Abstract
Background
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy (LVH). However, clinical signs can be subtle and differentiation from other causes of LVH is challenging.
Hypothesis
As diastolic dysfunction (DD) is an early sign in HCM, we aimed to find regional changes in relaxation pattern for differentiation from other entities of LVH.
Methods
In 148 patients (81 HCM, 55 arterial hypertension (AHT), 12 Fabry disease) and 63 healthy controls, relaxation patterns were assessed using regional tissue Doppler imaging. In 42 HCM patients, myocardial mass and fibrosis were quantified by cardiac magnetic resonance imaging and correlated with relaxation parameters.
Results
In HCM the septal to lateral isovolumic relaxation time (s/l IVRT) ratio was higher (1.5 ± 0.4) compared with AHT (1.1 ± 0.2), Fabry disease (1.0 ± 0.1), and controls (1.1 ± 0.2; P < 0.001), showing 77% sensitivity and 79% specificity to discriminate HCM‐related LVH from other entities. The s/l IVRT ratio was independent of global DD in HCM (HCM with DD: 1.5 ± 0.5, n = 52; HCM without DD: 1.5 ± 0.3, n = 29) and remained significantly different from other entities in a subgroup of HCM patients with maximum wall thickness < 20 mm (s/l ratio: 1.5 ± 0.5, n = 28). Regional IVRT did not correlate with the corresponding segmental myocardial mass or amount of fibrosis in cardiac magnetic resonance imaging.
Conclusions
HCM patients show a prolonged septal IVRT irrespective of the extent of LVH and even before developing global DD. The s/l IVRT ratio is significantly higher in HCM compared with AHT or Fabry disease, thus establishing segmental IVRT analysis as a potential parameter for differential diagnosis in LVH.
Keywords: Hypertrophic Cardiomyopathy, Arterial Hypertension, Fabry's Disease, Isovolumic Relaxation Time, Tissue Doppler Imaging
1. INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is the most common monogenetic cardiovascular disease, with a prevalence of ≥1:500, and is the most frequent cause of sudden cardiac death in the young, especially in athletes.1 The disease is characterized by left ventricular hypertrophy (LVH) with asymmetric thickening predominantly of the septal wall,2 leading to left ventricular (LV) outflow tract obstruction in almost 25% of patients. Diagnosis of HCM is primarily based on the magnitude of LVH with a maximum wall thickness of ≥15 mm in the absence of abnormal loading conditions or other cardiac or systemic disease that could produce the magnitude of hypertrophy evident.3 However, it often remains difficult to distinguish, especially between the nonobstructive form of HCM and other causes of LVH, such as arterial hypertension (AHT)4 or storage disorders.5 Due to its relatively high prevalence and potentially fatal outcome, early diagnosis of HCM and reliable distinction from phenotypes of similar disorders is crucial.
As impaired myocardial relaxation has been identified as an early manifestation of HCM,6 a variety of echocardiographic parameters for evaluation of diastolic dysfunction (DD), such as tissue Doppler imaging (TDI) and strain imaging, were recently shown to be useful in differentiation and early detection of the disease, even in mutation carriers without a clinical phenotype.7, 8, 9 Regional differences between the septal and lateral mitral annulus velocities showing longer IVRT, lower E′ and higher E/E′ ratios in the septal annulus can be observed in different entities of LVH.10 These TDI parameters have already been shown to be useful for discrimination between HCM and AHT and a prolonged IVRT has been proposed to be useful for discrimination from other entities.11 Likewise, we observed septal pronounced isovolumic relaxation time (IVRT) prolongation in HCM patients in our outpatient clinic. However, to date a differential analysis even in HCM patients without apparent DD has not been performed yet.
This study was designed to answer the following questions:
Are regional relaxation abnormalities in HCM visible before development of global DD?
Do echocardiographic changes in myocardial relaxation follow the same asymmetrical distribution as LVH in HCM patients, and are these relaxation patterns correlated with the amount of LVH and/or the amount of myocardial fibrosis?
