AIMS:Obesity increases the risk of heart failure (HF), partly due to hypervolaemia and excess epicardial adipose tissue (EAT).We aimed to investigate the effect of the sodium glucose co-transporter 2 inhibitor empagliflozin on estimated extracellular volume (eECV) and ventricular EAT mass in non-diabetic patients with overweight or obesity and risk of HF to evaluate the drug's potential for HF prevention. METHODS:In this randomised, double-blind, placebo-controlled trial, we recruited non-diabetic patients with body mass index (BMI) >28kg/m2 and risk of HF. Patients were randomised 1:1 to 180-days empagliflozin 10 mg or placebo. The primary endpoints were the baseline-adjusted mean differences in change of eECV and ventricular EAT mass in the intention-to-treat population with Bonferroni-adjustment for multiplicity. RESULTS:From September 2021 to July 2024, we randomised 191 patients (empagliflozin: 94, placebo: 97) with median age 68 years and median BMI 31·9 kg/m2. Analyses of eECV and EAT included 191 and 165 patients, respectively. Compared to placebo, empagliflozin significantly reduced eECV [empagliflozin, mean change (SD): -0·154 L (0·257); placebo, mean change: -0·029 L (0·261); estimated treatment difference (ETD): -0·123 L, 97.5% CI: -0·211 to -0·035, padj=0·004] but did not affect EAT mass [empagliflozin, mean change: -2·3 g (13·4); placebo, mean change: -3·7 g (15·8); ETD: 1·5 g, 97·5% CI: -3·8 to 6·7, padj=1.00]. CONCLUSION:In high-risk patients with overweight or obesity, treatment with empagliflozin resulted in a potentially favourable reduction in eECV compared to placebo. Meanwhile, the drug did not affect EAT mass.

Background: More than 13 million children have been born after assisted reproductive technologies (ART) worldwide. Whether ART affects cardiovascular health in offspring remains uncertain, especially during adolescence. We evaluated the blood pressure profiles and associated cardiac remodelling in late adolescents conceived after ART. Methods: We performed a cohort study with cross-sectional examinations of 24-h blood pressure, exercise blood pressure, and left ventricular mass (May-2022 to March-2025) in Danish singletons aged 15–17 years at invitation conceived by fresh or frozen embryo transfer and in age- and sex-matched naturally conceived controls identified through registries. We excluded adolescents with congenital heart defects or chromosomal anomalies. Adjustment for confounders was performed by linking examination results with registry data. Findings: We examined 277 adolescents: 113 conceived by fresh embryo transfer, 59 by frozen embryo transfer, and 105 by natural conception (53-60% female). Fresh and frozen embryo transfer were associated with higher adjusted 24-h systolic blood pressure, mean differences +3·2 mmHg (95% CI 1·0–5·4) and +2·8 mmHg (95% CI 0·2–5·3), respectively, and higher adjusted relative risk of arterial hypertension, 3·70 (95% CI 1·3–10·3) and 3·1 (95% CI 1·2–7·8), respectively, compared with natural conception, among whom the arterial hypertension prevalence was 6%. Adolescents conceived by fresh embryo transfer had higher exercise systolic blood pressure, mean difference +7·2 mmHg (95% CI 2·4 to 12·1) and left ventricular mass index, mean difference +4·2 g/m² (95% CI 1·5–6·9) compared with naturally conceived adolescents. Interpretation: Assisted reproductive technologies were associated with higher blood pressure burden, including a three-fold higher risk of arterial hypertension, and signs of hypertrophic cardiac remodelling by late adolescence. These findings support consideration of systematic blood pressure follow-up in ART-conceived offspring.

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.

