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Heart mass can be predicted from heart volume as measured from post-mortem computed tomography (PMCT), but with limited accuracy. Although related to heart mass, age, sex, and body dimensions have not been included in previous studies using heart volume to estimate heart mass. This study aimed to determine whether heart mass estimation can be improved when age, sex, and body dimensions are used as well as heart volume. Eighty-seven (24 female) adult post-mortem cases were investigated. Univariable predictors of heart mass were determined by Spearman correlation and simple linear regression. Stepwise linear regression was used to generate heart mass prediction equations. Heart mass estimate performance was tested using median mass comparison, linear regression, and Bland–Altman plots. Median heart mass (P = 0.0008) and heart volume (P = 0.008) were significantly greater in male relative to female cases. Alongside female sex and body surface area (BSA), heart mass was univariably associated with heart volume in all cases (R2 = 0.72) and in male (R2 = 0.70) and female cases (R2 = 0.64) when segregated. In multivariable regression, heart mass was independently associated with age and BSA (R2 adjusted = 0.46–0.54). Addition of heart volume improved multivariable heart mass prediction in the total cohort (R2 adjusted = 0.78), and in male (R2 adjusted = 0.74) and female (R2 adjusted = 0.74) cases. Heart mass estimated from multivariable models incorporating heart volume, age, sex, and BSA was more predictive of actual heart mass (R2 = 0.75–0.79) than models incorporating either age, sex, and BSA only (R2 = 0.48–0.57) or heart volume only (R2 = 0.64–0.73). Heart mass can be more accurately predicted from heart volume measured from PMCT when combined with the classical predictors, age, sex, and BSA.

Background The heart has an intrinsic ability to regenerate, orchestrated by progenitor or stem cells. However, the relative complexity of non-resident cardiac progenitor cell (CPC) therapy makes modulation of resident CPCs a more attractive treatment target. Thiamine analogues improve resident CPC function in pre-clinical models. In this double blinded randomised controlled trial (identifier: ACTRN12614000755639), we examined whether thiamine would improve CPC function in humans. Methods and results High dose oral thiamine (one gram twice daily) or matching placebo was administered 3–5 days prior to coronary artery bypass surgery (CABG). Right atrial appendages were collected at the time of CABG, and CPCs isolated. There was no difference in the primary outcome (proliferation ability of CPCs) between treatment groups. Older age was not associated with decreased proliferation ability. In exploratory analyses, isolated CPCs in the thiamine group showed an increase in the proportion of CD34−/CD105+ (endoglin) cells, but no difference in CD34−/CD90+ or CD34+ cells. Thiamine increased maximum force developed by isolated trabeculae, with no difference in relaxation time or beta-adrenergic responsiveness. Conclusion Thiamine does not improve proliferation ability of CPC in patients undergoing CABG, but increases the proportion of CD34−/CD105+ cells. Having not met its primary endpoint, this study provides the impetus to re-examine CPC biology prior to any clinical outcome-based trial examining potential beneficial cardiovascular effects of thiamine.

NEW FINDINGS What is the central question of this study? Are there specific contributions of β1 - and β2 -adrenoceptor subtypes to the impaired β-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the β1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the β2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. ABSTRACT Impaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β1 - and β2 -AR subtypes to β-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific β1 - and β2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the β-AR agonist isoprenaline (1 × 10-11 to 3 × 10-8 mol l-1 ) with or without the selective β1 -AR antagonist CGP20712A (3 × 10-8 mol l-1 ) or the β2 -AR antagonist ICI-118,551 (5 × 10-8 mol l-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216 ± 17 beats min-1 versus diabetic 151 ± 23 beats min-1 , P

