OBJECTIVE:To evaluate if metabolic cardiomyopathy comprises different phenotypes. METHODS:Data-driven cluster analysis with hierarchical clustering followed by gap and silhouette width analysis and clustering by k-means was conducted on cardiovascular variables in a cohort of 192 patients with type 2 diabetes (T2D). RESULTS:Two distinct clusters were identified. 59 % of patients with DM2 had small left ventricles and atria with normal mass, high heart rate with small stroke volumes, and only moderately impaired myocardial perfusion reserve (3.32 ± 1.20 vs. 5.07 ± 1.51 ml/min/g in normal controls, p < 0.01). With equal e/e and extracellular volumes, other 41 % of patients with T2D had eccentric hypertrophic large left ventricles with dilated left atria, high stroke volumes, and a mean 6 mmHg higher mean arterial blood pressure and mean 15 mmHg higher pulse pressure, lower heart rates and lower myocardial perfusion reserve (2.60 ± 0.87 mL/min/g, P < 0.01 vs. other groups). CONCLUSIONS:Two distinct types of cardiomyopathies were identified. The majority exhibited small left hearts with only moderate impairment in myocardial perfusion ratio. However, when stiff conductance arteries were present, cardiomyopathy with larger and eccentrically hypertrophic left ventricles and markedly reduced myocardial perfusion ratio was observed. Future research should seek to determine if these two phenotypes carry independent prognostic implications and should be treated differently.

Abstract Introduction Cardiovascular magnetic resonance (CMR) research including from our research group, has documented that patients (pts.) with type 2 diabetes (DM2) even without symptoms exhibit subtle to moderately increased myocardial extracellular volume (ECV). ECV is an imaging biomarker of diffuse fibrosis. Also, our prior research has revealed a prevalence of approx. 10% for non-ischemic late gadolinium enhancement (LGE). Intriguingly, these LGE lesions manifested in a distinct pattern, situated in the basal lateral or infero-lateral positions. We postulate that these lesions may represent the end-stage of severe diffuse fibrosis, potentially influenced by factors such as increased shear wall stress. Purpose To investigate if pts. with DM2 with known high global ECV had higher regional ECV in the basal and lateral or infero-lateral AHA segments compared to other segments. Method A case-control study of 20 healthy controls, 20 pts. with DM2 with low ECV (ECV<28%), 20 pts. with DM2 with high ECV (ECV>29%), and 20 pts. with DM2 with non-ischemic LGE (LGE+). Pts. were identified from a cross-sectional cohort of pts. with DM2. All subjects underwent physical examination and extensive CMR with T1 mapping before and after gadolinium contrast, and myocardial perfusion at rest and during adenosine stress. The regional ECV values for the basal and the mid-ventricular short axis slide were analysed using the AHA segments model: segments 1 to 12. Results All groups (grp.) had comparable age and sex distribution. In the DM2 grp. there was a difference between the no. of pts. with DM2 duration >10 years (low ECV 11(55%), high ECV 12(60%), LGE+ 16(80%), however statistically significant. Global ECV were: Controls (mean±sd) 26.7±1.6%, Low ECV 26.3±1.4%, High ECV 32.0±2.9%, LGE+ 29.5±2.6%, p<0.001. Control subjects had regional ECV between 24.4±2% to 27.3±2% (p<0.001), highest values in the septum. The DM2 grp. with low ECV had regional ECV values of 24.5±3% to 29.2±4%, highest values in the basal inferior and septal parts (segments 2-4). The high ECV grp. had regional ECV values between 28.3±4% and 35.3±6 % with very high values in the basal and the mid-ventricular septum, inferior, and inferolateral part (segments 2-5 and 8-11). The DM2 group LGE+ had values between 26.6±3% and 34.5±7%, highest values in the basal slice in the septum, inferior, and infero-lateral parts (segments 2-5). We found no significant difference in the regional myocardial perfusion reserve index. Conclusion This evidence indicates that diffuse fibrosis in DM2 cardiomyopathy tends to concentrate in the septum and inferolateral regions. However, among pts. with non-ischemic LGE lesions, we observed normal ECV in the anterior segments, in contrast to the high ECV group where all segments exceeded normal levels, albeit with notable regional variations. Subsequent investigations should prioritize uncovering the underlying reasons for this specific regional distribution of diffuse fibrosis.AHA segments 1-12 mapsAHA segments 1-12 maps

