Gender differences in hearts subjected to decreased NO-production and elevated blood pressure

Hypertension is one of the most important risk factors for heart failure in the general population. Hypertensive heart failure is associated with heart failure with preserved ejection fraction (HFpEF). Women have an increase proportion of HFpEF compared to men. Endothelial dysfunction thereby reduced NO production is proposed to play an important role in the pathophysiology of HFpEF. A suggested aetiology is related to cGMP´s important roles in myocardial cells. Females normally have higher constitutively activity of NOS and thereby NO production, an important stimulator of sGC and thereby cGMP. PKG1 is a cGMP-regulated protein that has cardio protective effects in rodents. In this experimental study we wanted to investigate gender differences when NOS was blocked. Adult rats, males, females and ovariectomized females were treated with L-NAME in drinking water for 4 weeks. Blood pressure was measured, and hearts investigated by echocardiography, histology and gene expression analysis at endpoint. MAP increased in all treatment groups; the increase was significantly larger in Males and Females Ovariectomized (OVX) compared to Females. Histological analysis of collagen showed no increase in interstitial or perivascular collagen. Gene expression analysis showed an increase in fibrosis genes, ANF and BNP, most pronounced in Females OVX and intact Females. There was also an isoform shift of MHC, more pronounced in Females OVX. Echocardiography showed a higher relative increase in LV mass in intact Females than Males. There was an increase in LV mass in all treatment groups, but no changes in diastolic or systolic diameter, suggesting concentric remodeling. There were no clinical signs of heart failure in treatment groups and cardiac output was maintained.This study confirm that with loss of NO production females developed more hypertrophy than males independent of blood pressure. Females also tended to have more extreme changes in expression of genes related to heart failure compared to males

Nitric Oxide Precursors and Dimethylarginines as Risk Markers for Accelerated Measured GFR Decline in the General Population

Introduction: Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, atherosclerosis, and chronic kidney disease (CKD). Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. We investigated the association of serum levels of endogenous inhibitors of NO, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), and precursors of NO, arginine, citrulline, and ornithine, with a decline in glomerular filtration rate (GFR) and new-onset CKD. Methods: In a prospective cohort study of 1407 healthy, middle-aged participants of Northern European origin in the Renal Iohexol Clearance Survey (RENIS), GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years. GFR decline rates were analyzed using a linear mixed model, new-onset CKD (GFR < 60 ml/min per 1.73 m2 ) was analyzed with interval-censored Cox regression, and accelerated GFR decline (the 10% with the steepest GFR decline) was analyzed with logistic regression. Results: Higher SDMA was associated with slower annual GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline (odds ratio [OR], 1.43; 95% confidence interval [CI] 1.16–1.76 per SD higher citrulline and OR 1.23; 95% CI 1.01 to 1.49 per SD higher ornithine). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.33 (95% CI 1.07–1.66) per SD higher citrulline. Conclusions: Associations between NO precursors and the outcomes suggest that NO metabolism plays a significant role in the pathogenesis of age-related GFR decline and the development of CKD in middleaged people

Overweight modifies the longitudinal association between uric acid and some components of the metabolic syndrome: The Tromsø Study

Published version. Source at http://dx.doi.org/10.1186/s12872-016-0265-8 Background: Elevated uric acid (UA) is associated with the presence of the metabolic syndrome (MetS). In a prospective cohort study, we assessed whether baseline and longitudinal change in UA were risk factors for development of MetS and its individual components. Methods: We included 3087 women and 2996 men who had UA measured in the population based Tromsø Study 1994–95. The participants were stratified according to body mass index (BMI). Endpoints were MetS and each component of the syndrome after 7 years, according to the revised National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATP III) definition. Results: Multiple logistic regression analyses showed that higher baseline UA was associated with higher odds of developing elevated blood pressure in overweight subjects (BMI ≥ 25 kg/m2, odds ratio [OR] per 59 μmol/L UA increase 1.44, 95 % confidence interval [CI] = 1.17–1.77, P = 0.001), but not in normal-weight subjects (BMI Conclusion: Increased levels of baseline UA independently predicted development of elevated blood pressure and higher fasting glycemia in the overweight, but not the normal-weight subjects. Baseline UA and longitudinal increase in UA over 7 years was associated with the development of MetS in all subjects. Whether increased UA should be treated differently in normal-weight and overweight persons needs further study

