OBJECTIVES:Our aim was to assess how pre-eclampsia, gestational hypertension, and chronic (pre-pregnancy) hypertension, compared to no hypertensive disorders during pregnancy, impact development of cardiovascular disease and all-cause mortality in type 1 diabetes (T1D). METHODS:We included 190 T1D women with median age of 29.4 (interquartile range 26.0-33.3) years at delivery between 1988 and 1994 at the Helsinki University Hospital, and who were later re-examined within the Finnish Diabetic Nephropathy Study. Of these, 43 (22.6%) had had pre-eclampsia, 32 (16.8%) gestational hypertension, 20 (10.5%) chronic hypertension, and 95 (50.0%) had remained normotensive during the index pregnancy. We retrieved follow-up data on cardiovascular events and mortality from national registries until the end of 2020. RESULTS:During a median 27.9 (25.4-30.7) years of follow-up, 46 (24.2%) experienced a composite cardiovascular event and 25 (13.2%) died from any cause. In Cox regression analysis, the risk of a cardiovascular event was increased for chronic hypertension [hazard ratio, HR 3.45 (95% CI 1.25-9.54)], gestational hypertension [HR 3.63 (1.55-8.51)], and pre-eclampsia [HR 5.07 (2.31-11.11)] compared with the non-hypertension group, after adjustment for delivery age and age at T1D onset. The corresponding risk of all-cause mortality was increased for chronic hypertension [HR 3.31 (1.06-10.35)] and pre-eclampsia [HR 2.92 (1.07-7.98)], but not for gestational hypertension [HR 1.26 (0.33-4.85)]. After further adjustment for diabetic kidney disease or diabetic retinopathy as a time-dependent covariate, the association with cardiovascular disease remained for pre-eclampsia and gestational hypertension, while for mortality, none of the associations were significant. CONCLUSION:Hypertension during pregnancy is associated with increased risk of cardiovascular events during long-term follow-up in women with T1D, with pre-eclampsia conferring the highest risk. For all-cause mortality, chronic hypertension and pre-eclampsia, but not gestational hypertension, increases the risk of death, yet not independently of diabetic kidney disease.

Cerebral small-vessel disease (SVD) is prevalent in type 1 diabetes and has been associated with the haptoglobin variant allele Hp1. Contrarily, the Hp2-allele has been linked to cardiovascular disease and the role of haptoglobin-genotype in asymptomatic SVD is unknown. We, therefore, aimed to evaluate the alleles’ association with SVD. This cross-sectional study included 179 neurologically asymptomatic adults with type 1 diabetes (women 53%, mean age 39 ± 7 years, diabetes duration 23 ± 10 years, HbA1c 8.1 ± 3.2% [65 ± 12 mmol/mol]). Examinations included genotyping (genotypes Hp1-1, Hp2-1, Hp2-2) by polymerase chain reaction, clinical investigation, and magnetic resonance brain images assessed for SVD manifestations (white matter hyperintensities, cerebral microbleeds, and lacunar infarcts). SVD prevalence was 34.6%. Haptoglobin genotype frequencies were 15.6% (Hp1-1), 43.6% (Hp1-2), and 40.8% (Hp2-2). Only diastolic blood pressure differed between the genotypes Hp1-1, Hp1-2, and Hp2-2 (81 [74–83], 75 [70–80], and 75 [72–81] mmHg, p = 0.019). Haptoglobin genotype frequencies by presence versus absence of SVD were 16.1%; 46.8%; 37.1% versus 15.4%; 41.9%; 42.7% (p = 0.758). Minor allele frequencies were 39.5% versus 36.3% (p = 0.553). Hp1 homozygotes and Hp2 carriers displayed equal proportions of SVD (35.7% vs 34.4%, p > 0.999) and SVD manifestations (white matter hyperintensities 14.3% vs 17.9%, p = 0.790; microbleeds 25.0% vs 21.9%, p = 0.904; lacunar infarcts 0% vs 3.6%, p > 0.999). Hp1-1 was not associated with SVD (OR 1.19, 95% CI 0.46–2.94, p = 0.712) when adjusting for age, blood pressure, and diabetic retinopathy. Although the SVD prevalence was high, we detected no significant association between SVD and haptoglobin-genotype.

