Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients

AIMS/INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. MATERIALS AND METHODS: Standardized CARTs (R-R response to paced breathing, Valsalva, postural changes) and digitized 12-lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R-R intervals (SDNN) and the root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG-derived CAN and CARTs-defined CAN. RESULTS: Participants with CARTs-defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P \u3c 0.001). The optimal cut-off points of ECG-derived CAN were \u3c17.13 and \u3c24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30-0.51) for the optimal cut-off point, showing fair agreement with CARTs-defined CAN. Combining SDNN and rMSSD optimal cut-off points does not provide additional predictive power for CAN. CONCLUSIONS: These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care

Caffeine Consumption Contributes to Skin Intrinsic Fluorescence in Type 1 Diabetes.

Background: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine. Materials and Methods: SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort. Results: Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10−32) and SIF14LED 456 nm[0.4, 0.8] (P=7×10−31) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10−12) and SIF14LED 456 nm[0.4, 0.8] (P=4×10−12), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P\u3c0.0001) in the replication cohort. Conclusions: Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes

Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented

Anti-Müllerian hormone and its relationships with subclinical cardiovascular disease and renal disease in a longitudinal cohort study of women with type 1 diabetes

Abstract Background Reproductive age may be a risk factor for vascular disease. Anti-Müllerian hormone (AMH) is produced by viable ovarian follicles and reflects reproductive age. We examined whether AMH concentrations were associated with markers of subclinical cardiovascular disease (CVD) and kidney disease among women with type 1 diabetes. Methods We performed a cross-sectional analysis of the Epidemiology of Diabetes Interventions and Complications Study. Participants included women with type 1 diabetes and ≥1 AMH measurement (n = 390). In multivariable regression models which adjusted for repeated measures, we examined the associations between AMH with CVD risk factors, estimated glomerular filtration rate, and albumin excretion ratio. We also examined whether initial AMH concentrations were associated with the presence of any coronary artery calcification (CAC) or carotid intima media thickness (cIMT). Results After adjustment for age, AMH was not associated with waist circumference, blood pressure, lipid profiles, or renal function. Higher initial AMH concentrations had borderline but non-significant associations with the presence of CAC after adjustment for age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00, 1.16) which were minimally altered by addition of other CVD risk factors, although women in the 3rd quartile of AMH had lower odds of CAC than women in the lowest quartile (OR 0.40, 95% CI 0.17, 0.94). After adjustment for age, higher AMH was associated with statistically significant but only slightly higher cIMT (0.005 mm, p = 0.0087) which was minimally altered by addition of other CVD risk factors. Conclusions Among midlife women with type 1 diabetes, AMH has slight but significant associations with subclinical measures of atherosclerosis. Future studies should examine whether these associations are clinically significant. Trial registration NCT00360815 and NCT00360893 Study Start Date April 1994.https://deepblue.lib.umich.edu/bitstream/2027.42/138004/1/40695_2017_Article_23.pd

Longitudinal Changes in Cardiac Structure and Function from Adolescence to Young Adulthood in Participants with Type 2 Diabetes Mellitus: The TODAY Follow-Up Study

Background: Heart failure is a prominent complication of type 2 diabetes mellitus (T2D). The goal of this study was to provide longitudinal data on cardiac structure and function (and cross-sectional comparison to normal-weight and obese controls without T2D) in individuals followed from adolescence with youth-onset T2D. Methods: In the TODAY study (Treatment Options for Type 2 Diabetes Mellitus in Adolescents and Youth), echocardiograms were performed at study years 4 to 5 and 9 to 10. Echocardiograms were also obtained at years 8 to 9 in a control population of age, race/ethnicity, and sex-matched normal-weight and obese individuals without diabetes mellitus. Study outcomes were measures of left ventricular structure and function. The cohort included 411 participants with T2D, 194 obese controls, and 51 normal-weight controls. Results: At follow-up, mean participant age was 23 years, 65% women, 20% non-Hispanic white, 35% non-Hispanic black, and 39% Hispanic. Ejection fraction was \u3c52% in 11.7% of male participants with T2D. Diastolic function declined during follow-up in participants with T2D (mitral valve lateral E/Em increased 0.72±0.12 in women and 0.50±0.17 in men; P\u3c0.01) and was significantly higher than obese controls (women, 6.65±1.89 versus 5.66±1.37; men, 6.15±1.90 versus 5.26±1.31; P\u3c0.0001). Predictors of adverse changes included hypertension, obesity, female sex, Hispanic and non-Hispanic black ethnicity, worse glycemic control, and elevated heart rate. Cardiac structural abnormalities, left ventricular hypertrophy, or concentric geometry, were highest in those with T2D (15.8% versus 5.7% obese versus 0% normal weight). Conclusions: Adverse changes in cardiac structure and function changed significantly from adolescence to early adulthood in participants with youth-onset T2D

