Characterization of skin sympathetic nerve activity in patients with cardiomyopathy and ventricular arrhythmia.

BACKGROUND: Heightened sympathetic nerve activity is associated with occurrence of ventricular arrhythmia (VA). OBJECTIVE: To investigate the association of skin sympathetic nerve activity (SKNA) and VA occurrence. METHODS: We prospectively enrolled 65 patients with severe cardiomyopathy. Of these, 39 had recent sustained VA episodes (VA-1 group), 11 had intractable VA undergoing sedation with general anesthesia (VA-2 group), and 15 had no known history of VA (VA-Ctrl group). All patients had simultaneous SKNA and electrocardiogram recording. SKNA was assessed using an average value (aSKNA), a variable value (vSKNA), and the number of bursts of SKNA (bSKNA). RESULTS: The VA-1 group had higher aSKNA and vSKNA compared with the VA-Ctrl group (aSKNA: 1.41 ± 0.53 µV vs 0.98 ± 0.41 µV, P = .003; vSKNA: 0.52 ± 0.22 µV vs 0.30 ± 0.16 µV, P < .001) and the VA-2 group (aSKNA: 0.83 ± 0.22 µV, P < .001; vSKNA: 0.23 ± 0.11 µV; P < .001). Although the VA-2 group had more VA episodes than the VA-1 group (median, 5 vs 2; P = .01), their SKNA was the lowest among the 3 groups. Multivariate Cox regression analysis showed that a higher aSKNA at baseline was an independent predictor of lower VA recurrence rate during a 417 ± 279-day follow-up (hazard ratio, 0.325; 95% confidence interval [CI], 0.119-0.883; P = .03). A >15% reduction in aSKNA after therapy was associated with a lower subsequent VA event rate (hazard ratio, 0.222; 95% CI, 0.057-0.864; P = .03). CONCLUSION: Patients with VA had increased SKNA as compared with control. Both SKNA and sustained VA could be suppressed by general anesthesia. The aSKNA at baseline was an independent predictor of VA recurrence.

Comparative outcomes of subcutaneous and transvenous cardioverter-defibrillators.

BACKGROUND: The comparative outcomes of subcutaneous implantable cardioverter-defibrillator (S-ICD) and transvenous ICD (T-ICD) have not been well studied. The aim of this study was to evaluate the safety and efficacy of currently available S-ICD and T-ICD. METHODS: The study included 86 patients who received an S-ICD and 1:1 matched to those who received single-chamber T-ICD by gender, age, diagnosis, left ventricular ejection fraction (LVEF), and implant year. The clinical outcomes and implant complications were compared between the two groups. RESULTS: The mean age of the 172 patients was 45 years, and 129 (75%) were male. The most common cardiac condition was hypertrophic cardiomyopathy (HCM, 37.8%). The mean LVEF was 50%. At a mean follow-up of 23 months, the appropriate and inappropriate ICD therapy rate were 1.2% vs. 4.7% (χ = 1.854, P = 0.368) and 9.3% vs. 3.5% (χ = 2.428, P = 0.211) in S-ICD and T-ICD groups respectively. There were no significant differences in device-related major and minor complications between the two groups (7.0% vs. 3.5%, χ = 1.055, P = 0.496). The S-ICD group had higher T-wave oversensing than T-ICD group (9.3% vs. 0%, χ = 8.390, P = 0.007). Sixty-five patients had HCM (32 in S-ICD and 33 in T-ICD). The incidence of major complications was not significantly different between the two groups. CONCLUSIONS: The efficacy of an S-ICD is comparable to that of T-ICD, especially in a dominantly HCM patient population. The S-ICD is associated with fewer major complications demanding reoperation.

Usefulness of Red Blood Cell Distribution Width to Predict Heart Failure Hospitalization in Patients with Hypertrophic Cardiomyopathy.