Sex Differences in Age-Related Loss of Kidney Function

Background - CKD is more prevalent in women, but more men receive kidney replacement therapy for kidney failure. This apparent contradiction is not well understood. Methods - We investigated sex differences in the loss of kidney function and whether any sex disparities could be explained by comorbidity or CKD risk factors. In the Renal Iohexol Clearance Survey (RENIS) in northern Europe, we recruited 1837 persons (53% women, aged 50–62 years) representative of the general population and without self-reported diabetes, CKD, or cardiovascular disease. Participants’ GFR was measured by plasma iohexol clearance in 2007–2009 (n=1627), 2013–2015 (n=1324), and 2018–2020 (n=1384). At each study visit, healthy persons were defined as having no major chronic diseases or risk factors for CKD. We used generalized additive mixed models to assess age- and sex-specific GFR decline rates. Results - Women had a lower GFR than men at baseline (mean [SD], 90.0 [14.0] versus 98.0 [13.7] ml/min per 1.73 m2; P2 per year in women and −1.20 (95% confidence interval [CI], −1.12 to −1.28) in men. Although the relationship between age and GFR was very close to linear in women, it was curvilinear in men, with steeper GFR slopes at older ages (nonlinear effect; P Conclusion - Among middle-aged and elderly individuals in the general population, decline in the mean GFR in women was slower than in men, independent of health status. CKD is projected to become the fifth leading cause of years of life lost in 2040. In most countries, more women than men develop CKD stage G3, which is defined as a reduced GFR, whereas more men start RRT. This apparent contradiction is poorly understood, but proposed explanations include gender disparities in access to health care and RRT, biologic differences between women and men leading to different GFR decline rates, bias in creatinine-based formulas to estimate the GFR, and overestimation of the CKD prevalence in women. In addition, sex and gender disparities in health status could cause differences in GFR loss. For example, women have a lower prevalence of myocardial infarction and a longer life expectancy than men. However, although cross-sectional population studies have found a higher mean GFR in healthy than in unhealthy persons, it is unknown whether good health is associated with preserved GFR during aging at the individual level, and whether this can explain the sex difference in CKD prevalence. Population-based longitudinal studies with repeated assessments of GFR in the same individuals are necessary to investigate the associations between sex, health status, and age-related GFR decline. The few existing studies on GFR change rates were not population based, did not investigate the association with health status, or used equations to calculate the eGFR on the basis of endogenous substances. These eGFR equations are biased by non–GFR-related factors, such as muscle mass, affecting men and women differently, particularly during aging. Measurements of GFR by an exogenous filtration marker, e.g., iohexol, avoid these methodologic problems. Accordingly, we investigated age- and sex-specific GFR decline rates in the Renal Iohexol Clearance Survey (RENIS), which is the only general population cohort with repeated measurements of GFR.The aim of the study was to report a reference range for age-related GFR decline in the general population and to investigate possible sex disparities in GFR decline rates by health status

Uric acid and adiponectin in cardiovascular disease

Uric acid, a product of metabolism, was discovered a quarter of a millennium ago and has been known to be a possible cardiovascular risk factor for well over a century. A much newer discovery, adiponectin, was discovered only a little more than 20 years ago as a protein hormone secreted by adipose tissue and has attracted substantial attention for its association with cardiovascular disease. This thesis will examine the modifying action of overweight on the relationship between uric acid levels and metabolic syndrome, the association between uric acid levels and adverse cardiovascular events and mortality in subjects with or without diastolic dysfunction, and the sex-specific association between adiponectin levels and diastolic dysfunction. In addition, this thesis will determine whether a relevant interaction between uric acid and adiponectin exists with respect to diastolic dysfunction. Paper 1, a seven-year prospective study with over 6,000 participants, examines whether overweight modifies the association between the uric acid levels and metabolic syndrome. In overweight but not normal-weight subjects, the baseline uric acid levels predicted the development of elevated blood pressure and elevated fasting glucose levels. The baseline uric acid levels and changes in the uric acid levels over seven years predicted metabolic syndrome and most of its components. A 19-year prospective study of 1,460 women and 1,480 men with endpoints of all-cause mortality, incident myocardial infarction and incident ischaemic stroke is described in Paper 2. Uric acid levels were a predictor of all-cause mortality in subjects with echocardiographic markers of diastolic dysfunction but not in subjects without these markers. Uric acid levels were a stronger predictor of incident ischaemic stroke in subjects with severely enlarged atria than in subjects with normal-sized atria. Paper 3 describes a cross-sectional study of 1,165 women and 896 men and the sex-specific relationship between adiponectin levels and diastolic dysfunction. Lower adiponectin levels were associated with greater odds of echocardiographic indices of diastolic dysfunction in women but lower odds of diastolic dysfunction in men. Additionally, lower adiponectin levels were associated with a higher left ventricular mass in women only. An interaction between uric acid and adiponectin levels was not observed for any marker of diastolic dysfunction. These findings support an association between uric acid levels and increased cardiovascular risk, with detrimental effects observed in subjects who already present a state of metabolic derangement and an elevated risk, such as overweight persons and subjects with diastolic dysfunction. Furthermore, adiponectin levels, and thus adipose tissue function, may provide a clue to why heart failure with preserved ejection fraction shows a female preponderance

