Cardiovascular autonomic neuropathy in diabetes: an update with a focus on management.

Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.

Determinants of Orthostatic Hypotension in Type 2 Diabetes: Is Cardiac Autonomic Neuropathy the Main Factor?

OBJECTIVES: To evaluate the determinants of orthostatic hypotension (OH) in type 2 diabetes (T2D) and the usefulness of Δheart rate (HR)/Δsystolic blood pressure (SBP), index of cardiac baroreflex function, in identifying neurogenic OH. METHODS: In 208 participants with T2D, we diagnosed early cardiovascular autonomic neuropathy (CAN) and confirmed CAN according to 1 and 2 HR-based cardiovascular reflex tests (HR-CARTs). Through OH test we defined OH as SBP falls of ≥20 and ≥30 mm Hg with supine SBPs of <140 and ≥140 mm Hg, respectively. In participants with OH, we used the lying-to-standing and OH test and its diagnostic accuracy for neurogenic OH (as OH plus confirmed HR-CAN). RESULTS: OH was present in 25 participants and associated with lower HR-CART scores, higher glycosylated hemoglobin level, the presence of CAN, retinopathy, and peripheral vascular disease, the absence of hypertension, and physical activity (all, P < .05) but not with interfering drugs and ß-blockers. In a multiple logistic regression, HR-CAN was the main determinant of OH (odds ratio, 4.74) with physical activity and hypertension (odds ratios, 0.16 and 0.23; R2 = 0.22). ΔHR/ΔSBP had a good diagnostic accuracy for neurogenic OH (area under the receiver operating characteristic curve, 0.816 ± 0.087) and, at the cutoff of 0.5 bpm/mm Hg, a sensitivity of 100% and specificity of 63.2%. CONCLUSION: CAN remains the primary determinant of OH in T2D but does not explain all its variance. The index ΔHR/ΔSBP may represent a useful clinical tool to identify neurogenic OH.

ATG5 gene expression analysis supports the involvement of autophagy in microangiopathic complications of type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) hyperglycaemia alters basal autophagy. Since autophagy is an essential cellular process, our aim was to investigate the ATG5 (autophagy-related 5) gene expression level and genetic variants in a cohort of diabetic patients, characterized for the presence of microangiopathic complications. METHODS AND RESULTS: the expression levels of ATG5 were evaluated in PBMCs from 48 T2D patients with an extensive evaluation for microangiopathic complications. Our analyses revealed a significant lower expression of ATG5 in T2D patients with retinopathy compared to those without retinopathy. We also highlighted a significant lower expression of ATG5 in T2D patients with early-cardiovascular autonomic neuropathy compared to those without it, after correction for sex, age, body mass index and levels of hemoglobin A1c. CONCLUSION: our results highlight that dysregulation in the autophagy process could be involved in the development of severe microangiopathic complications.

Clinical scoring systems for the risk of cardiovascular autonomic neuropathy in type 1 and type 2 diabetes: A simple tool.

This study was aimed at developing a clinical risk score for cardiovascular autonomic neuropathy (CAN) for type 1 and type 2 diabetes. In a retrospective cross-sectional one-centre study in an unselected population, 115 participants with type 1 diabetes (age 41.1 ± 12.2 years) and 161 with type 2 diabetes (age 63.1 ± 8.9 years), well-characterized for clinical variables, underwent standard cardiovascular reflex tests (CARTs). Strength of associations of confirmed CAN (based on 2 abnormal CARTs) with clinical variables was used to build a CAN risk score. CAN risk score was based on resting heart rate, HbA1c, retinopathy, nephropathy, cardiovascular disease in both type 1 and type 2 diabetes, and on HDL cholesterol, systolic blood pressure, and smoking in type 1 diabetes or insulin treatment and physical activity in type 2 diabetes (range 0-10). In type 1 diabetes, CAN risk score showed an area under the ROC curve (AUC) of 0.890 ± 0.034, and at cut-off of 4 sensitivity of 88%, specificity of 74.4%, and negative predictive value (NPV) of 95.7% for confirmed CAN. In type 2 diabetes, CAN risk score showed an AUC of 0.830 ± 0.051 and at the cut-off of 4 sensitivity and specificity of 78.6% and 73.5%, respectively, and NPV of 97.3% for confirmed CAN. These newly developed CAN risk scores are accessible in clinical practice and, if confirmed in a validation study, they might identify asymptomatic individuals with diabetes at greater risk of CAN to be referred to CARTs, thus limiting the burden of a universal screening.

