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Nisha Arenja, Thomas Fritz, Florian Andre, Johannes H Riffel, Fabian aus dem Siepen, Marco Ochs, Judith Paffhausen, Ute Hegenbart, Stefan Schönland, Matthias Müller-Hennessen, Evangelos Giannitsis, Arnt V Kristen, Hugo A Katus, Matthias G Friedrich, Sebastian J Buss, Myocardial contraction fraction derived from cardiovascular magnetic resonance cine images—reference values and performance in patients with heart failure and left ventricular hypertrophy, European Heart Journal - Cardiovascular Imaging, Volume 18, Issue 12, December 2017, Pages 1414–1422, https://doi.org/10.1093/ehjci/jew324
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Abstract
Left ventricular hypertrophy (LVH) has strong prognostic implications and is associated with heart failure. Recently, myocardial contraction fraction (MCF) was identified as a useful marker for specifically identifying cardiac amyloidosis (CA). The purpose of this study was to evaluate the diagnostic accuracy of MCF for the discrimination of different forms of LVH.
We analysed cardiovascular magnetic resonance (CMR) scans of patients with CA (n = 132), hypertrophic cardiomyopathy (HCM, n = 60), hypertensive heart disease (HHD, n = 38) and in 100 age- and gender-matched healthy controls. MCF was calculated by dividing left ventricular (LV) stroke volume by LV myocardial volume. The diagnostic accuracy of MCF was compared to that of LV ejection fraction (EF) and the mass index (MI). Compared with controls (136.3 ± 24.4%, P < 0.05), mean values for MCF were significantly reduced in LVH (HHD:92.6 ± 20%, HCM:80 ± 20.3%, transthyretin CA:74.9 ± 32.2% and light-chain (AL) CA:50.5 ± 21.4%). MCF performed better than LVEF (AUC = 0.96 vs. AUC = 0.6, P < 0.001) and was comparable to LVMI (AUC = 0.95, P = 0.4) in discriminating LVH from controls. There was a significant yet weak correlation between MCF and LVEF (r = 0.43, P < 0.0001). MCF outperformed LVEF and LVMI in discriminating between different etiologies of LVH and between AL and other forms of LVH (AUC = 0.84, P < 0.0001). Moreover, cut-off values for MCF <50% and LVEF <60% allowed to identify patients with high probability for CA.
In patients with heart failure MCF discriminates CA from other forms of LVH. As it can easily be derived from standard, non-contrast cine images, it may be a very useful marker in the diagnostic workup of patients with LVH.
Introduction
Left ventricular hypertrophy (LVH) is a common condition of various etiologies and has important prognostic implications for the patient, which is often closely related to the underlying etiology. It often represents the hemodynamic response of pressure overload in conditions such as aortic stenosis or arterial hypertension (AH), but may also be genetically determined in hypertrophic cardiomyopathy (HCM). Furthermore, infiltrative myocardial disease may lead to apparent LVH. One of the most important and clinically relevant infiltrative myocardial diseases is cardiac amyloidosis (CA) with its common forms of immunoglobulin light-chain (AL) as well as transthyretin (ATTR) amyloidosis and its subforms, wild-type (ATTRwt) and mutant-type (ATTRmt) CA.1–3
The necessity to differentiate between amyloidosis from other forms of LVH has a direct impact on therapeutic decision-making and outcome. The mere assessment of LV mass and its regional distribution may not provide definitive diagnostic clues and therefore, contrast-enhanced cardiovascular magnetic resonance (CMR) tissue characterization or even biopsy are required to establish the underlying cause of LVH.
CMR imaging is widely accepted as the modality of choice for the quantitative assessment of the heart and is also used for assessing the pathophysiology related to LVH. Besides the accurate and reproducible quantitative assessment of ventricular mass, volumes and global contractile function (ejection fraction, EF) using steady-state free precession (SSFP) cine images, CMR has the unique ability of myocardial tissue characterization.4 Late gadolinium enhancement (LGE) images allow for the differentiation of LVH based on disease-specific regional distribution patterns of myocardial fibrosis.5,6 LGE however requires the injection of contrast agents and its application is contraindicated in patients with severe renal dysfunction, which is often the case in patents with amyloidosis. Recently, T1 mapping has been introduced to identify diffuse or regional myocardial fibrosis in LVH.7–9 T1 mapping however is not widely available. Furthermore, T1 mapping of myocardial fibrosis still requires the administration of contrast agents. Moreover, tissue characterization does not include markers of functional abnormalities, especially subtle regional or global dysfunction. As standard functional parameters such as EF and cardiac index are not specific to LVH and do not reflect subtle changes, novel, specific markers for a reliable, safe, and cost-efficient characterization of ventricular dysfunction in LVH are desirable.