BACKGROUND:Increased left ventricular (LV) mass is a predictor of heart failure (HF). The preventive effect of sodium-glucose cotransporter 2 inhibitors remains unclear in subjects without HF. The aim of this study was to evaluate the effect of empagliflozin on LV mass index (LVMI) and LV volumes in individuals with overweight and considered at risk of HF. METHOD:An investigator-initiated, double-blinded, randomized, placebo-controlled, multicenter superiority trial [NCT05084235] comprised 191 older adult (60-84 years), overweight (body mass index [BMI] >28 kg/m2) individuals with at least 1 known risk factor for HF (hypertension, ischemic heart disease, stroke, chronic kidney disease). Study participants were randomized 1:1 to empagliflozin 10 mg or matching placebo for 180 days. Individuals with HF or type 2 diabetes were excluded. The primary endpoint was change in LVMI from baseline to 180 days assessed by cardiac magnetic resonance imaging, with between-group comparisons expressed as adjusted mean differences. Secondary endpoints were mean differences in changes in LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), and LV ejection fraction (LVEF). RESULTS:Of the 191 randomized, 165 individuals (median age, 68 years; median BMI, 31.8 kg/m2; 67% were male; and median LVEF, 65%) completed MRI (empagliflozin: 83; placebo: 82). Empagliflozin reduced LVMI with an estimated treatment difference of -1.9 g/m2 (97.5% confidence interval [CI]: -3.5 to -0.2; P = .01). No significant differences were observed for LV volumes or ejection fraction. CONCLUSION:Among older adults with overweight and cardiovascular disease, empagliflozin 10 mg daily compared with placebo for 180 days led to a significant reduction in LVMI.

The high mortality of systemic infection results from its associated cardiovascular depression. Cardiac depression typically normalizes if the patient recovers from the infection, but recent studies suggest that these patients have an increased long-term risk of developing cardiovascular disease after the septic episode. These findings have reignited interest in sepsis-associated cardiac function and myocardial blood flow, which remain poorly understood in humans. We studied cardiac function and myocardial microvascular perfusion using gadolinium-contrast magnetic resonance imaging in a cohort of patients during the initial recovery period of sepsis (n = 16) or septic shock (n = 5) and after full recovery 1-2 months later (n = 13). In addition, hepatic, splenic, and renal cortical perfusion were also assessed. With infection, cardiac output (+27%), the rate-pressure-product (+21%), and the left ventricle (LV) peak-ejection (+36%) and peak-filling (+35%) rates increased compared to full recovery (all p < 0.05). Onset of LV myocardial perfusion and the time to peak LV myocardial perfusion of gadolinium-contrast occurred earlier during initial than after recovery, with a numerically higher LV myocardium wash-in rate (23 ± 22 vs. 14 ± 14 s-1; p = 0.07). LV myocardial fibrosis was not seen in any patients. Renal cortical, splenic, and hepatic perfusion parameters including onset, time-to-peak, and wash-in rates of gadolinium contrast were comparable between initial and full recovery, except for a lower hepatic wash-in rate during initial recovery (13 ± 10 vs. 22 ± 16 s-1; p = 0.03). Our study supports that myocardial microvascular dysfunction is unlikely to contribute to cardiovascular disease after severe infection. Conversely, hepatic hypoperfusion during sepsis may explain the commonly observed hepatic dysfunction in sepsis.

AIMS:It is well known that patients with type 2 diabetes (T2D) have an increased risk of both ischemic and non-ischemic heart disease. We studied sex differences in the microvascular function and myocardial extracellular fibrosis that underlie cardiac dysfunction. METHODS:In a cross-sectional echocardiography and cardiovascular magnetic resonance imaging study, myocardial extracellular volume fraction (ECV), myocardial blood flow at rest (MBFrest) and during adenosine-induced stress (MBFstress), and the myocardial perfusion reserve (MPR) were determined in 221 patients with T2D without ischemic heart disease and 25 age-matched controls. We investigated sex-related differences in MBF, MPR, ECV, and diastolic and systolic function. RESULTS:Both in unadjusted analyses and after multiple linear regression analyses adjusted for known confounders, women with T2D had higher MBFrest, MBFstress, and ECV than men. The differences in microvascular function resulted in T2D men and women both having lower MPR compared to healthy controls, but the underlying causes differed. Female sex associated with lower lateral e' and higher E/e' independently of MBFstress and ECV. CONCLUSIONS:These findings highlight distinct sex-specific mechanisms of microvascular dysfunction and myocardial remodeling in T2D. Recognizing these differences may be critical for improving risk stratification and guiding targeted preventive strategies in diabetic cardiomyopathy.