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irrespective of ischemic changes, T2DM is associated with heart failure (HF) most commonly with preserved ejection fraction (HFpEF). Largely due to increasing population ages, hypertension, obesity and T2DM, HFpEF is becoming the most prevalent form of heart failure. Unfortunately, randomized controlled trials of HFpEF have largely been futile, and it now seems logical to address the important different phenotypes of HFpEF to understand their underlying pathophysiology. In the early phases, HFpEF is associated with a significantly impaired ability to increase cardiac output with exercise. The lowered cardiac output with exercise results from both cardiac and peripheral causes. T2DM is associated with left ventricular (LV) diastolic dysfunction based on LV hypertrophy with myocardial disperse fibrosis and significantly impaired ability for myocardial blood flow increments with exercise. T2DM is also associated with impaired ability for skeletal muscle vasodilation during exercise, and as is the case in the myocardium, such changes may be related to vascular rarefaction. The present review discusses the underlying phenotypical changes of the heart and peripheral vascular system and their importance for an adequate increase in cardiac output. Since many of the described cardiovascular changes with T2DM must be considered difficult to change if fully developed, it is suggested that patients with T2DM are early evaluated with respect to their cardiovascular compromise.

Abstract Introduction The epicardial adipose tissue (EAT) has unobstructed vascular connection to the myocardium and has a secretome very different from that of other fat depots. The EAT fat pad and its paracrine and vasocrine secretion of pro-inflammatory and profibrotic cytokines is suggested to contribute to heart failure with preserved ejection fraction (HFpEF) pathogenesis albeit via unknown mechanisms. Animal studies and magnetic resonance imaging studies in patients with type 2 diabetes mellitus (T2DM) have documented that important myocardial changes linking diabetic cardiomyopathy to systolic and diastolic dysfunction are myocardial microvascular dysfunction and myocardial fibrosis. Purpose To investigate whether a high volume of EAT is associated with impaired myocardial perfusion reserve (MPR) or disperse fibrosis in patients with T2DM. Methods 198 patients with T2DM but without ischemic heart disease were identified from a cross-sectional cardiovascular magnetic resonance imaging cohort study. 25 healthy controls were included for characterization of baseline characteristics. With gadolinium for contrast, MPR was determined by perfusion sequences and disperse fibrosis was determined from the myocardial extracellular volume (ECV). Volumes of EAT and pericardial adipose tissue (PAT) were determined from cine images. Results The T2DM patients (69% male) had a median age 59 IQR [50, 67] yrs, BMI 30.7 IQR [27.8, 33.7] kg/m2, and EAT of 17.3 IQR [14.2, 22.4] cm2. All patients had normal left ventricle ejection fraction. Compared to the healthy controls, patients with T2DM had higher BMI, abdominal circumference, ECV, EAT, and PAT volumes, and lower MPR (all p<0.001). In univariable regression analysis, EAT and PAT were both associated with higher BMI, abdominal circumference, and age (all p<0.02). In multivariable regression analysis, however, with adjustments for age, sex, BMI, and T2DM-duration, only EAT and MPR were significantly associated (P<0.01), whereas EAT and ECV were not. The PAT volume was not associated with MPR nor ECV. High-sensitive CRP was associated with the EAT volume (p<0.001), but hs-CRP was not associated with MPR or ECV. Conclusion An increased epicardial adipose tissue volume is in patients with T2DM associated with myocardial microvascular dysfunction. Irrespective of a generally heightened inflammatory level, the mechanism by which EAT contribute to development of HFpEF is therefore possibly via an EAT-induced impairment of the myocardial perfusion reserve. Randomized studies targeting a decreased epicardial adipose tissue volume are needed to demonstrate if this will improve myocardial microvascular dysfunction and hence limit development of HFpEF in patients with T2DM.Univariable analysis of EAT and ECVUnivariable analysis of EAT and MPR

Background Patients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain. Methods 211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified. Results Patients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls − 13.9 ± 2.0%, total cohort − 11.6 ± 3.0%; subgroup − 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22–1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54–2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) − 0.2 (− 0.3 to − 0.08), MPR (β (95% CI) − 0.5 (− 0.8 to − 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (− 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73). Conclusions Myocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.

