Neurological Prognostic Value of Adjusted Ca2+ Concentration in Adult Patients with Out-of-Hospital Cardiac Arrest.

Many patients are transferred to hospital due to out-of-hospital cardiac arrest (OHCA), and, unfortunately, most suffer from cerebral damage. Currently, it is difficult to predict the recovery of neurological function after return of spontaneous circulation (ROSC) in the acute phase. Increased intracellular Ca2+ induces cell death in the acute phase. Accordingly, we predicted that serum adjusted Ca2+ will decrease following Ca2+ influx into cells. Consequently, serum adjusted Ca2+ in the acute phase may be able to predict recovery of neurological function in patients with ROSC from OHCA. This is a retrospective and observational study from 2 centers. A total of 190 consecutive patients with ROSC from OHCA were recruited, with 33 patients meeting the inclusion criteria. The relationship between serum adjusted Ca2+ within 48 hours after ROSC and neurological function at discharge (as evaluated by the Glasgow-Pittsburgh cerebral performance category) was examined. Serum adjusted Ca2+ was measured every 4 hours within a 48-hour period after ROSC. There were no significant differences in hemodynamical state and laboratory data between the 2 groups. However, lowest serum adjusted Ca2+ within 48 hours after ROSC was significantly lower in the poor neurological outcome group (0.96 ± 0.06 versus 1.02 ± 0.06 mmol/L, P = 0.011). Thus, lowest serum adjusted Ca2+ within 48 hours after ROSC may be a predictive factor for recovery of neurological function at discharge in patients with ROSC from OHCA.

Diagnostic performance of calcification-suppressed coronary CT angiography using rapid kilovolt-switching dual-energy CT.

OBJECTIVES: Multi-detector-row computed tomography angiography (MDCTA) plays an important role in the assessment of patients with suspected coronary artery disease. However, MDCTA tends to overestimate stenosis in calcified coronary artery lesions. The aim of our study was to evaluate the diagnostic performance of calcification-suppressed material density (MD) images produced by using a single-detector single-source dual-energy computed tomography (ssDECT). METHODS: We enrolled 67 patients with suspected or known coronary artery disease who underwent ssDECT with rapid kilovolt-switching (80 and 140 kVp). Coronary artery stenosis was evaluated on the basis of MD images and virtual monochromatic (VM) images. The diagnostic performance of the two methods for detecting coronary artery disease was compared with that of invasive coronary angiography as a reference standard. RESULTS: We evaluated 239 calcified segments. In all the segments, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detecting significant stenosis were respectively 88%, 88%, 75%, 95% and 88% for the MD images, 91%, 71%, 56%, 95% and 77% for the VM images. PPV was significantly higher on the MD images than on the VM images (P < 0.0001). CONCLUSIONS: Calcification-suppressed MD images improved PPV and diagnostic performance for calcified coronary artery lesions. KEY POINTS: • Computed tomography angiography tends to overestimate stenosis in calcified coronary artery. • Dual-energy CT enables us to suppress calcification of coronary artery lesions. • Calcification-suppressed material density imaging reduces false-positive diagnosis of calcified lesion.

The Effectiveness of Non-ECG-Gated Contrast-Enhanced Computed Tomography for the Diagnosis of Non-ST Segment Elevation Acute Coronary Syndrome.

Non-ST segment elevation acute coronary syndrome (NSTE-ACS) can be difficult to diagnose accurately, especially in the hyper-acute phase. Non-ECG-gated contrast-enhanced computed tomography (non-ECG-gated CE-CT) has been used in many institutions for screening acute chest pain. Although early defects (EDs) observed in non-ECG-gated CE-CT have been reported as a sign of acute myocardial ischemia, the precise diagnostic value of this sign for acute coronary syndrome has not been fully elucidated. We investigated the usefulness of non-ECG-gated CE-CT for the diagnosis of NSTE-ACS. We retrospectively reviewed 556 patients who were hospitalized for acute-onset chest pain and who underwent emergent coronary angiography. Non-ECG-gated CE-CT was performed in 23 of these patients. Two readers independently analyzed CT images using a 5-point scale. Of the 23 patients, 13 were diagnosed with NSTE-ACS. The remaining 10 patients were diagnosed with other conditions. The sensitivity, specificity, positive predictive value, and negative predictive value, respectively, of EDs on non-ECG-gated CE-CT to detect NSTE-ACS were 84.6%, 90%, 91.7%, and 81.8%. The identification of EDs was consistent between the two readers. Non-ECG-gated CE-CT may be useful not only to triage patients with chest pain by ruling out other conditions, but also to accurately diagnose NSTE-ACS.

