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Yamagami D, Deguchi T, Arimura A, Nishio Y. Relationship between the progression of diabetic polyneuropathy and impaired circadian blood pressure variability. J Diabetes Investig 2025; 16:463-474. [PMID: 39696835 PMCID: PMC11871388 DOI: 10.1111/jdi.14282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/25/2024] [Accepted: 07/22/2024] [Indexed: 12/20/2024] Open
Abstract
AIMS/INTRODUCTION We evaluated the 24-h ambulatory blood pressure monitoring data of patients to investigate the relationship between the progression of diabetic polyneuropathy and impaired circadian blood pressure variability. MATERIALS AND METHODS This study included 154 patients with diabetes who were hospitalized for hyperglycemic control. Routine biochemical and hematological tests, ambulatory blood pressure monitoring, screening for diabetic complications, nerve conduction studies, and Holter electrocardiography were carried out on all patients. They were classified according to the Baba classification and the clinical staging for diabetic polyneuropathy, and their ambulatory blood pressure monitoring data were compared. RESULTS The patients were classified into stages 0 (n = 64), I (n = 42), II (n = 24), III (n = 11) and IV (n = 13) according to the Baba classification. As the severity of diabetic polyneuropathy progressed, the degree of nocturnal blood pressure reduction decreased and the percentage of patients with riser-type impaired circadian blood pressure variability increased. Similar results were observed in patients classified according to the clinical staging for diabetic polyneuropathy. In the multivariate logistic regression analysis, the severity of diabetic neuropathy and urinary albumin excretion were independently associated with the percentage of patients with riser-type. However, the adjusted odds ratio was the highest for Baba class I and decreased with increasing severity. CONCLUSIONS Patients with progressive diabetic polyneuropathy and renal impairment often show impaired circadian blood pressure variability. The progression of electrophysiological and clinical neuropathy is associated with riser-type circadian blood pressure variability independent of urinary albumin excretion, insulin therapy, renin-angiotensin-aldosterone system inhibitor medication and body mass index.
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Affiliation(s)
- Dai Yamagami
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahisa Deguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Aiko Arimura
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Yoshihiko Nishio
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
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Lithovius R, Groop PH. The many faces of hypertension in individuals with type 1 diabetes. Diabetes Res Clin Pract 2023; 197:110564. [PMID: 36738830 DOI: 10.1016/j.diabres.2023.110564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023]
Abstract
Several disturbed blood pressure (BP) patterns, including disparities between office and out-of-office BP measurements (such as white-coat and masked hypertension), disturbed circadian BP variability (such as abnormal dipping patterns and nocturnal hypertension) and treatment-resistant hypertension, are common in individuals with type 1 diabetes. Consequently, office or home BP measurements alone may not reflect real BP variation and may lead to inadequate diagnosis and treatment of hypertension. The early detection of these disturbed BP patterns is especially crucial in individuals with type 1 diabetes, as these patterns may indicate future development of adverse cardiovascular and renal outcomes. In this review we will describe these disturbed BP patterns and discuss recent findings on their prevalence and outcomes. We will also address critical areas for future research to determine the true prevalence and prognosis of disturbed BP patterns, and to optimize and improve the knowledge and management of high-risk individuals with type 1 diabetes and disturbed BP patterns.
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Affiliation(s)
- Raija Lithovius
- Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
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Bell DSH. Detecting and treating the protean manifestations of diabetic autonomic neuropathy. Diabetes Obes Metab 2023; 25:1162-1173. [PMID: 36748121 DOI: 10.1111/dom.15004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/17/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.
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Velayutham V, Benitez-Aguirre P, Craig M, Cho YH, Liew G, Donaghue K. Cardiac Autonomic Nerve Dysfunction Predicts Incident Retinopathy and Early Kidney Dysfunction in Adolescents With Type 1 Diabetes. Diabetes Care 2022; 45:2391-2395. [PMID: 35997303 DOI: 10.2337/dc22-0349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 07/10/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Cardiac autonomic neuropathy (CAN) may contribute to vascular complications in diabetes. We hypothesized that adolescents with CAN are at greater risk of diabetic retinopathy and early kidney dysfunction. RESEARCH DESIGN AND METHODS In this prospective longitudinal study of 725 adolescents with type 1 diabetes without retinopathy and albuminuria at baseline, early CAN was defined as one or more abnormalities in seven heart rate tests derived from a 10-min electrocardiogram. Retinopathy was defined as the presence of one or more microaneurysms, early kidney dysfunction as an albumin excretion rate (AER) >7.5 μg/min, and albuminuria as an AER >20 μg/min. Multivariable generalized estimating equations were used to examine the association between CAN and retinopathy or early kidney dysfunction. Cox proportional hazards regression analysis was used to assess cumulative risks of incident retinopathy and albuminuria. RESULTS At baseline, the mean age of the sample was 13.6 ± 2.6 years, 52% were male, and mean diabetes duration was 6.1 ± 3.3 years. Over a median follow-up of 3.8 (interquartile range 2.2-7.5) years, the complication rate 27% for retinopathy, 16% for early kidney dysfunction, and 3% for albuminuria. The mean study HbA1c was 72.3 ± 16 mmol/mmol (8.6 ± 1.4%). CAN predicted incident retinopathy (odds ratio 2.0 [95% CI 1.4, 2.9]) and early kidney dysfunction (1.4 [1.0, 2.0]) after adjusting for HbA1c and diabetes duration. CAN also predicted retinopathy (hazard ratio 1.57 [95% CI 1.09, 2.26]) and albuminuria (2.30 [1.05, 5.04]) independently of HbA1c. CONCLUSIONS CAN predicted incident retinopathy and kidney dysfunction in adolescents with type 1 diabetes, likely reflecting autonomic microvascular dysregulation contributing to complications. Therefore, screening and interventions to reduce CAN may influence the risk of complications.
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Affiliation(s)
- Vallimayil Velayutham
- The Children's Hospital at Westmead, Sydney, New South Wales, Australia.,Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.,Campbelltown Hospital, Campbelltown, New South Wales, Australia
| | - Paul Benitez-Aguirre
- The Children's Hospital at Westmead, Sydney, New South Wales, Australia.,Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia
| | - Maria Craig
- The Children's Hospital at Westmead, Sydney, New South Wales, Australia.,Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.,School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales, Australia
| | - Yoon Hi Cho
- The Children's Hospital at Westmead, Sydney, New South Wales, Australia.,Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia
| | - Gerald Liew
- Centre for Vision Research, Department of Ophthalmology, and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Kim Donaghue
- The Children's Hospital at Westmead, Sydney, New South Wales, Australia.,Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia
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Shi W, Zhang J, Chen D, Chen X, Duan W, Zhang H. Heart Rate Variability and Chronic Kidney Disease in Patients with Type 2 Diabetes. Appl Bionics Biomech 2022; 2022:2475750. [PMID: 35619730 PMCID: PMC9129959 DOI: 10.1155/2022/2475750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 11/17/2022] Open
Abstract
To evaluate whether heart rate variability (HRV) as a measure of cardiac autonomic neuropathy (CAN) is associated with chronic kidney disease (CKD) in Chinese adults with type 2 diabetes mellitus (T2DM) in China. 392 individuals of T2DM were entered in this study, all these subjects undertook the Holter electrocardiogram for 24 hours to get the HRV parameters. Of these T2DM patients, 126 (37.3%) had CKD, and most of the HRV parameters were lower in this group than in those without CKD. Decreased HRV parameters were strongly related with CKD in Spearman's correlation analysis. After adjustments for variables, the logistic regression showed that standard deviation of the averaged normal RR intervals for all 5-minute segments (SDANN) was independently associated with decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) (OR = 0.988; 95% CI, 0.978-0.998; P = 0.015) and increased urine albumin : creatinine ratio (UACR) ≥ 30 mg/g Cr (OR = 0.992; 95% CI, 0.985-0.998; P = 0.015). A decreased 24-hour time domain HRV parameter, SDANN, was strongly associated with both eGFR and UACR among Chinese T2DM.
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Affiliation(s)
- Wei Shi
- Department of Endocrinology, Hubei Integrated Traditional Chinese and Western Medicine Hospital, Hubei University of Chinese Medicine, 430015 Wuhan, Hubei, China
| | - Jing Zhang
- Department of Endocrinology, Hubei Integrated Traditional Chinese and Western Medicine Hospital, Hubei University of Chinese Medicine, 430015 Wuhan, Hubei, China
| | - Dan Chen
- Department of Endocrinology, Hubei Integrated Traditional Chinese and Western Medicine Hospital, Hubei University of Chinese Medicine, 430015 Wuhan, Hubei, China
| | - Xiaolei Chen
- Department of Endocrinology, Kunming First People's Hospital, Kunming Medical University, 650101 Kunming, Yunnan, China
| | - Wei Duan
- Department of Endocrinology, Hubei Integrated Traditional Chinese and Western Medicine Hospital, Hubei University of Chinese Medicine, 430015 Wuhan, Hubei, China
| | - Hongmei Zhang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 430015 Wuhan, Hubei, China
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Eun Jun J, Sun Choi M, Hyeon Kim J. Cardiovascular autonomic neuropathy and incident diabetic kidney disease in patients with type 2 diabetes. Diabetes Res Clin Pract 2022; 184:109181. [PMID: 34952039 DOI: 10.1016/j.diabres.2021.109181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/07/2021] [Accepted: 12/11/2021] [Indexed: 01/05/2023]
Abstract
AIMS We investigated the association between cardiovascular autonomic neuropathy (CAN) and incident diabetic kidney disease (DKD). METHODS This retrospective longitudinal study included 2,033 patients with type 2 diabetes (mean age 57.2 years, 57.4% male, and median diabetes duration 8.0 years), free of renal dysfunction or cardiovascular disease at initiation. Cardiovascular autonomic reflex tests were performed once at baseline, and CAN was defined as ≥ 2 abnormal parasympathetic test results. Urine ACR and eGFR were concurrently measured at baseline and every 3-6 months thereafter. Incident DKD was defined as the development of ACR ≥ 30 mg/g at two or more follow-up examinations or eGFR < 60 ml/min/1.73 m2 with ≥ 25% decrease from baseline. RESULTS During a median follow-up of 2.9 years (1.1 - 4.8), 290 (14.3%) patients developed DKD, comprising 79.7% (N = 231) cases of new-onset albuminuria alone, 14.5% (N = 42) cases of eGFR decline alone, and 5.8% (N = 17) cases of both. Compared to those without CAN, patients with CAN had a significantly higher risk of incident DKD in a multivariable Cox regression model (HR 1.56, 95% CI 1.15 - 2.12; P = 0.005). CONCLUSION CAN is may be a useful marker for long-term complications including DKD in patients with type 2 diabetes. Monitoring of CAN helps to identify high risk patients of future renal impairment.
