Association between heart rate-corrected QT interval and severe peripheral arterial disease in patients with type 2 diabetes and foot ulcers

in Endocrine Connections
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  • 1 Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  • 2 Department of Endocrinology, Ruian Traditional Chinese Medicine Hospital, Wenzhou, China

Correspondence should be addressed to H Zhu: zhuhong@wmu.edu.cn

*(J Hong, W-Y Liu and X Hu contributed equally to this work)

Background

A prolonged heart rate-corrected QT interval (QTc) has been associated with peripheral artery disease (PAD) in the general population. However, no study to date has identified a link between prolonged QTc and the severity of PAD in patients with diabetes mellitus and foot ulcers (DFUs). This study aimed to investigate this relationship.

Methods

This multicenter study enrolled 281 patients with DFUs. The severity of PAD was classified into no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion) based on duplex ultrasonography. The association of prolonged QTc with severe PAD was evaluated in a multivariable mixed-effect logistic regression model, with the hospital as a random effect. Directed acyclic graphs were used to drive the selection of variables to fit the regression model.

Results

Patients with severe PAD had longer QTc than those without. Based on the multivariable mixed-effect logistic regression model, a prolonged QTc was positively associated with severe PAD (odds ratio (OR) = 2.61; 95% CI: 1.07–6.35) and severe DFUs (Wagner grade score ≥ 3) (OR = 2.87; 95% CI: 1.42–5.81).

Conclusions

A prolonged QTc was associated with severe PAD in patients with DFUs. Further research is required to ascertain whether the association is causal.

Abstract

Background

A prolonged heart rate-corrected QT interval (QTc) has been associated with peripheral artery disease (PAD) in the general population. However, no study to date has identified a link between prolonged QTc and the severity of PAD in patients with diabetes mellitus and foot ulcers (DFUs). This study aimed to investigate this relationship.

Methods

This multicenter study enrolled 281 patients with DFUs. The severity of PAD was classified into no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion) based on duplex ultrasonography. The association of prolonged QTc with severe PAD was evaluated in a multivariable mixed-effect logistic regression model, with the hospital as a random effect. Directed acyclic graphs were used to drive the selection of variables to fit the regression model.

Results

Patients with severe PAD had longer QTc than those without. Based on the multivariable mixed-effect logistic regression model, a prolonged QTc was positively associated with severe PAD (odds ratio (OR) = 2.61; 95% CI: 1.07–6.35) and severe DFUs (Wagner grade score ≥ 3) (OR = 2.87; 95% CI: 1.42–5.81).

Conclusions

A prolonged QTc was associated with severe PAD in patients with DFUs. Further research is required to ascertain whether the association is causal.

Introduction

Diabetic foot disease, a common complication in patients with diabetes mellitus (DM) (1), is generally associated with a high prevalence of severe macroangiopathic comorbidities that result in high morbidity and mortality (2). About 49% of patients with DM and foot ulcers (DFUs) have coexisting peripheral artery disease (PAD) (3), which is usually asymptomatic. For these patients, the coexisting sensory neuropathy may mask the symptoms of intermittent claudication and ischemic rest pain. An earlier assessment of the severity of PAD is required to determine the need for revascularization to promote ulcer healing in patients with DFUs (4).

The QT interval, defined as the time between the beginning of the Q wave and the end of the T wave, represents the duration of electrical depolarization and repolarization of the ventricular walls (5). The prolongation of heart rate-corrected QT interval (QTc) is a possible consequence of cardiac autonomic neuropathy, and it is a predictor of lethal arrhythmias (6, 7). It has been demonstrated that patients with DM have a more frequent occurrence of QTc prolongation than those without (8). Patients with DFUs and prolonged QTc tend to have a higher prevalence of severe DFUs (Wagner grade 3–5) (9).

Few studies have addressed the association of QTc interval with arterial disease (10, 11, 12, 13). A clinical study found an association between the carotid intima-media thickness and QTc prolongation in patients with type 2 DM (11, 13). A prolonged QTc was found to be associated with PAD in the general population (10), but no study to date has identified a link between prolonged QTc and the severity of PAD in patients with DFUs.

It is important to understand the potential risk factors of the severity of PAD in patients with DFUs; this might be helpful for early identification and subsequent therapy initiation for patients with severe PAD. Therefore, this study was performed to assess the association of prolonged QTc with the risk of severe PAD in patients with type 2 DM and foot ulcers based on duplex ultrasonography.

Materials and methods

Study population

The study participants were patients diagnosed with DFUs according to the 2015 International Working Group on the Diabetic Foot diagnostic criteria (14) in one of the medical institutions in Wenzhou city, China (The First Affiliated Hospital of Wenzhou Medical University, Wenzhou People’s Hospital, Rui’an People’s Hospital, Rui’an Traditional Chinese Medicine Hospital, and Pingyang People’s Hospital). A total of 472 patients were consecutively enrolled from October 2015 to September 2019. The exclusion criteria included those with previous coronary heart disease, congenital long QT syndrome, pacemaker rhythms, atrial fibrillation, other types of arrhythmias, and hypokalemia before or during hospitalization, and persons under medication affecting the QTc interval (antiarrhythmic, beta-blocker, digitalis, quinolone antibiotics, and psychotropic drugs) within the past 6 months (15). Patients with an abnormal heart rate (<60 or >100 bpm) within 24 h of admission were excluded. A total of 281 patients with DFUs were included in this study.

