Systolic and diastolic left ventricular function in patients with type 2 diabetes mellitus: Changes over time and comparison with cardiac microcirculation

Denne PhD afhandling er baseret på 3 originale manuskripter baseret på studier, som er udført påKardiologisk Forskningsenhed på Odense Universitets Hospital Svendborg (OUH Svendborg).BaggrundPatienter med diabetes mellitus (DM) har en øget risiko for hjertekarsygdomme, herunderiskæmisk hjertesygdom, sammenlignet med baggrundsbefolkningen. Størstedelen af patienternemed DM har hjertekarsygdom pga. udvikling af åreforkalkninger i kranspulsårerne. Denne udviklinger primært drevet af kardiovaskulære risikofaktorer, såsom forhøjet blodtryk, forhøjet kolesterol,rygning og overvægt. Dog eksisterer der kun sparsomt med studier vedr. asymptomatiske patientermed DM uden betydende åreforkalkninger i kranspulsårerne. Det overordnede formål medafhandlingen var at vurdere venstre ventrikels systoliske og diastoliske funktion i relation til denkoronare mikrocirkulation (CFVR) samt inflammation hos asymptomatiske patienter med diabetes,især hos patienter med type 2 diabetes mellitus (T2DM).Formål- At vurdere betydningen af diabetes-relaterede mikrovaskulære komplikationer, CFVR,kardielle risikofaktorer og plaque byrde på global longitudinal strain (GLS) hos patientermed DM.- At vurdere sammenhængen mellem venstre ventrikel systoliske og diastoliske funktion,CFVR og inflammation hos patienter med T2DM.- At vurdere sammenhængen mellem ændringer i GLS i løbet af 1 års opfølgning i relation tilCFVR hos patienter med T2DM og ikke-diabetiske deltagere.MetodeDenne PhD afhandling er baseret på data fra et prospektivt observationelt studie udført i periodenfra marts 2016 til august 2017 med sidste opfølgning i september 2018 på OUH Svendborg. Asymptomatiske patienter med DM og ikke-diabetiske deltagere uden betydende åreforkalkninger ikranspulsårerne blev inkluderet. Alle blev undersøgt med ekkokardiografi, avanceretultralydsscanning af kranpulsårerne, hjerte-CT med kontrast, elektrokardiogram, urin ogblodprøver. Undersøgelserne blev gentaget ved opfølgningen med undtagelse af hjerte-CT hos deikke-diabetiske deltagere.Hovedfund1. En stigende byrde af diabetes-relaterede mikrovaskulære komplikationer (albuminuri,retinopati og neuropati) var associeret med reduceret GLS.2. Der var ingen lineær sammenhængen mellem plaque byrde og GLS.3. Ingen patienter havde diastolisk dysfunktion af venstre ventrikel.4. Der var ingen association mellem CFVR og venstre ventrikels systoliske og diastoliskefunktion.5. Traditionelle kardiovaskulære risikofaktorer var associeret med reduceret GLS.6. Der var ingen korrelation mellem CFVR og de inflammatoriske biomarkører neutrofil tillymfocyt-ratio (NLR) og højsensitiv C-reaktiv Protein (hs-CRP).7. Der var ingen klinisk betydende ændring i GLS i løbet af opfølgningsperioden uansetCFVR.KonklusionerAsymptomatiske patienter med DM og bevaret venstre ventrikel uddrivelsesfraktion havdereduceret GLS på trods af kun ubetydelig åreforkalkning i kranspulsårerne. Derudover vartilstedeværelsen og byrden af diabetes-relaterede mikrovaskulære komplikationer associeret medreduceret GLS. Traditionelle kardiovaskulære risikofaktorer var associeret med reduceret GLS.Inflammation kan være en del af mekanismen, men vi var ikke i stand til at påvise inflammation vedbrug af de simple inflammatoriske biomarkører NLR og hs-CRP fra den kliniske dagligdag. En stram kontrol af blodsukker og