Edited by: Ghazala Hayat, Saint Louis University, United States
Reviewed by: Janice C. Wong, Brigham and Women’s Hospital, United States; Holli A. Horak, University of Arizona, United States
Specialty section: This article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology
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The objective of this study was to investigate the potential involvement of cardiac structure and function by cardiac magnetic resonance (CMR) imaging in amyotrophic lateral sclerosis (ALS) patients. Our study included 35 patients with ALS without a history of cardiac disease and an age- and gender-matched healthy control group (
A common limiting factor for life expectancy of amyotrophic lateral sclerosis (ALS) patients is respiratory failure that is caused by paresis of respiratory muscles as well as aspiration and resulting pneumonia (
Cardiac magnetic resonance (CMR) imaging is a valuable tool in the diagnostic assessment of inflammatory myocarditis (
All patients included had possible, probable, or definite ALS according to the revised El Escorial criteria. Patients participating in the diagnostic assessment at the Department of Neurology, University of Ulm (Germany) and in the regional ALS registry (ALS Register Swabia REF) were prospectively screened and enrolled in the study. In total, 53 patients were screened and provided written informed consent. Eighteen of these patients had to be excluded due to claustrophobia or inability to lie supine because of respiratory dysfunction. The ALS Register Swabia and this CMR study were approved by the local Ethics Committee of the University of Ulm (protocols no. 11/10 and no. 05/11).
Exclusion criteria were contraindications for CMR or gadolinium-based contrast agent or pregnancy.
Blood levels of troponin T, creatine kinase (CK), myocardial creatine kinase (CK-MB), and
As controls, a cohort of age and gender matched patients was implemented. These patients exhibited no signs of cardiac insufficiency. Clinical characteristics of ALS patients and controls are presented in Table
Clinical characteristics of amyotrophic lateral sclerosis (ALS) patients and controls.
ALS patients ( |
Controls ( |
|
---|---|---|
Age (y), mean ± SD | 69.54 ± 10.64 | 68.06 ± 9.59 |
Females, |
18 (51.4) | 18 (52.9) |
Arterial hypertension, |
16 (45.7) | 11 (32.4) |
Diabetes, |
7 (20) | 1 (3) |
Body mass index mean ± SD (kg/m2) | 25.0 ± 5.3 | 25.8 ± 4.2 |
ALS functional rating scale, points | 32.4 ± 8.5 | – |
Forced vital capacity, % | 66.11 ± 25.30 | – |
Spinal/bulbar, |
23/12 | – |
Creatine kinase (norm <171), U/l | 244 ± 266 | – |
Myocardial creatine kinase (norm <25), U/l | 24 ± 14 | – |
Troponin T (norm <14), ng/l | 0 ± 0 | – |
N-terminal pro brain natriuretic peptide (norm 0–125), pg/ml | 149 ± 206 | – |
Angiotensin converting enzyme inhibitor and angiotensin 1 receptor blockers, |
10/35 | – |
Beta-blocker, |
8/35 | – |
Other antihypertensive medication, |
4/35 | – |
AVB grade II, |
0 | – |
Atrial fibrillation, |
0 | – |
Supraventricular tachycardia, |
0 | – |
NSVT, |
0 | – |
VCP/h (0–100), |
20/26 | – |
A 24-h Holter monitoring was performed using a Digi Trac XT recorder (Philips Healthcare). Holter monitoring was considered abnormal in the presence of; atrioventricular block grade I–III, atrial fibrillation/flutter (AF/AFL), other supraventricular tachyarrhythmia (SVT) [>30 supraventricular premature contractions (SVPC) per hour or runs of ≥20 SVPC], frequent ventricular premature contractions (VPCs) (≥30/h), and non-sustained ventricular tachycardy (NSVT).
Transthoracic echocardiography was performed using a CX 50 Ultrasound (Philips Healthcare Germany). Left ventricular (LV) cavity dimensions, mass and wall thickness and diastolic dysfunction were assessed in accordance with the recommendations of the European Association of Echocardiography (
An abnormal echocardiography was defined by the following diameters of the left ventricle: a left ventricular end-diastolic diameter (LVEDD) >56 mm, an interventricular septum (IVS) >11 mm and a left ventricular end systolic diameter (LVESD) >40 mm. The ejection fraction was visually evaluated. In addition, echocardiography was used to assess valve disease and fractional shortening (FS).