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 concept that the culprit lesion in non-ST segment elevation myocardial infarction (NSTEMI) is caused by sudden plaque rupture with acute thrombus formation has recently been challenged. While angiography is an old gold-standard for culprit identification it merely visualizes the lumen contour. Optical coherence tomography (OCT) provides a detailed view of culprit features. Combined with myocardial edema on cardiac magnetic resonance (CMR), indicating acute ischemia and thus culprit location, we aimed to characterize culprit lesions using OCT. Patients with NSTEMI referred for angiography were prospectively enrolled. OCT was performed on angiographic stenoses ≥50% and on operator-suspected culprit lesions. Hierarchical OCT-culprit identifiers were defined in case of multiple unstable lesions, including OCT-defined thrombus age. An OCT-based definition of an organizing thrombus as corresponding to histological early healing stage was introduced. Lesions were classified as OCT-culprit or non-culprit, and characteristics compared. CMR was performed in a subset of patients. We included 65 patients with 97 lesions, of which 49 patients (75%) had 53 (54%) OCT-culprit lesions. The most common OCT-culprit identifiers were the presence of acute (66%) and organizing thrombus (19%). Plaque rupture was visible in 45% of OCT-culprit lesions. CMR performed in 38 patients revealed myocardial oedema in the corresponding territories of 67% of acute thrombi and 50% of organizing thrombi. A culprit lesion was identified by OCT in 75% patients with NSTEMI. Acute thrombus was the most frequent feature followed by organizing thrombus. Applying specific OCT-criteria to identify the culprit could prove valuable in ambiguous cases.

Background: Coronary computed tomography angiography (CCTA) is recommended as the first-line diagnostic imaging modality in low-to-intermediate-risk individuals suspected of stable coronary artery disease (CAD). However, CCTA exposes patients to ionizing radiation and potentially nephrotoxic contrast agents. Invasive coronary angiography is the gold-standard investigation to guide coronary revascularisation strategy; however, invasive procedures incur an inherent risk to the patient. Coronary magnetic resonance angiography (CMRA) avoids these issues. Nevertheless, clinical implementation is currently limited due to extended scanning durations, inconsistent image quality, and consequent lack of diagnostic accuracy. Several technical CMRA innovations, including advanced respiratory motion correction with 100% scan efficiency (no data rejection), fast image acquisition with motion-corrected undersampled image reconstruction, and deep-learning-based automated planning, have been implemented and now await clinical validation in multi-center trials. Methods: The objective of the image navigator-based, automated CMRA prospective multi-center study is to evaluate the diagnostic accuracy of a newly developed, state-of-the-art, standardized, and automated CMRA framework compared to CCTA in 201 patients undergoing clinical investigation for CAD. The study protocol mandates the administration of oral beta-blockers to decrease heart rate to below 60 bpm and the use of sublingual nitroglycerine spray to induce vasodilation. Additionally, the study incorporates the utilization of standardized postprocessing with sliding-thin-slab multiplanar reformatting, in combination with evaluation of the source images, to optimize the visualization of coronary artery stenosis. Discussion: If proven effective, CMRA could provide a non-invasive, needle-free, yet also clinically viable, alternative to CCTA.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had similar to 17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; similar to 22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and similar to 37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.

