BACKGROUND AND AIMS:Statins and other lipid-modifying agents (LMAs) have traditionally been contraindicated during pregnancy due to concerns about harmful fetal effects; however, the risks associated with exposure to statins and other LMAs in human pregnancies remain unclear. Therefore, this study aimed to examine the associations between statin and LMA exposure in pregnancy and congenital malformations in offspring, while updating a 2022 meta-analysis with the results from the present study. METHODS:National registry data were linked for all pregnant women in Norway in 2005-18. Associations between first-trimester statin prescription fills and congenital malformations were estimated with mixed-effects logistic regression, adjusting for age, parity, pre-pregnancy folate use, smoking in early pregnancy, comorbidity, and co-medication. Meta-analyses were performed with the generic inverse-variance method and random-effects model. RESULTS:Congenital malformations occurred among 34 755 out of 803 830 (4.3%) statin non-exposed pregnancies, 74 out of 1255 (5.9%) statin-discontinuer pregnancies, and 19 out of 283 (6.7%) statin-exposed pregnancies. Adjusted odds ratios (ORs) for exposed vs non-exposed pregnancies were 1.30 [95% confidence interval (CI) .81-2.09] for any, 1.15 (.61-2.19) for major, and 1.47 (.75-2.89) for minor malformations. In analyses of exposed vs discontinuer pregnancies, there were no associations between statin exposure and any (adjusted OR 1.01, 95% CI .59-1.72), major (1.08, .52-2.25), or minor malformations (.94, .44-2.00). Results were similar across sensitivity analyses. There was also no association between any LMA exposure and heart malformations (adjusted OR 1.22, 95% CI .50-3.01). The updated meta-analysis suggested no increased risk of major (adjusted OR 1.06, 95% CI .86-1.31) or heart malformations (1.24, 95% CI .94-1.64). CONCLUSIONS:In this large, nationwide study and updated meta-analysis, no significant association was observed between first-trimester exposure to statins or other LMAs and congenital malformations. Although limited power may have prevented detection of weak but clinically relevant associations, the findings do not support a strong or independent association between statin exposure in pregnancy and congenital malformations.

AIM:The randomized controlled Cardiovascular Risk Reduction Diet in Pregnancy (CARRDIP) study demonstrated that a Mediterranean diet during pregnancy could alter maternal lipid levels, improve fetoplacental perfusion, and reduce preterm delivery rate. Here, we examine whether the intervention affected the children 3 years after the CARRDIP study. METHODS:Healthy pregnant women with no previous pregnancy complications were randomized to follow either a Mediterranean diet or their habitual diet during pregnancy. At 3 years of age, offspring blood pressure, heart rate, weight, and height were measured. Dietary intake was assessed using a food frequency questionnaire. RESULTS:Out of 269 mothers who completed the original study, 180 responded to the dietary assessment and 154 children attended the physical examination. There were no significant differences in blood pressure or anthropometric measurements between the children in the intervention (n = 69) and control (n = 85) groups. There was a lower intake of sugary beverages and sweets by the children in the intervention group compared to the control group. CONCLUSION:The Mediterranean diet intervention in pregnancy did not translate into differences between intervention and control group regarding blood pressure or anthropometrics in their offspring at the 3-year follow-up, although minor differences in children's diets were observed. TRIAL REGISTRATION:The CARRDIP study is registered in Clinicaltrials.gov (ID: NCT05030922).

