The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Control in the Hospital by Extensive Clinical rules for Unplanned hospitalizations in older Patients (CHECkUP); study design of a multicentre randomized study.

BACKGROUND: Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. METHODS: The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient's general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. DISCUSSION: This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .

Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

Study protocol for a multicentre prospective cohort study to identify predictors of adverse outcome in older medical emergency department patients (the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study).

BACKGROUND: Older patients (≥65 years old) experience high rates of adverse outcomes after an emergency department (ED) visit. Reliable tools to predict adverse outcomes in this population are lacking. This manuscript comprises a study protocol for the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study that aims to identify predictors of adverse outcome (including triage- and risk stratification scores) and intends to design a feasible prediction model for older patients that can be used in the ED. METHODS: The RISE UP study is a prospective observational multicentre cohort study in older (≥65 years of age) ED patients treated by internists or gastroenterologists in Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. After obtaining informed consent, patients characteristics, vital signs, functional status and routine laboratory tests will be retrieved. In addition, disease perception questionnaires will be filled out by patients or their caregivers and clinical impression questionnaires by nurses and physicians. Moreover, both arterial and venous blood samples will be taken in order to determine additional biomarkers. The discriminatory value of triage- and risk stratification scores, clinical impression scores and laboratory tests will be evaluated. Univariable logistic regression will be used to identify predictors of adverse outcomes. With these data we intend to develop a clinical prediction model for 30-day mortality using multivariable logistic regression. This model will be validated in an external cohort. Our primary endpoint is 30-day all-cause mortality. The secondary (composite) endpoint consist of 30-day mortality, length of hospital stay, admission to intensive- or medium care units, readmission and loss of independent living. Patients will be followed up for at least 30 days and, if possible, for one year. DISCUSSION: In this study, we will retrieve a broad range of data concerning adverse outcomes in older patients visiting the ED with medical problems. We intend to develop a clinical tool for identification of older patients at risk of adverse outcomes that is feasible for use in the ED, in order to improve clinical decision making and medical care. TRIAL REGISTRATION: Retrospectively registered on clinicaltrials.gov ( NCT02946398 ; 9/20/2016).

The Link Between Adipose Tissue Renin-Angiotensin-Aldosterone System Signaling and Obesity-Associated Hypertension.

Obese individuals frequently develop hypertension, which is for an important part attributable to renin-angiotensin-aldosterone system (RAAS) overactivity. This review summarizes preclinical and clinical evidence on the involvement of dysfunctional adipose tissue in RAAS activation and on the renal, central, and vascular mechanisms linking RAAS components to obesity-associated hypertension.

Atherosclerotic Renal Artery Stenosis: Should we Intervene Earlier?

PURPOSE OF REVIEW: Randomized trials have failed to show clinical benefit in patients with atherosclerotic renal artery stenosis who were treated with angioplasty with or without stenting. However, these studies were done in patients with a high-grade stenosis. This paper examines whether there are arguments to consider patients with low-grade stenosis for angioplasty. RECENT FINDINGS: Patients with low-grade (< 50%) atherosclerotic renal artery stenosis have an excess risk for cardiovascular and renal complications. This could be related to inflammatory factors being generated by the stenotic kidney. Moreover, even a kidney with low-grade stenosis clears less or produces more of the natural nitric oxide inhibitor ADMA. Patients with low-grade atherosclerotic renal artery stenosis have an increased risk for a variety of complications. In addition, the abnormality is progressive. There is a case for setting up a prospective trial to examine whether angioplasty confers benefit in patients with low-grade renal artery stenosis.

CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis.

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4+CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4+CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4+CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4+CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4+CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4+CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4+CD28null T cells are increased in AAV and related to the previous CMV infection.

Dietary proteins improve endothelial function under fasting conditions but not in the postprandial state, with no effects on markers of low-grade inflammation.