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy.

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One-hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 µS and/or feet ESC <70 µS) in 47.4%. Both the patterns-COMPASS 31+ESC and COMPASS 31 and/or ESC-were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.

Blood Pressure Variability and Autonomic Dysfunction.

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.

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.

Low expression levels of miRNA-155 and miRNA-499a are associated with obesity in Type 2 diabetes.

Background & aims: This study investigated a possible correlation between three circulating miRNAs, previously observed to be associated to diabetic polyneuropathy, and the obesity condition. Methods & results: The expression levels of miR-128a, miR-155 and miR499a were evaluated in 49 participants with Type 2 diabetes, divided into different groups based on the presence or absence of obesity and central obesity. The analyses revealed a significant decrease of miR-155 and miR-499a expression levels in obese subjects. In particular, the reduction appears to be even more significant in Type 2 diabetes subjects with central obesity. Conclusion: The results suggest that these miRNAs could be involved in obesity-driven pathogenetic mechanisms.

Does the Relationship of the Autonomic Symptoms Questionnaire COMPASS 31 with Cardiovascular Autonomic Tests Differ between Type 1 and Type 2 Diabetes Mellitus?

Background: The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Methods: Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis. Results: COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027). Conclusion: COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.

Painful and painless diabetic neuropathy: one disease or two?

Painful diabetic polyneuropathy (PDPN) is generally considered a variant of diabetic polyneuropathy (DPN) but the identification of distinctive aspects that characterize painful compared with painless DPN has however been addressed in many studies, mainly with the purpose of better understanding the mechanisms of neuropathic pain in the scenario of peripheral nerve damage of DPN, of determining risk markers for pain development, and also of recognizing who might respond to treatments. This review is aimed at examining available literature dealing with the issue of similarities and differences between painful and painless DPN in an attempt to respond to the question of whether painful and painless DPN are the same disease or not and to address the conundrum of why some people develop the insensate variety of DPN whilst others experience distressing pain. Thus, from the perspective of comparing painful with painless forms of DPN, this review considers the clinical correlates of PDPN, its distinctive framework of symptoms, signs, and nerve functional and structural abnormalities, the question of large and small fiber involvement, the peripheral pain mechanisms, the central processing of pain and some new insights into the pathogenesis of pain in peripheral polyneuropathies and PDPN.

Management of painful diabetic neuropathy: guideline guidance or jungle?

The treatment of painful diabetic polyneuropathy (PDPN) remains a major challenge. A number of reasons have made the guidelines on PDPN management of particular interest, including its high prevalence, health and socioeconomic impact, interdisciplinary nature and the need for updated evidence-based information to refine patient-tailored treatment by weighing up the risks of each treatment against its proven benefits, as well as optimizing the use of all available resources. The various guidelines on the management of neuropathic pain developed so far contain some differences in their work methodology and results. Some variations in the recommendations are to be expected but could be disorienting and confusing for stakeholders. In this review, a critical evaluation of the more recent guidelines on the management of PDPN is provided together with highlights on points of agreement and disagreement as well as insights into their clinical aspects.

Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations.

Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life.

Methods of investigation for cardiac autonomic dysfunction in human research studies.

This consensus document provides evidence-based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non-invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches.

Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

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.

SGLT2 inhibitors and the autonomic nervous system in diabetes: A promising challenge to better understand multiple target improvement.

The puzzle of the multifaceted actions of sodium-glucose cotransporter type-2 inhibitors (SGLT2is) is still incomplete. For diabetologists (who are accustomed to dealing with the burden of cardiovascular autonomic neuropathy), the relationship between SGLT2is and the autonomic nervous system (ANS) represents one of the most intriguing aspects of the multiple effects of this family of drugs, especially given the poor availability of disease-modifying treatments for such complication. Therefore, the present review has considered both preclinical and clinical studies of this topic with autonomic perspectives by exploring the pathophysiological background of the interactions between the ANS and SGLT2, including sympathetic control of kidney function and the role of renal afferent nerves, and also by providing insights into the effects of SGLT2is on 24-h blood pressure (BP) and heart rate variability (HRV), with particular attention focused on the EMBODY trial. Indeed, despite the difficulties of exploring such a complex network comprising the kidney, heart and the ANS while targeting a single outcome-circadian BP and HRV-the available studies do offer evidence that SGLT2i actions are in part mediated by neural circuitry and the ANS. Thus, at this time, the worthwhile incidental result of these (and future) studies has been to highlight the role of autonomic innervation in the pathophysiology of kidney and heart disease.

Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a MIR499A Gene Polymorphism.

Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the MIR499A. T2D patients show a decrease in the number of mtDNA copies compared to healthy controls (p = 2 × 10-10). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without (p = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of MIR499A correlates with a decrease in the number of mtDNA copies, particularly in T2D patients (p = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of MIR499A with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.

Morning blood pressure surge is associated with autonomic neuropathy and peripheral vascular disease in patients with diabetes.

Although vascular and autonomic nervous system have been involved in the regulation of morning surge in blood pressure (MBPS), data on clinical correlates of MBPS in diabetic population are scarce, in particular with regard to diabetic complications. This study was aimed at investigating predictors and correlates of MBPS in diabetes. In a cross-sectional study including 167 patients with diabetes (age 58.5 ± 11.1 years, duration 15.9 ± 12.1 years), clinical variables, diabetic and neuropathic complications, and MBPS (using 24-h ambulatory blood pressure monitoring) were measured. The upper quartile of MBPS (>30.5 mmHg) was associated with higher values of waist circumference (P = 0.027), triglycerides (P = 0.021), and Michigan Diabetic Neuropathy Score (P = 0.042), with lower HDL cholesterol (P = 0.030), and with the presence of cardiovascular autonomic neuropathy (CAN) (P = 0.016) and peripheral vascular disease (PVD) (P < 0.0001). In a logistic regression analysis, PVD (odds ratio: 10.2, P = 0.001), CAN (odds ratio: 6.09, P = 0.016), and diastolic blood pressure (BP) (odds ratio: 1.06, P = 0.022) predicted MBPS upper quartile (r2 = 0.20, P = 0.0005). In a multiple regression analysis, PVD (P = 0.002) and diastolic BP (P = 0.003) were the only determinants of MBPS (r2 = 0.20). MBPS upper quartile was associated with BP dipping (systolic BP day-night reduction > 10%) (P = 0.012), and MBPS was positively related to systolic (rho = 0.41, P < 0.0001) and diastolic BP day-night reduction. In conclusion, metabolic syndrome stigmata, diastolic BP, CAN and PVD are the main predictors of MBPS in the diabetic population. Excessive MBPS and nondipping are not concurrent 24-h BP alterations. Autonomic dysfunction might exert an exacerbating effect on MBPS phenomenon.

Expression study of candidate miRNAs and evaluation of their potential use as biomarkers of diabetic neuropathy.

Aim: To evaluate the expression of candidate miRNAs in relation to diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). Materials & methods: The expression of six candidate miRNAs has been evaluated in 49 Type 2 diabetes patients with neurological evaluation. Results: A higher expression of miR-128a was seen in patients with DPN compared with those without DPN (p = 0.015). miR-155 and miR-499a seemed to be down-expressed in patients with DPN (p = 0.04 and p = 0.05, respectively). A lower expression of miR-155 (p = 0.05) was observed even in patients with CAN with respect to CAN-negative. A higher expression of miR-155 was associated with the rs767649 polymorphism variant allele compared with the wild-type allele (p = 0.03). Conclusion: miR-128a, miR-155 and miR-499a might be involved in diabetic neuropathies development.

Management and Treatment of Patients With Major Depressive Disorder and Chronic Diseases: A Multidisciplinary Approach.

In patients with physical chronic diseases, the prevalence of major depressive disorder (MDD) is approximately 2- to 3-fold higher than in the general population, and it can reach up to 20-40%. The comorbidity of MDD with chronic medical diseases is associated with poorer quality of life, increased medical symptom burden, poor adherence to self-care regimens, increased risk of functional impairment, morbidity, and mortality, and also higher medical costs. Despite this evidence, in routine practice, psychological issues and concerns are frequently inadequately managed. This consensus document proposes that a proper diagnosis, a multidisciplinary approach, and a personalized treatment plan would allow patients with MDD and chronic comorbidities to be more compliant, to improve the outcomes, to reduce possible relapses in the long term, and to prevent or better manage complications and adverse events. This proposal might be useful for any health professionals who deal with patients with chronic diseases, as it can help to pay more attention to the emotional impact of these conditions, in particular in terms of depressive symptoms.