Myocardial contraction fraction (MCF) is a novel quantitative marker, which reflects the relationship between stroke volume and LV mass and is calculated by dividing LV stroke volume by the LV myocardial volume. MCF represents an index of fractional shortening of the myocardium and it has already been proven useful in echocardiography studies of patients with CA.10 Yet, no published data are available for CMR-derived results. This is of particular relevance as CMR provides more accurate and more reproducible quantitative data on volumes and is recommended as the initial diagnostic tool in HCM.11–13
The goal of our study was to evaluate the diagnostic performance of MCF in differentiation of a heterogeneous group of heart failure patients with LVH and controls.
Methods
Study population and design
The study population consisted of 230 consecutive patients with various etiologies of LVH, who received a CMR scan between June 2005 and October 2014 at the University of Heidelberg as part of a standard institutional protocol for the evaluation of cardiomyopathies.
CMR was performed as part of the routine diagnostic workup, unless one of the following contraindications to CMR was present: Cardiac pacemaker or implantable cardioverter defibrillator (ICD), other metallic implants not compatible with CMR, severe claustrophobia, severe obesity preventing patient entrance into the scanner bore, pregnancy and lactation. Chronic renal failure with an estimated GFR < 30 mL/min/1.73 m2 was added as an exclusion criterion for administration of intravenous CMR contrast agents after July 2007.
All patients were included retrospectively in the study, if they were in a clinically stable condition [New York Heart Association (NYHA) functional class ≤ III], older than 18 years and gave their written informed consent for the CMR study. Patients with more than mild valve heart disease were excluded from the analysis. The study was carried out after approval of the local Ethics Committee and in accordance with the Declaration of Helsinki.
Adjudication of the diagnosis
Amyloid protein and subtype were diagnosed by Congo red and immunohistological stain techniques. In patients without endomyocardial biopsy, cardiac involvement was non-invasively defined according to published consensus criteria.14 Patients were screened for amyloidogenetic TTR variants by sequencing of genomic DNA. The diagnosis of HCM was based on conventional criteria with a LV wall thickness ≥ 15 mm on two-dimensional echocardiography or CMR in the absence of another conditions accounting for LVH.15 The clinical workup also included electrocardiography (ECG), echocardiography and coronary angiography. The diagnosis of hypertensive heart disease (HHD) was established if patients had LVH with an established long-standing history of AH and in the absence of another cause of LVH.
Healthy controls
We compared the data of the heart failure patients with LVH with age- and gender matched healthy controls. Subjects older than 18 years with written informed consent were included in the study. Excluded criteria were signs, symptoms or a history of cardiac disease, any chronic or acute disease and any intake of regular medication. All subjects were screened by clinical history, physical examination, 12-lead electrocardiogram, blood pressure measurement, and CMR study.
CMR acquisition and analysis
CMR scans were acquired using standard institutional CMR protocols in a clinical 1.5 T MR system (Philips Achieva™, Philips Medical Systems International, Best, Netherlands) equipped with a cardiac phased array 5 or 32-channel receiver coil. Cine images were obtained using a breath-hold, segmented k-space, SSFP employing retrospective ECG gating in long axis planes (2, 4, and 3 chamber views) as well as in contiguous short axis slices covering the entire LV and right ventricle (RV) from the annulus of the atrioventricular valve to the apex, with 35 phases per cardiac cycle. The analysis was retrospective and performed on a commercially available clinical workstation. Results for LV volumes, EF and LV myocardial mass were derived from short axis slices by tracing endocardial and epicardial borders of the LV. Papillary muscles and trabeculations were excluded from LV mass.
Assessment of MCF
LV myocardial volume was defined as LV myocardial mass divided by the mean density of myocardium, which is 1.05 g/mL. To achieve the index, the result was multiplied by 100. MCF can be interpreted as a cardiac efficiency measure since it relates cardiac output to myocardial size.
Statistics
Categorical variables are expressed as number and percentage, continuous variables as mean ± standard deviation (SD). For the comparison of means between groups, two-tailed Student’s t-test was used. Proportions of categorical were compared using Chi-squared test. Correlations were assessed using Spearman's rank-correlation coefficient. Receiver operating characteristic curves (ROC) were generated to evaluate the area under the curve (AUC), sensitivity and specificity of MCF in LVH and controls. A P-value <0.05 was considered as statistically significant. Kappa statistics were used as a measure of interobserver reliability. Youden plots were performed to chart MCF and LVEF values of different LVH forms. All statistics were calculated using MedCalc 15 (MedCalc™, Mariakerke, Belgium).