All patients were examined in a 1.5-T whole-body scanner (Intera, Philips Medical Systems, Best, The Netherlands) using a 32-channel phased-array cardiac surface coil. Steady-state free precession cine sequences were acquired in a contiguous short axis orientation covering the LV and right ventricle for volumetric and functional analysis of both ventricles (repetition time 3.4 ms, echo time 1.7 ms, slice thickness 8 mm, no interslice gap, and acquisition in end-expiration breath-hold) as previously reported (
Ten minutes after an intravenous application of 0.2 mmol/kg body-weight gadolinium-based contrast agent (Dotarem, Guerbet, Villepinte, France), an inversion-recovery gradient-echo sequence for evaluation of late gadolinium enhancement (LGE) was acquired in a contiguous short axis orientation covering the entire left ventricle (repetition time 7.1 ms, echo time 3.2 ms, slice thickness 8 mm, respiratory navigator, and inversion time was individually adjusted for complete nulling of the myocardium) (
Cardiac magnetic resonance images (DICOM) were anonymized and transferred to a workstation. Two blinded and experienced readers (DB, PB) evaluated all images in consensus using commercially available software (cmr42, Circle, Cardiovascular Imaging, Calgary, AB, Canada). End-diastolic and end-systolic endocardial contours of the LV and right ventricle were drawn manually for evaluation of end-diastolic and end-systolic volumes, and the ejection fractions were calculated. In addition, end-diastolic LV epicardial contours were drawn for the assessment of LV myocardial mass.
For an early gadolinium enhancement compared to a thoracic skeletal muscle, early gadolinium enhancement ratio (EGEr) (
The inversion-recovery gradient-echo sequence was evaluated for the presence of a hyper-enhancement consistent with myocardial fibrosis. LGE volume was quantified as a percentage of the LV myocardial mass using a cutoff signal intensity increase of more than five SDs of remote myocardium (
All data are reported as a mean value ± SD in comparison to the control group. An unpaired
Twelve patients had bulbar onset and spinal onset was seen in 23 cases. Mean disease duration at CMR was 2.6 ± 2.2 years and mean ALS functional rating scale (ALSFRS)-R score was 32.4 ± 8.5 points. None of the patients had any cardiac complaints. Patients were characterized with respect to cardiovascular risk factors, antihypertensive co-medication, and vital capacity as indicated in Table
In particular, we did not find any abnormality on Holter monitoring in patients with ALS (
Several premature ventricular contractions were monitored (Table
Echocardiography revealed normal diameters of the ventricles. The systolic function was not diminished in the visual evaluation with normal values of FS. Slight insufficiencies of the aortic, tricuspidal and mitral valve were reported in several patients. All other documented values were in the normal range (Table
Results of echocardiography in 30 amyotrophic lateral sclerosis (ALS) patients.
ALS patients | |
---|---|
LA (norm <40), mean ± SD (mm) | 37.7 ± 6.4 |
LVEDD (norm <56 mm), mean ± SD (mm) | 46.2 ± 4.6 |
LVESD (norm <42 mm), mean ± SD (mm) | 26.2 ± 4.0 |
FS fractional shortening (LVEDD–LVESD) (norm > 25%), mean ± SD (%) | 40.4 ± 6.6 |
IVSDD (norm 5–11 mm), mean ± SD (mm) | 9.6 ± 2.0 |
AI (slight), |
7/30 |
MI (slight), |
13/30 |
TI (slight), |
15/30 |
Creatine kinase was elevated in 14/35 patients (mean 239 ± 265 U/l, normal range <171 U/l) and CK-MB in 6/22 (mean 24 ± 14 U/l, normal range <25 U/l). Troponin T was normal in all patients tested (
Cardiac magnetic resonance was completed in 35 ALS patients and 34 controls. Mean left and right ventricular ejection fractions (LVEF and RVEF) were in the normal range (Table
Cardiac magnetic resonance (CMR) characteristics of 35 ALS cases.
