The prevalence of type 2 diabetes (T2D) has reached a pandemic scale. These patients are at a substantially elevated risk of developing cardiovascular disease, with heart failure (HF) being a leading cause of morbidity and mortality. Even in the absence of traditional risk factors, diabetes still confers up to a twofold increased risk of developing HF. This has led to identifying diabetes as an independent risk factor for HF and recognition of the distinct clinical entity, diabetic cardiomyopathy. Despite a wealth of research interest, the prevalence and determinants of diabetic cardiomyopathy remain uncertain. This limited understanding of the pathophysiology of diabetic heart disease has also hindered development of effective treatments. Tight blood-glucose and blood-pressure control have not convincingly been shown to reduce macrovascular outcomes in T2D. There is, however, emerging evidence that T2D is reversible and that the metabolic abnormalities can be reversed with weight loss. Increased aerobic exercise capacity is associated with significantly lower cardiovascular and overall mortality in diabetes. Whether such lifestyle modifications as weight loss and exercise may ameliorate the structural and functional derangements of the diabetic heart has yet to be established. In this review, the link between T2D and myocardial dysfunction is explored. Insights into the structural and functional perturbations that typify the diabetic heart are first described. This is followed by an examination of the pathophysiological mechanisms that contribute to the development of cardiovascular disease in T2D. Lastly, the current and emerging therapeutic strategies to prevent or ameliorate cardiac dysfunction in T2D are evaluated. Recent estimates suggest that there are currently 451 million people with diabetes worldwide and this figure is projected to increase to 693 million by 2045.3 Globally, there are now more obese than underweight people4 and this dramatic rise in obesity and sedentary lifestyles, particularly in younger age groups, has resulted in up to a 10-fold increase in the prevalence of T2D in younger adults.5The vast majority (90%) of people with diabetes have type 2 diabetes (T2D), which is linked to increased sedentary behaviour and obesity and is largely preventable. Whereas T2D was once rare in young people, increasingly we are seeing the condition diagnosed in children, adolescents and adults under the age of 30 years.6 Atherosclerotic diseases  have typically been regarded as the predominant manifestations of CVD in T2D. However, recent data from the United Kingdom National Diabetes Audit 2015–2016, which includes data on over 2.7 million patients with diabetes, showed that heart failure (HF) is the commonest cardiovascular complication of T2D and a major cause of premature mortality.7 While the risk of death, myocardial infarction and stroke can be mitigated with strict risk-factor control in T2D, the excess risk of HF persists, in spite of good cardiovascular risk-factor management.8The most deleterious consequence of developing T2D is a substantially elevated risk of cardiovascular disease (CVD). The risk of cardiovascular complications is two to two-and-a-half times greater in people with T2D compared with the nondiabetic population. In a meta-analysis combing data from 4,549,481 people with T2D, almost one third (32.7%) suffered from CVD and half of all deaths were attributable to CVD.9 Importantly, unrecognized HF is highly prevalent in T2D, with over one quarter (27.7%) of over 60s having previously undiagnosed HF in one report.10 There is a high prevalence of diabetes in patients with both common forms of HF: impaired systolic left ventricular (LV) function and HF with preserved ejection fraction. Conversely, a high proportion  of patients with DM have undiagnosed LV dysfunction.10Patients with DM have up to a 74% increased risk of developing HF, and diabetic patients with HF are four times more likely to die than those without HF.1113 or the prevalence of other traditional risk factors, such as age, sex, hypertension, coronary artery disease (CAD) and dyslipidaemia that are inherent in diabetic subjects. Even after adjustment for these factors, diabetes still confers a two- to five-fold added risk for HF development.1113 This has led to the identification of diabetes as an independent risk factor for HF and the recognition of the distinct clinical entity of ‘diabetic cardiomyopathy’,14 a term originally coined by Lundbaek in 1954.15Large, population-based studies have shown that the occurrence of HF in diabetes cannot be accounted for solely by the increased atherosclerotic risk14 Four stages of diabetic cardiomyopathy are described, and there is overlap with the HF classifications of both the American College of Cardiology/American Heart Association Stage and New York Heart Association Class , increased body mass index, hypertension, CAD, longer duration of diabetes and the presence of microvascular complications are associated with HF development.21 There is now an abundance of data to support Rubler and coworkers’ initial findings and demonstrate that diabetes is associated with several alterations in LV geometry.The occurrence of structural changes of the diabetic myocardium were first observed by Rubler et al. in 1972. In four postmortem specimens from diabetic patients free from hypertension, CAD or valvular heart disease, Rubler and colleagues described findings of left ventricular (LV) hypertrophy and diffuse myocardial fibrosis.2224 and cardiovascular magnetic resonance imaging (CMR) studies.2527 A 1% rise in HbA1c level was associated with a 3.0 g [95% confidence interval (CI) 1.5–4.6 g] increase in LV mass in one report.23 While these changes in LV mass are modest, increased LV mass is a recognized predictor of cardiovascular morbidity and mortality,29 and is likely to be a key contributor to HF development in T2D. When the increased LV mass is indexed for body surface area, however, the differences between diabetics and controls become inconsistent. These inconsistencies arise because adjustment of LV mass for body surface area inherently ‘permits’ obese individuals to have higher LV mass;30 this is why indexing of LV mass/height is advocated.32Increased LV mass is independently associated with diabetes in many  echocardiographic33 relative wall thickness,3436 and septal thickness37 are all increased in diabetes. LV mass may be increased as a consequence of increased ventricular wall thickness or from chamber dilatation, that is, the spectrum of LV hypertrophy ranges from concentric to eccentric hypertrophy. While there is variation in both the degree and pattern of hypertrophy observed in patients with diabetes, concentric LV hypertrophy represents the main structural characteristic of diabetic cardiomyopathy. Concentric LV remodelling is associated with an increased risk of developing HF and other adverse cardiac events and appears to be the predominant remodelling pattern in diabetes.39 However, LV geometry is also altered by sex,40 ethnicity,41 obesity42 and hypertension,43 common confounders in diabetes, and controlling for these confounders may in fact prevent the development of LV remodelling.44 The lack of standardization in reported markers of LV remodelling makes comparisons between studies difficult45 and limits knowledge of LV remodelling patterns in diabetes.Other markers of LV remodelling are also apparent in diabetes; LV mass/volume,14Cardiac dysfunction in diabetes is thought to lie on a continuum , ranging46 Despite controlling metabolic risk factors in T2D , diastolic dysfunction persists in the absence of LV remodelling or systolic impairment.44 There are, however, inconsistencies in the prevalence of diastolic dysfunction found in asymptomatic subjects with T2D. Reported prevalence rates vary from 15% to 78%4750 and differ according to the technique used for diagnosis.47It is often stated that diastolic dysfunction is the earliest functional change occurring in diabetic cardiomyopathy. Observational studies have found an increased frequency of diastolic dysfunction in T2D by echo and CMR. The prevalence and severity of diastolic dysfunction was shown to be directly proportional to HbA1c level in one study of 1810 people with T2D.52 speckle tracking echocardiography53 and CMR33 data confirm systolic LV global longitudinal strain is lower in T2D than in nondiabetics. These impairments in global longitudinal strain worsen with time54 and vary across the glycaemic spectrum .23 These subclinical abnormalities in contractility are widely considered a precursor to the onset of clinical HF in diabetes. Indeed, longitudinal studies have found global longitudinal strain to be an independent predictor of cardiovascular events and may provide incremental prognostic value in asymptomatic people with T2D.56 However, in the first of these studies, the sample size was modest and there was significant risk of overfitting of the multivariable regression model,55 and in the second study, only echocardiographic parameters as predictors of outcomes were explored with no mention of clinical predictors.56 Importantly, the majority of cardiovascular events in these studies were atherosclerotic  and not HF-related events and it remains unclear why reductions in global longitudinal strain would predict atherothrombotic events independent of other clinical risk factors.Despite the association of T2D with HF, few studies have shown that T2D causes a reduction in global LV ejection fraction, which remains the most utilized measure of LV systolic performance. Using myocardial strain and strain-rate measurement, subclinical impairments in systolic function with normal ejection fraction are now frequently reported in T2D. Tissue Doppler imaging,5760 A small number have, however, reported reduced systolic strain without diastolic dysfunction.62 This could indicate that diastolic dysfunction is not the earliest functional change in the diabetic heart and is in fact preceded by impaired systolic strain. In most of these studies, diastolic function was determined by tissue Doppler velocities and not strain analyses, likely reducing the sensitivity of identifying diastolic impairments.62 Furthermore, it is acknowledged that different guidelines for grading diastolic dysfunction by echocardiography yield inconsistent results and may only be accurate for identifying the most severe cases.63 Assessment of diastolic strain rate may be a more sensitive measure of early diastolic impairment.26 Only one CMR study33 reported reduced LV systolic global longitudinal strain  and preserved diastolic strain rate , but these values are much lower than those seen in the prevailing echo and CMR literature where they are typically ~20% and 1.5–2.0 s−1, respectively, in controls.The vast majority of studies that have examined both have shown that impaired systolic strain is associated with diastolic dysfunction.64 Serum N-terminal pro-B-type natriuretic peptide levels are higher in asymptomatic T2D with isolated diastolic dysfunction compared with controls.66 At present B-type natriuretic peptide is often used in routine practice, however natriuretic peptide levels can be influenced by many other factors, several of which are more prevalent in diabetes, including obesity, increasing age, use of renin–angiotensin–aldosterone-system inhibitors and renal dysfunction.67 And diabetes itself is associated with elevated natriuretic peptide levels.67 Numerous other biomarkers are being evaluated in HF64 and specifically, diabetic HF. In one study comparing biomarker profiles between diabetic and nondiabetic patients with HF with preserved ejection fraction, endothelin-1 (a potent vasoconstrictor), galectin-3 and carboxy-terminal telopeptide of collagen type 1 (profibrotic biomarkers) were higher in patients with diabetes.17 Of more interest, is a biomarker analysis of the ADVANCE trial, which assessed the prediction of new and worsening HF in a nested case-control analysis.68 This study demonstrated that measurement of N-terminal pro-B-type natriuretic peptide gave a similar predictive accuracy as clinical risk factors and was of