Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial.

BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.

Negligible In Vitro Recovery of Macromolecules from Microdialysis Using 100 kDa Probes and Dextran in Perfusion Fluid.

Microdialysis is applied in neurointensive care to monitor cerebral glucose metabolism. If recoverable, macromolecules may also serve as biomarkers in brain disease and provide clues to their passage across the blood-brain barrier. Our study aimed to investigate the in vitro recovery of human micro- and macromolecules using microdialysis catheters and perfusion fluids approved for clinical use. In vitro microdialysis of a bulk solution containing physiological or supraphysiological concentrations of glucose, lactate, pyruvate, human IgG, serum albumin, and hemoglobin was performed using two different catheters and perfusion fluids. One had a membrane cut-off of 20 kDa and was used with a standard CNS perfusion fluid, and the other had a membrane cut-off of 100 kDa and was perfused with the same solution supplemented with dextran. The flow rate was 0.3 µl/min. We used both push and push-pull methods. Dialysate samples were collected at 2-h intervals for 6 h and analyzed for relative recovery of each substance. The mean relative recovery of glucose, pyruvate, and lactate was > 90% in all but two sets of experiments. In contrast, the relative recovery of human IgG, serum albumin, and hemoglobin from both bulk solutions was below the lower limit of quantification (LLOQ). Using a push-pull method, recovery of human IgG, serum albumin, and hemoglobin from a bulk solution with supraphysiological concentrations were above LLOQ but with low relative recovery (range 0.9%-1.6%). In summary, exchanging the microdialysis setup from a 20 kDa catheter with a standard perfusion fluid for a 100 kDa catheter with a perfusion solution containing dextran did not affect the relative recovery of glucose and its metabolites. However, it did not result in any useful recovery of the investigated macromolecules at physiological levels, either with or without a push-pull pump system.

Prevalence of visual snow syndrome in the UK.

BACKGROUND AND PURPOSE: Visual snow syndrome is a recently described condition of unknown prevalence. We investigated the prevalence in a representative population sample from the UK and tested the hypothesis that visual snow syndrome is associated with young age, headache, tinnitus and mood impairment. METHODS: Using a crowdsourcing platform, we recruited a representative sample of 1015 adult laypeople from the UK, matched for age, gender and ethnicity according to national census data. Participants were unprimed, i.e. were inquired about the 'frequency of certain medical conditions' but not 'visual snow syndrome'. RESULTS: A total of 38 of 1015 participants reported symptoms compatible with visual snow [3.7%; 95% confidence interval (CI), 2.7-5.2] and 22/1015 met criteria for visual snow syndrome (2.2%; 95% CI, 1.4-3.3). The female-to-male ratio for visual snow syndrome was 1.6:1. Subjects with visual snow syndrome were older (50.6 ± 14 years) than the population mean (44.8 ± 15 years), although this was not statistically different (P = 0.06). Of 22 participants with visual snow syndrome, 16 had mood symptoms (72.7%; P = 0.01), 12 had headache (54.5%; P = 0.06), including five with visual migraine aura (22.7%; P = 0.15) and 13 had tinnitus (59.1%; P < 0.001). No participant had diabetes or a cleft lip (control questions). Following a multivariable regression analysis to adjust for age and gender, only the association between visual snow syndrome and tinnitus remained significant (odds ratio, 3.93; 95% CI, 1.63-9.9; P = 0.003). CONCLUSIONS: The UK prevalence of visual snow syndrome is around 2%. We confirmed an association with tinnitus, but unprimed laypeople with visual snow syndrome are on average older than those seeking medical attention.

Baseline findings of the population-based, randomized, multifaceted Danish cardiovascular screening trial (DANCAVAS) of men aged 65-74 years.