Increased cardiac sympathetic nerve activity in type 2 diabetes mellitus (DM) suggests impaired autonomic control of the heart. However, the central regions that contribute to the autonomic cardiac pathologies in type 2 DM are unknown. Therefore, we tested the hypothesis that neuronal activation would be increased in central sympathoregulatory areas in a pre-clinical type 2 DM animal model. Immunohistochemistry in 20-week-old male Zucker diabetic fatty (ZDF) rats revealed an increased number of neurones expressing ΔFosB (a marker of chronic neuronal activation) in the intermediolateral column (IML) of the spinal cord in DM compared to non-diabetic (non-DM) rats (P < 0.05). Rostral ventrolateral medulla (RVLM) neurones activate IML neurones and receive inputs from the hypothalamic paraventricular nucleus (PVN), as well as the nucleus tractus solitarius (NTS) and area postrema (AP), in the brainstem. We observed more ΔFosB-positive noradrenergic RVLM neurones (P < 0.001) and corticotrophin-releasing hormone PVN neurones (P < 0.05) in DM compared to non-DM rats. More ΔFosB-positive neurones were also observed in the NTS (P < 0.05) and AP (P < 0.01) of DM rats compared to non-DM rats. Finally, because DM ZDF rats are obese, we also expected increased activation of pro-opiomelanocortin (POMC) arcuate nucleus (ARC) neurones in DM rats; however, fewer ΔFosB-positive POMC ARC neurones were observed in DM compared to non-DM rats (P < 0.01). In conclusion, increased neuronal activation in the IML of type 2 DM ZDF rats might be driven by RVLM neurones that are possibly activated by PVN, NTS and AP inputs. Elucidating the contribution of central sympathoexcitatory drive in type 2 DM might improve the effectiveness of pharmacotherapies for diabetic heart disease.

SummaryDiabetic heart disease is highly prevalent and characterized by diastolic dysfunction. The mechanisms of diabetic heart disease are poorly understood and no targeted therapies are available. Here we show that the diabetic myocardium (type 1 and type 2) is characterized by marked glycogen elevation and ectopic cellular localization - a paradoxical metabolic pathology given suppressed cardiomyocyte glucose uptake in diabetes. We demonstrate involvement of a glycogen-selective autophagy pathway (‘glycophagy’) defect in mediating this pathology. Genetically manipulated deficiency of Gabarapl1, an Atg8 autophagy homologue, induces cardiac glycogen accumulation and diastolic dysfunction. Stbd1, the Gabarapl1 cognate autophagosome partner is identified as a unique component of the early glycoproteome response to hyperglycemia in cardiac, but not skeletal muscle. Cardiac-targeted in vivo Gabarapl1 gene delivery normalizes glycogen levels, diastolic function and cardiomyocyte mechanics. These findings reveal that cardiac glycophagy is a key metabolic homeostatic process perturbed in diabetes that can be remediated by Gabarapl1 intervention.

Long-chain acylcarnitines (LCACs) are known to directly alter cardiac contractility and electrophysiology. However, the acute effect of LCACs on human cardiac function is unknown. We aimed to determine the effect of LCAC 18:1, which has been associated with cardiovascular disease, on the contractility and arrhythmia susceptibility of human atrial myocardium. Additionally, we aimed to assess how LCAC 18:1 alters Ca2+ influx and spontaneous Ca2+ release in vitro. Human right atrial trabeculae (n = 32) stimulated at 1 Hz were treated with LCAC 18:1 at a range of concentrations (1-25 µM) for a 45-min period. Exposure to the LCAC induced a dose-dependent positive inotropic effect on myocardial contractility (maximal 1.5-fold increase vs. control). At the 25 µM dose (n = 8), this was paralleled by an enhanced propensity for spontaneous contractions (50% increase). Furthermore, all LCAC 18:1 effects on myocardial function were reversed following LCAC 18:1 washout. In fluo-4-AM-loaded HEK293 cells, LCAC 18:1 dose dependently increased cytosolic Ca2+ influx relative to vehicle controls and the short-chain acylcarnitine C3. In HEK293 cells expressing ryanodine receptor (RyR2), this increased Ca2+ influx was linked to an increased propensity for RyR2-mediated spontaneous Ca2+ release events. Our study is the first to show that LCAC 18:1 directly and acutely alters human myocardial function and in vitro Ca2+ handling. The metabolite promotes proarrhythmic muscle contractions and increases contractility. The exploratory findings in vitro suggest that LCAC 18:1 increases proarrhythmic RyR2-mediated spontaneous Ca2+ release propensity. The direct effects of metabolites on human myocardial function are essential to understand cardiometabolic dysfunction.NEW & NOTEWORTHY For the first time, the fatty acid metabolite, long-chain acylcarnitine 18:1, is shown to acutely increase the arrhythmia susceptibility and contractility of human atrial myocardium. In vitro, this was linked to an influx of Ca2+ and an enhanced propensity for spontaneous RyR2-mediated Ca2+ release.

