Intensive Lifestyle Intervention Increases Plasma Midregional Proatrial Natriuretic Peptide Concentrations in Overweight Children.

Background Overweight adults have low circulating concentrations of ANP (atrial natriuretic peptide) and proANP fragments. We tested the hypothesis that an intensive lifestyle intervention with an intended weight loss would increase plasma concentrations of a proANP fragment in overweight children. Methods and Results We measured MR-proANP (midregional proANP) concentrations in plasma from overweight children who participated in the OOIS (Odense Overweight Intervention Study). OOIS randomized 115 overweight children (11-13 years, 55% girls) to an intensive day-camp intervention arm with increased physical activity and healthy diet or to a less intensive standard intervention arm for 6 weeks. We used linear mixed-effects modeling for repeated measures to estimate the difference in the mean change with 95% CIs in fasting plasma MR-proANP concentrations between the 2 arms, and we used partial least squares regression analysis to identify candidate mediators. Differences in weight, fitness, and metabolic factors were also analyzed. At baseline, fasting plasma MR-proANP concentrations were (median [interquartile range]) 35.0 pmol/L (26.8-42.0) in the day-camp intervention arm and 37.2 pmol/L (31.7-44.7) in standard intervention arm participants, respectively. After 6 weeks intervention, children in the day-camp intervention arm had increased their MR-proANP (5.4 pmol/L [0.8-10.0], P=0.022) and their fitness (2.33 mL O2/min per kg [0.52-4.14], P=0.012) and they had deceased their body mass index (-2.12 kg/m2 [-2.59 to -1.65], P<0.001) as compared with children in standard intervention arm. In the partial least squares analysis, decreases in fasting insulin and in estimated insulin resistance were associated with the observed increase in MR-proANP concentrations. Conclusions An intensive lifestyle intervention increases plasma MR-proANP among overweight children. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01574352.

Effect of Increased Potassium Intake on Adrenal Cortical and Cardiovascular Responses to Angiotensin II: A Randomized Crossover Study.

Background Increased potassium intake lowers blood pressure in patients with hypertension, but increased potassium intake also elevates plasma concentrations of the blood pressure-raising hormone aldosterone. Besides its well-described renal effects, aldosterone is also believed to have vascular effects, acting through mineralocorticoid receptors present in endothelial and vascular smooth muscle cells, although mineralocorticoid receptors-independent actions are also thought to be involved. Methods and Results To gain further insight into the effect of increased potassium intake and potassium-stimulated hyperaldosteronism on the human cardiovascular system, we conducted a randomized placebo-controlled double-blind crossover study in 25 healthy normotensive men, where 4 weeks treatment with a potassium supplement (90 mmol/day) was compared with 4 weeks on placebo. At the end of each treatment period, we measured potassium and aldosterone in plasma and performed an angiotensin II (AngII) infusion experiment, during which we assessed the aldosterone response in plasma. Hemodynamics were also monitored during the AngII infusion using ECG, impedance cardiography, finger plethysmography (blood pressure-monitoring), and Doppler ultrasound. The study showed that higher potassium intake increased plasma potassium (mean±SD, 4.3±0.2 versus 4.0±0.2 mmol/L; P=0.0002) and aldosterone (median [interquartile range], 440 [336-521] versus 237 [173-386] pmol/L; P<0.0001), and based on a linear mixed model for repeated measurements, increased potassium intake potentiated AngII-stimulated aldosterone secretion (P=0.0020). In contrast, the hemodynamic responses (blood pressure, total peripheral resistance, cardiac output, and renal artery blood flow) to AngII were similar after potassium and placebo. Conclusions Increased potassium intake potentiates AngII-stimulated aldosterone secretion without affecting systemic cardiovascular hemodynamics in healthy normotensive men. Registration EudraCT Number: 2013-004460-66; URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02380157.

Association of soluble urokinase plasminogen activator receptor levels with fibrotic and vascular manifestations in systemic sclerosis.

