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Objective: Treatment options in Graves' disease (GD) are limited and do not target the underlying autoimmunity, and relapse rates following a course of antithyroid drug (ATD) reach 50%. Previous research has shown promising results for a role of vitamin D in GD. We aimed to investigate whether vitamin D reduces failure to enter and sustain remission in patients with GD treated with ATD. Design: A multicenter, double-blinded, randomized placebo-controlled trial comparing vitamin D 70 mcg once daily (2800 IU) or placebo. The intervention was given first as add-on to ATD treatment, maximally 24 months, and then for 12 months after ATD cessation. Inclusion period was from 2015 to 2017 and study completion by December 2020. Patients included were adults with a first-time diagnosis of GD treated with ATD. Exclusion criteria included pregnancy and glucocorticoid treatment. The primary endpoint was failure to enter and sustain remission defined as relapse of hyperthyroidism within 12 months after ATD cessation, inability to stop ATD within 24 months, or radioiodine treatment or thyroidectomy. Two hundred seventy-eight patients were included in the study, and 4 patients withdrew consent. No adverse effects were found. Results: Participants were aged 44 ± 14 years at enrollment and 79% were female. The risk of failure to enter and sustain remission was 42% [95% confidence interval (CI) 33-50%] in the vitamin D group and 32% [CI 24-40%] in the placebo group corresponding to a relative risk of 1.30 [CI 0.95-1.78]. Conclusions: Vitamin D supplementation did not improve the treatment of GD in patients with normal or insufficient vitamin D status. Thus, supplementation with high-dose vitamin D cannot be recommended for GD. Study registration: ClinicalTrials.gov NCT02384668.

OBJECTIVE: Aortic pulse pressure (PP) represents the hemodynamic cardiac and cerebral burden more directly than cuff PP. The objective of this study was to investigate whether invasively measured aortic PP confers additional prognostic value beyond cuff PP for cardiovascular events and death. With increasing age, cuff PP progressively underestimates aortic PP. Whether the prognostic association between cuff PP and outcomes is age-dependent remains to be elucidated.METHODS: Cuff PP and invasively measured aortic PP were recorded in 21 908 patients (mean age 63 years, 58% men, 14% with diabetes) with stable angina pectoris undergoing elective coronary angiography during January 2001--December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination was assessed using Harrell's C-index.RESULTS: During a median follow-up period of 3.7 years (range 0.1-10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both cuff and aortic PP were associated with stroke, myocardial infarction, and death in crude analyses. However, only cuff PP remained associated with stroke (hazard ratio per 10 mmHg, 1.06 (95% confidence interval (CI) 1.01--1.12)] and myocardial infarction [hazard ratio per 10 mmHg 1.05 (95% CI 1.01--1.11)] in multivariate Cox models. Both cuff and aortic PP lost significance as predictors of death in multivariate models. Age did not modify the prognostic association between cuff PP and stroke, myocardial infarction, and death.CONCLUSION: Invasively measured aortic PP did not add prognostic information about cardiovascular outcomes and death beyond cuff PP in patients with stable angina pectoris.

OBJECTIVES: We studied cardiac autonomic changes in relation to metabolic factors, body composition and 24-hour ambulatory blood pressure measurements in Turner syndrome patients without known hypertension.DESIGN: Cross sectional.PATIENTS: Participants were 48 TS women and 24 healthy female controls aged over 18 years.METHODS: Short-term power spectral analysis was obtained in supine-standing-supine position. Bedside tests included three conventional cardiovascular reflex tests of heart rate response to standing up, heart rate response to deep breathing and blood pressure response to standing up. Mean heart rate during the last 2 minutes of work was used to calculate the maximal aerobic power (VO2max ).RESULTS: We found a significantly higher mean reciprocal of the heart rate per second (RR) in TS. Testing for interaction between position and status (TS or control), there were highly significant differences between TS and controls in high-frequency (HF) power, the coefficient of component variation (square root of HF power/mean RR) and low-frequency (LF): HF ratio, with a dampened decline in vagal activity among TS during standing. Bedside test showed TS had a significantly higher diastolic BP in the supine position compared to controls, and the adaptive rise in BP, when changing to upright position was reduced. VO2max and self-reported level of physical activity were significantly correlated to systolic ambulatory blood pressure both 24-hour and night diastolic ambulatory blood pressure.CONCLUSION: Vagal tone and modulation of the sympathovagal balance during alteration in body position are impaired in TS. These changes can be risk factors for cardiovascular disease.

