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  • 1. Carlsson, Axel C
    et al.
    Larsson, Anders
    Helmersson-Karlqvist, Johanna
    Lind, Lars
    Ingelsson, Erik
    Larsson, Tobias E
    Sundström, Johan
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Urinary kidney injury molecule 1 and incidence of heart failure in elderly men2013In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 15, no 4, p. 447-446Article in journal (Refereed)
    Abstract [en]

    AIMS: There is growing recognition of the clinical importance of cardiorenal syndrome-the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk.

    METHODS AND RESULTS: This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01-3.29; P < 0.05). Participants with a combination of low GFR (<60 mL/min/1.72 m(2)) and high KIM-1/creatinine (>128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 (P < 0.001).

    CONCLUSION: Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.

  • 2. Fall, Tove
    et al.
    Shiue, Ivy
    Bergeå Af Geijerstam, Per
    Sundström, Johan
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Larsson, Anders
    Melhus, Håkan
    Lind, Lars
    Ingelsson, Erik
    Relations of circulating vitamin D concentrations with left ventricular geometry and function2012In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 14, no 9, p. 985-991Article in journal (Refereed)
    Abstract [en]

    AIMS: Vitamin D deficiency has been associated with risk of overt cardiovascular disease (CVD), but associations with subclinical disease are not well characterized. Hence, we examined associations of circulating vitamin D concentrations and left ventricular (LV) geometry and function by echocardiography at baseline and after 5 years in a community-based study.

    METHODS AND RESULTS: In the PIVUS study, we measured serum 25-dihydroxyvitamin-D (25-OH D) at age 70 and performed echocardiography including LV mass, wall thickness, end-diastolic diameter, end-systolic diameter (LVESD), left atrial diameter, fractional shortening, ejection fraction, isovolumic relaxation time, and E/A ratio at both age 70 and 75. We included 870 participants (52% women) without prior myocardial infarctions, heart failure, or prevalent valvular disease. After adjusting for potential confounders, 25-OH D at baseline was found to be significantly associated with LVESD, fractional shortening, and ejection fraction (β, -0.42 mm, P = 0.03; β, 0.70%, P = 0.03; and β, 0.91% P = 0.01, respectively), per 1 SD increase in 25-OH D (SD = 20 nmol/L) at baseline. In longitudinal analyses, vitamin D levels at baseline were not significantly associated with change in LV geometry and function after 5 years. CONCLUSION: In our community-based study among the elderly, we found higher circulating vitamin D concentrations to be associated cross-sectionally with better LV systolic function and smaller LVESD at baseline. The association persisted after adjusting for several potential confounders, including cardiovascular risk factors and calcium, phosphate, and parathyroid hormone levels. Randomized clinical trials are needed to establish firmly or refute a causal relationship between vitamin D levels and changes in LV geometry and function.

  • 3. Ganna, Andrea
    et al.
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    de Faire, Ulf
    Reilly, Marie
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden.
    Sundström, Johan
    Hamsten, Anders
    Ingelsson, Erik
    Multilocus genetic risk scores for coronary heart disease prediction2013In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, no 9, p. 2267-2272Article in journal (Refereed)
    Abstract [en]

    Objective. Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. 

    Approach and Results. We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. 

    Conclusions. Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.

  • 4. Hagström, E
    et al.
    Hellman, P
    Larsson, T
    Ingelsson, E
    Berglund, L
    Sundström, J
    Melhus, H
    Held, C
    Lind, L
    Michaelsson, K
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Plasma parathyroid hormone and the risk of cardiovascular mortality in the community2009In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 119, no 21, p. 2765-2771Article in journal (Refereed)
    Abstract [en]

    Background: Diseases with elevated levels of parathyroid hormone (PTH) such as primary and secondary hyperparathyroidism are associated with increased incidence of cardiovascular disease and death. However, data on the prospective association between circulating PTH levels and cardiovascular mortality in the community are lacking.