BACKGROUND: The challenge of managing age-related diseases is increasing; routine checks by the general practitioner do not reduce cardiovascular mortality. The aim here was to reduce cardiovascular mortality by advanced population-based cardiovascular screening. The present article reports the organization of the study, the acceptability of the screening offer, and the relevance of multifaceted screening for prevention and management of cardiovascular disease. METHODS: Danish men aged 65-74 years were invited randomly (1 : 2) to a cardiovascular screening examination using low-dose non-contrast CT, ankle and brachial BP measurements, and blood tests. RESULTS: In all, 16 768 of 47 322 men aged 65-74 years were invited and 10 471 attended (uptake 62·4 per cent). Of these, 3481 (33·2 per cent) had a coronary artery calcium score above 400 units. Thoracic aortic aneurysm was diagnosed in the ascending aorta (diameter 45 mm or greater) in 468 men (4·5 per cent), in the arch (at least 40 mm) in 48 (0·5 per cent) and in the descending aorta (35 mm or more) in 233 (2·2 per cent). Abdominal aortic aneurysm (at least 30 mm) and iliac aneurysm (20 mm or greater) were diagnosed in 533 (5·1 per cent) and 239 (2·3 per cent) men respectively. Peripheral artery disease was diagnosed in 1147 men (11·0 per cent), potentially uncontrolled hypertension (at least 160/100 mmHg) in 835 (8·0 per cent), previously unknown atrial fibrillation confirmed by ECG in 50 (0·5 per cent), previously unknown diabetes mellitus in 180 (1·7 per cent) and isolated severe hyperlipidaemia in 48 men (0·5 per cent). In all, 4387 men (41·9 per cent), excluding those with potentially uncontrolled hypertension, were referred for additional cardiovascular prevention. Of these, 3712 (35·5 per cent of all screened men, but 84·6 per cent of those referred) consented and were started on medication. CONCLUSION: Multifaceted cardiovascular screening is feasible and may optimize cardiovascular disease prevention in men aged 65-74 years. Uptake is lower than in aortic aneurysm screening.

"FIFA 11 for Health" for Europe in the Faroe Islands: Effects on health markers and physical fitness in 10- to 12-year-old schoolchildren.

We evaluated effects of the school-based intervention "FIFA 11 for Health" for Europe on health and fitness profile in 10- to 12-year-old Faroese schoolchildren. 392 fifth-grade children were randomized into a control group (CG: n = 100, 11.1 ± 0.3 years, 149.0 ± 6.7 cm, 42.4 ± 10.2 kg) and an intervention group (IG: n = 292, 11.1 ± 0.3 years, 150.6 ± 6.9 cm, 44.2 ± 9.4 kg). IG underwent an 11-week intervention in which 2 weekly sessions of 45 minutes were included in the school curriculum focusing on health aspects, football skills, and 3v3 small-sided games. CG continued with their regular activities. Body composition, blood pressure, and resting heart rate, as well as Yo-Yo intermittent recovery children's test (YYIR1C) performance, horizontal jumping ability and postural balance were assessed pre and post intervention. Systolic blood pressure decreased more (-2.8 ± 9.9 vs 2.9 ± 8.4 mm Hg, P < .05) in IG than in CG. Lean body mass (1.0 ± 1.7 vs 0.7 ± 1.6 kg), postural balance (0.3 ± 3.9 vs -1.2 ± 5.9 seconds) and horizontal jump performance (5 ± 9 vs -5 ± 10 cm) increased more (P < .05) in IG than in CG. YYIR1C performance improved in CG (17%, 625 ± 423 to 730 ± 565 m) and IG (18%, 689 ± 412 vs 813 ± 391 m), but without between-group differences. A within-group decrease from 23.1 ± 8.4 to 22.5 ± 8.3% (P < .05) was observed in body fat percentage in IG only. In conclusion, the "FIFA 11 for Health" for Europe program had beneficial effects on SBP, body composition, jump performance and postural balance in 10- to 12-year-old Faroese schoolchildren, supporting the notion that school-based football interventions can facilitate health of children in a small-scale society and serve as an early step in the prevention of non-communicable diseases.

