Debulking surgery after muscular paraffin oil injections: Effects on calcium homeostasis and patient satisfaction.

OBJECTIVE: Cosmetic paraffin oil injections can lead to granuloma formation causing hypercalcemia and kidney failure. This study explores whether debulking surgery is an effective treatment for improving calcium homeostasis, inflammation and clinical symptoms. MATERIALS AND METHODS: In a retrospective study, we reviewed 33 patients undergoing debulking surgery. Changes in calcium, inflammatory markers, and renal function from baseline up to twelve months post-surgery were assessed. Patients were interviewed post-surgery. RESULTS: The patients were 34.6 years (SD 6.9) and had 1,104 grams (SD 591) of granuloma tissue removed following injection of 1,329 mL (SD 803) paraffin oil 7.9 years (SD 3.2) earlier. Seventeen patients had hypercalcemia and experienced a significant decline in ionized calcium from 1.48 mmol/L (SD 0.16) at baseline to 1.33 mmol/L (SD 0.03) at twelve months (p<0.002), although only four men (23.5%) became normocalcemic. Serum ferritin was reduced by 50% after twelve months (p=0.048). Sixteen patients were normocalcemic and had no change in calcium homeostasis but experienced a 20% drop in serum ferritin levels (p=0.025) after surgery. Fifteen patients completed all their planned surgeries within the study period and experienced a decline in serum ionized calcium (p=0.031), ferritin (p=0.011), and interleukin 2-receptor (p=0.037). A patient satisfaction survey showed that 55% of patients reported post-operative satisfaction scores of 10/10, and 59% of the patients reported reduced pain. CONCLUSION: Surgery improved calcium homeostasis in a fraction of patients, reduced inflammation and subjective symptoms such as pain and mental well-being in a patient group left with few treatment options except high-dose prednisolone.

Circulating metabolomic markers in association with overall burden of microvascular complications in type 1 diabetes.

INTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality. RESEARCH DESIGN AND METHODS: In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications-ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment. RESULTS: The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events. CONCLUSIONS: While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.

Ceramides as Risk Markers for Future Cardiovascular Events and All-Cause Mortality in Long-standing Type 1 Diabetes.

Ceramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and their ratios are associated with future development of cardiovascular (CV) disease (CVD). We examined the associations between serum ceramide levels with CVD, kidney failure, and all-cause mortality in individuals with long-standing type 1 diabetes (T1D). We included 662 participants with T1D and 6-year follow-up, with a mean age of 55 years and mean diabetes duration of 33 years. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured, and predefined ratios were calculated. Adjusted Cox regression analyses on ceramide levels in relation to future CV events (CVE), kidney failure, and all-cause mortality were performed, with and without adjustment for age, sex, BMI, LDL, triglycerides, systolic blood pressure, HbA1c, history of CVD, smoking status, statin use, estimated glomerular filtration rate (eGFR), and urinary albumin excretion rate (UAER). The ceramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (hazard ratio [HR] = 1.33, P = 0.01) and all-cause mortality (HR = 1.48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers eGFR and UAER. In this study, we demonstrate specific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts. ARTICLE HIGHLIGHTS: Improved tools for assessing risk for diabetes complication before onset will help in complication prevention. We investigated a set of six predefined ceramides and their ratios versus 6-year outcomes of cardiovascular events, kidney failure, and all-cause mortality in people with long-standing type 1 diabetes, using Cox regression with and without adjustment for potential confounders. We found that several ceramides and ceramide ratios associated with cardiovascular events and all-cause mortality. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust marker. These finding show that ceramides can be biomarkers of cardiovascular disease and all-cause mortality in individuals with long-standing type 1 diabetes.

Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes.

BACKGROUND: Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. METHODS: The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use. RESULTS: Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01-1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67-0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70-0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59-0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58-0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04-1.68], p = 0.02), was associated with an increased risk. CONCLUSIONS: Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.

Treatment options for hypercalcemia after cosmetic oil injections: Lessons from human tissue cultures and a pilot intervention study.