Red cell distribution width (RDW) has been associated with heart failure (HF) hospitalization in the general population, but the correlation to HF hospitalization in patients with hypertrophic cardiomyopathy (HCM) is unclear.Ninety-eight HCM patients without a history of HF were enrolled and RDW was assessed as a predictor.During a 16.8 ± 9.0 month follow-up period, 17 subjects were hospitalized due to HF. HF hospitalization patients had higher RDW than non-HF patients (14.7 ± 1.4% versus 13.0 ± 0.9%, P < 0.001). The cut-off value of RDW for predicting HF hospitalization was 14% with a sensitivity of 83.2% and a specificity of 82.7%. Multivariate analysis demonstrated that brain natriuretic protein (BNP) (HR 1.028, 95% CI 1.011-1.045, P = 0.001) and RDW (HR 1.711, 95% CI 1.042-2.809, P = 0.034) were predictors of HF hospitalization.High RDW is an independent predictor of HF hospitalization and might be useful for predicting the prognosis in HCM patients.

Main air pollutants and ventricular arrhythmias in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis.

OBJECTIVE: Previous studies of ambient air pollutants and ventricular arrhythmias in patients with implantable cardioverter-defibrillator (ICD) have yielded mixed results, and the association between air pollution and ventricular arrhythmias in these patients remains unclear. This study aimed to assess and quantify the association between exposure to major air pollutants [CO, inhalable particles (PM10), SO2, fine particulate matter (PM2.5), O3, and NO2] and the presence of ventricular arrhythmia in patients with ICD. METHODS: The Medline, PubMed, Web of Science, Global Health Library, Virtual Health Library, Population Information Online (POPLINE), and New York Academy of Medicine Grey Literature Report databases were searched to identify studies analyzing the association between ventricular arrhythmias in patients with ICD and the abovementioned main air pollutants. Pooled estimates were generated using a random-effects model or fixed-effects model, according to the value of heterogeneity. Heterogeneity within studies was assessed using Cochran's Q and I2 statistics. Funnel plots, Egger's regression test, and Begg's rank correlation method were used to evaluate publication bias. Sensitivity analyses were also conducted to evaluate the potential sources of heterogeneity. RESULTS: After a detailed screening of 167 studies, seven separate studies were identified. Ventricular arrhythmias in patients with ICD were found to be positively, but not significantly, associated with CO, PM10, SO2, PM2.5, and NO2, with a pooled estimate [odds ratio (OR) associated with each 10 µg/m3 increase in pollutant concentration, except for CO, which was associated with each 1 mg/m3 increase in concentration] of 1.03 [95% confidence interval (CI): 0.92-1.17, P = 0.59] for CO, 1.01 (95%CI: 0.97-1.05, P = 0.55) for PM10, 1.09 (95%CI: 0.95-1.24, P = 0.22) for SO2, 1.07 (95%CI: 0.95-1.21, P = 0.25) for PM2.5, and 1.06 (95%CI: 0.98-1.14, P = 0.16) for NO2. No increased risk of ventricular arrhythmias in patients with ICD was found to be associated with O3 (OR = 1.00; 95%CI: 0.98-1.01, P = 0.56). CONCLUSIONS: The results of this study provide little evidence that ambient air pollutants affect the risk of ICD discharges for treating ventricular arrhythmias.

RhoA/ROCK pathway regulates hypoxia-induced myocardial cell apoptosis.

OBJECTIVE: To observe the regulatory effects of RhoA/ROCK pathway on the apoptosis of cardiac myocyte induced by anoxia and its mechanism. METHODS: The model of cardiac myocyte anoxia was established. The beat pulsations and apoptosis rates after 1 h, 3 h, 6 h, 9 h and 12 h of anoxia were recorded and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspae-3 were detected, too. The apoptosis and the expressions of related proteins were detected after RNAi of RhoA and the inhibition of ROCK by Y-27632. RESULTS: The beat pulsations after 1 h, 3 h, 6 h, 9 h and 12 h decreased gradually but the apoptosis rates increased gradually, and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 were increasing along with the increasing duration of anoxia. The apoptotic rates after 1 h, 3 h, 6 h, 9 h and 12 h of anoxia were (4.360.98)%, (8.362.12)%, (15.323.62)%, (18.684.83)% and (24.566.22)%, respectively and decreased more significantly than control group in different time points of anoxia (P<0.05), and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 decreased significantly (P<0.05). The apoptosis rate and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 decreased significantly (P<0.05) after the inhibition of ROCK by Y-27632 (P<0.05). CONCLUSIONS: RhoA/ROCK pathway plays a critical role in the regulation of the apoptosis of cardiac myocyte induced by anoxia, which may be accompanied by regulating the activity of PI3K/AKT/Caspase-3 pathway.

