Visit-to-visit variability of clinical risk markers in relation to long-term complications in type 1 diabetes.

BACKGROUND: Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS: This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR <15 ml/min/1.73 m2 , chronic dialysis or kidney transplantation; eGFR decline ≥30%; and mortality. Adjustment included age, sex, cholesterol, HbA1c , SBP, body mass index, smoking, albuminuria, eGFR, and mean, intercept, slope of respective exposure variables and regression models. RESULTS: SBP VV was significantly associated with CVE (adjusted hazard ratio per 50% increase, (CI 95%); p: 1.21 [1.05-1.39]; p = 0.008), ESKD (1.51 [1.16-1.96]; p = 0.002) and mortality (1.25 [1.09-1.44]; p = 0.002). HbA1c VV was significantly associated with mortality (1.51 [1.30-1.75]; p < 0.001); albuminuria VV with eGFR decline (1.14 [1.08-1.20]; p = 0.024) and ESKD (1.14 [1.02-1.27]; p < 0.001), but neither CVE nor mortality. Adjusted eGFR VV was not associated with endpoints. CONCLUSION: In type 1 diabetes, higher variability of basic clinical risk markers adds important risk stratification information for the development of micro- and macrovascular complications.

The impact of the glucagon-like peptide-1 receptor agonist liraglutide on natriuretic peptides in heart failure patients with reduced ejection fraction with and without type 2 diabetes.

AIM: To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed. RESULTS: In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52). CONCLUSION: Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF.

Heart rate increases in liraglutide treated chronic heart failure patients: association with clinical parameters and adverse events.

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias. Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p<.005). Increases in HR correlated with liraglutide dose (p=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. Conclusions. During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study.

BACKGROUND: The glucagon-like peptide-1 analog liraglutide increases heart rate and may be associated with more cardiac events in chronic heart failure (CHF) patients. We studied whether this could be ascribed to effects on myocardial glucose uptake (MGU), myocardial blood flow (MBF) and MBF reserve (MFR). METHODS AND RESULTS: CHF patients with left ventricular ejection fraction ≤45% and without type 2 diabetes were randomized to liraglutide (N = 18) 1.8 mg once daily or placebo (N = 18) for 24 weeks in a double-blinded design. Changes in MGU during an oral glucose tolerance test (OGTT) and changes in MBF and MFR from baseline to follow-up were measured quantitatively by 18F-FDG and 15O-H2O positron emission tomography. Compared with placebo, liraglutide reduced weight (P = 0.03), HbA1c (P = 0.03) and the 2-hour glucose value during the OGTT (P = 0.004). Despite this, changes in MGU (P = 0.98), MBF (P = 0.76) and MFR (P = 0.89) from baseline to follow-up did not differ between groups. Furthermore, there was no association between the level of insulin resistance at baseline and changes in MGU in patients treated with liraglutide. CONCLUSION: Liraglutide did not affect MGU, MBF, or MFR in non-diabetic CHF patients. Any potential increase in cardiac events in these patients seems not to involve changes in MGU, MBF, or MFR. TRIAL REGISTRATION: Trial registry: http://www.ClinicalTrials.org . Identifier: NCT01472640. Url: https://clinicaltrials.gov/ct2/show/NCT01472640?term=NCT01472640&rank=1.

Heart failure patients with prediabetes and newly diagnosed diabetes display abnormalities in myocardial metabolism.