additive value, although the effects were attenuated when patients with levels > 400 pg/ml (in the HF diagnostic range) were excluded. Markers of inflammation  and myocardial damage (troponin) were not of added value.68 The identification of plasma biomarkers in HF is an area of intense research interest and may impact on clinical management in the future.64Several studies have investigated the role of natriuretic peptides in asymptomatic patients with T2D.69 These include myocardial lipotoxicity and glucotoxicity, damage from glycated end products and reactive oxygen species, impaired calcium homeostasis, mitochondrial dysfunction, activation of the renin–angiotensin–aldosterone system, altered myocardial substrate utilization, and cardiac autonomic neuropathy ,60 sex,34 presence of microalbuminuria,77 LV relative wall thickness,77 CAD78 and, again, myocardial triglyceride.33 Importantly, these findings were made on the basis of multivariate analyses, which have been limited by small sample sizes (seldom greater than 100 subjects) and incomplete datasets, with significant risk of overfitting the regression models.79Several inverse correlations with diastolic dysfunction in T2D have been identified: HbA1c level,80 In T2D, there is a shift toward increased free-fatty-acid utilization by the myocardium in T2D due to increased free-fatty-acid availability. This is less energy efficient with lower adenosine triphosphate (ATP) yield81 and leads to metabolic inefficiency in the diabetic heart.82Impaired myocardial substrate utilization and altered energy metabolism have recently been described in T2D and are likely to be contribute to the development of cardiac impairment. The normal heart derives 70% of its energy from free-fatty-acid metabolism and 30% from glucose metabolism.83 Decreased myocardial PCr/ATP ratios have been demonstrated in T2D and suggest that myocardial energetic impairment is a key component in the pathophysiology of diabetic cardiomyopathy.8486 Impairment in myocardial energetics has also been exacerbated by exercise86 and may reflect metabolic inflexibility in the diabetic heart. Importantly, a decreased PCr/ATP ratio has been linked to contractile dysfunction and is a predictor of mortality, although this was in patients with dilated cardiomyopathy.87Myocardial energetics can now be assessed non-invasively by phosphorus magnetic resonance spectroscopy. This enables assessment of the myocardial creatine phosphate (PCr)/ATP ratio, which is a sensitive index of the energetic state of the myocardium.88 There is an increased supply of free fatty acids and a shift towards fatty-acid oxidation in the myocyte.89 The supply of fatty acids, however, exceeds the oxidative capacity of the heart and nonoxidative lipid metabolism ensues.90 Products of nonoxidative lipid metabolism include ceramide and diacylglycerol, which are toxic to cardiomyocytes and can induce myocardial dysfunction, apoptosis and fibrosis  was first demonstrated in mouse models of DM92 and has emerged as a contributor to development of diabetic cardiomyopathy. Myocardial steatosis is mediated by microribonucleic acid (microRNA) dysregulation (such as miR-451 and miR-494-3p) and was linked with LV dysfunction in recent animal models of T2D and obesity,94 supporting a central role for microRNAs in the pathogenesis of diabetic cardiomyopathy.Metabolic dysregulation is central to the pathogenesis of DM. Insulin resistance results in decreased availability of glucose in the myocardium.fibrosis .91 Excesin vivo, and several studies have confirmed elevated myocardial triglyceride content in T2D  and an estimate of diffuse interstitial fibrosis using T1 mapping and calculation of myocardial extracellular volume.100 Patients with diabetes have shorter global contrast-enhanced myocardial T1 times compared with controls, indicative of a higher burden of diffuse interstitial myocardial fibrosis.101 This is independently associated with myocardial systolic101 and diastolic function.101 Subjects with T2D have a higher extracellular volume fraction than controls,103 although the differences found are small (1–2%),103 and there is a large degree of overlap when control subjects are well matched to those with diabetes.33 Elevated extracellular volume fraction is associated with increased admissions for HF and mortality, but this was in patients already referred for a clinical CMR with inevitable selection bias.103Myocardial fibrosis is thought to be mediated by damage from advanced glycation end products104 This buffering capacity of the thoracic aorta is essential for maintaining normal LV structure and function. Aortic stiffening is an increase in the elastic resistance of the aorta to deformation and naturally occurs with ageing but is additionally accelerated by the traditional cardiovascular risk factors.106 Increased aortic stiffness is a strong predictor of adverse cardiovascular events in several cohorts,107109 including T2D.111 Our group has previously shown a modest but significant correlation exists between mean aortic distensibility and peak early diastolic strain rate  in young adults with T2D.26 This suggests that increased aortic stiffness is an early change in diabetes, which contributes to subclinical cardiac dysfunction in T2D, independent of age and BP.The aorta is a conduit for the delivery of blood to peripheral tissues. In addition, the elastic properties of the aorta act to dampen the sudden fluctuations in BP generated by blood ejected from the LV during each cardiac cycle. This transforms the pulsatile stroke volume into continuous blood flow through the peripheral arterial tree.112 Reducing HbA1c levels may attenuate the progression of aortic stiffness and some studies have shown that aortic stiffness is modifiable by diabetes treatment.113116Poorer blood-glucose control is associated with accelerated aortic stiffness, particularly in younger adults with T2D.117 Aortic stiffening disturbs the arterial–ventricular interaction, augmenting ventricular afterload and supplementing the development of LVH. This results in increased LV filling pressures and impairment in the passive flow of blood from the left atrium to the LV in early diastole. Aortic stiffness therefore likely mediates the development of diabetic cardiomyopathy by stimulating LVH. We have recently confirmed this in a cross-sectional study of 80 young adults with T2D, where we have demonstrated that aortic stiffness is an independent predictor of concentric LV remodelling.118 Given that aortic stiffening is potentially reversible with aggressive BP reduction,119 this may yield a potential therapeutic strategy for preventing or treating diabetic cardiomyopathy.Despite the recognition that aortic stiffening is a key determinant of LV dysfunction in several diseases, the precise mechanisms linking aortic stiffness with adverse cardiovascular outcomes are unclear. The most prominent hypothesis for the pathophysiological basis linking aortic stiffness with adverse cardiovascular events in T2D is the development of LV remodelling.120 ADVANCE,121 ACCORD122 and VADT123 did not demonstrate an improvement in macrovascular outcomes with tight blood-glucose control. A meta-analysis of these four large trials, comprising over 27,000 patients assigned to more-intensive versus less-intensive blood-glucose control showed only modest reduction in major adverse cardiovascular events .124 This was primarily driven by a reduction in myocardial infarction, with no overall benefit on all-cause or cardiovascular death.124 Similarly, a meta-analysis of data from eight randomized trials comprising 37,229 people with T2D revealed no observed benefit of intensive glycaemic control on HF-related outcomes.125 Even with intensive glucose control, underlying epigenetic alterations that promote oxidative stress, myocardial inflammation and LV dysfunction persisted in a mouse model of diabetes. This may be a key mechanism driving the persistence of cardiac dysfunction in the context of tight glycaemic control; and targeting epigenetic networks has been proposed as a novel strategy to ameliorate LV dysfunction in T2D.126The majority of previous, large, multicentre, randomized-controlled trials such as UKPDS,127 and inhibitors of sodium–glucose cotransporter 2 (SGLT2 inhibitors)128 have shown exciting results with improved glycaemic control, as well as reduced cardiovascular mortality in patients with T2D.129 However, these recent trials were designed to assess the safety and tolerability of these novel drugs, and therefore the mechanisms behind the observed cardiovascular benefits are speculative. Nevertheless, the increased use of these agents has been advocated in recent guidelines of management of hyperglycaemia in T2D.Recently, new classes of glucose-lowering therapies, such as glucagon-like peptide-1 (GLP-1) agonists,130 In the randomized-controlled LEADER trial, patients with T2D and high cardiovascular risk treated with liraglutide had lower rates of cardiovascular death compared with those having placebo.127 Similarly, in high-risk T2D patients, cardiovascular event rates  were found to be significantly lower with semaglutide131 and albiglutide than for placebo.132 However, in the EXSCEL trial of the GLP-1, exenatide versus placebo, there was no overall cardiovascular risk benefit with the study drug, although this study included patients with or without a prior history of CVD133  lead to a reduction in intravascular volume and systolic BP. This in turn reduces preload and afterload, leading to improvements in myocardial oxygen supply and vascular function.142 A mediation analysis of the EMPA-REG OUTCOME trial has indeed demonstrated that changes in plasma volume are central to the CV risk benefits observed with empagliflozin.143 Furthermore, in a randomized trial of empagliflozin versus placebo in patients with T2D and uncontrolled nocturnal hypertension, empagliflozin was associated with significant 24 h ambulatory BP reductions compared with placebo .144 Others suggest that SGLT2 inhibitors, through a shift in myocardial metabolism towards ketones, have favourable effects on cardiac energetics.145 The results of these studies, while promising, should be viewed with a degree of caution. HF risk reduction was not the primary endpoint of either study and was based on investigator-reported HF events rather than objective measures (such as echocardiography or measurement of B-type natriuretic peptide levels). Nevertheless, several mechanistic studies are now underway to identify the specific cardiovascular effects of SGLT2 inhibitors. Whether the same cardiovascular benefits of SGLT2 inhibitors are seen in earlier stages of diabetic cardiomyopathy remains to be established.SGLT2 inhibitors lower blood-glucose levels by promoting urinary glucose excretion. Secondary effects include weight loss, a modest diuretic effect and BP reduction.146 Coexistence of these two conditions confers a greater risk of CVD, including CAD, LV hypertrophy, stroke and HF, compared with either diabetes or hypertension in isolation.147 Despite the high prevalence of hypertension in diabetes, there are inconsistencies in the recommended BP targets in these patients.148150 Previous recommendations favoured an intensive approach to BP management in diabetes given the high CVD risk profile of these patients. Indeed, in nondiabetic patients at high risk of CVD, intensive BP lowering (to a systolic BP < 120 mmHg) dramatically lowers cardiovascular risk and all-cause mortality.151 It has therefore been suggested that tighter BP control be targeted in patients with T2D,152 although there are limited data to support this strategy as a means of overall cardiovascular risk reduction.Patients with diabetes are twice as likely to suffer from hypertension than nondiabetics.153 The annual incidence of all-cause mortality was similar with either BP target . Intensive BP treatment was in fact harmful and led to increased incidence of syncope and hyperkalaemia.154 Even after longer-term follow up (median duration 8.8 years) was carried out for 3957 patients from the ACCORD study, there remained no reduction in the rate of a composite of fatal and