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Affiliation(s)
- Ji Eun Jun
- Division of Endocrinology and Metabolism, Department of Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | | | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.
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Zeng H, Liu J, Chen Z, Yu P, Liu J. Cardiac Autonomic Dysfunction Is Associated With Risk of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:900465. [PMID: 35846280 PMCID: PMC9283697 DOI: 10.3389/fendo.2022.900465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Evidence on the relationship between heart rate variability (HRV) and albumin-to-creatinine ratio (ACR) combined with estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus (T2DM) is rare. Thus, this study aimed to investigate the relationship between heart rate variability and the risk of diabetic kidney disease (DKD) progression in diabetes patients. METHOD Overall, 747 T2DM patients who were admitted to the Second Affiliated Hospital of Nanchang University underwent 24-hour dynamic electrocardiograms for HRV analysis. Time-domain HRV measures included mean heart rate, standard deviation of the R-R interval (SDNN), SDNN index, root mean squared difference of successive RR intervals (RMSSD), and percent of adjacent RR intervals with a difference greater than 50 ms (PNN50). Frequency-domain measures included low frequency (LF), very low frequency (VLF), high frequency (HF) components and LF-to-HF ratio. The risk of DKD progression was determined by combining ACR and eGFR and stratified as low risk (Group A), moderately increased risk (Group B), high risk (Group C), and very high risk (Group D) based on the Kidney Disease: Improving Global Outcomes guidelines. RESULT There were significant differences in HRV parameters among the four risk groups (SDNN: 113 ms vs 109 ms vs 101 ms vs 81 ms, P<0.01; LF: 240.2 ms2 vs 241.1 ms2 vs 155.2 ms2 vs 141.9 ms2, P<0.01; LF-to-HF ratio: 1.70 vs 1.24 vs 1.12 vs 0.93, P<0.01; VLF: 723.7 ms2 vs 601.1 ms2 vs 446.4 ms2 vs 356.3 ms2, P<0.01). A very high risk of DKD progression was significantly associated with a lower SDNN (β=-19.5, 95% CI: -30.0 to -10.0, P<0.01), and moderately increased, high, and very high risks were associated with lower LF-to-HF ratio and VLF (P<0.05). Logistic regression analysis showed that group D had a higher risk of reduced SDNN, LF-to-HF ratio, and VLF compared with group A after adjusting for systolic blood pressure, glycated haemoglobin, haemoglobin, high-density lipoprotein cholesterol, and age (odds ratio (95% CI): 0.989 (0. 983-0.996), 0.674 (0.498-0.913), and 0.999 (0.999-1.000), respectively). CONCLUSION Cardiac autonomic dysfunction is associated with a risk of DKD progression in adults with T2DM, and reduced heart rate variability increased such risk. Thus, HRV screening may be necessary in patients with T2DM, especially those with high proteinuria.
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Muramatsu T, Takahashi M, Kakinuma R, Sato T, Yamamoto M, Akazawa M, Tanaka K, Kikuchi T, Kushiyama A. Decline in renal function associated with cardiovascular autonomic neuropathy positively coordinated with proteinuria in patients with type 2 diabetes. J Diabetes Investig 2022; 13:102-111. [PMID: 34228899 PMCID: PMC8756322 DOI: 10.1111/jdi.13625] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/16/2021] [Accepted: 07/04/2021] [Indexed: 12/14/2022] Open
Abstract
AIMS/INTRODUCTION To investigate the association between cardiovascular autonomic neuropathy (CAN) assessed by the coefficient of variation of the R-R interval and the reduction in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. MATERIALS AND METHODS This retrospective observational cohort study enrolled type 2 diabetes patients who had their coefficient of variation of the R-R interval measured on an electrocardiogram from January 2005 to December 2018. CAN was defined using the reference coefficient of variation of the R-R interval value based on age and sex. The primary outcome was set as a 40% eGFR decline from baseline. Regression analyses using the Cox proportional hazards model were carried out to evaluate the association. RESULTS Of the 831 patients, 118 (14.2%) were diagnosed with CAN. In the analysis of the primary outcome, the median follow-up period was 5.3 years, and 25 (21.2%) patients with CAN and 78 (10.9%) patients without CAN developed a 40% eGFR decline. In the univariate regression analysis, CAN was significantly associated with a 40% eGFR decline (hazard ratio 2.42, 95% confidence interval 1.54-3.80). In the multivariate analysis, CAN remained almost significant after adjusting for the prognostic risk factors for CAN and the decline in the renal function, and an interaction with proteinuria was found. In analyses for the interaction effect between CAN and proteinuria, the presence of CAN synergistically increased the risk of an eGFR decline in patients with macroproteinuria. CONCLUSIONS CAN strongly increased the risk of a 40% eGFR decline from baseline, especially in type 2 diabetes patients with macroproteinuria.
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Affiliation(s)
- Taichi Muramatsu
- Department of PharmacotherapyMeiji Pharmaceutical UniversityKiyose CityJapan
| | - Masahiro Takahashi
- Department of PharmacotherapyMeiji Pharmaceutical UniversityKiyose CityJapan
| | - Rena Kakinuma
- Department of PharmacotherapyMeiji Pharmaceutical UniversityKiyose CityJapan
| | - Tomoyo Sato
- Divisoin of Clinical LaboratoryThe Institute for Medical ScienceAsahi Life FoundationChuo‐kuJapan
| | - Mitsuyo Yamamoto
- Divisoin of Clinical LaboratoryThe Institute for Medical ScienceAsahi Life FoundationChuo‐kuJapan
| | - Manabu Akazawa
- Department of Public Health and EpidemiologyMeiji Pharmaceutical UniversityKiyose CityJapan
| | - Kentaro Tanaka
- Higashikurume Ekimae ClinicHigashikurume CityJapan
- Divisoin of Diabetes and MetabolismThe Institute for Medical ScienceAsahi Life FoundationChuo‐kuJapan
| | - Takako Kikuchi
- Divisoin of Diabetes and MetabolismThe Institute for Medical ScienceAsahi Life FoundationChuo‐kuJapan
| | - Akifumi Kushiyama
- Department of PharmacotherapyMeiji Pharmaceutical UniversityKiyose CityJapan
- Higashikurume Ekimae ClinicHigashikurume CityJapan
- Divisoin of Diabetes and MetabolismThe Institute for Medical ScienceAsahi Life FoundationChuo‐kuJapan
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Chang HC, Huang CJ, Yang AC, Cheng HM, Chuang SY, Yu WC, Chiang CE, Chen CH, Sung SH. Role of Heart Rate Variability in Association Between Glomerular Hyperfiltration and All-Cause Mortality. J Am Heart Assoc 2021; 10:e021585. [PMID: 34889105 PMCID: PMC9075221 DOI: 10.1161/jaha.121.021585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF. Methods and Results We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24‐hour ambulatory electrocardiography. Clinical outcomes were defined as all‐cause mortality at 2 years. During a mean follow‐up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15–3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70–0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival. Conclusions Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.
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Affiliation(s)
- Hao-Chih Chang
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Department of Medicine Taipei Veterans General Hospital Yuanshan and Suao Branch Yilan Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan
| | - Chi-Jung Huang
- Center for Evidence-based Medicine Taipei Veterans General Hospital Taipei Taiwan
| | - Albert C Yang
- Digital Medicine Center and Institute of Brain Science National Yang Ming Chiao Tung University Taipei Taiwan
| | - Hao-Min Cheng
- Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Center for Evidence-based Medicine Taipei Veterans General Hospital Taipei Taiwan.,Department of Medical Education Taipei Veterans General Hospital Taipei Taiwan
| | - Shao-Yuan Chuang
- Institute of Population Health Science National Health Research Institutes Miaoli Taiwan
| | - Wen-Chung Yu
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan
| | - Chern-En Chiang
- Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,General Clinical Research Center Taipei Veterans General Hospital Taipei Taiwan
| | - Chen-Huan Chen
- Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Institute of Public Health National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Department of Medical Education Taipei Veterans General Hospital Taipei Taiwan
| | - Shih-Hsien Sung
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Institute of Public Health National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan
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Bonnet JB, Sultan A. Narrative Review of the Relationship Between CKD and Diabetic Foot Ulcer. Kidney Int Rep 2021; 7:381-388. [PMID: 35257052 PMCID: PMC8897302 DOI: 10.1016/j.ekir.2021.12.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/23/2021] [Accepted: 12/14/2021] [Indexed: 01/22/2023] Open
Abstract
Diabetic foot ulcer (DFU) and chronic kidney disease (CKD) are 2 significant complications of diabetes mellitus (DM). Up to 40% of patients with DM are expected to also develop CKD, and 19% to 34% will suffer from DFU during their lifetimes. However, data on the link between podiatric risk and the extent of CKD are scarce. Neuropathy, a key element of the International Working Group on the Diabetic Foot (IWGDF) classification, nevertheless appears to be related to the CKD stage. The incidence of DFU and its poor evolution also appear to be linked to the stage of CKD, with mortality reaching its peak in patients with end-stage renal disease (ESRD). Whatever, the decrease in the rate of diabetic foot amputation observed worldwide, especially for major amputations, is also observed in patients with ESRD. Specific actions taken for patients undergoing dialysis seems to improve the DFU prognosis. CKD and DFU share a number of elements of pathophysiology, the first of which is peripheral arterial disease (PAD). Uremic neuropathy and nutritional status also seem to create a link between the development of the 2 complications. This literature review provides an update on the complex and dynamic relationship between DFU and CKD. It examines the epidemiologic link between CKD and diabetic foot risk, CKD and DFU occurrence, and CKD and DFU prognosis. It focuses on the pathophysiological links between these 2 complications. Finally, it highlights the actions taken to improve management in the ESRD population that have reduced the rate of major amputations in this population by more than half.