Can echocardiographic parameters of regional diastolic impairment be used for discrimination of HCM from other LVH entities?
2. METHODS
2.1. Study population
A total of 211 individuals were retrospectively studied. All patients were recruited during a routine visit at the outpatient clinic at the University Heart Center Hamburg between July 2010 and September 2013. Medical histories were recorded, a 12‐lead electrocardiogram was performed, and patients were examined physically and by echocardiography.
The HCM group consisted of 81 patients with a clinical phenotype. In 20 patients a pathogenic mutation was genetically confirmed. According to current guidelines, HCM was defined as a maximum wall thickness of ≥15 mm in the absence of abnormal loading conditions or another cardiac or systemic disease that could produce the magnitude of hypertrophy evident.3, 12 Hypertrophy was either septal pronounced or concentric. Patients with other types of hypertrophy (eg, apical hypertrophy) were excluded.
The Fabry group included 12 patients with genetically confirmed Fabry disease and echocardiographic evidence of cardiac manifestation.
Fifty‐five patients with known AHT receiving antihypertensive medication were also recruited. These patients showed mild to moderate cardiac hypertrophy (wall thickness 11–15 mm) in the absence of any other disease that could have influenced the cardiac phenotype. Excluded were patients with a history of myocardial infarction, significant coronary heart disease, ventricular conduction asynchrony, moderate or severe valvular disease, left ventricular ejection fraction (LVEF) ≤45%, atrial fibrillation at the time of investigation, or systemic diseases with potential cardiac involvement. Also, 63 individuals without any cardiac pathology were included.
The study protocol was in line with the principles outlined in the Declaration of Helsinki and approved by the local ethics committee.
2.2. Echocardiographic studies
Two‐dimensional transthoracic echocardiography was performed using a Philips iE33 system (Philips Healthcare, Best, The Netherlands) and data were analyzed with Syngo Dynamics (Siemens Healthcare, Erlangen, Germany). LVEF was obtained with the Simpson method from 2‐dimensional apical images. 2D images were obtained from parasternal short axis to measure septal (SW) and lateral wall (LW) thickness. Left atrial diameter (LAD), as well as left ventricular end‐diastolic diameter (LVEDD) and end‐systolic diameter (LVESD) were measured using M‐mode in the same orientation. Peak early (E wave) and late (A wave) transmitral filling velocities and deceleration time of E (DT of E wave) were measured using pulsed‐wave Doppler of transmitral flow in the apical 4‐chamber view. TDI was used in the color‐guided pulsed‐wave Doppler mode to assess peak early (E′) and late diastolic (A′) mitral annulus velocities at the septal and lateral mitral valve annulus in the apical 4‐chamber view. The same tracing was also used to measure isovolumic contraction time and IVRT intervals. For each measurement, 2 to 3 beats were averaged and analyzed by 2 independent observers. DD was defined by published criteria.13 There were no patients with restrictive filling pattern in either group.
2.3. Cardiac MRI
A subset of 42 HCM patients underwent cardiac magnetic resonance (CMR) imaging using a 1.5‐T scanner (Achieva; Philips Healthcare). Images were obtained in the cardiac short‐axis, vertical long‐axis, and horizontal long‐axis planes using a breath‐hold balanced fast field sequence. After injection of 0.2 mL/kg body weight gadobenate dimeglumine (MultiHance; Bracco Diagnostics, Monroe Township, NJ), late gadolinium enhancement (LGE) images were acquired using a phase‐sensitive inversion recovery sequence. LGE images were acquired in the LV short‐axis orientation as well as in 2‐, 3‐, and 4‐chamber views. Endocardial and epicardial borders were manually traced in each slice. A region of interest was placed in normal‐appearing myocardium typically in the lateral LV wall, which was defined as a nonhypertrophied region without apparent LGE. LGE quantification was performed using a threshold method >2 SD above the signal intensity of normal‐appearing myocardium. The amount of fibrotic tissue of each patient was assessed in percent of LV myocardial mass (%LV) using the in‐house–developed Heart Analysis Tool (HeAT) software.14 Measurements were performed by 2 independent radiologists who were blinded to the echocardiographic results, patients' diagnoses, and the measurements performed by their colleague. To determine segmental distribution of myocardial mass and fibrosis detected by LGE, data were obtained for septal segments 3 and 9 as well as for lateral segments 6 and 12, following published recommendations.15
2.4. Statistical analysis
Continuous variables are reported as mean ± SD and categorical variables are presented as frequencies and percentages. To determine differences between HCM patients and all other patient groups (AHT, Fabry disease, control) in echocardiographic parameters, linear models adjusted for age, sex and quotient of septal to lateral wall thickness were used. Parameters were logarithmized if necessary.