nonfatal major cardiovascular events or mortality with intensive versus standard BP control.154 Similarly, patients with T2D and a history of CAD do not appear to benefit from an intensive BP-lowering-treatment strategy.155 Recent data suggest a U-shaped relationship between BP and cardiovascular outcomes in T2D, where systolic BP over 150 mmHg or less than 110 mmHg portends a poorer prognosis.156 Maintenance of BP within this range appears to be the most appropriate strategy in T2D. In view of these and other large prospective studies evaluating BP-lowering targets in DM, current National Institute for Health and Care Excellence (NG28) recommendations are that BP be maintained below 140/80 mmHg in uncomplicated T2D or below 130/80 mmHg if there is a history of kidney, eye or cerebrovascular disease.148In the ACCORD BP study, which specifically addressed the issue of intensive BP lowering in T2D, there was no demonstrable survival benefit with intensive BP reduction (systolic BP < 120 mmHg) compared with a standard BP reduction target (<140 mmHg) over a median follow-up period of 4.7 years in 4733 patients with T2D.158 and in a primary-care-led administration of a 825–853 kcal/day meal-replacement diet.159 The extent of weight loss is strongly linked to reversal of T2D. Insulin use, diabetes duration and high HbA1c levels reduce the chances of reversal.158 None of these reports, however, have assessed changes in cardiovascular function.T2D has long been regarded as a chronic condition capable of being ameliorated but not cured. However, proof that T2D is a reversible condition has been firmly established in patients undergoing bariatric surgery160 Improved diastolic function following weight loss in obesity has been associated with improved energetics161 and with reduced myocardial triglyceride content.162In obese subjects without T2D, sustained weight loss, either with diet or after surgery, has resulted in favourable reductions in CMR-measured LV mass, volumes, arterial stiffness and diastolic function.p = 0.02) in a small (n = 12) single-group study and was associated with improved diastolic filling on CMR.163 Interestingly, a recent brief report from the same group, suggests that in the first few days after commencing a very-low-energy diet, there may actually be an increase in steatosis and reduced diastolic mitral filling.164 However, it should be noted that there was a dramatic decrease in ventricular volumes, with a nonsignificant decrease in estimated filling pressure, which are both likely to have affected the diastolic filling rate.In patients with insulin-treated T2D, a 471 kcal/day very-low-energy diet has also been shown to reduce myocardial steatosis  is a recognized prognostic marker in subjects with CVD169 and in T2D.170 In a small study (n = 19), exercise capacity was significantly reduced in subjects with T2D having diastolic dysfunction compared with those having normal diastolic function.171 This suggests that improvements in exercise capacity may yield improvements in cardiac dysfunction in T2D; at the very least, in the early stages of diabetic cardiomyopathy. This is supported by a recent position paper from the European Association of Preventive Cardiology, which advocates the promotion of individualized exercise training programmes in people with T2D to improve both cardiovascular and metabolic function.172Large cohort studies have shown that increased aerobic exercise capacity is associated with significantly lower cardiovascular and overall mortality in men174 Importantly, these substantial benefits are maintained when exercise training does not result in weight loss.174 This is consistent with experimental studies that have elucidated key insulin-dependent and insulin-independent pathways linking physical activity to improved glucose regulation that do not act through adiposity.176Intervention studies have demonstrated a strong causal link between exercise training and glycaemic control in those with T2D. Exercise training has consistently been found to lower HbA1c by 0.6–0.7%, with greater effects seen with higher volumes of exercise.177 Similarly, just 4 weeks of exercise training has been shown to improve diastolic function in those with HF with similar improvements also observed in a matched cohort without HF.178While the benefits of exercise training on glycaemic control are well established, the effects on diastolic function are less well known, primarily due to insufficient data, differences in measurement and poor study design. However, encouraging data are starting to emerge in those with obesity and chronic disease. For example, an 8-week exercise training programme in obese men improved diastolic function to levels seen in lean controls, despite no weight loss.179 while another study found no overall effect.180 However in the latter study, a post hoc analysis revealed that change in moderate-intensity physical activity was significantly associated with change in myocardial strain rate, although it is unclear whether this was systolic, diastolic or both.180 This mirrors the wider evidence where light-to-moderate aerobic exercise training has repeatedly been demonstrated to improve diastolic function across a number of groups.179 The effectiveness of vigorous-intensity exercise or combined aerobic and resistance training is less well established, with at least one study showing the latter approach is not effective.181 Given this evidence base, it is important the efficacy of aerobic exercise training is investigated further.Only two studies have been conducted in T2D assessing the effects of exercise training on diastolic function. In a small pilot study, 3 months of aerobic exercise training reversed diastolic dysfunction in almost half (45%) of individuals with T2D and grade 1 diastolic dysfunction,versus a diabetes support programme were evaluated in 5145 overweight or obese  people with T2D over a median follow-up duration of 9.6 years. Disappointingly, there was no difference in the rate of cardiovascular events in the intensive-lifestyle-intervention arm, despite a greater extent of weight loss, increased fitness and improved glycaemic control.182 However, the mean weight loss achieved in the intensive-lifestyle-intervention arm was only 6% by the end of the trial, and both study groups had intensive medical management of cardiovascular risk factors, which may have limited the treatment effect in the intervention arm.Finally, in the randomized-controlled LookAHEAD trial, the effects of intensive-lifestyle intervention (which included a combined dietary weight loss and exercise programme) per se does not reduce the risk of developing HF, but newer pharmacologic agents reduce CV complications and SGLT2 inhibitors have been shown to decrease HF-related hospitalizations. Weight loss, either with low-calorie diets or bariatric surgery, is also an attractive option for reversing diabetes and the risk of HF, but further studies are needed.The rapid increase in prevalence of T2D now represents a global pandemic. These patients are at high risk of developing HF and dying prematurely, but the prevalence of subclinical cardiac dysfunction and the causes are uncertain. Improved glycaemic control


Quantitative results of cardiovascular magnetic resonance (CMR) image analysis influence clinical decision making. Image analysis is performed based on dedicated software. The manufacturers provide different analysis tools whose algorithms are often unknown. The aim of this study was to evaluate the impact of software on quantification of left ventricular (LV) assessment, 2D flow measurement and T1- and T2-parametric mapping.42, Siemens Healthineers: Argus, Medis: Qmass/Qflow) by one reader blinded to former results. Cine steady state free precession short axis images were analyzed regarding LV ejection fraction (EF), end-systolic and end-diastolic volume  and LV mass. Phase-contrast magnetic resonance images were evaluated for forward stroke volume (SV) and peak velocity (Vmax). Pixel-wise generated native T1- and T2-maps were used to assess T1- and T2-time. Forty-five data sets were evaluated twice (15 per software) for intraobserver analysis. Equivalence was considered if the confidence interval of a paired assessment of two sofware was within a tolerance interval defined by ±1.96 highest standard deviation obtained by intraobserver analysis.Thirty-one data sets of patients who underwent a CMR Scan on 1.5 T were analyzed using three different software  were considered equivalent for LV EF, EDV, ESV, mass, 2D flow SV and T2-time. Differences between software were detected in flow measurement for Vmax and in parametric mapping for T1-time. For Vmax, equivalence was given between software A and C and for T1-time equivalence was given between software B and C.Software had no impact on quantitative results of LV assessment, T2-time and SV based on 2D flow. In contrast to that, Vmax and T1-time may be influenced by software. CMR reports should contain the name and version of the software applied for image analysis to avoid misinterpretation upon follow-up and research examinations.ISRCTN12210850. Registered 14 July 2017, retrospectively registered.The online version of this article (10.1186/s12968-019-0522-y) contains supplementary material, which is available to authorized users. In the past years, cardiovascular magnetic resonance Imaging (CMR) has emerged as a broadly applied imaging modality in cardiac diagnostics . Due to The aim of the present study was to investigate the equivalence of three commercially available software used at our site for assessment of LV, 2D flow and T1- and T2-parametric mapping. We hypothesized that mean differences between software are smaller than intraobserver variability and hence, software can be considered as equivalent.2), cardiac metastases, known incompatibility for gadolinium contrast media and contraindication for CMR. We had to exclude short axis images (SAX) in one patient as they were not recorded continuously, T1-map in one patient due to an artifact and flow in one patient due to aliasing in flow measurement. In order to still match the required number of analyzed data, we included a 31st patient for analysis of SAX, T1-time and flow. A total of 31 data sets of patients  prior to the study. Ethical approval was given for the mentioned study by the local ethics committee of Charité Medical University Berlin . All patients gave their written informed consent before participating in the study.For logistical reasons, we chose at the beginning of this study the first available data sets of patients with histologically confirmed soft tissue sarcoma planned for anthracycline-based chemotherapy from an on-going study of our working group ISRCTN12210850) [0850 [21]3, flip angle 80 degrees). Segmented gradient-echo phase contrast CMR (PC-CMR) was performed at the sinotubular junction of the ascending aorta. The velocity encoding range was set at 150 cm/s in a through-plane direction [All CMR examinations were performed using a 1.5 Tesla scanner . Protocol and slice planning were identical in all cases according to institutional standards. In short, retrospective electrocardiographic (ECG) gated balanced steady state free precession (bSSFP) cine images covering the whole LV from basis to apex were obtained without gap in a breath-hold technique , (software A); Siemens Healthineers: Classic Argus  on SyngoMMWP version VE53A acquisition work place, (software B); and Medis medical imaging systems: Medis Suite 2.1 with the applications Qmass and Qflow version 8.1 , (software C). We analyzed software using the default settings. The software surfaces are presented in Fig. Three software packages were used for image analysis and quantitative assessment according to current institutional standards between June and December 2016 . All dat42 heart function [For LV assessment we used cvifunction , Argus Lfunction  and Qmasfunction . Endo- afunction .42 Flow [For 2D flow assessment, we used cvi42 Flow , Argus F42 Flow  and Qflo42 Flow . The asc42 Flow .42 (using T1- and T2-tool) [For T1 and T2 mapping the procedure was identical in cviT2-tool) , 31 and T2-tool) . Endo- aT2-tool) , a