Prediction of cardiovascular events from systolic or diastolic blood pressure.

Over time, a focus on blood pressure has transferred from diastolic pressure to systolic pressure. Formal analyses of differences in predictive value are scarce. Our goal of the study was whether office SBP adds prognostic information to office DBP and whether both 24-h ambulatory SBP and 24-h ambulatory DBP is specifically important. The authors examined 2097 participants from a population cohort recruited in Copenhagen, Denmark. Cause-specific Cox regression was performed to predict 10-year person-specific absolute risks of fatal and non-fatal cardiovascular (CV) events. Also, the time-dependent area under the receiver operator curve (AUC) was utilized to evaluate discriminative ability. The calibration plots of the models (Hosmer-May test) were calculated as well as the Brier score which combines (discrimination and calibration). Adding both 24-h ambulatory SBP and 24-h ambulatory diastolic blood pressure did not significantly increase AUC for CV mortality and CV events. Moreover, adding both office SBP and office DBP did not significantly improve AUC for both CV mortality and CV events. The difference in AUC (95% confidence interval; p-value) was .26% (-.2% to .73%; .27) for 10-year CV mortality and .69% (-.09% to 1.46%; .082) for 10-year risk of CV events. The difference in AUC was .12% (-.2% to .44%; .46) for 10-year CV mortality and .04% (-.35 to .42%; .85) for 10-year risk of CV events. Moreover, for both CV mortality and CV events, office SBP did not improve prognostic information to office DBP. In addition, the Brier scores of office BP in both CV mortality and CV events were .078 and .077, respectively. Furthermore, the Brier scores were .077 and .078 in CV mortality and CV events of 24-h ambulatory. For the average population as those participating in a population survey, the 10-year discriminative ability for long-term predictions of CV death and CV events is not improved by adding systolic to diastolic blood pressure. This finding is found for ambulatory as well as office blood pressure.

Renal Artery Stenting in Consecutive High-Risk Patients With Atherosclerotic Renovascular Disease: A Prospective 2-Center Cohort Study.

Background The aim of this study was to prospectively evaluate the effects of renal artery stenting in consecutive patients with severe atherosclerotic renal artery stenosis and high-risk clinical presentations as defined in a national protocol developed in 2015. Methods and Results Since the protocol was initiated, 102 patients have been referred for revascularization according to the following high-risk criteria: severe renal artery stenosis (≥70%) with true resistant hypertension, rapidly declining kidney function, or recurrent heart failure/sudden pulmonary edema. At baseline, the mean 24-hour ambulatory systolic blood pressure was 166.2 mm Hg (95% CI, 162.0-170.4), the defined daily dose of antihypertensive medication was 6.5 (95% CI, 5.8-7.3), and the estimated glomerular filtration rate was 41.1 mL/min per 1.73m2 (95% CI, 36.6-45.6). In 96 patients with available 3-month follow-up data, mean 24-hour ambulatory systolic blood pressure decreased by 19.6 mm Hg (95% CI, 15.4-23.8; P<0.001), the defined daily dose of antihypertensive medication was reduced by 52% (95% CI, 41%-62%; P<0.001), and estimated glomerular filtration rate increased by 7.8 mL/min per 1.73m2 (95% CI, 4.5-11.1; P<0.001). All changes persisted after 24 month follow-up. Among 17 patients with a history of hospitalization for acute decompensated heart failure, 14 patients had no new episodes after successful revascularization. Conclusions In this prospective cohort study, we observed a reduction in blood pressure and antihypertensive medication, an increase in estimated glomerular filtration rate, and a decrease in new hospital admissions attributable to heart failure/sudden pulmonary edema after renal artery stenting. Registration URL: https://clinicaltrials.gov. Identifier: NCT02770066.

Predictors of 10-Year Stent-Related Adverse Outcomes after Coronary Drug-Eluting Stent Implantation: The Importance of Stent Size.

