Kanae Noritake

Alcohol enhances characteristic releases of dopamine and serotonin in the central nucleus of the amygdala

The amygdaloid complex (AMY) is implicated in emotional and motivational aspects of behavior, including the formation of positive reinforcement association. AMY may also associated with brain rewarding circuitry. In the present study, the effect of ethanol (EtOH) on the release of dopamine (DA) and serotonin (5-HT) was studied in the central amygdaloid nucleus (CeAMY), and projecting excitatory afferents to the ventral tegmental area (VTA), of freely moving Wistar rats by brain microdialysis. Within 20 min of i.p. injection of EtOH (2 g/kg), the levels of DA and 5-HT in the CeAMY dialysate increased over the baseline value by 270 and 160% (N = 6-7), respectively. Addition of EtOH (25, 50 and 100 mM) to the microdialysis perfusion medium for 1 h caused a 115-150% dose-related increase in the extracellular level of DA in the CeAMY. 100 mM EtOH-induced CeAMY DA release continued to increase for 1 h after the perfusion medium was returned to normal perfusion medium. In contrast, the CeAMY 5-HT level was increased only by the addition of 100 mM EtOH for 1 h to 130% for 80 min. The stimulation of the CeAMY by EtOH through the microdialysis membrane showed delayed responses of DA and 5-HT compared with the i.p. injection of EtOH. Overall, the present findings are not sufficient to conclude whether EtOH acts directly or indirectly on the major monoamine nerve cells in the CeAMY, but the degree of acute EtOH action affected the differences in time at the peak response on EtOH-induced DA and 5-HT releases in the CeAMY via VTA.

Comparison of prognostic variables in children and adults with Fontan circulation

BACKGROUND Non-cardiac complications, such as hepato-renal and metabolic problems, are emerging late after the Fontan operation due to its unique hemodynamics. Consequently, associations between clinical variables and postoperative outcome may change during the prolonged postoperative course. METHODS AND RESULTS To determine if child and adult Fontan patients differ in the impact of cardiac and non-cardiac variables on clinical outcome, we prospectively evaluated associations between hemodynamics, neurohumoral factors, exercise variables, hepato-renal function and metabolic variables and unscheduled hospitalization, including death in 167 consecutive child and 116 adult Fontan patients. When compared with child patients, the adult patients showed higher rates of medications, lower cardiac index, higher values of natriuretic peptides, greater renal dysfunction, more cholestatic livers, and more impaired responses to exercise (p<0.05-0.0001). During the follow-up of 3.7 ± 2.1 years, 64 clinical events (37 in adults), including 13 deaths, occurred. A high CVP and low arterial oxygen satutration strongly predicted the child events (p<0.001), whereas these prognostic parameters were marginal in the adults. Instead, renal dysfunction and metabolic abnormality predicted adult events (p<0.05). Neurohumoral activation, low albumin, hyponatremia, and impaired exercise variables equally predicted clinical events in child and adult Fontan patients. CONCLUSIONS Distinctive differences in predictive value of clinical variables exist between child and adult Fontan patients. In addition to cardiac issues, we should consider non-cardiac determinents of clinical outcome to maximize our efforts to improve prognosis for adult Fontan survivors.

Prognostic value of exercise variables in 335 patients after the Fontan operation: a 23-year single-center experience of cardiopulmonary exercise testing.

BACKGROUND The prognostic value of cardiopulmonary exercise testing (CPX) for mortality risk remains controversial in Fontan patients. PURPOSE Our goal of the present study was to clarify the prognostic value of major CPX variables and the factors determining exercise capacity in a large cohort of Fontan patients. METHODS Since 1990, heart rate (HR), oxygen uptake (VO2 ), and ventilatory equivalent for carbon dioxide production (VE/VCO2 ) at peak exercise were determined in 335 Fontan patients (18 ± 5 years old), and the CPX variables were compared with the clinical profile and events. RESULTS When compared with 209 controls, peak HR (148 ± 24 bpm), VO2 (27 ± 7 mL/kg/minute, [61 ± 15%]), and VE/VCO2 (40 ± 8 [117 ± 24%]) were markedly impaired in the Fontan patients (P < .0001). During a follow-up of 3.1 ± 2.7 years, 62 Fontan pathophysiological-associated events requiring unscheduled hospitalization (USH) occurred, and 24 patients died. All the CPX variables predicted the USH and mortality (P < .001-.0001). On multivariate analysis, in addition to use of diuretics (P = .0007) and low cardiac index (P = .0426), peak VO2 independently predicted the USH (hazard ratio: 0.95 per %, 95% confidence interval: 0.91-0.99, P = .014), while for mortality, multivariate analysis revealed that, in addition to heterotaxy syndrome (P = .0128) and year at first Fontan operation (P = .0532), peak VO2 independently predicted mortality (hazard ratio: 0.88 per %, 95% confidence interval: 0.76-0.98, P = .0217). CONCLUSION Fontan patients exhibit markedly impaired CPX variables, and all the major variables, especially peak VO2 , predicted the risk of both morbidity and mortality.

