Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis.

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism.

The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

Divergent Dimethylarginine Dimethylaminohydrolase Isoenzyme Expression in the Central Nervous System.

The endogenous methylated derivative of ʟ-arginine, Nω,Nω'-dimethyl-ʟ-arginine (asymmetric dimethylarginine, ADMA), an independent risk factor in many diseases, inhibits the activity of nitric oxide synthases and, consequently, modulates the availability of nitric oxide. While most studies on the biological role of ADMA have focused on endothelial and inducible nitric oxide synthases modulation and its contribution to cardiovascular, metabolic, and renal diseases, a role in regulating neuronal nitric oxide synthases and pathologies of the central nervous system is less understood. The two isoforms of dimethylarginine dimethylaminohydrolase (DDAH), DDAH1 and DDAH2, are thought to be the main enzymes responsible for ADMA catabolism. A current impediment is limited knowledge on specific tissue and cellular distribution of DDAH enzymes within the brain. In this study, we provide a detailed characterization of the regional and cellular distribution of DDAH1 and DDAH2 proteins in the adult murine and human brain. Immunohistochemical analysis showed a wide distribution of DDAH1, mapping to multiple cell types, while DDAH2 was detected in a limited number of brain regions and exclusively in neurons. Our results provide key information for the investigation of the pathophysiological roles of the ADMA/DDAH system in neuropsychiatric diseases and pave the way for the development of novel selective therapeutic approaches.

COVID-19 and Therapeutic Apheresis.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is an unprecedented challenge for the global community. The pathogenesis of COVID-19, its complications and long term sequelae (so called Long/Post-COVID) include, in addition to the direct virus-induced tissues injury, multiple secondary processes, such as autoimmune response, impairment of microcirculation, and hyperinflammation. Similar pathological processes, but in the settings of neurological, cardiovascular, rheumatological, nephrological, and dermatological diseases can be successfully treated by powerful methods of Therapeutic Apheresis (TA). We describe here the rationale and the initial attempts of TA treatment in severe cases of acute COVID-19. We next review the evidence for the role of autoimmunity, microcirculatory changes and inflammation in pathogenesis of Long/Post COVID and the rationale for targeting those pathogenic processes by different methods of TA. Finally, we discuss the impact of COVID-19 pandemic on patients, who undergo regular TA treatments due to their underlying chronic conditions, with the specific focus on the patients with inherited lipid diseases being treated at the Dresden University Apheresis Center.

Precision Medicine Approach for Cardiometabolic Risk Factors in Therapeutic Apheresis.

Lipoprotein apheresis (LA) is currently the most powerful intervention possible to reach a maximal reduction of lipids in patients with familial hypercholesterolemia and lipoprotein(a) hyperlipidemia. Although LA is an invasive method, it has few side effects and the best results in preventing further major cardiovascular events. It has been suggested that the highly significant reduction of cardiovascular complications in patients with severe lipid disorders achieved by LA is mediated not only by the potent reduction of lipid levels but also by the removal of other proinflammatory and proatherogenic factors. Here we performed a comprehensive proteomic analysis of patients on LA treatment using intra-individually a set of differently sized apheresis filters with the INUSpheresis system. This study revealed that proteomic analysis correlates well with routine clinical chemistry in these patients. The method is eminently suited to discover new biomarkers and risk factors for cardiovascular disease in these patients. Different filters achieve reduction and removal of proatherogenic proteins in different quantities. This includes not only apolipoproteins, C-reactive protein, fibrinogen, and plasminogen but also proteins like complement factor B (CFAB), protein AMBP, afamin, and the low affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) among others that have been described as atherosclerosis and metabolic vascular diseases promoting factors. We therefore conclude that future trials should be designed to develop an individualized therapy approach for patients on LA based on their metabolic and vascular risk profile. Furthermore, the power of such cascade filter treatment protocols may improve the prevention of cardiometabolic disease and its complications.

Post COVID and Apheresis - Where are we Standing?

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods.

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study's objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation.

SGLT2 Inhibitors and Peripheral Vascular Events: A Review of the Literature.