The study protocol was approved by the ethics committee of the First Affiliated Hospital of Wenzhou Medical University. A written informed consent was obtained from all patients prior to their participation.

Data collection and measurements

All patients were assessed by diabetologists and diabetic care nurses. The patient's history included information about demographic characteristics, DM duration, coronary heart disease, hypertension, and lifestyle habits, including smoking, and alcohol use. The resting blood pressure was also recorded. Hypertension was defined as the use of hypertensive medications or a mean resting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg. Smoking was categorized as currently smoking or non-smoking (including ex-smokers). Alcohol use was categorized as currently drinking or no alcohol consumption. Diabetes mellitus therapy was categorized as (i) oral hypoglycemic agent (OHA) therapy only, (ii) insulin therapy only, (iii) both OHA and insulin therapy, and (iv) none or unclear. The laboratory parameters, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglyceride (TG), hemoglobin A1c (HbA1c), albumin (ALB), hemoglobin (Hb), and creatinine, were measured using the standard protocols. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (16).

Definition and grouping

Both lower extremity arteries (femoral artery, superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, and dorsalis pedis artery) of patients were examined by duplex ultrasonography for intima-media thickness, plaque occurrence, stenosis, blood vessel diameter, and filling defects in blood flow. Vascular stenosis was defined as the presence of any stenosis ≥ 50% of the lumen of lower extremity arteries. Occlusion was defined as the total obliteration of the lumen (absence of blood flow) in any segment of the lower extremity arteries. PAD was defined by qualified, experienced ultrasonic diagnostic experts. The degree of severity of PAD based on the duplex ultrasonography was classified as no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion). The degree of severity of DFUs was subdivided according to the Wagner classification (17) (grade score 0–5) and categorized as no severe DFUs group (Wagner grade score < 3) and severe DFUs group (Wagner grade score ≥ 3).

QTc measurement

All patients had a standard 12-lead resting ECG recorded within 24 h of admission. The ECGs were reviewed for rhythm analysis and measured by two independent cardiologists. The QT interval was calculated from the beginning of the QRS complex to the end of the T wave. Then, the value was corrected for heart rate according to the Bazett formula: QTc = QT interval/square root of the RR interval (QTc = QT/[RR]1/2). A QTc interval ≥ 450 ms in men or ≥460 ms in women was defined as prolonged QTc. A QTc interval < 450 ms in men or <460 ms in women was categorized as no prolonged QTc. To prevent the overestimation or underestimation of the QTc, patients with abnormal heart rates (<60 or >100 bpm) were excluded.

Statistical analysis

The one-sample Kolmogorov–Smirnov test was used to examine the normality of the distributions. The data are presented as n (%), mean ± s.d., or in the case of skewed variables, as median and interquartile range. A multivariable-adjusted logistic regression analysis using a mixed-effect model was performed. A random effect by the hospital was introduced to account for the clustering of patients at the hospital level. Directed acyclic graphs (DAGs) (Supplementary Figs 1and 2, see section on supplementary materials given at the end of this article) were constructed using an online DAGitty software (http://www.dagitty.net) to assess the minimally sufficient sets of variables (18), which included age, sex, hypertension, smoking, alcohol use, DM duration, eGFR, LDL, and HbA1c for severe PAD. The variables for severe DFUs were age, sex, smoking, alcohol use, DM duration, diabetic foot duration, eGFR, LDL, and HbA1c. The adjusted odds ratio (OR) and 95% CI were calculated. The statistical analyses were performed using SPSS (IBM, IL, USA) version 22 and R (3.6.0, R Core Team).

Results

Clinical characteristics of the study population

Based on the duplex ultrasonography, 122 out of 281 patients with DFUs (43.4%) had severe PAD. The clinical characteristics of the study population are shown in Table 1. Patients with severe PAD had longer diabetic foot duration, higher prevalence of hypertension, longer QTc, and lower eGFR than those without.

Table 1

Baseline characteristics of participants with and without severe PAD.

CharacteristicNo-severe PAD (n = 159)Severe PAD (n = 122)
Male (%)106 (66.7)71 (58.2)
Age (years)66 (56–74)72 (66–80)
Smoking (%)56 (35.4)38 (31.1)
Alcohol use (%)49 (30.8)31 (25.4)
Diabetes duration (years)10 (6–17)10 (8–20)
Diabetic foot ulcer duration (days)20 (7–30)30 (10–60)
Severe DFUs (%)66 (41.5)58 (47.5)
Hypertension (%)84 (52.8)96 (78.7)
SBP (mmHg)141 ± 22146 ± 21
DBP (mmHg)75 ± 1276 ± 11
Creatinine (μmol/L)69 (58–91)77 (59–107)
eGFR (EPI) mL/min/1.73m2)88.9 (67.4–100.3)78.4 (50.3–94.5)
ALB (g/L)34.4 (30.1–37.7)34.9 (31.1–37.9)
Hb (g/L)119.5 (104.8–133.3)118.0 (105.5–128.0)
HbA1c (%)9.5 (7.7–11.3)9.0 (7.3–11.4)
TC (mmol/L)4.2 (3.3–4.9)4.11 (3.30–5.16)
TG (mmol/L)1.22 (0.88–1.78)1.33 (0.91–1.88)
HDL-C (mmol/L)0.95 (0.75–1.19)0.93 (0.75–1.10)
LDL-C (mmol/L)2.29 (1.76–2.95)2.37 (1.67–3.05)
DM therapy
 OHA therapy (%)65 (40.9)58 (47.5)
 Insulin therapy (%)46 (28.9)35 (28.7)
 OHA and insulin therapy (%)34 (21.4)21 (17.2)
 None or unclear (%)14 (8.8)8 (6.6)
QTc interval (ms)429 (407–445)438 (423–455)

ALB, albumin; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OHA, oral hypoglycemic agent; PAD, peripheral arterial disease; QTc, heart rate-corrected QT interval; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.