kardiovaskulære risikofaktorer ser ud til at være det bedste middelmod fremtidig udvikling af CVD, selvom de bagvedliggende mekanismer ikke er helt kendte.This PhD thesis is based on 3 original manuscripts based on studies conducted at theCardiovascular Research Unit at Odense University Hospital Svendborg (OUH Svendborg).BackgroundPatients with diabetes mellitus (DM) have an increased risk of cardiovascular disease (CVD)including ischemic heart disease (IHD) compared to the background population. The majority ofpatients with DM suffer from CVD, because of the progression of coronary artery disease (CAD).This is mainly driven by the presence of cardiovascular (CV) risk factors such as hypertension,hyperlipidemia, smoking, and obesity. However, only sparse evidence exists on asymptomaticpatients with DM and verified non-obstructive CVD. The overall aim of this PhD thesis was toassess the left ventricle (LV) systolic and diastolic function in relation to the coronarymicrocirculation and inflammation in asymptomatic patients with DM with a particular focus onpatients with type 2 diabetes mellitus (T2DM).Objectives- To assess the impact of diabetes-related microvascular complications, coronarymicrocirculation, CV risk factors, and plaque burden on global longitudinal strain (GLS) inpatients with DM.- To assess the relationship between LV systolic and diastolic function, coronarymicrocirculation, and inflammation in patients with T2DM.- To assess the relationship between changes in GLS during 1-year of follow-up in relation tocoronary microcirculation in patients with T2DM and non-diabetic subjectsMethodsThis PhD thesis is based on data from a prospective observational study performed betweenMarch 2016 and August 2017 with end of follow-up in September 2018 at OUH Svendborg. Asymptomatic patients with DM and non-diabetic subjects with non-obstructive CAD were included. All participants were examined with echocardiography, coronary flow velocity reserve(CFVR), coronary computed tomography angiography (CCTA), electrocardiogram, urine and bloodsamples. Examinations were repeated at follow-up with the exemption of CCTA in the non-diabetic subjects.Main findings1. An increased burden of diabetes-related microvascular complications (albuminuria,retinopathy and neuropathy) was associated with reduced GLS.2. There was no linear relationship between plaque burden and GLS.3. No patients had LV diastolic dysfunction.4. No association was observed between CFVR and LV systolic and diastolic function.5. Traditional CV risk factors were associated with reduced GLS.6. No correlation was observed between CFVR and the inflammatory biomarkers neutrophilto-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP).7. There was no clinically relevant change in GLS during follow-up regardless of CFVR.ConclusionsAsymptomatic patients with DM and preserved LV ejection fraction had reduced GLS despitehaving no obstructive CAD. Additionally, the presence, but also the burden of diabetes-relatedmicrovascular complications, were associated with reduced GLS. Traditional CV risk factors wereassociated with reduced GLS. We were not able to detect an inflammatory response on thismechanism on the basis of ordinary biomarkers used in clinical practice, but inflammation couldstill be a possible mechanism. A tight glycemic control and optimization of CV risk factors seem tohave an important impact on future CVD, despite the underlying mechanisms are not fullyunderstood