Prevalence and predictors of haemostatic complications in 412 Fontan patients: their relation to anticoagulation and haemodynamics

OBJECTIVES Our aim in the present study was to determine the prevalence of haemostatic events in our Fontan patients, to identify predictive factors and to determine their association with haemodynamics and anticoagulant therapy. METHODS We retrospectively evaluated 424 Fontan patients and examined correlations between postoperative haemodynamics and anticoagulant regimens with haemostatic events. RESULTS After exclusion of 12 patients with a mechanical valve at the time of Fontan operation, our 412 patients were sub-divided into 21 groups based on the therapeutic duration of warfarin and antiplatelet agent therapy. During the early 5- to 10-year postoperative period, patients receiving warfarin showed higher central venous pressure and lower arterial oxygen saturation (Sat) (P < 0.05-0.001). During a mean follow-up of 11.2 years, 29 (7.0%) haemostatic events occurred. With regard to haemorrhagic events, haemoptysis was most common (n = 13, 45%), followed by cerebral bleeds in 3 (10%). Of thrombo-embolic events, thrombosis in the Fontan pathway was the most common (n = 7, 24%), followed by cerebral infarction in 3. Early haemorrhagic events were associated with late Fontan operation and use of preoperative renin-angiotensin system blockers, while late events were related to heterotaxy syndrome, male gender and low Sat (P < 0.05-0.01). A low Sat was the only predictor of early postoperative thrombo-embolic events (P = 0.0192). Among the three subgroup analyses of fixed anticoagulant regimens, the most frequent haemorrhagic events were associated with long-term use of warfarin (P = 0.0033). None of the anticoagulant regimens that included warfarin and/or antiplatelet agents were independently associated with haemostatic events throughout the follow-up. CONCLUSIONS Anticoagulant regimens in Fontan patients varied widely with a significant trend for warfarin use in patients with impaired haemodynamics. Low arterial oxygenation may predict haemostatic events. The relatively high prevalence of haemorrhagic complications indicates the need for individualized anticoagulant administration throughout the follow-up.

Impact of Central Venous Pressure on Cardiorenal Interactions in Adult Patients with Congenital Heart Disease after Biventricular Repair

BACKGROUND Cardiorenal interactions adversely impact the prognosis in heart failure patients an effect which crucially involves increased central venous pressure (CVP). However, it is unclear whether the same pathophysiology operates in adults with congenital heart disease (CHD). PURPOSE The present study was designed to assess cardiorenal interactions in adults with CHD after biventricular repair. METHODS AND RESULTS We measured the kidney length (KL, cm/m) and renal resistive index (RI) in 77 consecutive patients and 30 controls. We also measured hemodynamics, plasma B-type natriuretic peptide level, 24-hour creatinine clearance, and peak oxygen uptake in each patient. The CVP correlated with the KL (r = 0.44, P <.001) and the RI was greater in the patients (P <.0001). The high RI was independently determined by the CVP, aortic pressure, and cardiac index (P <.05-.001), and correlated with the 24-hour creatinine clearance (r = -0.30, P <.05). The RI correlated closely with the neurohumoral activations and peak oxygen uptake (|r| = 0.45-0.50, P <.0001), and the patients with a traditional criteria of high RI (≥0.70) had a higher incidence of cardiovascular events that required unscheduled hospitalization (hazard ratio = 2.78, 95% confidence interval 1.26-6.10, P <.05). Multivariate Cox model with the cutoff values of KL ≥68 cm/m and RI ≥0.74 revealed that a greater KL (hazard ratio = 4.03, 95% confidence interval 1.46-11.1, P <.01) as well as B-type natriuretic peptide (P <.001) independently predicted the events. CONCLUSIONS Hemodynamics, especially a high CVP, independently predicted the enlarged kidney and abnormal intrarenal flow dynamics that are closely associated with heart failure severity and cardiovascular events in adults with CHD after biventricular repair.