Association between prolonged QTc and severe PAD, severe DFUs

The unadjusted and multivariable-adjusted mixed-effects logistic regression analyses were performed to evaluate the relationship between prolonged QTc and severe PAD, severe DFUs (Table 2). The adjusted ORs for severe PAD and severe DFUs in prolonged QTc groups were 2.61 (95% CI: 1.07–6.35) and 2.87 (95% CI: 1.42–5.81), respectively.

Table 2

Association between prolonged QTc and severe PAD, severe DFUs in patients with DFUs.

Unadjusted OR95% CIAdjusted OR95% CI
Severe PAD
 No-prolonged QTc (Ref)1.001.00
 Prolonged QTc1.981.11–3.522.61a1.07–6.35
Severe DFUs
 No-prolonged QTc (Ref)1.001.00
 Prolonged QTc2.481.38–4.452.87b1.42–5.81

aThe multivariable mixed-effects logistic regression was adjusted for risk factors including age, sex, hypertension, smoking, alcohol use, diabetes duration, eGFR, LDL, HbA1c as fixed effect and hospital as random effect. bThe multivariable mixed-effects logistic regression was adjusted for risk factors including age, sex, smoking, alcohol use, diabetes duration, diabetic foot duration, eGFR, LDL, HbA1c as fixed effect and hospital as random effect.

Ref, reference.

Discussion

To our knowledge, this is the first study to reveal the associations between prolonged QTc and severe PAD in patients with DFUs based on duplex ultrasonography. In this study, a longer QTc was found in patients with DFUs and severe PAD. Prolonged QTc was significantly and positively associated with severe PAD based on multivariable logistic regression analyses in patients with DFUs.

Only few studies have focused on the QTc of patients with DFUs. Fagher et al. found that in patients with DFUs, QTc prolongation was associated with increased mortality (19, 20), and hyperbaric oxygen therapy might prevent QTc prolongation (21). Wang et al. (9) found that QTc prolongation was associated with a higher CVD mortality in patients with DFUs, but it cannot predict ulcer healing or recurrence. The present study extends the associations to the severity of PAD in patients with DFUs.

The mechanism underlying the association between prolonged QTc and severe PAD has not been fully elucidated. Atherosclerosis usually causes PAD. Other causes include inflammation (22), which can reduce the vascular nitric oxide bioavailability (23). It inhibits the Ca2+-ATPase and K+/Na+-ATPase, leading to an increase in cytosolic-free calcium and prolongation of myocardial repolarization (24). Accordingly, patients with severe PAD might have longer QTc. Patients with PAD have an equivalent cardiovascular risk compared to patients with previous myocardial infarction (25). Previous studies have indicated that QTc is associated with the risk of CVDs in different populations (26, 27, 28, 29). Patients with severe PAD are at a high risk for CVDs, which might affect the QTc. Studies have also indicated that QTc is associated with age (30), glycemic control (31), hypertension (8), hyperuricemia (32), hyperinsulinemia (33), and metabolic syndrome (34), which are the risk factors for the occurrence of PAD in patients with DM.

According to a previous study (9), which found that patients with DFUs and prolonged QTc tended to have a higher prevalence of severe DFUs (Wagner grade 3–5) in China, the multivariable regression analysis in this study found that a prolonged QTc was associated with severe DFUs; however, the underlying mechanism remains unknown. The severity of DFUs is affected by many factors, including other complications of DM and age. Which DM complication is most relevant to the severity of DFUs remains unclear (35). Studies have reported that QTc is associated with age (30), neuropathy, nephropathy, and multiplicity of microvascular complications (36). DM complications and age might play important roles in the relationship of prolonged QTc and severe DFUs.

This study has several strengths. First, PAD was diagnosed by more precise measurement, the duplex ultrasonography. Duplex ultrasonography is mostly used in detecting and localizing lesions in different territories of the vascular system and in quantifying the severity grade with the application of velocity and pressure gradient criteria. It can diagnose arterial diseases at a very early stage (37). Duplex ultrasonography is often recommended as the first-line non-invasive imaging for patients with PAD. It has 85–90% sensitivity and >95% specificity in detecting stenosis >50% (38). Secondly, the participants of this study were from different medical institutions. Therefore, the results may be applicable to general patients with DFUs. Thirdly, a random effect by the hospital was introduced to account for the clustering of patients at the hospital level. Fourthly, DAGs were used to guide the construction of multivariable logistic regression models. DAGs are transparent approaches to identify the confounding variables that rely on prior knowledge and assumed causal effects. DAGs can be preferred over the traditional methods (39).

In this study, the association between prolonged QTc and severe PAD was strengthened after adjusting for confounding variables suggested by DAGs. Confounding variables which may attenuate the association seem to be distinguished by DAGs. However, which variables play the critical roles remains unclear. The strengthened associations after adjustment have also been found in other studies. A previous study found that the association between diabetes and Alzheimer's disease was strengthened after adjusting for cardiovascular diseases (40). Sakhamuri et al. found that the association of a low forced vital capacity with a low BMI was strengthened in the adjusted model. In their view, this suggested a more direct association (41).