Conventional versus video laryngoscopy for tracheal tube exchange: Glottic visualization, success rates, complications, and rescue alternatives in the high-risk difficult airway patient

BACKGROUND: Tracheal tube exchange is a simple concept but not a simple procedure because hypoxemia, esophageal intubation, and loss of airway may occur with life-threatening ramifications. Combining laryngoscopy with an airway exchange catheter (AEC) may lessen the exchange risk. Laryngoscopy is useful for a pre-exchange examination and to open a pathway for endotracheal tube (ETT) passage. Direct laryngoscopy (DL) is hampered by a restricted line of sight ; thus, airway assessment and exchange may proceed blindly and contribute to difficulty and complications. We hypothesized that video laryngoscopy (VL), when compared with DL, will improve glottic viewing for airway assessment, and the VL-AEC method of ETT exchange will result in a reduction in airway and hemodynamic complications in high-risk patients when compared with a historical group of patients who underwent DL + AEC-assisted exchange. METHODS: Critically ill patients requiring an ETT exchange underwent DL-assisted pre-exchange airway assessment. If the DL-assisted pre-exchange assessment rendered a poor view, these patients underwent a VL-based airway assessment followed by a VL-assisted ETT exchange procedure. The DL and VL pre-exchange assessments were compared. The attempts, complications, and rescue devices required for ETT exchange were analyzed. These exchange results were then compared with a historical control group of patients who (1) were classified as a poor view on DL-assisted pre-exchange airway assessment; and (2) underwent a DL + AEC-assisted exchange. The airway assessment and ETT exchange were performed by a board-certified anesthesiologist from the Department of Anesthesiology alone or with anesthesia resident assistance. RESULTS: Three hundred twenty-eight patients with a poor view on initial DL examination underwent a subsequent VL with comparison of views with the 337 patients in the historical control group (DL + AEC). A majority (88%) had a full or near-full view on VL examination. The first-pass success rate for ETT exchange was greater in the VL group (91.5% vs 67.7% with DL; P = 0.0001) and the number of patients requiring 3+ attempts was lower (1.2% vs 6.8% with DL; P = 0.0003). A commensurate difference in the incidence of mild and severe hypoxemia, esophageal intubation, bradycardia, and the need for rescue airway device intervention was also observed with VL exchange procedures when compared with the historical DL + AEC group. CONCLUSIONS: These findings support the hypothesis that VL may result in better glottic viewing for airway assessment and may permit the ETT exchange procedure to be performed with fewer airway and hemodynamic complications. Execution of the ETT exchange over an AEC was augmented by improved glottic visualization to allow more efficient and timely ETT passage. Multiple attempts to resecure the airway increased the number of exchange complications. VL + AEC exchange led to fewer attempts and is consistent with the recommendation of the American Society of Anesthesiologists Difficult Airway Task Force to limit laryngoscopic attempts and, as a consequence, decrease complications. A VL-based pre-exchange airway assessment may be a valuable procedure for both planning the exchange and uncovering unrecognized airway maladies, for example, partial or complete self-extubation

Conventional Versus Video Laryngoscopy for Tracheal Tube Exchange: Glottic Visualization, Success Rates, Complications, and Rescue Alternatives in the High-Risk Difficult Airway Patient.