BACKGROUND AND AIMS:Sparse data exist on the risk of adverse pregnancy outcomes in women with familial hypercholesterolemia (FH). We investigated associations between FH and adverse pregnancy outcomes, and between statin exposure in pregnancy and adverse pregnancy outcomes among women with FH. METHODS:We studied 3869 pregnancies among 1869 women with genetically-proven FH and 68225 pregnancies among 33661 women from the general population. Data on adverse pregnancy outcomes were obtained during 1967-2018 from the Medical Birth Registry of Norway. Data on pharmacy-dispensed statins were obtained from the Norwegian prescription database (2004-2018) in 1051 women with FH. Associations were presented as odds ratio (OR) with 95 % CI from logistic regression adjusted for mother's age, parity, and offspring's birth year. RESULTS:Women with FH had a higher risk of preeclampsia (OR 1.21 [1.00-1.46]), but lower risk for gestational diabetes (OR 0.58 [0.36-0.92]) and intrapartum hemorrhage during delivery (OR 0.81 [0.71-0.92]) compared to controls. No excess risk of adverse pregnancy outcomes in offspring was observed for FH. Among women with FH, statin exposure (mainly in the first trimester) may be associated with higher risk of low birth weight in offspring born at term (OR 2.42 [0.51, 11.45]). CONCLUSIONS:Women with FH had lower risk of gestational diabetes and intrapartum hemorrhage, but a higher risk of preeclampsia compared to controls. No adverse birth outcomes were observed for offspring of mothers with FH, but the association between statin exposure in pregnant women with FH and low birth weight in offspring warrants further study.

Exposure to air pollution and an unhealthy built environment increase disease risk by impacting metabolic risk factors and inflammation, potentially via epigenetic modifications and effects on gene expression. We aimed to explore associations between fine particulate matter (PM2.5), black carbon, ozone, nitrogen dioxide, distance to nearest water body, normalized difference vegetation index, and impervious surface and gene expression profiles in adults. This study is a part of the LongITools project and includes cross-sectional data from the Rotterdam Study, a population-based cohort study, and NoMa, a randomized controlled trial. Environmental exposures were assigned using land-use regression (LUR) models and satellite data. Gene expression was assessed with whole blood RNA sequencing (Rotterdam Study, n = 758) and microarray analyses in peripheral blood mononuclear cells (NoMa, n = 100). We analysed transcriptomic profiles and enriched pathways associated with each of the environmental exposures. PM2.5 had the strongest gene expression associations, while only a few significant associations were observed for the other environmental exposures. In both populations, exposure to PM2.5 was associated with genes and pathways related to inflammation, oxidative stress, DNA metabolism, cell cycle regulation, histones, electron transport chain, oxidative phosphorylation, and neural signalling. This study is limited by different methods for RNA quantification, a cross-sectional design, and a small sample size. However, in both populations, exposure to PM2.5 resulted in the maximum number of associations with gene expression. In conclusion, PM2.5 is strongly associated with various gene expression profiles, which provide information about the underlying mechanisms of the detrimental health effects of exposure to PM2.5.

BACKGROUND AND AIMS:Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear. METHODS:Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD. RESULTS:Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations. CONCLUSIONS:Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.

Aims:Investigation of cardiovascular disease (CVD), all-cause death and use of statins and ezetimibe among young Norwegian individuals with heterozygous Familial hypercholesterolemia (FH). Methods:We included subjects with genetically verified FH born 1988-2008 and twenty controls per FH subject, with linkage to prescription data, hospitalization data and cause of death from national Norwegian health registries. Data on CHD and death during 2008-2018, and for dispensed prescriptions during 2004-2018, were collected. Results:1351 subjects with FH and 27,015 controls were included. Mean age (SD) at start of follow-up was 12.3 (5.4) years. There was one Coronary Heart Disease (CHD) event and 6 deaths in the FH-group and 3 CHD events and 53 deaths in the control group. CHD and all-cause death were non-significantly increased in the FH-group, hazard ratios (95 % confidence intervals) 6.68 (0.69-64.20) and 2.26 (0.98-5.28), respectively. None of the deaths in the FH-group were related to cardiovascular disease. 83 % of subjects with FH had been prescribed a statin, and 21 % ezetimibe. During the first year after the first prescription, 18.5 % of subjects did not refill their prescription within 180 days after the end date of the previous prescription. 69 % and 60 % of subjects with a prescription had >80 % of days covered with statins and ezetimibe, respectively. After 8 years, around 70 % of subjects were covered with statins. Conclusions:Results suggest increased risk of CHD in FH relative to controls, but measures are imprecise because of low absolute risks. Compliance with lipid lowering therapy was moderate.