OBJECTIVE: We assessed the association of suPAR (soluble urokinase plasminogen activator receptor) plasma levels with fibrotic and vascular manifestations in patients with systemic sclerosis (SSc). METHODS: suPAR plasma levels were measured in 121 consecutive patients with SSc and correlated to pulmonary and vascular features of SSc, including interstitial lung disease as characterized by percentage of predicted CO diffusing capacity (DLco) and forced vital capacity (FVC), pulmonary fibrosis by computed tomography, and pulmonary arterial hypertension, telangiectasias, and digital ulcers. RESULTS: Overall, 121 SSc patients (84% females; mean age, 57 ± 12 [range: 22-79] years) were enrolled; 35% had diffuse cutaneous SSc. suPAR plasma levels ranged from 1.3-10.2 [median: 2.9 (p25-p75: 2.3-3.9)] ng/mL. Log(suPAR) levels correlated with DLco (r = -0.41, p <0.0001) and FVC (r = -0.26, p = 0.004), also when adjusted for age, sex, and pulmonary hypertension. A suPAR cut-off level of >2.5 ng/mL showed a sensitivity of 91% for identifying patients with either DLco <50% or FVC < 60% of the predicted values. Similarly, 19 (90%) had a suPAR >2.5 ng/mL among those diagnosed with pulmonary fibrosis vs. 59 (60%) among those who did not (p = 0.008). suPAR values were not associated with vascular manifestations. CONCLUSION: suPAR levels strongly correlated with pulmonary involvement in SSc. Future studies should test if suPAR estimation can be used for surveillance of severe pulmonary involvement in SSc.

Arterial hypertension and morphologic abnormalities of cardiac chambers: results from the Copenhagen General Population Study.

OBJECTIVES: In patients with arterial hypertension (AH), hypertension-mediated organ damage may be manifested by cardiac chamber enlargement and/or remodeling. Cardiac computed tomography imaging has emerged as an important method for morphological assessment of cardiac chambers. We tested the hypothesis that prevalence of cardiac chamber abnormalities is specifically related to clinical categories of AH in the general population. METHODS: We studied 4747 individuals, mean age was 60 years (range: 40-93), 46% were men, undergoing 320-detector computed tomography in the Copenhagen General Population Study. Clinical categories of AH were: normotensive (n = 2484), untreated hypertensive (n = 1301), treated controlled hypertensive (n = 412) and treated uncontrolled hypertensive (n = 550). Chamber abnormalities in the form of left ventricular (LV) concentric remodeling, LV eccentric hypertrophy, LV concentric hypertrophy or left atrial enlargement were assessed, in addition to LV or right ventricular enlargement. RESULTS: Chamber abnormalities were present in 23% of all individuals. Combined LV and left atrial abnormalities were rare (<2%). LV concentric remodeling (10%) was the most prevalent abnormality, and most commonly found in individuals with treated hypertension. LV and right ventricular enlargements were unrelated to hypertension. The highest frequencies of chamber abnormalities were found in individuals of elevated blood pressure (BP) with (40%) or without (32%) treatment, as opposed to individuals of normal BP with (27%) or without (14%) treatment, P less than 0.0001. CONCLUSION: In a general population cohort, untreated or inadequately treated AH was associated with the highest prevalence of cardiac chamber enlargement and remodeling. These observations suggest a strong link between elevated BPs and development of hypertension-mediated organ damage.

Copeptin and renal function decline, cardiovascular events and mortality in type 1 diabetes.

BACKGROUND: Plasma copeptin is a surrogate of arginine vasopressin (AVP) secretion and is associated with a risk of renal and cardiovascular disease. We investigated associations between copeptin and renal events, cardiovascular events and mortality in type 1 diabetes (T1D). METHODS: We conducted a prospective cohort study on 658 individuals with T1D from Steno Diabetes Center Copenhagen. Plasma copeptin concentrations and conventional risk factors were assessed at baseline. The five endpoints were traced through national registries and electronic laboratory records. RESULTS: Baseline mean age was 55 ± 13 years and estimated glomerular filtration rate (eGFR) was 81 ± 26 mL/min/1.73 m2. The median follow-up was 6.2 years (interquartile range 5.8-6.7); 123 participants reached a combined renal endpoint [decline in eGFR ≥30%, end-stage kidney disease (ESKD) or all-cause mortality], 93 had a decrease in eGFR ≥30%, 21 developed ESKD, 94 experienced a combined cardiovascular endpoint and 58 died from all causes. Higher copeptin was associated with all endpoints in unadjusted Cox regression analyses. Upon adjustment for baseline eGFR, the associations were attenuated and remained significant only for the combined renal endpoint and decrease in eGFR ≥30%. Results were similar upon further adjustment for other risk factors, after which hazard ratios for the two renal endpoints were 2.27 (95% confidence interval 1.08-4.74) and 4.49 (1.77-11.4), respectively, for the highest versus the lowest quartile of copeptin. CONCLUSIONS: Higher copeptin was an independent risk marker for a combined renal endpoint and decline in renal function. AVP may be a marker of renal damage or a factor whose contribution to renal and cardiovascular risk is partially mediated by renal damage.