Background Microvascular impairment is well documented in hypertension. We investigated the effect of renal sympathetic denervation (RDN) on cardiac and peripheral microvasculature in patients with treatment-resistant essential hypertension (TRH). Methods A randomized, single centre, double-blinded, sham-controlled clinical trial. Fifty-eight patients with TRH (ambulatory systolic BP (ASBP) ≥ 145 mm Hg) despite stable treatment were randomized to RDN or SHAM. RDN was performed with the unipolar Medtronic Flex catheter. Coronary flow reserve (CFR) and coronary- and forearm minimum vascular resistance (C-Rmin and F-Rmin) were determined using transthoracic Doppler echocardiography and F-Rmin with venous occlusion plethysmography at baseline and at six-months follow-up. Results RDN was performed with 5.3 ± 0.2 lesions in the right renal artery and 5.4 ± 0.2 lesions in the left. Baseline ASBP was 152 ± 2 mm Hg (RDN, n = 29) and 154 ± 2 mm Hg (SHAM, n = 29). Similar reductions in MAP were seen at follow up (− 3.5 ± 2.0 vs. − 3.2 ± 1.8, P = 0.92). Baseline CFR was 2.9 ± 0.1 (RDN) and 2.4 ± 0.1 (SHAM), with no significant change at follow-up (0.2 ± 0.2 vs. − 0.1 ± 0.2, P = 0.57). C-Rmin was 1.9 ± 0.3 (RDN) and 2.7 ± 0.6 (SHAM) (mm Hg min/ml pr. 100 g) and did not change significantly (0.3 ± 0.5 vs. − 0.4 ± 0.8, P = 0.48). F-Rmin was 3.6 ± 0.2 (RDN) and 3.6 ± 0.3 (SHAM) (mm Hg min/ml pr. 100 ml tissue) and unchanged at follow-up (4.2 ± 0.4 vs. 3.8 ± 0.2, P = 0.17). Left ventricular mass index was unchanged following RDN (− 4 ± 7 (RDN) vs. 3 ± 5 (SHAM) (g/m2) P = 0.38). Conclusion The current study does not support positive effects of RDN on microvascular impairment in TRH.

OBJECTIVES: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension.METHODS: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity Flex(TM) catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor(®)-device.RESULTS: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. -0.6 ± 1.3 (RDN) m/s), systolic C-BP (-2 ± 17 (SHAM) vs. -8 ± 16 (RDN) mmHg), diastolic C-BP (-2 ± 9 (SHAM) vs. -5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN.CONCLUSIONS: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

BACKGROUND: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP.METHOD: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA).RESULTS: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [-6.2 ± 18.8 mmHg (RDN) vs. -6.0 ± 13.5 mmHg (SHAM)] and at 6 months [-6.1 ± 18.9 mmHg (RDN) vs. -4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)].RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial.CONCLUSION: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

Background: Pulse wave analysis from a brachial cuff permits ambulatory measurements of pulse wave velocity (PWV) and central blood pressure parameters. The diurnal variation of PWV in type 2 diabetes is unknown. Methods: We evaluated the Arteriograph24 which is a brachial cuff based equipment for estimating PWV and central blood pressure data without the use of a transfer function, in 22 type 2 diabetic patients, who had two 24 h measurements performed. Results: The mean number of valid day time and nighttime measurements were 29 (range 16–50) and 18 (11–25), respectively. 21 patients had at least one qualifying report. Nighttime PWV was significantly lower than during the day (9.1 vs. 9.7 ± 0.8 mm/s, p < 0.01). Systolic aortic blood pressure was 6 mmHg lower than brachial blood pressure in the day time (p < 0.01) and 4 mmHg lower during the night (p < 0.05). Each single measurement was standardized with the 24 h average as reference thus generating data from 1004 paired observations. The standardized PWV correlated with standardized values of heart rate (r = 0.24, p < 0.001) and systolic aorta blood pressure (r = 0.20, p < 0.001). A stepwise multiple regression model with standardized pulse wave velocity as dependent variable included standardized heart rate, systolic aorta blood pressure and a dummy variable for day/night status (R2 = 0.091, p < 0.001). Conclusion:The Arteriograph24 is applicable for research purpose. PVW in type 2 diabetes is modestly reduced during the night. The intraindividual variation of heart rate contributed independently to the variation of PWV.