The adipocytokine resistin is released from epicardial adipose tissue (EAT). Plasma resistin and EAT deposition are independently associated with atrial fibrillation. The EAT secretome enhances arrhythmia susceptibility and inotropy of human myocardium. Therefore, we aimed to determine the effect of resistin on the function of human myocardium and how resistin contributes to the proarrhythmic effect of EAT. EAT biopsies were obtained from 25 cardiac surgery patients. Resistin levels were measured by ELISA in 24-h EAT culture media ( n = 8). The secretome resistin concentrations increased over the culture period to a maximal level of 5.9 ± 1.2 ng/mL. Coculture with β-adrenergic agonists isoproterenol ( n = 4) and BRL37344 ( n = 13) had no effect on EAT resistin release. Addition of resistin (7, 12, 20 ng/mL) did not significantly increase the spontaneous contraction propensity of human atrial trabeculae ( n = 10) when given alone or in combination with isoproterenol. Resistin dose-dependently increased trabecula-developed force (maximal 2.9-fold increase, P < 0.0001), as well as the maximal rates of contraction (2.6-fold increase, P = 0.002) and relaxation (1.8-fold increase, P = 0.007). Additionally, the postrest potentiation capacity of human trabeculae was reduced at all resistin doses, suggesting that the inotropic effect induced by resistin might be due to altered sarcoplasmic reticulum Ca2+ handling. EAT resistin release is not modulated by common arrhythmia triggers. Furthermore, exogenous resistin does not promote arrhythmic behavior in human atrial trabeculae. Resistin does, however, induce an acute dose-dependent positive inotropic and lusitropic effect.

We aimed to investigate the correlation between epicardial adipose tissue (EAT) and body mass index (BMI) in different ethnic groups in New Zealand.The study included 205 individuals undergoing open heart surgery. Māori and Pacific groups were combined to increase statistical power. EAT was measured using 2D echocardiography.There were 164 New Zealand Europeans (NZE) and 41 Māori/Pacific participants. The mean (SD) age of the study group was 67.9 (10.1) years, 69.1 (9.5) for NZE and 63.5 (11.4) for Māori/Pacific. BMI was 29.6 (5.5) kg/m2 for NZE and 31.8 (6.2) for Māori/Pacific. EAT thickness was 6.2 (2.2) mm and 6.0 (1.8) mm for NZE and Māori/Pacific, respectively. Using univariate linear regression, BMI showed moderate correlation with EAT in NZE (R2=0.26, p0.001); however, there was no significant correlation between BMI and EAT in Māori/Pacific patients (R2=0.05, p=0.17). Using multivariate analysis, BMI remained a significant predictor of EAT thickness in NZE (R2 =0.27, p0.001).BMI was associated with EAT thickness in NZE patients, but not in Māori/Pacific patients. The same level of BMI can carry different connotations of risk in different ethnic groups, with BMI likely being an inconsistent measure of obesity in in Māori/Pacific patients.

Heart weight is routinely measured at postmortem examination and is critical to determine whether the heart is enlarged (ie, cardiomegaly). Cardiomegaly has the potential to cause sudden death by being electrically unstable, resulting in fatal arrhythmias. The majority of fatal cardiac arrhythmias is ventricular in origin and is assumed that ventricular size is disproportionately larger in cardiomegaly. This prospective study compared ventricular weight (VW) and total heart weight (THW) in 40 consecutive cases. The results, unexpectedly, showed that VW increases proportionally and linearly with THW in normal and enlarged hearts (THW, >500 g) and did not increase disproportionally with increased THW. The ratio of VW/THW did not have any significant correlation or difference with sex, height, weight, and cardiac causes of death but did have a negative correlation with age. Further studies are indicated to document the morphological changes when the heart enlarges, which may aid in understanding the pathophysiology of sudden death from cardiomegaly.