Serum B-type natriuretic peptide does not increase with higher systolic blood pressure in obese men despite evidence of blood pressure-related increases in left ventricular mass and filling pressure.

B-type natriuretic peptide (BNP) is a cardiac hormone secreted predominantly from the ventricles in response to increased ventricular pressure. Along this line, hypertensive patients with left ventricular hypertrophy typically have high circulating BNP concentrations. BNP has natriuretic and vasodilatory actions. Obese persons have low circulating BNP concentrations, and a relative lack of this natriuretic and vasodilatory factor could contribute to obesity-related hypertension. The relationship between BNP, BP, left ventricular mass (LVM), and left ventricular filling pressure among obese persons is not clear. To address this issue, we studied 98 healthy obese medication-free men with normal left ventricular ejection fraction. We measured BP using 24 -h ambulatory (A) BP recordings, LVM and E/e', an estimate of left ventricular filling pressure, using echocardiography, and fasting BNP in serum. Mean systolic ABP ± SD was 114 ± 4 mm Hg in 1st and 149 ± 8 mm Hg in 4th systolic ABP quartile, P < 0.001. LVM and E/e' increased across systolic ABP quartiles (mean LVM±SD: 81.5±13.7 g/m2 in 1st and 100.1 ± 26.7 g/m2 in 4th quartile, P = 0.018; mean E/e'±SD: 5.3±1.6 in 1st and 7.0 ± 2.0 in 4th quartile, P = 0.002). In contrast, serum BNP did not increase across systolic ABP quartiles (median (IQR): 6.7 (3.1-12.3) pg/ml in 1st and 5.3 (2.8-9.7) pg/ml in 4th quartile, P = 0.75). Unexpectedly, among healthy obese medication-free men, serum BNP does not increase with higher systolic ABP despite evidence of BP-related increases in LVM and E/e'. This further suggests that a relatively low amount of circulating BNP could contribute to obesity-related hypertension in its early stages.

Effect of increased potassium intake on the renin-angiotensin-aldosterone system and subcutaneous resistance arteries: a randomized crossover study.

BACKGROUND: Increased potassium intake lowers blood pressure (BP) in hypertensive patients. The underlying mechanism is not fully understood but must be complex because increased potassium intake elevates circulating concentrations of the BP-raising hormone aldosterone. METHODS: In a randomized placebo-controlled crossover study in 25 normotensive men, we investigated the effect of 4 weeks of potassium supplement (90 mmol/day) compared with 4 weeks of placebo on the renin-angiotensin-aldosterone system (RAAS), urine composition and 24-h ambulatory BP. Vascular function was also assessed through wire myograph experiments on subcutaneous resistance arteries from gluteal fat biopsies. RESULTS: Higher potassium intake increased urinary potassium excretion (144.7 ± 28.7 versus 67.5 ± 25.5 mmol/24-h; P < 0.0001) and plasma concentrations of potassium (4.3 ± 0.2 versus 4.0 ± 0.2 mmol/L; P = 0.0002), renin {mean 16 [95% confidence interval (CI) 12-23] versus 11 [5-16] mIU/L; P = 0.0047}, angiotensin II [mean 10.0 (95% CI 6.2-13.0) versus 6.1 (4.0-10.0) pmol/L; P = 0.0025] and aldosterone [mean 440 (95% CI 336-521) versus 237 (173-386) pmol/L; P < 0.0001]. Despite RAAS activation, systolic BP (117.6 ± 5.8 versus 118.2 ± 5.2 mmHg; P = 0.48) and diastolic BP (70.8 ± 6.2 versus 70.8 ± 6.3 mmHg; P = 0.97) were unchanged. In the wire myograph experiments, higher potassium intake did not affect endothelial function as assessed by acetylcholine [logarithmically transformed half maximal effective concentration (pEC50): 7.66 ± 0.95 versus 7.59 ± 0.85; P = 0.86] and substance P (pEC50: 8.42 ± 0.77 versus 8.41 ± 0.89; P = 0.97) or vascular smooth muscle cell reactivity as assessed by angiotensin II (pEC50: 9.01 ± 0.86 versus 9.02 ± 0.59; P = 0.93) and sodium nitroprusside (pEC50: 7.85 ± 1.07 versus 8.25 ± 1.32; P = 0.25) but attenuated the vasodilatory response of retigabine (pEC50: 7.47 ± 1.16 versus 8.14 ± 0.90; P = 0.0084), an activator of Kv7 channels. CONCLUSIONS: Four weeks of increased potassium intake activates the RAAS in normotensive men without changing BP and this is not explained by improved vasodilatory responses ex vivo.

SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease.

BACKGROUND: The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with presence and severity of coronary artery disease (CAD) and incident death and myocardial infarction (MI). We sought to validate this finding in a further cohort of patients with suspected CAD. METHODS: Plasma suPAR was available in 1635 patients (73% with CAD) undergoing coronary angiography at a single regional Danish hospital between 2003 and 2005. Patients were followed for adverse cardiovascular outcomes of death, cardiac death and MI over a median follow-up of 4.2 years. RESULTS: In multivariate Cox models, adjusted for established cardiovascular risk factors, the biomarkers C-reactive protein, troponin-T and N-terminal-pro brain natriuretic peptide and the number of stenotic vessels, suPAR was independently associated with the combined endpoint of death/MI, hazard ratio (HR) 1.88; cardiovascular death, HR 2.01; and non-fatal MI, HR 1.53; (all p ≤ .037) per doubling of suPAR concentration. A plasma cutoff for suPAR ≥ 3.5 ng/mL was also significantly associated with death/MI, HR 1.51; p = .005. The C-statistic for the multivariate model predicting death/MI improved from 0.712 to 0.730 (p for difference .008) after inclusion of suPAR. However, suPAR was not associated with presence or extent of CAD (p > .05). CONCLUSION: These results validate previous findings that demonstrate suPAR to be an independent predictor of death/MI in patients with suspected or known CAD, however suPAR was not associated with presence or extent of CAD in our cohort. Probably because suPAR reflects end organ damage rather than the degree of atherosclerosis. BRIEF SUMMARY: We demonstrate that the inflammatory biomarker soluble urokinase plasminogen activator receptor is an independent predictor of death/myocardial infarction in patients with suspected or known coronary artery disease, but is not associated with the presence or severity of coronary artery disease.

Plasma proatrial natriuretic peptide associates with lipid oxidation during exercise and cardiorespiratory fitness in healthy young adults.

Atrial natriuretic peptide (ANP) is known for its natriuretic, diuretic, and vasodilatory properties. However, ANP also has metabolic effects stimulating lipolysis and lipid oxidation. Overweight individuals have decreased circulating ANP concentrations. It has been proposed that this potential ANP deficiency could have biological consequences in overweight-related disorders, including decreased lipolysis and lipid oxidation. The purpose of this study was to investigate the relationships between ANP, exercise-induced lipid oxidation, and cardiorespiratory fitness in 562 20-28-year-old healthy community-based women and men. We measured fasting plasma concentrations of mid-regional proANP (MR-proANP), a stable marker of ANP secretion, the respiratory exchange ratio (RER) during sub-maximal exercise, which provides an estimate of lipid oxidation, and maximal oxygen consumption (VO2-max) at the end of a maximal exercise test, which is a measure of cardiorespiratory fitness. An increase of 10 pmol/L in fasting plasma MR-proANP concentrations was related to an increase in relative VO2-max of 0.78 (95% CI 0.36-1.09) ml O2/min/kg and a decrease in RER of -0.0094 (-0.014 to -0.0045) in age- and sex-adjusted analysis (P < 0.001). Further adjusted for body mass index, a rise of 10 pmol/L in fasting plasma MR-proANP concentrations was associated with a rise in relative VO2-max of 0.60 (0.28-0.92) ml O2/min/kg and a fall in RER of -0.0096 (-0.015 to -0.0048) (P < 0.001). Fasting plasma MR-proANP concentrations associate with lipid oxidation during exercise and cardiorespiratory fitness in healthy young adults. The data support the existence of important connections between the endocrine heart, hemodynamics, and metabolism.