Results
Patient’s population
The study cohort consisted of 230 consecutive patients with a confirmed diagnosis of HCM (n = 60), AL (n = 80), ATTRmt (n = 27), ATTRwt (n = 25), and HHD (n = 38). Results were compared to 100 healthy controls, matched for gender and age. The mean age of all patients was 59.5 ± 12.9 years, with only ATTR patients being significantly older (63.9 ± 11.3 years, P < 0.05). Among each group, AH was the most common cardiovascular risk factor and a high percentage of the study population was treated with beta-blockers and ACE-Inhibitors. All baseline characteristics of the study cohort are depicted in Table 1.
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
Age (years) | 56.4 ±16.9 | 58.7 ± 10.0 | 63.9 ± 11.3* | 60.4 ± 11.5 | 57.3 ± 6.7 |
BMI (kg/m2) | 27 ± 4.4* | 25.6 ± 4.0 | 25.3 ± 4.1 | 28.5 ± 4.1* | 25.4 ± 3 |
Male gender, n (%) | 42 (70) | 61 (76) | 38 (73) | 33 (87)* | 66 (66) |
Heart rate (beats per minute) | 67 ± 10 | 69 ± 12 | 65 ± 15 | 67 ± 9 | 67 ± 14 |
Arterial Hypertension, n (%) | 37 (62) | 25 (31) | 22 (42) | 38 (100) | |
Hyperlipidemia, (%) | 21 (35) | 11 (14) | 14 (27) | 19 (50) | |
Smoking, n(%) | 14 (23) | 3 (4) | 4 (8) | 23 (61) | |
Diabetes mellitus, n (%) | 6 (10) | 8 (10) | 3 (6) | 4 (11) | |
Beta blockers, n (%) | 41 (68) | 34 (43) | 33 (64) | 30 (79) | |
ACE-Inhibitors, n (%) | 32 (53) | 37 (46) | 21 (40) | 27 (71) | |
AT II blockers, n (%) | 11 (18) | 9 (11) | 11 (21) | 8 (21) | |
Spironolactone, n (%) | 5 (8) | 15 (19) | 13 (25) | 4 (11) | |
Diuretics, n (%) | 14 (23) | 43 (54) | 28 (54) | 10 (26) |
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
Age (years) | 56.4 ±16.9 | 58.7 ± 10.0 | 63.9 ± 11.3* | 60.4 ± 11.5 | 57.3 ± 6.7 |
BMI (kg/m2) | 27 ± 4.4* | 25.6 ± 4.0 | 25.3 ± 4.1 | 28.5 ± 4.1* | 25.4 ± 3 |
Male gender, n (%) | 42 (70) | 61 (76) | 38 (73) | 33 (87)* | 66 (66) |
Heart rate (beats per minute) | 67 ± 10 | 69 ± 12 | 65 ± 15 | 67 ± 9 | 67 ± 14 |
Arterial Hypertension, n (%) | 37 (62) | 25 (31) | 22 (42) | 38 (100) | |
Hyperlipidemia, (%) | 21 (35) | 11 (14) | 14 (27) | 19 (50) | |
Smoking, n(%) | 14 (23) | 3 (4) | 4 (8) | 23 (61) | |
Diabetes mellitus, n (%) | 6 (10) | 8 (10) | 3 (6) | 4 (11) | |
Beta blockers, n (%) | 41 (68) | 34 (43) | 33 (64) | 30 (79) | |
ACE-Inhibitors, n (%) | 32 (53) | 37 (46) | 21 (40) | 27 (71) | |
AT II blockers, n (%) | 11 (18) | 9 (11) | 11 (21) | 8 (21) | |
Spironolactone, n (%) | 5 (8) | 15 (19) | 13 (25) | 4 (11) | |
Diuretics, n (%) | 14 (23) | 43 (54) | 28 (54) | 10 (26) |
P < 0.05 between healthy controls and patients.