Acute myocardial infarction (MI) triggers an adverse increase in cardiac sympathetic nerve activity (SNA). Whereas β-adrenergic receptor (β-AR) blockers are routinely used for the management of MI, they may also counter β-AR-mediated vasodilation of coronary vessels. We have reported that ghrelin prevents sympathetic activation following MI. Whether ghrelin modulates coronary vascular tone following MI, either through the modulation of SNA or directly as a vasoactive mediator, has never been addressed. We used synchrotron microangiography to image coronary perfusion and vessel internal diameter (ID) in anesthetized Sprague-Dawley rats, before and then again 30 minutes after induction of an MI (left coronary artery ligation). Rats were injected with either saline or ghrelin (150 µg/kg, subcutaneously), immediately following the MI or sham surgery. Coronary angiograms were also recorded following β-AR blockade (propranolol, 2 mg/kg, intravenously). Finally, wire myography was used to assess the effect of ghrelin on vascular tone in isolated human internal mammary arteries (IMAs). Acute MI enhanced coronary perfusion to nonischemicregions through dilation of small arterioles (ID 50 to 250 µm) and microvessel recruitment, irrespective of ghrelin treatment. In ghrelin-treated rats, β-AR blockade did not alter the ischemia-induced vasodilation, yet in saline-treated rats, β-AR blockade abolished the vasodilation of small arterioles. Finally, ghrelin caused a dose-dependent vasodilation of IMA rings (preconstricted with phenylephrine). In summary, this study highlights ghrelin as a promising adjunct therapy that can be used in combination with routine β-AR blockade treatment for preserving coronary blood flow and cardiac performance in patients who suffer an acute MI.

New Findings What is the central question of the study? The sympathetic system regulates heart rate via β-adrenoceptors; this is impaired during diabetes. However, the specific β-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β1-adrenoceptor subtype, and not the β2-adrenoceptor, regulated the lower resting heart rate and increased β-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of β1- and β2-adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (β1- and β2-adrenoceptor agonist, 0.1–300 μg kg−1) in the presence of atenolol (β1-adrenoceptor antagonist, 2000 μg kg−1) or nadolol (β1- and β2-adrenoceptor agonist, 4000 μg kg−1) to determine the chronotropic contributions of the β-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min−1 non-diabetic versus diabetic, P

Epicardial adipose tissue (EAT) deposition has a strong clinical association with atrial arrhythmias; however, whether a direct functional interaction exists between EAT and the myocardium to induce atrial arrhythmias is unknown. Therefore, we aimed to determine whether human EAT can be an acute trigger for arrhythmias in human atrial myocardium. Human trabeculae were obtained from right atrial appendages of patients who have had cardiac surgery ( n = 89). The propensity of spontaneous contractions (SCs) in the trabeculae (proxy for arrhythmias) was determined under physiological conditions and during known triggers of SCs (high Ca2+, β-adrenergic stimulation). To determine whether EAT could trigger SCs, trabeculae were exposed to superfusate of fresh human EAT, and medium of 24 h-cultured human EAT treated with β1/2 (isoproterenol) or β3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and β1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute β3-adrenergic stimulation did not trigger SCs. Exposure of trabeculae to either superfusate of fresh human EAT or untreated medium of 24 h-cultured human EAT did not induce SCs; however, specific β3-adrenergic stimulation of EAT did trigger SCs in the trabeculae, either when applied to fresh (31%) or cultured (50%) EAT. Additionally, fresh EAT increased trabecular contraction and relaxation, whereas media of cultured EAT only increased function when treated with the β3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on β3-adrenergic rather than β1/2-adrenergic stimulation of EAT.

The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. 'Subclinical' changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.

Type 2 diabetes is associated with reduced left ventricular reserve. It is unclear whether exercise training improves left ventricular function in people with type 2 diabetes.This study aimed to determine whether 3 months of high-intensity interval training (HIIT) improves left ventricular function during exercise in adults with type 2 diabetes.Participants performed a V˙O2peak test and received a DXA scan and total blood volume measurement at baseline. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular stroke volume (LVSV) were then measured at rest and during low- and moderate-intensity semirecumbent exercise in adults with type 2 diabetes before and after 3 months of HIIT (n = 11) or no training (control) (n = 5). The effects of HIIT were determined using repeated-measures ANOVA.HIIT increased V˙O2peak by approximately 15% (P0.002) but did not change body composition or total blood volume. LVESV decreased and LVEDV and LVSV increased from rest to moderate-intensity exercise in both groups at baseline (all P0.01). Three months of HIIT increased LVEDV (P = 0.008) and LVSV (P = 0.02) at all conditions, but there was no difference in controls (all P0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P0.04), but LVESV was unchanged in controls. Increased LVEDV explained 51% of the change in LVSV after HIIT intervention. Mitral inflow parameters and mitral annular velocities were unaffected by HIIT (all P0.05).HIIT training increased the LVSV response to exercise in adults with type 2 diabetes. These data suggest that HIIT can improve LV filling and emptying during exercise and reverse early cardiac consequences of type 2 diabetes.