The DanCavas Pilot Study of Multifaceted Screening for Subclinical Cardiovascular Disease in Men and Women Aged 65-74 Years.

OBJECTIVE/BACKGROUND: This pilot study of a large population based randomised screening trial investigated feasibility, acceptability, and relevance (prevalence of clinical and subclinical cardiovascular disease [CVD] and proportion receiving insufficient prevention) of a multifaceted screening for CVD. METHODS: In total, 2060 randomly selected Danish men and women aged 65-74 years were offered (i) low dose non-contrast computed tomography to detect coronary artery calcification (CAC) and aortic/iliac aneurysms; (ii) detection of atrial fibrillation (AF); (iii) brachial and ankle blood pressure measurements; and (iv) blood levels of cholesterol and hemoglobin A1c. Web based self booking and data management was used to reduce the administrative burden. RESULTS: Attendance rates were 64.9% (n = 678) and 63.0% (n = 640) for men and women, respectively. In total, 39.7% received a recommendation for medical preventive actions. Prevalence of aneurysms was 12.4% (95% confidence interval [CI] 9.9-14.9) in men and 1.1% (95% CI 0.3-1.9) in women, respectively (p < .001). A CAC score > 400 was found in 37.8% of men and 11.3% of women (p < .001), along with a significant increase in median CAC score with age (p = .03). Peripheral arterial disease was more prevalent in men (18.8%, 95% CI 15.8-21.8) than in women (11.2%, 95% CI 8.7-13.6). No significant differences between the sexes were found with regard to newly discovered AF (men 1.3%, women 0.5%), potential hypertension (men 9.7%, women 11.5%), hypercholesterolemia (men 0.9%, women 1.1%) or diabetes mellitus (men 2.1%, women 1.3%). CONCLUSION: Owing to the higher prevalence of severe conditions, such as aneurysms and CAC ≥ 400, screening for CVD seemed more prudent in men than women. The attendance rates were acceptable compared with other screening programs and the logistical structure of the screening program proved successful.

Who are the cancer survivors? A nationwide study in Denmark, 1943-2010.

BACKGROUND: No nationwide studies on social position and prevalence of comorbidity among cancer survivors exist. METHODS: We performed a nationwide prevalence study defining persons diagnosed with cancer 1943-2010 and alive on the census date 1 January 2011 as cancer survivors. Comorbidity was compared by social position with the non-cancer population. RESULTS: Cancer survivors composed 4% of the Danish population. Somatic comorbidity was more likely among survivors (OR 1.59, 95% CI 1.57-1.60) and associated with higher age, male sex, short education, and living alone among survivors. CONCLUSIONS: Among cancer survivors, comorbidity is common and highly associated with social position.

Weight reduction and aortic stiffness in obese children and adolescents: a 1-year follow-up study.

Little is known about the effect of weight reduction on aortic stiffness and especially so in the young. The present study investigates whether weight reduction influences aortic stiffness in obese children and adolescents. Carotid-femoral pulse wave velocity (cfPWV) and augmentation index at heart rate 75 (AIx@HR75) were measured in 72 obese patients aged 10-18 years at baseline and after 1-year of lifestyle intervention (follow-up). We found that although the degree of obesity decreased (Δbody mass index z-score: -0.24±0.45, P<0.0001), cfPWV was higher at follow-up (ΔcfPWV: 0.27±0.47 m s(-1), P<0.0001), which was explained by the increase in age (ß=0.12 ms(-1) per year, 95% confidence interval (CI) 0.07-0.17, P<0.0001) and partly by changes in mean arterial pressure and heart rate. Changes in cfPWV were not related to changes in obesity measures. No significant change was found in AIx@HR75 (ΔAIx@HR75: 2.10±9.73%, P=0.072), but changes in AIx@HR75 were related to changes in abdominal fat (Δwaist/height ratio: ß=50.3, 95% CI 6.7-94.0, P=0.02) and changes in total body fat percent by dual energy X-ray absorptiometry scan (Δtotal body fat (%): ß=0.7, 95% CI 0.1-1.3, P=0.02) when adjusted for gender and relevant baseline confounders. In conclusion, no clear effect of weight reduction was found on aortic stiffness, although changes in AIx@HR75 were associated with changes in both abdominal fat and total body fat percent. The higher cfPWV at follow-up was related to the older age.