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Association between central non-dipping pattern and platelet morphology in adults with type 1 diabetes without cardiovascular disease: a cross-sectional study. Sci Rep 2021; 11:15416. [PMID: 34326364 PMCID: PMC8322100 DOI: 10.1038/s41598-021-94414-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 06/14/2021] [Indexed: 11/15/2022] Open
Abstract
The non-dipping pattern is nighttime systolic blood pressure (SBP) fall of less than 10%. Several studies showed that the non-dipping pattern, increased mean platelet volume (MPV), and platelet distribution width (PDW) are associated with elevated cardiovascular risk. Hypertensives with the non-dipping pattern have higher MPV than the dippers but this relationship was never investigated among people with type 1 diabetes mellitus (T1DM). This study aimed to investigate the association between the central dipping pattern and platelet morphology in T1DM subjects. We measured the central and brachial blood pressure with a validated non-invasive brachial oscillometric device—Arteriograph 24—during twenty-four-hour analysis in T1DM subjects without diagnosed hypertension. The group was divided based on the central dipping pattern for the dippers and the non-dippers. From a total of 62 subjects (32 males) aged 30.1 (25.7–37) years with T1DM duration 15.0 (9.0–20) years, 36 were non-dippers. The non-dipper group had significantly higher MPV (MPV (10.8 [10.3–11.5] vs 10.4 [10.0–10.7] fl; p = 0.041) and PDW (13.2 [11.7–14.9] vs 12.3 [11.7–12.8] fl; p = 0.029) than dipper group. Multivariable logistic regression revealed that MPV (OR 3.74; 95% CI 1.48–9.45; p = 0.005) and PDW (OR 1.91; 95% CI 1.22–3.00; p = 0.005) were positively associated with central non-dipping pattern adjusting for age, sex, smoking status, daily insulin intake, and height. MPV and PDW are positively associated with the central non-dipping pattern among people with T1DM.
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Mamilly L, Mastrandrea LD, Mosquera Vasquez C, Klamer B, Kallash M, Aldughiem A. Evidence of Early Diabetic Nephropathy in Pediatric Type 1 Diabetes. Front Endocrinol (Lausanne) 2021; 12:669954. [PMID: 33995287 PMCID: PMC8113955 DOI: 10.3389/fendo.2021.669954] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/10/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the most common microvascular complications in type 1 diabetes Mellitus (T1D). Urinary markers of renal damage or oxidative stress may signal early stages of DN. The association of these markers with blood pressure (BP) patterns and glycemic variability (GV) in children is yet to be explored. METHODS Subjects between the ages of 10 and 21 years with T1D were enrolled. Continuous glucose monitoring (CGM) and ambulatory blood pressure monitoring (ABPM) were performed on each subject. Urine samples were collected and analyzed for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) and pentosidine. RESULTS The study included 21 subjects (62% female) with median age of 16.8 (IQR: 14.5, 18.9). Median HbA1C was 8.4 (IQR: 7.5, 9.3). While microalbuminuria was negative in all but one case (4.8%), urinary NGAL/Cr and pentosidine/Cr ratios were significantly elevated (P<0.001) in diabetic patients despite having normal microalbuminuria, and they correlated significantly with level of microalbumin/Cr (r=0.56 [CI: 0.17, 0.8] and r=0.79 [CI: 0.54, 0.91], respectively). Using ABPM, none had hypertension, however, poor nocturnal systolic BP dipping was found in 48% of cases (95% CI: 28-68%). Urinary NGAL/Cr negatively correlated with nocturnal SBP dipping (r=-0.47, CI: -0.76, -0.03). Urine NGAL/Cr also showed a significant negative correlation with HbA1c measurements, mean blood glucose, and high blood glucose index (r=-0.51 [CI: -0.78, -0.09], r=-0.45 [CI: -0.74, -0.03], and r=-0.51 [CI: -0.77, -0.1], respectively). Median urinary NGAL/Cr and pentosidine/Cr ratios were higher in the high GV group but were not significantly different. DISCUSSION This pilot study explores the role of ABPM and urinary markers of tubular health and oxidative stress in early detection of diabetic nephropathy. GV may play a role in the process of this diabetic complication.
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Affiliation(s)
- Leena Mamilly
- Section of Pediatric Endocrinology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
- *Correspondence: Leena Mamilly,
| | - Lucy D. Mastrandrea
- Division of Endocrinology/Diabetes, UBMD Pediatrics and University at Buffalo/Oishei Children’s Hospital of Buffalo, NY, United States
| | - Claudia Mosquera Vasquez
- Section of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Brett Klamer
- Biostatistics Resource at Nationwide Children’s Hospital, Nationwide Children’s Hospital, Columbus, OH, United States
- Section of Pediatric Nephrology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Mahmoud Kallash
- Section of Pediatric Nephrology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Ahmad Aldughiem
- Section of Pediatric Nephrology, Dayton Children’s Hospital, Dayton, OH, United States
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Helleputte S, De Backer T, Lapauw B, Shadid S, Celie B, Van Eetvelde B, Vanden Wyngaert K, Calders P. The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review. Diabetes Metab Res Rev 2020; 36:e3301. [PMID: 32073212 DOI: 10.1002/dmrr.3301] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/28/2020] [Accepted: 02/04/2020] [Indexed: 02/06/2023]
Abstract
Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.
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Affiliation(s)
- Simon Helleputte
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Tine De Backer
- Department of Cardiology, Ghent University Hospital, Ghent, Belgium
| | - Bruno Lapauw
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Samyah Shadid
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Bert Celie
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Birgit Van Eetvelde
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Karsten Vanden Wyngaert
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Patrick Calders
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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Kim YS, Davis SCAT, Stok WJ, van Ittersum FJ, van Lieshout JJ. Impaired nocturnal blood pressure dipping in patients with type 2 diabetes mellitus. Hypertens Res 2018; 42:59-66. [PMID: 30401911 DOI: 10.1038/s41440-018-0130-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/28/2018] [Accepted: 06/29/2018] [Indexed: 01/21/2023]
Abstract
Hypertension is a common comorbidity of type 2 diabetes mellitus (T2DM). Both conditions are associated with an increased cardiovascular risk, which is reduced by tight blood pressure (BP) and glycemic control. However, nondipping BP status continues to be an enduring cardiovascular risk factor in T2DM. Cardiovascular autonomic neuropathy and endothelial dysfunction have been proposed as potential mechanisms. This study tested the hypothesis that microvascular disease rather than cardiovascular autonomic neuropathy interferes with the physiological nocturnal BP reduction. Cardiovascular autonomic function and baroreflex sensitivity were determined in 22 type 2 diabetic patients with (DM+) and 23 diabetic patients without (DM-) manifest microvascular disease. BP dipping status was assessed from 24-hour ambulatory BP measurements. Sixteen nondiabetic subjects served as controls (CTRL). Cardiovascular autonomic function was normal in all subjects. Baroreflex sensitivity was lower in DM- compared with CTRL (7.7 ± 3.3 vs. 12.3 ± 8.3 ms·mm Hg-1; P < 0.05) and was further reduced in DM + (4.6 ± 2.0 ms·mm Hg-1; P < 0.01 vs. DM- and CTRL). The nocturnal decline in systolic and diastolic BP was blunted in DM- (12% and 14% vs. 17% and 19% in CTRL; P < 0.05) and even more so in DM+ (8% and 11%; P < 0.05 vs. DM- and P < 0.001 vs. CTRL). A nocturnal reduction in pulse pressure was observed in CTRL and DM- but not in DM+ (P < 0.05 vs. DM- and P < 0.01 vs. CTRL). In T2DM, progression of microvascular disease interferes with the normal nocturnal BP decline and coincides with a persistently increased pulse pressure and reduced baroreflex sensitivity, contributing to their increased cardiovascular risk.
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Affiliation(s)
- Yu-Sok Kim
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands. .,Laboratory for Clinical Cardiovascular Physiology, Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands.
| | - Shyrin C A T Davis
- Laboratory for Clinical Cardiovascular Physiology, Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Wim J Stok
- Laboratory for Clinical Cardiovascular Physiology, Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Frans J van Ittersum
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands
| | - Johannes J van Lieshout
- Laboratory for Clinical Cardiovascular Physiology, Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands.,Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands.,MRC/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Queen's Medical Centre, School of Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom
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Abstract
PURPOSE OF REVIEW This review considers the relationship between abnormal blood pressure (BP) variability and autonomic dysfunction through an attempt to answer questions about its clinical relevance and pertinence to diabetes and cardiovascular autonomic neuropathy (CAN) and which therapeutic measures can lessen its cardiovascular impact. RECENT FINDINGS Office, ambulatory, and home BP monitoring identify posture-related, circadian, short-term, and long-term BP variabilities. Abnormal BP variability is a risk marker for organ damage, mortality, and cardiovascular events. Moreover, BP variability changes are common in diabetes and associated with CAN and possibly exacerbated by comorbidities like nephropathy, obstructive sleep apnoea syndrome, and chronic pain. The prognostic role of nondipping and reverse dipping is well documented in diabetes. Some findings suggest the possibility of restoring dipping with the dosage time of antihypertensive agents. Diabetes is a favorable scenario for altered BP variability, which might mediate the harmful effects of CAN. Preliminary data suggest the protective effect of targeting BP variability. However, further longitudinal outcome studies are needed. In the meantime, BP variability measures and practical expedients in antihypertensive treatment should be implemented in diabetes.