Antibiotikaforeskrivning hos norske allmennpraktikere: en kvalitativ studie

Norges allmennpraktikere er restriktive i sin antibiotikaforeskrivning. Denne studien ser på årsaken til deres restriktive holdning ved hjelp av den kvalitative metode. Studien baserer seg på intervjuer av sju norske allmennleger som er transkriberte og analyserte. Det blir vist at en restriktiv holdning til antibiotika blir sett på som en positiv verdi blant allmennpraktikerne, og den eneste faktoren utenfor pasienten som påvirker foreskrivningen er CRP-testen

Gender differences in hearts subjected to decreased NO-production and elevated blood pressure

Hypertension is one of the most important risk factors for heart failure in the general population. Hypertensive heart failure is associated with heart failure with preserved ejection fraction (HFpEF). Women have an increase proportion of HFpEF compared to men. Endothelial dysfunction thereby reduced NO production is proposed to play an important role in the pathophysiology of HFpEF. A suggested aetiology is related to cGMP´s important roles in myocardial cells. Females normally have higher constitutively activity of NOS and thereby NO production, an important stimulator of sGC and thereby cGMP. PKG1 is a cGMP-regulated protein that has cardio protective effects in rodents. In this experimental study we wanted to investigate gender differences when NOS was blocked. Adult rats, males, females and ovariectomized females were treated with L-NAME in drinking water for 4 weeks. Blood pressure was measured, and hearts investigated by echocardiography, histology and gene expression analysis at endpoint. MAP increased in all treatment groups; the increase was significantly larger in Males and Females Ovariectomized (OVX) compared to Females. Histological analysis of collagen showed no increase in interstitial or perivascular collagen. Gene expression analysis showed an increase in fibrosis genes, ANF and BNP, most pronounced in Females OVX and intact Females. There was also an isoform shift of MHC, more pronounced in Females OVX. Echocardiography showed a higher relative increase in LV mass in intact Females than Males. There was an increase in LV mass in all treatment groups, but no changes in diastolic or systolic diameter, suggesting concentric remodeling. There were no clinical signs of heart failure in treatment groups and cardiac output was maintained.This study confirm that with loss of NO production females developed more hypertrophy than males independent of blood pressure. Females also tended to have more extreme changes in expression of genes related to heart failure compared to males

Assessment of otoscopy: how does observation compare to a review of clinical evidence?

Background and Purpose: To investigate how much the method of observation agrees with a standardised review of evidence of clinical examination, for the assessment of clinical otoscopic competence. Methods: 65 medical students took part in an Objective Structured Clinical Examination (OSCE) station using patients with real pathology. Examiners assessed otoscopic competency in tympanic membrane examination solely by distant observation. An external examiner later reviewed candidates’ documented findings on a schematic drawing of the tympanic membranes. Observed agreement of the two methods and Cohen’s kappa coefficient were calculated. Results: Mean otoscopy scores for examiner 1 and examiner 2 were 67.7% and 29.4% respectively. There was a significant difference using the Mann-Whitney U-test. OSCE observation declared 47.7% of candidates (31/65) to be clinically competent. Drawing-based analysis however deemed only 4.6% (3/65) to have achieved this competency. This represented more than a ten-fold overestimation of clinical competency by OSCE assessment. Observed agreement between assessment methods was 59.6%. Cohen’s kappa coefficient was 0.1. Conclusions: OSCE observational assessment of otoscopic clinical competency correlates poorly with review of evidence from clinical examination. If evidence review is acceptable as a better marker for competency, observation should not to be used alone in OSCE assessment. Evidence review itself is vulnerable to candidate guesswork. OSCE could possibly explore candidate demonstration with explanation of findings, by use of digital otoscopy offering a shared view of the tympanic membranes, as an improved standard of clinical competency assessment