A cross-sectional survey on the prevalence of anxiety symptoms in Chinese patients with premature ventricular contractions without structural heart disease.

BACKGROUND: Anxiety appears to be more common in patients with coronary artery disease (CHD) than in the general population, and anxiety symptoms may precede onset of CHD and play an important role in development of CHD. Little is known about the prevalence of anxiety symptoms in Chinese patients with premature ventricular contractions (PVCs). Our objective was to study anxiety symptoms and potential risk factors in a Chinese population with PVCs but without structural heart disease. METHODS: The Zung self-rating anxiety scale (ZSAS) was used to assess anxiety symptoms. Correlation between anxiety symptoms and socio-demographics and medical factors were analyzed by Logistic regression. RESULTS: Of 1144 patients with PVCs (487 males and 657 females), age (53 ± 23) years old, disease duration 1 month to 24 years, a total of 381 (33.3%) patients were categorized as having anxiety symptoms. Anxiety symptoms increased with age, low income, low education level, nationality, PVC count/24 hours, bad social support, village settlement type (P < 0.05). Multivariate Logistic regression indicated that six variables-education level, ethnic minorities, dwelling place, age, PVC count/24 hours, and social support-significantly and independently related with anxiety symptoms (P < 0.05). CONCLUSIONS: In the Chinese population, anxiety symptoms in subjects with PVCs were frequent. Education level, ethnic minorities, dwelling place, age, PVC count/24 hours, and social support were independent risk factors for anxiety symptoms. Further research on the relationship between PVCs and anxiety symptoms in China is necessary.

Depressive symptoms and risk factors in Chinese patients with premature ventricular contractions without structural heart disease.

HYPOTHESIS: Our objective was to study depressive symptoms and potential risk factors in Chinese persons with premature ventricular contractions (PVCs) without structural heart disease. METHODS: The Zung self-rating depression scale (ZSDS) was used to assess depressive symptoms. Correlations between depressive symptoms and sociodemographic and medical factors were analyzed by logistic regression. BACKGROUND: Prevalence of depressive symptoms in coronary heart disease (CHD) is higher that in the general population and those for the majority of other chronic symptoms in patients with premature ventricular contractions (PUCS). RESULTS: Of 1,144 patients with PVCs (488 males, 656 females), age 51 +/- 23 years, disease duration 1 mo - 23 y, a total of 309 (27%) patients were categorized as having depressive symptoms. Depressive symptoms increased with age, income, education level, nationality, PVC count/24h, society support, and settlement type (p < 0.05). Univariate logistic regression showed that being female, level of education, age, settlement type, and PVC count/24h significantly correlated with depressive symptoms (p < 0.05). Multivariate logistic regression indicated that 5 variables-female sex, education level, settlement type, age, and PVC count/24h significantly and independently related with depressive symptoms (p < 0.05). CONCLUSIONS: In the Chinese population, depressive symptoms in subjects with PVCs were frequent. The village settlement type, female sex, age, PVC count/24h, and education level were independent risk factors for depressive symptoms. Further research on the relationship between PVCs and depressive symptoms in China is necessary.

Same ablation may be used for frequent premature ventricular contractions and supraventricular tachycardia.

Radiofrequency catheter ablation (RFCA) has been increasingly used for the treatment of various kinds of cardiac arrhythmias over the past 20 years. RFCA of symptomatic premature ventricular contractions (PVCs) has been reported to be a safe and effective treatment option and may be considered in patients with extremely symptomatic or incapacitating cases who do not respond to medications. Long-term prognosis in patients with truly idiopathic PVCs is excellent, despite frequent recurrences of tachycardia. Sudden death is rare in patients with initially normal left and right ventricular function, in such patients, occult cardiomyopathy is usually identified on postmortem examination. Similarly, progression to diffuse cardiomyopathy is rare. Ablation of PVCs may equal that of supraventricular tachycardia in terms of success rate, safety. These new views will help understand the diagnosis and treatment method for frequent PVCs in patients without heart disease.

Relationship between autonomic innervation in crista terminalis and atrial arrhythmia.

