We analysed data from 1255 haemodialysis patients with type 2 diabetes mellitus, who took part in the 4D study and experienced a high incidence of pre-specified and centrally adjudicated endpoints. In the present analysis, low baseline homoarginine concentration was a strong risk factor for SCD and death due to heart failure during 4 years of follow-up. In patients of the lowest homoarginine quintile, the risk of dying suddenly was more than twice as high, and the risk of death due to heart failure three times as high compared to those of the highest homoarginine quintile. Furthermore, there was a trend for low homoarginine concentrations to increase the risk of stroke; however, MI was not affected. The incidence of the combined primary endpoint was significantly higher at lower concentrations of homoarginine, and this was mainly explained by the effect of homoarginine on sudden cardiac and heart failure deaths.
In advanced chronic kidney disease and end-stage renal disease, the pattern and composition of cardiovascular risk is changing. It is determined by various components such as SCD, stroke, and MI, and may vary with changing proportions of these components. In the general population, cardiovascular risk is mainly determined by the incidence of MI, representing the most frequent cause of death. In contrast, dialysis patients pre-dominantly die of SCD, which as a single cause accounts for one quarter of all deaths.1,2
Various causes may account for SCD in dialysis patients, including microvascular and macrovascular disease, sympathetic over-activity, structural heart disease, cardiac fibrosis, and electrolyte and volume shifts due to the haemodialysis procedure.17,18
Furthermore, we have recently shown that poor glycaemic control and vitamin D deficiency were strongly associated with the incidence of SCD in dialysis patients.19,20
Despite these advances in the evaluation of risk factors, current knowledge is still limited, i.e. the known risk factors do not sufficiently explain the excess rate of SCD in dialysis patients.
The present work is the first study to identify low homoarginine concentrations as a novel risk factor for SCD in dialysis patients. Evidence suggests that homoarginine may increase NO availability, the lack of which is associated with endothelial, and myocardial dysfunction.9–12
In a previous study, we found an inverse association between homoarginine and markers of impaired endothelial function (ICAM-1 and VCAM-1).13
Furthermore, we found an association between indicators of inflammation including albumin and CRP, and low homoarginine concentration. Endothelial dysfunction and inflammation may increase the risk of SCD via the development of premature atherosclerosis and cytokine-induced plaque instability, or by direct effects on the myocardium, and electrical conduction system.21
Cytokines are also involved in the modulation of ion channel function and the generation of arrhythmias,22,23
as well as in the aggravation of sympathetic tone, leading to tachycardia and cardiac electrical instability. In our study, patients with low homoarginine concentrations more frequently had arrhythmias, particularly absence of sinus rhythm. Furthermore, we observed a high burden of CHF and increased levels of brain natriuretic peptide in patients in the lowest quintile of homoarginine concentration. These factors are known to be strong predictors of SCD and may, at least in part, reflect the effect of homoarginine on structural changes in the heart.17,18,24
The role of homoarginine affecting structural changes in the heart may also account for its association with heart failure. Besides the effect on endothelial dysfunction and the release of cytokines, low homoarginine may also affect blood pressure and insulin secretion, thus contributing to cardiac hypertrophy, and fibrosis as major predisposing conditions for heart failure. Furthermore, it is of high interest that the key enzyme for homoarginine synthesis, arginine:glycine amidinotransferase (AGAT), is upregulated in heart failure.25
One study found that myocardial AGAT mRNA expression, and enzyme activity were elevated in heart failure compared with controls and returned to normal after functional normalization and recovery. The data indicated that the expression of AGAT enabled the myocardium to synthesize creatine locally. This upregulation of myocardial AGAT expression was suggested to be an adaptive process, counteracting the decreased intracellular creatine availability in heart failure by local creatine production.25
The notion of AGAT being involved in cellular energy metabolism is supported by further data. An experimental study showed that AGAT mRNA was upregulated in the skeletal muscles of mice with Duchenne muscular dystrophy compared to mature mice.26
It has been argued that this process may help maintain muscle creatine levels and limit cellular energy failure in the leaky skeletal muscles of affected mice. Extending these data, our study adds important new knowledge by identifying low homoarginine as an important risk factor for death due to heart failure and also provides a new target for interventions.
In this context, it is not surprising that the increased risk of combined cardiovascular events associated with low homoarginine concentrations in our study was mainly explained by the impact of homoarginine concentration on sudden cardiac and heart failure deaths. Other studies have suggested that homoarginine plays a role in the pathogenesis of diabetes mellitus and arterial hypertension.8,27
Homoarginine has been shown to stimulate insulin secretion,27,28
with glycaemic state meaningfully increasing the incidence of SCD, but not of myocardial infarction.19
The risk of MI as a major macrovascular complication was not affected by low homoarginine in our study. There was a moderate effect on stroke, which is thought to result from both micro- and macrovascular complications. Therefore, the potential influence of homoarginine in glucose metabolism and the importance of microvascular complications may help to explain the effect on stroke in contrast to myocardial infarction. Furthermore, previous studies have found that administration of L-homoarginine increased urinary excretion of nitrate, the degradation product of NO, and reduced blood pressure in salt-sensitive hypertensive rats.8
This may explain why we observed in our study a trend for an association between low homoarginine concentrations and the incidence of stroke, which is in line with results from a previous study, identifying low homoarginine as a novel risk factor for fatal strokes in patients undergoing coronary angiography.29
As mentioned above, homoarginine plays a role in the metabolism of NO, which is—apart from the cardiac effects—critically involved in the regulation of cerebral blood flow and cell viability.30
Potential limitations of our study need to be acknowledged. It was a post-hoc analysis within a selected cohort of German patients with type 2 diabetes mellitus undergoing haemodialysis. Therefore, the relationship between low homoarginine and adverse outcomes may not be generalizable to other patient populations. In this context, potential effects of homoarginine on MI may not have been seen because of competing risks in diabetic dialysis patients. Despite careful adjustments for possible confounders, we cannot rule out residual confounding. However, since the known important confounders were considered, the effect of potential residual confounding is likely to be small. Furthermore, we cannot draw conclusions regarding causality from our data but our data indicate that low homoarginine levels reflect a novel pathophysiological process related to a poor cardiovascular outcome. Given that single-nucleotide polymorphisms (SNPs) or activity of the key enzyme for homoarginine synthesis have been previously related to renal and myocardial diseases supports a causal association between homoarginine metabolism and adverse health outcomes.The main strengths of this study are that we were able to analyse specific outcomes including SCD. Further strengths include the long-term follow-up, adequate sample size, and high incidence of pre-specified and centrally adjudicated endpoints.
In conclusion, low blood homoarginine concentrations were strongly associated with SCD and death due to heart failure in haemodialysis patients. Furthermore, there was a trend for low homoarginine concentrations to be associated with a higher risk of stroke, but not of myocardial infarction. The risk of combined cardiovascular events increased significantly at lower concentrations of homoarginine, and was mainly explained by the impact of homoarginine on sudden cardiac and heart failure deaths. Longitudinal assessment of homoarginine may be useful for risk monitoring of dialysis patients. Beyond this, homoarginine may become a promising novel target for therapeutic interventions in populations with high incidences of heart failure and SCD.