Uncontrolled hypertension is associated with coronary artery calcification and electrocardiographic left ventricular hypertrophy: a case-control study.

We conducted a 1:2 matched case-control study in order to evaluate whether the prevalence of coronary artery calcium (CAC) and electrocardiographic left ventricular hypertrophy (LVH) or strain was higher in patients with uncontrolled hypertension than in subjects from the general population, and evaluate the association between CAC and LVH in patients with uncontrolled hypertension. Cases were patients with uncontrolled hypertension, whereas the controls were random individuals from the general population without cardiovascular disease. CAC score was assessed using a non-contrast computed tomographic scan. LVH was evaluated using the Sokolow-Lyon voltage combination and Cornell voltage-duration product, respectively. Associations between CAC, LVH and traditional cardiovascular risk factors were tested by means of ordinal, conditional and classic binary logistic regression models. We found that uncontrolled hypertension was independently associated with both an ordinal CAC score category (odds ratio (OR) 3.9 (95% CI, 1.6-9.1), P = 0.002), the presence of CAC score>99 (OR 4.5 (95% CI, 1.4-14.7), P = 0.01) and electrocardiographic LVH (OR 10.1 (95% CI, 3.4-30.2), P < 0.001) on both univariate and multivariable analyses. There was, however, no correlation between CAC and LVH. The lack of an association between CAC and LVH suggests that they are markers of different complications of hypertension and may have independent predictive values. Patients with both CAC and LVH may be at higher risk than those in whom only one of these markers is present.

Loss of partner and breast cancer prognosis - a population-based study, Denmark, 1994-2010.

BACKGROUND: The extent to which experiencing a stressful life event influences breast cancer prognosis remains unknown, as the findings of the few previous epidemiological studies are inconsistent. This large population-based study examines the association between a common major life event, loss of a partner and breast cancer recurrence and all-cause mortality. METHODS: N=21,213 women diagnosed with a first primary breast cancer 1994-2006, who had a cohabiting partner in the 4 years before their breast cancer diagnosis, were followed for death and recurrence in population-based registers and clinical databases. Information on education, disposable income, comorbidity and prognostic risk factors were included in Cox regression analyses. RESULTS: Women who had lost a partner either before diagnosis or in subsequent years were not at significantly higher risk of recurrence or dying than women who had not lost a partner. CONCLUSION: Our results do not support the concern that experiencing a stressful life event, the loss of a partner, negatively affects prognosis of breast cancer.

NT-proBNP is associated with fibulin-1 in Africans: the SAfrEIC study.

OBJECTIVES: The N-terminal prohormone B-type natriuretic peptide (NT-proBNP) is involved in the regulation of volume load and secreted when systemic cardiac overload occurs. Fibulin-1 on the other hand is a component of many extracellular matrix proteins including those present in atherosclerotic lesions, expressed in elastin-containing fibres of blood vessels, and also in the heart. Due to an alarming prevalence of hypertensive heart disease in black South Africans, we investigated the associations of NT-proBNP with fibulin-1 and markers of arterial stiffness in Africans and Caucasians. METHODS: We included 231 Africans and 238 Caucasians from South Africa aged 22-77 years. Serum NT-proBNP and fibulin-1 levels were determined, and arterial compliance and pulse wave velocity were measured. RESULTS: Africans had significantly higher blood pressure and NT-proBNP levels than Caucasians and African men had higher fibulin-1 levels than Caucasian men. In single regression analysis, NT-proBNP was significantly associated with fibulin-1 in African men and Caucasian women. NT-proBNP correlated negatively with arterial compliance in all groups except Caucasian women. After partial adjustments, the association between NT-proBNP and fibulin-1 strengthened in African men only. After full adjustment in multiple regression analysis, the association of NT-proBNP with fibulin-1 was confirmed in African men (R(2)=0.41; ß=0.26; p<0.01) and also in younger women (R(2)=0.34; ß=0.251; p=0.012). CONCLUSIONS: Only Africans indicated a significant independent association between NT-proBNP and fibulin-1, suggesting that cardiovascular alterations are already present in this relatively young African population as opposed to Caucasians.