This study also has a limitation. The observed associations between QTc and severe PAD in patients with DFUs have limited causal inference given the nature of the study design.

Conclusion

This study demonstrated an independent positive association between prolonged QTc and the severity of PAD in patients with DFUs. Further studies are required to ascertain whether a prolonged QTc may help identify patients with DFUs who are at risk of severe PAD.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-21-0140.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by grants from the Wenzhou Municipal Science and Technology Bureau (Y20180609).

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of the First Affiliated Hospital of Wenzhou Medical University. Written informed consent was obtained from all patients prior to their participation.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Author contribution statement

J H: software, investigation, writing-original draft. W-Y L: software, investigation. X H: writing – review and editing. F-F J: data curation. Z-R X: data curation. F L: data curation. F-X S: supervision. H Z: conceptualization, writing – review and editing. All authors read and approved the final manuscript.

Acknowledgements

The authors like to acknowledge the helpful comments on this paper received from our reviewers and all the patients who participated in the study. The authors are grateful to Enago (www.enago.cn) for polishing the English of the manuscript. The authors also thank Dr Ji Zhang for his help for statistical analysis with the R (3.6.0, R Core Team).

References

  • 1

    Singh N, Armstrong DG & Lipsky BA Preventing foot ulcers in patients with diabetes. JAMA 2005 293 2172 2 8. (https://doi.org/10.1001/jama.293.2.217)

    • Search Google Scholar
    • Export Citation
  • 2

    Boulton AJ, Vileikyte L, Ragnarson-Tennvall G & Apelqvist J The global burden of diabetic foot disease. Lancet 2005 366 171917 24. (https://doi.org/10.1016/S0140-6736(0567698-2)

    • Search Google Scholar
    • Export Citation
  • 3

    Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, Edmonds M, Holstein P, Jirkovska A & Mauricio D et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 2007 50 1825. (https://doi.org/10.1007/s00125-006-0491-1)

    • Search Google Scholar
    • Export Citation
  • 4

    Brownrigg JR, Schaper NC & Hinchliffe RJ Diagnosis and assessment of peripheral arterial disease in the diabetic foot. Diabetic Medicine 2015 32 7387 47. (https://doi.org/10.1111/dme.12749)

    • Search Google Scholar
    • Export Citation
  • 5

    Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, Gorgels A, Hancock EW, Josephson M & Kligfield P et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. Journal of the American College of Cardiology 2009 53 9829 9 1. (https://doi.org/10.1016/j.jacc.2008.12.014)

    • Search Google Scholar
    • Export Citation
  • 6

    Pappachan JM, Sebastian J, Bino BC, Jayaprakash K, Vijayakumar K, Sujathan P & Adinegara LA Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis. Postgraduate Medical Journal 2008 84 2052 10. (https://doi.org/10.1136/pgmj.2007.064048)

    • Search Google Scholar
    • Export Citation
  • 7

    Veglio M, Chinaglia A & Cavallo-Perin P QT interval, cardiovascular risk factors and risk of death in diabetes. Journal of Endocrinological Investigation 2004 27 1751 81. (https://doi.org/10.1007/BF03346265)

    • Search Google Scholar
    • Export Citation
  • 8

    Festa A, D’Agostino Jr R, Rautaharju P, Mykkänen L & Haffner SM Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects. American Journal of Cardiology 2000 86 111711 22. (https://doi.org/10.1016/s0002-9149(0001170-x)

    • Search Google Scholar
    • Export Citation
  • 9

    Wang S, He Y, Xu L, Zhang S, Gu X, Gu J, Shi J, Shen Y & Tang Z Association between QTc interval prolongation and outcomes of diabetic foot ulcers: data from a 4-year follow-up study in China. Diabetes Research and Clinical Practice 2018 138 2634. (https://doi.org/10.1016/j.diabres.2018.01.021)

    • Search Google Scholar
    • Export Citation
  • 10

    Deng C, Niu J, Xuan L, Zhu W, Dai H, Zhao Z, Li M, Lu J, Xu Y & Chen Y et al. Association of QTc interval with risk of cardiovascular diseases and related vascular traits: a prospective and longitudinal analysis. Global Heart 2020 15 13. (https://doi.org/10.5334/gh.533)

    • Search Google Scholar
    • Export Citation
  • 11

    Strohmer B, Pichler M, Iglseder B & Paulweber B Relationship of QT interval duration with carotid intima media thickness in a clinically healthy population undergoing cardiovascular risk screening. Journal of Internal Medicine 2005 257 2382 46. (https://doi.org/10.1111/j.1365-2796.2004.01436.x)

    • Search Google Scholar
    • Export Citation
  • 12

    Maebuchi D, Arima H, Ninomiya T, Yonemoto K, Kubo M, Doi Y, Tanizaki Y, Matsumura K, Iida M & Kiyohara Y Arterial stiffness and QT interval prolongation in a general population: the Hisayama study. Hypertension Research 2008 31 133913 45. (https://doi.org/10.1291/hypres.31.1339)