INTRODUCTION: The predictors of stent treatment failure and their importance 10 years after treatment with drug-eluting stents (DESs) have not been reported in detail. METHODS: Data were retrieved from the SORT-OUT II database encompassing 2,849 non-left main coronary lesions in 2,073 unselected all-comer patients treated with first-generation DES and followed clinically for 10 years. Stent treatment failure (STF) was defined as definite or probable stent thrombosis, target lesion revascularization (TLR), or >70% restenosis left untreated. Target lesion failure (TLF) was defined as cardiac death, target vessel myocardial infarction, or TLR. Characteristics predicting higher hazard ratios (HRs) were identified by the multivariate Cox regression analysis. RESULTS: A stent diameter ≤2.5 versus ≥3.5 mm had STF 23.3 versus 11.8% and TLF 27.9 versus 18.8%. Stent length <20 versus >40 mm had STF 13.0 versus 29.0% and TLF 18.7 versus 34.6%. In multivariate analysis, decreasing stent diameter (HR: 1.24 [3.0 mm] to 2.12 [2.25 mm], reference ≥3.5 mm) and increasing stent length (HR: 1.15 [20-30 mm] to 2.07 [>40 mm], reference <20 mm) predicted STF together with diabetes (HR: 1.31), previous revascularization (HR: 1.31), restenotic (HR: 2.25), bifurcation (HR: 1.45), and chronically occluded lesions (HR: 1.54). A predictive score (PS) was calculated for each lesion from the HRs for the predictors present. The 10-year rates of STF were 10% in lesions with a PS ≤ 1.5 and 37% in those with PS ≥ 3.5. CONCLUSIONS: Ten-year outcomes show large variations depending on the stent size and a few patient and lesion characteristics. The calculation of a PS from these unambiguous variables may be used to improve the risk estimate in individual lesions and patients.

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.

Retinal arteriolar wall-to-lumen ratios at 16-17 years in the Copenhagen Child Cohort 2000 Study.

PURPOSE: To study the thickness of retinal arteriolar walls in a population-based cohort of adolescents. METHODS: This cross-sectional, observational study included 1217 participants aged 16-17 years from the Copenhagen Child Cohort 2000 Study. The wall thickness and lumen diameter of a major branch retinal arteriole were measured using adaptive optics imaging. The wall-to-lumen ratio was analyzed in relation to blood pressure and body composition variables using a general linear model. Overall in the study population, wall-to-lumen ratio was found to decrease by 0.49% per µm increase in arteriole diameter (P < 0.0001) and all subsequent analyzes were adjusted accordingly. RESULTS: The average outer and inner arteriole diameters were 117 ±â€Š19 and 96.6 ±â€Š18 µm (mean ±â€ŠSD), corresponding to a wall-to-lumen ratio of 0.21 ±â€Š0.024. There was no detectable difference between sexes. A higher wall-to-lumen ratio was associated with a higher BMI (+0.21% per kg/m, P = 0.0018), higher body fat percentage (+0.097% per 1% increase, P = 0.0052), wider hip circumference (+1.1% per 10 cm increase, P = 0.0006), wider waist circumference (+0.92% per 10 cm increase, P = 0.0009), higher SBP in girls (+1.1% per 10 mmHg increase, P = 0.0005), longer axial length (+0.70% per mm increase, P = 0.013), and younger age (+4.9% per year younger, P < 0.0001), adjusted for arteriole diameter, age, sex, and height. CONCLUSION: A higher retinal arteriolar wall-to-lumen ratio was associated with all registered indices of body fat proportion.

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 Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes.