Introduction Cerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain’s vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes. Research design and methods For this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33–45) years; 53% female; diabetes duration 21.6 (18.2–30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score). Results In type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20–61) vs 20 (20–35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20–65) vs 20 (20–35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts. Conclusions Presence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.

Diagnosing acute kidney injury remains a challenge since the established renal biomarkers, serum creatinine (sCr) and symmetric dimethylarginine (SDMA) reflect glomerular function and not tubular injury. Sensitive tubular markers such as urinary clusterin (uClust) and cystatin B (uCysB) have been proposed to detect AKI at an earlier stage. Since envenomation by the European adder (Vipera berus berus) could serve as a spontaneous disease model of AKI we investigated these new biomarkers in affected dogs. Concentrations of uClust and uCysB as well as sCr and SDMA were analyzed retrospectively in stored samples from 26 dogs with snake envenomation and 13 healthy controls. Higher concentrations of uClust (P < 0.012) and uCysB (P < 0.001) were observed in the snake-envenomed group. Normalization of uClust and uCysB to urinary creatinine did not alter the results. No differences were observed in sCr and SDMA between the snake-envenomed group and the healthy control group. Spearman rank correlation analysis revealed a strong association of uClust with uCysB in the snake-envenomed dogs (r = 0.75 P < 0.001) but not in the healthy controls. The high percentage of snake-envenomed dogs with increased uClust and uCysB concentrations in the absence of increased sCr and SDMA suggests renal tubular injury in the affected dogs. Larger prospective case-controlled studies are warranted to evaluate the clinical utility and prognostic value of these biomarkers.

Objective:Since its creation in December 2015, the European/International FMD Registry (EIFR) included 1005 patients from 45 centres in 21 countries, including Argentina, China, Israel, Japan, and Tunisia. We present here their main characteristics according to disease subtype and clinical presentat

Background and aims: Increased arterial stiffness contributes to diabetic vascular complications. We identified dietary factors related to arterial stiffness in individuals with type 1 diabetes, a population with high risk of cardiovascular disease. Methods and results: Altogether, 612 participants (40% men, mean +/- standard deviation age 45 +/- 13 years) completed a validated diet questionnaire and underwent measurements of arterial stiffness. Of these, 470 additionally completed a food record. Exploratory factor analysis was applied to identify dietary patterns from the diet questionnaires, and nutrient intakes were calculated from food record entries. Arterial stiffness was measured by applanation tonometry. Of the seven dietary factors formed, the factor scores of "Full-fat cheese and eggs" and "Sweet" patterns were negatively associated with measures of arterial stiffness. In the multivariable macronutrient substitution models, favouring carbohydrates over fats was associated with higher aortic mean arterial pressure and aortic pulse wave velocity. When carbohydrates were consumed in place of proteins, higher aortic pulse pressure, aortic mean arterial pressure, and augmentation index were recorded. Replacing energy from alcohol with proteins, was associated with lower aortic pulse pressure, aortic mean arterial pressure, and augmentation index. Relative distributions of dietary fatty acids were neutral with respect to the measures of arterial stiffness. Conclusion: The macronutrient distribution of the diet is likely to affect the resilience of the arteries. Our observations suggest that reducing energy intake from carbohydrates and alcohol may be beneficial. These observations, especially those dealing with dietary patterns, need to be confirmed in a longitudinal study. (C) 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background and purposeAcknowledging the conflicting evidence for diabetes as a predictor of short‐ and long‐term mortality following an intracerebral hemorrhage (ICH), we compared baseline characteristics and 30‐day and long‐term mortality between patients with and without diabetes after an ICH, paying special attention to differences between type 1 (T1D) and type 2 (T2D) diabetes.MethodsPatients with a first‐ever ICH were followed for a median of 2.3 years. Adjusting for demographics, comorbidities and documented ICH characteristics increasing mortality after ICH, logistic regression analysis assessed factors associated with case fatality and 1‐year survival among the 30‐day survivors. Diabetes was compared with patients without diabetes in separate models as (i) any diabetes and (ii) T1D or T2D.ResultsOf our 969 patients, 813 (83.9%) had no diabetes, 41 (4.2%) had T1D and 115 (11.9%) had T2D. Compared with patients without diabetes, those with diabetes were younger, more often men and more frequently had hypertension, coronary heart disease and chronic kidney disease, with similar ICH characteristics. Patients with T1D were younger, more often had chronic kidney disease and brainstem ICH, and less often had atrial fibrillation and lobar ICH, than did patients with T2D. Diabetes had no impact on case fatality. Any diabetes (odds ratio, 2.57; 1.19–5.52), T1D (odds ratio, 7.04; 1.14–43.48) and T2D (odds ratio, 2.32; 1.04–5.17) were independently associated with 1‐year mortality.ConclusionsPatients with ICH with diabetes exhibited a distinct pattern of comorbidities and disease characteristics with specific differences between T1D and T2D. Despite their younger age, T1D seems to carry a substantially higher likelihood of long‐term mortality after an ICH than does T2D.