The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men.

AIM: To explore the putative association of new-onset diabetes and the soluble urokinase plasminogen activator receptor (suPAR), which is a new and stable plasma marker of immune function and low-grade inflammation. This association has been previously suggested by using the less sensitive International Classification of Disease system to detect incident diabetes in the Danish MONICA 10 cohort. METHODS: The Danish National Diabetes Register enabled more accurate identification of incident diabetes during a median follow-up of 13.8 years in the Danish MONICA 10 cohort (n = 2353 generally healthy individuals). The soluble urokinase plasminogen activator receptor was measured by the ELISA method. To fulfil model assumptions, outcome analyses were stratified by age, and further by smoking, owing to the interaction between the soluble urokinase plasminogen activator receptor and smoking on new-onset diabetes (P < 0.0001). RESULTS: New-onset diabetes (n = 182) was associated with increased soluble urokinase plasminogen activator receptor levels (P = 0.013). Among 699 middle-aged (41 and 51 years) and 564 older (61 and 71 years) non-smokers, participants in the upper soluble urokinase plasminogen activator receptor quartile had a sex- and age-adjusted relative risk of 6.01 (95% CI 2.17-16.6, P < 0.0006) and relative risk of 3.25 (95% CI 1.51-6.98, P = 0.0025), respectively, for new-onset diabetes compared with participants in the lowest quartile. This relationship remained significant after additional adjustments for C-reactive protein and leukocytes or fasting glucose and insulin or BMI (P < 0.05). The soluble urokinase plasminogen activator receptor was not related to incident diabetes among smokers (P ≥ 0.85). CONCLUSIONS: In these explorative analyses, the soluble urokinase plasminogen activator receptor associated independently with incident diabetes in non-smokers, supporting an immune origin of Type 2 diabetes. Competing disease risk may explain lack of association among smokers.

Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events.

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) is a plasma marker of low grade inflammation and has been associated with cardiovascular risk. We wanted to investigate whether suPAR was associated with markers of subclinical organ damage. METHODS: In a population sample of 2038 individuals, aged 41, 51, 61 and 71 years, without diabetes, prior stroke or myocardial infarction, not receiving any cardiovascular, anti-diabetic or lipid-lowering medications, we measured urine albumin/creatinine ratio (UACR), carotid atherosclerotic plaques and carotid/femoral pulse wave-velocity (PWV) together with traditional cardiovascular risk factors and high sensitivity C-reactive protein (hsCRP). RESULTS: suPAR was significantly associated with the presence of plaques (P = 0.003) and UACR (P < 0.001), but not PWV (P = 0.17) when adjusting for age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio, smoking and hsCRP. However, suPAR explained only a small part of the variation in the markers of subclinical organ damage (R(2) 0.02-0.04). During a median follow-up of 12.7 years (5th-95th percentile 5.1-13.4 years) a total of 174 composite endpoints (CEP) of cardiovascular death, non-fatal myocardial infarction and stroke occurred. suPAR was associated with CEP independent of plaques, PWV, UACR, and hsCRP as well as age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio and smoking with a standardized hazard ratio of 1.16 (95% confidence interval 1.04-1.28, P = 0.006). CONCLUSION: suPAR was associated with subclinical organ damage, but predicted cardiovascular events independent of subclinical organ damage, traditional risk factors and hsCRP. Further studies must investigate whether suPAR plays an independent role in the pathogenesis of cardiovascular disease.