Systematic review of worldwide variations of the prevalence of wheezing symptoms in children

Background: Considerable variation in the prevalence of childhood asthma and its symptoms (wheezing) has been observed in previous studies and there is evidence that the prevalence has been increasing over time. Methods: We have systematically reviewed the reported prevalence and time trends of wheezing symptoms among children, worldwide and within the same country over time. All studies comprising more than 1000 persons and meeting certain other quality criteria published over a 16-year period, between January 1990 and December 2005, are reported and a comparison of ISAAC (International Study of Asthma and Allergies in Childhood) and non-ISAAC studies is made, in part as a way of expanding the power to examine time trends (the older studies tend to be non-ISAAC), but also to examine possible methodological differences between ISAAC and non-ISAAC questions. Results: A wide range of current prevalence of wheeze was observed between and within countries over time. The UK had the highest recorded prevalence of 32.2% in children aged 13–14 in 1994–5 and Ethiopia had the lowest prevalence, 1.7% in children aged 10–19 in 1996. All studies in Australia and the UK were compared using multiple logistic regression. ISAAC phase I and III studies reported significantly higher prevalence of current wheeze (OR = 1.638) compared with non-ISAAC studies, after adjusting for various other factors (country, survey year, age of child, parental vs child response to the survey). Australia showed a significantly higher prevalence of current wheezing (OR = 1.343) compared with the UK, there was a significant increase in the prevalence odds ratio per survey year (2.5% per year), a significant decrease per age of child (0.7% per year), and a significantly higher response in current wheezing if the response was self-completed by the child (OR = 1.290). These factors, when explored separately for ISAAC and non-ISAAC studies, showed very different results. In ISAAC studies, or non-ISAAC studies using ISAAC questions, there was a significant decrease in current wheezing prevalence over time (2.5% per year). In non-ISAAC studies, which tend to cover an earlier period, there was a significant increase (2.6% per year) in current wheezing prevalence over time. This is very likely to be a result of prevalence of wheezing increasing from the 1970s up to the early 1990s, but decreasing since then. Conclusion: The UK has the highest recorded prevalence of wheezing and Ethiopia the lowest. Prevalence of wheezing in Australia and the UK has increased from the 1970s up to the early 1990s, but decreased since then and ISAAC studies report significantly higher prevalences than non-ISAAC studies

Dysglycemia and increased left ventricle mass in normotensive patients admitted with a first myocardial infarction:prognostic implications of dysglycemia during 14 years of follow-up

BACKGROUND: Left ventricle mass (LVM) can be influenced by various conditions including hypertension and/or inherent cardiomyopathies. Dysglycemia is also thought to exert an anabolic effect on heart tissue by hyperinsulinemia and thereby promoting increased LVM. The primary aim of this study was to assess the influence of dysglycemia on LVM evaluated by an oral glucose tolerance test (OGTT) in patients admitted with a first myocardial infarction (MI) without hypertension. The secondary aim was to assess the impact of dysglycemia on major adverse cardiovascular events (MACE) and all-cause mortality during long-term follow-up.METHODS: Patients admitted with a first MI without known history of hypertension were included. All patients without previously known type 2 diabetes mellitus (T2DM) had a standardized 2-hour OGTT performed and were categorized as: normal glucose tolerance (NGT), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and newly detected T2DM (new T2DM). LVM was measured by echocardiography using Devereaux formula and indexed by body surface area. Multivariate linear regression analysis was used to assess the impact of confounders (dysglycemia by OGTT, known T2DM, age, sex and type of MI) on LVM. Cox proportional hazard model was used to assess the impact of dysglycemia on all-cause mortality and a composite endpoint of MACE (all-cause mortality, MI, revascularisation due to stable angina, coronary artery bypass graft, ischemic stroke or hemorrhagic stroke).RESULTS: Two-hundred-and-five patients were included and followed up to 14 years. In multivariate regression analysis, LVM was only significantly increased in patients categorized as new T2DM (β = 25.3; 95% CI [7.5-43.0]) and known T2DM (β = 37.3; 95% CI [10.0-64.5]) compared to patients with NGT. Patients with new T2DM showed higher rates of MACE and all-cause mortality compared to patients with IFG/IGT and NGT; however no significantly increased hazard ratio was detected.CONCLUSIONS: Dysglycemia is associated with increasing LVM in normotensive patients with a first acute myocardial infarction and the strongest association was observed in patients with new T2DM and patients with known T2DM. Dysglycemia in normotensive patients with a first MI is not an independent predictor of neither MACE nor all-cause mortality during long-term follow-up compared to normotensive patients without dysglycemia.</p

High-risk coronary artery plaque in asymptomatic patients with type 2 diabetes:clinical risk factors and coronary artery calcium score

