ObjectiveSodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.Methods and ResultsWe determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.ConclusionsCardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

Aims/hypothesis: An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na + Na þ i À Á handling. As no study has so far investigated this in type 2 diabetes, we examined susceptibility to ischaemia-reperfusion in isolated hearts from diabetic db/db and control db/+ mice and determined whether and to what extent the amount of Naincrease during a transient period of ischaemia could contribute to functional alterations upon reperfusion. Methods: Isovolumic hearts were exposed to 30-min global ischaemia and then reperfused. 23Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor Na þ i and 31 P NMR spectroscopy to monitor intracellular pH (pH i ). Results: A higher duration of ventricular tachycardia and the degeneration of ventricular tachycardia into ventricular fibrillation were observed upon reperfusion in db/db hearts. The recovery of left ventricular developed pressure was reduced. The increase in Na þ i induced by ischaemia was higher in db/db hearts than in control hearts, and the rate of pH i recovery was increased during reperfusion. The inhibition of Na + /H + exchange by cariporide significantly reduced Na þ i gain at the end of ischaemia. This was associated with a lower incidence of ventricular tachycardia in both heart groups, and with an inhibition of the degeneration of ventricular tachycardia into ventricular fibrillation in db/db hearts. Conclusions/ interpretation: These findings strongly support the hypothesis that increased Na þ i plays a causative role in the enhanced sensitivity to ischaemia observed in db/db diabetic hearts.

The risk factors were significantly different between initially diagnosed ACS and SAP. Smoking was a more important risk factor of initially diagnosed ACS. Smoking cessation might have a preventive effect on subsequent cardiac events. Also, we found that treatment with a calcium-channel blocker would help prevent ACS in Japanese patients.

ObjectiveThrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle.MethodsWe examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle.ResultsThe thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium.ConclusionsThe strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.

Background: A higher increase in intracellular Na + via Na

Diabetes mellitus is one of the most common chronic illnesses throughout the world. Diabetic cardiomyopathy is a specific syndrome, consisting of cardiomegaly, left ventricular dysfunction, electrical remodeling of the ventricle, and symptoms of congestive heart failure, that is seen in diabetic patients in the absence of other predisposing factors. Many researchers have suggested that inhibition of the renin-angiotensin-aldosterone system and the sympathetic nervous system may exert a therapeutic effect in individuals with diabetic cardiomyopathy. Indeed, angiotensin II and aldosterone blockade may be effective, partly because aldosterone blockade down-regulates Na(+)/H(+) exchanger 1 activity. Further study of the alterations in ion channel physiology in the context of diabetic cardiomyocytes may be of benefit.

Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia-reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10 K9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia-reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemiareperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia-reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

Hyperuricemia has recently been recognized to not only be a predictor of cardiovascular disease but also a marker of metabolic syndrome. We examined the association between uric acid levels and various clinical parameters, including the components of metabolic syndrome, in essential hypertension. One hundred forty-six untreated Japanese hypertensive patients (mean 58.3 years) without overt cardiovascular disease were divided into low and high uric acid groups by the median uric acid value (cut-off: 6.3 for men and 4.4 mg/dL for women). The high uric acid group had higher serum creatinine (0.74 vs. 0.67 mg/dL, p = 0.019) and a larger body mass index (BMI) (25.2 vs. 23.6 kg/m(2), p = 0.018) compared to the low group. Men from the high uric acid group were younger and had higher blood pressure (BP) than men from the low group. Uric acid levels were correlated with creatinine in both genders, with blood pressure, triglycerides in men only, and with BMI, fasting glucose in women only. Multiple regression analysis also indicated a significant correlation of uric acid with creatinine in both genders, with triglycerides in men, and with glucose in women. Metabolic syndrome (modified NCEP-ATPIII definition) was found in 37.0% of the high uric acid group (men 45.0, women 27.3%) and 20.8% of the low group. Results suggest that an increase of uric acid is associated with impaired renal function and constitutes a risk factor for metabolic syndrome. Uric acid may also be a useful index for initial risk stratification of untreated patients with essential hypertension.