    • Search Google Scholar
    • Export Citation
  • 13

    Takebayashi K, Aso Y, Matsutomo R, Wakabayashi S, Inukai T. Association between the corrected QT intervals and combined intimal-medial thickness of the carotid artery in patients with type 2 diabetes. Metabolism: Clinical and Experimental 2004 53 1152115 7. (https://doi.org/10.1016/j.metabol.2004.03.018)

    • Search Google Scholar
    • Export Citation
  • 14

    Lipsky BA, Aragón-Sánchez J, Diggle M, Embil J, Kono S, Lavery L, Senneville É, Urbančič-Rovan V, Van Asten SInternational Working Group on the Diabetic Foot, et al. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes/Metabolism Research and Reviews 2016 32 (Supplement 1) 4574. (https://doi.org/10.1002/dmrr.2699)

    • Search Google Scholar
    • Export Citation
  • 15

    Roden DM Drug-induced prolongation of the QT interval. New England Journal of Medicine 2004 350 101310 22. (https://doi.org/10.1056/NEJMra032426)

    • Search Google Scholar
    • Export Citation
  • 16

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F & Greene T et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009 150 6046 12. (https://doi.org/10.7326/0003-4819-150-9-200905050-00006)

    • Search Google Scholar
    • Export Citation
  • 17

    Bravo-Molina A, Linares-Palomino JP, Vera-Arroyo B, Salmerón-Febres LM & Ros-Díe E Inter-observer agreement of the Wagner, University of Texas and PEDIS classification systems for the diabetic foot syndrome. Foot and Ankle Surgery 2018 24 606 4. (https://doi.org/10.1016/j.fas.2016.10.009)

    • Search Google Scholar
    • Export Citation
  • 18

    Textor J, van der Zander B, Gilthorpe MS, Liskiewicz M & Ellison GT Robust causal inference using directed acyclic graphs: the R package ‘dagitty’. International Journal of Epidemiology 2016 45 188718 94. (https://doi.org/10.1093/ije/dyw341)

    • Search Google Scholar
    • Export Citation
  • 19

    Fagher K& Löndahl M The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers. Diabetologia 2013 56 1140114 7. (https://doi.org/10.1007/s00125-013-2860-x)

    • Search Google Scholar
    • Export Citation
  • 20

    Fagher K, Nilsson A & Löndahl M Heart rate-corrected QT interval prolongation as a prognostic marker for 3-year survival in people with Type 2 diabetes undergoing above-ankle amputation. Diabetic Medicine 2015 32 6796 85. (https://doi.org/10.1111/dme.12632)

    • Search Google Scholar
    • Export Citation
  • 21

    Fagher K, Katzman P & Löndahl M Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers. Journal of Diabetes and Its Complications 2015 29 11981 202. (https://doi.org/10.1016/j.jdiacomp.2015.07.023)

    • Search Google Scholar
    • Export Citation
  • 22

    Simon F, Oberhuber A, Floros N, Düppers P, Schelzig H & Duran M Pathophysiology of chronic limb ischemia. Gefasschirurgie 2018 23 (Supplement 1) 131 8. (https://doi.org/10.1007/s00772-018-0380-1)

    • Search Google Scholar
    • Export Citation
  • 23

    Shi Y& Vanhoutte PM Macro- and microvascular endothelial dysfunction in diabetes. Journal of Diabetes 2017 9 4344 4 9. (https://doi.org/10.1111/1753-0407.12521)

    • Search Google Scholar
    • Export Citation
  • 24

    Fiorentini A, Perciaccante A, Valente R, Paris A, Serra P & Tubani L The correlation among QTc interval, hyperglycaemia and the impaired autonomic activity. Autonomic Neuroscience 2010 154 949 8. (https://doi.org/10.1016/j.autneu.2009.11.006)

    • Search Google Scholar
    • Export Citation
  • 25

    Zemaitis MR, Boll JM & Dreyer MA Peripheral arterial disease. In StatPearls. Treasure Island (FL): StatPearls Publishing, 2020.

  • 26

    Cox AJ, Azeem A, Yeboah J, Soliman EZ, Aggarwal SR, Bertoni AG, Carr JJ, Freedman BI, Herrington DM & Bowden DW Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study. Diabetes Care 2014 37 145414 61. (https://doi.org/10.2337/dc13-1257)

    • Search Google Scholar
    • Export Citation
  • 27

    Beinart R, Zhang Y, Lima JA, Bluemke DA, Soliman EZ, Heckbert SR, Post WS, Guallar E & Nazarian S The QT interval is associated with incident cardiovascular events: the MESA study. Journal of the American College of Cardiology 2014 64 2111211 9. (https://doi.org/10.1016/j.jacc.2014.08.039)

    • Search Google Scholar
    • Export Citation
  • 28

    Wu J, Nizhamuding D, Liu P, Jiang Y, Qiang H, Sun C, Dai C & Yin Y QT interval prolongation in patients with acute ischemic stroke: a report in northwest China. Journal of International Medical Research 2019 47 598659 95. (https://doi.org/10.1177/0300060519879852)

    • Search Google Scholar
    • Export Citation
  • 29

    Ko GT, Chan JC, Critchley JA & Cockram CS Cardiovascular disease in Chinese type 2 diabetic women is associated with a prolonged QTc interval. International Journal of Cardiology 2000 76 7580. (https://doi.org/10.1016/s0167-5273(0000372-7)

    • Search Google Scholar
    • Export Citation
  • 30

    Vandael E, Vandenberk B, Vandenberghe J, Willems R & Foulon V Risk factors for QTc-prolongation: systematic review of the evidence. International Journal of Clinical Pharmacy 2017 39 1625. (https://doi.org/10.1007/s11096-016-0414-2)