What is the central question of this study? Are there specific contributions of βImpaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β

NEW FINDINGS What is the central question of the study? Is the reduced signalling of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in the heart, responsible for the reduced β-adrenergic responsiveness of the heart in obesity? What is the main finding and its importance? Inhibition of AMPK in isolated hearts prevented the reduced cardiac β-adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β-adrenergic responsiveness and AMPK signalling in the heart, and it suggests that AMPK might be an important target to restore the β-adrenergic responsiveness in the heart in obesity. ABSTRACT The obesity epidemic impacts heavily on cardiovascular health, in part owing to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart and is regulated by β-adrenoceptors (β-ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β-AR responsiveness, although it is unclear whether AMPK signalling, downstream of β-ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β-AR responsiveness to the β1 -AR agonist isoprenaline (ISO, 1 × 10-10 to 5 × 10-8 m) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 μm). The β1 -AR expression and AMPK phosphorylation were assessed by Western blot. β-Adrenergic responsiveness was reduced in the hearts of obese rats (logEC50 of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 × 10x m versus obese -8.35 ± 0.10 × 10x m ; P

Background Calcium/calmodulin-dependent kinase II-delta (CaMKIIδ) activity is enhanced during hyperglycemia and has been shown to alter intracellular calcium handling in cardiomyocytes, ultimately leading to reduced cardiac performance. However, the effects of CaMKIIδ on cardiac contractility during type 2 diabetes are undefined. Methods We examined the expression and activation of CaMKIIδ in right atrial appendages from non-diabetic and type 2 diabetic patients (n = 7 patients per group) with preserved ejection fraction, and also in right ventricular tissue from Zucker Diabetic Fatty rats (ZDF) (n = 5–10 animals per group) during early diabetic cardiac dysfunction, using immunoblot. We also measured whole heart function of ZDF and control rats using echocardiography. Then we measured contraction and relaxation parameters of isolated trabeculae from ZDF to control rats in the presence and absence of CaMKII inhibitors. Results CaMKIIδ phosphorylation (at Thr287) was increased in both the diabetic human and animal tissue, indicating increased CaMKIIδ activation in the type 2 diabetic heart. Basal cardiac contractility and relaxation were impaired in the cardiac muscles from the diabetic rats, and CaMKII inhibition with KN93 partially restored contractility and relaxation. Autocamtide-2-related-inhibitor peptide (AIP), another CaMKII inhibitor that acts via a different mechanism than KN93, fully restored cardiac contractility and relaxation. Conclusions Our results indicate that CaMKIIδ plays a key role in modulating performance of the diabetic heart, and moreover, suggest a potential therapeutic role for CaMKII inhibitors in improving myocardial function during type 2 diabetes.

Background Diabetes promotes progressive loss of cardiac cells, which are replaced by a fibrotic matrix, resulting in the loss of cardiac function. In the current study we sought to identify if excessive autophagy plays a major role in inducing this progressive loss. Methods and results Immunofluorescence and western blotting analysis of the right atrial appendages collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery showed a marked increase in the level of autophagy in the diabetic heart, as evidenced by increased expression of autophagy marker LC3B-II and its mediator Beclin-1 and decreased expression of p62, which incorporates into autophagosomes to be efficiently degraded. Moreover, a marked activation of pro-apoptotic caspase-3 was observed. Electron microscopy showed increased autophagosomes in the diabetic heart. In vivo measurement of autophagic flux by choloroquine injection resulted in further enhancement of LC3B-II in the diabetic myocardium, confirming increased autophagic activity in the type-2 diabetic heart. Importantly, in-vitro genetic depletion of beclin-1 in high glucose treated adult rat cardiomyocytes markedly inhibited the level of autophagy and subsequent apoptotic cell death. Conclusions These findings demonstrate the pathological role of autophagy in the type-2 diabetic heart, opening up a potentially novel therapeutic avenue for the treatment of diabetic heart disease.

This data article contains full list of autophagy related genes that are altered in diabetic heart. This article also shows data from in vitro cultured cardiomyocytes that are exposed the high glucose treatment to simulate hyperglycemic state in vitro. The interpretation of these data and further extensive insights into the regulation of SG biogenesis by AMPK can be found in “Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway” (Munasinghe et al., in press) [1].