BACKGROUND: The crista terminalis (CT) is known to initiate and maintain atrial arrhythmia, and is affected by autonomic tone, but the underlying mechanisms are poorly understood. This study sought to study the relation between autonomic innervation in CT and atrial arrhythmia. METHODS: Thirty adult canines were used in the present study. Tissues of the CT and the pectinate muscles (PM) were obtained from 10 dogs for electrophysiology studies. Furthermore, tissues of the superior CT, the inferior CT, and the PM were obtained from 10 dogs for immunohistochemistrical studies. Anti-growth-associated protein 43 (GAP43), anti-tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT) antibodies for immunocytochemical staining of cardiac nerves were performed to test the densities of autonomic nerve. Densities of I K,ACh in the superior CT, the inferior CT, and the PM cells were measured by patch clamp in the other 10 dogs. RESULTS: With the pacing cycle length decreased, the amplitude of delayed after depolarization (DAD) increased and DAD-induced triggered activity was induced in the CT but not in PM with norepinephrine administration. GAP-43 and TH-positive nerves in the superior CT and the inferior CT were all significantly higher than in the PM (GAP-43: 6,250 +/- 1,928 vs 1,247 +/- 747, 2,855 +/- 1,579 vs 1,247 +/- 747; TH: 3,140 +/- 1,240 vs 690 +/- 720, 1,210 +/- 980 vs 690 +/- 720; P < 0.01). Furthermore, the GAP-43 and TH-positive nerves in the superior CT were higher than in the inferior CT. However, there were no significant differences in ChAT-positive nerves and I K,ACh in the superior CT, the inferior CT, and the PM. CONCLUSIONS: The higher densities of adrenergic nerve in the CT play an important role in the genesis of atrial arrhythmia.

Effect of vagal stimulation and differential densities of M2 receptor and IK,ACh in canine atria.

OBJECTIVE: We investigated the electrophysiological effect of vagal stimulation (VS) on atrial myocardium in vivo and differential densities of M(2) receptor and acetylcholine-induced inward rectifier K(+) current (I(K,ACh)) to discuss the mechanisms of atrial fibrillation (AF). METHODS: With the monophasic action potential (MAP) recording technique, data from twenty-four sites, i.e. right atrial appendage (RAA), left atrial appendage (LAA), right atrium (RA) and left atrium (LA) were recorded by electrode probes, which were applied to the epicardial atrial surface of each dog. After cervical vagosympathetic cut, VS(1) (20 Hz, 0.2 ms pulse duration and at a voltage 10 V), VS(2) (20 Hz, 0.2 ms pulse duration and at a voltage 30 V) and sinus node (SN) damage were administrated respectively. MAP, dispersion of action potential duration (dAPD) and AF was recorded. Then, RAA, LAA, RA and LA were dissected. Finally, distribution of M(2) receptors and I(K,ACh) in atrial myocardium were measured by western blot and patch clamp respectively. RESULTS: During VS(1) and VS(2), AF could be induced at first in right atrial appendage (RAA) and right atrium (RA) without left atrial appendage (LAA) and left atrium (LA). Compared to the parameters in control group and VS(2) group, dAPD was increased significantly by VS(1) and SN damage, but there was no significant difference between control group and VS(2) group. However, AF was not evoked after SN damage. Densities of M(2) receptor and I(K,ACh) were higher in RAA, LAA than those in LA and RA (M(2) receptor: 1 and 1.01 over 0.83 and 0.51, P<0.05; I(K,ACh): 20+/-0.89, 19+/-0.82, 14+/-0.64, 9+/-0.45 pA/pF, P<0.05). Furthermore, densities of M(2) receptor and I(K,ACh) were higher in LA than those in RA (P<0.05). CONCLUSIONS: Decreased APD is the base in initiation of cholinergic AF by VS and increased dAPD alone can not induce AF. A greater abundance of M(2) receptor and I(KACh) in RAA and LAA imply atrial appendage plays an important role in initiation of cholinergic AF.

[Relationship between alpha- and beta-isoform of corticosteroid receptors and corticosteroid resistant allergic rhinitis].