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
Age (years) | 56.4 ±16.9 | 58.7 ± 10.0 | 63.9 ± 11.3* | 60.4 ± 11.5 | 57.3 ± 6.7 |
BMI (kg/m2) | 27 ± 4.4* | 25.6 ± 4.0 | 25.3 ± 4.1 | 28.5 ± 4.1* | 25.4 ± 3 |
Male gender, n (%) | 42 (70) | 61 (76) | 38 (73) | 33 (87)* | 66 (66) |
Heart rate (beats per minute) | 67 ± 10 | 69 ± 12 | 65 ± 15 | 67 ± 9 | 67 ± 14 |
Arterial Hypertension, n (%) | 37 (62) | 25 (31) | 22 (42) | 38 (100) | |
Hyperlipidemia, (%) | 21 (35) | 11 (14) | 14 (27) | 19 (50) | |
Smoking, n(%) | 14 (23) | 3 (4) | 4 (8) | 23 (61) | |
Diabetes mellitus, n (%) | 6 (10) | 8 (10) | 3 (6) | 4 (11) | |
Beta blockers, n (%) | 41 (68) | 34 (43) | 33 (64) | 30 (79) | |
ACE-Inhibitors, n (%) | 32 (53) | 37 (46) | 21 (40) | 27 (71) | |
AT II blockers, n (%) | 11 (18) | 9 (11) | 11 (21) | 8 (21) | |
Spironolactone, n (%) | 5 (8) | 15 (19) | 13 (25) | 4 (11) | |
Diuretics, n (%) | 14 (23) | 43 (54) | 28 (54) | 10 (26) |
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
Age (years) | 56.4 ±16.9 | 58.7 ± 10.0 | 63.9 ± 11.3* | 60.4 ± 11.5 | 57.3 ± 6.7 |
BMI (kg/m2) | 27 ± 4.4* | 25.6 ± 4.0 | 25.3 ± 4.1 | 28.5 ± 4.1* | 25.4 ± 3 |
Male gender, n (%) | 42 (70) | 61 (76) | 38 (73) | 33 (87)* | 66 (66) |
Heart rate (beats per minute) | 67 ± 10 | 69 ± 12 | 65 ± 15 | 67 ± 9 | 67 ± 14 |
Arterial Hypertension, n (%) | 37 (62) | 25 (31) | 22 (42) | 38 (100) | |
Hyperlipidemia, (%) | 21 (35) | 11 (14) | 14 (27) | 19 (50) | |
Smoking, n(%) | 14 (23) | 3 (4) | 4 (8) | 23 (61) | |
Diabetes mellitus, n (%) | 6 (10) | 8 (10) | 3 (6) | 4 (11) | |
Beta blockers, n (%) | 41 (68) | 34 (43) | 33 (64) | 30 (79) | |
ACE-Inhibitors, n (%) | 32 (53) | 37 (46) | 21 (40) | 27 (71) | |
AT II blockers, n (%) | 11 (18) | 9 (11) | 11 (21) | 8 (21) | |
Spironolactone, n (%) | 5 (8) | 15 (19) | 13 (25) | 4 (11) | |
Diuretics, n (%) | 14 (23) | 43 (54) | 28 (54) | 10 (26) |
P < 0.05 between healthy controls and patients.
Analysis of left ventricular function
Compared with healthy controls with a mean MCF of 136.3%, the mean value of MCF was highly reduced throughout all groups of LVH (P < 0.05 for all, Figure 1). The lowest MCF value was obtained in patients with AL (50.5%, P < 0.05 vs. all other groups). The LVEF in patients with HCM was comparable to controls (61.8% and 60.7%, P = 0.37) and only mildly reduced in patients with AL (55 ± 11%, P < 0.05), ATTR (53 ± 15%, P < 0.05), and HHD (57 ± 6%, P < 0.01). The CMR results are presented in Table 2. In patients with heart failure MCF was significantly reduced according to NYHA functional class (NYHA I 78.7 ± 26.7%, NYHA II 65.8 ± 27.4%, NYHA III 55.6 ± 24.1%, P < 0.001), while no significant difference was present in LVEF (NYHA I 58.8 ± 9.0%, NYHA II 56.4 ± 11.8%, NYHA III 55.1 ± 13.3%, P = 0.2) and LVMI (NYHA I 80.9 ± 29.6%, NYHA II 89.9 ± 31.8%, NYHA III 85.0 ± 28.7%, P = 0.5; Figure 2A–C).