Unit | ALS cohort |
Control cohort |
Unpaired |
|
---|---|---|---|---|
Age (years) | Mean ± SD | 69.54 ± 10.64 | 68.06 ± 9.59 | 0.55 |
Females, |
Frequency | 18 (51.4) | 18 (52.9) | 0.90 |
AHT, |
Frequency | 16 (45.7) | 11 (32.4) | 0.26 |
Diabetes, |
Frequency | 7 (20) | 1 (3) | |
LVEDV (ml) | Median (5; 95) | 99 (68; 158.2) | 136 (82.4; 213.6) | |
LVEDV index (ml/m2) | Median (5; 95) | 57.74 (29.09; 88.14) | 73.18 (42.78; 110.6) | |
LVSV (ml) | Mean ± SD | 68.30 ± 17.62 | 82.09 ± 20.66 | |
LVSV index (ml/m2) | Mean ± SD | 37.05 ± 9.737 | 44.75 ± 10.34 | |
Ventricular mass (g) | Mean ± SD | 79.38 ± 26.16 | 99.0 ± 27.30 | |
Ventricular mass index (g/m2) | Mean ± SD | 41.98 ± 16.04 | 50.3 ± 17.36 | |
LVEF (%) | Median (5; 95) | 64 (55.2; 74.7) | 62 (44.4; 75.6) | |
RVEDV (ml) | Median (5; 95) | 96 (67; 163.65) | 134 (68.6; 219.2) | |
RVEDV index (ml/m2) | Median (5; 95) | 55.63 (27.35; 88.23) | 77.63 (35.82; 115.7) | |
RVSV (ml) | Mean ± SD | 65.16 ± 18.59 | 82.59 ± 21.87 | |
RVSV index (ml/m2) | Mean ± SD | 35.53 ± 10.24 | 45.00 ± 11.06 | |
RVEF (%) | Median (5; 95) | 64 (55.15; 78.4) | 60 (45.4; 80.8) | 0.081 |
T1-ratio | Median (5; 95) | 4.8 (2.0; 14.13) | 3.6 (1.8; 10.6) | 0.076 |
T1 path., |
Frequency | 24/31 (77.4) | 8/30 (26.7) | |
PE, |
Frequency | 7 (21.9) | 6 (17.6) | 0.67 |
LGE, |
Frequency | 8 (23.5) | 3 (9.1) | 0.11 |
Reduced LV function (ejection fraction <60%) was observed in 6/33, and five of these patients also showed increased T1 enhancement.
The mean LVEF in ALS patients was 64% (range 52–80) compared to controls (mean 60%, range 27–85). Early myocardial gadolinium enhancement in T1 could be observed in 24/31 (77%) of ALS patients (Figure
T1 turbospinecho sequences in the transversal position before
8/35 patients had a pericardial effusion without a hemodynamic restriction (Figure
Pericardial effusion (arrow) in short axis view.
Late gadolinium enhancement patterns consistent with a myocardial fibrosis were detected in eight (23%) patients, but this abnormality did not reach significance, since three controls also had a pathological LGE. In four ALS patients, LGE was distributed in the basal inferolateral segments (Figure
A comparison of ALS patients with and without LGE and with or without increased T1 ratio did not show any statistical difference concerning heart function parameters and clinical severity (Table
A comparison of amyotrophic lateral sclerosis patients with and without late gadolinium enhancement (LGE) or increased T1 enhancement concerning heart function parameters and clinical severity.