Fifty articles comprising 18 randomized controlled trials (RCTs), 16 observational studies, and 16 meta-analyses on the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors were evaluated in the current review. Only one-fourth of the cohorts of recent trials had peripheral arterial disease (PAD), whereas this subgroup was at high risk for amputations. Despite a remarkable heterogeneity of RCTs, only 2 trials on canagliflozin suggested excess amputation rates, whereas several observational studies generated conflicting conclusions and remained short on possible explanations. Preliminary evidence from observational research suggested that patients with PAD may even benefit from SGLT-2 inhibitor treatment due to lower observed heart failure hospitalization rates.

Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II-induced cardiac hypertrophy and vascular remodeling.

Cardiovascular complications are the leading cause of death, and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2, and showed better endothelium-dependent relaxation. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.NEW & NOTEWORTHY We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.

Initiation of SGLT2 Inhibitors and the Risk of Lower Extremity Minor and Major Amputation in Patients with Type 2 Diabetes and Peripheral Arterial Disease: A Health Claims Data Analysis.

OBJECTIVE: To assess the association between long term risk of hospitalisation for heart failure (HHF) and lower extremity minor and major amputation (LEA) in patients initiating sodium glucose cotransporter 2 inhibitors (SGLT2i) suffering from type 2 diabetes and peripheral arterial disease (PAD). Outcomes were compared with patients without PAD and evaluated separately for the time periods before and after the official warning of the European Medicines Agency (EMA) in early 2017. METHODS: This study used BARMER German health claims data including all patients suffering from type 2 diabetes initiating SGLT2i therapy between 1 January 2013 and 31 December 2019 with follow up until the end of 2020. New users of glucagon like peptide 1 receptor agonists (GLP1-RAs) were used as active comparators. Inverse probability weighting with truncated stabilised weights was used to adjust for confounding, and five year risks of HHF and LEA were estimated using Cox regression. Periods before and after the EMA warning were analysed separately and stratified by presence of concomitant PAD. RESULTS: In total, 44 284 (13.6% PAD) and 56 878 (16.3% PAD) patients initiated SGLT2i or GLP1-RA, respectively. Before the EMA warning, initiation of SGLT2i was associated with a lower risk of HHF in patients with PAD (hazard ratio, HR, 0.85, 95% confidence interval, CI, 0.73 - 0.99) and a higher risk of LEA in patients without PAD (HR 1.79, 95% CI 1.04 - 2.92). After the EMA warning, the efficacy and safety endpoints were no longer statistically different between groups. CONCLUSION: The results from this large nationwide real world study highlight that PAD patients exhibit generally high amputation risks. This study refutes the idea that the presence of PAD explains the excess LEA risk associated with initiation of SGLT2i. The fact that differentials among study groups diminished after the EMA warning in early 2017 emphasises that regulatory surveillance measures worked in everyday clinical practice.

Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: an early marker of cardiometabolic disease.

Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.

The ACE-2 in COVID-19: Foe or Friend?

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT1R axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT1R axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.

Inflammatory Cell Infiltration of Adrenals in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originated in November-December 2019 in Wuhan, China, and has rapidly spread around the world causing severe health and socioeconomical damage to the entire civilization. The key feature of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is upper respiratory tract infection, which may be complicated by bilateral pneumonia. Angiotensin converting enzyme 2 (ACE2) has been identified as a key host factor, required for virus entry into cells. Interestingly, ACE2 is expressed not only in the respiratory system, but also in the other organs and systems including adrenal glands. Here we provide the first description of the pathomorphological changes in adrenal glands in patients with severe COVID-19 characterized by perivascular infiltration of CD3+ and CD8+ T-lymphocytes. Due to the central role of the adrenals in the stress response of the organism, this finding is of potential clinical relevance, because infection with the SARS-CoV-2 virus might critically impair adrenal function under pathophysiological conditions.

Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic affects people around the world. However, there have been striking differences in the number of infected individuals and deaths in different countries. Particularly, within Central Europe in countries that are similar in ethnicity, age, and medical standards and have performed similar steps of containment, such differences in mortality rates remain inexplicable. We suggest to consider and explore environmental factors to explain these intriguing variations. Countries like Northern Italy, France, Spain, and UK have suffered from 5 times more deaths from the corona virus infection than neighboring countries like Germany, Switzerland, Austria, and Denmark related to the size of their respective populations. There is a striking correlation between the level of environmental pollutants including pesticides, dioxins, and air pollution such as NO2 known to affect immune function and healthy metabolism with the rate of mortality in COVID-19 pandemic in these European countries. There is also a correlation with the use of chlorination of drinking water in these regions. In addition to the improvement of environmental protective programs, there are possibilities to lower the blood levels of these pollutants by therapeutic apheresis. Furthermore, therapeutic apheresis might be an effective method to improve metabolic inflammation, altered vascular perfusion, and neurodegeneration observed as long-term complications of COVID-19 disease.