Changes in electrocardiographic left ventricular hypertrophy and risk of major cardiovascular events in isolated systolic hypertension: the LIFE study.

The predictive value of changes in the severity of electrocardiographic left ventricular hypertrophy (ECG-LVH) during antihypertensive therapy remains unclear in isolated systolic hypertension (ISH). In a Losartan Intervention For Endpoint reduction in hypertension substudy, we included 1320 patients aged 54-83 years with systolic blood pressure (BP) of 160-200 mm Hg, diastolic BP <90 mm Hg and ECG-LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria, randomized to losartan- or atenolol-based treatment with a mean follow-up of 4.8 years. The composite end point of cardiovascular death, non-fatal myocardial infarction (MI) or stroke occurred in 179 (13.6%) patients. In Cox regression models controlling for treatment, Framingham risk score, as well as baseline and in-treatment BP, less severe in-treatment ECG-LVH by Cornell product and Sokolow-Lyon voltage was associated with 17 and 25% risk reduction for the composite end point (adjusted hazard ratio (HR) 0.83, 95% confidence interval (95% CI:) 0.75-0.92, P=0.001 per 1050 mm × ms (1 s.d.) lower Cornell product; and HR 0.75, 95% CI: 0.65-0.87, P<0.001 per 10.5 mm (1 s.d.) lower Sokolow-Lyon voltage). In parallel analyses, lower Cornell product and Sokolow-Lyon voltage were associated with lower risks of cardiovascular mortality and MI, and lower Sokolow-Lyon voltage with lower risk of stroke. Lower Cornell product and Sokolow-Lyon voltage during antihypertensive therapy are associated with lower likelihoods of cardiovascular events in patients with ISH.

Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.

BACKGROUND: Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. OBJECTIVE: The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. DESIGN: This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. SETTING: General adult Caucasian population. PARTICIPANTS: The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. MEASUREMENTS: Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. RESULTS: Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. LIMITATION: Further validation in ethnic populations other than Caucasians is needed. CONCLUSION: The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

Clustered metabolic abnormalities blunt regression of hypertensive left ventricular hypertrophy: the LIFE study.

BACKGROUND AND AIMS: Clusters of metabolic abnormalities resembling phenotypes of metabolic syndrome predicted outcome in the LIFE study, independently of single risk markers, including obesity, diabetes and baseline ECG left ventricular hypertrophy (LVH). We examined whether clusters of two or more metabolic abnormalities (MetAb, including obesity, high plasma glucose without diabetes, low HDL-cholesterol) in addition to hypertension were associated to levels of ECG LVH reduction comparable to that obtained in hypertensive subjects without or with only one additional metabolic abnormality (no-MetAb). METHODS AND RESULTS: We studied 5558 non-diabetic participants without MetAb (2920 women) and 1235 with MetAb (751 women) from the LIFE-study cohort. MetAb was defined by reported LIFE criteria, using partition values from the ATPIII recommendations. Time-trends of Cornell voltage-duration product (CP) over 5 years was assessed using a quadratic polynomial contrast, adjusting for age, sex, prevalent cardiovascular disease and treatment arm (losartan or atenolol). At baseline, despite similar blood pressures, CP was greater in the presence than in the absence of MetAb (p<0.0001). During follow-up, despite similar reduction of blood pressure, CP decreased less in patients with than in those without MetAb, even after adjustment for the respective baseline values (both p<0.002). Losartan was more effective than atenolol in reducing CP independently of MetAb. CONCLUSIONS: Clusters of metabolic abnormalities resembling phenotypes of metabolic syndrome are related to greater initial ECG LVH in hypertensive patients with value of blood pressure similar to individuals without metabolic abnormalities, and are associated with less reduction of ECG LVH during antihypertensive therapy, potentially contributing to the reported adverse prognosis of metabolic syndrome.