Addition of losartan to angiotensin-converting enzyme inhibitors improves insulin resistance in patients with chronic heart failure treated without ß-blockers.

BACKGROUND: Angiotensin II and insulin resistance (IR) have clinical implications in the pathophysiology of chronic heart failure (CHF). However, it is still unclear whether the combination of an angiotensin-receptor blocker and angiotensin-converting enzyme inhibitor (ACEI) improves IR in CHF patients who do not receive ß-blockers. Thus, the aim of the present study was to evaluate the effects of losartan on glucose metabolism and inflammatory cytokines in CHF patients treated with ACEI but not ß-blockers. METHODS AND RESULTS: The effect of losartan treatment for 16 weeks on IR was analyzed in 16 CHF patients in a randomized crossover trial. Insulin level and homeostasis model IR index (HOMA-IR) decreased significantly (P<0.05), but fasting plasma glucose did not change significantly. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels were significantly decreased with losartan (P<0.05). Furthermore, the changes in IL-6 and MCP-1 levels were significantly correlated with the reduction in HOMA-IR (P<0.05), but the change in TNF-α levels was not significantly correlated. CONCLUSIONS: The addition of losartan to ACEI therapy improved IR and decreased inflammatory cytokines in CHF patients who did not receive ß-blockers.

Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes: lack of effects in cells from spontaneously hypertensive rats.

We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. [125I]Ang II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 (AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l. This inhibition was abolished by the AT, antagonist RNH6270 but not at all by the AT2 antagonist PD123319. Treatment of cells with pertussis toxin or a synthetic decapeptide corresponding to the carboxyl-terminus of Gialpha-3 abolished the inhibition by Ang II, indicating the role of a Gi-dependent signaling pathway. Accordingly, Ang II failed to inhibit IK1 in the presence of forskolin, dibutyryl-cAMP or protein kinase A catalytic subunits. In spite of the increased binding capacities for [125I]Ang II, Ang II failed to affect IKI in cells from spontaneously hypertensive rats (SHR). AT, immunoprecipitation from atrial extracts revealed decreased amounts of Gialpha-2 and Gialpha-3 proteins associated with this receptor in SHR as compared with controls. The reduced coupling of AT, with Gialpha. proteins may underlie the unresponsiveness of atrial IK1 to Ang II in SHR cells.

Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure.

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.

Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study.

BACKGROUND: Hyperuricemia is common in chronic heart failure (CHF), and it is a strong independent marker of prognosis. Upregulated xanthine oxidase (XO) activity and impaired renal excretion have been shown to account for increased serum uric acid (UA) levels in CHF. Therapeutic interventions with allopurinol to reduce UA levels by XO inhibition have been shown to be beneficial. Discussions are ongoing whether UA itself is actively involved or it is a mere marker of upregulated XO activity within CHF pathophysiology. Therefore, the aim of this study was to test the effect of lowering UA by uricosuric treatment without XO inhibition on hemodynamic and metabolic characteristics of CHF. Impaired renal excretion of UA was taken into account. METHODS AND RESULTS: Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (Cl(UA)) were measured in 82 patients with CHF. SUA was significantly increased compared with controls of similar age (control, 5.45+/-0.70 mg/dL; New York Heart Association I, 6.48+/-1.70 mg/dL; New York Heart Association II, 7.34+/-1.94 mg/dL; New York Heart Association III, 7.61+/-2.11 mg/dL; P<0.01). Patients with CHF showed lower uUA excretion and Cl(UA). On multivariate analysis, insulin, brain natriuretic peptide (P<0.01), and creatinine levels (P=0.05) showed independent correlation with SUA. The treatment effect of the uricosuric agent benzbromarone was tested in 14 patients with CHF with hyperuricemia in a double-blind, placebo-controlled, randomized crossover study design. Benzbromarone significantly decreased SUA (P<0.01). Brain natriuretic peptide, left ventricular ejection fraction, and dimensions in echocardiographic assessment did not change after benzbromarone therapy. In contrast, fasting insulin (placebo, 18.8+/-8.9 microU/mL; benzbromarone, 11.0+/-6.2 microU/mL; P<0.05), homeostasis model assessment of insulin resistance index (placebo, 5.4+/-2.6; benzbromarone, 3.0+/-1.7; P<0.05), and tumor necrosis factor-alpha (placebo, 2.59+/-0.63 pg/mL; benzbromarone, 2.14+/-0.51 pg/mL; P<0.05) improved after benzbromarone, and the changes in tumor necrosis factor-alpha levels were correlated with reduction of SUA (P<0.05). CONCLUSIONS: These results show that UA lowering without XO inhibition may not have an effect on hemodynamic impairment in CHF pathophysiology. To the extent that these data are correct, this finding suggests that upregulated XO activity rather than UA itself is actively involved in hemodynamic impairment in CHF. Clinical Trial Registration- clinical trials.gov. Identifier: NCT00422318.

