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T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease and Hypertrophic Cardiomyopathy

Findings From the International T1 Multicenter Cardiovascular Magnetic Resonance Study
Originally published Cardiovascular Imaging. 2015;8:e003285



    The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects.

    Methods and Results—

    Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P− subjects (P<0.0001) and 65% of G+P− subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls.


    Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.


    Differential diagnosis of left ventricular (LV) hypertrophy (LVH) remains challenging in clinical practice, in particular between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness (LVWT) because of systemic hypertension. Reactive LVH that develops in response to an extrinsic increase in cardiac work, such as in hypertension, is distinguished from LVH because of familial HCM, in which the stimulus for increase in LVWT is intrinsic to the genetically altered cardiomyocyte.1 HCM is characterized by diffuse myocardial disease, defined by structurally dysmorphic myocytes, architectural loss of parallel arrangement, and disarray of fibers and fascicles, as well as genetically driven alterations of extracellular matrix with accumulation of interstitial fibrosis.19 Cardiovascular magnetic resonance (CMR) provides means of phenotyping the complex underlying pathophysiology and may be able to discern the fundamentally different substrates based on the different pathophysiological pathways in these 2 conditions (Figure 1).812 Although T1 mapping supports detection of diffuse myocardial disease, late gadolinium enhancement (LGE) helps with visualizing regional changes, such as replacement fibrosis in phenotypically subexpressed HCM gene carriers (G+P− subjects) and overt HCM disease. In compensated LVH because of hypertension—that is before extensive structural and metabolic remodeling with cavity dilatation and functional impairment (eccentric remodeling)—findings reflect physiological adaptations with an increased cellular size because of addition of new, but functional myofibrilles in-parallel and in-series, enabling the ventricle to generate greater forces and to outweigh the increased wall stress.11,1317 Interstitial fibrosis and the expansion of extracellular space in hypertension herald decompensation with eccentric remodeling and heart failure.1215,18–22 In this study, we investigated the ability of CMR to discern hypertrophic phenotypes based on detection of diffuse myocardial disease and regional fibrosis by myocardial T1 mapping and LGE, respectively, first, in overt LVH, and second, in phenotypically subexpressed HCM gene carriers.

    See Editorial by Schelbert and Moon

    See Clinical Perspective

    Figure 1.

    Figure 1. Representatives images of hypertensive LVH (HTN) and hypertrophic cardiomyopathy (HCM). Top, End-diastolic cine images. Bottom, Late gadolinium enhancement (LGE) imaging. A, HTN. Arrows highlight an ischemic scar in the lateral wall. B, Concentric HCM with no areas of LGE. C, HCM with areas of LGE. Arrows highlight the areas of LGE in the superior and inferior right ventricular insertion points.


    Consecutive subjects enrolled in the International T1 multicentre CMR study and meeting inclusion criteria below were included in this study. The multicenter-imaging consortium has been described previously (details in the Data Supplement).23 The study protocol was reviewed and approved by the respective institutional ethics committees and written informed consent was obtained from all participants. All procedures were carried out in accordance with the Declaration of Helsinki (2000). Inclusion criteria for respective patients groups were based on accepted diagnostic criteria1,2426 using CMR measurements:

    Group 1

    Patients with HCM (n=95), by demonstration of an LVH (>15 mm) associated with a nondilated LV in the absence of increased LV wall stress or another cardiac or systemic disease that could result in a similar magnitude of hypertrophy.1,24 All patients with HCM had an expressed phenotype with typically asymmetrical septal hypertrophy of increased LVWT, permitting unequivocal clinical diagnoses. HCM patients with previous septal ablation or myectomy were not included.

    Group 2

    Patients With Hypertension and Compensated LVH

    Evidence of treated essential hypertension (n=69; systolic blood pressure of >140 mm Hg; diastolic blood pressure of >95 mm Hg) and the presence of concentric LVH defined as >12 mm in the basal septal and inferolateral segments25 and without evidence of dilated LV cavity (end-diastolic diameter≤5.4 cm for women and ≤5.9 cm for men)26,27 on transthoracic echocardiography.

    Group 3

    G+P− first-degree relatives of patients with HCM, identified carriers of the relevant sarcomere–gene mutations, but had no evidence of LVH (LVWT≤13 mm; n=23).1,79

    Group 4

    Twenty-three normotensive age- and sex-matched healthy subjects, not taking any regular medications and normal CMR findings including normal LV mass indices, served as the control group to group 3. The datasets of control subjects were included in a previously published article.23

    Exclusion criteria for all subjects were history of athletic activity, known diagnosis of amyloidosis or Anderson–Fabry disease, known history of coronary artery disease or previous coronary intervention, as well as the generally accepted contraindications to CMR (implantable devices, cerebral aneurysm clips, cochlear implants, and severe claustrophobia), or a history of renal disease with a current epidermal growth factor receptor of <30 mL/min per 1.73 m2.

