A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5–6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Lactobacillus helveticus LBK-16H-fermented milk products containing tripeptides isoleucine-proline-proline and valine-proline-proline lower blood pressure in hypertensive subjects using office and home blood pressure registration. The present study was aimed to evaluate the effects of two doses of these lactotripeptides on 24-h ambulatory blood pressure and lipidomics profiles in mildly hypertensive subjects. In a randomized, double-blind, placebo-controlled parallel group study, 89 mildly hypertensive subjects ingested, after a 1-month run-in period, a fermented milk drink with 5 mg per day of lactotripeptides during 3 months, and a milk drink with 50 mg per day of lactotripeptides for the following 3 months, or a placebo milk drink without lactotripeptides. Ambulatory blood pressure (24 h) was recorded at baseline and at the end of the intervention periods. Lipidomics profiles were characterized before and after the 6-month intervention. After the second intervention period (50 mg per day of lactotripeptides), systolic and diastolic 24-h blood pressures decreased significantly in the peptide, but not in the placebo group. However, the treatment effects −2.6 mm Hg (95% confidence interval (CI): −5.7 to 0.4) in systolic and −1.3 mm Hg (95% CI: −3.4 to 0.8) in diastolic blood pressure did not reach statistic significance. Ingestion of 5 mg per day of lactotripeptides for 3 months did not lower blood pressure. The peptide group was dominated by decrease in multiple phospholipids (PL). Ingestion of fermented milk with daily dose of 50 mg of lactotripeptides appears to lower elevated blood pressure slightly from the baseline, but not significantly compared with the placebo group and to induce significant decreases in multiple PL.

The milk casein-derived biologically active tripeptides, isoleucyl-prolyl-proline (Ile-Pro-Pro) and valyl-prolyl-proline (Val-Pro-Pro), have documented antihypertensive effect probably related to reduced angiotensin formation. It has been suggested that these tripeptides may reduce arterial stiffness and improve endothelial function. Our aim was to evaluate whether the milk-based drink containing Ile-Pro-Pro and Val-Pro-Pro influence arterial stiffness, measured as augmentation index (AIx), and endothelial function in man. In a double-blind parallel group intervention study, 89 hypertensive subjects received daily peptide milk containing a low dose of tripeptides (5 mg/day) for 12 weeks and a high dose (50 mg/day) for the following 12 weeks, or a placebo milk drink to titrate the dose–response effect. Arterial stiffness was assessed by pulse wave analysis at the beginning and end of each intervention period. Endothelial function was tested by examining pulse wave reflection response to sublingual nitroglycerin and salbutamol inhalation. Blood pressure was measured by using office and 24-h ambulatory blood pressure measurement. At the end of the second intervention period, AIx decreased significantly in the peptide group compared with the placebo group (peptide group −1.53% (95% confidence interval (CI) −2.95 to −0.12), placebo group 1.20% (95% CI 0.09–2.32), P=0·013). No change in endothelial function index was observed (peptide group 0.02 (95% CI −0.06 to 0.08), placebo group 0.04 (95% CI −0.04 to 0.12), P=0.85). There were no statistically significant differences between the effects of the peptide and placebo treatment on office and 24-h ambulatory blood pressure. Long-term treatment with Lactobacillus helveticus-fermented milk containing bioactive peptides reduces arterial stiffness expressed as AIx in hypertensive subjects.

The effects of a spread containing bioactive tripeptides isoleucine–proline–proline (IPP), valine–proline–proline (VPP) and plant sterols were studied in subjects with mild hypertension and elevated LDL cholesterol. Sixty-two subjects consumed 20g/day spread containing 4.2mg milk peptides and 2g plant sterol esters or placebo for 10 weeks. Blood pressure was measured twice a week. Arterial stiffness was assessed by pulse wave analysis and by pulse wave velocity. Blood samples were analysed for serum lipids and high-sensitive CRP. A significant decrease was seen in systolic blood pressure (p=0.026), but not in diastolic blood pressure (p=0.53). Total cholesterol (p=0.003) and LDL cholesterol (p=0.002) decreased, whereas HDL cholesterol, triacylglycerols and CRP remained unchanged. No overall effects on arterial stiffness were seen. The results suggest that a spread containing bioactive milk peptides and plant sterols has a beneficial effect on two major cardiovascular risk factors, blood pressure and plasma lipids, in hypertensive, dyslipidemic subjects. Functional foods affecting two major risk factors can be valuable tools in managing cardiovascular risk.