BACKGROUND The SphygmoCor is used for noninvasive assessment of ascending aortic blood pressure (BP). However, the validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with substantial imprecision of central BP estimates. We hypothesized that different noninvasive calibration strategies might improve the accuracy of the estimated ascending aortic BPs. METHODS In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor device and compared these data with invasively recorded data. The validity of the transfer function was assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of noninvasive calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs. DBP+MBP using a form factor (ff) of 0.33 and 0.40, respectively. RESULTS When calibrating with invasive BP, the difference between estimated and invasively measured ascending aortic SBP and DBP was -2.3±5.6/1.0±0.9 mm Hg. When calibrating with oscillometric brachial BPs, the differences were -9.6±8.1/14.1±6.2 mm Hg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1 mm Hg (DBP and MBP; ff = 0.33), and 1.9±12.2/14.1±6.2 mm Hg (DBP and MBP; ff = 0.40), respectively. Calibration with the average of 3 brachial BPs did not improve accuracy. CONCLUSIONS The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Noninvasive calibration with DBP and MBP (ff = 0.40) enables accurate estimation of mean ascending aortic SBP at the group level. However, the wide limits of agreement indicate limited accuracy in the individual patient. CLINICAL TRIALS REGISTRATION Clinical Trials No. NCT01538290.

Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease (CVD). We examined the predictive ability of 24-hour ambulatory pulse pressure (24-h PP), ambulatory arterial stiffness index (AASI) and diurnal blood pressure (BP) parameters for fatal and non-fatal CVD in patients with type 2 diabetes mellitus. A total of 108 patients with type 2 diabetes mellitus (mean duration 6.6 years) were followed for 9.5 (0.5–14.5) years. At baseline, all patients underwent ambulatory BP monitoring. During follow-up, 45 patients had cardiovascular (CV) events (35 non-fatal and 10 fatal). In bivariate analysis, events during follow-up were predicted by 24-h PP (P

Hermida et al. (1) have recently shown an impressive reduction of asleep blood pressure and associated reduction of cardiovascular disease (CVD) events in type 2 diabetic patients treated with at least one antihypertensive drug at bedtime compared with patients who ingested all drugs in the morning. This is a subgroup analysis of the diabetic patients (20%) enrolled in the MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares [Ambulatory Blood Pressure Monitoring for …

BACKGROUND: Elevated pulse pressure (PP) is strongly associated with micro- and macrovascular complications in type 2 diabetic patients. We examined the effect of 12 months of dual blockade with candesartan and lisinopril vs. high-dose lisinopril monotherapy on ambulatory PP in hypertensive type 2 diabetic patients from the CALM (Candesartan and Lisinopril Microalbuminuria Trial) II study.METHODS: The CALM II study was a 12-month prospective, randomized, parallel-group, double-masked study that included 75 type 1 and type 2 diabetic subjects with hypertension. Participants were randomized for treatment with either high-dose lisinopril (40 mg once daily (o.d.)) or for dual blockade treatment with candesartan (16 mg o.d.) and lisinopril (20 mg o.d.). In this article, we present data from the post-hoc subgroup of 51 type 2 diabetic subjects who completed the full 12-month study period with successful ambulatory blood pressure (BP) measurements at both baseline and follow-up visits.RESULTS: Baseline 24-h BP values were similar in the two groups (24-h systolic BP (SBP) 130 +/- 12 vs. 127 +/- 9, 24-h diastolic BP (DBP) 77 +/- 8 vs. 74 +/- 7, and 24-h PP 53 +/- 8 vs. 53 +/- 7 mm Hg, for the lisinopril and dual blockade groups, respectively, P > 0.2 for all). Compared with lisinopril monotherapy, dual blockade treatment caused a highly significant reduction in 24-h PP levels (-5 +/- 5 mm Hg, P = 0.003), albeit the difference in the BP lowering effect between the treatment groups did not differ significantly for 24-h systolic (P = 0.21) or diastolic (P = 0.49) BP. Dual blockade treatment significantly lowered 24-h SBP (-5 +/- 11 mm Hg, P = 0.03), but not 24-h DBP (-2 +/- 7 mm Hg, P = 0.29), whereas in the lisinopril group, the opposite effect was observed (24-h SBP -1 +/- 9 mm Hg, P = 0.45, 24-h SBP -3 +/- 7 mm Hg, P = 0.03).CONCLUSIONS: Twelve months of dual blockade with candesartan and lisinopril significantly reduced PP when compared with high-dose monotherapy with lisinopril. Larger studies are needed to confirm this observation, and to evaluate whether this effect translates into a greater degree of end-organ protection from dual blockade treatment than from conventional angiotensin-converting enzyme (ACE) inhibition.