ROI wT2-tool) , 35.42 in our working group and from literature assuming that the distribution of the available data is comparable to other software types [The sample size calculation for the equivalence test was based on reference values obtained with cvire types , 36, 37.re types .p-values were given. Area of T1- and T2-mapping was recorded if applicable and compared for differences by paired t-test with α = 0.05. Statistical analysis was performed by Graph Pad Prism 6, version 6.0.7 for windows [Normality was checked based on visual inspection of the data using Quantile-Quantile-plots (QQ-plots). No strong deviations from normal distribution were noted thus parametric methods were used. The Pearson’s correlation coefficient (r) was calculated for correlation analysis and Bland-Altman plots were generated to assess the bias (mean difference) and the 95% limits of agreement between each pair of software for each parameter. Equivalence limits were determined as ±1.96 maximum intraobserver SD variability across the three software, which corresponds to the largest observed 95% tolerance interval with 95% coverage of repeated measurements with the same software. Following the approach outlined by Walker and Nowacki , Bonferr windows .For each parameter 30 data sets were available and could be analyzed with each software Fig. .Fig. 2SiAll software showed a strong positive correlation for EF , mass , EDV  and ESV . For EF, Bland-Altman analysis revealed narrowest limits of agreement between software A/C Fig. b. SmalleAll software showed a very strong positive correlation for Vmax  and SV . For Vmax, bias of software A/C was close to zero and presented narrowest limits of agreement Fig. b. Softwap < 0.001, respectively). Within one software, the measured area did not differ between first and second measurement of T1- and T2-time .Software B/C showed highest correlation for T1-time  and for T2-time . Software A had longer T1- and T2-time and best agreement was detected between software B/C  all three software were equivalent for LV assessment , (ii) all three software were equivalent for SV, but only two software for Vmax, (iii) equivalence was given for all software in quantification of T2-time, but only two software for T1-time.It is well known that different post-processing SW are used world-wide in clinical routine and research. They differ e.g. regarding pixel definition settings, contour detection and other algorithms. Each pixel of a cardiac image displayed by the post-processing software provides information about its size and specific value, such as maximum velocity in case of flow measurement or T1-time in case of T1-mapping. For quantitative image analysis contours intersect pixels. Depending on the software type, different pixel inclusion methods for calculations can be used, e.g. to involve the pixel partly or entirely. In a clinical setting it is crucial to know if these potential differences could impact the results. Previous studies compared the relation between software using correlations, intra-class-coefficient and significant differences. We applied an equivalence testing approach using the intraobserver variability to define equivalence margins to identify deviations between software. In the present study there is no impact of scan procedure related technical influences  as we anFor LV assessment, all three software showed a high correlation and equivalence for LV EF, EDV, ESV and mass. Our results are supported by previous studies using different software. Messali et al. revealed a high correlation of LV function and volume without significant differences between ViewForum (Philips) and Argus in 46 patients . Kara etHemodynamics can be assessed by PC-CMR to evaluate shunt fraction, valve regurgitation or stenosis . We used42 provided a tool for endo- and epicardial border delineation. Argus has no such specific tool yet. However, within one software, the delineated area was consistent between two measurements. Another explanation for discrepancies might be the different ranges of the values for T1- and T2-time. This is supported by the fact that the relation of our maximum intraobserver SD to the recently published segment based normal values of our group was much smaller for T1- than for T2-time accounting for narrower equivalence limits for T1-time  [42 [CMR enables tissue characterization using parametric mapping techniques. Myocardial T2-mapping can detect edema in acute myocardial infarction or inflammation . Native T2-time) , 53. Theime) [42 , 11, 54.ime) [42 . TherefoCurrently there is a lack of an internationally accepted gold standard for software, like phantoms for the different cardiac structure and function. Therefore, we used intraobserver variability of an experienced reader as gold standard to assess equivalence testing. We investigated only a certain number of SW, being aware that there are many others on the market. Further, our findings were specific for the particular software version, knowing that software packages evolve continuously. We did not analyze different cardiovascular diseases but among the selected patients 52% suffered from cardiac alterations. The potential influence of multiple observers and other pathologies on the comparability of results from different software systems was not considered in this study but should be subject to continuative analyses.42 version 5.6, Classic Argus and Medis Suite 2.1 for LV evaluation, forward stroke volume in 2D flow measurement and T2-time in T2 parametric mapping. We conclude that different pixel inclusion methods of the software do not substantially affect calculation of the mentioned parameters but might influence results of T1-time. Vessel contours and the peak velocity measuring square in each phase of flow measurement should be checked carefully, particularly when contour propagation is used. Software users should be aware of the current setting of voxel averaging techniques during flow analysis. Our results underline the need of standardization and indicate that the individual analysis software (including version) and specific settings should be mentioned in clinical reports to avoid misinterpretation upon follow-up examinations and to assure comparability of CMR studies.We could demonstrate exchangeability of cviAdditional file 1:Intraobserver analysis. Bland-Altman plots of LV function (EF), mass, end-diastolic (EDV) and end-systolic volume (ESV) (PDF 369 kb)Additional file 2:Intraobserver analysis. Bland-Altman plots of peak velocity (Vmax), stroke volume (SV), T1-time and T2-time (PDF 368 kb)


The effects of the water–binder ratio and different graphene oxide (GO) sizes on the mechanical properties of GO-cement composites were systematically studied by preparing GO-cement mortars. The scanning electron microscopy observation (SEM) of the surface and fracture surface of cement pastes was carried out to study the morphology of cement hydration crystals in GO-cement systems under different space conditions. It was found that GO nanosheets significantly improved the compressive, flexural, and tensile strengths of cement mortars. When the dosage of GO nanosheets was 0.03% by weight of cement, the compressive, flexural, and tensile strengths at 28 days increased by 21.37%, 39.62%, and 53.77%, respectively, but GO was not found to be able to regulate the formation of flower-like cement hydration crystals. It was only shown that the growth space had an important influence on the morphology of hydrates. A possible working mechanism was proposed by which GO nanosheets prevented the expansion of microcracks in the cement pastes via a shield effect, thus enhancing the strength and toughness of the cement composites. Cement-based materials are regarded as one of the most important building materials due to their simple construction process, low-energy consumption, and the wide range of raw materials from which they can be synthesized. With the wide application of cement-based concrete, its defects, such as large self-weight, high brittleness, and low tensile strength, urgently need to be improved . Micro-nIn recent years, the use of GO as a reinforcing material for cement-based composites also attracted the attention of scholars, and some results have been published. Lv et al.  reported3). The growth space largely affects the morphology of cement hydrates, and the effect of the preparation process of the cement pastes is very large [Studies have shown that graphene oxide nanosheets are very effective in enhancing the mechanical properties of cement-based materials due to their atom-thick two-dimensional structure . Howeverry large . TherefoSome researchers reported that GO had no effect on the cement hydration process. For example, Horszczaruk et al.  reportedIn this paper, the effects of the water-binder ratio and different GO sizes on the mechanical properties of GO-cement composites were systematically studied by preparing GO-cement mortars. Then, thermogravimetric analysis and pore structure tests were used to study the effect of GO on cement hydration. Moreover, through SEM observation of the surface and fracture surface of the cement pastes, as well as the fracture surface of the low-and high-water–binder-ratio cement pastes, the morphologies of the cement hydration products of the GO-cement system under different space conditions were studied. Previously-reported related studies were compared to explore the strengthening mechanism of GO on cement-based materials.The cement used in this study was Portland cement type II 42.5R produced by Guangda Cement Co., Ltd. . The chemical composition of the cement is listed in The crystal structure and interlayer distance of the GO were analyzed by a Brook D8 ADVANCE double-path powder X-ray diffractometer  with a 40 kV, 40 mA Cu radiation source. The molecular structure and functional groups of GO were characterized by a Nicolet Model 380 infrared spectroscopy analyzer . The surface morphology of GO was observed using a JEM-2100F field-emission transmission electron microscope (FE-TEM) manufactured by JEOL  with an acceleration voltage of 200 kV. The graphene oxide solution (5.0 mg/mL) was diluted 1000 times, sonicated for 30 min, and two or three drops were dropped onto the copper mesh.The GO-cement pastes were composed of cement, water, and GO. The water–binder ratio was 0.55 or 0.2. The 450 g of cement and 247.5 g/90 g water and GO (0.03% by weight of cement with an average size of >50 μm) were mixed using standard curing for 28 days, and the control groups were plain cement pastes. SEM observation specimens were prepared using the surface method and the fracture surface method, and SEM fracture surface specimens were prepared with different water–binder ratios. The surface morphology with sufficient hydrate growth space and an appropriate internal morphology offering a limited growth space of the GO-cement pastes were studied.The surface specimen preparation uniform stirred cement pastes being smeared onto cut 5 mm × 5 mm glass sheets with a glass rod, placed in a foam box, and covered with a moist towel to prevent water loss. The curing temperature was 20 ± 2 °C and the specimens were taken out after 3 days. The fracture surface specimen preparation involved uniform stirred cement pastes with a size of approximately 2 cm × 2 cm × 2 cm being prepared 28 days after being crushed. The specimens were kept in a standard curing room  until SEM observation was performed.A Phenom Pharos desktop scanning electron microscope, produced by Thermo Fisher Scientific , was used to analyze the microscopic morphology of the specimens. The specimens were immersed in absolute ethanol and taken out for drying, and a platinum conductive layer (about 10 nm thick) was sprayed onto the specimens before the test.In order to study the hydration reaction of cement pastes, the specimens were ground and subjected to quantitative thermogravimetric analysis (TGA). The samples were heated from 60 °C to 800 °C in an Ar atmosphere at a constant heating rate of 10 °C per minute by a synchronous thermal analyzer model STA449F1, produced by Germany NETZSCH Instrument Manufacturing Co., Ltd. . The Thermogravimetric-differential