OBJECTIVE: Granuloma formation following self-administered cosmetic oil injections can lead to severe hypercalcemia and renal calcifications due to extra-renal vitamin D activation. This translational study aims to identify Prednisolone sparing therapeutics for hypercalcemia after development of granulomatous disease secondary to paraffin oil injections. MATERIALS AND METHODS: Granuloma tissue isolated from five men were cultured ex vivo and treated with selected drugs to block generation of activated vitamin D (1,25(OH)2D3). In a retrospective study, we included data before and during different treatments of 21 men with paraffin oil induced granulomatous hypercalcemia (46 treatment courses) where serum calcium, parathyroid hormone, vitamin D metabolites, creatinine and inflammatory markers were measured. RESULTS: Addition of Ketoconazole or Ciclosporin to granuloma tissue ex vivo culture, significantly suppressed production of 1,25(OH)2D3 after 48 h (both p < 0.05). Prednisolone was the first treatment option in most men and lowered serum levels of ionized calcium after 1, 2, 3 and 6 months compared with baseline (p < 0.05). Ketoconazole or Hydroxychloroquine had no significant effect on serum calcium levels and were unable to reduce the concomitant daily Prednisolone doses (p > 0.05). Azathioprine did not reduce calcium levels. However, addition of Tacrolimus to Prednisolone treatment enabled a reduction in Prednisolone dose after 3 months (p = 0.014), but with no additional effect on calcium homeostasis. CONCLUSION: This study verifies that Prednisolone is an effective treatment and suggests that calcineurin inhibitors may be used as Prednisolone sparing treatment for paraffin oil-induced granulomatous hypercalcemia. Randomized clinical trials are needed to determine clinical efficacy.

Hypercalcemia After Cosmetic Oil Injections: Unraveling Etiology, Pathogenesis, and Severity.

Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH)2 D3 may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle. Moreover, granuloma tissue from three men was cultured for 48 hours ex vivo to determine 1,25(OH)2 D3 production supported by qPCR and immunohistochemistry of vitamin D metabolism and immune cell populations after treatment with 14 different drugs. The 88 men were stratified into men with hypercalcemia (34%), whereas normocalcemic men were separated into men with either normal (42%) or suppressed parathyroid hormone (PTH) (24%). All men had high calcium excretion, and nephrolithiasis was found in 48% of hypercalcemic men, 22% of normocalcemic men with normal PTH, and 47% of normocalcemic men with suppressed PTH. Risk factors for developing hypercalcemia were oil volume injected, injection of heated oil, high serum interleukin-2 receptor levels, and high urine calcium. High 1,25(OH)2 D3 /25OHD ratio, calcium excretion, and low PTH was associated with nephrolithiasis. The vitamin D activating enzyme CYP27B1 was markedly expressed in granuloma tissue, and 1,25(OH)2 D3 was released in concentrations corresponding to 40% to 50% of the production by human kidney specimens. Dexamethasone, ketoconazole, and ciclosporin significantly suppressed granulomatous production of 1,25(OH)2 D3 . In conclusion, this study shows that injection of large oil volumes alters calcium homeostasis and increases the risk of nephrolithiasis. Hypercalciuria is an early sign of disease, and high granulomatous 1,25(OH)2 D3 production is part of the cause. Prospective clinical trials are needed to determine if ciclosporin, ketoconazole, or other drugs can be used as prednisolone-sparing treatment. © 2020 American Society for Bone and Mineral Research (ASBMR).

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.

Carotid-Femoral Pulse Wave Velocity as a Risk Marker for Development of Complications in Type 1 Diabetes Mellitus.