The adjusted septal/lateral (s/l) IVRT ratio was estimated from the linear model for each group as well as in the setting in which the HCM patients were further divided into the subgroups “with DD” and “without DD” and septal wall thickness < 20 and ≥20 mm. A receiver operating curve (ROC) was created to evaluate the ability of the s/l IVRT ratio to discriminate patients suffering from HCM from those with LVH caused by AHT or Fabry disease. The area under the curve was determined, and specificity and sensitivity of the IVRT ratio were calculated at various cutoffs.
For the subgroup of HCM patients where CMR data were available, a linear model adjusted for age and sex was estimated to examine if IVRT was associated with myocardial fibrosis and/or mass.
A 2‐tailed P value <0.05 was considered statistically significant. As this analysis was performed in an explorative way, no adjustment for multiple testing was made. All analyses were carried out using Stata version 14.1 (StataCorp LP, College Station, TX).
3. RESULTS
3.1. Patients
HCM and AHT patients were older than patients with Fabry disease or controls. Aside from the control group, all patient groups comparably suffered from concomitant diseases. Baseline characteristics are listed in Table 1.
Table 1.
Patient characteristics and baseline echocardiographic characteristics
| HCM, n = 81 | AHT, n = 55 | Fabry, n = 12 | Control, n = 63 | P Value, Group | P Value for HCM vs | |||
|---|---|---|---|---|---|---|---|---|
| AHT | Fabry | Control | ||||||
| Age, y | 54.1 ± 15.2 | 60.1 ± 12.4 | 48.3 ± 9.5 | 42.3 ± 12.7 | <0.001 | 0.011 | 0.165 | <0.001 |
| Male sex | 44 (54.3) | 33 (60.0) | 6 (50.0) | 29 (46.0) | 0.495 | — | — | — |
| At least 1 concomitant disease: | 41 (50.6) | 55 (100.0) | 8 (66.7) | 0 (0.0) | 0.305 | — | — | — |
| AHT | 37 (45.7) | 55 (100.0) | 6 (50.0) | 0 (0.0) | 0.780 | — | — | — |
| CAD | 7 (8.6) | 7 (12.7) | 2 (16.7) | 0 (0.0) | 0.604 | — | — | — |
| AF | 6 (7.4) | 4 (7.3) | 1 (8.3) | 0 (0.0) | 0.992 | — | — | — |
| DM | 6 (7.4) | 11 (20.0) | 0 (0.0) | 0 (0.0) | 0.036 | 0.035 | NE | NE |
| At least 1 medication: | 68 (84.0) | 52 (94.5) | 8 (66.7) | 0 (0.0) | 0.039 | 0.072 | 0.159 | NE |
| β‐Blocker | 47 (58.0) | 35 (63.6) | 4 (33.3) | 0 (0.0) | 0.177 | — | — | — |
| Ca blocker | 23 (28.4) | 29 (52.7) | 3 (25.0) | 0 (0.0) | 0.012 | 0.005 | 0.807 | NE |
| ACEI/ARB | 26 (32.1) | 43 (78.2) | 6 (50.0) | 0 (0.0) | <0.001 | <0.001 | 0.230 | NE |