scanning calorimetry (TG-DSC) curves were plotted and the weight losses of the specimens were calculated. As different hydrates in the cement pastes corresponded to different decomposition weight losses, the degree of cement hydration could be qualitatively evaluated.The GO-cement composites consisted of cement, water, sand, and GO with a sand–binder ratio of 3. In this paper, the effects of different dosages of GO  on the mechanical properties of cement-based materials were investigated. Different water–binder ratios  were designed to study the effects of W/B on the mechanical properties of GO-cement composites. In order to decrease the effects of the addition of GO on fluidity , 1% to 2The GO dispersion solution, water, and superplasticizer required for preparing the GO-cement composites were uniformly mixed and stirred at a low speed for 30 s. Following this, the sand was added to the mixtures for 30 s, and the mortars were again stirred at a high speed for 30 s. After cessation of stirring for 90 s, the mixtures were stirred again at a high speed for 60 s to obtain GO-cement mortars. The mixed cement mortars were injected into the mortar test mold, slightly inserted, formed on the vibrating table, and smoothed. The specimens were kept in a standard curing room  until the specified testing age was reached. According to the GB/T17671-1999 standard , the mixThe test mold used to determine the tensile strength of the mortars was 78 mm in length and 22.5 × 22.2 mm in the mid-section of the mortar eight-shaped mold, according to the ASTM C307 standard , as showThe pore structures of the cement mortars were measured by mercury intrusion porosimetry (MIP), and the porosity and pore size distribution of the cement mortars were tested using an Autopore IV 9500 automatic mercury instrument produced by Micromeritics Instrument Co. .The X-ray diffraction (XRD) patterns of graphite and graphene oxide (GO) are plotted in −1, 1053 cm−1, 1617 cm−1, 1734 cm−1, and 3373 cm−1, respectively. The pattern recognized that these vibrational peaks were caused by the stretching vibration of epoxy groups (–O–), C–O, C–C/C=C, C = O, and –OH, respectively. The presence of these characteristic peaks indicated that, during preparation of GO, graphite was successfully oxidized due to the introduction of oxygen-containing groups, such as carboxyl groups, hydroxyl groups, epoxy groups and carbonyl groups; therefore, the GO nanosheets had good hydrophilicity.The Fourier-transform infrared spectroscopy (FTIR) pattern of GO is shown in The transmission electron micrograph (TEM) images of graphene oxide are shown in The influences of the water–binder ratio on the compressive and flexural strengths of the GO-cement system at 28 days are shown in The effects of different diameters of GO on the compressive and flexural strengths of the GO-cement system at 28 days are shown in With the increase in the diameter of graphene oxide, the strengths of the cement mortars increased gradually, indicating that the large-diameter graphene oxide had a significant effect on the mechanical properties of cement mortars, especially regarding the improvement of the flexural strength. This phenomenon may be due to the fact that the large-diameter graphene oxide had a more obvious effect on the bridging and blocking of microcracks , which nThe effects of different dosages of GO (>50 μm) on the tensile strength of cement mortars are shown in 2), another hydration product. The third weight loss occurred at about 700–800 °C, which was equivalent to decarbonization from the cement clinker, calcium carbonate [As can be seen from the TG-DSC curves at 28 days in arbonate . QuantitThe weight losses of the cement pastes are summarized in The effects of the GO nanosheets on the pore structure of the cement mortars were investigated, and the results are shown in According to the difference in pore sizes, the pores in the cement mortars were divided into gel pores (<10 nm), capillary pores (10–1000 nm), and macropores (>1000 nm), and the capillary pores were further divided into large pores (>100 nm) and small pores (10–100 nm) . As showSEM images of a plain cement slurry surface after curing for three days at a water–binder ratio of 0.55 are shown in In this paper, the surface morphology of cement pastes with GO was observed by SEM. Evidence that GO nanosheets regulated the morphology of CH, C-S-H, and AFt hydrates was not found, only that the growth space had an important influence on the hydrate morphology. Cement pastes are a complex heterogeneous system, and the growth of hydrates is bound to be limited by environmental space. The original fracture surface of the cement pastes more realistically reflected the growth state of the hydrates under the limited space available inside the pastes. Therefore, the SEM observation of the original fracture surface of the cement pastes was used to study the hydration mechanism of the GO-–cement pastes.Combined with the above research, this paper believes that GO had no obvious promoting effect on the cement hydration process, and it was difficult to improve the strength of cement-based materials by regulating the growth of cement hydration products. The reason why it achieved the enhanced effect was due to the other important effects of GO on cement pastes. GO, a two-dimensional nanomaterial, has a larger specific surface area than carbon nanotubes and contains a large amount of oxygen-containing functional groups with good hydrophilicity, therefore it can be better dispersed in cement pastes. Microcracks that expanded in cement-based materials were more likely to encounter GO, so the probability of preventing microcrack propagation was greater, hereafter referred to as the cracking probability. Rafiee et al.  also repAdding GO improved the compressive, flexural, and tensile strengths of cement mortars, with the increase in tensile strength being greater than that of the flexural and compressive strengths. The compressive, flexural, and tensile strengths of cement mortars incorporating 0.03% by weight of cement GO after curing for 28 days increased by 21.37%, 39.62%, and 53.77%, respectively, compared to that of mortars with GO. Comparing the effect of the different water–binder ratios and different sizes of GO on the mechanical properties of cement mortars, it was seen that the mechanical properties were more improved in the case of a low water–binder ratio or incorporation of large-diameter GO.2 content generated during cement hydration at 28 days. Cement mortars containing GO (0.03% bwoc) exhibited about a 0.78% decrease in porosity compared with that of the control cement specimens by MIP testing. It was indicated that the incorporation of GO had no significant effect on the hydration process of cement.According to the TGA results, GO has no significant effects on the Ca(OH)The surface and fracture surface morphology of the cement pastes with GO were almost the same as that of the plain cement pastes. It was easy to observe the flower-like hydrates from the surface of cement pastes with GO and plain cement pastes by SEM, and the flower-like crystals could be seen on the fracture surface of the plain cement pastes at a high water–binder ratio. GO was not found to regulate the morphology of crystals, which only indicated that the growth space had an important influence on the morphology of the hydrates.GO nanosheets have a high probability of preventing microcrack propagation; the mechanism of GO on cement-based composites to achieve this is mainly to prevent the expansion of microcracks via the shield effect to achieve strengthening and toughening. There are few studies regarding the use of GO to prepare high-performance concrete, which also calls for further research.From the results of this study, the following conclusions can be drawn:


Magnetic resonance imaging (MRI) can provide objective continuous intervertebral disc (IVD) measures in low back pain (LBP) patients. However, there are limited studies comparing quantitative IVD measures of symptomatic and asymptomatic individuals.This study aimed to investigate possible differences in IVD tissue composition in patients with chronic LBP and controls using quantitative MRI and correlate IVD measures with the phenotype High-Intensity Zone (HIZ).The lumbar spine of 25 LBP-patients  and 12 controls  was examined with T2-mapping on a 1.5T MRI scanner. The mean T2-map value and standard deviation were determined in three midsagittal IVD slices and five sub-regions dividing each IVD in the sagittal plane. The distribution of T2-map values over the IVD was also determined with histogram analysis (Δμ = distribution width).When compared to controls, patient IVDs displayed lower values for all metrics, with significant differences for the T2-map value, standard deviation (p = 0.026) and Δμ (p = 0.048). Significantly different T2-map values were found between cohorts in the region representing nucleus pulposus and the border zone between nucleus pulposus and posterior annulus fibrosus (p = 0.047–0.050). Excluding all IVDs with HIZs resulted in no significant difference between the cohorts for any of the analyzed metrics (p = 0.053–0.995). Additionally, the T2-map values were lower in patients with HIZ in comparison without HIZ.Differences in IVD characteristics, measured with quantitative MRI, between LBP patients and controls were found. The T2-differences may reflect altered IVD function associated with HIZ. Future studies are recommended to explore IVD functionality in relation to HIZ and LBP. Howevernthesis)  and thisResearch has aimed to establish the relationship between IVD degeneration and LBP through gross morphological IVD measures. Also, Modic changes  as well In the last decade, various quantitative MRI methods have been developed that provide new objective and continuous IVD measures –11. HoweThe aim of this work was to study possible differences in IVD tissue composition between patients with chronic LBP and controls using detailed T2-mapping analysis and correlate possible differences in IVD measures with the phenotype HIZ.Twenty-five LBP patients  and 12 controls  were included. All patients suffered from chronic LBP (minimum six months of continuous pain) of non-specific character, i.e. patients with apparent LBP causes, other than IVDs with herniation, bulging or degenerated IVD disease, were not included in this study. Two IVDs were excluded due to severe degeneration causing segmentation difficulties. The control cohort included in this study were originally recruited for another study that investigates possible effects of axial loading on the lumbar spine. In this study, the T2-maps from the unloaded examinations were further analyzed.