Background The value of carotid-femoral pulse wave velocity (cfPWV) as risk factor for development of complications in type 1 diabetes mellitus remains to be determined. We investigated associations between cfPWV and renal outcomes, cardiovascular events, and all-cause mortality in people with type 1 diabetes mellitus. Methods and Results cfPWV was measured with SphygmoCor in 633 people with type 1 diabetes mellitus. Median (interquartile range) follow-up was 6.2 (5.8-6.7) years. End points included progression in albuminuria group, decline in estimated glomerular filtration rate (eGFR) ≥30%, end-stage kidney disease, cardiovascular event, mortality, and a composite renal end point. Hazard ratios (HRs) were calculated per 1-SD increase in cfPWV. Adjustments included age, sex, hemoglobin A1c, mean arterial pressure, body mass index, low-density lipoprotein cholesterol, smoking, urine albumin excretion rate, and eGFR. The cohort included 45% women, mean (SD) age was 54 (13) years, mean (SD) eGFR was 83.2 (27.9) mL/min per 1.73 m2, and mean (SD) cfPWV was 10.4 (3.3) m/s. Median (interquartile range) albumin excretion rate was 17 (17-63) mg/24 h. After adjustment, higher cfPWV was associated with increased hazard of progression in albuminuria (HR, 1.59; 95% CI, 1.10-2.32); decline in eGFR ≥30% (HR, 1.38; 95% CI, 1.06-1.79); cardiovascular event (HR, 1.31; 95% CI, 1.01-1.70); mortality (HR, 1.36; 95% CI, 1.00-1.85); and the composite renal end point (HR, 1.30; 95% CI, 1.04-1.63), but not with end-stage kidney disease (HR, 1.18; 95% CI, 0.62-2.26). Higher cfPWV was associated with steeper yearly increase in albumin excretion and steeper yearly decline in eGFR after adjustment (P=0.002 and P=0.01, respectively). Conclusions cfPWV was associated with increased hazard of renal outcomes, cardiovascular event, and mortality. cfPWV may be suited for risk stratification in type 1 diabetes mellitus.

Uric acid is not associated with diabetic nephropathy and other complications in type 1 diabetes.

BACKGROUND: To examine the association between plasma uric acid (UA) and the presence of diabetic complications including diabetic nephropathy and cardiovascular risk factors in patients with type 1 diabetes. METHODS: This study, which is cross-sectional in design, included 676 Caucasian type 1 diabetes patients from the Steno Diabetes Center Copenhagen. Participants with UA within the three lowest sex-specific quartiles were compared with participants with levels in the highest quartile. Unadjusted and adjusted linear regression analyses were applied. Adjustment included sex, age, diabetes duration, body mass index, high-density lipoprotein cholesterol, smoking, haemoglobin A1c, 24-h pulse pressure, urinary albumin excretion rate (UAER), estimated glomerular filtration rate (eGFR) and treatment with renin-angiotensin-aldosterone system blockers. RESULTS: Of the 676 patients, 372 (55%) were male, mean ± SD age was 55 ± 13 years and eGFR was 82 ± 26 mL/min/1.73 m2. The median UA was 0.30 (interquartile range 0.23-0.37) mmol/L. UA in the upper sex-specific quartile was associated with lower eGFR, higher UAER and carotid-femoral pulse wave velocity and lower 24 h and daytime diastolic blood pressure (BP) in unadjusted analyses (P < 0.001). Moreover, UA in the upper sex-specific quartile was associated with higher nighttime systolic BP and the presence of cardiovascular disease in unadjusted analyses (P ≤ 0.01), but significance was lost after adjustment (P ≥ 0.17). UA was higher across the retinopathy groups [nil (n = 142), simplex (n = 277), proliferative (n = 229) and blind (n = 19)] in unadjusted analyses (P < 0.0001), but not after adjustment (P = 0.12). Patients with an accelerated decline in eGFR (≥3 mL/min/year) had significantly higher UA at baseline (P = 0.006) compared with slow decliners (<3 mL/min/year), but significance was lost after adjustment (P = 0.10). CONCLUSIONS: In type 1 diabetes patients, higher UA was associated with lower kidney function and other diabetic complications. The association between higher UA and lower eGFR and lower diastolic BP was independent of traditional risk factors.

Arterial-ventricular coupling in type 1 diabetes: arterial stiffness is associated with impaired global longitudinal strain in type 1 diabetes patients-the Thousand & 1 Study.