BACKGROUND: In type 2 diabetes, a decrease in myocardial glucose uptake (MGU) may lower glucose oxidation and contribute to progression of chronic heart failure (CHF). However, it is unsettled whether CHF patients with prediabetes have abnormal MGU and myocardial blood flow (MBF) during normal physiological conditions. METHODS AND RESULTS: We studied 35 patients with CHF and reduced left ventricular ejections fraction (34 ± 9%) without overt T2D (mean HbA1c: 40 ± 4 mmol/mol) using echocardiography and quantitative measurements of MGU by 18F-FDG-PET and perfusion by 15O-H2O-PET. An oral glucose tolerance test (OGTT) was performed during the FDG-PET, which identified 17 patients with abnormal and 18 patients with normal glucometabolic response. Global MGU was higher in patients with normal OGTT response (0.31 ± 0.09 µmol/g/min) compared with patients with abnormal OGTT response (0.25 ± 0.09 µmol/g/min) (P = 0.05). MBF (P = 0.22) and myocardial flow reserve (MFR) (P = 0.83) were similar in the study groups. The reduced MGU in prediabetic patients was attributable to reduced MGU in viable myocardium with normal MFR (P < 0.001). CONCLUSION: CHF patients with prediabetes have reduced MGU in segments with preserved MFR as compared to CHF patients with normal glucose tolerance. Whether reversal of these myocardial abnormalities can improve outcome needs to be investigated in large-scale studies.

Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy.

High-sensitivity troponin T (hsTnT) is a marker of cardiovascular disease (CVD) and in type 2 diabetes also a marker of renal events, but has not been evaluated in type 1 diabetics. We therefore reviewed a type 1 diabetes cohort of 442 without and 458 with diabetic nephropathy. Baseline samples were analyzed for hsTnT levels. Cox regression analyses assessed predictive value in relation to the development of end-stage renal disease (ESRD) in 99 patients, all-cause mortality in 178, and CVD events in 134 after up to 12 years of follow-up. To assess if hsTnT improved risk prediction beyond traditional clinical risk markers, we calculated c statistics and relative integrated discrimination improvement. HsTnT was significantly higher in patients with diabetic nephropathy compared to normoalbuminuria (median 8.9 vs 3.1 ng/L). For a doubling in hsTnT levels, and after adjustment for well-known risk factors, including NT-proBNP and hsCRP, the hazard ratio for ESRD at 1.26 was not significant in the diabetic nephropathy group, but there was a significant association with GFR decline after adjustment during follow-up (2.9 ml/min/1.73 m2 annual decline per doubling in hsTnT). The unadjusted and adjusted hazard ratios for mortality (1.64 and 1.32, respectively) were significant in patients with, but not for patients without, nephropathy. Adjusted hazard ratios for fatal and non-fatal CVD events were significant for the whole cohort (1.13), and those with nephropathy (1.14), but not significant for normoalbuminuria (1.06). Addition of hsTNT to traditional risk factors significantly increased the area under the curve by 0.01 in a receiver-operating characteristic curve for mortality. The relative integrated discrimination improvement was increased 15.7% for mortality, 6.3% for CVD, and 1.9% for ESRD (all significant). Thus, higher hsTnT is an independent predictor of renal decline and cardiovascular events in patients with type 1 diabetes and diabetic nephropathy.

Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure.

Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may also have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischaemic heart failure (CIHF). In a parallel group study, 22 patients with compensated CIHF and 21 matched control subjects without heart failure or ischemic heart disease were evaluated by cardiac magnetic resonance imaging, cardiopulmonary exercise testing, skeletal muscle function testing, blood pressure measurement and blood sampling before and after 28 ± 4 days of once daily RIC treatment. RIC was conducted as four cycles of 5 min upper arm ischemia followed by 5 min of reperfusion. RIC did not affect left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) in patients with CIHF (p = 0.63 and p = 0.11) or matched controls (p = 0.32 and p = 0.20). RIC improved GLS in the subgroup of patients with CIHF and with NT-proBNP plasma levels above the geometric mean of 372 ng/l (p = 0.04). RIC did not affect peak workload or oxygen uptake in either patients with CIHF (p = 0.26 and p = 0.59) or matched controls (p = 0.61 and p = 0.10). However, RIC improved skeletal muscle power in both groups (p = 0.02 for both). In patients with CIHF, RIC lowered systolic blood pressure (p < 0.01) and reduced NT-proBNP plasma levels (p = 0.02). Our findings suggest that long-term RIC treatment does not improve LVEF but increases skeletal muscle function and reduces blood pressure and NT-proBNP in patients with compensated CIHF. This should be investigated in a randomized sham-controlled trial.