    • Search Google Scholar
    • Export Citation
  • 31

    Su JB, Yang XH, Zhang XL, Cai HL, Huang HY, Zhao LH, Xu F, Chen T, Cheng XB & Wang XQ et al. The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes. PLoS ONE 2017 12 e0183055. (https://doi.org/10.1371/journal.pone.0183055)

    • Search Google Scholar
    • Export Citation
  • 32

    Guo X, Li Z, Liu Y, Yu S, Yang H, Zheng L, Zhang Y & Sun Y Sex-specific association between serum uric acid and prolonged corrected QT interval: result from a general rural Chinese population. Medicine 2016 95 e5568. (https://doi.org/10.1097/MD.0000000000005568)

    • Search Google Scholar
    • Export Citation
  • 33

    van Noord C, Sturkenboom MC, Straus SM, Hofman A, Kors JA, Witteman JC & Stricker BH Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly. European Journal of Endocrinology 2010 162 24124 8. (https://doi.org/10.1530/EJE-09-0878)

    • Search Google Scholar
    • Export Citation
  • 34

    Guo X, Li Z, Guo L, Yu S, Yang H, Zheng L, Pan G, Zhang Y, Sun Y & Pletcher MJ Effects of metabolically healthy and unhealthy obesity on prolongation of corrected QT interval. American Journal of Cardiology 2017 119 11991 204. (https://doi.org/10.1016/j.amjcard.2016.12.033)

    • Search Google Scholar
    • Export Citation
  • 35

    Jalilian M, Ahmadi Sarbarzeh P & Oubari S Factors related to severity of diabetic foot ulcer: a systematic review. Diabetes, Metabolic Syndrome and Obesity 2020 13 183518 42. (https://doi.org/10.2147/DMSO.S256243)

    • Search Google Scholar
    • Export Citation
  • 36

    Kobayashi S, Nagao M, Asai A, Fukuda I, Oikawa S & Sugihara H Severity and multiplicity of microvascular complications are associated with QT interval prolongation in patients with type 2 diabetes. Journal of Diabetes Investigation 2018 9 9469 51. (https://doi.org/10.1111/jdi.12772)

    • Search Google Scholar
    • Export Citation
  • 37

    Vlachopoulos C, Georgakopoulos C, Koutagiar I & Tousoulis D Diagnostic modalities in peripheral artery disease. Current Opinion in Pharmacology 2018 39 6876. (https://doi.org/10.1016/j.coph.2018.02.010)

    • Search Google Scholar
    • Export Citation
  • 38

    Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, Berry E, Gough M, Kleijnen J & Westwood M A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease. Health Technology Assessment 2007 11 iiiiv, xi, xixiii, 1184. (https://doi.org/10.3310/hta11200)

    • Search Google Scholar
    • Export Citation
  • 39

    Suttorp MM, Siegerink B, Jager KJ, Zoccali C & Dekker FW Graphical presentation of confounding in directed acyclic graphs. Nephrology, Dialysis, Transplantation 2015 30 141814 23. (https://doi.org/10.1093/ndt/gfu325)

    • Search Google Scholar
    • Export Citation
  • 40

    Tolppanen AM, Lavikainen P, Solomon A, Kivipelto M, Uusitupa M, Soininen H & Hartikainen S History of medically treated diabetes and risk of Alzheimer disease in a nationwide case-control study. Diabetes Care 2013 36 2015201 9. (https://doi.org/10.2337/dc12-1287)

    • Search Google Scholar
    • Export Citation
  • 41

    Sakhamuri S, Lutchmansingh F, Simeon D, Conyette L, Burney P & Seemungal T Reduced forced vital capacity is independently associated with ethnicity, metabolic factors and respiratory symptoms in a Caribbean population: a cross-sectional study. BMC Pulmonary Medicine 2019 19 62. (https://doi.org/10.1186/s12890-019-0823-9)

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

     Society for Endocrinology

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  • 1

    Singh N, Armstrong DG & Lipsky BA Preventing foot ulcers in patients with diabetes. JAMA 2005 293 2172 2 8. (https://doi.org/10.1001/jama.293.2.217)

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    • Export Citation
  • 2

    Boulton AJ, Vileikyte L, Ragnarson-Tennvall G & Apelqvist J The global burden of diabetic foot disease. Lancet 2005 366 171917 24. (https://doi.org/10.1016/S0140-6736(0567698-2)

    • Search Google Scholar
    • Export Citation
  • 3

    Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, Edmonds M, Holstein P, Jirkovska A & Mauricio D et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 2007 50 1825. (https://doi.org/10.1007/s00125-006-0491-1)

    • Search Google Scholar
    • Export Citation
  • 4

    Brownrigg JR, Schaper NC & Hinchliffe RJ Diagnosis and assessment of peripheral arterial disease in the diabetic foot. Diabetic Medicine 2015 32 7387 47. (https://doi.org/10.1111/dme.12749)

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  • 5

    Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, Gorgels A, Hancock EW, Josephson M & Kligfield P et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. Journal of the American College of Cardiology 2009 53 9829 9 1. (https://doi.org/10.1016/j.jacc.2008.12.014)

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  • 6

    Pappachan JM, Sebastian J, Bino BC, Jayaprakash K, Vijayakumar K, Sujathan P & Adinegara LA Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis. Postgraduate Medical Journal 2008 84 2052 10. (https://doi.org/10.1136/pgmj.2007.064048)