| Diuretic | 12 (14.8) | 26 (47.3) | 1 (8.3) | 0 (0.0) | <0.001 | <0.001 | 0.552 | NE |
| Other | 7 (8.6) | 20 (36.4) | 0 (0.0) | 0 (0.0) | <0.001 | <0.001 | NE | NE |
| LVEF >55%/45%–54% | 78/3 | 55/0 | 12/0 | 63/0 | NE | NE | NE | NE |
| SW, mm | 22.5 ± 5.4 | 13.9 ± 2.4 | 15.3 ± 3.4 | 9.6 ± 1.2 | <0.001 | <0.001 | <0.001 | <0.001 |
| LW, mm | 15.3 ± 3.7 | 13.2 ± 2.4 | 14.3 ± 2.5 | 9.2 ± 1.3 | <0.001 | <0.001 | 0.286 | <0.001 |
| SW/LW | 1.5 ± 0.4 | 1.1 ± 0.1 | 1.1 ± 0.1 | 1.0 ± 0.1 | <0.001 | <0.001 | <0.001 | <0.001 |
| LVEDD, mm | 45.1 ± 7.6 | 50.8 ± 5.7 | 47.3 ± 7.2 | 48.8 ± 4.6 | <0.001 | <0.001 | 0.278 | <0.001 |
| LVESD, mm | 25.3 ± 7.7 | 30.6 ± 5.4 | 26.8 ± 7.1 | 31.3 ± 3.9 | <0.001 | <0.001 | 0.458 | <0.001 |
| LAD, mm | 47.1 ± 8.8 | 41.6 ± 5.2 | 41.4 ± 8.0 | 34.2 ± 4.8 | <0.001 | <0.001 | 0.009 | <0.001 |
| DD grade, 0/1/2/3 | 29/13/37/0 | 0/26/29/0 | 8/1/3/0 | 63/0/0/0 | 0.051 | — | — | — |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; AHT, arterial hypertension; ARB, angiotensin II receptor blocker; Ca, calcium; CAD, coronary artery disease; DD, diastolic dysfunction; DM, diabetes mellitus; HCM, hypertrophic cardiomyopathy; LAD, left atrial diameter; LVEDD, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic diameter; LW, lateral wall thickness; NE, not estimable; SD, standard deviation; SW, septal wall thickness.
Data are presented as n (%) or mean ± SD.
3.2. Echocardiography
Apart from 3 HCM patients with a moderately reduced LVEF, all patients in the disease groups showed LVH with a normal ejection fraction. SW thickness and the ratio of SW to LW thickness were higher in all HCM patients compared with the other groups. LADs were highest in HCM but were also increased in AHT and Fabry disease compared with controls. The diameters of the LV chamber were similar among all 4 groups (Table 1).
3.3. Diastolic function
Markers of DD, such as E/A ratio, DT of E wave, E′, E/E′ ratio, and IVRT were significantly altered in all disease groups compared with healthy controls. Mean E′ was significantly reduced in HCM compared with healthy controls and AHT patients due to a significant reduction in septal E′. However, the ratio of septal to lateral E′ did not show any significant differences between groups. In HCM patients E/E′ was significantly higher in both, septal and lateral TDI in comparison to AHT and controls but not to Fabry disease, probably due to the small number of Fabry patients (Table 2).
Table 2.