    Cardiovascular Magnetic Resonance

    All subjects underwent a routine clinical protocol for volumes and mass and tissue characterization using a 3-tesla MR scanner equipped with advanced cardiac package and multitransmit technology (Achieva, Philips Healthcare, Best, The Netherlands) after professional recommendation for standardized acquisition28 and as previously described.23,29 Details of imaging acquisition and postprocessing are provided in the Data Supplement. Cine imaging was used for complete coverage of gapless short-axis slices as well as long-axis views. LGE imaging was performed in identical geometries ≈20 minutes after administration of 0.2 mmol/kg body weight gadobutrol (Gadovist, Bayer Healthcare, Leverkusen, Germany) T1 mapping was performed by using modified Look-Locker imaging ((3(3)3(3)5)) acquisition in a single midventricular short-axis slice, before contrast administration and to scar imaging, respectively.

    Image Analysis

    Assessment of cardiac volumes and LV mass was performed after recommendations for standardized postprocessing30 using commercially available software (CircleCVI 42, Calgary, Canada; for details see Data Supplement). LGE images were visually examined for the presence of regional fibrosis showing as bright areas within the myocardium in corresponding longitudinal views and by exclusion of potential artifacts.31 LGE was quantified using regions defined as >50% of maximal signal intensity of the enhanced area (full width at half maximum).30,31 Myocardial crypts were considered present as visually as structural abnormalities consisting of narrow, deep blood–filled invaginations considered on cine viewing to penetrate >50% of the thickness of adjoining myocardium during diastole, perpendicular (45–135°) to the endocardial border of otherwise normal compacted myocardium and evidence of subtotal or total obliteration during systole by surrounding tissue, as previously described.32

    T1-mapping analysis was performed blinded to the underlying diagnosis (including the cine and LGE imaging) by measuring myocardial T1 relaxation in a midventricular short-axis slice using conservative septal sampling, as previously described and validated (details in the Data Supplement).23,29,33 T1 values were also reported for the complete midventricular short-axis slice. A total of 4 HCM subjects, where LGE overlapped with the septal region of interest for T1 mapping, were excluded. In addition to native T1, the hematocrit-corrected extracellular volume fraction (ECV), a marker of extracellular contrast agent accumulation, was also calculated.23,34

    Statistical Analysis

    Descriptive analysis, comparisons of the groups and assessment of associations have been performed using standard approaches (details in the Data Supplement). Categorical data are expressed as percentages, and continuous variables as mean±SD or median (interquartile range). All tests were 2-tailed and a P value of <0.05 was considered significant. Univariate and multivariate logistic regression was used to test the ability of CMR measures to discriminate between the HCM and hypertensive groups, as well as controls versus G+P− subjects. Sensitivity, specificity and discriminatory accuracy, cut-off values and area under the curve, were derived using receiver-operating characteristics curve analysis. Results of further subgroup analyses are presented in the Data Supplement.


    Subject characteristics are presented in Table 1. Compared with patients with hypertension, those with HCM had higher LV mass and LVWT (P<0.0001). Both LVH groups had diastolic impairment; more patients with HCM had grade II. G+P− subjects were similar to controls in functional and morphological measures. LGE was present in 68% of patients with HCM, 46% of which showed areas of LGE at one or both right ventricular insertion points. In the hypertensive group, 16 patients demonstrated LGE of which 10 were demonstrating an ischemic pattern. Two G+P− subjects of patients with HCM showed a nonischemic patch of LGE (Figure 2).

    Table 1. Patient Characteristics, Global Morphological, and Functional Measures Based on Cardiovascular Magnetic Resonance Measurements

    Controls (n=23)G+P− subjects (n=23)HCM (n=95)HTN (n=69)Significance (P value)
    Age, y44±1541±1855±1454±13<0.0001
    Sex, male n (%)14 (61)16 (69)64 (68)45 (65)0.6
    BSA, m21.6±0.11.8±0.11.96±0.22.01±0.20.03
    Systolic BP, mm Hg119±10120±15120±20*147±200.003
    Diastolic BP, mm Hg79±777±978±1283±100.24
    Heart rate, bpm65±1167±1770±1274±150.05
    NYHA, stage
     Stage I (n, %)23(100)19 (83)62 (65)39 (57)<0.001
     Stage II (n, %)4 (17)21 (22)27 (39)
     Stage III (n, %)12 (13)3 (4)
    Diastolic dysfunction, grade
     Normal (n, %)23(100)17 (74)†19 (20)15 (22)<0.001
     Grade I (inverted E/A ratio) (n, %)6 (26)58 (61)50 (72)
     Grade II (pseudonormalization) (n, %)18 (19)*4 (6)
     E/E′ (septal)5±27±413±411±60.007
     Deceleration time (ms)153±13161±12212±16199±10<0.001
     LV-EDV index, mL/m277±1280±1775±1774±220.22
     LV ejection fraction %63±862±864±1062±110.7
     RV ejection fraction %61±1060±966±963±90.001
     LV mass index, mg/m258±1656±1497±29*70±19<0.0001
     Maximal LVWT, mm8±19±219±4*14±5<0.0001
     Present (n, %)02 (9)65 (68)*16 (23)<0.0001
     LGE extent (FWHM)1.1±0.95.5±4.8*2.6±2.0 <0.001
     RV insertion points (n, %)0030 (46)*1 (1)<0.0001
     Ischemic pattern (n, %)003 (3)*7 (10)<0.0001
    T1 mapping
     Septal native T1 (ms)1044±181105±17†1169±41*1058±29<0.0001
     SAX native T1 (ms)1023±441055±551102±58*1033±680.001
     Septal postcontrast T1 (ms)446±70434±67379±47*429±60<0.001
     SAX postcontrast T1 (ms)466±37424±79390±44422±660.07
     Septal λ0.43±0.10.45±0.080.52±0.09*0.44±0.07<0.0001
     Septal ECV0.24±0.060.25±0.040.31±0.06*0.24±0.04<0.0001
     SAX λ0.44±0.10.46±0.10.51±0.10.46±0.10.25
     SAX ECV0.23±0.070.24±0.060.30±0.090.24±0.060.31
     Abnormal native T123 (n, %)0 (0)15 (65)†92 (98)*3 (4)<0.0001
     Abnormal native T123 (n, %)0 (0)15 (65)†92 (98)*3 (4)<0.0001