Cardiovascular Manifestations of Systemic Sclerosis: A Danish Nationwide Cohort Study.

Background Cardiovascular involvement in systemic sclerosis (SSc) comprises a wide range of manifestations with prevalence and incidence that remain uncertain. Methods and Results In the Danish administrative registries between 1995 and 2015, all patients aged ≥18 years with a first diagnosis of SSc were matched by age and sex with controls (1:5) from the general population. Prevalence of cardiovascular diseases at the time of the SSc diagnosis and incidence during follow-up were assessed by in- and outpatient discharge diagnoses. Conditional logistic and Cox proportional hazards regression models were used respectively to calculate odds ratios for prevalent cardiovascular diseases and hazard ratios (HRs) for incident diseases associated with SSc. Patients with SSc (n=2778; 76% women; mean±SD age: 55±15 years) had more established cardiovascular risk factors than their respective controls at baseline, including greater prevalence of hypertension (31.2% versus 21.0%, P<0.0001) and treated dyslipidemia (9.8% versus 8.5%, P=0.02). SSc was associated with an increased relative risk of developing most cardiovascular diseases, including myocardial infarction (HR: 2.08; 95% CI, 1.65-2.64), peripheral vascular disease (HR: 5.73; 95% CI, 4.63-7.09), pulmonary hypertension (HR: 21.18; 95% CI, 14.73-30.45), mitral regurgitation (HR: 4.60; 95% CI, 3.12-6.79), aortic regurgitation (HR: 3.78; 95% CI, 2.55-5.58), aortic stenosis (HR: 2.99; 95% CI, 2.25-3.97), pericarditis (HR: 8.78; 95% CI, 4.84-15.93), heart failure (HR: 2.86; 95% CI, 2.43-3.37), atrial fibrillation (HR: 1.75; 95% CI, 1.51-2.04), and venous thromboembolism (HR: 2.10; 95% CI, 1.65-2.67). Additional adjustment for medications and comorbidities yielded results similar to the main analyses. Conclusions In this nationwide study, SSc was associated with greater risks of distinct cardiovascular diseases for patients than for matched controls, suggesting a significant disease-related adverse impact across the vascular bed and specific cardiac structures.

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations.

BACKGROUND: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS: 1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research.

Association of copeptin, a surrogate marker for arginine vasopressin secretion, with insulin resistance: Influence of adolescence and psychological stress.

In middle-aged and elderly individuals, circulating copeptin concentrations, a surrogate marker for arginine vasopressin (AVP) secretion, associates with insulin resistance (IR). Whether this association is present in adolescents and young adults is unclear. Because psychological stress associates with higher circulating copeptin concentrations and IR, it has been speculated that increased AVP secretion could be a link between psychological stress and IR. We measured plasma copeptin concentrations in 351 14-16-year-old adolescents and 617 20-28-year-old young adults from the Danish site of the European Youth Heart Study, a population-based cardiovascular risk factor study in adolescents and young adults. IR was determined by the homeostatic model assessment method. Among the young adults, we used symptoms of depression, evaluated by means of the Major Depression Inventory (MDI) scale, as a measure of psychological stress. We applied linear regressions to examine associations, expressed as unstandardized regression coefficients (B) with 95% confidence intervals (CIs), between variables of interest, stratified by age group and adjusting for age, sex and Tanner stages. Copeptin and IR were log-transformed. Among the young adults, copeptin associated with IR (B (95%CI) = 0.19 (0.11 to 0.27), P < 0.001). This association was not found among the adolescents (B=-0.01 (-0.12 to 0.09), P = 0.78). MDI score associated with IR (B = 0.010 (0.004 to 0.016), P < 0.001) and copeptin (B=0.010 (0.004 to 0.015); P<0.002) in the young adults. Adjusted for copeptin, the strength of the association between MDI score and IR somewhat diminished (to B=0.008). In conclusion, adolescence and psychological stress appear to influence the association between copeptin and IR.

Serum proatrial natriuretic peptide concentrations during oral glucose-induced acute hyperinsulinemia in lean and obese men.

