***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: AIMS Low blood concentrations of the naturally occurring amino acid L-homoarginine ( L-hArg ) are related to impaired cardiovascular outcome and mortality in humans and animals .  L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro . The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation . METHODS In a double-blind , r and omized , placebo-controlled crossover study , 20 young volunteers received 125 mg L-hArg once daily for 4 weeks . Kinetic parameters ( Cmax , Tmax and AUC0 - 24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint . Secondary endpoints that were evaluated were routine laboratory , L-arginine , asymmetric dimethylarginine ( ADMA ) , pulse wave velocity ( PWV ) , augmentation index ( AIx ) , flow-mediated vasodilatation ( FMD ) , corticospinal excitability , i.e. motor threshold ( MT ) , and cortical excitability , i.e. intracortical inhibition ( ICI ) and facilitation ( ICF ) . RESULTS One hour after ingestion ( Tmax ) , L-hArg increased the baseline L-hArg plasma concentration ( 2.87 ± 0.91 μmol l-1 , mean ± SD ) by 8.74 ± 4.46 [ 95 % confidence intervals 6.65 ; 10.9 ] and 17.3 ± 4.97 [ 14.9 ; 19.6 ] μmol l-1 ( Cmax ) , after single and multiple doses , respectively . Once-only and 4 weeks of supplementation result ed in AUCs0 - 24h of 63.5 ± 28.8 [ 50.0 ; 76.9 ] and 225 ± 78.5 [ 188 ; 2624 ] μmol l-1 * h , for single and multiple doses , respectively . Routine laboratory parameters , L-arginine , ADMA , PWV , AIx , FMD , MT , ICI and ICF did not change by L-hArg supplementation compared to baseline . CONCLUSION Once daily orally applied 125 mg L-hArg raises plasma L-hArg four- and sevenfold after single dose and 4 weeks of supplementation , respectively , and is safe and well tolerated in young volunteers In renal transplant recipients ( RTR ) , we recently found that low urinary excretion of homoarginine ( hArg ) is associated with mortality and graft failure . However , it is not known whether such prospect i ve associations also hold true for plasma concentrations of hArg . In the present study , we therefore determined plasma concentrations of hArg in the same cohort , i.e. in 687 RTR ( functioning graft ≥1 year ) , and in 140 healthy donors , before and after kidney donation . Plasma hArg concentrations were significantly lower in RTR compared to healthy controls [ 1.24 ( 0.95–1.63 ) µM vs. 1.58 ( 1.31–2.03 ) µM , P < 0.001 ] , and kidney donation result ed in a decrease in plasma hArg concentration to 1.41 ( 1.10–1.81 ) µM ( P < 0.001 ) . In RTR , multivariable linear regression analysis revealed BMI ( β = 0.124 ) , heart rate ( β = −0.091 ) , pre-emptive transplantation ( β = 0.078 ) , antidiabetic medication ( β = −0.091 ) , eGFR ( β = 0.272 ) , plasma PTH ( β = −0.098 ) , uric acid ( β = 0.137 ) , alkaline phosphatase ( β = −0.100 ) , HDL ( β = −0.111 ) , NT-pro-BNP ( β = −0.166 ) , and urinary urea excretion ( β = 0.139 ) as main determinants of plasma hArg ( all P < 0.05 ) . In RTR , plasma hArg concentration was inversely associated with all-cause [ hazard ratio ( HR ) 0.59 ( 95 % CI 0.50–0.70 ) , P < 0.001 ] and cardiovascular mortality [ HR 0.50 ( 0.39–0.66 ) , P < 0.001 ] , both expressed per st and ard deviation change in log-transformed hArg , independent of potential confounders . To conclude , our results suggest that the kidney is a major hArg production site and an important modulator of hArg homeostasis in the renal and cardiovascular systems . Moreover , low plasma hArg is independently associated with increased risk of cardiovascular mortality in RTR , which corroborates the cardiovascular importance of preserving kidney function after transplantation BACKGROUND Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis . Lesion-related risk factors for such events are poorly understood . METHODS In a prospect i ve study , 697 patients with acute coronary syndromes underwent  three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention . Subsequent major adverse cardiovascular events ( death from cardiac causes , cardiac arrest , myocardial infa rct ion , or rehospitalization due to unstable or progressive angina ) were adjudicated to be related to either originally treated ( culprit ) lesions or untreated ( nonculprit ) lesions . The median follow-up period was 3.4 years . RESULTS The 3-year cumulative rate of major adverse cardiovascular events was 20.4 % . Events were adjudicated to be related to culprit lesions in 12.9 % of patients and to nonculprit lesions in 11.6 % . Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline ( mean [ ±SD ] diameter stenosis , 32.3±20.6 % ) . However , on multivariate analysis , nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70 % or greater ( hazard ratio , 5.03 ; 95 % confidence interval [ CI ] , 2.51 to 10.11 ; P<0.001 ) or a minimal luminal area of 4.0 mm(2 ) or less ( hazard ratio , 3.21 ; 95 % CI , 1.61 to 6.42 ; P=0.001 ) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas ( hazard ratio , 3.35 ; 95 % CI , 1.77 to 6.36 ; P<0.001 ) . CONCLUSIONS In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention , major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions . Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild , most were thin-cap fibroatheromas or were characterized by a large plaque burden , a small luminal area , or some combination of these characteristics , as determined by gray-scale and radiofrequency intravascular ultrasonography . ( Funded by Abbott Vascular and Volcano ; Clinical Trials.gov number , NCT00180466 . ) BACKGROUND High serum concentrations of l-arginine and l-homoarginine increase nitric oxide ( NO ) availability and thereby improve endothelial function . Information about the association of these markers with peripheral arterial disease ( PAD ) and related outcomes is sparse . METHODS l-arginine , its metabolites and l-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes-matched controls . After the baseline investigation PAD patients were prospect ively followed ( median 7 years ) . The association of these markers with symptomatic PAD at baseline , incident cardiovascular events and all-cause mortality was assessed . RESULTS At baseline each increase of ln-l-homoarginine and l-arginine by one st and ard deviation was associated with symptomatic PAD : OR=0.75 , 95%CI 0.59 - 0.96 , P=0.02 and OR=1.36 , 95%CI 1.07 - 1.73 , P=0.01 , respectively ( both models adjusted for ln-CRP , GFR , HDL cholesterol , and current smoking ) . Only l-arginine remained significant after additional adjustment for ln-NT-proBNP and hs-cTnT : OR=1.49 , P=0.002 . In the Cox regression analysis elevated ln-l-homoarginine significantly reduced the risk to die ( n=38 ) even independent from ln-NT-proBNP and hs-cTnT : HR=0.59 , 95%CI 0.41 - 0.84 , P=0.004 . l-arginine was significantly predicting incident cardiovascular events ( n=65 ) : HR=1.68 , 95%CI 1.35 - 2.10 , P < 0.001 . CONCLUSIONS This study in male patients with intermittent claudication and age- and diabetes-matched controls showed an association of l-homoarginine and l-arginine with PAD . During follow-up , l-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity . l-homoarginine was related to all-cause mortality implying a broader role in metabolic processes besides endothelial function 
    Output:
    
This meta- analysis of observational studies showed an inverse association between circulating homoarginine concentrations and all-cause mortality .