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  • 7

    Veglio M, Chinaglia A & Cavallo-Perin P QT interval, cardiovascular risk factors and risk of death in diabetes. Journal of Endocrinological Investigation 2004 27 1751 81. (https://doi.org/10.1007/BF03346265)

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  • 8

    Festa A, D’Agostino Jr R, Rautaharju P, Mykkänen L & Haffner SM Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects. American Journal of Cardiology 2000 86 111711 22. (https://doi.org/10.1016/s0002-9149(0001170-x)

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  • 9

    Wang S, He Y, Xu L, Zhang S, Gu X, Gu J, Shi J, Shen Y & Tang Z Association between QTc interval prolongation and outcomes of diabetic foot ulcers: data from a 4-year follow-up study in China. Diabetes Research and Clinical Practice 2018 138 2634. (https://doi.org/10.1016/j.diabres.2018.01.021)

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  • 10

    Deng C, Niu J, Xuan L, Zhu W, Dai H, Zhao Z, Li M, Lu J, Xu Y & Chen Y et al. Association of QTc interval with risk of cardiovascular diseases and related vascular traits: a prospective and longitudinal analysis. Global Heart 2020 15 13. (https://doi.org/10.5334/gh.533)

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  • 11

    Strohmer B, Pichler M, Iglseder B & Paulweber B Relationship of QT interval duration with carotid intima media thickness in a clinically healthy population undergoing cardiovascular risk screening. Journal of Internal Medicine 2005 257 2382 46. (https://doi.org/10.1111/j.1365-2796.2004.01436.x)

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  • 12

    Maebuchi D, Arima H, Ninomiya T, Yonemoto K, Kubo M, Doi Y, Tanizaki Y, Matsumura K, Iida M & Kiyohara Y Arterial stiffness and QT interval prolongation in a general population: the Hisayama study. Hypertension Research 2008 31 133913 45. (https://doi.org/10.1291/hypres.31.1339)

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  • 13

    Takebayashi K, Aso Y, Matsutomo R, Wakabayashi S, Inukai T. Association between the corrected QT intervals and combined intimal-medial thickness of the carotid artery in patients with type 2 diabetes. Metabolism: Clinical and Experimental 2004 53 1152115 7. (https://doi.org/10.1016/j.metabol.2004.03.018)

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  • 14

    Lipsky BA, Aragón-Sánchez J, Diggle M, Embil J, Kono S, Lavery L, Senneville É, Urbančič-Rovan V, Van Asten SInternational Working Group on the Diabetic Foot, et al. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes/Metabolism Research and Reviews 2016 32 (Supplement 1) 4574. (https://doi.org/10.1002/dmrr.2699)

    • Search Google Scholar
    • Export Citation
  • 15

    Roden DM Drug-induced prolongation of the QT interval. New England Journal of Medicine 2004 350 101310 22. (https://doi.org/10.1056/NEJMra032426)

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  • 16

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F & Greene T et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009 150 6046 12. (https://doi.org/10.7326/0003-4819-150-9-200905050-00006)

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  • 17

    Bravo-Molina A, Linares-Palomino JP, Vera-Arroyo B, Salmerón-Febres LM & Ros-Díe E Inter-observer agreement of the Wagner, University of Texas and PEDIS classification systems for the diabetic foot syndrome. Foot and Ankle Surgery 2018 24 606 4. (https://doi.org/10.1016/j.fas.2016.10.009)

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  • 18

    Textor J, van der Zander B, Gilthorpe MS, Liskiewicz M & Ellison GT Robust causal inference using directed acyclic graphs: the R package ‘dagitty’. International Journal of Epidemiology 2016 45 188718 94. (https://doi.org/10.1093/ije/dyw341)

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  • 19

    Fagher K& Löndahl M The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers. Diabetologia 2013 56 1140114 7. (https://doi.org/10.1007/s00125-013-2860-x)

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  • 20

    Fagher K, Nilsson A & Löndahl M Heart rate-corrected QT interval prolongation as a prognostic marker for 3-year survival in people with Type 2 diabetes undergoing above-ankle amputation. Diabetic Medicine 2015 32 6796 85. (https://doi.org/10.1111/dme.12632)

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  • 21

    Fagher K, Katzman P & Löndahl M Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers. Journal of Diabetes and Its Complications 2015 29 11981 202. (https://doi.org/10.1016/j.jdiacomp.2015.07.023)

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  • 22

    Simon F, Oberhuber A, Floros N, Düppers P, Schelzig H & Duran M Pathophysiology of chronic limb ischemia. Gefasschirurgie 2018 23 (Supplement 1) 131 8. (https://doi.org/10.1007/s00772-018-0380-1)

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  • 23

    Shi Y& Vanhoutte PM Macro- and microvascular endothelial dysfunction in diabetes. Journal of Diabetes 2017 9 4344 4 9. (https://doi.org/10.1111/1753-0407.12521)

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  • 24

    Fiorentini A, Perciaccante A, Valente R, Paris A, Serra P & Tubani L The correlation among QTc interval, hyperglycaemia and the impaired autonomic activity. Autonomic Neuroscience 2010 154 949 8. (https://doi.org/10.1016/j.autneu.2009.11.006)

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  • 25

    Zemaitis MR, Boll JM & Dreyer MA Peripheral arterial disease. In StatPearls. Treasure Island (FL): StatPearls Publishing, 2020.