Associations of urinary orosomucoid, N-acetyl-β-D-glucosaminidase, and albumin with blood pressure and hypertension during 7 years of follow-up. The Tromsø Study

Purpose: Subclinical chronic kidney disease is known to exacerbate hypertension and progression of kidney damage. In order to initiate timely interventions, early biomarkers for this vicious circle are needed. Our aim was to describe the cross-sectional associations of urinary orosomucoid and urinary N-acetyl-b-D-glucosaminidase (NAG) with blood pressure and the longitudinal associations of urinary orosomucoid and NAG to hypertension after 7 years, and to compare the strength of these associations to the urinary albumin excretion (UAE). Material and methods: The Tromsø Study is a population-based, prospective study of inhabitants of the municipality of Tromsø, Northern Norway. Morning spot urine samples were collected on three consecutive days in the Tromsø 6 survey (2007–2008). We assessed the crosssectional associations of urinary orosomucoid, NAG and UAE with blood pressure in Tromsø 6. In a cohort of participants attending Tromsø 6 and Tromsø 7 (2015–2016), we studied whether urinary biomarkers were longitudinally associated with hypertension. Results: A total of 7197 participants with a mean age of 63.5 years (SD 9.2), and a mean blood pressure of 141/78 mmHg (SD 23.0/10.6), were included in the study. Orosomucoid and UAE, but not NAG, was significantly associated with systolic and diastolic blood pressure in all the crude and multivariable cross-sectional analyses. Orosomucoid had consistently, although marginally, stronger associations with blood pressure. Incident hypertension at follow-up (Tromsø 7) was consistently significantly associated with urinary orosomucoid, but not urinary NAG or UAE. However, the standardized regression coefficients for orosomucoid were only marginally stronger than the standardized regression coefficients for ACR. Conclusion: In a cohort from the general population urine orosomucoid had a stronger crosssectional association with blood pressure than UAE. After 7 years, urine orosomucoid showed the strongest association with incident hypertension. There were varying and weak associations between U-NAG, blood pressure and hypertension

The Association between Urinary Sodium-Potassium Ratio, Kidney Function, and Blood Pressure in a Cohort from the General Population

Introduction: Subclinical kidney dysfunction may contribute to salt-sensitive hypertension. We assessed the association between the urinary sodium-potassium ratio (Na/K ratio) and blood pressure (BP) in a general population cohort without diabetes, chronic kidney disease, cardiovascular disease, or treated hypertension. We investigated whether any such association was mediated by the kidney function markers measured glomerular filtration rate (mGFR), urinary albumin-creatinine ratio (ACR), and urinary epidermal growth factor-creatinine ratio (EGF-Cr). Methods: The Tromsø Study is a population-based study of inhabitants of the municipality of Tromsø, Northern Norway. Participants aged 50–62 years, without diabetes, chronic kidney disease, or cardiovascular disease, were invited to the substudy Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6; 2007–09). For the present study, we excluded participants reporting the use of 1 or more antihypertensive agents, leaving 1,311 RENIS-T6 participants for a cross-sectional analysis. We measured office BP, 24-h ambulatory blood pressure (ABP), and mGFR using iohexol clearance. Na/K ratio, ACR, and EGF-Cr were measured in morning urine samples. Results: Urinary Na/K ratio was significantly associated with systolic office BP and ABP independently of cardiovascular risk factors and kidney function markers. A one-standard deviation unit increase in the Na/K ratio was associated with increased systolic ABP by 1.0 (0.3–1.6) mm Hg. Urinary Na/K ratio showed a stronger association with office BP than ABP. EGF-Cr, ACR, and mGFR did not mediate the relationship between urinary Na/K ratio and systolic BP. Conclusions: In a representative sample of the middle-aged North-European population without diabetes, chronic kidney disease, cardiovascular disease, or treated hypertension, there was a consistent association between urinary Na/K ratio and BP. The association with BP was not mediated through kidney function measures, suggesting a relationship between a diet with high sodium and low potassium and higher BP regardless of kidney function