BACKGROUND AND AIMS:Cholesterol screening in children, with subsequent genetic testing of top percentile, has been suggested as an efficient universal screening approach in familial hypercholesterolaemia (FH). The potential cholesterol-based screening efficacy was investigated in a national genetically based screening programme. METHODS:Data were from the Norwegian national family cascade screening programme in FH children from 1998 to 2023. Cholesterol levels [umbilical cord in newborns (n = 113) and venous blood in children 1-12 years old (n = 1346)] in variant positive and variant negative children were compared. RESULTS:LDL cholesterol (LDL-C) was higher in FH newborns vs non-FH newborns [1.22 (.48) vs .68 (.32) mmol/L, P < .001], but overlapped widely. Cut-off levels corresponding to the 95th and 85th percentile would only identify 55.7% and 75.4% of newborns with FH, respectively. Screening efficacy in newborns did not differ in subgroups: boys and girls, null and non-null variants, variant gene, and neither for total cholesterol nor for non-HDL cholesterol. In all other age groups (from 1 to 12 years), LDL-C discriminated highly between mutation FH and non-FH children. Cut-off levels corresponding to 95th and 85th percentile of LDL-C would identify 88.4% and 94.1% of 1-12-year-old children with FH, respectively. CONCLUSIONS:Previous studies investigating lipid or genetic screening approaches for FH have limitations of only performing genetic testing in children with high LDL-C levels. The present study is the first to show the true LDL-C overlap in children with FH vs non-FH by utilizing unique data from a national family cascade screening programme. Cholesterol-based screening approaches for FH only seem feasible from 1 year of age onward.

Background and aims: There is limited data regarding the vitamin D status of infants and young children in Norway. We aimed to assess vitamin D status among Norwegian children at approximately 6 and 12 months of age and explore associations between child vitamin D status, dietary factors, and maternal vitamin D status. Methods: Mothers/parents completed a food frequency questionnaire for their 6/12-month-old child. Dried blood spot samples were collected from the mother and child. Results: The mean serum 25-hydroxyvitamin D (S-25(OH)D) concentration was 81 nmol/L (standard deviation [SD] 22 nmol/L) for 6-month-old children (n = 84) and 72 nmol/L (SD 22 nmol/L) for 12-month-old children (n = 56) (P = 0.03 for difference between age groups). In the younger and older age groups, 94 and 88% of the children, respectively, had a S-25(OH)D concentration ≥ 50 nmol/L. The mean dietary vitamin D intake was 12 μg/day for the 6-month-olds and 14 μg/day for the 12-month-olds. Adjusted linear regression models showed that for every μg/day increase in dietary vitamin D intake, serum 25(OH)D (nmol/L) increased by around one nmol/L for both age groups (P = 0.002 for the younger age group and P = 0.04 for the older age group). Use of vitamin D supplements was associated with higher S-25(OH)D concentrations in both age groups, while a higher S-25(OH)D concentration among formula users was found only in the youngest age group. Breastfeeding was not associated with S-25(OH)D concentration in either age group. Small positive correlations between child and maternal vitamin D status were observed for both the younger (r = 0.22) and the older (r = 0.28) age groups (P = 0.04 for both groups). Conclusion: While there was a wide range in S-25(OH)D concentrations among children, most were within the sufficient range. Adequate vitamin D intake should be encouraged both in the first and second year of life.

Unhealthy dietary patterns are a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). International guidelines recommend reducing saturated fatty acid intake while increasing polyunsaturated and monounsaturated fatty acids (MUFAs) to mitigate cardiovascular risk. However, evidence regarding MUFAs and risk of ASCVD remains conflicting, with recent studies raising concern about a potential higher risk associated with MUFA intake. The aim of this narrative review is to provide an overview of current knowledge and gaps in the literature regarding MUFAs and the risk of ASCVD with a focus on intake, individual types, and content in adipose tissue as a biomarker of endogenous exposure. Main findings reveal that most studies have inappropriately combined all MUFAs together, despite individual MUFA types having different biological effects and showing varying correlations between dietary intake and adipose tissue content. Adipose tissue composition may serve as a biomarker of long-term MUFA exposure, reflecting cumulative intake over one to two years while minimizing biases inherent in dietary assessments. However, tissue levels reflect both dietary intake and endogenous synthesis, complicating interpretation. Importantly, the source of MUFAs appears critical, with plant-derived MUFAs potentially offering advantages over animal-derived sources. In conclusion, we suggest that future research should focus on individual MUFA types rather than treating them as a homogeneous group, investigate their specific dietary sources and associations with ASCVD risk, and use adipose tissue biomarkers to improve exposure assessment and clarify causal relationships while considering overall dietary patterns.