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Affiliation(s)
- Vincenza Spallone
- Endocrinology, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
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16
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Jaiswal M, Ang L, Mizokami-Stout K, Pop-Busui R. Is there an association between non-dipping blood pressure and measures of glucose variability in type 1 diabetes? J Diabetes Complications 2018; 32:947-950. [PMID: 30087063 PMCID: PMC6138528 DOI: 10.1016/j.jdiacomp.2018.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/23/2018] [Accepted: 07/24/2018] [Indexed: 10/28/2022]
Abstract
AIM To assess the relationship between glucose variability (GV) and non-dipping of blood pressure (BP) as a marker of cardiovascular autonomic neuropathy (CAN) among patients with type 1 diabetes (T1D). METHODS Forty-one subjects with T1D (age 34 ± 13 years, duration 13 ± 6 years, HbA1c 8 ± 1.2%) without cardiovascular disease, dyslipidemia, or hypertension at baseline were enrolled in a 3-year observational cohort study. Subjects were phenotyped for CAN with heart rate variability, cardiovascular autonomic reflex tests, and 24-h BP profiles at baseline and during follow-up. Non-dipping was defined as nocturnal systolic and diastolic BP fall of ≤10%. Reverse dipping BP was defined as a <0% change in the day to night for systolic and diastolic BP. Indices of GV were derived from 5-day continuous glucose monitoring obtained at 3-month intervals, and serum inflammatory biomarkers in all subjects. RESULTS At baseline 10% of the T1D subjects were non-dippers. The dippers and non-dippers were similar in age, diabetes duration, glucose control, traditional cardiovascular risk factors, GV and inflammatory markers. No significant correlations were found at baseline between non-dipping nocturnal blood pressure and measures of GV. At 3 years there were no differences in risk factor profile of subjects who were non-dippers over time (progressors) and those who were dippers (non-progressors). CONCLUSION In a cohort of contemporary patients with T1D following the current standard of care in diabetes, the prevalence of non-dipping is relatively low. There were no clear phenotypes that explained the difference in the risk for non-dipping, including GV. Ambulatory blood pressure monitoring could be used as a tool for improved CVD risk stratification and development of therapeutic interventions in these patients.
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Affiliation(s)
- Mamta Jaiswal
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America
| | - Lynn Ang
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, United States of America
| | - Kara Mizokami-Stout
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, United States of America
| | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, United States of America.
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Katayama S, Hatano M, Issiki M. Clinical features and therapeutic perspectives on hypertension in diabetics. Hypertens Res 2018; 41:213-229. [PMID: 29402981 PMCID: PMC8075885 DOI: 10.1038/s41440-017-0001-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 01/10/2023]
Abstract
Over 50% of patients with diabetes mellitus, either type 1 or 2, ultimately develop hypertension as a complication. In diabetics, this further increases the incidence of cardiovascular disease (CVD) by 2- to 3-fold and accelerates the progression of diabetic nephropathy. Arteriosclerosis, a clinical feature of hypertension in diabetics, develops and advances from a young age. Therefore, in providing treatment, it is necessary to evaluate the degree of arteriosclerosis. Diabetic patients are encouraged to strictly control their blood glucose levels. Recently developed drugs, such as GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors, also have hypotensive actions, making them ideal for use in diabetics with hypertension. SGLT2 inhibitors and GLP-1 receptor agonists reportedly suppress the onset and progression of CVD, as well as diabetic nephropathy. The possibility of hypoglycemia triggering blood pressure elevation and arrhythmia has been noted, so a key point here is not to cause hypoglycemia. In selecting hypotensive agents, we must choose types that do not aggravate insulin resistance and engage in hypotensive treatment that also considers both nocturnal and morning hypertension. In addition, facing the onset of an aging society, there is a growing need for treatments that do not cause excessive blood pressure reduction or hypoglycemia. Favorable lifelong blood pressure and glucose control are increasingly important for the treatment of diabetes accompanied by hypertension.
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Affiliation(s)
| | - Masako Hatano
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Masashi Issiki
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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18
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Costa A, Bosone D, Ramusino MC, Ghiotto N, Guaschino E, Zoppi A, D'Angelo A, Fogari R. Twenty-four-hour blood pressure profile, orthostatic hypotension, and cardiac dysautonomia in elderly type 2 diabetic hypertensive patients. Clin Auton Res 2016; 26:433-439. [PMID: 27624333 DOI: 10.1007/s10286-016-0381-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 07/24/2016] [Indexed: 11/24/2022]
Abstract
PURPOSE The aim of this study was to evaluate the relationship between orthostatic hypotension (OH), defined as a decrease in systolic blood pressure (SBP) ≥20 mmHg and/or a decrease in diastolic blood pressure (DBP) ≥10 mmHg, and 24-h ambulatory BP profile in elderly hypertensive type 2 diabetic patients. METHODS After a 2-week antihypertensive wash-out period, 200 hypertensive well-controlled diabetic outpatients, aged 65-75 years, underwent a clinical examination, including BP measurements, ECG, 24-h ABP monitoring (ABPM), an orthostatic test, and three tests for cardiovascular autonomic function assessment [deep breathing, heart rate (HR) variability, resting HR]. RESULTS According to their nighttime BP profile, patients were divided into three groups: dippers (n = 86) (BP fall during nighttime ≥10 %), non-dippers (n = 80) (BP fall during nighttime 0-10 %), and reverse dippers (n = 34) (nighttime BP > daytime BP). Orthostatic test produced a significantly greater orthostatic SBP fall in dippers and even more in reverse dippers. In these latter, a significant fall was observed also in DBP. Prevalence of OH was 9.3 % in dippers, 30 % in non-dippers, and 79.4 % in reverse dippers. CONCLUSIONS In elderly hypertensive type 2 diabetics, a blunted nocturnal BP fall is associated with OH and autonomic dysfunction. These data suggest that ABPM should be performed in the assessment of hypertensive diabetic patients in whom the cardiovascular dysautonomia is suspected or the signs of it are present (such as OH).
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Affiliation(s)
- Alfredo Costa
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Daniele Bosone
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Matteo Cotta Ramusino
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Natascia Ghiotto
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Elena Guaschino
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Annalisa Zoppi
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Angela D'Angelo
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy
| | - Roberto Fogari
- Department of Neurosciences and Behavior, National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, Via Mondino, 2, 27100, Pavia, Italy.
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19
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Ge X, Chen H, Zhang K, Tang ZH. The analysis of blood pressure profiles and their severity in relation to diabetic cardiovascular autonomic neuropathy in the Chinese population: preliminary analysis. J Endocrinol Invest 2016; 39:891-8. [PMID: 26940214 DOI: 10.1007/s40618-016-0444-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/08/2016] [Indexed: 11/25/2022]
Abstract
BACKGROUND The study sought to investigate the associations of blood pressure profiles and its severity with diabetic cardiovascular autonomic neuropathy (DCAN) in a Chinese population. METHODS We conducted a community-based, cross-sectional study for risk factor analysis of DCAN in 455 individuals recruited from a Chinese population. Blood pressure profile risk score (BPRS) was calculated for associations between severity of blood pressure profile and DCAN. Multivariable logistic regression (MLR) was carried out to analyze the associations of blood pressure profiles and its severity with DCAN. RESULTS In category variable models, participants with high SBP have significantly higher DCAN prevalence as compared to participants with low SBP (25.66 vs. 31.69 %, P = 0.011). MLR demonstrated that there was significant associations between SBP and DCAN controlling for potential confounding factors (P = 0.016). Moreover, MLR assessed significant associations of BPRS-0 or BPRS-2 with DCAN (P value = 0.014 for BPRS-0 and P value = 0.031 for BPRS-2). CONCLUSION Our findings indicated that SBP and severity of BP profiles were significantly and independently associated with DCAN, respectively. These suggested BP profile may influence the progression of DCAN and also provided insight into biological functions. ClinicalTrials.gov Identifier NCT02461472.
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Affiliation(s)
- X Ge
- Department of Emergency, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - H Chen
- Department of Cardiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - K Zhang
- Department of Endocrinology and Metabolism, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Z-H Tang
- Department of Endocrinology and Metabolism, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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20
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Wheelock KM, Jaiswal M, Martin CL, Fufaa GD, Weil EJ, Lemley KV, Yee B, Feldman E, Brosius FC, Knowler WC, Nelson RG, Pop-Busui R. Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes. J Diabetes Complications 2016; 30:873-9. [PMID: 27041674 PMCID: PMC4912901 DOI: 10.1016/j.jdiacomp.2016.03.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/04/2016] [Accepted: 03/09/2016] [Indexed: 12/15/2022]
Abstract
AIMS Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN. METHODS Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial. RESULTS Global glomerular sclerosis was negatively associated with sdNN (partial r=-0.35, p=0.01) and LF (r=-0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=-0.28 to -0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=-0.27, p=0.04). CONCLUSIONS CAN associates with DN lesions.