    One-way ANOVA or χ2 tests, as appropriate for the type of the data, P<0.05 is considered significant. BP indicates blood pressure; BSA, body surface area; , ECV, extracellular volume; EDV, end-diastolic volume; FWHM, full width at half maximum; HCM, hypertrophic cardiomyopathy; HTN, hypertensive LVH; LV, left ventricular, NYHA, New York Heart Association; LGE, late gadolinium enhancement; LVWT, LV wall thickness; RV, right ventricular; and SAX, short-axis slice.

    Post-hoc tests for significant differences between *HCM vs HTN and †for G+P− subjects vs controls, respectively.

    Figure 2.

    Figure 2. Representative images of hypertrophic cardiomyopathy (HCM) relatives (G+P− subjects). Top, End-diastolic cine. Bottom, Late gadolinium enhancement (LGE) imaging. A, HCM relative with 12-mm left ventricular wall thickness (LVWT) at the septum (line) and no areas of LGE. B, HCM relative with normal LVWT and areas of subtle and diffuse LGE in the lateral wall (arrows).

    Comparisons of the Groups for T1 Mapping Indices

    Native T1 and ECV were significantly higher in HCM compared with hypertensive patients (Table 1; Figure 3; P<0.0001), including in subanalysis of subjects without visible LGE (HCMLGE− versus hypertensionLGE−, native T1 [ms]: 1165±36 versus 1059±29; ECV: 0.31±0.06 versus 0.26±0.04; P<0.0001 for all; Figures in the Data Supplement). There was no difference in T1-mapping indices in HCM patients with or without LGE (HCMLGE+ versus HCMLGE−, native T1 [ms]: 1170±44 versus 1165±36; ECV: (%) 0.32±0.06 versus 0.31±0.06; P>0.05 for all). Various morphological types of HCM (concentric, septal, apical, or mid-LVH) were similar in T1 values (P>0.05 for all). Ninety-three patients with HCM (98%) had abnormal T1 values.23 Controlling for the magnitude of LVWT (≥15 mm),1,24 Patients with HCM had significantly higher T1-mapping indices compared with hypertension15mm subgroup (HCM versus hypertension15mm [n=19]; native T1 [ms]: 1169±41 versus 1059±38; ECV: 0.32±0.04 versus 0.26±0.04; P<0.001 for all).

    Figure 3.

    Figure 3. Box plots for native T1 (A) and extracellular volume fraction (ECV; B) in controls, G+P− subjects, hypertrophic cardiomyopathy (HCM) and hypertensive (HTN) patients.

    Comparisons Between G+P− Subjects versus Controls

    Compared with controls, native T1 was significantly higher in G+P− subjects (P<0.0001), whereas ECV values were similar (P=0.49). A total of 15 G+P− subjects (65%) had an abnormal native T1 value.23

    Compared with hypertension13mm subgroup (n=24, age, years: 49±9), G+P− subjects had significantly raised native T1 (native T1 [ms], G+P− subjects versus hypertension13mm: 1105±17 versus 1056±31; P<0.0001), whereas ECV values were similar between the groups (P=0.62). T1 values were similar in the hypertension13mm and hypertension15mm subgroups (native T1 [ms]: 1056±31 versus 1059±18; P=0.51; ECV: 0.24±3 versus 0.24±4; P=0.79). Reproducibility results are provided in the Data Supplement.

    Analysis of Relationships

    In HCM subjects, there was positive association between native T1 and indexed LV mass (r=0.47, P<0.001), maximal LVWT (r=0.44, P<0.001), and E/E′ (r=0.33, P=0.034), whereas patients with hypertension showed no significant associations between these variables (r=0.19, r=0.13, r=0.01, P>0.05, respectively; Figure 4). New York Heart Association showed no association with native T1 in any group.

    Figure 4.

    Figure 4. Bivariate correlation between native T1 and left ventricle (LV) mass and LV wall thickness. Hypertrophic cardiomyopathy (HCM) subjects showed a positive correlation between native T1 and indexed LV mass (r=0.47, P<0.01) and maximal left ventricular wall thickness (LVWT; r=0.44, P<0.01). Patients with hypertensive LVH (HTN) showed no significant associations between native T1 and indexed LV mass and LVWT.