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
LV EDVI (mL/m2) | 92.1 ± 23.4* | 71.3 ± 16.8* | 82.3 ± 23.4 | 112.5 ± 32.4* | 86 ± 14.7 |
LV ESVI (mL/m2) | 36.2 ± 16.2 | 32.6 ± 13.2 | 40.7 ± 22.0* | 50.1 ± 22.9* | 34.1 ± 8.8 |
LVEF (%) | 61.8 ± 9.5 | 55 ± 11* | 52.9 ± 14.7* | 57 ± 5.6* | 60.7 ± 5.6 |
LVMI (g/m2) | 79.3 ± 32.6* | 89.6 ± 28.6* | 92.7 ± 33.0* | 73.2 ± 20.7* | 41.2 ± 9.4 |
MCF (%) | 80 ± 20.3*# | 50.5 ± 21.4* | 74.9 ± 32.2*# | 92.6 ± 20*# | 136.3 ± 24.4# |
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
LV EDVI (mL/m2) | 92.1 ± 23.4* | 71.3 ± 16.8* | 82.3 ± 23.4 | 112.5 ± 32.4* | 86 ± 14.7 |
LV ESVI (mL/m2) | 36.2 ± 16.2 | 32.6 ± 13.2 | 40.7 ± 22.0* | 50.1 ± 22.9* | 34.1 ± 8.8 |
LVEF (%) | 61.8 ± 9.5 | 55 ± 11* | 52.9 ± 14.7* | 57 ± 5.6* | 60.7 ± 5.6 |
LVMI (g/m2) | 79.3 ± 32.6* | 89.6 ± 28.6* | 92.7 ± 33.0* | 73.2 ± 20.7* | 41.2 ± 9.4 |
MCF (%) | 80 ± 20.3*# | 50.5 ± 21.4* | 74.9 ± 32.2*# | 92.6 ± 20*# | 136.3 ± 24.4# |
P < 0.05 between healthy controls and patients.
P < 0.05 between light-chain amyloidosis and others.
EDVI, end-diastolic volume index; ESVI, end-systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; MCF, myocardial contraction fraction.
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
LV EDVI (mL/m2) | 92.1 ± 23.4* | 71.3 ± 16.8* | 82.3 ± 23.4 | 112.5 ± 32.4* | 86 ± 14.7 |
LV ESVI (mL/m2) | 36.2 ± 16.2 | 32.6 ± 13.2 | 40.7 ± 22.0* | 50.1 ± 22.9* | 34.1 ± 8.8 |
LVEF (%) | 61.8 ± 9.5 | 55 ± 11* | 52.9 ± 14.7* | 57 ± 5.6* | 60.7 ± 5.6 |
LVMI (g/m2) | 79.3 ± 32.6* | 89.6 ± 28.6* | 92.7 ± 33.0* | 73.2 ± 20.7* | 41.2 ± 9.4 |
MCF (%) | 80 ± 20.3*# | 50.5 ± 21.4* | 74.9 ± 32.2*# | 92.6 ± 20*# | 136.3 ± 24.4# |
. | Hypertrophic cardiomyopathy (n = 60) . | Light-chain amyloidosis (n = 80) . | Transthyretin amyloidosis (n = 52) . | Hypertensive heart disease (n = 38) . | Healthy controls (n = 100) . |
---|---|---|---|---|---|
LV EDVI (mL/m2) | 92.1 ± 23.4* | 71.3 ± 16.8* | 82.3 ± 23.4 | 112.5 ± 32.4* | 86 ± 14.7 |
LV ESVI (mL/m2) | 36.2 ± 16.2 | 32.6 ± 13.2 | 40.7 ± 22.0* | 50.1 ± 22.9* | 34.1 ± 8.8 |
LVEF (%) | 61.8 ± 9.5 | 55 ± 11* | 52.9 ± 14.7* | 57 ± 5.6* | 60.7 ± 5.6 |
LVMI (g/m2) | 79.3 ± 32.6* | 89.6 ± 28.6* | 92.7 ± 33.0* | 73.2 ± 20.7* | 41.2 ± 9.4 |
MCF (%) | 80 ± 20.3*# | 50.5 ± 21.4* | 74.9 ± 32.2*# | 92.6 ± 20*# | 136.3 ± 24.4# |
P < 0.05 between healthy controls and patients.
P < 0.05 between light-chain amyloidosis and others.
EDVI, end-diastolic volume index; ESVI, end-systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; MCF, myocardial contraction fraction.