Atrial natriuretic peptide (ANP) is primarily seen as a hormone involved in salt and water homeostasis and blood pressure regulation. Evidence supports a link between metabolism and ANP. Circulating ANP concentrations are low in obese individuals with insulin resistance and hyperinsulinemia. The dynamic relationship between insulin and ANP has been sparsely studied. We therefore measured circulating concentrations of midregional proatrial natriuretic peptide (MR-proANP), a stable marker of ANP secretion, and insulin in lean and obese men during an oral glucose challenge. One hundred and three obese men (body mass index (BMI) ≥30.0 kg/m2) were compared with 27 lean men (BMI = 20.0-24.9 kg/m2). During a 75 g oral glucose challenge, circulating concentrations of MR-proANP and insulin were measured at baseline and every half hour for 2 h. Fasting MR-proANP concentrations were lower in the obese men as compared with the lean men (median (interquartile range): 51.2 (38.7-64.7) pmol/L vs. 69.3 (54.3-82.9) pmol/L, P = 0.002). During the oral glucose challenge, serum MR-proANP concentrations fell steadily in the obese men (P < 0.0001), whereas there was no significant fall in the lean men (P = 0.14). However, the time-course curves of MR-proANP did not display a clear reciprocal relation to the time-course curves of insulin. Adjusted for age, the area under curve (AUC) for MR-proANP was inversely correlated with AUC for insulin (r = -0.38, P < 0.0001). In conclusion, during an oral glucose challenge, serum MR-proANP concentrations drop significantly in obese individuals, but the time-course curves of MR-proANP do not display a reciprocal relationship to the time-course curves of insulin.

Ten-year clinical outcome of patients treated with a drug-eluting stent in the proximal left anterior descending artery segment compared with patients stented in other non-left main coronary segments.

AIMS: The aim of the study was to determine whether patients treated with drug-eluting stents in the proximal left anterior descending artery (LAD) carried a different long-term prognosis from patients treated in other coronary artery segments. METHODS AND RESULTS: Ten-year clinical outcome expressed as all-cause mortality and major adverse cardiac events (MACE: cardiac death, acute myocardial infarction, or target vessel revascularisation) was determined for 1,479 patients with a single non-left main coronary stenosis treated with a first-generation drug-eluting stent in the SORT OUT II trial. The outcome of patients treated with stents in the proximal LAD (n=365) was compared with that of patients treated in a non-proximal LAD segment (n=1,114). Follow-up was 99.3% complete. All-cause mortality was 24.9% in the proximal LAD group vs. 26.3% in the non-proximal LAD group (p=0.60). MACE occurred less frequently in the proximal LAD group, 24.6% vs. 31.0% with a hazard ratio of 0.77 (95% confidence interval [CI]: 0.61-0.97, p=0.024). After multivariate analysis which included baseline characteristics that were unevenly distributed between the groups, the hazard ratio for MACE was 0.82 (95% CI: 0.65-1.03, p=0.09). CONCLUSIONS: Patients treated with a drug-eluting stent in the proximal LAD have similar, if not better, long-term clinical outcome compared with patients stented in other coronary artery segments.

Effect of simvastatin and ezetimibe on suPAR levels and outcomes.

BACKGROUND AND AIMS: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown. METHODS: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). RESULTS: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%-11.5%) in the placebo group, but only by 4.1% (1.9%-6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17-3.61); MCE 1.40 (1.01-1.92); and AVE 1.42 (1.02-1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE. CONCLUSIONS: Simvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677).

SuPAR predicts postoperative complications and mortality in patients with asymptomatic aortic stenosis.

Background: We evaluated whether early measurement of soluble urokinase plasminogen activator receptor (suPAR) could predict future risk of postoperative complications in initially asymptomatic patients with mild-moderate aortic stenosis (AS) undergoing aortic valve replacement (AVR) surgery. Methods: Baseline plasma suPAR levels were available in 411 patients who underwent AVR surgery during follow-up in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox analyses were used to evaluate suPAR in relation to all-cause mortality and the composite endpoint of postoperative complications (all-cause mortality, congestive heart failure, stroke and renal impairment) occurring in the 30-day postoperative period. Results: Patients with initially higher levels of suPAR were at increased risk of postoperative mortality with a HR of 3.5 (95% CI 1.4 to 9.0, P=0.008) and postoperative complications with a HR of 2.7 (95% CI 1.5 to 5.1, P=0.002), per doubling in suPAR. After adjusting for the European System for Cardiac Operative Risk Evaluation or Society of Thoracic Surgeons risk score, suPAR remained associated with postoperative mortality with a HR 3.2 (95% CI 1.2 to 8.6, P=0.025) and 2.7 (95% CI 1.0 to 7.8, P=0.061); and postoperative complications with a HR of 2.5 (95% CI 1.3 to 5.0, P=0.007) and 2.4 (95% CI 1.2 to 4.8, P=0.011), respectively. Conclusion: Higher baseline suPAR levels are associated with an increased risk for postoperative complications and mortality in patients with mild-moderate, asymptomatic AS undergoing later AVR surgery. Further validation in other subsets of AS individuals are warranted. Trial registration number: NCT00092677; Post-results.