BACKGROUND:Patients with type 1 diabetes have shown an increase in circulating cytokines, altered lipoprotein metabolism and signs of vascular dysfunction in response to high-fat meals. Intestinal alkaline phosphatase (IAP) regulates lipid transport and inflammatory responses in the gastrointestinal tract. We therefore hypothesized that changes in IAP activity could have profound effects on gut metabolic homeostasis in patients with type 1 diabetes.METHODS:Faecal samples of 41 nondiabetic controls and 46 patients with type 1 diabetes were analysed for IAP activity, calprotectin, immunoglobulins and short-chain fatty acids (SCFAs). The impact of oral IAP supplementation on intestinal immunoglobulin levels was evaluated in C57BL/6 mice exposed to high-fat diet for 11 weeks.RESULTS:Patients with type 1 diabetes exhibited signs of intestinal inflammation. Compared to controls, patients with diabetes had higher faecal calprotectin levels, lower faecal IAP activities accompanied by lower propionate and butyrate concentrations. Moreover, the amount of faecal IgA and the level of antibodies binding to oxidized LDL were decreased in patients with type 1 diabetes. In mice, oral IAP supplementation increased intestinal IgA levels markedly.CONCLUSION:Deprivation of protective intestinal factors may increase the risk of inflammation in the gut - a phenomenon that seems to be present already in patients with uncomplicated type 1 diabetes. Low levels of intestinal IgA and antibodies to oxidized lipid epitopes may predispose such patients to inflammation-driven complications such as cardiovascular disease and diabetic nephropathy. Importantly, oral IAP supplementation could have beneficial therapeutic effects on gut metabolic homeostasis, possibly through stimulation of intestinal IgA secretion.

Objective: Baroreflex activation therapy (BAT) modulates the autonomic nervous system to restore sympathovagal balance. The aim of this study is to explore the long-term effects of BAT on blood pressure (BP) in patients with refractory (true resistant) hypertension (RH). Design and Method: This academic (independent of industry support) randomized, double-blind, 1:1 parallel-design clinical trial will include 100 patients with RH from 5 hypertension centers in the Nordic countries. A Barostim Neo® System will be implanted and after 1 month of stabilization patients will be randomized to either BAT (BAT on) for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by the BAT (BAT on) for 8 months. Eligible patients will be 18–70 years and have a daytime systolic ambulatory blood pressure (ABMP) of 145 mmHg or more, and/or a daytime diastolic ABMP of 95 mmHg or more, after witnessed intake of antihypertensive treatment (including at least 3 antihypertensive drug classes, preferably including a diuretic), with no changes in medication for a minimum of 4 weeks prior to enrolment. Patients with secondary causes of hypertension, severe renal insufficiency, untreated sleep apnea, type 1 diabetes, alcohol abuse, severe valvular diseases will be excluded. Results: The primary end point is to test whether BAT reduces 24-hour systolic ABMP at 8 months of follow-up compared to pharmacotherapy. Secondary and tertiary end points are the effects of BAT on home and office blood pressure, measures of autonomic function, arterial and cardiac structure and function during follow-up, and extended long-term follow-up. Two patients have been included in the study so far. An interim analysis will be done after 50 patients. Preliminary results are thus awaited during the year 2018. Conclusions: This initiative will increase the understanding of the mechanisms and role of BAT in the treatment of RH. (ClinicalTrials.gov identifier NCT02572024).