BACKGROUND: Tracheal tube exchange is a simple concept but not a simple procedure because hypoxemia, esophageal intubation, and loss of airway may occur with life-threatening ramifications. Combining laryngoscopy with an airway exchange catheter (AEC) may lessen the exchange risk. Laryngoscopy is useful for a pre-exchange examination and to open a pathway for endotracheal tube (ETT) passage. Direct laryngoscopy (DL) is hampered by a restricted line of sight ; thus, airway assessment and exchange may proceed blindly and contribute to difficulty and complications. We hypothesized that video laryngoscopy (VL), when compared with DL, will improve glottic viewing for airway assessment, and the VL-AEC method of ETT exchange will result in a reduction in airway and hemodynamic complications in high-risk patients when compared with a historical group of patients who underwent DL + AEC-assisted exchange. METHODS: Critically ill patients requiring an ETT exchange underwent DL-assisted pre-exchange airway assessment. If the DL-assisted pre-exchange assessment rendered a poor view, these patients underwent a VL-based airway assessment followed by a VL-assisted ETT exchange procedure. The DL and VL pre-exchange assessments were compared. The attempts, complications, and rescue devices required for ETT exchange were analyzed. These exchange results were then compared with a historical control group of patients who (1) were classified as a poor view on DL-assisted pre-exchange airway assessment; and (2) underwent a DL + AEC-assisted exchange. The airway assessment and ETT exchange were performed by a board-certified anesthesiologist from the Department of Anesthesiology alone or with anesthesia resident assistance. RESULTS: Three hundred twenty-eight patients with a poor view on initial DL examination underwent a subsequent VL with comparison of views with the 337 patients in the historical control group (DL + AEC). A majority (88%) had a full or near-full view on VL examination. The first-pass success rate for ETT exchange was greater in the VL group (91.5% vs 67.7% with DL; P = 0.0001) and the number of patients requiring 3+ attempts was lower (1.2% vs 6.8% with DL; P = 0.0003). A commensurate difference in the incidence of mild and severe hypoxemia, esophageal intubation, bradycardia, and the need for rescue airway device intervention was also observed with VL exchange procedures when compared with the historical DL + AEC group. CONCLUSIONS: These findings support the hypothesis that VL may result in better glottic viewing for airway assessment and may permit the ETT exchange procedure to be performed with fewer airway and hemodynamic complications. Execution of the ETT exchange over an AEC was augmented by improved glottic visualization to allow more efficient and timely ETT passage. Multiple attempts to resecure the airway increased the number of exchange complications. VL + AEC exchange led to fewer attempts and is consistent with the recommendation of the American Society of Anesthesiologists Difficult Airway Task Force to limit laryngoscopic attempts and, as a consequence, decrease complications. A VL-based pre-exchange airway assessment may be a valuable procedure for both planning the exchange and uncovering unrecognized airway maladies, for example, partial or complete self-extubation

Urogenital Autonomic Dysfunction in Diabetes.

This review details the epidemiology, possible mechanisms, and risk factors associated with urogenital autonomic dysfunction in diabetes. Autonomic neuropathy in diabetes is associated with various urological complications including bladder and sexual dysfunction. Several studies have reported the high prevalence of bladder and sexual dysfunction in both men and women. The DCCT/EDIC UroEDIC study examined the association between cardiovascular autonomic neuropathy and bladder and sexual dysfunction in a large cohort of participants with type 1 diabetes and was the first to report significant associations. Future studies are needed to further evaluate the association of urogenital complications and autonomic dysfunction in diabetes

The minimum intensity of a mixed exposure that increases the risk of an outcome

Semi-quantitative exposures, such as smoking and alcohol consumption, are common in clinical studies. Their association with outcomes is captured using either a single quantitative variable that includes nonexposed with a value of zero, or using two variables by adding an additional binary variable exposed versus not exposed. Herein, we propose two approaches to determine a lower bound on the amount of such an exposure (eg, number of cigarettes smoked per day) that significantly increases the risk of outcomes. Using smoking as illustration, the first approach consists of sequentially testing the effect of 1, 2, and so on, cigarettes per day, which requires an adjustment for multiplicity to protect the overall type-I error. An alternative gatekeeping approach is also described. The proposed methods are illustrated for the association of smoking with clinically confirmed neuropathy in a logistic regression model, and for the association of smoking with the risk of CVD in a Cox PH regression model

Mediation of the Association of Smoking and Microvascular Complications by Glycemic Control in Type 1 Diabetes.

Studies have demonstrated the adverse effects of smoking on the risk of microvascular complications; however, few have also examined the potential mediating effects of glycemic control. Using data from the Diabetes Control and Complications Trial (DCCT 1983–1993), we describe the acute and long-term risks of smoking on glycemic control and microvascular complications in a well-characterized cohort of participants with type 1 diabetes. The DCCT recorded self-reported smoking behaviors, glycemic exposure based on HbA1c, and complications status. Generalized linear mixed models were used to assess whether time-dependent measurements of smoking predict HbA1c levels. Cox proportional hazard models were used to assess time-dependent smoking exposures as predictors of retinopathy and nephropathy. During a mean of 6.5 years of follow-up, current smokers had consistently higher HbA1c values and were at a higher risk of retinopathy and nephropathy compared with former and never smokers. These risk differences were attenuated after adjusting for HbA1c suggesting that the negative association of smoking on glycemic control is partially responsible for the adverse association of smoking on the risk of complications in type 1 diabetes. These findings support the potential for a beneficial effect of smoking cessation on complications in type 1 diabetes.</div