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 Study question Is cardiometabolic health in children conceived after frozen embryo transfer (FET) different from children conceived after fresh embryo transfer (fresh-ET) and natural conception (NC)? Summary answer FET-children had similar anthropometrics, glucose- and lipid profile in childhood compared to fresh-ET and NC. Blood pressure was higher in FET-girls compared to fresh-ET-girls. What is known already Children conceived after assisted reproductive technology (ART) with FET are more often born large-for-gestational age (LGA) while children born after fresh-ET are at risk of being small-for-gestational age (SGA).In general, children born LGA or SGA are at increased risk of obesity, diabetes and cardiovascular disease later in life. Smaller studies on the whole ART-population have raised concerns about premature vascular aging, increased risk of insulin resistance and higher blood pressure. The long-term cardiometabolic health of children born after ART and especially FET is scarcely explored. Study design, size, duration This study was part of the large cohort study “Health in Childhood following Assisted Reproductive Technology” (HiCART) which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lastet from January 2019 to September 2021. Participants/materials, setting, methods The children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging and blood pressure measurement. Furthermore a whole-body dual-energy x-ray absorptiometry-scan (DXA) was performed and a fasting blood sample was drawn. Anthropometric measurements and blood pressure were converted to standard deviation scores (SDS) using a Danish reference. The three study groups were compared pairwise using univariate linear regression model. Main results and the role of chance Data is presented as mean (SD). Children conceived after FET had significantly higher birth weight (SDS) (0.20 SDS (1.09)) compared to children conceived after fresh-ET (-0.22 SDS (1.00), mean difference: 0.42 SDS (95% CI: 0.21; 0.62)) and NC-children (-0.16 SDS (1.09), mean difference: 0.35 SDS (95% CI: 0.14; 0.57)). At 7-10 years height (SDS), weight (SDS) and BMI (SDS) were similar between the groups. Fat percentage (DXA) and waist-to-height ratio were also comparable between the groups. Markers of glucose metabolism were similar in the groups including fasting glucose, C-peptide, HbA1c and insulin resistance (HOMA-IR). Lipid profiles including, cholesterol, LDL and HDL were also similar. Blood pressure was comparable between the three groups, but stratified on sex girls conceived after FET had significantly higher systolic blood pressure (SDS) (0.75 SDS (0.84)) compared to girls concieved after fresh-ET (0.49 SDS (0.61), mean difference: 0.25 SDS (95% CI: 0.05; 0.45)) and significantly higher diastolic blood pressure (SDS) (FET: 0.54 SDS (0.57), fresh-ET: 0.38 (0.58), mean difference: 0.16 SDS (0.00; 0.31)). Puberty had started in 17% of the girls, equally distributed in the three groups. Limitations, reasons for caution As the participation rate was between 18-42% in the three groups, selection bias cannot be excluded. We currently do not have information regarding endometrial preparation protocol in the FET-cycles which may bias the results. Due to multiple testing type I errors cannot be excluded. Wider implications of the findings Higher birth weight in children conceived after FET did not translate into differences in anthropometrics, glucose- or lipid profile in children ages 7-10 years. However, the higher systolic- and diastolic blood pressure (SDS) found in girls concieved after FET compared to fresh-ET is of concern and should be further explored. Trial registration number NNF18OC0034092, NFF19OC0054340

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

Abstract Study question Are children conceived through assisted reproductive technology (ART) at higher risk of minor congenital heart defects (CHD) compared with naturally conceived (NC) children? Summary answer Contrary to previous studies children conceived through ART had similar risk of minor CHDs compared with children conceived naturally. What is known already Congenital heart defects (CHD) may precipitate cardiac arrhythmias, lead to thromboembolic events, culminate in heart failure or even sudden cardiac demise. A systematic review and meta-analysis showed an elevated odds ratio (OR) for diagnosis of any CHD among children conceived through in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared with NC children. Other studies indicate that ART is associated with an increased arterial blood pressure and vascular dysfunction in the pulmonary and systemic arterial vasculature. This association persists throughout childhood, adolescence, and early adulthood in individuals conceived through ART; this indicates a lasting impact on the cardiovascular circulatory system. Study design, size, duration The present study is a sub-study to the Copenhagen Baby Heart Study (CBHS), a prospective population-based cohort study of > 25 000 children born in the three main maternity wards in Copenhagen, Denmark, in 2016–2018. Transthoracic echocardiography (TTE) was performed on all children within 60 days of delivery and diagnosis of CHD was reviewed by a specialist in paediatric cardiology. Information regarding parental health, pregnancy, delivery, and the newborn was collected through Danish patient registries. Participants/materials, setting, methods This study includes all children conceived by ART in the CBHS (n = 1 784), and a matched group (1:4 by maternal age at birth) of NC children (n = 7 141). Exclusion criteria were genetic or chromosomal syndromes and heart surgery. Minor CHD was defined as an atrial (ASD) or ventricular septum defects (VSD), bicuspid aortic valve, coarctation of the aorta, pulmonary stenosis, or patent ductus arteriosus. We calculated ORs using logistic regression analyses. Main results and the role of chance The mean maternal age at birth was 34.9 (standard deviation [SD] ±4.4) and 35.1 years (SD ± 4.6) and the newborn mean age at TTE was 12.1 (SD ± 9.3) and 12.2 days (SD ± 9.4) in the ART and NC population, respectively. Parental CHD was registered in 40 (2.2 %) children in the ART group and 121 (1.7 %) in the NC group. Overall, 165 (9.2%) children conceived by ART and 611 (8.6%) NC children were diagnosed with a minor CHD. The most prevalent CHDs were VSD and ASD which accounted for 38.8 % and 35.2 % in children with CHD in the ART group, respectively, and 36.8 % and 33.9 % in children with CHD in the NC group. The unadjusted OR for minor CHD was 1.09 (95% CI 0.91–1.30). Adjustments for maternal age and parental CHD did not change the OR. There were no differences in ORs when stratifying by minor CHD type. We stratified by the method of ART: ICSI and IVF and frozen embryo transfer and fresh embryo transfer, and calculated risk of minor CHD comparing the methods and with NC children. We found no difference in any ORs, crude or adjusted. Limitations, reasons for caution Children born preterm, and children with severe minor and major CHDs, were underrepresented in the cohort indicating parents of such children chose not to participate in a research project that would include another hospital visit. Residual confounding is plausible because parental CHD diagnoses were retrieved from patient registries. Wider implications of the findings The number of children conceived through ART is increasing each year and previous research have found an increased risk of CHD in children conceived through ART. Our findings indicate no increased risk of minor CHD, providing comforting and significant information for advising individuals considering or undergoing ART treatment. Trial registration number NCT02753348