Decreased left ventricular long-axis function may be the earliest stage in subclinical heart failure in Type II diabetes. To assess whether a decrease in SBP (systolic blood pressure) or a change in metabolic control would improve the long-axis function, 48 Type II diabetic patients participating in the CALM II (Candesartan and Lisinopril Microalbuminuria II) study were included in the present study. Patients were examined with tissue Doppler echocardiography at baseline and after 3 and 12 months of follow-up. Corresponding blood pressure, fructosamine and HbA1c (glycated haemoglobin) values were obtained. During the follow-up period, a decrease in SBP of 8 mmHg was seen (from 141±11 mmHg at baseline to 133±12 mmHg; P

AIMS: To characterize left ventricular function in hypertensive patients with Type 2 diabetes and normal ejection fraction, and to relate these findings to pathogenic factors and clinical risk markers.METHODS: We examined 70 hypertensive patients with Type 2 diabetes mellitus with ejection fraction > 0.55 and fractional shortening > 0.25, all without any cardiac symptoms. Thirty-five non-diabetic subjects served as control subjects. Left ventricular longitudinal function was examined by tissue Doppler derived myocardial strain rate and peak systolic velocities.RESULTS: Hypertensive patients with diabetes had a significantly higher systolic strain rate (-1.1 +/- 0.3 s(-1) vs. -1.6 +/- 0.3 s(-1), P < 0.001) and lower systolic peak velocities (3.3 +/- 1.0 vs. 5.6 +/- 1.0 cm/s, P < 0.001) compared with control subjects. Myocardial systolic strain rate correlated significantly to left ventricular mass (r = 0.40, P < 0.01) and to both HbA1c (r = 0.43, P < 0.01), and fructosamine (r = 0.40, P < 0.01), but was not related to serum levels of carboxymethyllysine, albuminuria, blood pressure (dipping/non-dipping), or oral hypoglycaemic therapy. Patients with diastolic dysfunction had significantly higher levels of urine albumin [21.0 (5-2500) mg/l, vs. 9.5 (1-360), P < 0.01], heart rate (78 +/- 13 vs. 67 +/- 10 b.p.m., P < 0.005), and seated diastolic blood pressure (85 +/- 6 vs. 81 +/- 7 mmHg, P < 0.05) and non-dipping diastolic blood pressure was more frequent.CONCLUSIONS: Long axis left ventricular systolic function was significantly decreased in hypertensive patients with Type 2 diabetes mellitus, and is associated with hyperglycaemia and left ventricular hypertrophy. Diastolic dysfunction was closely related to increased diastolic blood pressure, non-dipping and increased urinary albumin excretion.