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by Regional Ethics Review Board Gothenburg. Oral and written informed consent was obtained from all individual participants included in the study.in vivo on a 1.5 T MRI scanner . All subjects were examined with conventional sagittal T1-weighted (T1W) and T2-weighted (T2W) imaging (The lumbar spine (L1 to S1) of all individuals were examined  imaging . AdditioThe degeneration of each IVD was evaluated on T2W images according to the Pfirrmann scale  by a senPost-processing of the image data was performed using the MATLAB software R2016b . Using semi-automated segmentation based on a combination of a region-growing algorithm and manual adjustment, each IVD included in this study was outlined on three consecutive mid-sagittal morphological T1W-images . During To evaluate the impact of degeneration regionally on the IVD, each ROI was divided into five, in the sagittal direction, equally sized sub-regions stretching from posterior to anterior IVD . This isi.e. mean, SD and histogram distribution of the T2-map values over the segmented ROIs and sub-regions. To enable robust and consistent evaluation of histogram distribution of the T2-map values as well as reduce the risk of potential miscalculation of the IVD metrics, all T2-maps were truncated to remove bright noise before being further analyzed.Detailed analysis of the IVD-tissue was performed by calculating metrics that had the potential to characterize differences in IVD degeneration, The mean T2-map value was determined by calculating the average of all T2-map values of the voxels inside each ROI or sub-region in all three slices. The SD was determined by calculating the standard deviation of all T2-map values of the voxels inside each ROI or sub-region in all three slices. The distribution of the mean T2-map value and SD in the sub-regions was plotted to show the regional behavior in the cohorts. Moreover, the distribution of IVD T2-map values was evaluated using the histogram analysis method proposed by Waldenberg et al. . The metThe mean IVD T2-map values, SD and Δμ were plotted as a function of the Pfirrmann grade and compared between patients and controls.An additional regional analysis of the patient measurements was performed to further investigate the influence of HIZ on IVD composition and the IVD T2-map values.Mann-Whitney’s U-test was performed to test statistical significance (P<0.05) between patient and control IVDs for each Pfirrmann grade and each sub-region. Significance was not tested for Pfirrmann grade 5 due to too few IVDs with this degeneration grade.The intra- and inter-observer reliability of the Pfirrmann grading was determined with Cohen's kappa coefficient (κ). The coefficients were interpreted according to Landis and Koch . Kappa vReliability of the segmentation measurements for intra- and inter-rater agreement was performed using intraclass correlation coefficients (ICC) with 95% confidence intervals. ICC model 2 was used with single measurement to determine the absolute agreement. The coefficients were interpreted according to Cicchetti . ICC valThe analyzed IVDs displayed a normal distribution of Pfirrmann grades with the largest number of IVDs rated Pfirrmann grade 2 and lowest number rated Pfirrmann grade 5 .For the Pfirrmann grading, the intra-observer agreement was substantial (κ = 0.74) and the inter-observer agreement was moderate (κ = 0.56). For the segmentation of the IVDs, the inter- and intra-observer agreement was excellent (ICC 0.94–0.98).On a group level, patients displayed lower IVD-values for all metrics when compared to controls, with significant differences for SD (p = 0.026) and Δμ (p = 0.048), but no significant difference for the mean T2-map value (p = 0.115) . When IVFor the entire IVD, the mean T2-map value, SD and Δμ decreased with increasing degeneration in both cohorts .Analysis of each separate sub-region revealed significantly different SD p = 0.024) and near significant mean T2-map value (p = 0.050) between the two cohorts for sub-region 3  and 4 in the control cohort  . All HIZAs only four IVDs in the control group had HIZ, a comparison between patient HIZ IVDs and control HIZ IVDs could not be performed. Instead, additional analysis regarding patient IVDs with and without HIZ was performed. Since all HIZs were located within Pfirrmann grade 3–5, patient IVDs with HIZ were only compared to patient IVDs without HIZ graded Pfirrmann grade 3–5. In this additional analysis, significantly lower mean T2-map values were found in four sub-regions of IVDs with HIZ when compared to IVDs with no HIZ  .This MRI study, comparing detailed IVD characteristics between patients and controls, present small but relevant quantitative differences. When analyzing the entire IVD on a group level, significantly lower quantitative values (mean SD and Δμ) were found in the patient cohort in comparison to the control cohort, reflecting increased tissue homogeneity (SD) and reduced tissue distinction (Δμ). The presence of HIZ was associated with altered IVD characteristics and matrix composition, foremost in the NP region. When all HIZ IVDs were excluded from the analysis, no significant differences between the cohorts were found. Also, the sub-analysis of patient IVDs suggest that HIZ IVDs are different in their matrix composition, foremost regarding NP region, compared to IVDs without HIZ.Several studies promote HIZ as a promising marker for discogenic pain , 20 as HIn this study, the presence of HIZ was associated with altered IVD characteristics, mainly in the NP region. The observed T2-decrease in regions occupied by NP, probably reflecting reduced hydration in IVDs with HIZ, is in concordance with earlier studies , 26. In All analyzed metrics correlated well with IVD degeneration, measured in terms of Pfirrmann grade, and followed the same trend. That is, they decreased with increased degeneration, suggesting that all present metrics can be used to study IVD matrix development in a detailed, objective and continuous way, providing more information regarding matrix structure and heterogeneity compared to traditional metrics. Especially the heterogeneity measures SD and Δµ, which revealed differences between cohorts even when the mean T2-map value did not, seemed to be sensitive metrics for longitudinal studies of the IVD.The deviant metric values in the central IVD parts, shown in the current study, could reflect impaired microstructure of the IVD associated with HIZ. In order to evaluate the findings of this feasibility study and the metrics potential clinical value as pain markers, a large cohort-study with equal distributions of HIZ in matched groups of asymptomatic and symptomatic individuals is encouraged.Reliable quantitative T2-mapping has been a long-standing challenge as the measurements can be influenced by several factors, including relaxation effects during excitation –31, radiThe study included a smaller control cohort when compared to the patient cohort (12 controls versus 25 patients). This is due to the fact that the control cohort was originally recruited to a different study. However, the smaller control cohort size was accounted for during the statistical analysis. The control cohort was slightly younger (median age 31 years versus 36 years) which might partly explain the differences between the groups. However, the cohort mean age was matched and it is not likely that the clear differences in the analyzed metrics can be fully explained by the small difference in median age or other factors such as sex or BMI. It is possible that delineation of the ROI boundaries in the posterior regions of the IVDs was influenced by the detection of a HIZ. Especially the presence of vertical annular tears may aid in identifying the true edge of the posterior IVD. However, vertical tears were uncommon among the recruited individuals and in case of doubt, the contour was contracted to minimize the risk of including foreign tissue inside the ROI.We found differences in IVD characteristics, measured with detailed T2-mapping, between LBP patients and controls. The differences found between the cohorts may reflect an altered function of the IVD associated with HIZ. Future studies are recommended to further explore the IVD functionality in relation to HIZ and LBP.S1 Dataset(MAT)Click here for additional data file.


It is postulated that ILD causes PA dilatation independent of the presence of pulmonary hypertension (PH), so the use of PA size to screen for PH is not recommended. The aims of this study were to investigate the association of PA size with the presence and severity of ILD and to assess the diagnostic accuracy of PA size for detecting PH.Incident patients referred to a tertiary PH centre underwent baseline thoracic CT, MRI and right heart catheterisation (RHC). Pulmonary artery diameter was measured on CT pulmonary angiography and pulmonary arterial areas on MRI. A thoracic radiologist scored the severity of ILD on CT from 0 to 4, 0 = absent, 1 = 1–25%, 2 = 26–50%, 3 = 51–75%, and 4 = 76–100% extent of involvement. Receiver operating characteristic analysis and linear regression were employed to assess diagnostic accuracy and independent associations of PA size.p =< 0.001, and AUC 0.835, p =< 0.001, respectively, as was MRI diastolic PA area, AUC 0.897, p =< 0.001, and AUC 0.857, p =< 0.001, respectively Significant correlations were identified between mean pulmonary arterial pressure (mPAP) and PA diameter in ILD , and non-ILD cohort . PA size was independently associated with mPAP (p < 0.001) and BSA (p = 0.001), but not with forced vital capacity % predicted (p = 0.597), Transfer factor of the lungs for carbon monoxide (TLCO) % predicted (p = 0.321) or the presence of ILD on CT (p = 0.905). The severity of ILD was not associated with pulmonary artery dilatation .110 had suspected PH due to ILD (age 65 years (SD 13), M:F 37:73) and 379 had suspected PH without ILD (age 64 years (SD 13), M:F 161:218). CT derived main PA diameter was accurate for detection of PH in patients both with and without ILD - AUC 0.873, LCO, or disease severity on CT. Pulmonary arterial diameter has diagnostic value in patients with or without ILD and suspected PH.Pulmonary arterial pressure elevation leads to pulmonary arterial dilation, which is not independently influenced by the presence or severity of ILD measured by FVC, T Pulmonary hypertension (PH) is defined on right heart catheterisation (RHC), as a resting mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg . PH commCT is used to diagnose and phenotype suspected ILD, and is often part of the workup of patients with unexplained breathlessness and suspected PH . DilatatThe aim of this study was to investigate the role of main pulmonary arterial size in patients with ILD and suspected pulmonary hypertension. Firstly, by investigating the factors associated with main pulmonary arterial dilatation, including markers of disease severity in interstitial lung disease. Secondly, to compare the diagnostic accuracy of PA size in patients with suspected pulmonary hypertension with and without ILD.Consecutive patients who were referred to a pulmonary hypertension centre from 24 April 2012 to 30 March 2016 were identified from the ASPIRE registry  and non-specific interstitial pneumonia (NSIP). These groups were prospectively separated to examine for differences between these groups.The majority of CTPA scans (76.8%) were conducted at Sheffield’s Pulmonary Vascular Disease Unit with a further 114 cases performed at the referring hospitals in Wales or the North of England. All Sheffield CTPA cases were performed on a 64-slice MDCT scanner , with standard acquisition parameters: 100 mA with automated dose reduction, 120 kV, pitch 1, rotation time 0.5 s and 0.625 mm slice thickness. A 400 × 400 mm field of view was used with an acquisition matrix of 512 × 512. 