Abstract Background Patients with diabetes often develop heart failure with preserved ejection and often demonstrate early indications of myocardial dysfunction by decreased strain, notably the global longitudinal (GLS). The underlying myocardial phenotypical changes in patients with diabetes are coronary microvascular dysfunction and myocardial interstitial fibrosis. The relation of these to strain-indicators of early systolic dysfunction is not established. Purpose We hypothesized that coronary microvascular function and interstitial fibrosis contribute to the subclinical myocardial dysfunction seen in patients with diabetes. Method With gadolinium contrast and adenosine-stress magnetic resonance imaging, we determined myocardial blood flow (MBF) and perfusion ratio (MPR) and extracellular volume (ECV; an imaging biomarker of diffuse fibrosis) in 211 patients with type 2 diabetes without macrovascular coronary artery disease and 25 control subjects. Left ventricular (LV) function was determined from its ejection fraction and 3D feature tracking of GLS, circumferential (GCS), and radial strains (GRS). Results Without a significant age- or sex-differences to control subjects, patients (median age 57 years [IQR 50, 67], 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. LV ejection fraction was normal and similar to controls. Compared to control subjects (GLS -13.9±2.0%), GLS, GCS and GRS were reduced in the total diabetes cohort, and GLS was reduced also in the subgroup of patients without any diabetes complications (total -11.6±3.0%; without-complications -12.3±2.6%). GLS, but not GCS or GRS or LVEF, was associated with albuminuria (b (95%CI) 1.09 (0.22-1.96)) and autonomic neuropathy (b (95%CI) 1.43 (0.54-2.31)). Independently of ECV, a 10% increase in MBF at adenosine-stress and MPR was associated with improved GLS in uni- and multivariable regression analyses. A 10% increase in ECV was associated with a decrease in GLS in univariable and multivariable regression analysis, but this was abolished when adjusted for MPR. GLS showed a moderate ability to discriminate a significantly lowered myocardial blood flow at stress defined as <1.49 mL/min/g (AUC 0.72, GLS threshold -11.5%; sensitivity 75% and specificity 53%) and myocardial perfusion ratio defined as as <2.1 (AUC 0.73, GLS threshold -10.8% resulted in a sensitivity of 71% and a specificity of 70%). GLS had a poor ability to predict increased extracellular volume defined as > 31% (AUC 0.60, GLS threshold -13.5 resulted in a sensitivity of 72% and a specificity of 34%). Conclusion Of the two important phenotypical changes seen with type 2 diabetes, microvascular dysfunction and fibrosis, coronary microvacular dysfunction demonstrates the more important relation to early systolic compromise as determined from the left ventricle global longitudinal strain.Associations of Systolic parametersROC curve

Abstract Background Diffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole. Methods In this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e’ and average E/e’, and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes. Results In multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV (rest: β = − 4.0%, stress: β = − 7.9%), LAmax /BSA (rest: β = 4.8%, stress: β = 5.8%), and circumferential (β = − 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e′ (β = 1.4%) and average E/e’ (β = − 1.4%) and a 10% MPR increase to lateral e′ (β = 2.7%), and average E/e’ (β = − 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction. Conclusion In patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis. Trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.

