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 (1, 2). Another common cause of death in ALS is sudden cardiac death (1, 3). In recent years, several studies have shown that the autonomic nervous system is also involved in ALS, since increased heart rate variability (4) and increased QTc intervals in electrocardiogram (ECG) have been reported (5). Decreased heart rate variability and a loss of correlation between blood pressure and heart rate also have been described (6, 7). Cardiac involvement has been reported in ALS by ECG, echocardiography (8), and postmortem examination (5). The involvement of the autonomic nervous system could increase the risk of heart rhythm disturbances or sudden cardiac death (9, 10). Subclinical cardiac involvement has been reported (11, 12), including non-specific ECG and echocardiographic abnormalities. In summary, cardiac involvement in ALS seems to be frequent, but systematic information on functional and structural deficits does not seem to be present.

Cardiac magnetic resonance (CMR) imaging is a valuable tool in the diagnostic assessment of inflammatory myocarditis (13–16) and for the detection of cardiac involvement in systemic muscle diseases (17, 18). The aim of this study was to characterize cardiac involvement in ALS using a comprehensive CMR protocol.

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 1. Holter monitoring was performed on 26 patients and did not show any abnormalities. Healthy controls were clinically characterized for arterial hypertension (AHT) and diabetes.

As the rather frequent occurrence [10% according to Ref. (3)] of cardiac deaths in ALS is not well understood (1), this study was performed in order to characterize myocardial tissue by CMR in ALS patients without any cardiac complaints. No significant abnormalities in the routine cardiac assessment with Holter monitoring and echocardiography could be found except slight valve insufficiencies in up to half of the patients. Recent studies have shown that CMR is an important diagnostic tool for detecting cardiac involvement in systemic diseases, such as cardiomyopathies and amyloidosis (22, 24–26). Abnormalities in CMR were frequent in ALS, in particular early gadolinium enhancement (77%) as a parameter of enhanced extracellular volume, that is either capillary leakage or fibrosis. Pericardial effusions were detected in 22% and LGE in 23.5% as a marker of diffuse myocardial fibrosis. The latter abnormalities did not differ significantly from controls (17.6% effusions and 9.1% LGE). None of the patients displayed any characteristics of cardiac ischemia that could account for the observed myocardial changes (ischemic pattern with a subendocardial and/or transmural enhancement).

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) (27).

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 (28), but our control group did not differ with regard to BMI. Reduced muscle mass or malnutrition, therefore, are not the cause for loss of myocardial mass in our cohort, as also shown by the statistically different indexes in Table 3.

The function and the size of the heart show a regression in healthy inactive persons even without any structural heart disease (29). Therefore, we assume that significantly reduced heart mass and ejection volumes are a consequence of more sedentary/inactive behavior in ALS patients if compared to healthy adults.

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 (30, 31). Since the frequency of diabetes differed significantly in cases and controls (p = 0.03), some of the reported abnormalities in ALS patients might be due to diabetic complications. With respect to CMR, a subclinical diastolic dysfunction but no significant fibrosis in LGE has been reported in diabetes (32). With respect to ALS, this finding has to be seen in the context of the association between diabetes (type 2) and ALS as previously reported (33, 34), but the data of our study cannot add substantially to this discussion.

With respect to the origin of the detected increased myocardial T1 values, typical patterns of myocardial infarction [subendocardial or transmural LGE pattern (35)] were not detected. In a disease with denervation as the main muscular pathology, early gadolinium enhancement is likely to be associated with denervation edema (36–38).

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 (9, 39, 40). Additional studies reported primary sympathetic-impaired autonomic control in ALS patients by ECG abnormalities (6, 41). In a SOD1 mouse model of ALS, preganglionic sympathetic denervation was histologically confirmed (42). Tamsulosin hydrochloride as a selective alpha 1-adrenoceptor blocker was shown to be useful for suppressing central sympathetic hyperactivity but it was not tested for the long-term outcome of ALS patients (43).

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 (44, 45).

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.