The role of Na+/H+ exchanger in Ca2+ overload and ischemic myocardial damage in hearts from type 2 diabetic db/db mice.

BACKGROUND: A higher increase in intracellular Na(+) via Na(+)/H(+) exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts. We investigated the role of NHE in inducing changes in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and alterations in ventricular function during ischemia-reperfusion in type 2 diabetic mouse hearts. METHODS: Hearts from male type 2 diabetic db/db (12-15 weeks old) and age-matched control db/+ mice were subjected to Langendorff perfusion and loaded with 4 µM of the Ca(2+) indicator fura-2. The hearts were exposed to no-flow ischemia for 15 minutes and then reperfused. [Ca(2+)](i) was measured by monitoring fura-2 fluorescence at 500 nm (excitation wavelengths of 340 and 380 nm), while left ventricular (LV) pressure was simultaneously measured. RESULTS: db/db hearts exhibited a lower recovery of LV developed pressure than db/+ hearts during reperfusion following ischemia. Diastolic [Ca(2+)](i) was increased to a greater level in diabetic hearts than in the control hearts during ischemia and reperfusion. Such an increase in cytoplasmic Ca(2+) overload during ischemia-reperfusion in diabetic hearts was markedly reduced in the presence of the NHE inhibitor cariporide. This was accompanied by a significantly improved recovery of ventricular function on reperfusion, as shown by a lower increase in diastolic pressure and increased recovery of developed pressure. CONCLUSION: NHE plays a key role in enhancing cytoplasmic Ca(2+) overload during ischemia-reperfusion and severely impairing post-ischemic cardiac function in hearts from type 2 diabetic db/db mice.

Association of uric acid with risk factors for chronic kidney disease and metabolic syndrome in patients with essential hypertension.

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.

Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats.

BACKGROUND: Sensitivity to ischemia and its underlying mechanisms in type 2 diabetic hearts are still largely unknown. Especially, correlation between reperfusion induced ventricular arrhythmia and changes in intracellular pH has not been elucidated. METHODS AND RESULTS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 16 and 32 weeks of age were used along with age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. Hearts from rats in these 4 groups were perfused in the working heart mode, thus inducing whole heart ischemia. At 16 weeks of age, no differences in blood glucose levels or incidence and duration of reperfusion arrhythmia were found between the strains. At 32 weeks of age, both impaired glucose tolerance and obesity were observed in the OLETF rats. Further, the duration of reperfusion-induced ventricular fibrillation (VF) was significantly longer in the OLETF rats, while the pH level was significantly lower and proton contents were significantly higher in coronary effluent during ischemia in those rats. Following treatment with troglitazone, improvements in pH and proton level in coronary effluent during ischemia were observed, as was the duration of reperfusion-induced VF in OLETF rats at 32 weeks of age. CONCLUSION: The hearts of spontaneously diabetic OLETF rats were found to be more susceptible to ischemic insult. Troglitazone treatment improved ischemic tolerance by improving glucose metabolism in the myocardium of those rats.

Atrial pacing failure following termination of atrial fibrillation by acute administration of disopyramide phosphate.

Atrial pacing failure occurred after termination of atrial fibrillation by acute administration of disopyramide phosphate in a 71-year-old woman implanted with an AAI pacemaker for sick sinus syndrome. The atrial pacing threshold showed an 810% increase; however, the serum concentration of disopyramide corresponded to therapeutic level. Infusion of the same dose of disopyramide phosphate used during the period of atrial pacing rhythm did not increase the atrial pacing threshold. In the present patient, we supposed that atrial pacing failure did not occur by the effect of disopyramide alone, but rather was a reciprocal action in response to atrial fibrillation.

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice.

OBJECTIVE: Sodium-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 RESULTS: We 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. CONCLUSIONS: Cardiac 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.

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts.

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(-9) 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 ischemia-reperfusion, 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.

An immunohistochemical analysis of tissue thrombin expression in the human atria.

OBJECTIVE: Thrombin, 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.

Difference in risk factors between acute coronary syndrome and stable angina pectoris in the Japanese: smoking as a crucial risk factor of acute coronary syndrome.

BACKGROUND AND PURPOSE: Metabolic syndrome and chronic kidney disease (CKD) have received attention as new risk factors for cardiovascular disease. This study evaluated differences in key risk factors between acute coronary syndrome (ACS) and stable angina pectoris (SAP) by using traditional coronary risk factors, metabolic syndrome, and CKD. METHODS: Among 1890 consecutive patients admitted to our institution, we studied 140 patients with initially diagnosed ACS and 163 patients with initially diagnosed SAP and compared risk factors between the two groups. Next, the relationship between smoking status after the initial diagnosis of coronary artery disease (CAD) and the incidence of subsequent cardiac event was examined after discharge in 284 patients. RESULTS: Adjusted multivariate analysis showed that only current smoking was an independent predictor of ACS (odds ratio, 2.20; 95% CI, 1.28-3.78; p=0.004) among all risk factors we examined. Treatment with a calcium-channel blocker had a preventive effect on ACS (odds ratio, 0.44; 95% CI, 0.26-0.75; p=0.003), but treatment with a beta-blocker did not. Patients who continued to smoke after CAD was diagnosed had a risk of cardiac events about 5 times that of smokers who quit (adjusted hazard ratio, 5.05; 95% CI, 1.33-19.20; p=0.02). CONCLUSIONS: 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.

Cardiac metabolism in diabetes mellitus.

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.

Pericarditis causing congestive heart failure as an initial manifestation of systemic lupus erythematosus.

Pericarditis is a common complication in systemic lupus erythematosus (SLE) patients, however, that causing congestive heart failure (CHF) is a rare initial manifestation of SLE. We treated a patient whose initial manifestation of SLE was pericardial effusion causing CHF, which improved following prednisolone therapy that led to a dramatic decrease in pericardial effusion and improvement in left ventricular diastolic dysfunction as shown in Doppler echocardiography findings. Further, the plasma brain natriuretic peptide level became normalized.