OBJECTIVE: To clarify the relationship between the expression of alpha- and beta-isoform of corticosteroid receptors (CS) in peripheral blood mononuclear cell (PBMC) and response to corticosteroid in patients with allergic rhinitis (AR). METHODS: Semi-quantitative RT-PCR was used to detect the expression of CS-alpha, beta in PBMC in patients with AR and to observe the different responses to corticosteroid in controls. Immunocytochemical assay was used to detect the expression of protein of CS-alpha and CS-beta. RESULTS: 1) The expression of CS-alpha mRNA was detected in the sensitive group and the resistant group of patients with AR and the controls with CS-alpha/GAPDH mRNA (x +/- s) 1.15 +/- 0.75, 1.63 +/- 0.78, 1.27 +/- 0.51 respectively. 2) The expression of CS-beta mRNA in PBMC in the resistant group of patients with AR was significantly higher than that in the sensitive group and the controls (P < 0.05), with CS-beta/GAPDH mRNA 1.42 +/- 0.73, 0.82 +/- 0.59, 0.80 +/- 0.68 respectively. 3) The number of CS-beta-positive PBMC in the resistant group was significantly higher than that in the sensitive group and the controls (P < 0.01), with the number of CS-beta-positive PBMC 28.8% +/- 9. 9%, 5.9% +/- 3.2%, 5.5% +/- 6.8% respectively. CONCLUSIONS: It is shown that the excessive expression of CS-beta may serve as a novel predictor of corticosteroid resistance in patients with AR.

The research of molecular and ionic mechanisms in vagally mediated atrial fibrillation in canine.

BACKGROUND: The reentrant mechanism of vagally mediated AF is not clearly elucidated. METHODS AND RESULTS: After vagal stimulation, thirty dogs were divided AF group (AF could be induced) and control group (AF could not be induced). Western blot and patch clamp were used to determine M(2) receptor and I(K,ACh) in left atrial appendage (LAA), right atrial appendage (RAA), left atrium (LA), right atrium (RA), pulmonary veins (PVs) and superior vena cava (SVC). In control group, the densities of M(2) receptor and I(K,ACh) in LAA, RAA and LA were higher than that in RA, PVs and SVC. However, there was no significant difference in LAA, RAA and LA. In AF group, the densities of M(2) receptor and I(K,ACh) in LAA, RAA and LA were higher than that in RA, PVs and SVC. Furthermore, the densities of the M(2) and I(K,ACh) in LAA and RAA were higher than that in LA. CONCLUSIONS: Atrial appendage perhaps play an important role in initiation of cholinergic AF. However, PVs and SVC less often play an important role in vagotonic paroxysmal AF.

Quality of life and cost for patients with premature ventricular contractions by radiofrequency catheter ablation.

OBJECTIVE: To evaluate the quality of life (QoL), health-care resource utilization, and cost for the patients with premature ventricular contractions (PVCs) by radiofrequency catheter ablation (RFCA). METHODS: RFCA was performed in 58 patients with symptomatic PVCs that were refractory/easy to medication. A 24-hour ambulatory electrocardiographic monitoring, QoL, health-care resources utilization, and cost were assessed at a screening visit and 3 and 12 months after RFCA. RESULTS: RFCA was successfully performed in 56 patients (96.6%). This resulted in a significant improvement in the QoL at 3 and 12 months after the procedure. There were no major complications related to the procedure. Nine patients (15.5%) had residual arrhythmia. Seven of them underwent repeated ablation with successful results. It also improved the QoL and reduced health-care resource utilization and cost. CONCLUSIONS: RFCA is a safe and effective treatment for PVCs, and it is a viable alternative to drugs in the presence of disabling symptoms.

Differential densities of muscarinic acetylcholine receptor and I(K,ACh) in canine supraventricular tissues and the effect of amiodarone on cholinergic atrial fibrillation and I(K,ACh).