Background: Persons with diabetes have a high risk of complications related to the micro- and macrovascular circulation. One of the pathological processes involved in these complications is the onset of abnormal extracellular matrix (ECM) remodeling in different organs, leading to fibrosis. The quantification of ECM remodeling may identify patients that are at higher risk for adverse outcomes. Method: We measured biomarkers of collagen type III (PRO-C3) and VI (PRO-C6) formation and MMP-mediated degradation of type I (C1M) , III (C3M) , and IV (C4M and Tumstatin; TUM) in serum from 267 persons with T2DM from the CMR in T2DM study (NCT02684331) . Myocardial fibrosis (LGE) and ECV were determined by gadolinium-contrast CMR. Serum samples from 79 healthy controls were measured for comparison. Results: Levels of all biomarkers were significantly elevated in persons with T2DM compared to healthy controls (all P<0.0001) . Some of the markers were associated with complications, PRO-C6 levels were: significantly elevated in patients with hypertension compared to persons without known CVD (P<0.0001) ; could discriminate patients with CKD - eGFR < 60 ml/min/1.73m2 with an AUC of 0.83 (P<0.001) ; were significantly increased in patients with ischemic LGE (P<0.05) , suggesting an association of PRO-C6 with fibrosis; and in a multiple linear regression analysis, higher PRO-C6 levels were significantly associated with higher HbA1c (r=0.15, P=0.0397) , lower eGFR (r=−0.41, P<0.0001) , higher proANP (r=0.24, P=0.0005) , and higher ECV (r=0.24, P=0.0006) . PRO-C3 levels were significantly elevated in patients with CKD compared to non-CKD, and levels of C3M and C4M increased significantly with presence of albuminuria. Conclusion: Biomarkers of ECM remodeling, particularly PRO-C6, may identify persons with active pro-fibrotic processes at risk for complications related to T2DM. The potential of the biomarkers to predict adverse outcomes will be investigated once follow-up data have been collected. Disclosure A.Møller: None. A.S.Bojer: None. F.Genovese: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. M.H.Sørensen: None. P.Gæde: Advisory Panel; AstraZeneca, Research Support; Novo Nordisk. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. P.L.Madsen: None. D.G.Rasmussen: Employee; Nordic Bioscience A/S.

Introduction: Myocardial interstitial fibrosis expands the extracellular volume (ECV) and is in patients with type 2 diabetes implicated in the development of heart failure. ECV can be determined with gadolinium-contrast magnetic resonance imaging. Hypothesis: We investigated if known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes. Methods: 296 patients with type 2 diabetes and 21 healthy sex and age-matched controls were included in a cross-sectional magnetic resonance imaging study. The influence of risk factors on ECV was investigated by multiple regression analysis. Results: Controls and patients with type 2 diabetes without complications had similar ECV (27.1±2.1% vs. 27.9±2.6%, p=0.2). Compared to patients without, ECV was significantly increased in patients with 1≥ complication (29.0±3.3%, p=0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (ß=2.0%-point 95%CI 0.7 to 3.3). Former smokers had similar ECV than never smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis but after adjustment for medication suspected to affect ECV the association to albuminuria was no longer significant (p=0.1). There was a trend toward SGLT2i treatment being associated with reduced ECV (-0.8% 95%CI -1.7 to 0.06, p=0.067). Conclusions: Patients with complications to diabetes have increased ECV not seen in patients without. Active but not former smoking was highly associated with increased ECV but also Ischemic heart disease, and autonomic neuropathy.

Overweight and diabetes (DM) result in premature cardiovascular disease. Even if unaccompanied by ischaemic heart disease, DM stiffens the circulation, which may result in heart failure with preserved ejection fraction. Magnetic resonance imaging studies have documented cardiac hypertrophy, myocardial vascular rarefaction, and myocardial fibrosis in patients with type 2 DM. All three phenotypical changes seem noteworthy targets for early intervention. "Diabetic cardiomyopathy" is years underway and hence early detection may be needed to secure adequate treatment of the metabolic syndrome.