AIMS/HYPOTHESIS: The excess mortality in diabetes is mainly due to cardiovascular causes and almost confined to patients with abnormal albuminuria. Compared to healthy subjects, diabetic patients have a prolonged QT interval and increased QT dispersion. In non-diabetic subjects, as well as in Type 1 diabetic patients with overt nephropathy, a prolonged QT interval and increased QT dispersion are associated with cardiac morbidity and mortality. There is an increasing number of studies on effects of beta blocker treatment on QT interval and QT dispersion in non-diabetic subjects. In contrast, there are no studies on the effects of beta blocker treatment on QT interval and QT dispersion in patients with diabetes. The aim of our study was to describe the effects of metoprolol treatment on QT interval and QT dispersion in a group of well-characterised Type 1 diabetic patients with elevated urine albumin excretion.METHODS: We studied the effects of 6 weeks of treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in a randomised, placebo-controlled, double blind, crossover trial including 20 Type 1 diabetic patients. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording and 24-h fractionated urine collections. On days of investigation 12-lead electrocardiograms were recorded and autonomic tests performed.RESULTS: We found strong associations between both daytime and night-time blood pressure and heart-rate-corrected QT interval dispersion (QTc dispersion). Heart rate variability parameters indicating sympathetic and parasympathetic modulation showed strong correlations with heart-rate-corrected QT interval (QTc interval) and with QTc dispersion. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion.CONCLUSIONS/INTERPRETATION: This study is the first to address the QTc interval and QTc dispersion in Type 1 diabetic patients treated with metoprolol. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. These results may in part explain the pronounced cardioprotective effect of beta blocker treatment in diabetic patients with cardiovascular disease.

Significant changes in both blood pressure, autonomic function and kidney ultrastructure are observed in insulin-dependent diabetic (IDDM) patients with microalbuminuria. Intervention strategies are evaluated at even earlier stages of disease. Identification of patients at risk of developing microalbuminuria must be based on a thorough knowledge of the relations between key pathophysiological parameters in patients with normoalbuminuria. The aim of the present study was to characterize the interactions of urinary albumin excretion (UAE), 24-h ambulatory blood pressure (AMBP), and sympathovagal balance in a large group of normoalbuminuric IDDM patients. In 117 normoalbuminuric (UAE < 20 micrograms/min) patients we performed 24-h AMBP (Spacelabs 90207), with assessment of diurnal blood pressure and heart rate (HR) variation, and short-term (three times 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (HR variation to deep breathing, postural HR and blood pressure response). Patients with UAE above the median (4.2 micrograms/min) had significantly higher 24-h systolic and diastolic AMBP (125 +/- 10.1/76 +/- 7.2 mmHg) compared to the low normolbuminuric group (120 +/- 8.4/74 +/- 5.1 mmHg), p < 0.01 and 0.02, respectively. Patients with UAE above the median had significantly reduced short-term RR interval variability including both the high frequency component (5.47 +/- 1.36 vs 6.10 +/- 1.43 ln ms2), and low frequency component (5.48 +/- 1.18 ln ms2 compared to 5.80 +/- 1.41 ln ms2), p < 0.02 and p = 0.04 (ANOVA). In addition, patients with high-normal UAE had reduced mean RR level (faster heart rates) 916 +/- 108 compared to 963 +/- 140 ms, p < 0.04. These differences were not explained by age, duration of diabetes, gender, level of physical activity, or cigarette smoking. HbA1c was significantly higher (8.6 +/- 1.2 vs 8.2 +/- 1.0%, p = 0.03) in the group with high normal UAE. Comparing normoalbuminuric IDDM patients with UAE above and below the median value, we found significantly higher AMBP in combination with significant differences in sympathovagal balance and significantly poorer glycaemic control in the group with high-normal albumin excretion. Our data demonstrate interactions between albumin excretion, blood pressure, autonomic function, and glycaemic status, already present in the normoalbuminuric range and may describe a syndrome indicative of later complications.

Female nondiabetic and streptozotocin diabetic Wistar rats received 200 units heparin two times daily by subcutaneous injection for 6 mo. Mesangial volume fraction was reduced in heparin-treated control (CH) compared with untreated control (C) animals (CH 0.18 +/- 0.02 vs. C 0.24 +/- 0.02, P < 0.05), but other histological parameters were similar. In the heparin-treated diabetic (DH) group, wet kidney weight was increased compared with the untreated diabetic (D) group (DH 1,156 +/- 39 vs. D 1,050 +/- 30 mg, P < 0.05), as were absolute, but not fractional, glomerular volume (P < 0.05) and capillary volume (P < 0.05). Basement membrane thickness (DH 193 +/- 3 vs. D 231 +/- 9 nm, P < 0.01) and mesangial/glomerular volume fraction (P < 0.001) were decreased. Urinary albumin excretion was increased in the heparin-treated control animals compared with control animals [CH 980 (range 150-4,448) vs. C 221 (range 86-654) micrograms/24 h, P < 0.001] and in the heparin-treated diabetic animals compared with the diabetic animals [DH 12,785 (range 4,495-29,520) vs. D 899 (range 450-1,335) micrograms/24 h, P < 0.001]. Thus the possibly deleterious increases in glomerular capillary volume and albumin excretion may negate the beneficial effects of heparin on mesangial and basement membrane structures.