With LGE | Without LGE | Unpaired |
With increased T1 ratio | Without increased T1 ratio | Unpaired |
|
---|---|---|---|---|---|---|
Cases, |
8 (23.5) | 26 (76.4) | 24 (77.4) | 7 (22.6) | ||
Mass, g (mean ± SD) | 77 ± 31 | 81 ± 25 | 0.5366 | 77 ± 33 | 76 ± 18 | 0.9446 |
LVEF% (mean ± SD) | 63.9 ± 5.4 | 65.0 ± 6.2 | 0.5725 | 61.8 ± 8.3 | 64.1 ± 5.6 | 0.4910 |
RVEF% (mean ± SD) | 67.9 ± 11.6 | 63.5 ± 6,2 | 0.0676 | 59.3 ± 10.7 | 62.3 ± 6.4 | 0.4913 |
T1-ratio (Norm <4) (mean ± SD) | 5.4 ± 3.7 | 5.8 ± 3.7 | 0.8907 | – | – | – |
LGE, |
– | – | – | 3 (13) | 1 (14) | 0.9053 |
ALSFRS-R (points) (mean ± SD) | 33.5 ± 11.1 | 32.0 ± 7.8 | 0.6676 | 31.6 ± 8.6 | 32.4 ± 8.7 | 0.8235 |
ALS duration (years) (mean ± SD) | 1.4 ± 0.7 | 3.0 ± 2.3 | 0.0775 | 2.4 ± 1.9 | 3.6 ± 2.9 | 0.2136 |
As the rather frequent occurrence [10% according to Ref. (
In comparison with healthy controls, ALS patients showed significantly lower left and right ventricular volumes and ventricular mass. Since the heart scales with the size of the body and, therefore, with height and weight, we used the index of ventricular mass and volumes as a ratio to body surface area (BSA) for comparison with controls (Index = mass/BSA or volume/BSA) (
Even after indexing these values to BSA, which may be lower in ALS patients, these differences remained. ALS hearts had lower myocardial mass than control hearts, and ejection volumes in the left and right heart were decreased in ALS patients. It is possible that reduced body weight or reduced physical activity may account for these abnormalities. There are studies implying that BMI is a strong predictor for heart mass (
The function and the size of the heart show a regression in healthy inactive persons even without any structural heart disease (
At a higher age, even healthy persons show alterations in CMR as can be observed in our age-matched control cohort. Increased myocardial T1 values or LGE may be attributed to unrecognized cardiac events (myocarditis, infarction) and hypertension (
With respect to the origin of the detected increased myocardial T1 values, typical patterns of myocardial infarction [subendocardial or transmural LGE pattern (
One explanation for denervation would be increased sympathetic activity induced by respiratory weakness and, therefore, pulmonary hypertension, but no signs of pulmonary hypertension could be detected in our patient cohort. Primary involvement of the autonomic cardiac nerves may be an explanation for postulated sympathetic hyperactivity. Several groups have detected evidence of sympathetic hyperactivity even at the time of the initial ALS diagnosis (
Studies of pTDP-43 pathology in the brain and the associated neuronal loss have revealed involvement of amygdala and the hypothalamus as central sympathetic structures (
Given that sympathetic hyperactivity can be associated with stress-induced cardiomyopathy and sudden cardiac death, this hypothesis may explain why sudden cardiac death is one of the main causes of death in ALS after respiratory insufficiency.
Laboratory parameters have shown increased level of CK, as expected in ALS patients, whereas troponin T as an acute cardiac marker was not increased. Heart failure leading to increased NT-pro BNP was rarely detected and could be attributed to (preexisting) structural defects. Therefore, CMR seems to be more sensitive for the detection of cardiac involvement in ALS than cardiac parameters in blood tests.
Limitations of this study are the inability to differentiate the gadolinium enhancement with regard to the underlying pathophysiology. Furthermore, our results probably underestimate cardiac changes due to relatively unaffected respiration of the ALS participants, since severely affected ALS patients could no longer lie flat in CMR.
In summary, functional cardiac involvement with a tendency toward lower ejection volumes in ALS hearts and an increase in early myocardial T1 contrast enhancement appears to be a common finding in ALS. The late enhancement distribution did not correspond to typical ischemic patterns with subendocardial involvement. Hence, the changes are unlikely due to cardiac ischemia and do not correlate with the clinical severity of ALS. We suggest that the most likely mechanism is a primary dysfunction of sympathetic heart regulation. If sympathetic hyperactivity is the cause for these alterations, therapeutic beta- or alpha-blocking strategies should be considered and might be studied in future clinical trials.
This study was carried out in accordance with the recommendations of the Ethics Committee of the University of Ulm with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the University of Ulm (protocols no. 11/10 and no. 05/11).
AR: acquisition of data, data analysis, writing of the manuscript draft, study supervision, and critical revision of manuscript. BS: acquisition of data, data analysis, interpretation of data, and writing of the manuscript draft. DB: acquisition of data, data analysis, writing of the manuscript draft, and critical revision of manuscript. JK: interpretation of data and critical revision of manuscript. WR: study concept and design, study supervision, and critical revision of manuscript. PB and AL: study concept and design, interpretation of data, study supervision, and critical revision of manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Kelly Del Tredici-Braak for the critical reading of the manuscript.