Circulating matrix metalloproteinases are associated with arterial stiffness in patients with type 1 diabetes: pooled analysis of three cohort studies.

BACKGROUND: Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. METHODS: Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. RESULTS: After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [ß per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [ß per 1 SD higher lnMMP-1 and lnMMP-2 = - 0.83 mmHg (95% CI - 1.50; - 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. CONCLUSIONS: MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets.

Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.

AIMS: In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels. METHODS AND RESULTS: We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59 µM, range: 14-694 µM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P = 0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P = 0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P = 0.02]. For every 100 µmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [ß: 238 (95% CI: 185-292), P < 0.0001], age [ß: 2.43 (95% CI: 1.14-3.72), P < 0.0001], plasma insulin {ß: -0.28 [95% CI: -0.54-(-0.02)], P = 0.036}, body mass index {ß: -3.15 [95% CI: -5.26-(-0.05)], P = 0.046}, diabetes [ß: 44.49 (95% CI: 14.84-74.14), P = 0.003], glycosylated haemoglobin [ß: 1.92 (95% CI: 0.24-3.59), P = 0.025], New York Heart Association class [ß: 26.86 (95% CI: 5.99-47.72), P = 0.012], and NT-proBNP [ß: 0.03 (95% CI: 0.01-0.04), P = 0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [ß: 216 (95% CI: 165-268), P > 0.001]. CONCLUSIONS: In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels.

A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.

Soluble CD40 ligand is elevated in type 1 diabetic nephropathy but not predictive of mortality, cardiovascular events or kidney function.

Soluble CD40 ligand (sCD40L) derived from platelets mediates atherothrombosis, leading to proinflammatory and proatherosclerotic responses. We investigated the predictive value of plasma sCD40L for all-cause mortality, cardiovascular mortality and morbidity, progression towards end-stage renal disease (ESRD) and rate of decline in glomerular filtration rate (GFR) in patients with type 1 diabetes (T1DM) and nephropathy. The study was a prospective, observational follow-up study of 443 T1DM patients with diabetic nephropathy (274 men; age 42.1 ± 10.5 years [mean ± SD], duration of diabetes 28.3 ± 8.9 years, GFR 76 ± 33 ml/min/1.73 m2) and a control group of 421 patients with longstanding type 1 diabetes and persistent normoalbuminuria (232 men; age 45.4 ± 11.5 years, duration of diabetes 27.7 ± 10.1 years) at baseline. sCD40L was measured by ELISA. Plasma sCD40L levels were higher in patients with diabetic nephropathy compared to normoalbuminuric patients (median (range) 1.54 (0.02-13.38) vs. 1.30 (0.04-20.65) µg/L, respectively p = 0.004). The patients were followed for 8.1 (0.0-12.9) years (median (range)). Among normoalbuminuric patients, sCD40L levels did not predict all-cause mortality (p = 0.33) or combined fatal and non-fatal cardiovascular disease (CVD) (p = 0.27). Similarly, among patients with diabetic nephropathy, the covariate adjusted sCD40L levels did not predict all-cause mortality (p = 0.86) or risk of fatal and non-fatal CVD (p = 0.08). Furthermore, high levels of sCD40L did not predict development of ESRD (p = 0.85) nor rate of decline in GFR (p = 0.69). Plasma sCD40L is elevated in T1DM nephropathy but is not a predictor of all-cause mortality, cardiovascular mortality and morbidity or deterioration of kidney function

Optimizing heart failure treatment following cardiac resynchronization therapy.