Diagnostic accuracy of MCF
The diagnostic values for MCF (AUC = 0.96, 95%CI 0.94–0.98) and LVEF (AUC = 0.6, 95%CI 0.54–0.67, P < 0.001) in discriminating LVH from controls are depicted in Figure 3. Table 3 reports values of ROC analysis for discriminating LVH groups from controls. MCF showed an especially high diagnostic accuracy in patients with AL (AUC = 0.99, sensitivity 95% and specificity 99%), HCM (AUC = 0.97, sensitivity 87%, specificity 95%), and ATTR (AUC = 0.94, sensitivity 81%, specificity 94%). In patients with HHD the AUC value of MCF was also high and comparable with LVMI (0.92 vs. 0.93, P = 0.53). In discriminating HCM from healthy controls, MCF (AUC = 0.97) reached a better diagnostic accuracy than LVEF (AUC = 0.55, P < 0.0001) and showed a trend for a better accuracy when compared with the LV mass index (MI) (AUC = 0.93, P = 0.08).
. | Area under the curve . | Threshold . | Sensitivity . | Specificity . |
---|---|---|---|---|
Hypertrophic cardiomyopathy (n = 60) | ||||
MCF | 0.97 | ≤ 99.64 | 86.7 | 95 |
LVEF | 0.55 | ≤ 66 | 40 | 85 |
LVMI | 0.93 | > 59.1 | 78.3 | 98 |
Light-chain amyloidosis (n = 80) | ||||
MCF | 0.99 | ≤ 96.3 | 96 | 97 |
LVEF | 0.65 | ≤ 51.9 | 36.3 | 95 |
LVMI | 0.98 | > 56.5 | 90 | 96 |
Transthyretin amyloidosis (n = 52) | ||||
MCF | 0.94 | ≤ 100.8 | 80.8 | 94 |
LVEF | 0.67 | ≤ 50 | 44.2 | 100 |
LVMI | 0.96 | >58 | 88.5 | 97 |
Hypertensive heart disease (n = 38) | ||||
MCF | 0.92 | ≤ 114.8 | 89.5 | 80 |
LVEF | 0.63 | ≤ 56.5 | 47.4 | 78 |
LVMI | 0.93 | > 52 | 86.8 | 88 |
. | Area under the curve . | Threshold . | Sensitivity . | Specificity . |
---|---|---|---|---|
Hypertrophic cardiomyopathy (n = 60) | ||||
MCF | 0.97 | ≤ 99.64 | 86.7 | 95 |
LVEF | 0.55 | ≤ 66 | 40 | 85 |
LVMI | 0.93 | > 59.1 | 78.3 | 98 |
Light-chain amyloidosis (n = 80) | ||||
MCF | 0.99 | ≤ 96.3 | 96 | 97 |
LVEF | 0.65 | ≤ 51.9 | 36.3 | 95 |
LVMI | 0.98 | > 56.5 | 90 | 96 |
Transthyretin amyloidosis (n = 52) | ||||
MCF | 0.94 | ≤ 100.8 | 80.8 | 94 |
LVEF | 0.67 | ≤ 50 | 44.2 | 100 |
LVMI | 0.96 | >58 | 88.5 | 97 |
Hypertensive heart disease (n = 38) | ||||
MCF | 0.92 | ≤ 114.8 | 89.5 | 80 |
LVEF | 0.63 | ≤ 56.5 | 47.4 | 78 |
LVMI | 0.93 | > 52 | 86.8 | 88 |
. | Area under the curve . | Threshold . | Sensitivity . | Specificity . |
---|---|---|---|---|
Hypertrophic cardiomyopathy (n = 60) | ||||
MCF | 0.97 | ≤ 99.64 | 86.7 | 95 |
LVEF | 0.55 | ≤ 66 | 40 | 85 |
LVMI | 0.93 | > 59.1 | 78.3 | 98 |
Light-chain amyloidosis (n = 80) | ||||
MCF | 0.99 | ≤ 96.3 | 96 | 97 |
LVEF | 0.65 | ≤ 51.9 | 36.3 | 95 |
LVMI | 0.98 | > 56.5 | 90 | 96 |
Transthyretin amyloidosis (n = 52) | ||||
MCF | 0.94 | ≤ 100.8 | 80.8 | 94 |
LVEF | 0.67 | ≤ 50 | 44.2 | 100 |
LVMI | 0.96 | >58 | 88.5 | 97 |
Hypertensive heart disease (n = 38) | ||||
MCF | 0.92 | ≤ 114.8 | 89.5 | 80 |
LVEF | 0.63 | ≤ 56.5 | 47.4 | 78 |
LVMI | 0.93 | > 52 | 86.8 | 88 |
. | Area under the curve . | Threshold . | Sensitivity . | Specificity . |
---|---|---|---|---|
Hypertrophic cardiomyopathy (n = 60) | ||||
MCF | 0.97 | ≤ 99.64 | 86.7 | 95 |
LVEF | 0.55 | ≤ 66 | 40 | 85 |
LVMI | 0.93 | > 59.1 | 78.3 | 98 |
Light-chain amyloidosis (n = 80) | ||||
MCF | 0.99 | ≤ 96.3 | 96 | 97 |
LVEF | 0.65 | ≤ 51.9 | 36.3 | 95 |
LVMI | 0.98 | > 56.5 | 90 | 96 |
Transthyretin amyloidosis (n = 52) | ||||
MCF | 0.94 | ≤ 100.8 | 80.8 | 94 |
LVEF | 0.67 | ≤ 50 | 44.2 | 100 |
LVMI | 0.96 | >58 | 88.5 | 97 |
Hypertensive heart disease (n = 38) | ||||
MCF | 0.92 | ≤ 114.8 | 89.5 | 80 |
LVEF | 0.63 | ≤ 56.5 | 47.4 | 78 |
LVMI | 0.93 | > 52 | 86.8 | 88 |
MCF for discrimination between AL, HCM, and HHD