OBJECTIVE Myocardial interstitial fibrosis expands the extracellular volume (ECV) and is in patients with type 2 diabetes implicated in the development of heart failure. ECV can be determined with gadolinium-contrast magnetic resonance imaging. We investigated which known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS 296 patients with type 2 diabetes and 25 sex and age-matched controls were included in a cross-sectional magnetic resonance imaging study. The influence of risk factors on ECV was investigated by multiple regression analysis. RESULTS Controls and patients with type 2 diabetes without complications had similar ECV (27.4±2.1% vs 27.9±2.6%, p=0.4). Compared to patients without, ECV was significantly increased in patients with 1≥ complication (29.0±3.3%, p=0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy, and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (ß=2.0%-point 95% CI 0.7 to 3.3). Former smokers had similar ECV as never-smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis, but after adjustment for medication suspected to affect ECV, the association with albuminuria was no longer significant (p=0.1). SGLT2i treatment was not significantly associated with reduced ECV (-0.8% 95%CI -1.7 to 0.06, p=0.067). CONCLUSION Patients with complications of diabetes have increased ECV not seen in patients without complications. Ischemic heart disease, autonomic neuropathy, and active but not former smoking was highly associated with increased ECV.

Purpose: In recent years, cardiac magnetic resonance (CMR) has been used to assess LV diastolic function. In this systematic review, studies were identified where CMR parameters had been evaluated in healthy and/or patient groups with proven diastolic dysfunction or known to develop heart failure with preserved ejection fraction. We aimed at describing the parameters most often used, thresholds where possible, and correlation to echocardiographic and invasive measurements. Methods and results: A systematic literature review was performed using the databases of PubMed, Embase, and Cochrane. In total, 3808 articles were screened, and 102 studies were included. Four main CMR techniques were identified: tagging; time/volume curves; mitral inflow quantification with velocity-encoded phase-contrast sequences; and feature tracking. Techniques were described and estimates were presented in tables. From published studies, peak change of torsion shear angle versus volume changes in early diastole (−dφ′/dV′) (from tagging analysis), early peak filling rate indexed to LV end-diastolic volume <2.1 s−1 (from LV time-volume curve analysis), enlarged LA maximal volume >52 mL/m2, lowered LA total (<40%), and lowered LA passive emptying fractions (<16%) seem to be reliable measures of LV diastolic dysfunction. Feature tracking, especially of the atrium, shows promise but is still a novel technique. Conclusion: CMR techniques of LV untwisting and early filling and LA measures of poor emptying are promising for the diagnosis of LV filling impairment, but further research in long-term follow-up studies is needed to assess the ability for the parameters to predict patient related outcomes.

Aim To investigate if short-term treatment with liraglutide, a glucagon-like peptide-1 receptor agonist, improves left ventricular diastolic function. Materials and Methods An investigator-initiated, double-blind, randomized, placebo-controlled trial on the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in patients with type 2 diabetes with signs of diastolic dysfunction (echo-Doppler determined E/e ' >= 9 and/or lateral e ' <= 10 cm/s). Primary outcomes were improved left ventricle filling (the early peak filling rate [ePFR]) and left atrium ease of emptying (the passive emptying fraction [LA(PEF)]), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress. Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness and echocardiographic diastolic variables. Results Forty patients were randomized to liraglutide subcutaneously 1.8 mg/day (n = 20) or placebo (n = 20). Liraglutide reduced HbA1c (-0.47%, 95% CI [-0.88% to -0.06%] [-5.1, 95% CI {-9.7 to -0.62} mmol/mol]) and weight (-2.9, 95% CI [-4.6 to -1.2] kg); both P < .03. Liraglutide did not change ePFR at rest (-24 +/- 60 vs. -6 +/- 46 mL/s), during stress (2 +/- 58 vs. -2 +/- 38 mL/s), or the changes from rest to stress (12.9 +/- 72.5 vs. 4.7 +/- 104.0; all P > .05). LA(PEF) decreased with liraglutide during stress (-3.1% [-9.0%, 1.1%] vs. 1.0% [-2.9%, 6.1%]; P = .049), but no changes were evident at rest (-4.3% [-7.9%, 1.9%] vs. -0.6% [-3.1%, 2.2%]; P = .19), or for the changes from rest to stress (-1.7 +/- 8.4 vs. 0.8 +/- 8.2; P = .4). Secondary outcomes were unchanged by liraglutide. Conclusions Short-term treatment with liraglutide did not improve left ventricular diastolic function, suggesting the cardioprotective effect is not exerted through the improvement in diastolic dysfunction.