AIMS: Diabetes is associated with higher arterial stiffness-an early marker of cardiovascular disease. The coupling between arterial stiffness and myocardial function is still unresolved. We investigate associations between arterial stiffness and early myocardial impairment assessed with advanced echocardiography. METHODS: In 305 type 1 diabetes (T1D) patients without known heart disease and with normal left ventricular ejection fraction (LVEF) (biplane LVEF > 45%), we measured arterial stiffness as pulse wave velocity (PWV) and performed conventional and speckle-tracking echocardiography assessing global longitudinal strain (GLS) as a measure of systolic myocardial function. Associations between PWV and myocardial function were reported as standardized beta values from adjusted regression models including age, sex, mean arterial pressure, body mass index, HbA1c, diabetes duration, estimated glomerular filtration rate, degree of albuminuria, total cholesterol, heart rate and smoking. RESULTS: Patients were 54 (12) years [mean (SD)], 152 (50%) females, diabetes duration 31 (16) years, HbA1c 65 (12) mmol/mol, LVEF 58 (5) %, GLS -18.2 (2.6) % and PWV 10.2 (3.4) m/s. There was no association between PWV and LVEF (p = 0.93). Conversely, there was a highly significant association between PWV and GLS in crude and multivariable models (standardized ß-coefficient 0.25, p < 0.001 and 0.16, p = 0.036, respectively). Also, diastolic function measured as E/e' was highly associated with PWV in crude and multivariable models (standardized ß-coefficient 0.43, p < 0.001 and 0.17, p = 0.016, respectively). CONCLUSIONS: In T1D patients with normal LVEF and without known heart disease, higher arterial stiffness is independently associated with early systolic and diastolic myocardial impairment detectable by advanced echocardiography. Although unable to demonstrate causality, we display a relationship between diabetic angiopathy and diabetic cardiomyopathy (H-3-2009-139 and PROFIL-H-B-2009-056).

Increased plasma concentrations of midregional proatrial natriuretic Peptide is associated with risk of cardiorenal dysfunction in type 1 diabetes.

BACKGROUND: To examine possible associations between midregional proatrial natriuretic peptide (MR-proANP) and diabetic complications at baseline and risk of mortality and end-stage renal disease (ESRD) during follow-up in type 1 diabetes. METHODS: Observational study including 667 patients, with plasma MR-proANP measured at baseline. Complications were defined as micro- (n = 168) or macroalbuminuria (n = 190) (urinary albumin excretion rate (UAER) 30-299 or ≥ 300 mg/24h), previous cardiovascular disease (CVD) (n = 143), cardiac autonomic dysfunction (heart rate variability < 11 beats/min) (n = 369), and retinopathy (n = 523). Adjustments included gender, age, systolic blood pressure, estimated glomerular filtration rate (eGFR), UAER, HbA1c, total cholesterol, 24-hour urinary sodium excretion (24h-U(Na)), body mass index, daily insulin dose, antihypertensive treatment, and smoking in linear regression analyses and analysis of covariance models. Development of ESRD (dialysis, renal transplantation, or GFR/eGFR < 15 ml/min/1.73 m(2)) and mortality was recorded through national registers. RESULTS: The cohort included 293 (44%) females, aged 55 ± 13 years. Plasma MR-proANP (median (interquartile)) was 74.7 (49.2-116.8) pmol/L. Adjusted, MR-proANP correlated positively with age and UAER and negatively with eGFR, 24h-U(Na), total cholesterol, and HbA1c (P < 0.05). Moreover, MR-proANP levels increased with albuminuria degree and were higher in patients with previous CVD (P ≤ 0.001), but similar in patients with or without autonomic dysfunction or retinopathy (P ≥ 0.076). During follow-up (3.5 (3.1-4.0) years), higher MR-proANP concentrations predicted ESRD and mortality combined (n = 35) adjusted for gender, age, systolic blood pressure, eGFR, and previous CVD (hazard ratio per 1SD increase in logANP: 2.8 (1.6-4.7; P < 0.001)). CONCLUSIONS: Increased plasma MR-proANP was associated with impaired renal function, increased albuminuria, and previous CVD. Moreover, MR-proANP concentrations were associated with increased risk of development of ESRD and mortality combined during follow-up.

Treatment with continuous subcutaneous insulin infusion is associated with lower arterial stiffness.