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 Study question Is bone health in children conceived after frozen embryo transfer (FET) different from children conceived after fresh embryo transfer (fresh-ET) and natural conception (NC)? Summary answer FET-children had higher bone mineral density (BMD) and bone mineral content (BMC) compared to fresh-ET-children. Insulin-like-growth-factor-I (IGF-I) levels and lean bodymass were similar between groups. What is known already Children conceived after assisted reproductive technology (ART) with FET have a higher average birthweight (BW) and increased risk of being born large-for-gestational-age (LGA) while children born after fresh-ET are more often born small-for-gestational-age (SGA). In general, BW is a determinant of BMD and BMC in childhood with LGA being associated with higher BMD and BMC compared to children born appropriate-for-gestational-age. The relationship between BW and BMD and BMC may be mediated by IGF-I levels and lean bodymass as IGF-I is an important regulator of muscle and bone development. Bone health in children born after ART is scarcely explored. Study design, size, duration This study was part of the large Danish cohort study “Health in Childhood following Assisted Reproductive Technology” (HiCART) which included 606 singletons (292 boys) born in Denmark between 2009 and 2013. The children were conceived after FET (n = 200), fresh-ET (n = 203) and NC (n = 203) and matched for birth year and sex. The study examinations were performed from January 2019 to September 2021. Participants/materials, setting, methods The children underwent a clinical examination at 7-10 years of age with anthropometric measurements, pubertal staging, a fasting blood sample and a whole-body dual-energy x-ray absorptiometry-scan (DXA). Anthropometric measurements and circulating growth factors were converted to standard deviation scores (SDS) using Danish reference material. The study groups were compared pairwise using univariate linear regression and multiple linear regression adjusting for relevant confounders including sex, age, puberty, maternal pregestational BMI, breastfeeding and BW (SDS). Main results and the role of chance Children conceived after FET had significantly higher BW (SDS) (mean, SD: 0.20 SDS, 1.09) compared to children conceived after fresh-ET (-0.22 SDS, 1.00), mean difference: 0.42 SDS (95% CI: 0.21; 0.62) and NC (-0.16 SDS, 1.09), mean difference: 0.35 SDS (95% CI: 0.14; 0.57). In the adjusted model, children born after FET had significantly higher total BMD (g/cm2) (mean difference 0.01, 95% CI: 0.00; 0.03) and size-adjusted BMC (BMC/height, g/m) (mean difference 0.21, 95% CI: 0.01; 0.40) compared to children born after fresh-ET. There was no significant difference in total BMD or BMC/height when comparing FET and fresh-ET to NC children, respectively. There was a trend towards higher lean bodymass (g) in children born after FET and lower lean bodymass in children born after fresh-ET compared to NC children, however this did not reach the level of significance. IGF-I (SDS), IGF-binding-protein-3 (SDS) and serum calcium (mmol/L) levels were comparable between the groups. In the entire cohort, there was a significantly positive correlation between BW (SDS) and size-adjusted BMC (BMC/height, g/m) (b: 0.21, 95% CI: 0.14; 0.27) and total lean bodymass (g) (b: 755, 95% CI: 531; 978), while a significantly negative correlation with IGF-I (SDS) (b: -0.07, 95% CI: -0.13; -0.01). Limitations, reasons for caution The study was powered to detect a clinically relevant difference in BMI (SDS), the primary outcome. Hence, secondary analyses are exploratory by nature. We have no information regarding endometrial preparation protocol in the FET-cycles which may bias the results. Multiple testing may increase our risk of type I errors. Wider implications of the findings Reassuringly, BMD and size-adjusted BMC in children born after ART with FET and fresh-ET were comparable to NC children. Potential determinants of BMD and BMC (IGF-I and lean bodymass) were also similar. Increased BMD and size-adjusted BMC in FET compared to fresh-ET suggests that the different BW-profiles play a role. Trial registration number NCT03719703