    Discrimination Between Hypertrophic Phenotypes

    In multivariate binary logistic regression analysis including ECV, the presence of LGE, maximal LVWT, and LV mass index (Tables 2 and 3), native T1 was identified as the independent parameter in discrimination between HCM and hypertension with sensitivity 96%, specificity 98%, and discriminatory accuracy 97%. In discrimination between G+P− subjects and controls native T1 was the only significant variable (Tables 2 and 3; Figures 5). Results of further subgroup analyses are included in the Data Supplement.

    Table 2. Results of ROC and Binary Logistic Regression Analysis of CMR Parameters for Discrimination in HCM vs HTN Subjects

    BiomarkersAUC (95% CI)Cut-Off ValuesSpecificity (95% CI)Sensitivity (95% CI)PPV (95% CI)NPV (95% CI)Diagnostic Accuracy (95% CI)
    HCM vs HTN
    Univariate analysis
     Septal native T1, ms0.97 (0.94–1.00)**111098 (94–99)96 (90–98)97 (93–98)98 (91–99)97 (92–99)
     SAX native, ms0.79 (0.70–0.89)**106777 (67–89)71 (58–82)71 (58–82)73 (63–81)71 (61–81)
     Septal ECV0.76 (0.67–0.84)**0.2971 (63–81)76 (67–84)74 (65–81)71 (61–81)73 (63–82)
     SAX ECV0.66 (0.54–0.75)0.3063 (49–70)70 (58–78)72 (59–73)61 (54–67)63 (51–73)
     LGE (present)0.76 (0.64–0.82)**68 (61–74)76 (67–84)80 (72–87)63 (56–70)71 (64–78)
     Maximal LVWT, mm0.93 (0.92–0.99)**1684 (78–88)91 (81–95)92 (85–96)81 (73–85)87 (79–90)
     LV mass (index), g/m20.82(0.73–0.87)**0.8464 (54–71)80 (73–86)75 (68–80)71 (60–78)73 (65–79)
    Multivariate analysis
    WaldExp(B) (95% CI)
    Native T1, ms26.11.121 (1.057–1.217)**98 (94–99)96 (90–99)96 (90–99)98 (94–99)97 (93–99)

    For further subgroup analyses see Data Supplement. Variables not included (significance [P value]): ECV (0.173); LGE (present; 0.01); Maximal LVWT (0.003); LV mass (index; 0.60). For the model: χ2: 127, P<0.001; −2Log LH: 47.9, Cox and Snell R2: 0.63, Nagelkerke R2: 0.85. AUC indicates area under the curve; CI, confidence interval; CMR, cardiovascular magnetic resonance; ECV, extracellular volume fraction; HCM, hypertrophic cardiomyopathy; HTN, hypertensive LVH; LGE, late gadolinium enhancement; LH, likelihood; LV, left ventricle; LVWT, LV wall thickness; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver-operating characteristics; and SAX, short-axis slice.

    P value of <0.05 was considered significant. *P<0.05, **P<0.01.

    Table 3. Results of ROC and Binary Logistic Regression Analysis of CMR Parameters for Discrimination in Controls vs G+P− Subjects

    BiomarkersAUC (95% CI)Cut-Off ValuesSpecificity (95% CI)Sensitivity (95% CI)PPV (95% CI)NPV (95% CI)Diagnostic Accuracy (95% CI)
    Controls vs G+P− subjects
     Septal native T1, ms0.97 (0.94–1.00)**108996 (91–99)87 (79–91)92 (79–97)97 (92–99)92 (81–98)
     SAX native T1, ms0.78 (0.69–0.87)**105676 (64–88)69 (56–77)67 (54–75)70 (61–78)68 (56–78)
     Septal ECV0.65 (0.48–0.82)
     SAX ECV
     Native T1, ms0.97 (0.94–1.00)**108996 (91–99)87 (79–91)92 (79–97)97 (92–99)92 (81–98)
     ECV0.65 (0.48–0.82), NS
     LGE (present)0.54 (0.38–0.71), NS
     Maximal LVWT, mm0.75 (0.61–0.89)NS
     LV mass (index), g/m20.49 (0.31–0.65), NS
    Multivariate analysis
    WaldExp(B) (95% CI)
    Native T1, ms11.21.139 (1.055–1.230)**91 (78–96)91 (79–98)92 (79–98)91 (77–98)92 (77–98)

    For further subgroup analyses see Data Supplement. Variables not included (significance [P value]): ECV (0.51); LGE (present; 0.87); Maximal LVWT (0.004); LV mass (index; 0.32). For the model: χ2: 45.5, P<0.001; −2Log LH: 18.3, Cox and Snell R2: 0.63, Nagelkerke R2: 0.84. AUC indicates area under the curve; CI, confidence interval; CMR, cardiovascular magnetic resonance; ECV, extracellular volume fraction; LGE, late gadolinium enhancement; LH, likelihood; LV, left ventricle; LVWT, LV wall thickness; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver-operating characteristics; and SAX, short-axis slice.