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Affiliation(s)
| | - Mamta Jaiswal
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Catherine L Martin
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Gudeta D Fufaa
- Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ
| | - E Jennifer Weil
- Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ
| | - Kevin V Lemley
- Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA
| | - Berne Yee
- Southwest Kidney Institute, Phoenix, AZ
| | - Eva Feldman
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI
| | - Frank C Brosius
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | | | - Robert G Nelson
- Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.
| | - Rodica Pop-Busui
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
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21
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Felício JS, Koury CC, Carvalho CT, Abrahão Neto JF, Miléo KB, Arbage TP, Silva DD, de Oliveira AF, Peixoto AS, Figueiredo AB, Ribeiro Dos Santos ÂKC, Yamada ES, Zanella MT. Present Insights on Cardiomyopathy in Diabetic Patients. Curr Diabetes Rev 2016; 12:384-395. [PMID: 26364799 PMCID: PMC5101638 DOI: 10.2174/1573399812666150914120529] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/27/2015] [Accepted: 09/14/2015] [Indexed: 12/22/2022]
Abstract
The pathogenesis of diabetic cardiomyopathy (DCM) is partially understood and is likely to be multifactorial, involving metabolic disturbances, hypertension and cardiovascular autonomic neuropathy (CAN). Therefore, an important need remains to further delineate the basic mechanisms of diabetic cardiomyopathy and to apply them to daily clinical practice. We attempt to detail some of these underlying mechanisms, focusing in the clinical features and management. The novelty of this review is the role of CAN and reduction of blood pressure descent during sleep in the development of DCM. Evidence has suggested that CAN might precede left ventricular hypertrophy and diastolic dysfunction in normotensive patients with type 2 diabetes, serving as an early marker for the evaluation of preclinical cardiac abnormalities. Additionally, a prospective study demonstrated that an elevation of nocturnal systolic blood pressure and a loss of nocturnal blood pressure fall might precede the onset of abnormal albuminuria and cardiovascular events in hypertensive normoalbuminuric patients with type 2 diabetes. Therefore, existing microalbuminuria could imply the presence of myocardium abnormalities. Considering that DCM could be asymptomatic for a long period and progress to irreversible cardiac damage, early recognition and treatment of the preclinical cardiac abnormalities are essential to avoid severe cardiovascular outcomes. In this sense, we recommend that all type 2 diabetic patients, especially those with microalbuminuria, should be regularly submitted to CAN tests, Ambulatory Blood Pressure Monitoring and echocardiography, and treated for any abnormalities in these tests in the attempt of reducing cardiovascular morbidity and mortality.
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Affiliation(s)
- João Soares Felício
- Hospital Universitário João de Barros Barreto - Universidade Federal do Pará, Mundurucus Street, 4487 - Postal Code: 66073-000 - Guamá - Belém - PA - Brazil.
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22
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Afsar B. Disruption of circadian blood pressure, heart rate and the impact on glycemic control in type 1 diabetes. Diabetes Metab Syndr 2015; 9:359-363. [PMID: 25470635 DOI: 10.1016/j.dsx.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Patients with type 1 diabetes (DM-1) have an increased mortality and morbidity risk compared to non-diabetic subjects. Even not recognized clinically at the early period of disease; patients with DM-1 show subtle neurological and cardiovascular abnormalities which is partly responsible for the increased mortality. One of these abnormalities is the disruption of circadian rhythms. Various factors such as autonomic dysfunction, sleep disturbance, smoking, cardiac and kidney function, atherosclerosis, arterial stiffness are suggested to cause these disturbances. Additionally these abnormalities have also implications regarding target organ damage such as microalbuminuria, retinopathy, and structural changes in glomeruli. Surprisingly, there are scarce data regarding the effect of tight blood glucose control and insulin on circadian rhythms in patients with DM-1. By the light of aforementioned data this review will try to summarize causes and consequences of disruption of circadian rhythms and the impact on glycemic control on these issues in patients with DM-1.
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Affiliation(s)
- Baris Afsar
- Konya Numune State Hospital, Department of Nephrology, Turkey.
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23
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Vimalavathini R, Gitanjali B. Effect of glycaemic control on the diurnal blood pressure variation and endogenous secretory receptor for advanced glycation end product (esRAGE) levels in type 1 diabetes mellitus. Int J Diabetes Dev Ctries 2015. [DOI: 10.1007/s13410-015-0436-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Cho YH, Craig ME, Davis EA, Cotterill AM, Couper JJ, Cameron FJ, Benitez-Aguirre PZ, Dalton RN, Dunger DB, Jones TW, Donaghue KC. Cardiac autonomic dysfunction is associated with high-risk albumin-to-creatinine ratio in young adolescents with type 1 diabetes in AdDIT (adolescent type 1 diabetes cardio-renal interventional trial). Diabetes Care 2015; 38:676-81. [PMID: 25573882 DOI: 10.2337/dc14-1848] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10-17 years, mean duration 6.9 years; mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. RESULTS The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm; P < 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02; RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69 mmol/mmol) in the upper tertile vs. 8.3% (67 mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (β = 2.5, 95% CI 0.2-4.8, P = 0.03) and lower RMSSD (β = -9.5, 95% CI -18.2 to -0.8, P = 0.03), independent of age and HbA1c. CONCLUSIONS Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic profile, indicating sympathetic overdrive, compared with the lower-risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of interventions in this population.
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Affiliation(s)
- Yoon Hi Cho
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Maria E Craig
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Elizabeth A Davis
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
| | - Andrew M Cotterill
- Department of Paediatric Endocrinology, Mater Children's Hospital, Brisbane, Queensland, Australia
| | - Jennifer J Couper
- Endocrinology and Diabetes Centre, Women's and Children's Hospital, and Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Fergus J Cameron
- Department of Endocrinology and Diabetes, Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, Australia The University of Melbourne, Melbourne, Victoria, Australia
| | - Paul Z Benitez-Aguirre
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia
| | - R Neil Dalton
- WellChild Laboratory, St Thomas' Hospital, London, U.K
| | - David B Dunger
- University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, U.K
| | - Timothy W Jones
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
| | - Kim C Donaghue
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia
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Yun JS, Ahn YB, Song KH, Yoo KD, Kim HW, Park YM, Ko SH. The association between abnormal heart rate variability and new onset of chronic kidney disease in patients with type 2 diabetes: a ten-year follow-up study. Diabetes Res Clin Pract 2015; 108:31-7. [PMID: 25656759 DOI: 10.1016/j.diabres.2015.01.031] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/02/2014] [Accepted: 01/18/2015] [Indexed: 01/08/2023]
Abstract
AIMS We investigated the association between cardiovascular autonomic neuropathy (CAN) and the future development of chronic kidney disease (CKD) in patients with type 2 diabetes. METHODS From Jan 2003 to Dec 2004, 1117 patients with type 2 diabetes without CKD (estimated glomerular filtration rate [eGFR] ≥ 60 ml/min/1.73 m(2)), aged 25-75 years, were consecutively enrolled. A cardiovascular autonomic function test (AFT) was performed using heart rate variability parameters. The eGFR was measured at least more than once every year, and new onset CKD was defined as eGFR < 60 ml/min/1.73 m(2) using a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS Among the 755 (67.6%) patients who completed the follow-up evaluation for 9.6 years, 272 patients (36.0%) showed a CKD stage ≥3. The patients who developed CKD were older, had a longer duration of diabetes, had hypertension, received more insulin and ACE inhibitor/angiotensin receptor blocker (ARB) treatment, and exhibited lower baseline eGFR, HbA1c, and albuminuria levels. Compared to patients without CKD, more patients with CKD at follow-up had CAN at baseline. In a multivariate analysis, after adjustment for age, sex, diabetes duration, presence of hypertension, mean HbA1c, diabetic complications, use of insulin, ACE inhibitor/ARB, statin, and baseline eGFR, the development of CKD was significantly associated with the presence of CAN (HR 2.62, 95% CI 1.87-3.67, P<0.001). CONCLUSIONS In this prospective, longitudinal, observational cohort study, we demonstrated that diabetic CAN was an independent prognostic factor for the future development of CKD in type 2 diabetes.
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Affiliation(s)
- Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu-Bae Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki-Ho Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki-Dong Yoo
- Division of Cardiology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Hyung-Wook Kim
- Division of Nephrology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Yong-Moon Park
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Abstract
In spite of new therapy options the life expectancy of patients with diabetes mellitus is clearly reduced compared to the average population. In addition to coronary heart disease and diabetic cardiomyopathy, cardiac autonomic neuropathy (CAN) is also a factor in patients with diabetes mellitus. The CAN is an impairment of cardiovascular control. A reduced variability of heart rate up to the point of a fixed heart rate are symptoms of CAN. In addition symptomatic hypotension, a reduced left ventricular ejection fraction, cardiac arrhythmia and sudden cardiac death are also signs of CAN. Prevalence rates of CAN increase with age and are approximately 38 % in patients 40-70 years old with diabetes mellitus type 1 and 44 % in patients with diabetes mellitus type 2. The disease is usually documented using miscellaneous cardiovascular autonomic tests so that therapy can be started as soon as possible.
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Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis 2014; 238:370-9. [PMID: 25558032 DOI: 10.1016/j.atherosclerosis.2014.12.023] [Citation(s) in RCA: 226] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 11/17/2014] [Accepted: 12/12/2014] [Indexed: 12/22/2022]
Abstract
Arterial stiffness is an age-related process that is a shared consequence of numerous diseases including diabetes mellitus (DM), and is an independent predictor of mortality both in this population and in the general population. While much has been published about arterial stiffness in patients with DM, a thorough review of the current literature is lacking. Using a systematic literature search strategy, we aimed to summarize our current understanding related to arterial stiffness in DM. We review key studies demonstrating that, among patients with established DM, arterial stiffness is closely related to the progression of complications of DM, including nephropathy, retinopathy, and neuropathy. It is also becoming clear that arterial stiffness can be increased even in pre-diabetic populations with impaired glucose tolerance, and in those with the metabolic syndrome (METS), well before the onset of overt DM. Some data suggests that arterial stiffness can predict the onset of DM. However, future work is needed to further clarify whether large artery stiffness and the pulsatile hemodynamic changes that accompany it are involved in the pathogenesis of DM, and whether interventions targeting arterial stiffness are associated with improved clinical outcomes in DM. We also review of the potential mechanisms of arterial stiffness in DM, with particular emphasis on the role of advanced glycation endproducts (AGEs) and nitric oxide dysregulation, and address potential future directions for research.
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Affiliation(s)
- Stuart B Prenner
- University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 6 Penn Tower, Philadelphia, PA 19104, USA
| | - Julio A Chirinos
- University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 6 Penn Tower, Philadelphia, PA 19104, USA; Philadelphia VA Medical Center, Division of Cardiology - Suite 8B111, University & Woodland Avenues, Philadelphia, PA 19104, USA.