Background: High-risk coronary artery plaque (HRP) is associated with increased risk of acute coronary syndrome. We aimed to investigate the prevalence of HRP in asymptomatic patients with type 2 diabetes (T2D), and its relation to patient characteristics including cardiovascular risk factors, diabetes profile, and coronary artery calcium score (CACS). Methods: Asymptomatic patients with T2D and no previous coronary artery disease (CAD) were studied using coronary computed tomography angiography (CCTA) in this descriptive study. Plaques with two or more high-risk features (HRP) defined by low attenuation, positive remodeling, spotty calcification, and napkin-ring sign were considered HRP. In addition, total atheroma volume (TAV), proportions of dense calcium, fibrous, fibrous-fatty and necrotic core volumes were assessed. The CACS was obtained from non-enhanced images by the Agatston method. Cardiovascular and diabetic profiles were assessed in all patients. Results: In 230 patients CCTA was diagnostic and 161 HRP were detected in 86 patients (37%). Male gender (OR 4.19, 95% CI 1.99–8.87; p &lt; 0.01), tobacco exposure in pack years (OR 1.02, 95% CI 1.00–1.03; p = 0.03), and glycated hemoglobin (HbA1c) (OR 1.04, 95% CI 1.02–1.07; p &lt; 0.01) were independent predictors of HRP. No relationship was found to other risk factors. HRP was not associated with increased CACS, and 13 (23%) patients with zero CACS had at least one HRP. Conclusion: A high prevalence of HRP was detected in this population of asymptomatic T2D. The presence of HRP was associated with a particular patient profile, but was not ruled out by the absence of coronary artery calcium. CCTA provides important information on plaque morphology, which may be used to risk stratify this high-risk population. Trial registration This trial was retrospectively registered at clinical trials.gov January 11, 2017 trial identifier NCT03016910.</p

Diabetic microvascular complications are associated with reduced global longitudinal strain independent of atherosclerotic coronary artery disease in asymptomatic patients with diabetes mellitus:a cross-sectional study

Background: Reduced left ventricular function, assessed by global longitudinal strain (GLS), is sometimes observed in asymptomatic patients with diabetes mellitus (DM) and is often present in patients with diabetes-related microvascular complications. Our aim was to assess the association between microvascular complications, coronary artery plaque burden (PB) and GLS in asymptomatic patients with DM and non-obstructive coronary artery disease (CAD). Methods: This cross-sectional study included patients with DM without any history, symptoms or objective evidence of obstructive CAD. All patients were identified in the outpatient Clinic of Endocrinology at Odense University Hospital Svendborg. An echocardiography and a coronary computed tomography angiography were performed to assess GLS and the degree of CAD, respectively. A coronary artery stenosis &lt; 50% was considered non-obstructive. A linear regression model was used to evaluate the impact of potential confounders on GLS with adjustment of body mass index (BMI), mean arterial pressure (MAP), microvascular complications, type of diabetes, tissue Doppler average early diastolic mitral annulus velocity (e’) and PB. Results: Two hundred and twenty-two patients were included, of whom 172 (77%) had type 2 DM and 50 (23%) had type 1 diabetes. One hundred and eleven (50%) patients had microvascular complications. GLS decreased as the burden of microvascular complications increased (P-trend = 0.01): no microvascular complications, GLS (− 16.4 ± 2.5%), 1 microvascular complication (− 16.0 ± 2.5%) and 2–3 microvascular complications (− 14.9 ± 2.8%). The reduction in GLS remained significant after multivariable adjustment (β 0.50 [95% CI 0.11–0.88], p = 0.01). BMI (β 0.12 [95% CI 0.05–0.19]) and MAP (β 0.05 [95% CI 0.01–0.08]) were associated with reduced GLS. In addition, an increased number of microvascular complications was associated with increased PB (β 2.97 [95% CI 0.42–5.51], p = 0.02) in a univariable linear regression model, whereas there was no significant association between PB and GLS. Conclusions: The burden of microvascular complications was associated with reduced GLS independent of other cardiovascular risk factors in asymptomatic patients with DM and non-obstructive CAD. In addition, the burden of microvascular complications was associated with increasing PB, whereas PB was not associated with GLS.</p