    Methods and Results: The Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (mean age, 71 years; n=958), was used to investigate the association between plasma PTH and cardiovascular mortality. During follow-up (median, 9.7 years), 117 participants died of cardiovascular causes. In Cox proportional-hazards models adjusted for established cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease), higher plasma PTH was associated with higher risk for cardiovascular mortality (hazard ratio for 1-SD increase in PTH, 1.38; 95% confidence interval, 1.18 to 1.60;P<0.001). This association remained essentially unaltered in participants without previous cardiovascular disease and in participants with normal PTH (<6.8 pmol/L) with no other signs of a disturbed mineral metabolism (normal serum calcium, 2.2 to 2.6 mmol/L; normal glomerular filtration rate, >50 mL · min−1 · 1.73 m−2 and without vitamin D deficiency, plasma 25-OH vitamin D >37.5 nmol/L). Interestingly, elevated plasma PTH (>5.27 pmol/L) accounted for 20% (95% confidence interval, 10 to 26) of the population-attributable risk proportion for cardiovascular mortality.

    Conclusions: Plasma PTH levels predict cardiovascular mortality in the community, even in individuals with PTH within the normal range. Further studies are warranted to evaluate the clinical implications of measuring PTH in cardiovascular risk prediction and to elucidate whether PTH is a modifiable risk factor.

  • 5. Hållmarker, Ulf
    et al.
    Michaëlsson, Karl
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    James, Stefan
    Cardiac arrest in a long-distance ski race (Vasaloppet) in Sweden2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 15, p. 1431-1432Article in journal (Refereed)
  • 6. Ingelsson, E
    et al.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, J
    Risérus, U
    Michaelsson, K
    Byberg, L
    Relative importance and conjoint effects of obesity and physical inactivity for development of insulin resistance.2009In: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, no 1, p. 28-33Article in journal (Refereed)
  • 7.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Risérus, Ulf
    Ingelsson, Erik
    Helmersson, Johanna
    Nerpin, Elisabet
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men2009In: European Society of Cardiology Congress, Uppsala, 2009Conference paper (Other academic)
    Abstract [en]

    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men Conclusion: Higher serum levels of Cathepsin S were independently associated with higher CRP and IL-6 in a community– based sample of elderly men. Our data provides support for the notion that Cathepsin S is involved in inflammatory processes, possibly leading to atherosclerosis and cardiovascular disease. Background: Cathepsin S is a lysosomal protease that has been suggested to play a key role in the development of atherosclerosis and cardiovascular disease by degradation of vascular extracellular matrix. Previous studies have suggested that cathepsin S provides a molecular link between obesity and atherosclerosis, possibly via increased inflammatory activity. Yet, the association between circulating cathepsin S and inflammation markers has not previously been reported in the community. Aim: To investigate the association between plasma levels of cathepsin- S, C-reactive protein (CRP) and Interleukin 6 (IL-6), in the community. Methods: Serum levels of cathepsin S, CRP, IL-6 were measured in frozen samples from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (n=999, mean age 71 years). Results: Cross-sectional association between Cathepsin S, CRP and IL-6 at age 70 showed that one standard deviation (SD) higher serum Cathepsin S was significantly associated with 0.14 SD higher serum CRP and 0.07-0.08 SD higher serum IL-6 when adjusting for age, life style factors (body mass index, physic activity and smoking), cardiovascular risk factors (hypertension, dyslipidemia, previous cardiovascular disease and diabetes and smoking), and the combination of all covariates

  • 8.
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    The kidney in different stages of the cardiovascular continuum2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum.

    The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death.

    This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).

    The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress.

    In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease.

    Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

  • 9.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Helmersson-Karlqvist, Johanna
    Sundström, Johan
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Association between glomerular filtration rate and endothelial function in an elderly community cohort2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 1, p. 242-246Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Endothelial dysfunction is prevalent among individuals with chronic kidney disease. However, the association between glomerular filtration rate and endothelial function in the community is unclear and needs to be investigated in the general population.

    METHODS: In the community-based Prospective Investigation of the Vasculature of Uppsala Seniors study (PIVUS, n = 952, mean age 70, women 49.3%), we investigated cross-sectional associations between estimated cystatin C-based glomerular filtration rate (eGFR), and 3 measures representing different aspects of endothelial function (endothelial-dependent vasodilation [EDV], endothelial independent vasodilatation [EIDV], and flow-mediated dilatation [FMD]). We also performed pre-specified sub-group analyses in participants with normal eGFR (>60 ml/min/1.73 m(2)).