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Rana I, Badoer E, Alahmadi E, Leo CH, Woodman OL, Stebbing MJ. Microglia are selectively activated in endocrine and cardiovascular control centres in streptozotocin-induced diabetic rats. J Neuroendocrinol 2014; 26:413-25. [PMID: 24762326 DOI: 10.1111/jne.12161] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/20/2014] [Accepted: 04/16/2014] [Indexed: 12/30/2022]
Abstract
Type 1 and 2 diabetes are associated with dysfunction in multiple hormone systems, as well as increased sympathetic nerve activity, which may contribute to the development of diabetic complications. In other pathologies, such as myocardial infarction, increased sympathetic drive is associated with neuroinflammation and microglial activation in the hypothalamic paraventricular nucleus (PVN), a brain region that regulates sympathetic drive and multiple endocrine responses. In the present study, we used immunohistochemistry to study microglial and neuronal activation in the PVN and related brain regions in streptozotocin (STZ)-induced diabetic rats. As expected, STZ treatment was associated with elevated blood glucose within 1 week. STZ injections also caused neuronal activation in the PVN and superoptic nucleus (SON) but not in the nucleus tractus solitarius (NTS), which was evident by 6 weeks. STZ-treated rats showed increased plasma osmolarity, which would be expected to activate PVN and SON neurones. There was no apparent increase in histochemical markers of microglial activation, including phospho-p38, phospho-extracellular signal regulated kinase, P2X4 receptor or interleukin 1-β even at 10 weeks after STZ-treatment. However, we did see a significant increase in the percentage of microglia with an activated morphology in the PVN, SON and NTS, although not in surrounding hypothalamic, brainstem or cortical regions. These morphological changes included a significant reduction in microglial process length and were evident by 8 weeks but not 6 weeks. The delayed onset of microglial changes compared to neuronal activation in the PVN and SON suggests the over-excitation of neurones as a mechanism of microglial activation. This delayed microglial activation may, in turn, contribute to the endocrine dysregulation and the elevated sympathetic nerve activity reported in STZ-treated rats.
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Affiliation(s)
- I Rana
- School of Medical Sciences and Health Innovations Research Institute, RMIT University, Melbourne, Australia
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Tahrani AA, Dubb K, Raymond NT, Begum S, Altaf QA, Sadiqi H, Piya MK, Stevens MJ. Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study. Diabetologia 2014; 57:1249-56. [PMID: 24623102 DOI: 10.1007/s00125-014-3211-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 02/21/2014] [Indexed: 12/15/2022]
Abstract
AIMS/HYPOTHESIS The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. METHODS We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR) < 60 ml min(-1) 1.73 m(-2). CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability. RESULTS Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (-9.0 ± 17.8% vs -3.3 ± 10.3%, p = 0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (β = -3.5, p = 0.03). Spectral analysis variables were also independent predictors of eGFR decline. CONCLUSIONS/INTERPRETATION CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.
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Affiliation(s)
- Abd A Tahrani
- Centre of Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK,
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Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. [PMID: 24567799 PMCID: PMC3932425 DOI: 10.4239/wjd.v5.i1.17] [Citation(s) in RCA: 191] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/02/2013] [Accepted: 12/12/2013] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
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Time-of-day of energy intake: association with hypertension and blood pressure 10 years later in the 1946 British Birth Cohort. J Hypertens 2013; 31:882-92. [PMID: 23385650 DOI: 10.1097/hjh.0b013e32835ecc06] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVES The role of circadian rhythm of energy and macronutrient intake in influencing cardiometabolic risk factors is increasingly recognized. However, little is known of the association between time of energy intake and blood pressure. We examined the association between time-of-day of energy intake and subsequent hypertension and change in blood pressure. METHODS The analysis included 517 men and 635 women from the 1946 British birth cohort. Diet was assessed using 5-day estimated diaries. Diaries were divided into seven meal slots: breakfast, mid-morning, lunch, mid-afternoon, dinner, late evening and extras. Time-of-day of energy intake at age 43 years was related to hypertension prevalence at 43 years and incidence at age 53 years and 10-year changes in SBP and DBP using logistic regression and censored regression controlling for medication use. RESULTS Cohort members in the highest quintile of energy intake at breakfast at age 43 years had 30% lower odds of hypertension prevalence compared with those in the lowest. Cohort members in the highest quintile of energy intake at late evening had higher odds of incident hypertension at age 53 years [odds ratio = 1.55; 95% confidence interval (CI) 0.93-2.61; P for linear trend = 0.052]. Compared to the lowest quintile, the highest quintile of energy intake late in the evening was related to a greater rise in SBP (β = 5.09; 95% CI 1.25-8.93) and DBP (43-53 years) (β = 2.08; 95%CI 0.27-5.32). CONCLUSION Higher energy intake at breakfast is associated with lower hypertension prevalence. Greater energy intake late in the evening is associated with higher hypertension prevalence, incidence and greater increases in blood pressure.
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Jiang Y, Gao H, Krantz AM, Derbenev AV, Zsombok A. Reduced GABAergic inhibition of kidney-related PVN neurons in streptozotocin-treated type 1 diabetic mouse. J Neurophysiol 2013; 110:2192-202. [PMID: 23966668 DOI: 10.1152/jn.00013.2013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Activity of presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus is known to play an important role in the regulation of sympathetic outflow. Sympathetic overactivity is associated with many pathophysiological conditions such as diabetes mellitus and hypertension; however, the underlying synaptic mechanisms are poorly understood. In this study, we examined the GABAergic inhibitory synaptic control of kidney-related presympathetic PVN neurons in the streptozotocin-treated type 1 diabetic mouse model, using patch-clamp slice electrophysiology in combination with retrograde labeling. Type 1 diabetes resulted in decreased frequency of miniature inhibitory postsynaptic currents (mIPSCs). Our data also demonstrated a reduction of mIPSC amplitude and mean inhibitory current without alteration of input resistance. Furthermore, our data revealed decreased tonic GABAergic inhibition of kidney-related PVN neurons in diabetic conditions, which was consistent with the observed increased excitability of the presympathetic PVN neurons. In summary, our data demonstrated decreased phasic and tonic inhibitory control of kidney-related presympathetic PVN neurons that suggest altered sympathetic circuitry in type 1 diabetes.
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Affiliation(s)
- Yanyan Jiang
- Neuroscience Program, School of Science and Engineering, Tulane University, New Orleans, Louisiana; and
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Putz Z, Németh N, Istenes I, Martos T, Gandhi RA, Körei AE, Hermányi Z, Szathmári M, Jermendy G, Tesfaye S, Tabák ÁG, Kempler P. Autonomic dysfunction and circadian blood pressure variations in people with impaired glucose tolerance. Diabet Med 2013; 30:358-62. [PMID: 23278478 DOI: 10.1111/dme.12111] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2012] [Indexed: 12/11/2022]
Abstract
AIMS To assess circadian blood pressure variability in people with impaired glucose tolerance and a healthy control population. METHODS Seventy-five people with impaired glucose tolerance and 40 healthy volunteers (frequency matched on 10-year age bands and sex) underwent a detailed neurological assessment. Autonomic neuropathy was detected by the five standard cardiovascular autonomic tests and heart rate variability was characterized by the triangle index. Diurnal indices were assessed by 24-h ambulatory blood pressure monitoring. Systolic and diastolic diurnal indices were defined as: (mean daytime blood pressure - mean night-time blood pressure) × 100/mean daytime blood pressure. RESULTS Mean 24-h systolic and diastolic blood pressure was significantly higher in the group with impaired glucose tolerance compared with the control group [126 ± 12 (mean ± SD) vs. 117 ± 10, 75 ± 7 vs. 71 ± 6 mmHg, both P < 0.05). Systolic and diastolic diurnal indices and heart rate variability triangular index were significantly lower in people with impaired glucose tolerance compared with control subjects (9.1 ± 7.8 vs. 13.2 ± 5.4, 14.5 ± 9.7 vs. 18.4 ± 7.1 mmHg, 28.0 ± 8.4 vs. 39.5 ± 9.3, all P < 0.05). Differences in mean diastolic blood pressure, heart rate variability triangular index and the frequency of non-dippers between those with impaired glucose tolerance and control subjects seemed to be independent of BMI and the presence of cardiovascular autonomic neuropathy, as simultaneous adjustment for BMI and cardiovascular autonomic neuropathy had no major effect on the results. CONCLUSION Our data suggest that people with impaired glucose tolerance have increased diastolic blood pressure and abnormal circadian blood pressure regulation, independent of obesity and the presence of cardiovascular autonomic neuropathy.
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Affiliation(s)
- Z Putz
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
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Ljungberg LU, Östgren CJ, Nyström FH, Länne T. Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients. J Renin Angiotensin Aldosterone Syst 2013; 15:61-8. [PMID: 23358739 DOI: 10.1177/1470320312474052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p≤0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype.
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Affiliation(s)
- Liza U Ljungberg
- 1Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Science, Linköping University, Sweden
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36
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Van Buren PN, Toto RD. The pathogenesis and management of hypertension in diabetic kidney disease. Med Clin North Am 2013; 97:31-51. [PMID: 23290728 DOI: 10.1016/j.mcna.2012.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hypertension commonly coexists with diabetes, and its prevalence is even higher in the presence of diabetic kidney disease. The pathogenesis of hypertension in this population stems from increased extracellular volume and increased vasoconstriction that results from mechanisms that may be attributed to both diabetes and the eventual impairment of renal function. Antihypertensive therapy aimed at reducing blood pressure remains a primary goal in preventing the incidence of diabetic kidney and slowing its progression. Initial therapy should consist of an ACE inhibitor or ARB titrated to the maximally tolerated dose. Using combination RAAS therapy further reduces proteinuria, but the benefits of this strategy compared with the potential risks of hyperkalemia and acute deterioration of renal function are still unknown. Endothelin receptor antagonists also lower proteinuria, but these can be associated with volume overload and edema with no clear long-term benefit on renal function yet identified. Further large clinical trials are needed to better understand how progression to ESRD can be slowed or halted in patients with diabetic kidney disease.