Aims Evidence suggests that chronic hyperglycaemia predicts not only microvascular disease but also macrovascular disease, however it is not known whether it is the glucose variability per se or the total glucose exposure that confers risk. The objective of this study was to investigate whether daily glucose variability influence blood pressure and arterial stiffness, an early sign of macrovascular disease, at baseline and during a hyperglycaemic clamp in patients with type 1 diabetes. Methods Twenty-two non-smoking male patients with type 1 diabetes without any diabetic complications, participated in the study. The patients were monitored for 72-h using a continuous glucose monitoring system. Before and during a 2-h hyperglycaemic clamp, blood pressure as well as pulse wave analysis and pulse wave velocity (PWV) were performed to assess arterial stiffness. Results No correlation was observed between mean amplitude of glycaemic excursions (MAGE) and arterial stiffness at baseline. There was a correlation between mean daily glucose and aortic PWV even after adjusting for BMI, HbA1c, and duration of diabetes in a multiple regression analysis (r = 0.48; P < 0.01). MAGE (r = 0.52; P < 0.01) correlated independently with the change in aortic DBP during the clamp. Conclusions This study suggests that high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness in patients with T1D. Daily glucose variability is positively associated with the change in central blood pressure during a hyperglycaemic clamp.

The degree of proteinuria during preeclampsia has been considered to be a marker of severity of the disease and of endothelial dysfunction. The aim of the study was to assess whether the degree of proteinuria in preeclamptic pregnancy is related to impairment of vascular dilatation and/or kidney function years after the index pregnancy. Thirty women with a history of severe preeclampsia divided into low (n=8, dU-prot <5 g/day) and high (n=22, dU-prot >/=5 g/day) proteinuric groups and 21 women with previous normotensive pregnancy were studied 5-6 years after index pregnancy. Renal function and blood pressure were assessed together with venous occlusion plethysmography, where changes in brachial artery blood flow, induced by intra-arterial infusions of an endothelium-independent (sodium nitroprusside) and an endothelium-dependent (acetylcholine) vasodilator, were measured. The results showed similar renal function in all groups. There was no difference in vasodilation between preeclamptic groups and controls or correlation between degree of proteinuria during index pregnancy and present vasodilation. We conclude that the degree of proteinuria during preeclampsia does not predict vascular dilatation or renal function 5-6 years after preeclamptic pregnancy.

Aims Patients with Type 1 diabetes have an increased risk of cardiovascular mortality. Notably, a prolonged heart rate adjusted QT interval (QTc) is a predictor of sudden cardiovascular death. Therefore, the objectives of this study were to investigate whether acute hyperglycaemia affects the QTc duration and the QTc dispersion in patients with Type 1 diabetes and in healthy volunteers.Methods Acute hyperglycaemia (15 mmol/l) for 120 min was induced in 35 males (22 men with Type 1 diabetes and 13 age-matched non-diabetic volunteers). All participants were non-smokers without any diabetic complications. Electrocardiogram recordings were performed at normoglycaemia and at 0, 60 and 120 min of hyperglycaemia.Results Compared with normoglycaemia, acute hyperglycaemia increased the QTc interval in both patients with Type 1 diabetes (390 +/- 6 vs. 415 +/- 5 ms, P < 0.001) and in healthy volunteers (378 +/- 5 vs. 412 +/- 8 ms, P < 0.01). During hyperglycaemia, the QTc dispersion was prolonged in healthy volunteers (36 +/- 4 ms vs. 54 +/- 7 ms, P < 0.05) but not in patients with Type 1 diabetes (45 +/- 3 ms at baseline vs. 48 +/- 5 ms, NS).Conclusions Acute hyperglycaemia alters myocardial ventricular repolarization in patients with Type 1 diabetes and in healthy volunteers and might consequently be an additional risk factor for cardiovascular events.

Aims/hypothesis Our aim was to study whether pre-eclampsia and pregnancy-induced hypertension are predictors of diabetic nephropathy in type 1 diabetic women.Materials and methods A total of 203 type 1 diabetic women, who were pregnant between 1988 and 1996 and followed at the Department of Obstetrics and Gynaecology in Helsinki, were re-assessed after an average of 11 years within the nationwide, multi-centre Finnish Diabetic Nephropathy Study. Diabetic nephropathy was defined as microalbuminuria, macroalbuminuria or end-stage renal disease.Results Patients with prior pre-eclampsia had diabetic nephropathy more often than patients with a normotensive pregnancy (diabetic nephropathy vs normal albumin excretion rate: 41.9% vs 8.9%; p < 0.001), whereas patients with a history of pregnancy-induced hypertension did not (10.3% vs 8.9%; p=0.81). CHD was more prevalent in patients with a history of pre-eclampsia than in patients with a normotensive pregnancy (12.2% vs. 2.2%; p=0.03). Pre-eclampsia (odds ratio [OR] 7.7, 95% CI 1.6-36.1; p=0.01) and HbA(1c) (OR 2.0, 95% CI 1.1-3.8; p < 0.05) were associated with incident diabetic nephropathy even when adjusted for follow-up time, BMI, smoking, diabetes duration and age.Conclusions/interpretation These data suggest that a history of pre-eclamptic pregnancy but not pregnancy-induced hypertension is associated with an elevated risk of diabetic nephropathy.