    RESULTS: In the whole cohort, 10 ml/min/1.73 m(2) higher eGFR was associated with 3% higher EDV (p = 0.001) and 2% higher EIDV (p = 0.007), adjusted for age and sex. The associations were attenuated and no longer statistically significant after adjusting for established cardiovascular risk factors. In participants with eGFR >60 ml/min/1.73 m(2), 10 ml higher eGFR was associated with 2% higher EDV (p = 0.04) after adjusting for sex and age. eGFR was not associated to FMD in any model or sub-sample.

    CONCLUSION: This community-based study suggests that eGFR is associated with endothelial function also in persons with normal kidney function, but that this association is largely explained by confounding by established cardiovascular risk factors. Thus, our data do not support the notion of a direct causal interplay between renal and vascular function prior to the development of CKD.

  • 10.
    Strömsöe, Anneli
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Förbättrade resultat för patienter som drabbats hjärtstopp utanför sjukhus – en uppföljning från 1992 till 20112013Conference paper (Refereed)
    Abstract [sv]

    Syfte: Att beskriva patienter som drabbats av hjärtstopp utanför sjukhus och dess resultatsförändringar i behandling och överlevnad.

    Metod: Patienter (n=59 926) som drabbats av hjärtstopp utanför sjukhus i samtliga Sveriges län och som rapporterats till Svenska hjärt-lungräddningsregistret från 1992 till 2011.

    Resultat: Antalet rapporterade hjärtstopp utanför sjukhus ökade från 27 (1992) till 52 (2011) per 100 000 invånare och år. Vidare så ökade bevittnandegraden av hjärtstopp utanför sjukhus av ambulanspersonalen, en ökad förekomst av hjärtlungräddning innan ambulansen kom fram till patienten samt att tiden ökade från larm till dess att ambulansen kom fram till patienten.

    1-månads-överlevnad ökade från 4,8% (1992) till 10,7% (2011). De som framförallt överlevde 1 månad eller mer var de patienter som levde vid ankomst till sjukhus. Av de patienter som drabbats av hjärtstopp utanför sjukhus mellan 2008 till 2010, var det 41% som genomgick kylbehandling på sjukhus samt 28% som behandlades med ballongvidgning av hjärtats kranskärl. De patienter som överlevde (2008-2011), hade 94% en god eller relativ god hjärnfunktion.

    Sammanfattning: De patienter som drabbats av hjärtstopp utanför sjukhus 1992-2011, påvisar en fördubblad överlevnad. De patienter som framförallt överlever, är de som lever vid ankomst till sjukhus och som senare läggs in på vårdavdelning.   

  • 11.
    Strömsöe, Anneli
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Validity of reported data in the out-of-hospital cardiac arrest register in chosen parts in Sweden: [HLR-registrets tillförlitlighet]2013Conference paper (Refereed)
    Abstract [en]

    Aim: To describe differences between reported and non reported data in the out-of-hospital cardiac arrest (OHCA) register in Sweden.

    Methods: Prospective and retrospective data of treated OHCA patients in Sweden, 2008-2010 were compared in the Swedish OHCA register. Data were investigated in three Swedish counties with various recording models. Prospective data are those reported by the ambulance crew and retrospective data those missed by the ambulance crew but discovered afterwards by crosschecking with the local ambulance register.

    Result: In 2008-2010, the number of prospective reported cases was n=2, 398 and retrospective cases n=3, 198 which indicates a 25% missing rate.

    When comparing the two groups, the mean age was higher in patients who were reported retrospectively (69 years versus 67 years; p=0.003). There was no difference between groups with regard to sex, time of day and year of OHCA, witnessed status or initial rhythm.

    However, bystander CPR was more frequent among patients in who were reported prospectively (65% versus 60%; p= 0.023) where as survival to 1 month was higher among patients who were reported retrospectively (9,2% versus 11,9%;p=0.035)

     

    Conclusion: Among 3, 198 cases of OHCA in three regions in Sweden 800 (25%) were not reported prospectively by the ambulance crew but retrospectively when discovered as missing cases. Patients who were reported retrospectively differed from prospectively reported cases by being older, less frequently receiving bystander CPR but having a higher survival. Our data suggest that patients who suffer OHCA and are prospectively reported to a quality register may be influenced by selection bias.

  • 12.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Cathepsin S as a biomarker: where are we now and what are the future challenges2012In: Biomarkers in Medicine, ISSN 1752-0363, Vol. 6, no 1, p. 9-11Article, review/survey (Refereed)
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