New Findings What is the central question of this study? Can bilateral renal denervation, an effective antihypertensive treatment in clinical and experimental studies, improve cardiac β-adrenoceptor responsiveness in a diabetic model with underlying hypertension? What is the main finding and its importance? Bilateral renal denervation did not affect β-adrenergic responsiveness in the diabetic hypertensive rat heart, but denervation reduced the hypertension-induced concentric hypertrophic remodelling. This suggests that the positive haemodynamic changes induced by renal denervation are most likely to reflect an attenuation of sympathetic effects on the systemic vasculature and/or the renal function rather than direct sympathetic modulation of the heart. Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac β-adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rats. Bilateral renal denervation or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren-2 rats with or without streptozotocin (STZ)-induced diabetes (4 × n = 7); Sprague–Dawley rats (n = 6) served as control animals. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incremental concentrations of the β-AR agonist isoprenaline (from 10−10 to 10−7 m) or the β3-AR agonist BRL37344 (from 10−13 to 10−6 m). Expression levels of β1-AR were determined by Western blot. Both inotropic and lusitropic β-AR responsiveness was reduced in the hypertensive diabetic hearts, but these responses were unaltered after BRD. Expression levels of β1-AR were increased after BRD (Sham, 0.85 ± 0.11 versus 1.01 ± 0.05 a.u.; BRD, 1.45 ± 0.11 versus 1.46 ± 0.07 a.u.; Ren-2 versus Ren-2 STZ, P

Expansion of physiological knowledge increasingly requires examination of processes in the normal, conscious state. The current study describes a novel approach combining surgical implantation of radio-telemeters with vascular access ports (VAPs) to allow repeated hemodynamic and pharmacological measures in conscious rats. Dual implantation was conducted on 16-week-old male lean and obese Zucker rats. Continued viability one month after surgery was observed in 67% of lean and 44% of obese animals, giving an overall 54% completion rate. Over the five-week measurement period, reliable and reproducible basal mean arterial pressure and heart rate measures were observed. VAP patency and receptor-independent vascular reactivity were confirmed by consistent hemodynamic responses to sodium nitroprusside (6.25 µg/kg). Acutely, minimal hemodynamic responses to repeated bolus administration of 0.2 mL saline indicated no significant effect of increased blood volume or administration stress, making repeated acute measures viable. Similarly, repeated administration of the β-adrenoceptor agonist dobutamine (30 µg/kg) at 10 min intervals resulted in reproducible hemodynamic changes in both lean and obese animals. Therefore, our study demonstrates that this new approach is viable for the acute and chronic assessment of hemodynamic and pharmacological responses in both lean and obese conscious rats. This technique reduces the demand for animal numbers and allows hemodynamic measures with minimal disruption to animals’ welfare, while providing reliable and reproducible results over several weeks. In conclusion, dual implantation of a radio-telemeter and VAP introduces a valuable technique for undertaking comprehensive studies involving repeated pharmacological tests in conscious animals to address important physiological questions.

Epicardial adipose tissue (EAT) deposition has a strong association with aspects of metabolic dysfunction, including obesity. The size of the EAT adipocytes in relation to obesity, however, has rarely been researched. Therefore, to contextualise EAT within the broader framework of pathophysiological adipocyte size changes in obesity, we aimed to determine whether EAT adipocyte size is associated with body mass index (BMI).During routine post-mortem examination, adipose tissue biopsies were obtained from four depots of 43 cases, including EAT, as well as pericardial (PAT), appendix mesenteric (AAT), and clavicular subcutaneous (SAT) adipose tissues. Tissues were fixed, sectioned, and stained using haematoxylin and eosin. The size (measured as area) of each adipocyte imaged from the depots was analysed in relation to BMI.Mean size of EAT adipocytes was significantly smaller than that from SAT and AAT depots, while not differing from PAT adipocytes. BMI positively correlated with the size of adipocytes isolated from SAT (r=0.5893, P.0001), PAT (r=0.5854, P.0001), and AAT (r=0.5829, P.0001) depots, but not from EAT (r=0.1242, P=.4274), even after multivariate adjustment for age and sex.EAT adipocyte size is not associated with increased BMI despite significant associations within adipocytes from other adipose depots.

a Department of Physiology — HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand b Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand c Department of Medicine — HeartOtago, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand d NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom

Esophageal intramural pseudodiverticulosis is a rare disease that may lead to esophageal stenosis and dysphagia. The aim of the study was to evaluate the endoscopic diagnosis, treatment and clinical course of intramural pseudodiverticulosis. We retrospectively studied endoscopic criteria of intramural pseudodiverticulitis, associated diseases, and the clinical course, particularly in patients with dysphagia because of esophageal stenosis in a period from 2002 to 2012. In 23 patients, the diagnosis was made according to endoscopic criteria. As risk factors, alcohol and tobacco consumption were present in all patients. Concomitant candida infection was present in six (26%) patients. In 12 (52%) patients esophageal stenosis was present, which was localized in the upper half of the esophagus. In 11 patients bougienage has been performed with excellent improvement of the dysphagia score from 3.7 to 1.3 (P = 0.002). However, dysphagia was recurrent in four patients with need for repeated bougienage. About half of the patients with intramural pseudodiverticulosis present with stenosis of the esophagus at the time of diagnosis. In patients with proximal esophageal stenosis and a typical risk constellation, intramural pseudodiverticulosis should be suspected. Treatment of stenosis with bougienage is effective to resolve dysphagia, but repeated bougienage may be necessary.

Stem cell therapy is one of the promising regenerative strategies developed to improve cardiac function in patients with ischemic heart diseases (IHD). However, this approach is limited in IHD patients with diabetes due to a progressive decline in the regenerative capacity of stem cells. This decline is mainly attributed to the metabolic memory incurred by diabetes on stem cell niche and their systemic cues. Understanding the molecular pathways involved in the diabetes-induced deterioration of stem cell function will be critical for developing new cardiac regeneration therapies. In this review, we first discuss the most common molecular alterations occurring in the diabetic stem cells/progenitor cells. Next, we highlight the key signaling pathways that can be dysregulated in a diabetic environment and impair the mobilization of stem/progenitor cells, which is essential for the transplanted/endogenous stem cells to reach the site of injury. We further discuss the possible methods of preconditioning the diabetic cardiac progenitor cell (CPC) with an aim to enrich the availability of efficient stem cells to regenerate the diseased diabetic heart. Finally, we propose new modalities for enriching the diabetic CPC through genetic or tissue engineering that would aid in developing autologous therapeutic strategies, improving the proliferative, angiogenic, and cardiogenic properties of diabetic stem/progenitor cells.

What is the central question of the study? The sympathetic system regulates heart rate via β-adrenoceptors; this is impaired during diabetes. However, the specific β-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β

Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). Purpose: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to β-adrenergic stimulation. Methods: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and V˙O2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental β-adrenergic stimulation (dobutamine). Results: V˙O2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. Conclusions: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to β-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.

Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart. Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-β receptor-1 (TGFβR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFβR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts. Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart. * α-SMA, : α-smooth muscle actin; CM, : conditioned medium; CTGF, : connective tissue growth factor; ECM, : extracellular matrix; HG, : high glucose; IHD, : ischaemic heart disease; LV, : left ventricle; MI, : myocardial infarction; miR, : microRNA; ND, : non-diabetic; NG, : normal glucose; RAA, : right atrial appendage; Scr, : scrambled sequence; SIRT1, : sirtuin 1; TGFβR1, : transforming growth factor-β receptor-1

Background Emerging evidence suggests that microRNAs (miRs) could be a potential biomarker to identify early molecular alterations in the heart. HDL are the major carriers for miRs into the circulation. This study tested whether changes in the level of HDL could affect the diagnostic sensitivity of miRs. Methods and results Peripheral blood samples were collected from 20 diabetic and 22 age and gender matched non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery for ischemic heart disease (IHD). Total RNA was extracted from the separated plasma and stored in −80°C. Reverse transcription and amplification using specific primers against cardio-enriched miR-1, -34a, -126, -133, and -499 showed significant correlation between HDL levels and miR-1, -133 and -499. Importantly, normalization of miR levels with HDL showed a significant downregulation of miR-1, -133 and -499 in diabetic plasma, which was not observed before normalization with HDL levels. Conclusion Normalization of circulating miR levels with HDL increases the diagnostic sensitivity of circulating miRs.

Cardiac muscle functions as a molecular machine that converts an electrical stimulus into a Ca2+-dependent mechanical contraction. This article is protected by copyright. All rights reserved