Abstract Background/Introduction The cardioprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes is still not well explained. In these patients, diastolic dysfunction is significant and linked to outcome, and the cardioprotective effect of GLP-1 receptor agonists may be by improving diastolic function. Purpose To investigate if short-term treatment of liraglutide a GLP-1 receptor agonist improves left ventricular diastolic function. Methods In an investigator-initiated double-blind randomized placebo-controlled trial the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in type 2 diabetes patients and echocardiographic signs of diastolic dysfunction (echo-Doppler determined E/e'≥9 or/and lateral e'≤10 cm/sec). Primary outcomes were improved left ventricle filling (the early peak filling rate, ePFR) and left atrium ease of emptying (the passive emptying fraction, LAPEF), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress (glycopyrrolate 4 mg/kg; a cholinergic receptor antagonist increasing heart rate, and thereby inducing chronotropic stress without also affecting contractility). Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness, and echocardiographic diastolic parameters. Results Forty patients were randomized to liraglutide s.c. 1.8 mg/day (n=20) or placebo (n=20). Liraglutide reduced HbA1c (−0.47% 95% CI (−0.88 to −0.06)) and weight (−2.9kg 95% CI (−4.6 to −1.2)), both p<0.03). Liraglutide did not change ePFR at rest −24±60 vs. −6±46 ml/sec, during stress 2±58 vs. −2±38 ml/sec, or the changes from rest and stress 12.9±72.5 vs. 4.7±104.0, all p>0.05. LAPEF decreased with liraglutide during stress (median (Q1, Q3)) −3.1 (−9.0, 1.1) vs. 1.0 (−2.9, 6.1) %, p=0.049, but no changes were evident at rest −4.3 (−7.9, 1.9) vs. −0.6 (−3.1, 2.2) %, p=0.19, or for the changes from rest to stress −1.7±8.4 vs. 0.8±8.2, p=0.4. All secondary outcomes were unchanged by liraglutide. Conclusions Short-term treatment with liraglutide did not improve diastolic function in patients with type 2 diabetes and echocardiographic signs of diastolic dysfunction. This suggests that the cardioprotective effect seen in long-term studies of liraglutide is not related to the improvement of left ventricular diastolic function. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): ASB has received funding from the Danish Heart Association [16-R107-A6790-22002, and 18-R125-A8444-22110]. Novo Nordisk supported the study by an unrestricted grant covering the costs of CMR scans and blood analyses. Novo Nordisk provided free study medication and matching placebo pens. None of the funding sources played any role in the process of conduction, interpretation of results or publishing the study Primary OutcomesSecondary Outcomes

As part of normal ageing, conductance arteries lose their cushion function, left ventricle (LV) filling and also left atrial emptying are impaired. The relation between conductance artery stiffness and LV diastolic function is normally explained by arterial hypertension and LV hypertrophy as needed intermediaries. We examined whether age-related aortic stiffening may influence LV diastolic function in normal healthy subjects. Aortic distensibility and pulse wave velocity (PWV) were related to LV emptying and filling parameters and left atrial emptying parameters as determined by magnetic resonance imaging in 36 healthy young (< 35 years) and 16 healthy middle-aged and elderly (> 35 years) with normal arterial blood pressure and myocardial mass. In the overall cohort, total aorta PWV correlated to a decrease in LV peak-emptying volume (r = 0.43), LV peak-filling (r = 0.47), passive atrial emptying volume (r = 0.66), and an increase in active atrial emptying volume (r = 0.47) (all p < 0.001). PWV was correlated to passive atrial emptying volume even if only the > 35-year-old were considered (r = 0.53; p < 0.001). Total peripheral resistance demonstrated similar correlations as PWV, but in a regression analysis only the total aorta PWV was related to left atrial (LA) passive emptying volume. Via impaired ventriculo-arterial coupling, the increased aortic PWV seen with normal ageing hence affects atrio-ventricular coupling, before increased aortic PWV is associated with significantly increased arterial blood pressure or LV hypertrophic remodelling. Our findings reinforce the existence of atrio-ventriculo-arterial coupling and suggest aortic distensibility should be considered an early therapeutic target to avoid diastolic dysfunction of the LV.