Dopamine and serotonin uptake inhibitors on the release of dopamine and serotonin in the nucleus accumbens of young and aged rats

Nucleus accumbens (ACC) of young (4 months old) and aged (24 months old) Wistar rats were perfused with dopamine (DA) uptake blocker, cocaine, or the serotonin (5-HT) selective reuptake inhibitor, fluoxetine, through the microdialysis probe membrane, used to assess the dopamine transporter (DAT) or serotonin transporter (SERT) modulation. The basal extracellular DA release in the ACC was significantly lower in aged rats than young rats. Analysis of DA and 5-HT concentrations in the ACC with increased positive GFAP revealed that DA and DOPAC levels of aged rats were decreased to 55 and 60% of those in young rats, respectively. After co-perfusion with cocaine, both DA and 5-HT releases in the ACC were increased in the young and aged groups. However, the magnitude of the increased DA release was lower in aged rats than young rats. Co-perfusion with fluoxetine showed lower magnitude of the increased DA release in aged rats. It appears that the DAT and SERT system responds initially to ACC cell loss with age, and that especially ACC DAT in the aged rat is more degenerative compared with the young rats. These findings suggest that the serotonergic system with SERT in the remaining ACC neurons show an early adaptive response and resistance to the normal aging and maintain the multiple regulatory system in the ACC despite neural loss since the dopaminergic neurons in the aged animals are vulnerable to aging.

Low fasting plasma glucose level predicts morbidity and mortality in symptomatic adults with congenital heart disease

BACKGROUND Adults with complex congenital heart disease (ACHD) have a high prevalence of abnormal glucose regulation (AGR: impaired glucose tolerance and diabetes mellitus). However, the impact of AGR on the prognosis remains unclear. PURPOSE Our purpose was to clarify the prognostic value of AGR in ACHD. METHODS AND RESULTS We performed a 75 g oral glucose tolerance test in 438 consecutive patients with ACHD (age 26 ± 8 years), including 38 unrepaired, 148 Fontan, 252 biventricular, and 27 healthy subjects and investigated associations between AGR and clinical events that required hospitalization or caused deaths from all-causes. When compared with the healthy group, fasting blood glucose level (FPG, mg/dl) was lower in the unrepaired and Fontan subjects (p<0.05-0.01) and the prevalence of low FPG (≤ 80 mg/dl) was also higher in the unrepaired (58%), Fontan (47%), and biventricular group (33%) than in the healthy control (11%) (p<0.0001). Postprandial hyperglycemia (area under the curve of glucose: PG-AUC) was higher in all ACHD groups (p<0.0001 for all). New York Heart Association class and lower FPG independently predicted the hospitalization (FPG ≤ 84 mg/dl) and mortality (FPG ≤ 80 mg/dl) (p<0.05-0.0001), while the PG-AUC was not an independent predictor. When compared with the asymptomatic ACHD, symptomatic ACHD with lower FPG had high hazard ratios of 2.2 (95% confidence interval [CI]: 1.3-3.8, p<0.002) and 3.3 (95% CI: 1.2-11.9, p<0.03) for the hospitalizations and all-cause mortality, respectively. CONCLUSIONS Low FPG is not uncommon in ACHD and the low FPG predicts the morbidity and all-cause mortality in symptomatic ACHD.

Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy.

BACKGROUND The left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood. METHODS We reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study. RESULTS DCM onset ranged from 8 to 16 months. Initial treatment of their acute heart failure was successful in all 5 but 4 patients relapsed despite the usual dose of carvedilol (induction 0.02-maintenance 0.4mg/kg/day), and developed worsening heart failure. Brain natriuretic peptide (BNP) levels which increased again after the acute treatment had fallen subsequent to discontinuing or decreasing carvedilol. Over 24 months, LVFS had increased from 11±2% (mean±SD) to 34±5% (p<0.05), and %LVDd decreased from 149±27% to 108±11% (p<0.05). CONCLUSIONS LVRR was found at 2 years after the onset of DCM. Usual dose induction of carvedilol therapy can sometimes worsen heart failure after successful initial conventional treatment for the acute heart failure in DCM. Close control of carvedilol treatment may determine the prognosis of infantile DCM around 12 months old. It is prudent to increase low-dose carvedilol slowly corresponding with the BNP level.