Objective: Sympathetic tone is one of the main determinants of blood pressure (BP) variability. The aim of our study was to assess the changes in BP variability after renal sympathetic denervation (RDN) in resistant hypertensive patients, and, conversely, to look for the predictive value of baseline BP variability on mean BP changes after RDN. Design and method: Twenty-four hour BP measurements were analyzed in 167 resistant hypertensive patients recruited at 11 expert centers within the European Network Coordinating research on Renal Denervation (ENCOReD) (mean age 56.7 years; 40 % women; mean baseline office BP: 172/98 mmHg; 24-h ambulatory BP: 152/90 mmHg), both at baseline and after RDN. Blood pressure variability was assessed by the weighted standard deviation (SDw), average real variability (ARV), coefficient of variation (CV) and variability independent of the mean (VIM) of 24-h ambulatory BP. Results: After an average follow up of 6.7 months, mean office and 24-h ambulatory BP fell by 15.4/6.6 mmHg and 5.5/3.7 mmHg respectively (P < 0.0001 for both). Whereas no significant changes in ARV or CV were observed, SDw and VIM for 24-h systolic BP decreased by −1.29 mmHg (95%CI: −2.17 to −0.42; P < 0.01) and −1.11 mmHg (95%CI: −1.92 to −0.30; P < 0.01), respectively. Decrease in these systolic BP variability estimates remained significant in multivariable-adjusted analyses and was paralleled by similar changes for 24-h diastolic BP. Finally, baseline SDw (P = 0.0006), ARV (P = 0.012) and VIM (P = 0.04) were significantly correlated with mean changes in diastolic - but not systolic - BP after RDN. Conclusions: Renal denervation was associated with a significant decrease in BP variability independent of the mean, which in the long term may decrease cardiovascular risk. Furthermore, baseline BP variability was predictive of diastolic BP changes after RDN. These results are consistent with the known influence of sympathetic nervous system on BP variability and peripheral vascular resistances. Our findings need confirmation in randomized controlled studies testing second-generation RDN catheters, preferably including younger patients with higher sympathetic tone and less advanced vascular damage.

Objective: Renal denervation (RDN) has been shown to be a feasible treatment in resistant hypertensive patients. Renal accessory arteries (RAs) are frequent (20–27%) but seldom accessible to RDN. As such, they may constitute an unaddressed source of sympathetic overactivity. The aim of this study was to investigate if the presence of accessory RAs influences blood pressure response to RDN in patients with resistant hypertension. Design and method: Patients were recruited from 6 expert centres, within the European Network Coordinating research on Renal Denervation (ENCOReD). All patients underwent 24-h BP measurements at baseline and 6 months after RDN. Patients were classified in type A (main RA > = 20 mm length and > = 4 mm diameter) or type B (main RA < 20 mm length or < 4 mm diameter) according to renal anatomy (Okada classification). Subtypes include A1 (no accessory RAs), A2 (with accessory RAs < 3 mm diameter), A3 (with accessory RAs > = 3 mm diameter), B1 (main RA < 20 mm in length) and B2 (RA < 4 mm diameter). Results: 114 resistant hypertensive patients (age 58.1 ± 11.2, 46% women) were included in the analysis. Seventy-six (66%) patients did not have accessory RAs (type A1) and 39 (34%) patients did have accessory RAs (on one or both sides). 24-hour ambulatory systolic/diastolic BP after RDN dropped by -6.4/-4.0 mmHg in patients with no accessory RAs (p < 0.006), compared to a non-significant + 0.2/-0.7 mmHg (p > 0.70) in patients with accessory RAs. (p > 0.08 for the baseline adjusted between-group difference). When adjusted for sex, age, body mass index, baseline 24-h systolic ambulatory blood pressure as fixed effects, and for centre as random effect, the difference in decrease in 24-h systolic ambulatory blood pressure between the 2 groups was -3.8 mmHg (95% CI: -10.7 to 3.1, p = 0.27). Conclusions: A significant blood pressure decrease after RDN was observed only in patients without RAs. However, the difference between blood pressure changes in patients with or without RAs did not reach statistical significance. Ongoing analyses will include more subjects, as well as information on performance of RDN in accessory RAs and the number of ablations on each side.