There is general agreement that a fall rate in glomerular filtration rate (GFR) is the principal endpoint in diabetics with renal disease, and that abnormal albuminuria (including microalbuminuria) is an important intermediate end-point. The relative roles of blood pressure (BP) elevation and abnormal albuminuria in the prediction and genesis of renal disease are a matter of debate, and are further analysed in this paper. New studies show that neither genetic predisposition to hypertension (parental BP) nor parental abnormal albuminuria can be used to predict renal disease in patients with type 1 (insulin-dependent) diabetes. However, parental predisposition to proteinuria seems to be important to certain types of patients with type 2 (non-insulin-dependent) diabetes. Cross-sectional as well as follow-up studies document that GFR is generally well preserved in microalbuminuria (in both type 1 and type 2 patients), while the transition to clinical proteinuria is associated with a decline in GFR. Thus, prevention of overt proteinuria is important in clinical trials in microalbuminuric patients. In type 1 diabetes clear ultrastructural changes have been documented with microalbuminuria and a good correlation between abnormal albuminuria and structural damage is seen. Structural damage in normo- and microalbuminuric patients correlates poorly with BP. New studies in type 1 diabetes document that microalbuminuria (but not elevated BP) predicts not only clinical diabetic nephropathy but also end-stage renal failure and mortality. In type 2 diabetes microalbuminuria is the strongest predictor of mortality, whereas BP elevation is not a predictor. Several studies now document that antihypertensive treatment, especially with inhibitors of angiotensin converting enzyme, is able to reverse or reduce abnormal albuminuria, even in non-hypertensive type 1 patients, and possibly preserve GFR. Therefore, microalbuminuria may be the main indicator for starting antihypertensive treatment in these patients. With respect to organ damage in the retina, abnormal albuminuria is an important indicator of the risk of severe diabetic retinopathy. BP elevation seems not to be an initiating factor, but rather aggravates established retinopathy. Left ventricular hypertrophy has a stronger correlation with BP elevation than normoalbuminuria, suggesting that left ventricular hypertrophy is at least partially a phenomenon secondary to elevated BP in diabetic patients with abnormal albuminuria. Generally, abnormal albuminuria is a strong indicator of cardiovascular renal damage in diabetic patients and in most organs is a stronger factor than elevated BP.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Background To investigate aortic dimensions in women with Turner syndrome (TS) in relation to aortic valve morphology, blood pressure, karyotype, and clinical characteristics. Methods and results A cross sectional study of 102 women with TS (mean age 37.7; 18-62 years) examined by cardiovascular magnetic resonance (CMR- successful in 95), echocardiography, and 24-hour ambulatory blood pressure. Aortic diameters were measured by CMR at 8 positions along the thoracic aorta. Twenty-four healthy females were recruited as controls. In TS, aortic dilatation was present at one or more positions in 22 (23%). Aortic diameter in women with TS and bicuspid aortic valve was significantly larger than in TS with tricuspid valves in both the ascending (32.4 ± 6.7 vs. 26.0 ± 4.4 mm; p < 0.001) and descending (21.4 ± 3.5 vs. 18.8 ± 2.4 mm; p < 0.001) aorta. Aortic diameter correlated to age (R = 0.2 - 0.5; p < 0.01), blood pressure (R = 0.4; p < 0.05), a history of coarctation (R = 0.3; p = 0.01) and bicuspid aortic valve (R = 0.2-0.5; p < 0.05). Body surface area only correlated with descending aortic diameter (R = 0.23; p = 0.024). Conclusions Aortic dilatation was present in 23% of adult TS women, where aortic valve morphology, age and blood pressure were major determinants of the aortic diameter.

Background: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined.Methods: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses.Results: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 μg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 μg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 μg/mL increase in plasma fibulin-1, p