BACKGROUND: Device therapy in addition to medical treatment improves prognosis in a subset of patients with heart failure and reduced ejection fraction. However, some patients remain symptomatic or their heart failure even progresses despite cardiac resynchronization therapy (CRT). The aim of the study was to evaluate the proportion of patients who could benefit from optimization of medical therapy using sacubitril/valsartan, ivabradine, or both following CRT implantation. METHODS: We conducted a post hoc analysis of a single-centre, patient and outcome-assessor blinded, randomized-controlled trial, in which patients scheduled for CRT were randomized to empiric (n = 93) or imaging-guided left-ventricular lead placement (n = 89). All patients underwent clinical evaluation and blood sampling at baseline and 6 months following CRT implantation. The proportion of patients meeting the indication for sacubitril/valsartan (irrespective of angiotensin-converting enzyme inhibitor or angiotensin 2 receptor blocker dosage) and/or ivabradine according to current guidelines was evaluated at baseline and after 6 months. RESULTS: Of 182 patients with an indication for CRT, 146 (80%) also had an indication for optimization of medical therapy at baseline by adding sacubitril/valsartan, ivabradine, or both. Of the 179 survivors at 6 months, 136 (76%) were still symptomatic after device implantation; of these, 51 (38%) patients had an indication for optimization of medical therapy: sacubitril/valsartan in 37 (27%), ivabradine in 7 (5%), and both drugs in 7 (5%) patients. Seven (18%) patients without indication at baseline developed an indication for medical optimization 6 months after CRT implantation. CONCLUSION: In the present study, 38% of those who remained symptomatic 6 months after CRT implantation were eligible for optimization of medical therapy with sacubitril/valsartan, ivabradine, or both. Patients with CRT may benefit from systematic follow-up including evaluation of medical treatment.

The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes.

Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion >300 mg/24h) and 319 controls with persistent normoalbuminuria (<30 mg/24h), despite > or =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.

Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial.

BACKGROUND: Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation. The aim of our study was to establish if spironolactone affects the ability to autoregulate GFR. METHODS: Sixteen hypertensive type 1 diabetic patients with persistent normoalbuminuria (presumed normal autoregulation) completed this randomized, double-masked, crossover trial. After a 4-week wash-out period, patients received spironolactone 25 mg o.d. and matched placebo for 4 weeks in random order. After each treatment period, the ability to autoregulate GFR was determined by measuring GFR ((51)Cr-EDTA clearance) before (basal) and after acute blood pressure reduction by intravenous injection of clonidine. RESULTS: During placebo, the mean (SE) basal GFR was 115 (5) ml/min/1.73 m(2) and the BP was 146 (4)/81 (2) mmHg corresponding to a MAP of 103 (2) mmHg. Spironolactone did not significantly reduce GFR or BP. Injection of clonidine induced a significant reduction in the MAP of 17 (2) and 19 (1) mmHg during placebo and spironolactone treatment, respectively, and an overall reduction in GFR of 11 and 15 ml/min/1.73 m(2) (both comparisons NS between treatment periods). Signs of impaired autoregulation were present in nine patients during placebo and in nine patients during spironolactone treatment. Relative changes in GFR on placebo treatment correlated with diabetes duration (R = 0.67, P < 0.01) but were not related to duration of hypertension, baseline BP, GFR, HbA1c or to changes in BP. CONCLUSION: Spironolactone did not change the overall ability to autoregulate GFR in 16 hypertensive type 1 diabetic patients with normoalbuminuria. Our data are suggestive that the ability to autoregulate GFR is gradually impaired with increasing diabetes duration, a phenomenon not previously described in normoalbuminuric patients.

Quantitative estimation of extravascular lung water volume and preload by dynamic 15O-water positron emission tomography.