The risk of developing coronary artery disease (CAD) is increased in type 1 diabetes, due to accelerated atherosclerosis. The molecular mechanisms are yet to be unraveled, but potential functional and quantitative abnormalities in lipoproteins are suggested to be involved. Some individuals have coronary arteries free from atherosclerosis even after living with type 1 diabetes for many decades. We therefore aimed to investigate the associations between a set of lipoproteins and metabolites and the presence of coronary arteries free from atherosclerosis in individuals with long-term type 1 diabetes. Cross-sectional, controlled study of 102 participants with type 1 diabetes and 61 control subjects. We used a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform to quantify circulating lipids and metabolites in serum. In participants without previously established coronary heart disease (CHD) we performed computed tomography coronary angiography (CTCA). In the diabetes group, mean age was 62 (7) [mean (standard deviation, SD)] year and diabetes duration 50.6 (4.9) years. Lower particle concentration of all LDL subclass particles associated significantly with higher odds of having coronary arteries free from atherosclerosis (p < 0.05). Low particle concentration of all LDL subclasses also associated significantly with normal Coronary Artery Calcium (CAC) score (p < 0.05 for all), after adjustment for age, sex, BMI, eGFR and statin treatment. The whole diabetes group, independent of presence of CAD, had significantly lower particle concentration of IDL and all LDL and VLDL subclass particles compared to the control group (p < 0.05 for all). In this cohort of long-term survivors of type 1 diabetes, lower levels of all types of LDL particles associated significantly with higher odds of having coronary arteries free from atherosclerosis, after adjustment for statin treatment. These results emphasize the importance of early treatment start and lipid management in the development of CAD in type 1 diabetes and suggest a subgroup of long-term survivors of type 1 diabetes to may hold environmental or genetic protective beneficial traits, independent of statin use. More research on the role of lipoproteins in the development of atherosclerosis in patients with type 1 diabetes is needed.

ABSTRACTBackgroundDuring lactation, maternal requirements for many nutrients increase due to the physiological demands of breast milk production, reflected in dietary recommendations. BMI is negatively associated with dietary quality postpartum, and 40% of women in Norway have pre‐pregnancy overweight and obesity. Currently, there is limited data on dietary intake among lactating women in Norway and whether they meet nutritional requirements. We aimed to evaluate the nutrient intake in a study sample of lactating women with overweight and obesity, compared with the Nordic Nutrition Recommendations (NNR 2023).MethodsIn this cross‐sectional analysis, we included baseline data from 112 lactating women with a pre‐pregnancy BMI of 25–35 kg/m2, participating in a weight loss and breastfeeding promotion intervention trial in Oslo, Norway. Data were collected at 2 weeks postpartum (subject characteristics, anthropometry and dietary supplement use), at 7 weeks postpartum (dietary assessment) and post‐weaning (retrospective dietary supplement use). Dietary data were obtained from a 4‐day dietary record before randomisation to dietary treatment for weight loss. Nutrient intake was compared to the dietary reference values for lactating women in NNR 2023. Increased risk of inadequate intake of micronutrients was assessed as the proportion of women with intakes below the average requirement (AR), with and without dietary supplements.ResultsMean ± SD BMI at 2 weeks postpartum was 30.7 ± 2.5 kg/m2. At 7 weeks postpartum the women reported a mean energy intake of 9.2 ± 2.0 MJ/day, with a higher intake of saturated fat and a lower intake of carbohydrate, dietary fibre and docosahexaenoic acid than recommended. The majority had an increased risk of inadequate intake of vitamin A (92%), folate (92%), vitamin D (84%), selenium (87%) and iodine (71%) from the diet alone. When dietary supplements were taken into account, ≥ 50% of the women still had an increased risk of inadequate intake of vitamin A, folate and selenium.ConclusionsThe high proportion of lactating women with overweight and obesity failing to meet the newly updated Nordic Nutrition Recommendations highlights the need to raise awareness among new mothers and healthcare professionals about the increased maternal nutritional demands during lactation and hence, the importance of nutrient‐dense diets.