  • 26

    Cox AJ, Azeem A, Yeboah J, Soliman EZ, Aggarwal SR, Bertoni AG, Carr JJ, Freedman BI, Herrington DM & Bowden DW Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study. Diabetes Care 2014 37 145414 61. (https://doi.org/10.2337/dc13-1257)

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  • 27

    Beinart R, Zhang Y, Lima JA, Bluemke DA, Soliman EZ, Heckbert SR, Post WS, Guallar E & Nazarian S The QT interval is associated with incident cardiovascular events: the MESA study. Journal of the American College of Cardiology 2014 64 2111211 9. (https://doi.org/10.1016/j.jacc.2014.08.039)

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  • 28

    Wu J, Nizhamuding D, Liu P, Jiang Y, Qiang H, Sun C, Dai C & Yin Y QT interval prolongation in patients with acute ischemic stroke: a report in northwest China. Journal of International Medical Research 2019 47 598659 95. (https://doi.org/10.1177/0300060519879852)

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  • 29

    Ko GT, Chan JC, Critchley JA & Cockram CS Cardiovascular disease in Chinese type 2 diabetic women is associated with a prolonged QTc interval. International Journal of Cardiology 2000 76 7580. (https://doi.org/10.1016/s0167-5273(0000372-7)

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  • 30

    Vandael E, Vandenberk B, Vandenberghe J, Willems R & Foulon V Risk factors for QTc-prolongation: systematic review of the evidence. International Journal of Clinical Pharmacy 2017 39 1625. (https://doi.org/10.1007/s11096-016-0414-2)

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  • 31

    Su JB, Yang XH, Zhang XL, Cai HL, Huang HY, Zhao LH, Xu F, Chen T, Cheng XB & Wang XQ et al. The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes. PLoS ONE 2017 12 e0183055. (https://doi.org/10.1371/journal.pone.0183055)

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  • 32

    Guo X, Li Z, Liu Y, Yu S, Yang H, Zheng L, Zhang Y & Sun Y Sex-specific association between serum uric acid and prolonged corrected QT interval: result from a general rural Chinese population. Medicine 2016 95 e5568. (https://doi.org/10.1097/MD.0000000000005568)

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  • 33

    van Noord C, Sturkenboom MC, Straus SM, Hofman A, Kors JA, Witteman JC & Stricker BH Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly. European Journal of Endocrinology 2010 162 24124 8. (https://doi.org/10.1530/EJE-09-0878)

    • Search Google Scholar
    • Export Citation
  • 34

    Guo X, Li Z, Guo L, Yu S, Yang H, Zheng L, Pan G, Zhang Y, Sun Y & Pletcher MJ Effects of metabolically healthy and unhealthy obesity on prolongation of corrected QT interval. American Journal of Cardiology 2017 119 11991 204. (https://doi.org/10.1016/j.amjcard.2016.12.033)

    • Search Google Scholar
    • Export Citation
  • 35

    Jalilian M, Ahmadi Sarbarzeh P & Oubari S Factors related to severity of diabetic foot ulcer: a systematic review. Diabetes, Metabolic Syndrome and Obesity 2020 13 183518 42. (https://doi.org/10.2147/DMSO.S256243)

    • Search Google Scholar
    • Export Citation
  • 36

    Kobayashi S, Nagao M, Asai A, Fukuda I, Oikawa S & Sugihara H Severity and multiplicity of microvascular complications are associated with QT interval prolongation in patients with type 2 diabetes. Journal of Diabetes Investigation 2018 9 9469 51. (https://doi.org/10.1111/jdi.12772)

    • Search Google Scholar
    • Export Citation
  • 37

    Vlachopoulos C, Georgakopoulos C, Koutagiar I & Tousoulis D Diagnostic modalities in peripheral artery disease. Current Opinion in Pharmacology 2018 39 6876. (https://doi.org/10.1016/j.coph.2018.02.010)

    • Search Google Scholar
    • Export Citation
  • 38

    Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, Berry E, Gough M, Kleijnen J & Westwood M A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease. Health Technology Assessment 2007 11 iiiiv, xi, xixiii, 1184. (https://doi.org/10.3310/hta11200)

    • Search Google Scholar
    • Export Citation
  • 39

    Suttorp MM, Siegerink B, Jager KJ, Zoccali C & Dekker FW Graphical presentation of confounding in directed acyclic graphs. Nephrology, Dialysis, Transplantation 2015 30 141814 23. (https://doi.org/10.1093/ndt/gfu325)

    • Search Google Scholar
    • Export Citation
  • 40

    Tolppanen AM, Lavikainen P, Solomon A, Kivipelto M, Uusitupa M, Soininen H & Hartikainen S History of medically treated diabetes and risk of Alzheimer disease in a nationwide case-control study. Diabetes Care 2013 36 2015201 9. (https://doi.org/10.2337/dc12-1287)

    • Search Google Scholar
    • Export Citation
  • 41

    Sakhamuri S, Lutchmansingh F, Simeon D, Conyette L, Burney P & Seemungal T Reduced forced vital capacity is independently associated with ethnicity, metabolic factors and respiratory symptoms in a Caribbean population: a cross-sectional study. BMC Pulmonary Medicine 2019 19 62. (https://doi.org/10.1186/s12890-019-0823-9)

    • Search Google Scholar
    • Export Citation