AIMS: To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. METHODS: Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER ≥30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. RESULTS: CSII- versus MDI-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old (mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA1c 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) (P ≥ 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly (P = 0.038) associated with lower PWV, whereas HbA1c-level was not (P = 0.93). CONCLUSIONS: In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA1c was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA1c-level affect arterial stiffness. This needs confirmation in randomised prospective studies.

Pulse wave reflection is associated with diabetes duration, albuminuria and cardiovascular disease in type 1 diabetes.

AIMS: We investigate associations between the pulse-wave-derived measures augmentation pressure (AP) and augmentation index, and diabetic complications in type 1 diabetes. METHODS: This cross-sectional study from 2009-2011 included 676 type 1 diabetes patients. SphygmoCor (Atcor Medical, Australia) measured AP and heart rate-adjusted augmentation index (AI75). Diabetic complications were micro- or macroalbuminuria [urinary albumin excretion rate (UAER) 30-299 or ≥300 mg/24-h], cardiovascular disease (CVD) (previous revascularization, myocardial infarction, peripheral arterial disease or stroke), autonomic dysfunction (heart rate variability <11 beats/min), or retinopathy (simple, proliferative or blindness). Adjustments included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication, and smoking. RESULTS: AP and AI75 measurements were available in 636 (94.1 %) patients and were 9.9 ± 7.6 mmHg and 16.9 ± 12.0, respectively. After adjustment, AP and AI75 were independently associated with diabetes duration and albuminuria (p ≤ 0.001). Furthermore, higher AP and AI75 were associated with previous CVD [adjusted odds ratios (95 % confidence interval) (per 1 SD increase) 1.9 (1.3-2.7) and 1.5 (1.0-2.2) (p ≤ 0.039)], but not with autonomic dysfunction or retinopathy (p ≥ 0.12). CONCLUSIONS: In type 1 diabetes, augmentation pressure and heart rate-adjusted augmentation index were associated with diabetes duration, albuminuria, and CVD, independently of conventional risk factors. ClinicalTrials.gov:NCT01171248.

Central hemodynamics are associated with cardiovascular disease and albuminuria in type 1 diabetes.

BACKGROUND: We sought to investigate associations between central hemodynamic parameters (estimated from radial pulse wave analyses (PWAs)), cardiovascular disease (CVD), and albuminuria in type 1 diabetes. METHODS: We conducted an observational study of 636 type 1 diabetes patients. Central hemodynamics were measured by PWA as central aortic systolic pressure (CASP), central aortic pulse pressure (CPP), central aortic diastolic pressure (CADP), and subendocardial viability ratio (SEVR). CVD included revascularization, myocardial infarction, peripheral arterial disease, and stroke. Albuminuria was urinary albumin excretion rate ≥30 mg/24 hours. We computed standardized odds ratios (ORs) adjusted for sex, age, mean arterial pressure (MAP), heart rate, height, estimated glomerular filtration rate, glycated hemoglobin (HbA1c) total cholesterol, antihypertensive medication, and smoking. At follow-up, development of end-stage renal disease (ESRD) and mortality was traced through electronic medical records. RESULTS: Patients were aged a mean of 54±13 years, and 289 (45%) were women. The mean ± SD was 118±17 mm Hg for CASP, 75±10 mm Hg for CADP, 43±14 mm Hg for CPP, and 150±32 for SEVR. In fully adjusted models, increased CASP and CPP and decreased CADP and SEVR were associated with presence of CVD (n = 132; P ≤ 0.02) and presence of albuminuria (n = 335; P < 0.001). During follow-up, median (range) (2.8 (0.7-3.8) years), SEVR predicted ESRD or mortality combined (n = 26) after adjustment for sex, age, and MAP (P = 0.001), whereas CASP, CPP, and CADP did not (P ≥ 0.13). CONCLUSIONS: In type 1 diabetes patients, increased CASP and CPP and decreased CADP and SEVR were independently associated with history of CVD and albuminuria. Furthermore, SEVR predicted mortality and ESRD during follow-up. Future studies are needed to determine whether targeting central hemodynamics improves outcome.