particularly in patients with myocardial dysfunction. Indeed, patients with preserved LVEF (≥50%) did not present greater ECV than control subjects, even though all of them were at a high clinical probability. Whether those patients had no disease or simply early stages of LVNC is undetermined, yet the information of a ‘normal’ ECV may be important in clinical practice in terms of prognosis (not diagnosis) at this time point. Similarly, despite the prognostic value, increased ECV in patients with LVEF < 50% can simply reflect the presence of an established cardiomyopathy (not specifically LVNC). Our results are in line with previous pathological studies that documented interstitial diffuse changes in LVNC hearts.25,26 Also, a previous CMR study with T1 mapping in LVNC,27 only evaluating native T1, also found native T1 changes in patients with absence of focal fibrosis (LGE-negative). However, in that study, conclusions regarding diffuse interstitial fibrosis were not provided due to the absence of ECV measurements. Histologically, LGE is usually linked to replacement fibrosis in cardiomyopathies,28,29 which seems to be not modifiable after treatment. On the other hand, T1 mapping plays an important role in recognizing subclinical diffuse myocardial changes,30–32 potentially treatable. Our data describe in more detail the underlying pathophysiology of LVNC and also warrant further studies to investigate this potential role of T1 mapping and ECV in addition to LGE in LVNC, which is usually a marker of irreversible damage and advanced disease. We also demonstrated that ECV in LVNC was strongly associated with LV systolic function and was the only independent predictor LV systolic dysfunction in the multivariate analysis. These findings are in agreement with other cardiomyopathies, in which a strong relationship between abnormal T1-mapping, LV remodelling, and poor outcomes was also demonstrated.33–35 Interestingly, we found a considerable effect of beta-blocker use in positively modifying the relationship between ECV and LVEF, but regrettably this study was not sufficiently powered for this analysis and only a trend was observed (P for interaction = 0.08). Although limited studies are available, this finding parallels the beneficial effect of beta-blocker therapy in LVNC in terms of limiting adverse LV remodelling36 and, recently, modulating the cardiac metabolism.37 Besides the lack of association between trabeculated myocardium and LVEF, we have also found higher levels of ECV and native T1 in basal and mid-LV segments, where low degree or even no trabeculations were found. These findings reinforce previous data that non-compacted segments are not more importantly ‘diseased’,37,38 being likely only an epiphenomenon, rather than a mediator of adversity. ECV changes in our patients with LVNC were also associated with VA over and above LGE. A recent study39 evaluating the electrocardiographic impact of myocardial diffuse fibrosis by T1 mapping and scar (LGE-positive) showed lower QRS voltage in patients with expanded ECV and longer QT interval among those with scar. Likewise, describing electrophysiology features and outcomes of catheter ablation in a small cohort of nine patients with LVNC,40 one patient (with LGE-negative) presented abnormal T1-derived indices (compatible with increased interstitial fibrosis) and that region was found to have a low unipolar voltage. All these electrophysiologic abnormalities have been associated with more adverse outcomes and, hence, we believe these findings support a potential incremental value of ECV over LGE in triggering VA in LVNC. There were limitations in our study. Firstly, although the region of interest was carefully drawn, T1 analysis in apical slices might suffer from some blood contamination due to the limited spatial resolution in thinner layers and, consequently, increase ECV values in those areas. However, the mean thickness of compacted myocardium in those segments was reasonable (3.2 mm) in comparison to the CMR spatial resolution (∼2.0 mm) and, in addition, LV segments with high degree of trabeculations were not significantly associated with high T1-derived values. Secondly, sensitivity by Petersen criteria is lower than Jacquier’s (86% vs. 93.7%), which may have led to a lower proportion of patients correctly classified as having LVNC. Nevertheless, in high pre-test scenarios (such our study population), the post-test probability of Petersen criteria is much higher, enhancing the role of CMR as a rule-in test.41 Thirdly, our relative small sample size is a real limitation. Despite the large confidence interval of the interaction term of beta-blocker use suggests that the effect may be substantial, the evidence of this study is limited and it was penalized by the sample size. Similarly, we recognize that results of the multivariate analysis should be interpreted as an exploratory analysis and hypothesis-generating. Prospective properly designed studies with larger patient cohorts are needed to further validate the prognostic implications of our findings. Conclusion In conclusion, tissue characterization by T1 mapping provided new insights into the pathophysiology of LVNC, suggesting a myocardial extracellular expansion by diffuse fibrosis. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Mar 6, 2018

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