Case Report: Generalised panniculitis as a post-COVID-19 presentation in Aicardi-Goutières Syndrome treated with ruxolitinib

Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case

Insulin resistance is associated with high-risk coronary artery plaque composition in asymptomatic men between 65 and 75 years and no diabetes:A DANCAVAS cross-sectional sub-study

Background and aims: Insulin resistance (IR) and pre-diabetes are associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate vulnerable plaque composition in relation to IR and pre-diabetes in asymptomatic non-diabetic men. Methods: All participants underwent a contrast-enhanced coronary computed tomography angiography (CCTA) to evaluate coronary artery plaque burden and plaque composition (necrotic core, dense calcium, fibrotic and fibrous-fatty volume). Homeostasis model assessment of IR (HOMA-IR) was used, and participants were stratified into tertiles. Participants underwent a standard oral glucose tolerance test (OGTT) and were categorized into 2 groups (normal glucose tolerance (NGT) or pre-diabetes). A multivariable linear regression model was used to evaluate the association between vulnerable plaque composition and IR or glycemic group. Results: Four-hundred-and-fifty non-diabetic men without known CAD were included. The mean age was 70 ± 3 years. Participants in the higher HOMA-IR tertile (H-IR) had higher median necrotic plaque volume compared to the lower HOMA-IR tertile (L-IR) (18.2 vs. 11.0 mm3, p = 0.02). H-IR tertile (β 0.37 [95% CI 0.10–0.65], p = 0.008), pack-years (β 0.07 [95% CI 0.007–0.14], p = 0.03) and total atheroma volume (TAV) (β 0.47 [95% CI 0.36–0.57], p &lt; 0.001) remained associated with necrotic plaque volume in the multivariable linear regression model. Conclusions: IR was associated with necrotic plaque volume in asymptomatic men without diabetes. Thus, even in asymptomatic men without diabetes, IR seems to have an incremental effect on necrotic plaque volume and vulnerable plaque composition.</p

Pericoronary adipose tissue attenuation predicts compositional plaque changes:a 12-month longitudinal study in individuals with type 2 diabetes without symptoms or known coronary artery disease

BACKGROUND: Pericoronary adipose tissue attenuation (PCATa), derived from coronary computed tomography angiography (CCTA), is a novel marker of inflammation in the coronary arteries. Patients with type 2 diabetes mellitus (T2DM) are at elevated risk of coronary artery disease (CAD), potentially due to systemic inflammation. This study evaluated whether baseline PCATa predicts changes in plaque composition and burden over 12 months.METHODS: This prospective longitudinal study included 200 participants with T2DM, who had neither symptoms nor a prior diagnosis of CAD (mean age 61 ± 9.4 years, 72% male). PCATa was measured at the baseline scan along the proximal 40 mm of each major coronary artery, and the values were averaged to calculate the participant-level PCATa. High PCATa levels were determined using the validated cut-off of -70.1 Hounsfield units. Compositional plaque changes were quantified as the differences between baseline and 12-month scans, and plaque burden was calculated as the normalized atheroma volume. Multivariable regression analyses assessed the associations between baseline PCATa and compositional plaque changes and evaluated risk factors, including high PCATa, in predicting non-calcified plaque burden progression.RESULTS: Plaque compositional volumes and burden increased over 12 months, while PCATa remained stable. After multivariable adjustments, baseline PCATa was significantly associated with changes in total plaque volume (β = 0.005, p = 0.005), non-calcified plaque volume (β = 0.006, p = 0.007), total plaque burden (β = 1.7, p = 0.007), and non-calcified plaque burden (β = 2.0, p = 0.006), but not with calcified plaque volume or burden. High baseline PCATa was observed in 44 participants (22%) and was the only independent predictor of non-calcified plaque burden progression (odds ratio 3.5, p = 0.002).CONCLUSIONS: Baseline PCATa is significantly associated with increases in total and non-calcified plaque volumes and burden over 12 months in participants with T2DM without symptoms or known CAD. High PCATa levels uniquely predict non-calcified plaque burden progression, suggesting that PCATa may serve as a marker for subclinical atherosclerosis progression. This warrants further investigation into PCATa for cardiovascular risk assessment, particularly in high-risk populations such as individuals with T2DM.TRIAL REGISTRATION: Trial registration: NCT06644651.RESEARCH INSIGHTS: What is currently known about this topic? 1. Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) share inflammatory mechanisms. 2. Individuals with T2DM face a two- to four-fold increased risk of CAD compared with those without T2DM. 3. Pericoronary adipose tissue attenuation (PCATa) is a novel marker of coronary inflammation. What is the key research question? Can baseline PCATa predict compositional plaque changes over 12 months in T2DM without known CAD? What is new? 1. Baseline PCATa relates to higher total and non-calcified plaque (NCP) volumes after adjustment. 2. Baseline PCATa associates with increased total- and NCP burden after multivariable adjustment. 3. High baseline PCATa (&gt; -70.1 HU) independently predicts NCP burden progression. How might this study influence clinical practice? PCATa may be a marker for subclinical atherosclerosis progression.</p