Background:Epitranscriptomics, with m6A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m6A RNA-regulation during myocardial infarction (MI). Methods:In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3-7 days, and from healthy control subjects (n=3). RNA was isolated, and m6A sites were analyzed using human m6A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Results:Compared with controls, patients with STEMI had a strikingly different pattern of m6A deposition. In total, 845 m6A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m6A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3-7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m6A deposition. Conclusions:In this hypothesis generating study, m6A deposition differs STEMI patients and healthy controls. The m6A pattern changes over the course of 3-7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

Introduction Familial hypercholesterolaemia (FH) is a common genetic condition causing elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease. Little is currently known about how persons with FH are counselled by their healthcare professionals regarding pregnancy and breastfeeding, and how FH impacts the partner relationship and family planning. Current guidelines advise interrupting most cholesterol-lowering medication during conception, pregnancy, and breastfeeding. The guidelines, however, do not provide guidance on how healthcare professionals should address family planning, pregnancy, and breastfeeding with persons with FH and their partners in their day-to-day practice. Therefore, whether and how these topics are communicated in clinical practice remains unclear. This study aims to investigate FH awareness, knowledge, and current practices of care concerning family planning, pregnancy, and breastfeeding among persons with FH, their partners, and healthcare professionals.Methods and analysis This is the protocol of a global, mixed-methods study conducted in the Netherlands, Norway, and Australia in persons with FH, their partners, and their treating healthcare professionals. Persons with FH are interviewed about their current experiences with FH care related to family planning until inductive thematic saturation is achieved. A minimum of 120 partners of persons with FH will participate in an anonymous survey about the impact of FH on their relationship and family planning. In addition, a minimum of 120 healthcare professionals will be surveyed about their current practices and counselling of persons with FH on family planning, pregnancy, and breastfeeding.Ethics and dissemination All applicable ethics committees (Erasmus University Medical Center (MEC-2023-0070), Royal Perth Hospital human research ethics committee (RGS0000005951), and Oslo University Hospital (23/28008)) approved this study prior to its commencement. The results of this study will be disseminated via peer-reviewed journal articles, research seminars, conference presentations, and relevant media. Community dissemination is envisaged through FH patient and advocacy groups involved in community engagement in each study country.

Background and aims:Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD). While current LDL-C levels usually guides therapy, the cumulative exposure to LDL-C (the LDL-C burden) is suggested to offer a more precise estimate of cardiovascular risk in people with FH. Therefore, using real-world data, this study aimed to estimate the LDL-C burden at different ages in elderly FH patients with and without CHD, and to assess the LDL-C burden at CHD onset. Methods:Data was retrospectively collected from the medical records of elderly (>60 years) FH patients at the Lipid Clinic in Oslo. The LDL-C burden (mM-years) was estimated based on repeated LDL-C measurements and information on lipid-lowering medication. Time-weighted average (TWA) LDL-C was calculated as LDL-C burden divided by years. Results:We included 112 FH patients, of which 55 (49 %) had experienced at least one CHD-event, and 58 (52 %) were females. Median age at first and last visit were 50 years and 68 years, respectively, with a median of 9 (range; 2-14) available LDL-C measurements. Subjects with CHD had higher LDL-C burden at all ages tested (45, 50 and 60 years) compared with the non-CHD group (p < 0.01, also after adjusting for sex), and had higher TWA LDL-C before treatment at the Lipid Clinic (p = 0.004), but not during follow-up (p = 0.6). There were no sex differences in LDL-C burden at all ages tested, also after adjusting for CHD (p > 0.1). However, women had higher TWA LDL-C during follow-up at the Lipid Clinic (p = 0.01). Median LDL-C burden at CHD onset was 352 mM-years; numerically lower in women than in men (320 vs. 357 mM-years, respectively. p = 0.1). Conclusion:Elderly FH patients with CHD had higher estimated LDL-C burden compared with FH patients without CHD, due to higher burden prior to treatment, highlighting the importance of earlydetection and treatment.