Importance: Blood pressure (BP) is a known risk factor for overall mortality and cardiovascular (CV)-specific fatal and nonfatal outcomes. It is uncertain which BP index is most strongly associated with these outcomes. Objective: To evaluate the association of BP indexes with death and a composite CV event. Design, Setting, and Participants: Longitudinal population-based cohort study of 11 135 adults from Europe, Asia, and South America with baseline observations collected from May 1988 to May 2010 (last follow-ups, August 2006-October 2016). Exposures: Blood pressure measured by an observer or an automated office machine; measured for 24 hours, during the day or the night; and the dipping ratio (nighttime divided by daytime readings). Main Outcomes and Measures: Multivariable-adjusted hazard ratios (HRs) expressed the risk of death or a CV event associated with BP increments of 20/10 mm Hg. Cardiovascular events included CV mortality combined with nonfatal coronary events, heart failure, and stroke. Improvement in model performance was assessed by the change in the area under the curve (AUC). Results: Among 11 135 participants (median age, 54.7 years, 49.3% women), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a CV event over a median of 13.8 years of follow-up. Both end points were significantly associated with all single systolic BP indexes (P < .001). For nighttime systolic BP level, the HR for total mortality was 1.23 (95% CI, 1.17-1.28) and for CV events, 1.36 (95% CI, 1.30-1.43). For the 24-hour systolic BP level, the HR for total mortality was 1.22 (95% CI, 1.16-1.28) and for CV events, 1.45 (95% CI, 1.37-1.54). With adjustment for any of the other systolic BP indexes, the associations of nighttime and 24-hour systolic BP with the primary outcomes remained statistically significant (HRs ranging from 1.17 [95% CI, 1.10-1.25] to 1.87 [95% CI, 1.62-2.16]). Base models that included single systolic BP indexes yielded an AUC of 0.83 for mortality and 0.84 for the CV outcomes. Adding 24-hour or nighttime systolic BP to base models that included other BP indexes resulted in incremental improvements in the AUC of 0.0013 to 0.0027 for mortality and 0.0031 to 0.0075 for the composite CV outcome. Adding any systolic BP index to models already including nighttime or 24-hour systolic BP did not significantly improve model performance. These findings were consistent for diastolic BP. Conclusions and Relevance: In this population-based cohort study, higher 24-hour and nighttime blood pressure measurements were significantly associated with greater risks of death and a composite CV outcome, even after adjusting for other office-based or ambulatory blood pressure measurements. Thus, 24-hour and nighttime blood pressure may be considered optimal measurements for estimating CV risk, although statistically, model improvement compared with other blood pressure indexes was small.

Soluble Urokinase Plasminogen Activator Receptor Predicts Cardiovascular Events, Kidney Function Decline, and Mortality in Patients With Type 1 Diabetes.

OBJECTIVE: Soluble urokinase plasminogen activator receptor (suPAR) is an important inflammatory biomarker implicated in endothelial and podocyte dysfunction. However, suPAR's predictive qualities for complications in type 1 diabetes have yet to be determined. We investigated the prognostic value of suPAR for the development of cardiovascular events, decline in renal function, and mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We included 667 patients with type 1 diabetes with various degrees of albuminuria in a prospective study. End points were cardiovascular events (cardiovascular death, nonfatal acute myocardial infarction, nonfatal stroke, or coronary or peripheral arterial interventions), estimated glomerular filtration rate (eGFR) decline ≥30%, progression from lower to higher albuminuric state, development of end-stage renal disease (ESRD), and mortality. Follow-up was 5.2-6.2 years. Results were adjusted for known risk factors. Hazard ratios (HRs) are presented per doubling of suPAR with 95% CI. Relative integrated discrimination improvement (rIDI) was calculated. RESULTS: Quantification of suPAR was available in all participants; median (interquartile range) was 3.4 ng/mL (2.7-4.5). The adjusted HR (95% CI) for cardiovascular events (n = 94), progression in albuminuria (n = 36), eGFR decline (n = 93), ESRD (n = 23), and mortality (n = 58) were 3.13 (1.96-5.45, P < 0.001), 1.27 (0.51-3.19, P = 0.61), 2.93 (1.68-5.11, P < 0.001), 2.82 (0.73-11.9, P = 0.13), and 4.13 (1.96-8.69, P < 0.001), respectively. rIDI was significant for cardiovascular events (22.6%, P < 0.001), eGFR decline (14.4%, P < 0.001), and mortality (23.9%, P < 0.001). CONCLUSIONS: In patients with type 1 diabetes and a broad range of albuminuria, a higher level of suPAR is a significant and independent risk factor for cardiovascular events, decline in eGFR ≥30%, and mortality. In addition, suPAR contributes significantly to discrimination for the end points.

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.