Inotropic and lusitropic, but not arrhythmogenic, effects of adipocytokine resistin on human atrial myocardium.

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 ß-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.

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility.

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+, ß-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 ß1/2 (isoproterenol) or ß3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and ß1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute ß3-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 ß3-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 ß3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on ß3-adrenergic rather than ß1/2-adrenergic stimulation of EAT.

Relationship between epicardial adipose tissue thickness and epicardial adipocyte size with increasing body mass index.

Macroscopic deposition of epicardial adipose tissue (EAT) has been strongly associated with numerous indices of obesity and cardiovascular disease risk. In contrast, the morphology of EAT adipocytes has rarely been investigated. We aimed to determine whether obesity-driven adipocyte hypertrophy, which is characteristic of other visceral fat depots, is found within EAT adipocytes. EAT samples were collected from cardiac surgery patients (n = 49), stained with haematoxylin & eosin, and analysed for mean adipocyte size and non-adipocyte area. EAT thickness was measured using echocardiography. A significant positive relationship was found between EAT thickness and body mass index (BMI). When stratified into standardized BMI categories, EAT thickness was 58.7% greater (p = 0.003) in patients from the obese (7.3 ± 1.8 mm) compared to normal (4.6 ± 0.9 mm) category. BMI as a continuous variable significantly correlated with EAT thickness (r = 0.56, p < 0.0001). Conversely, no correlation was observed between adipocyte size and either BMI or EAT thickness. No difference in the non-adipocyte area was found between BMI groups. Our results suggest that the increased macroscopic EAT deposition associated with obesity is not caused by adipocyte hypertrophy. Rather, alternative remodelling via adipocyte proliferation might be responsible for the observed EAT expansion.

ß2 -Adrenoceptors indirectly support impaired ß1 -adrenoceptor responsiveness in the isolated type 2 diabetic rat heart.

NEW FINDINGS: What is the central question of this study? Are there specific contributions of ß1 - and ß2 -adrenoceptor subtypes to the impaired ß-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 ß1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the ß2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. ABSTRACT: Impaired ß-adrenoceptor (ß-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of ß1 - and ß2 -AR subtypes to ß-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific ß1 - and ß2 -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 ß-AR agonist isoprenaline (1 × 10-11 to 3 × 10-8  mol l-1 ) with or without the selective ß1 -AR antagonist CGP20712A (3 × 10-8  mol l-1 ) or the ß2 -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 < 0.05). However, the ß-AR-induced increase in HR was similar and was completely blocked by the ß1 -AR antagonist, but not by the ß2 -AR antagonist. The ß-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the ß1 -AR antagonist and partly impaired by the ß2 -AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non-diabetic 1.62 ± 0.19 a.u. versus diabetic 2.30 ± 0.25 a.u., P < 0.05). In conclusion, the ß1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic ß-AR responses in the healthy heart and the type 2 diabetic heart. The ß2 -AR subtype indirectly supports the ß1 -AR functional response in the diabetic heart. This suggests that ß2 -ARs could be an indirect target to improve the function of the heart in type 2 diabetes.

Chronic bilateral renal denervation attenuates renal injury in a transgenic rat model of diabetic nephropathy.

Bilateral renal denervation (BRD) has been shown to reduce hypertension and improve renal function in both human and experimental studies. We hypothesized that chronic intervention with BRD may also attenuate renal injury and fibrosis in diabetic nephropathy. This hypothesis was examined in a female streptozotocin-induced diabetic (mRen-2)27 rat (TGR) shown to capture the cardinal features of human diabetic nephropathy. Following diabetic induction, BRD/sham surgeries were conducted repeatedly (at the week 3, 6, and 9 following induction) in both diabetic and normoglycemic animals. Renal denervation resulted in a progressive decrease in systolic blood pressure from first denervation to termination (at 12 wk post-diabetic induction) in both normoglycemic and diabetic rats. Renal norepinephrine content was significantly raised following diabetic induction and ablated in denervated normoglycemic and diabetic groups. A significant increase in glomerular basement membrane thickening and mesangial expansion was seen in the diabetic kidneys; this morphological appearance was markedly reduced by BRD. Immunohistochemistry and protein densitometric analysis of diabetic innervated kidneys confirmed the presence of significantly increased levels of collagens I and IV, α-smooth muscle actin, the ANG II type 1 receptor, and transforming growth factor-ß. Renal denervation significantly reduced protein expression of these fibrotic markers. Furthermore, BRD attenuated albuminuria and prevented the loss of glomerular podocin expression in these diabetic animals. In conclusion, BRD decreases systolic blood pressure and reduces the development of renal fibrosis, glomerulosclerosis, and albuminuria in this model of diabetic nephropathy. The evidence presented strongly suggests that renal denervation may serve as a therapeutic intervention to attenuate the progression of renal injury in diabetic nephropathy.