[Clinical features of coronary artery ectasia].

OBJECTIVES: To investigate the clinical significance of coronary artery ectasia in Japanese patients. METHODS: Coronary artery ectasia was found in 54 of 3,778 (1.4%) consecutive patients who underwent coronary angiography. The clinical characteristics and the coronary angiographic findings of these patients were studied. Follow-up data were obtained for 49 patients, who were separated into two groups: Group A subsequently suffered a follow-up major cardiac event, and Group B did not develop such an event. RESULTS: Among the coronary artery ectasia patients, 65% had myocardial infarction, 91% had coronary artery disease, and 48% had single-vessel disease. Seventy-six percent had single-vessel involvement with coronary artery ectasia. Eighteen patients (37%) suffered 22 follow-up major events. Seventy-two percent of the first follow-up event cases occurred within 4 years after the first cardiac event. The follow-up event in 78% of cases was acute coronary syndrome. There were no significant differences in age and prevalence of each coronary artery risk factor between Groups A and B. There were no significant differences in the incidence of follow-up event between the patients with single-vessel disease and the patients with multi-vessel disease, nor between the patients with single-vessel involvement with coronary artery ectasia and the patients with multi-vessel involvement with coronary artery ectasia. There was no significant difference in the percentage of patients in whom the culprit vessel of the cardiac event was the same as the ectatic vessel between the first cardiac event and follow-up cardiac events (41% vs 62%). CONCLUSIONS: Coronary artery ectasia is not benign and must be carefully monitored. Coronary atherosclerosis may contribute to the occurrence of subsequent cardiac events.

Transient left ventricular apical ballooning in a patient with bicuspid aortic valve created a left ventricular thrombus leading to acute renal infarction.

A 44-year-old woman had tako-tsubo-like ventricular dysfunction with chest pain and ST segment elevation on the ECG. Echocardiography revealed a bicuspid aortic valve with moderate to severe aortic regurgitation. She developed mild heart failure during the clinical course, but the medication (furosemide, enalapril, and asprin) had to be stopped because of skin eruptions. Four weeks after ceasing the antiplatelet agent, she was re-admitted with acute renal infarction. Enhanced chest computed tomography revealed a filling defect in the left ventricle and echocardiography showed a high echogenic mass in the left ventricular apical wall. These findings strongly suggested that the renal infarction was caused by an embolism derived from a left ventricular thrombus that formed during the clinical course of the transient left ventricular apical ballooning. Anticoagulation therapy with urokinase and warfarin successfully lysed the thrombus. Left ventricular thrombus should be considered a complication of transient left ventricular apical ballooning, especially in patients with organic heart disease.

Allopurinol improves cardiac dysfunction after ischemia-reperfusion via reduction of oxidative stress in isolated perfused rat hearts.