MCF outperformed both LVEF and LVMI in differentiating between AL and LVH (Figure 4A–C). The diagnostic performance of MCF for discriminating AL from HCM (the difference (delta) in AUC 0.84, P < 0.0001) was significantly higher than that of LVEF (delta AUC 0.67, P = 0.0002) and LVMI (delta AUC 0.62, P = 0.02).
Figure 5A–C depict the Youden plots for MCF and LVEF values in patients with AL and other LVH forms. Cut-off value for MCF <50% and for LVEF <60% could best identify patients with a high probability for CA.
Correlation of MCF with LVEF and LVMI and observer agreement
In the entire LVH study population, a significant yet weak correlation was found between MCF and LVEF (r = 0.43, 95%Cl 0.28–0.47, P < 0.0001). The correlation analysis between MCF and LVEF in each LVH group was best for patients with HHD (r = 0.64, 95%Cl 0.4–0.8, P < 0.0001). While there was no correlation between both parameters in HCM patients (r = 0.2, 95%Cl 0.05–0.4, P = 0.1). For MCF and LVMI, a moderate correlation was found in all LVH patients (r = –0.62, 95%Cl 0.69–0.54, P < 0.0001). In contrast, the correlation coefficient was greatest in HCM (r = –0.75, 95%Cl 0.84–0.61, P < 0.0001) and moderate in CA (r = –0.6, 95%Cl 0.7–0.48, P < 0.0001) as well as in HHD (r = –0.54, 95%Cl 0.73–0.27, P = 0.0005).
The interobserver agreement was assessed in 20 randomly selected subjects, who were reanalysed by another investigator, blinded to other informations. The interobserver agreement as expressed by kappa values was 0.82 (95%Cl-0.75–0.89).
Reference values and age- and gender-related differences
Additionally, the cohort of 100 age- and gender-matched healthy controls were analysed regarding reference values for MCF (136.3 ± 24.4%). Mean MCF values for women were significantly higher (155.0 ± 18.7% vs. 126.6 ± 21.2%, P < 0.0001). There was no correlation of MCF with age (r = –0.02, 95%Cl -0.22-0.17, P = 0.8).
Discussion
Our study indicates that in heart failure patients, MCF has an excellent diagnostic accuracy to identify LVH and discriminates patients with AL from patients with other forms of LVH. As it encompasses information on global LV function, MCF may be particularly useful in forms of LVH, which affect LV function.
MCF represents the relationship between stroke volume and myocardial volume. Stroke volume is a measure of ventricular performance and determines the output of blood of each myocardial contraction. By eliminating LV myocardial volume from the shortening assessment, MCF represents an index of myocardial function that delineates a volumetric index of myocardial shortening. In LVH, a decrease in MCF would indicate abnormal myocardial shortening, due to abnormalities in the ventricular function and the geometry. However, LVEF may still remain normal even in advanced stages because of progressive reductions in ventricular capacitance.
Although myocardial volume is unspecific and stroke volume is affected by a number of physiological variables, our study shows that MCF has the ability to discriminate AL from other forms of LVH. This may be justified by a higher grade of LV geometric deformation or a greater level of contractility dysfunction in AL. The thickening of the LV wall with an increase in LV mass and a decrease in end-diastolic LV volume appears more pronounced in AL than in other forms of LVH. On the other hand, cardiac medication has a direct influence on stroke volume. Our results indicate no difference in cardiac medication between the LVH etiologies. These results might depict a limited benefit of heart failure medication in patients with AL.