Background: Cardiovascular magnetic resonance imaging (CMR) have described non-ischaemic late gadolinium enhancement (LGE) lesions of prognostic importance in various non-ischaemic cardiomyopathies. Ischaemic LGE lesions are prevalent in diabetes (DM), but non-ischaemic LGE lesions have not previously been systematically studied. Methods: 296 patients with type 2 DM (T2DM) and 25 controls underwent echocardiography and CMR including adenosine-stress perfusion, T 1 -mapping and LGE. Findings: 264 patients and all controls completed the CMR. 78.4% of patients with T2DM had no LGE lesions; 11.0% had ischaemic LGE lesions only; 9.5% had non-ischaemic LGE lesions only; and 1.1% had both ischaemic and non-ischaemic lesions. The non-ischaemic LGE lesions were situated mid-myocardial in the basal and lateral or inferolateral part of the left ventricle. The affected segments showed normal and normal contraction. Patients with non-ischaemic LGE lesions in comparison with patients without LGE lesions had increased myocardial mass (150±34 vs. 133±33 g, P=0·02), average E/e’(9·9 IQR8·7-12·6 vs. 8·8 IQR7·4-10·7, P=0·04), left atrial maximal volume (102 IQR84·6-115·2 vs. 91 IQR75·2-100·0 mL, P=0·049), NT-proBNP (8·9 IQR5·9-19·7 vs. 5·9 IQR5·9-10·1 µmol/L, P=0·02) and high-sensitive troponin (15·6 IQR13·0-26·1 vs. 13·0 IQR13·0-14·6 ng/L, P=0·007) and a higher prevalence of retinopathy (48 vs. 25 %, p=0·009) and autonomic neuropathy (52 vs. 30·5%, P=0·005). Interpretation: A severe variant of the diabetic cardiac phenotype is associated with a specific LGE pattern with lesions in the basal and lateral or inferolateral part of the left ventricle. Funding: By NSR hospitals’ local research committee, the regional research committee of Region Zealand, and the Danish Heart Association.Declaration of Interests: We declare no competing interests.Ethical Approval Statement: After written informed consent, patients were included between January 2016 and August 2019. The study complies with the Declaration of Helsinki and was approved by The Zealand Ethics Committee (SJ-490).

Abstract Background Increased myocardial extracellular volume (ECV) likely is suggested to be of importance for cardiac function in type 2 diabetes (T2DM). Purpose We analysed the effect of increasing ECV on cardiac myocardial structure and function and association to typical complications related to diabetes Methods 296 patients (pt.) with T2DM and 25 controls were recruited. Cardiac magnetic resonance scan with adenosine stress and gadolinium was performed. Left ventricle (LV) diastolic function was evaluated by echo Doppler. Results 246 pt. scan and all control scans were available for analysis. ECV was significantly different between pts. and controls (29.5±3.3 vs 26.1±1.5, P&lt;0.001). Pts. were grouped in ECV percentiles: ≤25, 25–75, and ≥75. Pts. with ECV in the highest percentile had lowered LV ejection fraction (LVEF) and increased LV end-diastolic (EDV) and end-systolic (ESV) volumes, and left atrial (LA) maximal volume. No difference was found on LV mass. With increasing ECV a lowered LV myocardial perfusion index (MPRI) and an increased prevalence of albuminuria, retinopathy, and autonomic neuropathy was found. Of interest, with increasing ECV lateral as well as septal e' were lowered and the E/e' increased. Conclusions In combination with lowered myocardial perfusion but independently of myocardial hypertrophy, myocardial interstitial diffuse fibrosis is related to the diastolic dysfunction of diabetic cardiomyopathy. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): NSR hospital, Denmark and the Danish Heart Foundation