AIMS: Left ventricular filling pressure (preload) can be assessed by pulmonary capillary wedge pressure (PCWP) during pulmonary arterial catheterization (PAC). An emerging method [pulse indexed contour cardiac output (PICCO)] can estimate preload by global end-diastolic volume (GEDV) and congestion as extravascular lung water (EVLW) content. However, no reliable quantitative non-invasive methods are available. Hence, in a porcine model of pulmonary congestion, we evaluated EVLW and GEDV by positron emission tomography (PET). The method was applied in 35 heart failure (HF) patients and 9 healthy volunteers. METHODS AND RESULTS: Eight pigs were studied. Pulmonary congestion was induced by a combination of beta-blockers, angiotensin-2 agonist and saline infusion. PAC, PICCO, computerized tomography, and 15O-H2O-PET were performed. EVLW increased from 521 ± 76 to 973 ± 325 mL (P < 0.001) and GEDV from 1068 ± 170 to 1254 ± 85 mL (P < 0.001). 15O-H2O-PET measures of EVLW increased from 566 ± 151 to 797 ± 231 mL (P < 0.001) and GEDV from 364 ± 60 to 524 ± 92 mL (P < 0.001). Both EVLW and GEDV measured with PICCO and 15O-H2O-PET correlated (r2 = 0.40, P < 0.001; r2 = 0.40, P < 0.001, respectively). EVLW correlated with Hounsfield units (HU; PICCO: r2 = 0.36, P < 0.001, PET: r2 = 0.46, P < 0.001) and GEDV with PCWP (PICCO: r2 = 0.20, P = 0.01, PET: r2 = 0.29, P = 0.002). In human subjects, measurements were indexed (I) for body surface area. Neither EVLWI nor HU differed between chronic stable HF patients and healthy volunteers (P = 0.11, P = 0.29) whereas GEDVI was increased in HF patients (336 ± 66 mL/m2 vs. 276 ± 44 mL/m2, P = 0.01). CONCLUSION: The present study demonstrates that 15O-H2O-PET can assess pulmonary congestion and preload quantitatively. Hence, prognostic information from 15O-H2O-PET examinations should be evaluated in clinical trials.

Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes.

OBJECTIVE: Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota-derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models. RESULTS: After 15.0 (6.7-19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R 2 = 0.29; P < 0.001). CONCLUSIONS: In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.

Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type I diabetes and diabetic nephropathy.

Adiponectin levels are increased in patients with type I diabetes especially in the presence of microangiopathy. Here we determined the predictive value of serum adiponectin levels and 8 adiponectin gene polymorphisms for mortality, cardiovascular events and end-stage renal disease in type I diabetic patients. This prospective, observational follow-up study of type I diabetics consisted of 438 patients with overt diabetic nephropathy that were compared to 440 type I patients with normal albumin excretion. These two groups were followed an average of 8 years and generally matched for gender, age and duration of diabetes. Cox regression analysis of 373 patients showed a covariate-adjusted hazard ratio for all-cause mortality of 1.46 for a change of one standard deviation in log10 of serum adiponectin. There was no association with cardiovascular events; however, serum adiponectin levels predicted end stage renal disease in a covariate-adjusted analysis. Two of eight gene polymorphisms, found in the 878 patients, were associated with increased serum adiponectin levels but none of the polymorphisms were associated with a renal or cardiovascular outcome. These studies show that high serum adiponectin levels predict mortality and progression to end stage renal disease in type I diabetic patients.

Heart Failure: Epidemiology, Pathophysiology, and Management of Heart Failure in Diabetes Mellitus.

This article briefly discusses the epidemiology of heart failure and diabetes and summarizes the key findings from the recent cardiovascular outcome trials in patients with type 2 diabetes, with a focus on heart failure as an endpoint.

Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease in Individuals With Type 1 Diabetes: A 12-Year Follow-up Study.

Methylglyoxal (MGO), a major precursor for advanced glycation end products, is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline and recorded fatal and nonfatal CVD over a median follow-up of 12.3 years (interquartile range 7.6-12.5 years). Data were analyzed by Cox regression, with adjustment for sex, age, HbA1c, DN, diabetes duration, smoking, systolic blood pressure, antihypertensive medication, and BMI. During follow-up, 73 individuals suffered at least one CVD event (36 fatal and 53 nonfatal). Higher MGO levels were associated with total, fatal, and nonfatal incident CVD (hazard ratios [HRs] 1.47 [95% CI 1.13-1.91], 1.42 [1.01-1.99], and 1.46 [1.08-1.98], respectively). We observed a similar trend for total mortality (HR 1.24 [0.99-1.56]). This study shows for the first time in our knowledge that plasma MGO levels are associated with cardiovascular events in individuals with type 1 diabetes. MGO may explain, at least in part, the increased risk for CVD in type 1 diabetes.