It has been reported that the xanthine oxidase inhibitor, allopurinol, has a protective effect on ischemia - reperfusion injury, but the precise mechanism of its action is still unclear. Therefore, in the present study the mechanisms of the myocardial protection of allopurinol were evaluated in isolated perfused rat hearts. Allopurinol significantly inhibited myocardial xanthine oxidase activity, and improved left ventricular dysfunction after ischemia - reperfusion. In addition, the lactate dehydrogenase content in the coronary effluent obtained after reperfusion was significantly decreased. ATP, ADP, AMP and IMP significantly decreased, whereas inosine, hypoxanthine and xanthine significantly increased after ischemia in both the control and allopurinol groups. The concentration of xanthine was significantly decreased after ischemia - reperfusion in the allopurinol group; however, allopurinol did not affect the other purine metabolites. To evaluate the accumulation of oxidative stress, thiobarbituric acid reactive substances (TBARS) production in myocardial tissue was measured and allopurinol significantly decreased TBARS formation after ischemia - reperfusion. Finally, myocardial hydroxyl radicals were directly measured by electron spin resonance spectroscopy with the nitroxide radical 4-hydroxy-2, 2,6,6-tetramethyl-piperidine-N-oxyl. Hydroxyl radicals significantly increased immediately after reperfusion, but were significantly decreased in the allopurinol group. In conclusion, allopurinol reduced myocardial injury after ischemia-reperfusion by suppressing oxidative stress, but not by salvage of ATP. These findings may lead to the development of new therapeutic strategies for myocardial ischemia - reperfusion injury.

Neurohumoral profiles in patients with hypertrophic cardiomyopathy: differences to hypertensive left ventricular hypertrophy.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) or hypertensive heart disease (HHD) have increased concentrations of various neurohumoral factors. Thus, the aim of the present study was to evaluate the differences in the neurohumoral profiles of HCM and HHD. METHODS AND RESULTS: Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II and endothelin-1 were measured in 40 patients with HCM, 35 with HHD, and 15 controls. Additionally, the concentrations of these neurohumoral factors in the coronary sinus and aortic root were measured in 12 HCM patients and 10 controls. Plasma concentrations of norepinephrine, ANP and BNP were significantly higher in HCM than HHD and controls. In HCM, there was no significant correlation between the left ventricular mass index and any neurohumoral factor. The plasma BNP concentration significantly correlated with left intraventricular pressure gradient in HCM. There were significant differences in the plasma concentrations of ANP and BNP between HCM with and without left ventricular diastolic dysfunction. Transcardiac production of BNP was significantly higher in patients with obstructive HCM than in those with non-obstructive HCM. CONCLUSIONS: The significant neurohumoral differences between HCM and HHD were the plasma concentrations of norepinephrine, ANP and BNP. In HCM patients, the plasma BNP concentration may reflect the intraventricular pressure gradient and left ventricular diastolic dysfunction whereas the plasma ANP concentration reflects only the left ventricular diastolic dysfunction.

Troglitazone improves cardiac function in patients with congestive heart failure.

Troglitazone increased cardiac output and stroke volume, as a result of decreased peripheral resistance, in diabetic patients with normal cardiac function. The cardiovascular effects of troglitazone in patients with heart failure are unknown. The aim of the study was to evaluate the cardiovascular effects of troglitazone in patients with heart failure. Blood pressure and echocardiographic findings were evaluated before and 1, 2, 3 and 4 hours after a single dose of troglitazone (400 mg) or placebo, in eight type II diabetic patients with congestive heart failure. The plasma catecholamines and coefficient of variance of RR intervals (CVRR) were also measured. Neither heart rate nor blood pressure changed after the administration of troglitazone. Left ventricular (LV) end-diastolic dimension did not change either, however, the LV end-systolic dimension significantly decreased compared with its baseline value and with that of the placebo group. On the other hand, the % fractional shortening and the E/A ratio increased significantly after troglitazone. The LV end-diastolic volume did not change, whereas the LV end-systolic volume significantly decreased. The stroke volume and the LV ejection fraction significantly increased compared with its baseline value and with that of the placebo group. The peripheral vascular resistance did not change after the administration of troglitazone, whereas plasma catecholamines significantly decreased, and CVRR remained unchanged in both groups. These hemodynamic changes suggest that a single oral dose of troglitazone induced inotropy without activation of the sympathetic nervous system.