100 ml of intravenous contrast agent  was administered at a rate of 5 ml/sec through a wide bore cannula, into a large central vein, typically in the ante-cubital fossa. The scan was then timed using a bolus tracking technique. HRCT was reconstructed using the contrast-enhanced acquisitions with 1.25 mm collimation from the apex of the lung to the diaphragm. In order to be included, any CTPA from an outside Trust had to be of diagnostic quality, as decided by a radiologist and slice thickness ≤5 mm. In the 23.2% (114) CTPAs performed outside of Sheffield, CT scanner and detailed acquisition parameters were not available for reporting.Cardiac magnetic resonance (CMR) imaging was performed on a 1.5T whole body scanner GE HDx , using an 8-channel cardiac coil. Patients were in the supine position with a surface coil and with retrospective ECG gating. A retrospective cardiac gated multi-slice balanced steady state free precession (bSSFP) sequence was performed orthogonal to the main pulmonary artery. The bSSFP sequence parameters were: TR 2.8 ms, TE 1.0 ms, Flip angle of 50°, FOV = 48 × 43.2, 256 × 256 matrix, 125 kHz bandwidth and slice thickness of 10 mm .LCO) were calculated. The gender, age and physiology (GAP) score is a simple tool for estimating mortality in ILD from demographic and pulmonary function metrics and was calculated as previously described , and transfer factor of the lungs for carbon monoxide  imaging on CE stamped Barco diagnostic monitors. The observer was blinded to the all other clinical and imaging data.The main pulmonary artery was measured proximal to bifurcation, perpendicular to the direction of the vessel at the point where largest diameter is most consistent. The ascending aorta diameter was also measured on the same CT slice, see Image analysis was performed on a GE Advantage Workstation 4.4 and GE Advantage Workstation Report Card. Scans were defined as non-diagnostic when image quality significantly affected cardiac measurements or volumetric analysis could not be accurately performed. From the magnitude phase imaging images, the maximal (systolic) and minimal (diastolic) PA areas were measured, and relative area change (RAC) was defined by the following equation: RAC = (maximum area-minimum area)/minimum area .t-test for continuous data and the chi-square for categorical data. ANOVA with Bonferroni correction was used for multiple group comparison. Pearson’s correlation coefficient was used to assess the correlation between CT and MRI pulmonary arterial measurements and mPAP. Pearson correlations were conducted for cohorts of ILD, non-ILD and radiological subtypes against CT and MRI derived metric variables. Receiver operating characteristic (ROC) analysis was performed to determine diagnostic accuracy of CT and MRI pulmonary arterial size measurements with area under the ROC curve (AUC) results presented. Multiple t-tests were used to assess intergroup variance of PA diameter, PA to Aorta (PA:AA) ratio and PA relative to body mass index (PA index). The relationship between PA diameter with candidate predictors mPAP, ILD severity of CT, FVC TLCO, and age, sex and body surface area (BSA) was assessed using multivariate linear regression analysis.The differences in CT and MRI pulmonary arterial size between the patients with and without ILD were analysed using an independent p-value of <0.05 was considered statically significant.Statistical analysis was performed in IBM SPSS Statistics 22  and graphed in GraphPad Prism . A two-tailed n = 1), asbestosis (n = 1), desquamative interstitial pneumonia (n = 1), chronic extrinsic allergic, alveolitis (n = 1), silicosis (n = 1), Langerhans cell histiocytosis (n = 1), radiotherapy (n = 1) and post infective interstitial disease and scarring (n = 4). 379 patients with suspected PH had no CT evidence of ILD (319 patients with pulmonary hypertension and 60 patients without) as shown in Figure 2. From the ASPIRE database 489 patients with suspected PH were identified, including 198 males and 291 females. 420 patients had pulmonary hypertension. The mean age for the whole cohort was 65 (SD - SD 13). One hundred and ten patients had CT features of ILD (101 patients with pulmonary hypertension and 9 patents without), of which 46 patients had UIP and 43 had NSIP radiological subtypes. Chronic EAA (p < 0.001) In the ILD cohort, there was no significance between PA size diameters in different semi-quantitative radiological severity scores of ILD, see (p = 0.630 and NSIP p = 1.000.Patients with PH had larger pulmonary arteries (33 mm) than patients without PH (27 mm) (p < 0.001), which improved when the pulmonary artery diameter was indexed to body surface area . MRI derived systolic and diastolic pulmonary artery area also correlated significantly with mPAP in the ILD cohort, . In the pathological subtypes, PA diameter correlated with mPAP for both UIP  and NSIP . Each are shown in Figure 4. In the non-ILD cohort, the correlation between mPAP and PA diameter was weaker but still significant, r = 0.426 (p < 0.001). p = 0.301) or TLCO  respectively, as shown in p < 0.001), non-ILD , UIP , NSIP .CT derived main PA diameter correlated positively with mPAP in the ILD cohort . The optimal threshold identified was 30mm, providing 76.3% sensitivity and 73.3% specificity. A previous threshold of 29mm tested in the ILD cohort resulted in 75.2% sensitivity, 88.9% specificity, 98.7% positive predictive values and 24.0% negative predictive value. In the non-ILD cohort, pulmonary arterial diameter was also accurate for the diagnosis of PH, with AUC=0.835  and BSA of 0.249 (p = 0.001).At multivariate linear regression analysis, mPAP and body surface area were independent predictors of pulmonary arterial size, [11.1 +  + (6.7 × BSA)]. Age, sex, GAP score, ILD severity on CT, FVC %predicted and Tdiameter . Table 4LCO, or GAP score.In this retrospective study of 491 patients with suspected pulmonary hypertension referred to a tertiary referral centre, we show that main pulmonary arterial diameter has similar diagnostic utility in patients with and without ILD. In our cohort, pulmonary arterial diameter is independently associated with mean pulmonary arterial pressure and body size. The size of the pulmonary artery was not independently influenced by semi-quantitative radiological severity score of ILD, FVC, TIt has been postulated that in patients with pulmonary fibrosis the pulmonary artery dilates in the absence of elevated pulmonary arterial pressure, as consequence of architectural distortion of the lung parenchyma. In contrast, in this cohort of patients, we have found that pulmonary arterial diameter is diagnostic of pulmonary hypertension in ILD, to a similar accuracy as seen in patients with pulmonary hypertension who do not have ILD (AUC 0.874 for ILD cohort and AUC 0.835 for non-ILD cohort), irrespective of the underlying radiological ILD pattern. UIP is typified by significant parenchymal distortion, including honeycombing, traction bronchiectasis and volume loss , therefoLCO and FVC were lower in the patients with ILD than those without. However, the ILD and non-ILD cohorts were well-matched in terms of PH severity, as defined by their RHC metrics. The clinical and radiological markers of ILD severity  had weak correlations with pulmonary arterial diameter . Furthermore, there is a strong correlation between PA diameter and mean PA pressure within the ILD cohort (r = 0.608). On multivariate linear regression, the clinical and radiological markers of disease severity were not independent predictors of pulmonary arterial size. In fact, the independent predictors were body surface area and pulmonary arterial pressure.As expected, TBoth CT and MRI derived pulmonary arterial size metrics were assessed. MRI variables showed high diagnostic accuracy with both systolic and diastolic pulmonary arterial area having diagnostic utility in both ILD and non-ILD cohorts. MRI derived diastolic pulmonary arterial area, was the most accurate diagnostic variable across the whole study cohort, regardless of the presence of ILD. Diastolic pulmonary arterial size was of systematically marginally higher diagnostic accuracy than systolic. We postulate that this is because of greater pulsatility of the pulmonary artery of a patient without pulmonary hypertension, allowing the pulmonary artery to reduce in size in diastole to a greater extent relative to a patient with pulmonary hypertension.PA size measured on MRI also correlated well with RHC derived mean pulmonary arterial pressure and showed similar diagnostic accuracy to CT derived PA diameter. This trend was similar in both patients with and without interstitial lung disease. A limitation of routine CT pulmonary angiography is lack of cardiac gating; MRI with cardiac gating has provided additional proof of the equivalent utility of PA diameter in interstitial lung disease and non- interstitial lung diseaseThe pulmonary artery can dilate over time in a patient with elevated pulmonary arterial pressure . Hence tThis study is limited by its retrospective design at a single tertiary referral centre, although in order to reduce bias from the retrospective analysis, the cohort is made up of consecutive patients. As this was performed in a pulmonary hypertension referral centre, there is a bias towards the presence of PH and as such there are only a few patients with no PH, so these results are only valid in the setting of a PH referral centre. It is expected, however that the strong correlation between mPAP and PA size in this cohort of patients would be similar in a non-selected patient cohort. A study in a non-PH centre, in a cohort with more even distribution of patients with and without pulmonary hypertension would be of benefit.Interstitial lung diseases are a heterogeneous group of diseases with idiopathic and known-cause aetiologies. We have grouped the largest cohorts of fibrotic ILDs here to explore if the architectural destruction of UIP had a greater influence on PA dilatation than NSIP, but in practice these are not clinical diagnoses. However, in practice these are the patterns most likely to lead to fibrotic-driven architectural distortion and so we have taken a pragmatic approach in separating these. Further work evaluating the impact of varying forms of ILD, such as scleroderma related and drug induced ILD on the pulmonary vasculature, in terms of PA size and haemodynamic changes would be of value.LCO, or disease severity on CT. Pulmonary arterial diameter has diagnostic value in patients with or without ILD, key for the screening of suspected PH.Pulmonary arterial pressure elevation leads to pulmonary arterial dilation, which is not independently influenced by the presence or severity of ILD measured by FVC, TThis study was carried out in accordance with the recommendations of “North Sheffield Ethics Committee”. The protocol was approved by the “Sheffield Hospitals institutional review board”.AS and DK conceived the idea for the study. AS, MC, NW, SB, BC and CJ participated in the study design. AS, DC acquired the MRI data. Image analysis was performed by AS, MC, BC, CJ. AS, MC, SR, CE, CJ, RC, DK, NW, JMW analysed and interpreted the MR data. AS, MC, SR, CE, CJ, NW, RC, DK, JMW, SB drafted the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Adaptive servo-ventilation (ASV), a novel respiratory support therapy for sleep disorders, may improve cardiac function in heart failure (HF). However, the reasons that ASV improves cardiac function have not been fully studied especially in sympathetic nervous function (SNF). The purpose of the present study was to investigate the effects of ASV therapy on cardiac SNF in patients with HF.11C-hydroxyephedrine (HED) PET as a presynaptic function marker and planar 123I-metaiodobenzylguanidine (MIBG) to evaluate washout rate.We evaluated ASV therapeutic effects before and 6 months after ASV therapy in 9 HF patients . We performed echocardiography, polysomnography, biomarkers, 123I-MIBG imaging, the early heart/mediastinum (H/M) ratio increased after ASV therapy . Washout rate did not change . Global 11C-HED retention index (RI) improved from 0.068 ± 0.033/s to 0.075 ± 0.034/s (P = 0.029).ASV therapy reduced apnea-hypopnea index (AHI) and improved plasma brain natriuretic peptide (BNP) concentration. In ASV reduced AHI and improved BNP. ASV might initially improve presynaptic cardiac sympathetic nervous function in HF patients after 6 months of treatment.The online version of this article (10.1007/s12350-017-1132-4) contains supplementary material, which is available to authorized users. Sympathetic nervous function (SNF) is an important compensatory mechanism to maintain cardiovascular homeostasis in chronic heart failure (HF).Sleep-related breathing disorders are one of the comorbidities that worsen HF via inducing alterations in loading conditions, hypoxia, and SNF activation.123I-metaiodobenzylguanidine (123I-MIBG) single-photon and 11C-hydroxyephedrine positron emission tomography (11C-HED PET) have enabled the assessment of cardiac sympathetic nerve function (SNF).17123I-MIBG planar imaging is considered a standard approach to evaluating cardiac SNF and predicting prognosis in HF patients.18–123I-MIBG imaging. It is well known that 123I-MIBG imaging has insufficient image quality and the accuracy of semi-quantitative parameters is suboptimal. In contrast, 11C-HED PET has emerged as a novel modality providing a high-quality image and it can be used to accurately quantitatively evaluate cardiac SNF including the retention index (RI).11C-HED PET cannot be used to assess the washout rate because of its short physical half-life.11C-HED PET and 123I-MIBG imaging, it should be possible to measure precise presynaptic cardiac sympathetic nervous function and sympathetic turnover. Accordingly, we examined the effects of ASV therapy on cardiac SNF using 11C-HED PET as a quantitative presynaptic function parameter and 123I-MIBG