Echocardiographic parameters of DD
| HCM, n = 81 | AHT, n = 55 | Fabry, n = 12 | Control, n = 63 | P Value for HCM vs | |||
|---|---|---|---|---|---|---|---|
| AHT | Fabry | Control | |||||
| E wave, m/s | 85.7 ± 28.3 | 83.6 ± 26.4 | 88.4 ± 21.6 | 84.0 ± 14.5 | 0.590 | 0.778 | 0.716 |
| A wave, m/s | 80.8 ± 30.0 | 85.7 ± 26.7 | 74.8 ± 18.0 | 60.3 ± 17.4 | 0.385 | 0.255 | <0.001 |
| E/A | 1.2 ± 0.6 | 1.1 ± 0.6 | 1.2 ± 0.4 | 1.5 ± 0.6 | 0.837 | 0.337 | 0.002 |
| DT of E wave, ms | 241.8 ± 76.8 | 221.4 ± 49.6 | 208.5 ± 29.2 | 188.6 ± 38.1 | 0.038 | 0.109 | <0.001 |
| Septal E′, cm/s | 5.1 ± 1.9 | 5.7 ± 1.9 | 6.0 ± 1.3 | 10.2 ± 2.3 | 0.004 | 0.081 | <0.001 |
| Lateral E′, cm/s | 7.9 ± 3.2 | 8.2 ± 3.3 | 9.5 ± 4.2 | 14.9 ± 3.7 | 0.064 | 0.366 | <0.001 |
| Septal E′/lateral E′, cm/s | 0.7 ± 0.2 | 0.7 ± 0.3 | 0.7 ± 0.3 | 0.7 ± 0.2 | 0.690 | 0.942 | 0.388 |
| Mean E′, cm/s | 6.5 ± 2.4 | 7.0 ± 2.4 | 7.8 ± 2.3 | 12.6 ± 2.6 | 0.025 | 0.311 | <0.001 |
| Septal E/E′, cm/s | 19.0 ± 9.3 | 16.2 ± 7.4 | 15.3 ± 4.3 | 8.5 ± 2.0 | 0.009 | 0.345 | <0.001 |
| Lateral E/E′, cm/s | 12.8 ± 7.1 | 11.8 ± 6.6 | 10.6 ± 4.7 | 5.9 ± 1.6 | 0.031 | 0.404 | <0.001 |
| Mean E/E′, cm/s | 15.0 ± 7.5 | 13.3 ± 6.4 | 12.1 ± 4.1 | 6.9 ± 1.6 | 0.010 | 0.303 | <0.001 |
| Septal IVRT, ms | 152.5 ± 49.3 | 111.1 ± 29.9 | 113.3 ± 20.1 | 81.5 ± 15.8 | <0.001 | 0.021 | <0.001 |
| Lateral IVRT, ms | 106.5 ± 37.3 | 105.1 ± 30.9 | 111.2 ± 16.7 | 76.8 ± 17.7 | 0.570 | 0.079 | 0.006 |
| Mean IVRT, ms | 129.5 ± 40.3 | 108.1 ± 28.3 | 112.2 ± 17.3 | 79.1 ± 15.6 | 0.004 | 0.580 | <0.001 |
| Septal/lateral IVRT, s/l ratio | 1.5 ± 0.4 | 1.1 ± 0.2 | 1.0 ± 0.1 | 1.1 ± 0.2 | <0.001 | <0.001 | <0.001 |
Abbreviations: AHT, arterial hypertension; DD, diastolic dysfunction; DT, deceleration time; E, early transmitral filling velocity; E′, peak early mitral annulus velocity; HCM, hypertrophic cardiomyopathy; IVRT, isovolumic relaxation time; l, lateral; s, septal; SD, standard deviation.
Data are presented as mean ± SD.
P values result from linear models.
3.4. Segmental differences in IVRT
Comparison of IVRT in septal and lateral mitral valve annulus TDI revealed most prominent prolongation in the septal wall resulting in a significantly higher s/l IVRT ratio in HCM patients compared with all other groups (Table 2; Figure 1). ROC analysis was performed to demonstrate that the s/l IVRT ratio allows discrimination of patients suffering from HCM from those with LVH caused by AHT or Fabry disease (Figure 2).
Figure 1.
Forest plots for segmental IVRT. Adjusted IVRT ratios from linear models together with 95% CIs are presented for (A) all HCM patients, (B) HCM patients with and without DD, and (C) HCM patients with a septal wall thickness of ≤20 mm or >20 mm compared with patients with AHT, Fabry disease, and healthy controls. Abbreviations: AHT, arterial hypertension; CI, confidence interval; DD, diastolic dysfunction; HCM, hypertrophic cardiomyopathy; IVRT, isovolumic relaxation time; sw, septal wall
Figure 2.