    P value of <0.05 was considered significant. *P<0.05, **P<0.01.

    Figure 5.

    Figure 5. Receiver-operating characteristics (ROC) curves in discrimination between hypertrophic cardiomyopathy (HCM) vs hypertensive LVH (HTN; A) and controls vs G+P− subjects (B). ECV, extracellular volume fraction; LGE, late gadolinium enhancement; and LVWT, left ventricular wall thickness.


    In selected patient populations with hypertrophic phenotypes, we provide a proof-of-concept that myocardial T1 mapping can be instrumental in discrimination between HCM and hypertension: first, T1-mapping indices are significantly different, and second, native T1 was identified as the strongest independent discriminator, also when controlling for LGE and similar magnitudes of LVWT. We further show that G+P− subjects have significantly raised native T1 compared with controls, as well as patients with mild hypertension. This important finding may support detection of subexpressed disease as well as separation of these subjects from borderline cases with mild hypertension. Our findings propose a novel systematic approach toward discrimination of common conditions presenting with overt or borderline hypertrophic phenotypes and potentially supporting differential management pathways, in terms of screening and treatment, respectively.

    Difficulties in discrimination of overt hypertrophic phenotypes preclude the appropriate diagnosis, risk assessment, and clinical management. Currently, the diagnosis of HCM is based on the finding of LVH with LVWT≥15 mm in the absence of increase in LV wall stress. This approach commonly fails to support unequivocal confirmation of disease, or alternatively, its exclusion.1,24 The complex underlying histopathology16 and the consequent functional changes in HCM provide a conundrum of myocardial abnormalities, including replacement fibrosis, reduced ventricular deformation, and increased diastolic stiffness.712 Detecting these abnormalities have all been shown to help with disease confirmation in overt LVH.1,24 Visualization of replacement fibrosis by LGE, most commonly located in right ventricular insertion points, is particularly helpful in differential diagnosis,1,11 as well as risk stratification.3537 However, ≈40% of patients with HCM show no evidence of LGE. Although the LGE relates to the regionally separated myocardial abnormality, T1-mapping techniques support noninvasively detection of diffuse myocardial involvement.79,12,18,19 We and others have previously shown that patients with HCM have abnormal T1 indices concordant with diffuse myocardial disease, even in the absence of LGE, as well as in the areas outside overt LGE.79,12 We now provide a further evidence that T1 mapping can support clinically relevant discrimination between HCM and hypertension, also in the subset of subjects without overt LGE and when controlling for similar magnitudes of LVWT. Of note, HCM patients group exhibited increased native T1 between 2 and 5 SD above the mean of the reference range, whereas in patients with hypertension native T1 were concentrated within the 2 SD.23 Our findings further resonate with a recent study in patients with hypertension, which demonstrated native T1 values were higher compared with their respective normotensive reference group, however, within 2 SD of the respective reference range.38 In summary, these findings accord with existing knowledge on the respective underlying pathophysiology.46,13

    Previous studies revealed that the genetically driven diffuse myocardial process is fundamental in development of HCM and an early consequence of sarcomere mutations rather than a downstream response to the LVH, outflow obstruction, or sequel to microvascular disease.79 Our findings corroborate the observations of previous reports by showing the relationship between native T1 and LVWT and LV mass, indicating association between diffuse myocardial involvement and phenotypic expression of disease.12,20,39 In this study, diffuse myocardial abnormalities, evidenced by abnormally high native T1,23 were found in nearly all patients with HCM (98%), indicating that overt HCM with native T1 within the normal range is exceedingly rare. Two thirds of G+P− subjects in our study exhibited abnormal native T1, suggesting that diffuse disease is present and detectable in the absence of an overt phenotype.79 As more families undergo genetic testing and phenotypic assessment for HCM, a new preclinical population is growing.1,24 Genetic diagnosis aids to identify the relevant sarcomere mutations in subexpressed relatives, potentially at risk for development of future disease. Native T1 may serve to identify those with subclinical myocardial abnormalities, complementary to genetic testing in identifying the subclinical expression of disease. Given that diffuse myocardial remodeling may be a dynamic process, monitoring native T1 as oppose to LVWT might provide a more reliable means of monitoring disease progression.

    Previous observations revealed higher prevalence of myocardial crypts in patients with HCM and G+P− subjects, suggesting that they represent markers of HCM disease.32,40,41 Although not reproduced in larger and broader cohorts,32,40 none of G+P− subjects in the present cohort showed crypts, and the proportion of these were similar between hypertensive and HCM groups, indicating that crypts are more visible with increased LVWT as well as preserved global systolic function.32,40

    A few limitations apply to this study. Prospective studies in large and broad populations are required to validate our findings for widespread use. We strived to exclude patients with overt LVH phenocopies including subjects with history of substantial athletic activity,42 as well as known cardiac amyloidosis or known Anderson–Fabry disease.1,24 A small number of patients excluded because of overlap of LGE with septal region of interest is unlikely to have caused a significant bias; on the contrary, this approach permitted a blinded read to the underlying diagnosis and the proof-of-concept, that the effects found are not because of the LGE type of scar. The chosen LVWT cut-offs, although based on the diagnostic criteria, may seem arbitrary against the increasingly apparent recognition that HCM represents a continuum of disease across the spectrum of LVWT.810 Superior discrimination based on native T1 compared with ECV may relate to the T1-mapping methodology based on modified Look-Locker imaging and its greater precision of native myocardial measurements, concordant with the previous results in discrimination between normal and diffusely diseased myocardium of us and others.12,20,29,33,38,39 We recognize that native T1 and ECV are complementary measures of different, but related aspects of the myocardium. Our demonstration that native T1 can detect the earliest changes in HCM myocardium endorses the importance of considering both parameters in defining the natural history of myocardial changes in genopositive individuals. Such an integrated approach is essential to develop timely interventions targeting underlying molecular and structural events to halt or reverse disease progression and improve outcomes.