imaging as a partial reflection of NF turnover parameter in patients with HF.Eleven consecutive patients with chronic HF were prospectively enrolled in the current study at Hokkaido University Hospital between August 2010 and August 2013. HF was defined as New York Heart Association function (NYHA) class II or III, left ventricular ejection fraction (LVEF) < 50%, and plasma brain-type natriuretic peptide (BNP) concentration > 100 pg/mL. Major exclusion criteria included uncontrolled decompensated HF, active ischemic heart disease with exertion chest pain and requiring coronary revascularization, severe pulmonary disease, neurological or musculoskeletal disease, severe valvular regurgitation, stroke, respiratory failure, end-stage renal disease treated by hemodialysis, and inability to tolerate ASV. All patients had received optimal medical therapy to stabilize their symptoms and signs of HF before participating in the study.The study was approved by the Ethics Committee of Hokkaido University Hospital. All participants provided written informed consent.2O and inspiratory positive airway pressure of 3–10 cmH2O. We instructed the patients to use ASV > 4 h per night during the study period. Data regarding compliance of ASV and effectiveness were stored in the device, downloaded and analyzed. Adequate adherence to ASV was defined as > 4 hours per night.11C-HED PET/computed tomography (CT), 123I-MIBG imaging, laboratory tests, polysomnography, and echocardiography in all patients before and after 6 months of ASV treatment. All the imaging data obtained before and after ASV therapy were blindly analyzed in order to avoid interpreter bias.Patients received nocturnal ASV treatment for 6 months. Pharmacological therapy was not changed during the study period. ASV  was used without oxygenation and administered via a fitted nasal mask (Teijin Pharma) in the default mode, with expiratory positive airway pressure of 5 cmHPlasma concentrations of BNP and norepinephrine and the urinary concentration of norepinephrine were measured at baseline and after 6 months of ASV treatment.Patients underwent overnight polysomnography using a cardiopulmonary monitoring device  comprising a pressure sensor for nasal flow, two stress-sensitive belts for the ribcage and abdomen, and a continuous pulse oximeter.27We measured left ventricle (LV) end-diastolic dimension, LV end-systolic dimension, LVEF, interventricular septal thickness, LV posterior wall thickness, and the ratio between early and late diastolic transmitral flow velocity using echocardiography . We also measured the ratio of maximal early diastolic filling wave velocity to maximal early diastolic myocardial velocity, and deceleration time. LVEF was measured from apical four- and two-chamber images using the biplane method of disks.123MIBG  at rest under fasting conditions.123MIBG injection, planar images and SPECT data acquisitions were performed using a dual-head scanner . Whole cardiac 123I-MIBG uptake was measured as the H/M ratio using a planar image. The region of interest (ROI) was manually traced for the whole LV and a rectangular ROI was placed in the upper mediastinum in the early image.123I-MIBG planar image. The H/M ratio was calculated by dividing the count density of the whole heart by that of the mediastinum, and standardized using the calibration phantom method.Patients received 111 MBq of washout rate = ([H-M] at 15 min − [H-M] at 4 h/(H-M) at 15 min × 100,where H = mean counts per pixel in the left ventricle and M = mean counts per pixel in the upper mediastinum.29123MIBG imaging data with planar and SPECT, we did not use SPECT data for evaluation. We did not apply a physical decay correction for the H/M calculation and the method of washout rate.Although we obtained 11C-HED was produced from [11C] methyl iodide and metaraminol (free base) using standard methods with high purity and high specific activity. Patients were instructed to fast overnight. 11C-HED PET/CT imaging was performed with a 64-slice PET/CT scanner . Low-dose CT was also performed for attenuation correction. CT co-registered standard orthogonal PET images were re-sliced into series of short-axis, horizontal long-axis, and vertical long-axis images.11C-HED, 40-min three-dimensional list-mode PET acquisition was performed.11C-HED PET/CT uptake was assessed using the 17-segment model recommended by the American Society of Nuclear Cardiology. Then, the LV wall was subdivided into four segments: anterior, septum, inferior, and lateral wall. The 11C-HED RI was calculated asImmediately after intravenous administration of 5 mCi (185 MBq) 11C-HED retention. The LV wall was divided into 17 segments based on ASNC guidelines using in-house software23This equation yields a value for the RI based on mean tracer counts within the myocardial ROI between 30 and 40 min divided by the integrated metabolite-corrected time-plasma radioactivity curve from 0 to 40 min after injection.P value < 0.05 was considered statistically significant. All analyses were performed using JMP 11.0 .Values are mean ± standard deviation. Categorical variables are presented as frequencies with percentages. Since BNP levels showed non-linearity, plasma BNP levels were calculated using log-transformation.We enrolled total 11 HF patients who met the inclusion criteria. Among 11 patients, 2 patients did not use ASV > 4 hours per night. Therefore, 9 patients completed the study protocol, and we analyzed these 9 patients in the current study.The underlying causes of HF were dilated cardiomyopathy in five patients (55.6%), dilated hypertrophic cardiomyopathy in one patient 11.1%), ischemic cardiomyopathy in one patient (11.1%), and others in two patients (22.2%). NYHA functional class was II in six patients (66.7%) and III in three patients 33.3%). Mean LVEF was 36.1 ± 5.3% ranging from 22% to 48%. Medical treatment included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in nine patients (100%), beta blockers in nine patients (100%), and diuretics in six patients (66.7%)  and minimum peripheral oxygen saturation increased .Clinical characteristics at baseline and after 6 months of ASV treatment are shown in Table P = 0.096). LV end-diastolic volume  and LV end-systolic volume  tended to decrease after the ASV therapy. In addition, plasma and urinary norepinephrine concentrations did not change before and after ASV treatment (Table P = 0.048) after ASV treatment.There were no significant changes in heart rate and systolic or diastolic blood pressure Table . LVEF te123I-MIBG scintigraphy, the early H/M ratio significantly increased  . The whole LV 11C-HED RI significantly increased  after ASV treatment. In addition, the RI significantly increased in the anterior region , and decreased in the septal region   means numbers of apnea and hypopnea per hour. AHI reflects the severity of sleep apnea disorders and AHI > 15 is defined as sleep apnea.36123I-MIBG imaging and 11C-HED PET are useful modalities for non-invasive evaluation for cardiac SNF.123I-MIBG imaging can be used to stratify risk in patients with HF. The low H/M ratio as determined through 123I-MIBG planar images can predict sudden cardiac death in HF regardless of LVEF.123I-MIBG imaging, and to reduce mortality in HF patients.123I-MIBG imaging study, Koyama et al reported that ASV therapy ameliorated SNF in HF patients.123I-MIBG imaging is a reliable diagnostic tool for evaluating cardiac SNF and prognosis in HF. In those studies, most investigators have used planar cardiac images and made semi-quantitative assessment of global LV sympathetic nervous function such as the H/M ratio and washout rate.39–41Among recent applications of diagnostic, imaging is the non-invasive evaluation of cardiac SNF in HF patients. In particular, both 11C-HED PET/CT has emerged as a new modality to evaluate cardiac SNF. It has a high spatial resolution and can also be used to accurately quantify cardiac SNF at both the LV global and regional levels. In particular, the RI in 11C-HED PET has been closely correlated with cardiovascular events in HF.11C-HED PET/CT11C-HED is 20 min, 11C-HED cannot provide washout parameters as 123I-MIBG imaging can.11C-HED PET as a quantitative marker of presynaptic function, and 123I-MIBG imaging as a washout parameter in the current study regarding to previous studies.42–As the physical short half-life of 11C-HED PET/CT RI improved after 6 months of ASV therapy. The early H/M ratio also significantly increased, a finding that aligns with those of a previous study.123I-MIBG imaging, we confirmed previous reports using precise quantitative assessment using 11C-HED PET/CT. Reduced AHI from using ASV may have contributed to improving presynaptic sympathetic nervous function. In contrast, the delayed H/M ratio and washout rate did not change in 123I-MIBG imaging. The reasons for this finding are unclear. It is possible that improvements in 123I-MIBG washout appear later than do improvements in presynaptic function via uptake-1. This means that both global 11C-HED PET RI and the early H/M ratio determined by 123I-MIBG may indicate improvements of presynaptic cardiac SNF during the early phase of ASV therapy in HF patients. Long-term observational studies are required to confirm this hypothesis. The early H/M did not reach statistically significant improvement but the mean value was improved after the ASV therapy in the current study. Thus, another possible explanation for this discrepancy could be the small sample size of the current studyWe found that the global 11C-HED PET/CT data. This finding provides additional insights beyond those of the previous study by Koyama et al.11C-HED PET, with the lowest RI reported in the inferoapical region.11C-HED PET/CT. In contrast, among 9 cases, 4 cases actually reduced HED RI in septum. In HF patients, increased LV end-diastolic pressure and associated pulmonary edema will cause pulmonary hypertension, and the septum is stretched to become dysfunctional by making the helix fibers more transverse. Furthermore, as the left ventricle becomes dilate, the septum will encroach on the RV cavity in the chronic period. Therefore, the left ventricular septum could be more susceptible to damage than other left ventricular wall due to the left ventricular pressure and volume loading.In the current study, ASV therapy improved cardiac sympathetic function in the anterior LV region as well as global LV SNF based on 11C HED PET.11C HED PET and 123I MIBG scintigraphy was demonstrated. However, the small sample size may have had impacts on the data with early H/M and washout rate. In this regard, a larger population is required to confirm the results. The extent to which improvements in cardiac SNF influence prognosis in patients with HF treated with ASV is not known. Cowie et al. reported that ASV therapy did not influence mortality in patients with chronic HF and central sleep apnea.This study was a single-center study with a small sample size. While the number of patients was small, PET measurements can provide segment-by-segment assessment of absolute RI. When combined with a repeated measures analysis, in which each myocardial segment within each patient can serve as its own control, the study design may provide a valid assessment of the effects of ASV therapy despite the limited sample size. A similar sample size was used in previous studies evaluating sympathetic nervous function changes after therapeutic interventions using 123I-MIBG H/M ratio and 11C-HED RI significantly improved, whereas 123I-MIBG washout ratio did not change with ASV. A comprehensive approach using a combination of 11C-HED PET and 123I-MIBG imaging could be used to evaluate cardiac SNF and provide regional and global SNF uptake parameters and global washout parameters in HF patients. ASV therapy may mediate its beneficial effects in HF by initially improving presynaptic SNF.ASV reduced AHI in HF patients. Early 11C-HED PET and 123I-MIBG imaging may play a role in the detection of presynaptic cardiac sympathetic nervous function for the evaluation of new heart failure therapy.The combined use of Supplementary material 1 (PPTX 2292 kb)Below is the link to the electronic supplementary material.