Background Metabolic effects of empagliflozin treatment include lowered glucose and insulin concentrations, elevated free fatty acids and ketone bodies and have been suggested to contribute to the cardiovascular benefits of empagliflozin treatment, possibly through an improved cardiac function. We aimed to evaluate the influence of these metabolic changes on cardiac function in patients with T2D. Methods In a randomized cross-over design, the SGLT2 inhibitor empagliflozin (E) was compared with insulin (I) treatment titrated to the same level of glycemic control in 17 patients with type 2 diabetes, BMI of > 28 kg/m 2 , C-peptide > 500 pM. Treatments lasted 5 weeks and were preceded by 3-week washouts (WO). At the end of treatments and washouts, cardiac diastolic function was determined with magnetic resonance imaging from left ventricle early peak-filling rate and left atrial passive emptying fraction (primary and key secondary endpoints); systolic function from left ventricle ejection fraction (secondary endpoint). Coupling between cardiac function and fatty acid concentrations, was studied on a separate day with a second scan after reduction of plasma fatty acids with acipimox. Data are Mean ± standard error. Between treatment difference (ΔT: E–I) and treatments effects (ΔE: E-WO or ΔI: I -WO) were evaluated using Students’ t-test or Wilcoxon signed rank test as appropriate. Results Glucose concentrations were similar, fatty acids, ketone bodies and lipid oxidation increased while insulin concentrations decreased on empagliflozin compared with insulin treatment. Cardiac diastolic and systolic function were unchanged by either treatment. Acipimox decreased fatty acids with 35% at all visits, and this led to reduced cardiac diastolic (ΔT: −51 ± 22 ml/s (p < 0.05); ΔE: −33 ± 26 ml/s (ns); ΔI: 37 ± 26 (ns, p < 0.05 vs ΔE)) and systolic function (ΔT: -3 ± 1% (p < 0.05); ΔE: −3 ± 1% (p < 0.05): ΔI: 1 ± 2 (ns, ns vs ΔE)) under chronotropic stress during empagliflozin compared to insulin treatment. Conclusions Despite significant metabolic differences, cardiac function did not differ on empagliflozin compared with insulin treatment. Impaired cardiac function during acipimox treatment, could suggest greater cardiac reliance on lipid metabolism for proper function during empagliflozin treatment in patients with type 2 diabetes. Trial registration: EudraCT 2017-002101-35, August 2017.

STUDY QUESTION Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)?SUMMARY ANSWER Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC.WHAT IS KNOWN ALREADY Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging.STUDY DESIGN, SIZE, DURATION This study was part of the cohort study 'Health in Childhood following Assisted Reproductive Technology' (HiCART), which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lasted from January 2019 to September 2021.PARTICIPANTS/MATERIALS, SETTING, METHODS The included children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses.MAIN RESULTS AND THE ROLE OF CHANCE Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06-0.64), boys: 0.35, 95% CI (0.03-0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03-0.47), heart rate: 4.53, 95% CI (0.94-8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty.LIMITATIONS, REASONS FOR CAUTION The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely.WIDER IMPLICATIONS OF THE FINDINGS The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings.STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT03719703.

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