Endothelial dysfunction (ED) and low-grade inflammation (LGI) have a role in the development of CVD. The two studies reported here explored the effects of dietary proteins and carbohydrates on markers of ED and LGI in overweight/obese individuals with untreated elevated blood pressure. In the first study, fifty-two participants consumed a protein mix or maltodextrin (3×20 g/d) for 4 weeks. Fasting levels and 12 h postprandial responses of markers of ED (soluble intercellular adhesion molecule 1 (sICAM), soluble vascular cell adhesion molecule 1 (sVCAM), soluble endothelial selectin and von Willebrand factor) and markers of LGI (serum amyloid A, C-reactive protein and sICAM) were evaluated before and after intervention. Biomarkers were also combined into mean Z-scores of ED and LGI. The second study compared 4 h postprandial responses of ED and LGI markers in forty-eight participants after ingestion of 0·6 g/kg pea protein, milk protein and egg-white protein. In addition, postprandial responses after maltodextrin intake were compared with a protein mix and sucrose. The first study showed significantly lower fasting ED Z-scores and sICAM after 4 weeks on the high-protein diet (P≤0·02). The postprandial studies found no clear differences of ED and LGI between test meals. However, postprandial sVCAM decreased more after the protein mix compared with maltodextrin in both studies (P≤0·04). In conclusion, dietary protein is beneficial for fasting ED, but not for fasting LGI, after 4 weeks of supplementation. On the basis of Z-scores, postprandial ED and LGI were not differentially affected by protein sources or carbohydrates.

Angiotensin-(1-7) as a strategy in the treatment of hypertension?

PURPOSE OF REVIEW: The renin-angiotensin system plays an important role in cardiovascular disease via the production of angiotensin II. Over the past decades, however, more and more evidence has accumulated suggesting an important role for another angiotensin: Angiotensin-(1-7) [Ang-(1-7)]. In this review, we discuss the recent findings on the effects of Ang-(1-7) and the angiotensin-converting enzyme2/Ang-(1-7)/Mas axis on the cardiovascular system. RECENT FINDINGS: Recent studies demonstrated that Ang-(1-7) exerts a vasodilatory and antiproliferative effect via stimulation of the Mas receptor and inhibition of the effects of angiotensin-type 1 receptor stimulation by angiotensin II. This results in a dynamic equilibrium between Ang-(1-7) and angiotensin II. Various animal studies have demonstrated that Ang-(1-7) has beneficial effects on blood pressure, kidney function, and the prevention of cardiovascular disease. Although targeting the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis has been difficult so far, several new therapeutic strategies are being developed. Promising results of these new strategies on blood pressure and cardiovascular disease were demonstrated in animal studies. SUMMARY: The beneficial effects of the angiotensin-converting enzyme2/Ang-(1-7)/Mas axis have been widely demonstrated in animal studies and provide a promising basis for further development of drugs targeting this axis of the renin-angiotensin system. Further research in humans, however, is necessary to make a serious step forward. VIDEO ABSTRACT: http://links.lww.com/CONH/A8.

Differential effects of proteins and carbohydrates on postprandial blood pressure-related responses.

Diet composition may affect blood pressure (BP), but the mechanisms are unclear. The aim of the present study was to compare postprandial BP-related responses to the ingestion of pea protein, milk protein and egg-white protein. In addition, postprandial BP-related responses to the ingestion of maltodextrin were compared with those to the ingestion of sucrose and a protein mix. We hypothesised that lower postprandial total peripheral resistance (TPR) and BP levels would be accompanied by higher plasma concentrations of nitric oxide, insulin, glucagon-like peptide 1 (GLP-1) and glucagon. On separate occasions, six meals were tested in a randomised order in forty-eight overweight or obese adults with untreated elevated BP. Postprandial responses of TPR, BP and plasma concentrations of insulin, glucagon, GLP-1 and nitrite, nitroso compounds (RXNO) and S-nitrosothiols (NO(x)) were measured for 4 h. No differences were observed in TPR responses. Postprandial BP levels were higher after the ingestion of the egg-white-protein meal than after that of meals containing the other two proteins (P≤ 0·01). The ingestion of the pea-protein meal induced the highest NO(x) response (P≤ 0·006). Insulin and glucagon concentrations were lowest after the ingestion of the egg-white-protein meal (P≤ 0·009). Postprandial BP levels were lower after the ingestion of the maltodextrin meal than after that of the protein mix and sucrose meals (P≤ 0·004), while postprandial insulin concentrations were higher after the ingestion of the maltodextrin meal than after that of the sucrose and protein mix meals after 1-2 h (P≤ 0·0001). Postprandial NO(x), GLP-1 and glucagon concentrations were lower after the ingestion of the maltodextrin meal than after that of the protein mix meal (P≤ 0·008). In conclusion, different protein and carbohydrate sources induce different postprandial BP-related responses, which may be important for BP management. Lower postprandial BP levels are not necessarily accompanied by higher NO(x), insulin, glucagon or GLP-1 responses.