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Affiliation(s)
- Peter N Van Buren
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8516, USA.
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Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-78. [PMID: 22644723 DOI: 10.1007/s12265-012-9367-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 12/16/2022]
Abstract
Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Hsiao JY, Tien KJ, Hsiao CT, Weng HH, Chung TC, Hsieh MC. The relationship between diabetic autonomic neuropathy and diabetic risk factors in a Taiwanese population. J Int Med Res 2012; 39:1155-62. [PMID: 21986117 DOI: 10.1177/147323001103900403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
This study looked at spectral analysis of heart rate variability (HRV) between patients with type 2 diabetes mellitus (DM) and healthy controls. The association between diabetic autonomic neuropathy (DAN) with HRV parameter changes and DM risk factors (including nephropathy) was investigated. HRV parameters were compared between 271 patients with DM and 160 controls. A statistically significant difference was found between the two groups for each parameter. Patients with DM were then divided into three groups by the levels of individual risk factors: body mass index, total cholesterol, 2-h postprandial plasma glucose concentration, glycosylated haemoglobin, duration of DM and the albumin-creatinine ratio. HRV parameters decreased significantly in patients with DM as the risk factor level progressed. This study identified previously known and new potential risk factors for the development of DAN, which may be important for the development of risk reduction strategies.
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Affiliation(s)
- J-Y Hsiao
- Division of Endocrinology and Metabolism, Ture Generation Hospital, Kaohsiung, Taiwan
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Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011; 27:639-53. [PMID: 21695768 DOI: 10.1002/dmrr.1239] [Citation(s) in RCA: 595] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 05/10/2011] [Indexed: 12/14/2022]
Abstract
The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN.
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Affiliation(s)
- Vincenza Spallone
- Department of Internal Medicine, University of Tor Vergata, Rome, Italy.
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Van Buren PN, Toto R. Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management. Adv Chronic Kidney Dis 2011; 18:28-41. [PMID: 21224028 PMCID: PMC3221014 DOI: 10.1053/j.ackd.2010.10.003] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 10/08/2010] [Accepted: 10/12/2010] [Indexed: 02/07/2023]
Abstract
Hypertension is highly prevalent in patients with diabetic nephropathy. Diabetic nephropathy is the leading cause of CKD and end-stage kidney disease in the United States. The etiology of hypertension in diabetic nephropathy involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction. The management of hypertension in these patients is focused on treatments that target these mediators. Clinical trials have established that drugs that inhibit the renin-angiotensin-aldosterone system should be used as first-line agents on the basis of their ability to slow down progression of kidney disease and lower albuminuria. There is further interest into how the combination of drugs that inhibit this pathway at multiple steps will contribute further to the management of hypertension and diabetic nephropathy. This article presents an updated review of the mechanisms involved in hypertension in patients with diabetic nephropathy. It also reviews the past clinical trials using single agents as therapeutics and the more recent trials involving novel drugs or drug combinations used to treat these patients. Retrospective analyses of multiple studies are included to better examine the significance of the currently proposed blood pressure targets for patients with diabetic nephropathy.
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Affiliation(s)
- Peter N Van Buren
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8523, USA
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Ayad F, Belhadj M, Pariés J, Attali JR, Valensi P. Association between cardiac autonomic neuropathy and hypertension and its potential influence on diabetic complications. Diabet Med 2010; 27:804-11. [PMID: 20636962 DOI: 10.1111/j.1464-5491.2010.03027.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIMS To examine the association between cardiac autonomic neuropathy and hypertension and the role of this association in diabetic complications. METHODS We included 310 patients, 138 with Type 1 and 172 with Type 2 diabetes, 62 of them with hypertension. Cardiac autonomic neuropathy was assessed by analysing heart rate variations during three standard tests (deep breathing, lying to standing and Valsalva) and looking for postural hypotension. RESULTS Cardiac autonomic neuropathy was present in 123 patients and 39 also had hypertension. The prevalence of a cardiac autonomic neuropathy/hypertension association was higher in Type 2 patients (P < 0.002). The prevalence of hypertension increased with the severity of cardiac autonomic neuropathy. In multiple logistic regression analysis, cardiac autonomic neuropathy was an independent risk factor for hypertension [odds ratio 2.86 (1.54-5.32); P < 0.001]. Only confirmed or severe cardiac autonomic neuropathy (two or more abnormal function tests, respectively) were independent risk factors for hypertension (P < 0.005 and < 0.0001). Cardiac autonomic neuropathy was found in most of the patients with macrovascular complications, retinopathy or nephropathy, but a large majority of the patients with these complications exhibited the cardiac autonomic neuropathy/hypertension profile. This profile was more prevalent among the patients with coronary or peripheral artery disease or antecedent stroke than among those free of these complications (P < 0.001). In logistic regression analyses, the cardiac autonomic neuropathy/hypertension profile associated significantly with macro- and microvascular complications. CONCLUSIONS These data are strongly in favour of the role of cardiac autonomic neuropathy in hypertension in diabetic patients. The association of the cardiac autonomic neuropathy/hypertension profile with vascular complications is consistent with a deleterious effect on vascular hemodynamics and structure, additional to the effects of hypertension.
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Affiliation(s)
- F Ayad
- Department of Internal Medicine, University Hospital, Oran, Algeria
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Monteagudo PT, Moisés VA, Kohlmann O, Ribeiro AB, Lima VC, Zanella MT. Influence of autonomic neuropathy upon left ventricular dysfunction in insulin-dependent diabetic patients. Clin Cardiol 2009; 23:371-5. [PMID: 10803447 PMCID: PMC6655188 DOI: 10.1002/clc.4960230513] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic, vascular, and hypertensive disease. HYPOTHESIS The study was undertaken to test the relationship among autonomic neuropathy (AN), 24-h blood pressure (BP) profile, and left ventricular function. METHODS Nineteen type-1 diabetic patients underwent autonomic tests and echocardiographic examination. Patients were divided according to the presence (AN+) or absence (AN-) of AN. RESULTS In the AN+ group (n = 8), the E/A ratio at echo was lower than in the AN- group (n = 11) (1.1 +/- 0.3 vs. 1.6 +/- 0.3; p < 0.005). Systolic and diastolic BP reductions during sleep were smaller in the AN+ than in the AN- group (6.6 +/- 6.6 vs. 13.0 +/- 4.3%; p < 0.03 for systolic and 12.8 +/- 6.8 vs. 20.0 +/- 4.0% for diastolic BP reduction; p < 0.03, respectively). Considering all patients, the E/A ratio correlated inversely with awake diastolic BP (r - 0.63; p = 0.005); sleep systolic BP (r - 0.48; p = 0.04), and sleep diastolic BP (r - 0.67; p = 0.002). The AN correlated with diastolic interventricular septum thickness (r 0.57; p = 0.01), sleep systolic BP (r 0.45; p = 0.05), sleep diastolic BP (r 0.54; p = 0.02), and correlated inversely with systolic and diastolic sleep BP reduction (r - 0.49; p = 0.03 and r - 0.67; p = 0.002, respectively). Finally, E/A ratio and AN score correlated between themselves (r - 0.6; p = 0.005). CONCLUSION Our results suggest that left ventricular diastolic dysfunction may be detected very early in type-1 diabetic patients with AN. Parasympathetic lesion and nocturnal elevations in BP could be the link between AN and diastolic ventricular dysfunction.
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Affiliation(s)
- P T Monteagudo
- Department of Medicine, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil
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Kanbay M, Turgut F, Uyar ME, Akcay A, Covic A. Causes and mechanisms of nondipping hypertension. Clin Exp Hypertens 2009; 30:585-97. [PMID: 18855262 DOI: 10.1080/10641960802251974] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Growing evidence indicates that nondippers have worsened cardiovascular outcomes than dippers. Ambulatory blood pressure monitoring with a lack of nocturnal BP fall (nondipping) have also been shown to be more closely associated with target organ damage and worsened cardiovascular outcome than in patients with essential hypertension with dipping pattern. The underlying pathogenetic mechanisms potentially linking nondipping with cardiovascular disease are not fully understood. There are multiple possible underlying pathophysiologic mechanisms in the impaired BP decline during the night. Extrinsic and intrinsic factors including abnormal neurohormonal regulation, lack of physical activity, nutritional factors such as increased dietary sodium intake, and smoking of tobacco have been implicated for blunted circadian rhythm of BP. Certain diseases such as diabetes and chronic renal diseases also affect the circadian BP rhythm. Currently, the clinical importance of nondipping is known well; however, the relationship between certain disease states and nondipping has not been fully explained yet. This paper will attempt to address to clarify the underlying basis for nondipping and the specific associations with various disease states.
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Affiliation(s)
- Mehmet Kanbay
- Department of Internal Medicine, Section of Nephrology, Fatih University School of Medicine, Ankara, Turkey.
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Kim YK, Lee JE, Kim YG, Kim DJ, Oh HY, Yang CW, Kim KW, Huh W. Cardiac autonomic neuropathy as a predictor of deterioration of the renal function in normoalbuminuric, normotensive patients with type 2 diabetes mellitus. J Korean Med Sci 2009; 24 Suppl:S69-74. [PMID: 19194565 PMCID: PMC2633204 DOI: 10.3346/jkms.2009.24.s1.s69] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Accepted: 01/12/2009] [Indexed: 01/13/2023] Open
Abstract
Our study was performed to determine whether cardiac autonomic neuropathy can predict deterioration of the renal function in normoalbuminuric, normotensive people with type 2 diabetes mellitus (DM). One hundred and fifty-six normoalbuminuric, normotensive people with type 2 DM were included in our retrospective longitudinal study. We categorized normal patterns, early patterns, and definite or severe patterns according to the results of the cardiac autonomic function test. Of 156 patients included, 54 had normal patterns, 75 had early patterns, 25 had definite or severe patterns, and 2 had atypical patterns. During a median follow-up of nine years, glomerular filtration rates (GFR) remained stable in the normal and early pattern groups (mean changes, 4.50% and 0.77%, respectively) but declined in those with definite or severe patterns (mean change, -10.28%; p=0.047). An abnormal heart response to the deep breathing test of the cardiac autonomic function tests was an independent predictor of GFR decline. Our data suggest that cardiac autonomic neuropathy, especially with a definite or severe pattern, might be associated with a subsequent deterioration in renal function in normoalbuminuric, normotensive people with type 2 DM.