ROC curve for predicting HCM in patients with LVH by s/l IVRT ratio. Abbreviations: CI, confidence interval; HCM, hypertrophic cardiomyopathy; IVRT, isovolumic relaxation time; l, lateral; LVH, left ventricular hypertrophy; ROC, receiver operating characteristic; s, septal
Subgroup analysis of 52 HCM patients with echocardiographic evidence of global DD and 29 HCM patients without DD revealed that, even in HCM patients without global DD, septal IVRT was >100 ms, which is usually ascribed to mild to moderate DD.16 The s/l IVRT ratio in this subgroup of HCM patients was as high as in HCM patients with global DD and differed from AHT, Fabry, and healthy controls, respectively (Table 3). The same calculations were repeated with 27 genetically positive HCM patients. We found that these patients also had a mean s/l IVRT ratio of 1.5 ± 0.3, which did not differ from the IVRT ratio in the whole HCM cohort.
Table 3.
Segmental IVRT in HCM subgroups
| HCM | ||||
|---|---|---|---|---|
| With DD, n = 52 | Without DD, n = 29 | ≤20 mm, n = 28 | >20 mm, n = 53 | |
| Septal IVRT, ms | 164.7 ± 47.5 | 130.7 ± 45.5 | 143.0 ± 35.8 | 157.6 ± 54.8 |
| Lateral IVRT, ms | 116.6 ± 39.6 | 88.3 ± 24.1 | 99.0 ± 30.5 | 110.5 ± 40.1 |
| Mean IVRT, ms | 140.7 ± 40.1 | 109.5 ± 32.6 | 121.0 ± 28.5 | 134.0 ± 44.9 |
| Septal/lateral IVRT | 1.5 ± 0.5 | 1.5 ± 0.3 | 1.5 ± 0.5 | 1.5 ± 0.3 |
Abbreviations: DD, diastolic dysfunction; HCM, hypertrophic cardiomyopathy; IVRT, isovolumetric relaxation time; SD, standard deviation.
Data are presented as mean ± SD.
As patients with AHT or Fabry disease had thinner septum diameters than HCM patients, we further analyzed a subgroup of HCM patients with a septum thickness of <20 mm (n = 28). The s/l IVRT ratio also showed the ability to differentiate these HCM patients with a thinner septum from other causes of LVH (Table 3, Figure 1). Of note, medial wall thickness in this group was, at 17.3 mm (SD, 2.2 mm), significantly smaller than medial wall thickness of the remaining HCM patients with thicker LV walls (25.3 mm; SD, 4.4 mm; P < 0.001), whereas the s/l IVRT ratio was identical in both groups. The observation that a prolonged septal IVRT was independent of a regional increase in myocardial mass was supported by the results obtained in a subgroup of 42 HCM patients who underwent CMR imaging. No significant association was observed between septal and lateral IVRT with segmental myocardial mass (septal: 1.01, 95% confidence interval [CI]: 1‐1.02, P = 0.09; lateral: 1.03, 95% CI: 0.99‐1.01, P = 0.62) or fibrosis visualized by LGE in CMR (septal: 1.02, 95% CI: 1‐1.05, P = 0.09; lateral: 1.03, 95% CI: 0.99‐1.08, P = 0.14).
4. DISCUSSION
4.1. Regional changes of myocardial relaxation in HCM are independent of overall DD
This echocardiographic study of diastolic relaxation in different entities of LVH revealed a significantly prolonged IVRT in septal mitral annulus TDI in all HCM patients, irrespective of their global diastolic function. Most interesting, a prolongation of septal IVRT is already prominent in HCM patients with an overall still‐normal diastolic function. These results are in line with the idea of subtle regional changes in diastolic function prior to the evidence of global diastolic dysfunction.7 According to previous studies, IVRT is prolonged in HCM patients, particularly in the septal mitral annulus,11, 17 and regional differences in relaxation abnormalities in HCM patients have already been reported by others. In line with our data, Saccheri et al. described a septal pronounced decrease of E′ in HCM patients18 compared with healthy individuals. Further, heterogeneous IVRT intervals both in patients with HCM as well as in AHT were reported by Nunez et al.11 However, we could not find any septal‐to‐lateral differences for E′, E/E′, and E′/A′ among different entities of LVH.