    In conclusion, our study demonstrates that T1-mapping indices may discriminate between overt LVH because of HCM or hypertension with high accuracy. We further show that native T1 value may serve as a novel, noninvasive, and clinically robust biomarker to detect early expression of diffuse myocardial involvement in subexpressed G+P− subjects.


    The Data Supplement is available at

    Correspondence to Valentina O. Puntmann, MD, PhD, Division of Internal Medicine III, Department of Cardiology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany. E-mail


    • 1. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H; Authors/Task Force Members. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35:2733–2779.CrossrefMedlineGoogle Scholar
    • 2. Noureldin RA, Liu S, Nacif MS, Judge DP, Halushka MK, Abraham TP, Ho C, Bluemke DA.The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance.J Cardiovasc Magn Reson. 2012; 14:17. doi: 10.1186/1532-429X-14-17.CrossrefMedlineGoogle Scholar
    • 3. Moravsky G, Ofek E, Rakowski H, Butany J, Williams L, Ralph-Edwards A, Wintersperger BJ, Crean A.Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR.JACC Cardiovasc Imaging. 2013; 6:587–596. doi: 10.1016/j.jcmg.2012.09.018.CrossrefMedlineGoogle Scholar
    • 4. Teare D.Asymmetrical hypertrophy of the heart in young adults.Br Heart J. 1958; 20:1–8.CrossrefMedlineGoogle Scholar
    • 5. Wigle ED, Silver MD.Myocardial fiber disarray and ventricular septal hypertrophy in asymmetrical hypertrophy of the heart.Circulation. 1978; 58(3 pt 1):398–402.CrossrefMedlineGoogle Scholar
    • 6. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ.Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease.Heart. 2000; 84:476–482.CrossrefMedlineGoogle Scholar
    • 7. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, Kwong R, González A, Colan SD, Seidman JG, Díez J, Seidman CE.Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy.N Engl J Med. 2010; 363:552–563. doi: 10.1056/NEJMoa1002659.CrossrefMedlineGoogle Scholar
    • 8. Ho CY, Abbasi SA, Neilan TG, Shah RV, Chen Y, Heydari B, Cirino AL, Lakdawala NK, Orav EJ, González A, López B, Díez J, Jerosch-Herold M, Kwong RY.T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy.Circ Cardiovasc Imaging. 2013; 6:415–422. doi: 10.1161/CIRCIMAGING.112.000333.LinkGoogle Scholar
    • 9. Ellims AH, Iles LM, Ling LH, Chong B, Macciocca I, Slavin GS, Hare JL, Kaye DM, Marasco SF, McLean CA, James PA, du Sart D, Taylor AJ.A comprehensive evaluation of myocardial fibrosis in hypertrophic cardiomyopathy with cardiac magnetic resonance imaging: linking genotype with fibrotic phenotype.Eur Heart J Cardiovasc Imaging. 2014; 15:1108–1116. doi: 10.1093/ehjci/jeu077.CrossrefMedlineGoogle Scholar
    • 10. Hinojar R, Botnar R, Kaski JC, Prasad S, Nagel E, Puntmann VO.Individualized cardiovascular risk assessment by cardiovascular magnetic resonance.Future Cardiol. 2014; 10:273–289. doi: 10.2217/fca.13.102.CrossrefMedlineGoogle Scholar
    • 11. Puntmann VO, Jahnke C, Gebker R, Schnackenburg B, Fox KF, Fleck E, Paetsch I.Usefulness of magnetic resonance imaging to distinguish hypertensive and hypertrophic cardiomyopathy.Am J Cardiol. 2010; 106:1016–1022. doi: 10.1016/j.amjcard.2010.05.036.CrossrefMedlineGoogle Scholar
    • 12. Puntmann VO, Voigt T, Chen Z, Mayr M, Karim R, Rhode K, Pastor A, Carr-White G, Razavi R, Schaeffter T, Nagel E.Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy.JACC Cardiovasc Imaging. 2013; 6:475–484. doi: 10.1016/j.jcmg.2012.08.019.CrossrefMedlineGoogle Scholar
    • 13. Dorn GW. The fuzzy logic of physiological cardiac hypertrophy.Hypertension. 2007; 49:962–970. doi: 10.1161/HYPERTENSIONAHA.106.079426.LinkGoogle Scholar
    • 14. Hill JA, Olson EN.Cardiac plasticity.N Engl J Med. 2008; 358:1370–1380. doi: 10.1056/NEJMra072139.CrossrefMedlineGoogle Scholar
    • 15. Coelho-Filho OR, Shah RV, Mitchell R, Neilan TG, Moreno H, Simonson B, Kwong R, Rosenzweig A, Das S, Jerosch-Herold M.Quantification of cardiomyocyte hypertrophy by cardiac magnetic resonance: implications for early cardiac remodeling.Circulation. 2013; 128:1225–1233. doi: 10.1161/CIRCULATIONAHA.112.000438.LinkGoogle Scholar