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Affiliation(s)
- Yong Kyun Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Eun Lee
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Goo Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dae Joong Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ha-Young Oh
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chul Woo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kwang-Won Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wooseong Huh
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Deyneli O, Yazici D, Toprak A, Yuksel M, Aydin H, Tezcan H, Yavuz DG, Akalin S. Diurnal Blood Pressure Abnormalities Are Related to Endothelial Dysfunction in Patients with Non-Complicated Type 1 Diabetes. Hypertens Res 2008; 31:2065-73. [DOI: 10.1291/hypres.31.2065] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Istenes I, Keresztes K, Hermányi Z, Putz Z, Vargha P, Gandhi R, Tesfaye S, Kempler P. Relationship between autonomic neuropathy and hypertension--are we underestimating the problem? Diabet Med 2008; 25:863-66. [PMID: 18513306 DOI: 10.1111/j.1464-5491.2008.02458.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Cardiac autonomic neuropathy (CAN) is associated with significant morbidity and mortality in diabetes and the risk is even greater in those with hypertension. AIMS The aim of our study was to investigate the relationship between CAN and 24-h blood pressure profile in normoalbuminuric patients with Type 2 diabetes mellitus. METHODS Seventy patients with Type 2 diabetes (31 without CAN, 39 with CAN), who had no history of hypertension, and 29 healthy volunteers underwent five standard cardiovascular reflex tests to assess autonomic function and 24-h ambulatory blood pressure monitoring. RESULTS Twenty-four-hour mean systolic blood pressure, blood pressure load and hyperbaric impact values were significantly higher in diabetic patients with CAN compared with control subjects and diabetic patients without CAN (P < 0.05). In spite of normal clinic blood pressures, 54% of diabetic subjects with CAN and 29% without CAN were hypertensive (systolic blood pressure load > 20%, P < 0.05). In the diabetes group as a whole, Valsalva ratio, postural systolic blood pressure changes and diastolic blood pressure responses during sustained handgrip correlated significantly and negatively with 24-h mean systolic blood pressure (P < 0.01, P < 0.001, P < 0.05) and blood pressure load (P < 0.05, P < 0.001, P < 0.05). CONCLUSIONS Cardiovascular autonomic neuropathy is independently associated with hypertension in normoalbuminuric Type 2 diabetic patients with no history of hypertension. Relying on clinic blood pressures in subjects with CAN could lead to a failure to diagnose hypertension in over half of cases. All normotensive patients with CAN should be screened for hypertension using ambulatory blood pressure monitoring in order to institute early aggressive interventions to improve their long-term outlook.
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Affiliation(s)
- I Istenes
- First Department of Medicine, Semmelweis University, Budapest
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Bilal N, Erdogan M, Ozbek M, Cetinkalp S, Karadeniz M, Ozgen AG, Saygili F, Yilmaz C, Tüzün M, Kabalak T. Increasing severity of cardiac autonomic neuropathy is associated with increasing prevalence of nephropathy, retinopathy, and peripheral neuropathy in Turkish type 2 diabetics. J Diabetes Complications 2008; 22:181-5. [PMID: 18413163 DOI: 10.1016/j.jdiacomp.2006.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2006] [Revised: 11/10/2006] [Accepted: 12/21/2006] [Indexed: 11/29/2022]
Abstract
BACKGROUND Cardiac autonomic neuropathy (CAN) is the most frequent and clinically important form of diabetic autonomic neuropathy. CAN is associated with increased frequency of other microvascular complications of diabetes mellitus (DM). In this study, we evaluated the prevalence diabetic nephropathy, retinopathy, and peripheral neuropathy, and measured gastric emptying time and bladder emptying time in type 2 diabetic patients with varying degrees of CAN. PATIENTS AND METHODS Fifty-three patients with DM complicated by CAN (30 women and 23 men; mean age, 58.8+/-9.15 years; duration of diabetes, 13.9+/-7.7 years) were included in this study. The patients were grouped according to the degree of CAN as early, definite, and severe CAN. RESULTS There were significant differences regarding the prevalence of nephropathy, retinopathy, and peripheral neuropathy diagnosed by EMG among those groups (P<.05). However, there was no significant difference regarding the prevalence of peripheral neuropathy diagnosed by neurological examination (P>.05), and scintigraphic measurements of gastric and bladder emptying time were comparable among the groups (P>.05). CONCLUSION The prevalence of other diabetic microvascular complications increase as the severity of CAN increases in patients with type 2 DM. This study emphasizes the need for an early screening for peripheral neuropathy, retinopathy, and nephropathy in type 2 diabetic patients with CAN, especially with severe involvement.
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Affiliation(s)
- Nevzat Bilal
- Ege University Medical School, Endocrinology and Metabolism Disease
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Eguchi K, Pickering TG, Hoshide S, Ishikawa J, Ishikawa S, Schwartz JE, Shimada K, Kario K. Ambulatory blood pressure is a better marker than clinic blood pressure in predicting cardiovascular events in patients with/without type 2 diabetes. Am J Hypertens 2008; 21:443-50. [PMID: 18292756 DOI: 10.1038/ajh.2008.4] [Citation(s) in RCA: 147] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The prognostic significance of ambulatory blood pressure (ABP) has not been established in patients with type 2 diabetes (T2DM). METHODS In order to clarify the impact of ABP on cardiovascular prognosis in patients with or without T2DM, we performed ABP monitoring (ABPM) in 1,268 subjects recruited from nine sites in Japan, who were being evaluated for hypertension. The mean age of the patients was 70.4 +/- 9.9 years, and 301 of them had diabetes. The patients were followed up for 50 +/- 23 months. We investigated the relation between incidence of cardiovascular diseases (CVDs) and different measures of ABP, including three categories of awake systolic blood pressure (SBP <135, 135-150, and >150 mm Hg), sleep SBP (<120, 120-135, and >135 mm Hg), and dipping trends in nocturnal blood pressure (BP) (dippers, nondippers, and risers). Cox regression models were used in order to control for classic risk factors. RESULTS Higher awake and sleep SBPs predicted higher incidence of CVD in patients with and without diabetes. In multivariable analyses, elevated SBPs while awake and asleep predicted increased risk of CVD more accurately than clinic BP did, in both groups of patients. The relationships between ABP level and CVD were similar in both groups. In Kaplan-Meier analyses, the incidence of CVD in nondippers was similar to that in dippers, but risers experienced the highest risk of CVD in both groups (P < 0.01). The riser pattern was associated with a approximately 150% increase in risk of CVD, in both groups. CONCLUSIONS These findings suggest that ABPM is a better predictor of cardiovascular risk than clinic BP, and that this holds true for patients with or without T2DM.
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Karavanaki K, Kazianis G, Konstantopoulos I, Tsouvalas E, Karayianni C. Early signs of left ventricular dysfunction in adolescents with type 1 diabetes mellitus: the importance of impaired circadian modulation of blood pressure and heart rate. J Endocrinol Invest 2008; 31:289-96. [PMID: 18475045 DOI: 10.1007/bf03346360] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic heart disease or hypertension. Moreover impaired circadian blood pressure (BP) variation has been associated with autonomic dysfunction. The aim of our study was to evaluate diurnal BP fluctuations and autonomic function and their association with left ventricular function in adolescents with Type 1 diabetes mellitus (T1DM). In 48 normotensive, normoalbuminuric diabetic adolescents, with a mean (+/-SD) age of 17.3 (+/-4.1) yr and a mean (+/-SD) diabetes duration of 8.5 (+/-3.3) yr, 24-h ambulatory BP was recorded. Moreover 24-h heart rate (HR) monitoring was performed. Myocardial structural parameters were studied by echocardiogram. Left ventricular end-diastolic (EDDLV) and end-systolic diameters (ESDLV) were estimated and left ventricular mass index (LVMI) was calculated using the Devereux formula. The patients were divided into 2 groups according to the absence of decrease (non-dippers) or the decrease (dippers) of nocturnal diastolic BP (DBP). The non-dippers showed, in comparison with the dippers, reduced mean 24-h HR (79.6 vs 84.0 beats/min, p=0.05) and reduced mean day-time HR (81.3 vs 86.0 beats/min, p=0.05). The nondippers also presented greater ESDLV (28.7 vs 25.9 mm, p=0.001) and EDDLV (47.8 vs 45.1 mm, p=0.040), and LVMI (90.2 vs 78.3 g/m2, p=0.044), in comparison with the dippers. During stepwise multiple regression, the most important variables affecting LVMI were mean HR (day): (b=-0.40, p=0.001), high frequency domain variable of HR variability (b=0.38, p=0.016) and glycosylated hemoglobin (b=0.67, p=0.001). In conclusion, we found that a group of normotensive diabetic adolescents with impaired nocturnal BP reduction, also had autonomic dysfunction, together with impaired left ventricular function. These findings suggest that there is a close relationship between autonomic function and left ventricular remodeling in patients with T1DM, which may be attributed to altered diurnal BP profile, autonomic neuropathy and poor glycemic control.
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Affiliation(s)
- K Karavanaki
- Diabetic Clinic, Second Department of Pediatrics, University of Athens, P&A Kyriakou Children's Hospital, Athens, Greece.
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Dipping in type II diabetes: autonomics and diuretics. J Hypertens 2008; 26:826; author reply 826-7. [DOI: 10.1097/hjh.0b013e3282f55f81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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