INTRODUCTION:Early and lifelong treatment is essential in patients with familial hypercholesterolaemia (FH) due to genetically elevated low-density lipoprotein cholesterol (LDL-C) from the first years of life. In women with FH, lipid-lowering treatment is interrupted during childbearing years due to contraindication of the medication during conception, pregnancy and breastfeeding. However, little is known about the impact of breastfeeding on lipid profile and other risk markers for atherosclerotic cardiovascular disease (ASCVD) in women with FH compared with women without hypercholesterolaemia, and to what extent statins transfer into breast milk.We aim to investigate (1) the association between breastfeeding and serum lipid profile in women with and without FH; (2) the association between breastfeeding and other ASCVD risk markers in women with and without FH and (3) the concentration of statins in breast milk of women with FH. METHODS AND ANALYSIS:FH-FEMINA is a prospective study aiming to include 50 women with FH in Norway, the Netherlands and the Czech Republic. Additionally, 20 women without hypercholesterolaemia will be enrolled as a control group in Norway. Women will be included at the first study visit in gestational week 36, and follow-up visits will be scheduled at 2-4 weeks, and at 3, 6, 9 and 12 months postpartum. Information on lifestyle factors, treatment history and current and previous pregnancies will be collected. At each visit, a non-fasting blood sample, breast milk sample and information on diet, body mass index and blood pressure will be collected. Additional blood samples will be collected from the women with FH at 2, 4, 5, 7, 8, 10 and 11 months postpartum for as long as they are breastfeeding. At (re-)initiation of statin treatment, breast milk samples from women with FH will be collected for drug concentration measurements. ETHICS AND DISSEMINATION:Ethical approval will be obtained prior to study start in all three countries. Participants will be informed about the study and receive ample time to ask questions before the informed consent form is signed. The findings from this study will be disseminated to healthcare professionals, researchers and patients via peer-reviewed scientific article(s), conferences, patient organisations and social media. TRIAL REGISTRATION NUMBER:NCT05367310.

Specialized pro-resolving mediators (SPMs) are key effectors of resolution of inflammation. This is highly relevant for cardiac and vessel remodeling, where the net inflammatory response contributes to determine disease outcome. Herein, we used a mice model of angiotensin (Ang)-II-induced hypertension to study the effect of the SPM Resolvin D2 (RvD2), on hypertension and cardiac remodeling. By using subcutaneous osmotic minipumps, mice were treated with PBS or Ang-II in combination with or without RvD2 for two weeks. Mice receiving RvD2 gained less blood pressure increase compared to Ang-II alone. Surprisingly, however, examination of intracardiac arteries revealed that RvD2 treatment in combination with Ang-II exacerbated Ang-II-induced fibrosis. Measures of vascular smooth muscle cell dedifferentiation correlated with the level of vascular remodeling, indicating that this dedifferentiation, including increased proliferation and migration, is a contributing factor. RNA sequencing of left ventricle cardiac tissue supported these findings as pathways related to cell proliferation and cell differentiation were upregulated in mice treated with Ang-II in combination with RvD2. Additionally, the RNA sequencing also showed upregulation of pathways related to SPM metabolism. In line with this, Mass spectrometry analysis of lipid mediators showed reduced cardiac levels of the arachidonic acid derived metabolite leukotriene E4 in RvD2 treated mice. Our study suggests that continuous infusion through osmotic minipumps should not be the recommended route of RvD2 administration in future studies.