Understanding childhood asthma in focus groups: perspectives from mothers of different ethnic backgrounds

BACKGROUND: Diagnosing childhood asthma is dependent upon parental symptom reporting but there are problems in the use of words and terms. The purpose of this study was to describe and compare understandings of childhood 'asthma' by mothers from three different ethnic backgrounds who have no personal experience of diagnosing asthma. A better understanding of parents' perceptions of an illness by clinicians should improve communication and management of the illness. METHOD: Sixty-six mothers living in east London describing their ethnic backgrounds as Bangladeshi, white English and black Caribbean were recruited to 9 focus groups. Discussion was semi-structured. Three sessions were conducted with each ethnic group. Mothers were shown a video clip of a boy with audible wheeze and cough and then addressed 6 questions. Sessions were recorded and transcribed verbatim. Responses were compared within and between ethnic groups. RESULTS: Each session, and ethnic group overall, developed a particular orientation to the discussion. Some mothers described the problem using single signs, while others imitated the sound or made comparisons to other illnesses. Hereditary factors were recognised by some, although all groups were concerned with environmental triggers. Responses about what to do included 'normal illness' strategies, use of health services and calls for complementary treatment. All groups were concerned about using medication every day. Expectations about the quality of life were varied, with recognition that restrictions may be based on parental beliefs about asthma, rather than asthma itself. CONCLUSION: Information from these focus groups suggests mothers know a great deal about childhood asthma even though they have no personal experience of it. Knowledge of how mothers from these ethnic backgrounds perceive asthma may facilitate doctor – patient communication with parents of children experiencing breathing difficulties

Biomarkers of tolerance in kidney transplantation – are we predicting tolerance or response to immunosuppressive treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing differential-expression of B-cell related genes and relative expansions of B-cell subsets. However, in all of these studies, the index group, namely the tolerant recipients, were not receiving immunosuppressive (IS) treatment unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene-expression in three independent kidney transplant patient cohorts (232-recipients +14-tolerants), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B-cells. We have defined and validated a new gene-expression signature that was independent of drug effects and also differentiated tolerant patients from healthy controls (Cross-validated-AUC=0.81). In a prospective cohort we have demonstrated that the new signature remained stable before and after steroid withdrawal. Concisely, we report on a validated and highly accurate gene-expression signature that could be used reliably to identify patients suitable for IS reduction (~12% stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS-minimization safe, and hence allow critical improvements in kidney post-transplant management