4.2. Regional changes in IVRT are not associated with LVH or fibrosis
Our data provide evidence that IVRT prolongation is not confined only to hypertrophied segments. Hence, as also shown previously, regional differences in IVRT in HCM can be interpreted as a sign of relaxation abnormalities occurring independently of LVH.17
The influence of LVH on diastolic function has been discussed controversially. As De Marchi et al. reported an association,19 several studies claimed that relaxation abnormalities precede the development of LVH,8, 9, 18, 20 which is consistent with experimental data and theoretic reflections.2, 21 Based on our observations, we could not confirm an association of regional myocardial relaxation abnormalities in HCM patients with the corresponding segmental myocardial mass in CMR. Furthermore, we could not find any significant correlation between IVRT and fibrosis visualized by LGE, although an association between diastolic function and myocardial fibrosis was suggested by others.22, 23 In this regard, reduced myocardial velocities may reflect impairment of sarcomeric function rather than fibrosis.
4.3. The s/l IVRT ratio for discrimination of different entities of LVH
The s/l IVRT ratio in HCM was significantly higher compared with patients with LVH in AHT and/or Fabry disease. These data raise evidence that a higher s/l IVRT ratio reflects a unique HCM‐specific phenotype that differs from normal hearts as well as from other entities of LVH, such as AHT and Fabry disease. The best threshold according to ROC analysis lies between 1.2 (sensitivity 76.5%, specificity 79.1%) and 1.3 (sensitivity 63%, specificity 91%; Figure 2). Supposing that in a clinical setting a higher specificity would be of greater value than a high sensitivity, we recommend an s/l IVRT ratio of 1.3 as a possible lower threshold for discrimination of HCM from other causes of hypertrophy. Although clinical diagnosis of HCM was performed thoroughly, the HCM genotype was known only in 27 patients. However, medial IVRT ratio in these genetically positive patients was comparable with the IVRT ratio of the entire HCM cohort underlining our result.
As in patients with AHT or Fabry disease, hypertrophy was less pronounced than in the majority of HCM patients, a subgroup analysis in HCM patients with less hypertrophy (15–19 mm) was performed. Even in these patients, a significantly higher s/l IVRT ratio was prominent, suggesting this ratio as a potential parameter for differential diagnosis of LVH even in earlier stages of the disease.
4.4. Study limitations
HCM and AHT patients with DD were older than patients without DD, which is probably because DD increases with age. Younger age in the HCM group without DD might also account for less frequent concomitant diseases. Differences in medication among groups are explained by divergent treatment options for the specific diseases. In this context a potential limitation of this study is the continuous administration of cardiac drugs, which may alter diastolic function throughout all disease groups.
CMR was only performed in a subgroup of HCM patients and not in the other groups; therefore, general conclusions based on our observations from CMR imaging are limited.
We would further like to stress that the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines recommend a different approach for the evaluation of diastolic function in patients with HCM than we chose. However, the aim of our study was to compare parameters of diastolic function in patients with LVH to differentiate between the different entities, which was only possible when using the same method for all patients.
5. CONCLUSION
HCM patients with asymmetric septal LVH show a septal pronounced IVRT prolongation, which occurs independent of global DD and which is independent of regional myocardial mass and fibrosis. The s/l IVRT ratio is significantly higher in HCM patients compared with other entities of LVH, such as AHT or storage disorders, and also differs from healthy individuals. Hence, the s/l IVRT ratio might be a useful additional parameter for differential diagnosis of LVH, especially in HCM patients with lesser extent of hypertrophy and irrespective of their global diastolic function. Furthermore, these results may shed more light on the pathophysiologic understanding of DD in HCM.
Author contributions
Christian Voigt and Julia Münch contributed equally to this article.
Conflicts of interest
The authors declare no potential conflicts of interest.
Voigt C., Münch J., Avanesov M., et al. Early segmental relaxation abnormalities in hypertrophic cardiomyopathy for differential diagnostic of patients with left ventricular hypertrophy. Clin Cardiol. 2017;40:1026–1032. 10.1002/clc.22761
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