BACKGROUND: Vagal nerve plays an important role in the induction and maintenance of atrial fibrillation (AF). This study investigated the differential densities of M2 receptor and acetylcholine-induced inward rectifier K+ current (I(K,ACh)) in atrial appendage, atrium, pulmonary vein (PV) and super vena cava (SVC) to discuss the role of atrial appendage and PV in cholinergic AF. METHODS AND RESULTS: In 10 dogs, action potential duration was determined at 24 sites during bilateral cervical vagal stimulation and amiodarone administration. AF could be induced at first in right atrial appendage (RAA) and right atrium (RA) without left atrial appendage (LAA) and left atrium (LA). Amiodarone decreased the initiation of AF in vivo. Western blot and patch clamp were used to determine M2 receptor and I(K,ACh) in RAA, LAA, RA, LA, PV and SVC. The densities of M2 receptor and I(K,ACh) in LAA, RAA and LA were higher than that in RA, PV and SVC (21.34 +/- 0.92 vs. 8.24 +/- 0.45 pA/pF, p < 0.05). Furthermore, the densities of the M2 receptor and I(K,ACh) in LAA and RAA were higher than that in LA (21.34 +/- 0.92 vs. 14.17 +/- 0.65 pA/pF, p < 0.05). After amiodarone administration, densities of I(K,ACh) in LA and RA were not different, but densities of I(K,ACh )were also less in atrium than in atrial appendage. CONCLUSIONS: Densities of the M2 receptor and I(K,ACh) are higher in atrial appendage than other sites. Atrial appendage perhaps plays an important role in initiation of cholinergic AF. However, PV and SVC less often play an important role in vagotonic paroxysmal AF. Reduced dispersion of I(K,ACh) is the mechanism for amiodarone to therapy AF.

Effects of venlafaxine on p90Rsk activity in rat C6-gliomas and brain.

The intracellular actions of the antidepressant, venlafaxine, were studied in C6-gliomas using a phosphoproteomics approach. Long-term pre-treatment of C6-gliomas with venlafaxine followed by an acute challenge with isoproterenol (a beta-adrenoceptor agonist), resulted in increased p90Rsk phosphorylation (three-fold) versus control levels (isoproterenol alone). The effect of venlafaxine pre-treatment on p90Rsk activity was dose-dependent (EC(50)=3.75nM) in C6 gliomas. In rat brain sections, intense immunoreactive phospho-p90Rsk labeling was observed for both neurons and glia, especially in cortical layers II/III and hippocampal formations. In vivo studies demonstrated an intense but similar distribution pattern of phospho-p90Rsk staining after chronic venlafaxine dosing of rats compared to naives and no region-specific drug effect was observed in vivo. In conclusion, our findings suggest that some of the centrally-mediated benefits of venlafaxine in depression may be due to its intracellular properties especially on the neuro-glial circuitry and MAPK/p90Rsk-dependent pathways at an early stage.

Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies.

It is recognized that monoamine reuptake inhibitors (MARIs) exert beneficial effects in the treatment of major depression and general anxiety disorder. The aim of this study was to identify proteins regulated by this class of antidepressant using a proteome differential profiling approach. Either venlafaxine or fluoxetine was administered systemically to adult rats for 2 weeks, and protein patterns from rat hippocampal cytosolic extracts were compared by two-dimensional gel electrophoresis. Silver-stained protein spots displaying differential expression were identified by mass spectrometry. Thirty-three protein spots were modulated by both drug treatments compared to controls. The classification of several proteins that were sorted by function suggested convergent pathway activities for both MARIs at the post-receptor level. These included proteins associated with neurogenesis (insulin like growth factor 1 (IGF-1), glia maturation factor [GMF]-beta), outgrowth/maintenance of neuronal processes (hippocampal cholinergic neurostimulating peptide [HCNP], PCTAIRE-3), and with neural regeneration/axonal guidance collapsin response mediator protein (CRMP-2) systems. Other modulated proteins indicated an increase in neuronal vesicular cell trafficking and synaptic plasticity (Ras-related protein 4a (Rab4a), Ras-related protein 1b (Rab1b), heat shock protein 10 [HSP10]), as well as neurosteroidogenic (hydroxysteroid sulfotransferase A) and possible anti-apoptotic (dimethylargininase-1 L-N,N-dimethylarginine dimethylaminohydrolase-1 [DDAH-1], pyruvate dehydrogenase-E1 [PDH-E1], antioxidant protein-2 [AOP-2]) pathway-mediated regulatory events. Parallel studies to investigate further the effects of venlafaxine and fluoxetine on adult hippocampal neurogenesis in vivo by quantitative bromodeoxyuridine immunolabeling revealed a significant drug-induced increase in the proliferation rate and long-term survivability of progenitor stem cells located in the subgranular zone. These data suggest that MARIs share wide-ranging proteome changes within the hippocampal formation, beyond 5-HT/NE neurotransmission. This may reflect long-term functional adaptations required for antidepressant activity.