    • 16. Lorell BH, Carabello BA.Left ventricular hypertrophy: pathogenesis, detection, and prognosis.Circulation. 2000; 102:470–479.LinkGoogle Scholar
    • 17. Rossi MA, Carillo SV.Cardiac hypertrophy due to pressure and volume overload: distinctly different biological phenomena?Int J Cardiol. 1991; 31:133–141.CrossrefMedlineGoogle Scholar
    • 18. Iles LM, Ellims AH, Llewellyn H, Hare JL, Kaye DM, McLean CA, Taylor AJ.Histological validation of cardiac magnetic resonance analysis of regional and diffuse interstitial myocardial fibrosis.Eur Heart J Cardiovasc Imaging. 2015; 16:14–22. doi: 10.1093/ehjci/jeu182.CrossrefMedlineGoogle Scholar
    • 19. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA.Assessment of myocardial fibrosis with cardiovascular magnetic resonance.J Am Coll Cardiol. 2011; 57:891–903. doi: 10.1016/j.jacc.2010.11.013.CrossrefMedlineGoogle Scholar
    • 20. Ellims AH, Shaw JA, Stub D, Iles LM, Hare JL, Slavin GS, Kaye DM, Taylor AJ.Diffuse myocardial fibrosis evaluated by post-contrast t1 mapping correlates with left ventricular stiffness.J Am Coll Cardiol. 2014; 63:1112–1118. doi: 10.1016/j.jacc.2013.10.084.CrossrefMedlineGoogle Scholar
    • 21. Rudolph A, Abdel-Aty H, Bohl S, Boyé P, Zagrosek A, Dietz R, Schulz-Menger J.Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular hypertrophy relation to remodeling.J Am Coll Cardiol. 2009; 53:284–291. doi: 10.1016/j.jacc.2008.08.064.CrossrefMedlineGoogle Scholar
    • 22. Maceira AM, Mohiaddin RH.Cardiovascular magnetic resonance in systemic hypertension.J Cardiovasc Magn Reson. 2012; 14:28. doi: 10.1186/1532-429X-14-28.CrossrefMedlineGoogle Scholar
    • 23. Dabir D, Child N, Kalra A, Rogers T, Gebker R, Jabbour A, Plein S, Yu CY, Otton J, Kidambi A, McDiarmid A, Broadbent D, Higgins DM, Schnackenburg B, Foote L, Cummins C, Nagel E, Puntmann VO.Reference values for healthy human myocardium using a T1 mapping methodology: results from the International T1 Multicenter cardiovascular magnetic resonance study.J Cardiovasc Magn Reson. 2014; 16:69. doi: 10.1186/s12968-014-0069-x.CrossrefMedlineGoogle Scholar
    • 24. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kühl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A.Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.Eur Heart J. 2008; 29:270–276. doi: 10.1093/eurheartj/ehm342.CrossrefMedlineGoogle Scholar
    • 25. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Rydén L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA.2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).Eur Heart J. 2013; 34:2159–2219. doi: 10.1093/eurheartj/eht151.CrossrefMedlineGoogle Scholar
    • 26. Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM,, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease); Society of Cardiovascular Anesthesiologists. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol.2006; 48:1–148.CrossrefMedlineGoogle Scholar
    • 27. Puntmann VO, Gebker R, Duckett S, Mirelis J, Schnackenburg B, Graefe M, Razavi R, Fleck E, Nagel E.Left ventricular chamber dimensions and wall thickness by cardiovascular magnetic resonance: comparison with transthoracic echocardiography.Eur Heart J Cardiovasc Imaging. 2013; 14:240–246. doi: 10.1093/ehjci/jes145.CrossrefMedlineGoogle Scholar
    • 28. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E; Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols. Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update.J Cardiovasc Magn Reson. 2013; 15:91. doi: 10.1186/1532-429X-15-91.CrossrefMedlineGoogle Scholar
    • 29. Rogers T, Dabir D, Mahmoud I, Voigt T, Schaeffter T, Nagel E, Puntmann VO.Standardization of T1 measurements with MOLLI in differentiation between health and disease–the ConSept study.J Cardiovasc Magn Reson. 2013; 15:78. doi: 10.1186/1532-429X-15-78.CrossrefMedlineGoogle Scholar
    • 30. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, Plein S, Nagel E.Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing.J Cardiovasc Magn Reson. 2013; 15:35. doi: 10.1186/1532-429X-15-35.CrossrefMedlineGoogle Scholar
    • 31. Neilan TG, Coelho-Filho OR, Danik SB, Shah RV, Dodson JA, Verdini DJ, Tokuda M, Daly CA, Tedrow UB, Stevenson WG, Jerosch-Herold M, Ghoshhajra BB, Kwong RY.CMR quantification of myocardial scar provides additive prognostic information in nonischemic cardiomyopathy.JACC Cardiovasc Imaging. 2013; 6:944–954. doi: 10.1016/j.jcmg.2013.05.013.CrossrefMedlineGoogle Scholar