Variable effect of the post-partum menstrual cycle on aldosterone and renin in women with recent preeclampsia.

The purpose of the present study is to identify the impact of the postpartum menstrual cycle on aldosterone, renin, and their ratio of women with and without a preeclamptic pregnancy in the past. To this end, we analysed the data from 59 women with a history of preeclampsia and 39 healthy parous controls. Five to seven months post-partum, we measured aldosterone, renin, and the aldosterone-to-renin ratio during both the follicular and the luteal phase of the menstrual cycle. All measurements were taken in the supine position in the morning. Patients had maintained a standardized sodium diet in the week prior to the measurements. Our results show that in both post-partum women with recent preeclampsia and controls, average levels of renin and aldosterone are significantly elevated in the luteal phase as compared to the follicular phase. The aldosterone-to-renin ratio does not differ between the two phases in either group. Compared to controls, women with recent preeclampsia have significantly lower levels of renin, aldosterone, and aldosterone-to-renin ratio in the follicular phase. This remained consistent in the luteal phase, except for renin. A close correlation existed between the luteal and follicular aldosterone-to-renin ratio in the control group but not in the preeclampsia group. We conclude that both renin and aldosterone are significantly affected by the menstrual cycle whereas the resulting aldosterone-to-renin ratio is not. Post-partum women with recent preeclampsia tend to have lower values for aldosterone and the aldosterone-to-renin ratio than controls.

Blood pressure decreases more after high-carbohydrate meals than after high-protein meals in overweight adults with elevated blood pressure, but there is no difference after 4 weeks of consuming a carbohydrate-rich or protein-rich diet.

The replacement of dietary carbohydrates with proteins can lower blood pressure (BP), but the mechanisms remain unclear. This randomized, double-blind, parallel-group study aimed to compare 12-h postprandial sympathetic and hemodynamic responses after high-protein (HP) meals and high-carbohydrate (HC) meals. Fifty-two men and women with untreated elevated BP were tested on d 1 and after 4 wk of supplementation [3 × 20 g protein (HP) or maltodextrin (HC) per day]. No between-group differences were found in postprandial plasma norepinephrine on d 1 and at wk 4. On d 1, postprandial mean arterial pressure (MAP) decreased more in the HC group than in the HP group (P = 0.002). This difference was not present at 4 wk, because the postprandial decline in MAP tended to become larger in the HP group after 4 wk of supplementation (P = 0.07). On both test days, postprandial total peripheral resistance tended to decrease more in the HC group (P < 0.08). After 4 wk of supplementation, cardiac output tended to increase more in the HC group (P = 0.08). In conclusion, ingestion of an HP diet induced a smaller decrease in BP on d 1 than did ingestion of an HC diet. This difference disappeared after 4 wk due to a more pronounced decrease in BP in the HP group after 4 wk than on d 1. These findings cannot explain the BP-lowering effect ascribed to dietary proteins.

The effect of age, sex and BMI on the aldosterone-to-renin ratio in essential hypertensive individuals.

OBJECTIVE: The aldosterone-to-renin ratio (ARR) is widely used as a screening test for primary aldosteronism, but its determinants in patients with essential hypertension are not fully known. The purpose of the present investigation is to identify the impact of age, sex and BMI on renin, aldosterone and the ARR when measured under strict, standardized conditions in hypertensive patients without primary aldosteronism. METHODS: We analysed the data of 423 consecutive hypertensive patients with no concomitant cardiac or renal disorders from two different hospitals (Rotterdam and Maastricht) who had been referred for evaluation of their hypertension. Those who were diagnosed with secondary causes of hypertension, including primary aldosteronism, were excluded from analysis. Patients who used oral contraceptives or had hormonal replacement therapy were excluded as well. Plasma aldosterone concentration (PAC), active plasma renin concentration (APRC) and the ARR were measured under standardized conditions. All measurements were taken in the supine position at 10.00 h in the morning, with one subgroup of patients adhering to a sodium-restricted diet (55 mmol/day) for no less than 3 weeks, and the other subgroup maintaining an ad libitum diet. In those who were receiving antihypertensive treatment, all medications were discontinued at least 3 weeks before testing. RESULTS: In neither group did aldosterone correlate with age. Renin, however, was inversely related to age both during low-salt diet ( P  < 0.001) and during ad lib salt intake ( P  = 0.05). This resulted in a significant positive correlation between age and the ARR in both groups. Although on both dietary regimens, PAC and APRC were significantly higher in men when compared with women, the ARR was not significantly different between the two sexes. The age-relationships of renin and the ARR were comparable in men and women on both diets, albeit with greater variability in women. There was an upward trend between BMI and the ARR, which reached statistical significance only in men on low-salt diet. In multivariable regression analysis, age remained the only independent determinant of the ARR. CONCLUSION: In our essential hypertensive population, the ARR increased significantly with age but was not affected by sex or BMI.