Obese Hypertensive Men Have Lower Circulating Proatrial Natriuretic Peptide Concentrations Despite Greater Left Atrial Size.

BACKGROUND: Obese persons have lower circulating natriuretic peptide (NP) concentrations. It has been proposed that this natriuretic handicap plays a role in obesity-related hypertension. In contrast, hypertensive patients with left atrial enlargement have higher circulating NP concentrations. On this background, we investigated whether obese hypertensive men could have lower circulating NP concentrations despite evidence of pressure-induced greater left atrial size. METHODS: We examined 98 obese men (body mass index [BMI] ≥ 30.0 kg/m2) and 27 lean normotensive men (BMI 20.0-24.9 kg/m2). All men were healthy, medication free, with normal left ventricular ejection fraction. We measured blood pressure using 24-hour ambulatory blood pressure (ABP) recordings. Hypertension was defined as 24-hour ABP ≥ 130/80 mm Hg, and normotension was defined as 24-hour ABP < 130/80 mm Hg. We determined left atrial size using echocardiography, and we measured fasting serum concentrations of midregional proatrial NP (MR-proANP). RESULTS: Of the 98 obese men, 62 had hypertension and 36 were normotensive. The obese hypertensive men had greater left atrial size (mean ± SD: 28.7 ± 6.0 ml/m2) compared with the lean normotensive men (23.5 ± 4.5 ml/m2) and the obese normotensive men (22.7 ± 5.1 ml/m2), P < 0.01. Nevertheless, despite evidence of pressure-induced greater left atrial size, the obese hypertensive men had lower serum MR-proANP concentrations (median [interquartile range]: 48.5 [37.0-64.7] pmol/l) compared with the lean normotensive men (69.3 [54.3-82.9] pmol/l), P < 0.01, whereas the obese normotensive men had serum MR-proANP concentrations in between the 2 other groups (54.1 [43.6-62.9] pmol/l). CONCLUSIONS: Despite greater left atrial size, obese hypertensive men have lower circulating MR-proANP concentrations compared with lean normotensive men.

Trends in incidence, mortality, and causes of death associated with systemic sclerosis in Denmark between 1995 and 2015: a nationwide cohort study.

BACKGROUND: To investigate the incidence and the mortality-rates of systemic sclerosis (SSc), its primary causes of death, and the temporal trends in events in Denmark during the last decades. METHODS: Using the Danish National Patient Registry, we identified all persons aged ≥18 years with a first-time diagnosis of SSc (ICD-10 code M34, excluding M34.2) between 1995 and 2015. RESULTS: A total of 2778 incident SSc cases were identified. The mean age at time of SSc diagnosis was 56 (standard deviation 15) years and 76% were women. The overall incidence rate (per 1,000,000 person-years) of diagnosed SSc was 24.4 (95% confidence interval 23.6-25.4), with a slight increase over the study period, age- and sex-adjusted incidence rate ratio 1.02 (95% confidence interval 1.01-1.02) per 1-year increase. The 1-year all-cause mortality rate per 100 person-years decreased from 6.1 (3.1-12.2) in 1995 to 5.3 (2.5-11.1) in 2015, sex- and age-adjusted hazard ratio 0.96 (95% CI 0.94-0.98) per 1-year increase. Over the period, the average age at SSc diagnosis increased and the proportion of women decreased, whereas the burden of comorbidities increased. One fifth of all deaths were attributable to cardiovascular causes, a fourth to pulmonary diseases, and 15% were due to cancer. CONCLUSIONS: Within the last few decades, the incidence of SSc has increased and the 1-year mortality rate has decreased slightly in Denmark. Almost half of all deaths were attributable to cardiopulmonary causes.