Aims/hypothesis Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects.Methods Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured.Results At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (-5 +/- 2.7 vs -20 +/- 2.8%, p < 0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (-5 +/- 2.7 vs 8 +/- 2.5%, p < 0.001) and healthy volunteers (-20 +/- 2.8 vs 6 +/- 8.8%, p < 0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 +/- 1.2 vs 8.0 +/- 1.0 m/s, p < 0.001), but not in healthy men (7.4 +/- 1.7 vs 7.3 +/- 1.4 m/s, NS).Conclusions/interpretation Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels.

Physically active persons have a reduced risk of atherosclerotic disease. Arterial stiffness and endothelial dysfunction are important risk factors for cardiovascular disease. A high proportion of type I (slow‐twitch) muscle fibers in skeletal muscle is associated with a favorable cardiovascular risk profile. We tested physical activity and muscle fiber‐type distribution as determinants of endothelial function and arterial stiffness in middle‐aged men. Fifty‐four men (median age 58) who underwent a muscle biopsy in 1984 were re‐studied in 2003. Aortic pulse wave velocity (PWV) and pulse wave reflection were assessed by applanation tonometry. Endothelial function was tested by examining the effects of salbutamol and nitroglycerin on pulse wave reflection. In multiple regression analyses aortic PWV (R2=0.51) correlated positively with age (P=0.017), BMI (P=0.001), and systolic blood pressure (P=0.004). A high augmentation index (R2=0.33) was associated with smoking (P<0.001), high LDL cholesterol (P=0.02), and elevated diastolic blood pressure (P=0.03). Impaired endothelial function (R2=0.37) was associated with high age (P=0.04), high LDL cholesterol (P=0.017), high triglycerides (P=0.027), and high physical activity (P=0.005). Muscle fiber‐type distribution is not a determinant of arterial stiffness or endothelial function. Impaired endothelial function was observed in physically active men, underlining the need for further research.

The present study evaluated the 10-week-treatment effect of Lactobacillus helveticus fermented milk containing the tripeptides isoleucyl-prolyl-proline (Ile-Pro-Pro) and valyl-prolyl-proline (Val-Pro-Pro) on ambulatory arterial stiffness index (AASI) by using the ambulatory 24-h blood pressure registration. The AASI improved significantly in the peptide milk group (p=0.043), but not in the placebo group (p=0.47), suggesting a mechanism for the antihypertensive effects of these peptides.

Objective The mechanisms underlying increased cardiovascular risk among women with a history of pre-eclampsia remain unclear. Impaired endothelial function has been observed in both pre-eclampsia and atherosclerosis, and provides a plausible link between the two conditions. We studied endothelial function and arterial compliance in non-pregnant, previously pre-eclamptic women. Design A study of 30 women with a history of pre-eclampsia and 21 women with a previous normotensive, uncomplicated pregnancy was carried out. Methods Changes in brachial artery blood flow, induced by intra-arterial infusions of an endothelium-independent (sodium nitroprusside) and an endothelium-dependent (acetylcholine) vasodilator, were measured by venous occlusion plethysmography. Arterial stiffness was assessed by pulse-wave analysis. Results Vasodilatation was impaired in women with previous pre-eclampsia; at low and high concentrations of endothelium-independent (P = 0.004 and P = 0.057, respectively) and endothelium-dependent (P = 0.045 and P = 0.02) vasodilators, respectively. There was no difference in arterial stiffness between the groups (P = 0.45). In multiple regression analyses both endothelium-independent and endothelium-dependent vasodilatations were independently associated with a history of pre-eclampsia and parity. There was no correlation with blood pressure, body mass index (BMI), smoking or age. Conclusions The finding of impaired vascular dilatation several years after a pre-eclamptic pregnancy could contribute to the higher risk of cardiovascular disease in these women.

The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.

OBJECTIVE - Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS - A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion.(in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression.RESULTS - in patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (it = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (> 3 ml (.) min(-1.) year(-1)) was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria.CONCLUSIONS - Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.