    • 32. Child N, Muhr T, Sammut E, Dabir D, Ucar EA, Bueser T, Gill J, Carr-White G, Nagel E, Puntmann VO.Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance.J Cardiovasc Magn Reson. 2014; 16:66. doi: 10.1186/s12968-014-0066-0.CrossrefMedlineGoogle Scholar
    • 33. Child N, Yap ML, Dabir D, Rogers T, Suna G, Sandhu B, Higgins DM, Mayr M, Nagel E, Puntmann VO.T1 values by conservative septal postprocessing approach are superior in relating to the interstitial myocardial fibrosis: findings from patients with severe aortic stenosis.J Cardiovasc Magn Reson. 2015; 17(S1):49.CrossrefMedlineGoogle Scholar
    • 34. Jerosch-Herold M, Sheridan DC, Kushner JD, Nauman D, Burgess D, Dutton D, Alharethi R, Li D, Hershberger RE.Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy.Am J Physiol Heart Circ Physiol. 2008; 295:H1234–H1242. doi: 10.1152/ajpheart.00429.2008.CrossrefMedlineGoogle Scholar
    • 35. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H.Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy.J Am Coll Cardiol. 2010; 56:875–887. doi: 10.1016/j.jacc.2010.05.007.CrossrefMedlineGoogle Scholar
    • 36. Green JJ, Berger JS, Kramer CM, Salerno M.Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy.JACC Cardiovasc Imaging. 2012; 5:370–377. doi: 10.1016/j.jcmg.2011.11.021.CrossrefMedlineGoogle Scholar
    • 37. Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas T, Lesser JR, Gruner C, Crean AM, Rakowski H, Udelson JE, Rowin E, Lombardi M, Cecchi F, Tomberli B, Spirito P, Formisano F, Biagini E, Rapezzi C, De Cecco CN, Autore C, Cook EF, Hong SN, Gibson CM, Manning WJ, Appelbaum E, Maron MS.Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy.Circulation. 2014; 130:484–495. doi: 10.1161/CIRCULATIONAHA.113.007094.LinkGoogle Scholar
    • 38. Kuruvilla S, Janardhanan R, Antkowiak P, Keeley EC, Adenaw N, Brooks J, Epstein FH, Kramer CM, Salerno M.Increased extracellular volume and altered mechanics are associated with LVH in hypertensive heart disease, not hypertension alone.JACC Cardiovasc Imaging. 2015; 8:172–180. doi: 10.1016/j.jcmg.2014.09.020.CrossrefMedlineGoogle Scholar
    • 39. Puntmann VO, Arroyo Ucar E, Hinojar Baydes R, Ngah NB, Kuo YS, Dabir D, Macmillan A, Cummins C, Higgins DM, Gaddum N, Chowienczyk P, Plein S, Carr-White G, Nagel E.Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy.Hypertension. 2014; 64:762–768. doi: 10.1161/HYPERTENSIONAHA.114.03928.LinkGoogle Scholar
    • 40. Petryka J, Baksi AJ, Prasad SK, Pennell DJ, Kilner PJ.Prevalence of inferobasal myocardial crypts among patients referred for cardiovascular magnetic resonance.Circ Cardiovasc Imaging. 2014; 7:259–264. doi: 10.1161/CIRCIMAGING.113.001241.LinkGoogle Scholar
    • 41. Maron MS, Rowin EJ, Lin D, Appelbaum E, Chan RH, Gibson CM, Lesser JR, Lindberg J, Haas TS, Udelson JE, Manning WJ, Maron BJ.Prevalence and clinical profile of myocardial crypts in hypertrophic cardiomyopathy.Circ Cardiovasc Imaging. 2012; 5:441–447. doi: 10.1161/CIRCIMAGING.112.972760.LinkGoogle Scholar
    • 42. Caselli S, Maron MS, Urbano-Moral JA, Pandian NG, Maron BJ, Pelliccia A.Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy.Am J Cardiol. 2014; 114:1383–1389. doi: 10.1016/j.amjcard.2014.07.070.CrossrefMedlineGoogle Scholar


    Using selected patient populations with hypertrophic phenotypes, we provide a proof-of-concept that myocardial T1 mapping may be instrumental in discrimination between HCM and hypertension. T1-mapping indices are significantly higher in HCM in comparison with hypertension also when controlling for LGE and similar magnitudes of LVWT. Native T1 was the strongest independent discriminator between these 2 conditions. We further show that a majority of gene positive subjects have raised native T1 in the absence of phenotypically expressed disease (G+P−). Our findings propose a novel systematic approach toward discrimination of common conditions presenting with overt or borderline hypertrophic phenotypes, potentially supporting differential treatment pathways, as well as a screening tool for subclinical cardiomyopathy in G+P− subjects.