Is Homoarginine a Protective Cardiovascular Risk Factor?

A series of recent epidemiological studies have implicated the endogenous nonproteinogenic amino acid l-homoarginine as a novel candidate cardiovascular risk factor. The association between homoarginine levels and the risk of adverse cardiovascular outcomes is inverse (ie, high cardiovascular risk is predicted by low rather than high homoarginine levels), which makes it plausible to normalize systemic homoarginine levels via oral supplementation. The emergence of homoarginine as a potentially treatable protective cardiovascular risk factor has generated a wave of hope in the field of cardiovascular prevention. Herein, we review the biochemistry, physiology, and metabolism of homoarginine, summarize the strengths and weaknesses of the epidemiological evidence linking homoarginine to cardiovascular disease and its potential protective cardiovascular effects, and identify priorities for future research needed to define the clinical utility of homoarginine as a prognostic factor and therapeutic target in cardiovascular disease.

The role of alanine glyoxylate transaminase-2 (agxt2) in ß-alanine and carnosine metabolism of healthy mice and humans.

PURPOSE: Chronic ß-alanine supplementation leads to increased levels of muscle histidine-containing dipeptides. However, the majority of ingested ß-alanine is, most likely, degraded by two transaminases: GABA-T and AGXT2. In contrast to GABA-T, the in vivo role of AGXT2 with respect to ß-alanine metabolism is unknown. The purpose of the present work is to investigate if AGXT2 is functionally involved in ß-alanine homeostasis. METHODS: Muscle histidine-containing dipeptides levels were determined in AGXT2 overexpressing or knock-out mice and in human subjects with different rs37369 genotypes which is known to affect AGXT2 activity. Further, plasma ß-alanine kinetic was measured and urine was obtained from subjects with different rs37369 genotypes following ingestion of 1400 mg ß-alanine. RESULT: Overexpression of AGXT2 decreased circulating and muscle histidine-containing dipeptides (> 70% decrease; p < 0.05), while AGXT2 KO did not result in altered histidine-containing dipeptides levels. In both models, ß-alanine remained unaffected in the circulation and in muscle (p > 0.05). In humans, the results support the evidence that decreased AGXT2 activity is not associated with altered histidine-containing dipeptides levels (p > 0.05). Additionally, following an acute dose of ß-alanine, no differences in pharmacokinetic response were measured between subjects with different rs37369 genotypes (p > 0.05). Interestingly, urinary ß-alanine excretion was 103% higher in subjects associated with lower AGXT2 activity, compared to subjects associated with normal AGXT2 activity (p < 0.05). CONCLUSION: The data suggest that in vivo, ß-alanine is a substrate of AGXT2; however, its importance in the metabolism of ß-alanine and histidine-containing dipeptides seems small.

New horizons in arginine metabolism, ageing and chronic disease states.

The elucidation of the metabolic pathways of the amino acid arginine and their role in health and disease have been an intensive focus of basic and clinical research for over a century. The recent advent of robust analytical techniques for biomarker assessment in large population cohorts has allowed the investigation of the pathophysiological role of specific arginine metabolites in key chronic disease states in old age, particularly those characterised by a reduced synthesis of endothelial nitric oxide, with consequent vascular disease and atherosclerosis. Two arginine metabolites have been increasingly studied in regard to their potential role in risk stratification and in the identification of novel therapeutic targets: the methylated arginine asymmetric dimethylarginine (ADMA) and the arginine analogue homoarginine. Higher circulating concentrations of ADMA, a potent inhibitor of nitric oxide synthesis, have been shown to predict adverse cardiovascular outcomes. By contrast, there is emerging evidence that homoarginine might exert cardioprotective effects. This review highlights recent advances in the biological and clinical role of ADMA and homoarginine in cardiovascular disease and other emerging fields, particularly chronic obstructive pulmonary disease, dementia, and depression. It also discusses opportunities for future research directions with the ultimate goal of translating knowledge of arginine metabolism, and its role in health and disease, into the clinical care of older adults.

The Second Life of Methylarginines as Cardiovascular Targets.

Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.