Heart failure with preserved right ventricular ejection fraction in postoperative adults with congenital heart disease: A subtype of severe right ventricular pathophysiology

BACKGROUND Right ventricle (RV) may determine heart failure (HF) severity in adults with congenital heart disease (ACHD). However, the association of RV properties with clinical profiles remains unclear. PURPOSE To clarify the associations of RV properties with biomarkers, exercise capacity, and unscheduled hospitalization (USH) in postoperative ACHD patients. METHODS AND RESULTS We evaluated determinants of RV end-diastolic volume (EDVI, ml/m(2)) and pressure (EDP, mmHg) in 260 patients who were divided into 4 groups, i.e., those with RVEDVI<100 and EDP≥10 (A, n=49, 19%), those with RVEDVI≥100 with EDP≥10 (B, n=22), those with RVEDVI<100 and EDP<10 (C, n=134), and those with RVEDVI≥100 and EDP<10 (D, n=55). EDVI, EDP, and ejection fraction (EF, %) of the RV were independently associated with the corresponding value of the left ventricle (LV) (p<0.0001 for all). Group A had a RV-EF of 53±8 and was defined HF with preserved RV-EF (RV-HFpEF). Younger age, lower platelet count, and elevated plasma γ-glutamyltransferase independently predicted the RV-HFpEF. When the presence of pulmonary hypertension and LV-HFpEF was included in the analysis, these two factors independently predicted the presence of RV-HFpEF (p<0.05-0.001). On multivariate analysis, older age, number of surgeries, cardiac index, and RV systolic pressure independently determined peak oxygen uptake (PVO2, p<0.05) and RV outflow reconstruction independently predicted USH. The RV-HFpEF group showed the lowest PVO2 and highest incidence of USH among the 4 groups (p<0.05). CONCLUSIONS Impaired RV characteristics, especially RV-HFpEF, with liver dysfunction and lower platelet count predicted lower exercise capacity with a poorer prognosis in postoperative ACHD patients.

Hyperuricemia reflects global Fontan pathophysiology and associates with morbidity and mortality in patients after the Fontan operation

BACKGROUND Serum uric acid (UA, mg/dl) levels associate with the pathophysiology and prognosis in patients with chronic heart failure. PURPOSE To clarify the clinical significance of hyperuricemia (HUA, UA>7.0) in Fontan patients. METHODS AND RESULTS We prospectively measured UA in 197 child and 102 adult Fontan patients and compared the results with the clinical variables, including hemodynamics, exercise capacity, and plasma levels of norepinephrine (NE) and brain natriuretic peptide, and unscheduled hospitalization (USH), including all-cause mortality. The mean UA was 5.8 ± 1.7 and 66 patients (22%, 34% in the adults) showed HUA. HUA was associated with lower peak oxygen uptake only in adults (r = -0.35, p < 0.0001). In children the use of diuretics, central venous pressure, liver enzymes, NE, and plasma creatinine (Cr) independently associated with UA. Of those, in addition to hypoxia, the use of diuretics and Cr independently predicted HUA (p < 0.05-0.001). In adults, hypoxia, plasma levels of sodium and Cr independently determined UA. Of those, hypoxia and hyponatremia independently predicted HUA (p < 0.05-0.001). During a follow-up of 49 ± 27 months, 67 USH, including 17 deaths, occurred. In all patients, on univariate analysis, HUA predicted mortality (hazard ratio: 3.2, 95% confidence interval: 1.2-8.6, p = 0.0193). HUA predicted USH in all, adult and child Fontan patients (p<0.05-0.0001), however, these prognostic values, including for mortality, were not independent in the multivariate analyses. CONCLUSIONS UA reflects global postoperative Fontan pathophysiology, including the prognosis, with some differences between child and adult patients. However, the prognostic value of HUA may be limited in multivariate models in this particular cohort.