New risk markers may change the HeartScore risk classification significantly in one-fifth of the population.

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P<0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P<0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P<0.001) (P<0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACR> or =0.73/1.06 mg mmol(-1) or hsCRP> or =6.0/7.3 mg l(-1) identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNP> or =110/164 pg ml(-1) (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients with left ventricular hypertrophy and diabetes.

In type 2 diabetes the degree of albuminuria is strongly related to progression of diabetic renal disease, as well as to the risk for cardiovascular complications. If normoalbuminuria is maintained, the risk of diabetic nephropathy is very low. In individuals with microalbuminuria, the rate of decline in glomerular filtration rate is closely related to the degree of albuminuria, and regression to normoalbuminuria slows down the rate of decline in renal function. Data from the LIFE-diabetes subgroup showed that levels of albuminuria well below what is usually defined as microalbuminuria, strongly predicted risk for cardiovascular complications. This indicates that when albuminuria is used as a risk predictor for cardiovascular events, so called normal values should be redefined. Traditional values for normo-micro-macroalbuminuria are primarily defined as predictors for the risk of development of diabetic nephropathy. In the LIFE-diabetes subgroup we found that reduction in albuminuria was more pronounced in losartan-based as compared with atenolol-based treatment. The benefit in favor of losartan was partly related to its major influence on albuminuria. Individuals with the highest baseline values of albuminuria had the greatest benefit in terms of reduction in cardiovascular morbidity and mortality on losartan as compared with atenolol. The level of albuminuria during treatment was closely related to the risk for cardiovascular events. We conclude that tiny amounts of albuminuria, well below traditional levels for microalbuminuria, predict cardiovascular morbidity and mortality. Reduction in albuminuria during treatment translates to reduction in cardiovascular events. Monitoring of albuminuria should be an integrated part of management of hypertension in diabetic as well as nondiabetic patients.

Impact of the metabolic syndrome on the predictive values of new risk markers in the general population.

Although the metabolic syndrome (MetS) is positively associated with high-sensitivity C-reactive protein (hsCRP), negatively associated with N-terminal pro-brain natriuretic peptide (Nt-proBNP) and inconsequently related to urine albumin/creatinine ratio (UACR) they are all associated with cardiovascular events. Therefore, we wanted to determine the influence of MetS on the predictive values of UACR, hsCRP and Nt-proBNP. On the basis of the definition of MetS by the International Diabetes Federation, a Danish population sample of 1983 apparently healthy subjects was divided into three groups: 530 subjects without any elements of MetS, 1093 subjects with some elements of MetS and 360 subjects with MetS. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (composite cardiovascular end point, CEP) occurred in 204 subjects. In Cox-regression analyses adjusting for age, gender and smoking, all three cardiovascular risk markers predicted CEP independently of MetS. Despite no significant interaction with MetS, high log(hsCRP) was associated with CEP primarily in subjects without any elements of MetS (hazard ratio (HR)=4.5 (1.5-14.0), P<0.01), log(Nt-proBNP) primarily in subjects with some elements of MetS (HR=3.0 (1.6-5.6), P<0.01), and logUACR independently of elements of MetS. Pre-specified gender-adjusted (men/women) cutoff values of hsCRP > or = 6.0/7.3 mg l(-1) predicted CEP in subjects without elements of MetS with positive and predictive values of 11.5 and 98%, respectively. UACR > or = 0.73/1.06 mg mmol(-1) predicted CEP in subjects with MetS with positive and predictive values of 23.5 and 93%, respectively. In apparently healthy subjects, high hsCRP was associated with CEP primarily in subjects without MetS, high Nt-proBNP in subjects with elements of MetS and UACR independently of MetS.