OBJECTIVE To examine differences in myocardial blood flow (MBF) at rest and during stress between patients with type 2 diabetes and control subjects, and to identify potential predictors of changes in MBF at rest and during stress. RESEARCH DESIGN AND METHODS A cross-sectional study was conducted of 193 patients with type 2 diabetes and 20 age- and sex-matched control subjects. Cardiovascular magnetic resonance was used to evaluate left ventricular structure and function and MBF at rest and during adenosine-induced stress. MBF was derived as the mean of the flow within all segments of a midventricular slice. RESULTS Patients with type 2 diabetes had higher global MBF at rest (0.81 ± 0.19 mL/min/g) and lower global MBF during stress (2.4 ± 0.9 mL/min/g) than control subjects (0.61 ± 0.11 at rest, 3.2 ± 0.8 mL/min/g under stress; both P < 0.01). Patients with macroalbuminuria had lower MBF during stress (1.6 ± 0.5 mL/min/g) than did patients with microalbuminuria (2.1 ± 0.7 mL/min/g; P = 0.04), who in turn had lower MBF during stress than did normoalbuminuric patients (2.7 ± 0.9 mL/min/g; P < 0.01). Patients with severe retinopathy had lower MBF during stress (1.8 ± 0.6 mL/min/g) than patients with simplex retinopathy (2.3 ± 0.7 mL/min/g; P < 0.05) and those who did not have retinopathy (2.6 ± 1.0 mL/min/g; P < 0.05). Albuminuria and retinopathy were associated with reduced MBF during stress in a multiple regression analysis. Stress-related MBF inversely correlated with myocardial extracellular volume (P < 0.001; R2 = 0.37), a measure of diffuse myocardial fibrosis. A trend toward lower basal MBF was observed in patients treated with sodium–glucose cotransporter 2 inhibitors (P = 0.07). CONCLUSIONS Patients with type 2 diabetes have higher global MBF at rest and lower maximal MBF during vasodilator-induced stress than control subjects. Reduced MBF during stress is associated with diabetes complications (albuminuria and retinopathy) and is inversely correlated with diffuse myocardial fibrosis.

AIMS Coronary microvascular disease (CMD) is a known complication in type 2 diabetes mellitus (T2DM). We examined the relationship between diabetic complications, left ventricular (LV) function and structure and myocardial perfusion reserve (MPR) as indicators of CMD in patients with T2DM and control subjects. METHODS AND RESULTS This was a cross-sectional study of 193 patients with T2DM and 25 controls subjects. Patients were grouped as uncomplicated diabetes (n = 71) and diabetes with complications (albuminuria, retinopathy, and autonomic neuropathy). LV structure, function, adenosine stress, and rest myocardial perfusion were evaluated by cardiovascular magnetic resonance. Echocardiography was used to evaluate diastolic function. Patients with uncomplicated T2DM did not have significantly different LV mass and E/e* but decreased MPR (3.8 ± 1.0 vs. 5.1 ± 1.5, P < 0.05) compared with controls. T2DM patients with albuminuria and retinopathy had decreased MPR (albuminuria: 2.4 ± 0.9 and retinopathy 2.6 ± 0.7 vs. 3.8 ± 1.0, P < 0.05 for both) compared with uncomplicated T2DM patients, along with significantly higher LV mass (149 ± 39 and 147 ± 40 vs. 126 ± 33 g, P < 0.05) and E/e* (8.3 ± 2.8 and 8.1 ± 2.2 vs. 7.0 ± 2.5, P < 0.05). When entered in a multiple regression model, reduced MPR was associated with increasing E/e* and albuminuria and retinopathy were associated with reduced MPR. CONCLUSIONS Patients with uncomplicated T2DM have reduced MPR compared with control subjects, despite equivalent LV mass and E/e*. T2DM patients with albuminuria or retinopathy have reduced MPR and increased LV mass and E/e* compared with patients with uncomplicated T2DM. E/e* and MPR are significantly associated after adjustment for age, hypertension, and LV mass, suggesting a link between CMD and cardiac diastolic function. CLINICAL TRIAL REGISTRATION https://www.clinicaltrials.org. Unique identifier: NCT02684331.