The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in a hyperin ammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-in ammatory and antithrombotic properties, have been studied in the setting of other viral infections and ARDS, but their bene t has not been assessed in COVID-19. Thus, we sought to determine whether antecedent statin use is associated with lower in-hospital mortality in patients hospitalized for COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1 st through May 12 th , 2020 with study period ending on June 11 th , 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline socio-demographic and clinical characteristics, and outpatient medications. The primary endpoint included in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users,

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function; however, the profile of cMyBP-C degradation after myocardial infarction (MI) is unknown. We hypothesized that cMyBP-C is sensitive to proteolysis and is specifically increased in the bloodstream post-MI in rats and humans. Under these circumstances, elevated levels of degraded cMyBP-C could be used as a diagnostic tool to confirm MI. To test this hypothesis, we first established that cMyBP-C dephosphorylation is directly associated with increased degradation of this myofilament protein, leading to its release in vitro. Using neonatal rat ventricular cardiomyocytes in vitro, we were able to correlate the induction of hypoxic stress with increased cMyBP-C dephosphorylation, degradation, and the specific release of N′-fragments. Next, to define the proteolytic pattern of cMyBP-C post-MI, the left anterior descending coronary artery was ligated in adult male rats. Degradation of cMyBP-C was confirmed by a reduction in total cMyBP-C and the presence of degradation products in the infarct tissue. Phosphorylation levels of cMyBP-C were greatly reduced in ischemic areas of the MI heart compared to non-ischemic regions and sham control hearts. Post-MI plasma samples from these rats, as well as humans, were assayed for cMyBP-C and its fragments by sandwich ELISA and immunoprecipitation analyses. Results showed significantly elevated levels of cMyBP-C in the plasma of all post-MI samples. Overall, this study suggests that cMyBP-C is an easily releasable myofilament protein that is dephosphorylated, degraded and released into the circulation post-MI. The presence of elevated levels of cMyBP-C in the blood provides a promising novel biomarker able to accurately rule in MI, thus aiding in the further assessment of ischemic heart disease.

Background-L-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD. Methods and Results-The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-Arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine-and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; Pϭ0.024). Conclusions-In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.

Background-Peripheral arterial disease (PAD) is common but commonly unrecognized. Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find PAD-associated biomarkers. Methods and Results-Plasma was collected from PAD patients (ankle brachial index of Ͻ0.90; nϭ45) and subjects with risk factors but without PAD (nϭ43). Plasma was analyzed with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to quantify 1619 protein peaks. The peak intensity of a 12-kDa protein was higher in PAD patients. Western blot analyses and immunoaffinity studies confirmed that this protein was ␤2-microglobulin (B2M). In a validation study, B2M was measured by ELISA in plasma in age-and gender-matched PAD (nϭ20) and non-PAD (nϭ20) subjects. Finally, we studied a larger cohort of subjects (nϭ237) referred for coronary angiography but without known PAD. Plasma B2M levels were higher in PAD patients than in non-PAD patients with coronary artery disease. Plasma B2M correlated with ankle brachial index and functional capacity. Independent predictors of PAD were diabetes mellitus, age, and the combination of B2M and C-reactive protein level. Conclusions-In PAD patients, circulating B2M is elevated and correlates with the severity of disease independent of other risk factors. These findings might provide a needed biomarker for PAD and new insight into its pathophysiology. Further studies in other populations are needed to confirm the utility of measuring B2M in cardiovascular disease risk assessment.

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We thank Dr Teerlink for his comments regarding the unexpected results of our study. 1 Pre-clinical studies and short-term trials in patients with coronary or peripheral arterial disease showed that supplemental L-arginine improved endothelium-dependent vasodilation and increased nitric oxide (NO) production. Accordingly, we hypothesized that long-term administration of L-arginine would improve vascular function and enhance collateral blood flow, thereby increasing walking distance in patients with peripheral arterial disease. To our surprise, long-term L-arginine supplementation tended to impair vascular function and to limit the improvement in walking distance over time in patients with peripheral arterial disease.As Dr Teerlink commented, the metabolic fate of L-arginine is highly complex and tightly regulated. 2 However, plasma L-arginine levels rose in the supplemented group, so it is unlikely that induction of intestinal arginase activity fully explains our findings. Despite the increased plasma L-arginine levels, citrulline did not rise in the L-arginine-treated group. Furthermore, as compared with the placebo group, there was a significant decrement in endotheliumdependent vasodilation and nitric oxide production. These observations indicate the presence of a countervailing mechanism that opposed an arginine-induced increase in NO production. The apparent reversal of arginine-induced NO production could be due to an opposing increase in asymmetric dimethylarginine (the endogenous NOS inhibitor). 3 Although plasma asymmetric dimethylarginine levels were elevated at baseline in both peripheral arterial disease groups, there were no group differences after treatment. Another possible explanation may be that vascular arginase expression and/or activity was increased, as Dr Teerlink suggested. Increased endothelial arginase II expression has been shown to downregulate endothelial NO synthase activity. 4 It is also possible that an increase in arginine metabolites such as ornithine may have led to adverse vascular effects as Dr Teerlink suggests. However, this would not explain the failure of citrulline and NO to rise in the L-argininetreated group, unless the elevated ornithine levels somehow led to NO synthase inhibition.Whatever mechanisms are invoked to explain the surprising findings in this double-blind, randomized clinical trial, the results are clinically relevant, as L-arginine supplements are available over the counter and are currently being taken by a range of subject groups.

Background Peripheral arterial disease (PAD) is associated with major cardiovascular morbidity and mortality. Abnormalities in nitric oxide metabolism due to excess of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) may be pathogenic in PAD. We explored the association between ADMA levels and markers of atherosclerosis, function, and prognosis. Methods and Results 133 patients with symptomatic PAD were enrolled. Ankle brachial index (ABI), walking time, vascular function measures (arterial compliance and flow-mediated vasodilatation) and plasma ADMA level were assessed for each patient at baseline. ADMA correlated inversely with ABI (r = −0.238, p=0.003) and walking time (r = −0.255, p = 0.001), independent of other vascular risk factors. We followed up 125 (94%) of our 133 initial subjects with baseline measurements (mean 35 months). Subjects with ADMA levels in the highest quartile (>0.84 μmol/L) showed significantly greater occurrence of MACE compared to those with ADMA levels in the lower 3 quartiles (p = 0.001). Cox proportional-hazards regression analysis revealed that ADMA was a significant predictor of MACE, independent of other risk factors including age, gender, blood pressure, smoking history, diabetes and ABI (Hazard ratio = 5.1, p<0.001). Measures of vascular function, such as compliance, FMVD and blood pressure, as well as markers of PAD severity, including ABI and walking time, were not predictive. Conclusion Circulating levels of ADMA correlate independently with measures of disease severity and major adverse cardiovascular events. Agents that target this pathway may be useful for this patient population.