In patients with heart failure, LV dysfunction alone, typically represented by an impaired LVEF, is considered the key diagnostic marker for risk stratification and clinical decision-making regarding prevention.16–18
However, the measurement of LVEF alone gives an incomplete representation of the complex process of myocardial deformation and dysfunction.19 Furthermore, LVEF is often preserved in LVH, especially in HCM and CA. Thus, diagnostic markers would be helpful, which combine information on LV function and hypertrophy, ideally at an early stage. Moreover, we present a striking relationship between MCF and NYHA functional class, which suggest an important correlation between MCF and symptoms of heart failure.
MCF was first described by King etal. as a volumetric measure of myocardial shortening for investigating myocardial performance in LVH.20 MCF was estimated using freehand contours and 3D echocardiographic LV reconstruction algorithms. In a heterogeneous group of various pathologies and controls, MCF was lower in hypertensive hypertrophy compared with normal subjects. Therefore, the authors concluded that MCF may be useful in assessing differences in myocardial performance in other patients with hypertrophy. Tendler et al. investigated the prognostic value of MCF in CA (34 AL and 32 ATTR subjects).10 LV mass was measured in standard 2D echocardiography using the formula described by Devereux et al. [1.05 x (LVEDD + IVST + PWT)3–(LVEDD3)].21 They concluded that MCF is superior to LVEF in predicting overall survival among patients with AL. Beside this, MCF was studied in healthy controls.22 Both studies by King et al. and Tendler et al. were based on echocardiography measurements, which is known to provide quantitative data of limited accuracy and reproducibility, especially when compared to CMR as the accepted gold.23 Specifically, the calculation of LV mass by M-mode or 2D echocardiography based on geometric assumptions has been hampered by poor accuracy and interstudy reproducibility.
CMR calculation of LV mass is superior to 2D echocardiography and associated with accurate and reproducible quantitative assessment and even the more recent approaches using 3D echocardiography show only limited performance, suffering from substantial variability and underestimation.12,24 Therefore, we assume that MCF as derived from CMR images is more accurate and reproducible. Our results illustrate a good diagnostic accuracy of MCF compared with LV mass.
MCF can be quickly and easily determined from standard cine CMR images, without the need for contrast agents or specific post-processing software. As many patients with CA and congestive heart failure suffer from renal failure due to low cardiac output and consequently cannot receive contrast agents, MCF may reduce the need for contrast-enhanced studies in this patient group. The remarkable ability of a combination of MCF and LVEF to identify patients with LVH renders MCF a clinical marker with a strong potential.
Our data also include MCF reference values in a large group of age- and gender-matched healthy controls. Our results are consistent with Framingham Heart Study data, which demonstrated higher MCF values in female participants and an association with cardiovascular events.22 The event-free survival was shorter in lowest-quartile MCF, but not in lowest-quartile LVEF. Interestingly however, MCF in our normal population was higher than in the Framingham Heart Study, which may be first due to the imaging sequence difference, as the analysis of MCF in the Framingham Heart Study was based on gradient echo and not SSFP and second due to selection bias. The controls of our study were all without any comorbidities, while up to one third of the Framingham Heart Study controls suffered from cardiovascular risk factors. In addition, we may have include some physically highly active healthy controls. Yet, the fact that we excluded trabecular tissue and papillary muscles from LV mass may also have introduced a systematic underestimation of LV mass and thus overestimation of MCF.
Limitations
The analysis was a single centre study, retrospective and included white Caucasians only. Thus, it may not be applicable to other specific patient groups or other ethnicities. The calculated thresholds of our study cannot be generalized and further prospective studies are needed to confirm our results. Trabecular tissue and papillary muscles were excluded from LV mass and thus actual LV mass may be underestimated and MCF overestimated. We did not compare data with strain measurements or novel tissue markers such as native T1 or extracellular volume fraction. Finally, athletes were not included in the analysis.
Conclusions
In patients with heart failure, myocardial contraction fraction (the ratio of LV stroke volume and myocardial volume) discriminates LV hypertrophy caused by amyloidosis from other forms of LVH. As it can easily be derived from standard, non-contrast cine images, it may be a very useful marker in the diagnostic workup of patients with LVH.
Acknowledgement
We thank Mach-Gaensslen Foundation Switzerland for finical support in CMR training and research.
Conflict of interest: None declared.