Urinary Sodium Excretion and Salt Intake Are Not Associated With Blood Pressure Variability in a White General Population.

Background Salt restriction may lower blood pressure variability (BPV), but previous studies have shown inconsistent results. Therefore, we investigated in an observational study and intervention trial whether urinary sodium excretion and salt intake are associated with 24-hour BPV. Methods and Results We used data from the cross-sectional population-based Maastricht Study (n=2652; 60±8 years; 52% men) and from a randomized crossover trial (n=40; 49±11 years; 33% men). In the observational study, we measured 24-hour urinary sodium excretion and 24-hour BPV and performed linear regression adjusted for age, sex, mean blood pressure, lifestyle, and cardiovascular risk factors. In the intervention study, participants adhered to a 7-day low- and high-salt diet (50 and 250 mmol NaCl/24 h) with a washout period of 14 days, 24-hour BPV was measured during each diet. We used linear mixed models adjusted for order of diet, mean blood pressure, and body mass index. In the observational study, 24-hour urinary sodium excretion was not associated with 24-hour systolic or diastolic BPV (ß, per 1 g/24 h urinary sodium excretion: 0.05 mm Hg [95% CI, -0.02 to 0.11] and 0.04 mm Hg [95% CI, -0.01 to 0.09], respectively). In the intervention trial, mean difference in 24-hour systolic and diastolic BPV between the low- and high-salt diet was not statistically significantly different (0.62 mm Hg [95% CI, -0.10 to 1.35] and 0.04 mm Hg [95% CI, -0.54 to 0.63], respectively). Conclusions Urinary sodium excretion and salt intake are not independently associated with 24-hour BPV. These findings suggest that salt restriction is not an effective strategy to lower BPV in the White general population. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02068781.

Angiogenic T-cells and putative endothelial progenitor cells in hypertension-related cerebral small vessel disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. METHODS: We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3(+)/CD31(+)/CD184(+)) and putative EPC (CD31(+)/CD34(+)/CD45(-)/KDR(+)) by flow cytometry and determined EPC vitality by in vitro cluster formation. RESULTS: Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7(.)10(3)/mL versus 13±6(.)10(3)/mL [median±interquartile range]; P=0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25(.)10(9)/mL versus 0.78±0.50(.)10(9)/mL; P=0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012-0.627). CONCLUSIONS: Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency.

Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the (133)Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (ß) = -0.22 (95% confidence intervals: -0.41, -0.04) and ß = -0.66 (95% confidence intervals: -0.83, -0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [ß = 0.21 (95% confidence intervals: 0.02, 0.40)]. In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ.

Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans.

Vascular calcification is a marker of increased cardiovascular risk. Vitamin K-dependent matrix Gla protein (MGP) is important in inhibiting calcification. Because MGP activation is vitamin K dependent, we performed a cross-sectional study investigating the relationship between the use of vitamin K antagonists and extracoronary vascular calcification. From the Dutch thrombosis services we selected 19 patients younger than 55 years who had no other cardiovascular risk factors and who had used coumarins for more than 10 years, and compared these to 18 matched healthy controls. MGP was measured, and a plain x-ray of the thighs was taken to assess femoral arterial calcifications. The odds ratio for calcification in patients versus controls was 8.5 (95% confidence interval [CI] 2.01-35.95). Coumarin use and MGP were associated with calcification, even after adjusting for other risk factors. We conclude that long-term use of coumarins is associated with enhanced extracoronary vascular calcification, possibly through the inhibition of MGP carboxylation.