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ContextPrimary aldosteronism (PA) patients have a higher degree of arterial stiffness, which can be reversed after adrenalectomy.ObjectiveWe aimed to compare the reversal of arterial stiffness between surgically and medically treated PA patients and to identify the predictors of effective medical treatment.MethodsWe prospectively enrolled 445 PA patients and collected data on baseline clinical characteristics, biochemistry, blood pressure, and pulse wave velocity (PWV) before treatment and 12 months after treatment. In the mineralocorticoid receptor antagonist (MRA)-treated patients, the relationship between the change in PWV after 1 year (ΔPWV) and posttreatment renin activity was explored using the restricted cubic spline (RCS) method.ResultsOf the 445 enrolled PA patients, 255 received adrenalectomy (group 1) and 190 received MRAs. In the RCS model, posttreatment plasma renin activity (PRA) 1.5 ng/mL/h was the best cutoff value. Therefore, we divided the MRA-treated patients into 2 groups: those with suppressed PRA (< 1.5 ng/mL/h, group 2), and those with unsuppressed PRA (≥ 1.5 ng/mL/h, group 3). Only group 1 and group 3 patients had a statistically significant improvement in PWV after treatment (both P < .001), whereas no significant improvement was noted in group 2 after treatment (P = .151). In analysis of variance and post hoc analysis, group 2 had a significantly lower ΔPWV than group 1 (P = .007) and group 3 (P = .031). Multivariable regression analysis of the MRA-treated PA patients identified log-transformed posttreatment PRA, age, and baseline PWV as independent factors correlated with ΔPWV.ConclusionThe reversal of arterial stiffness was found in PA patients receiving adrenalectomy and in medically treated PA patients with unsuppressed PRA.

Background: Coronary cameral fistula is a rare cardiovascular anomaly, and usually needs advanced image modalities, such as computerized tomography and/or angiography, to confirm its existence. A few reports in the literature have addressed the role of medical ultrasound in the diagnosis of this disease, without a comprehensive summary of all the valuable echocardiographic features in its diagnosis. Case presentation: Hereby, we presented an 80-year-old lady with exertional dyspnea and angina. We diagnosed coronary cameral fistula from the left anterior descending artery into the left ventricle by echocardiography with “intramyocardial vascular channel and the diastolic flow”, and “multiple diastolic flow jets into heart chamber from heart wall”. We confirmed the diagnosis with coronary angiography later. In the discussion, we make a comprehensive summary to conclude all the echocardiographic findings of this disease into 3 categories. Conclusion: We believe the identification of those findings will prompt the early diagnosis of this rare anomaly.

Primary aldosteronism is the most common secondary endocrine form of hypertension and causes many cardiovascular injuries. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma. However, their impacts on left ventricular remodeling precluding the interference of age, sex, and blood pressure are still uncertain. We enrolled 184 aldosterone-producing adenoma patients who received adrenalectomy. Clinical, biochemical, and echocardiographic data were analyzed preoperatively and 1 year postoperatively. KCNJ5 gene sequencing of aldosterone-producing adenoma was performed. After propensity score matching for age, sex, body mass index, blood pressure, hypertension duration, and number of hypertensive medications, there were 60 patients in each group with and without KCNJ5 mutations. The mutation carriers had higher left ventricular mass index (LVMI) and inappropriately excessive LVMI (ieLVMI) and lower e′ than the noncarriers. After adrenalectomy, the mutation carriers had greater decreases in LVMI and ieLVMI than the noncarriers. In addition, only mutation carriers had a significant decrease in E/e′ after surgery. In multivariate analysis, baseline LVMI correlated with KCNJ5 mutations, the number of hypertensive medications, and systolic blood pressure. Baseline ieLVMI correlated with KCNJ5 mutations and the number of hypertensive medications. The regression of both LVMI and ieLVMI after surgery was mainly correlated with KCNJ5 mutations and changes in systolic blood pressure. Aldosterone-producing adenoma patients with KCNJ5 mutations had higher LVMI and ieLVMI and a greater regression of LVMI and ieLVMI after adrenalectomy than those without mutations. The patients with KCNJ5 mutations also benefited from adrenalectomy with regard to left ventricular diastolic function, whereas noncarriers did not.

Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with worse cardiovascular outcomes. The elevated aldosterone in PA leads to left ventricular (LV) remodeling and dysfunction. In recent decades, clinical studies have demonstrated worse LV remodeling including increased LV mass and cardiac fibrosis in patients with PA compared to patients with essential hypertension. Several mechanisms may explain the process of aldosterone-induced LV remodeling, including directly profibrotic and hypertrophic effects of aldosterone on myocardium, increased reactive oxygen species and profibrotic molecules, dysregulation of extracellular matrix metabolism, endothelium dysfunction and circulatory macrophages activation. LV remodeling causes LV diastolic and systolic dysfunction, which may consequently lead to clinical complications such as heart failure, atrial fibrillation, ischemic heart disease, and other vascular events. Adequate treatment with adrenalectomy or medical therapy can improve LV remodeling and dysfunction in PA patients. In this review, we discuss the mechanisms of aldosterone-induced LV remodeling and provide an up-to-date review of clinical research about LV remodeling-related heart structural changes, cardiac dysfunction, and their clinical impacts on patients with PA.

Primary aldosteronism (PA) is the most common cause of secondary hypertension. Increasing evidence has demonstrated an increased cardiovascular risk in patients with PA compared to those with essential hypertension (EH), including atrial fibrillation (AF), the most prevalent arrhythmia among adults that is associated with an elevated risk of subsequent cerebro-cardiovascular adverse events. The mechanisms of increased prevalence of AF in PA patients are complex. Excessive aldosterone production is regarded to be a key component in the pathogenesis of AF, in addition to arterial hypertension and electrolyte imbalance. In addition, several translational and clinical studies have reported that structural remodeling with atrial fibrosis and electrical remodeling with arrhythmogenicity induced by an excess of aldosterone also play major roles in AF genesis. Clinical studies from several registries and meta-analysis have reported an increased prevalence and risk of AF in PA patients compared to EH patients. Recent trials have further demonstrated a reduction in the risk of new-onset atrial fibrillation (NOAF) after adrenalectomy, while the results of medical treatment with mineralocorticoid receptor antagonists (MRAs) have been inconsistent. This review outlines the current evidence of the relationship between PA and AF, and highlights recent progress in the management of PA with regards to the development of AF.

Excessive aldosterone secretion causes endothelial dysfunction, vascular inflammation, and vascular fibrosis in patients with primary aldosteronism (PA). Endothelial function is closely related to endothelial mitochondria. However, the effects of elevated aldosterone levels on endothelial mitochondria remain unclear. In this study, we used primary cultured human umbilical vein endothelial cells (HUVECs) to investigate the effects of aldosterone on endothelial mitochondria. Mineralocorticoid receptor (MR) small interfering (si)RNA or glucocorticoid receptor (GR) siRNA were used to confirm the pathway by which aldosterone exerts its effects on the mitochondria of HUVECs. The results showed that excess aldosterone suppressed mitochondrial DNA copy numbers, anti-mitochondrial protein, and SOD2 protein expression in a dose- and time-dependent manner. These effects were attenuated by treatment with MR siRNA, but not with GR siRNA. Furthermore, it was attenuated by treatment with a mitochondria-targeted antioxidant (Mito-TEMPO, associated with mitochondrial reactive oxygen species (ROS) production), but not N-acetyl-L-cysteine (associated with cytosolic ROS production), which suggests that the process was through the mitochondrial ROS pathway, but not the cytosolic ROS pathway. In conclusion, aldosterone excess suppressed endothelial mitochondria through the MR/mitochondrial ROS pathway.

Background: Aldosterone excess in primary aldosteronism (PA) has been linked to insulin resistance, and diabetes mellitus has been associated with increased arterial stiffness and worse cardiovascular outcomes. However, the impact of diabetes on baseline and post-treatment arterial stiffness in patients with PA is unknown. Methods: This study prospectively enrolled 1071 PA patients, of whom 177 had diabetes and 894 did not. Clinical, biochemical, and brachial-ankle pulse wave velocity (baPWV) data were analyzed at baseline and 1 year after PA-specific treatment. After propensity score matching of age, sex, body mass index, systolic and diastolic blood pressure, hypertension duration, and number of antihypertensive medications, 144 patients with diabetes and 320 without diabetes were included for further analysis. Results: After propensity score matching, the baseline characteristics were balanced between the diabetes and nondiabetes groups except for fasting glucose, HbA1c, and lipid profiles. The patients with diabetes had significantly worse baseline baPWV compared with those without diabetes. After multivariable linear regression, the presence of diabetes mellitus remained a significant predictor of worse baseline mean baPWV (β: 46.3, 95% confidence interval: 2.9–89.7, p = 0.037). After 1 year of PA-specific treatment, only the nondiabetes group had significant recovery of mean baPWV (1661.8 ± 332.3 to 1565.0 ± 329.2 cm/s, p Conclusion: The presence of diabetes mellitus in PA patients was associated with worse baseline and less post-treatment recovery of arterial stiffness.

ObjectivePrimary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status.MethodsWe enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed.ResultsAfter propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, PConclusionKCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.

Objective The presence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is common and potentially associated with poor outcomes. The aim of this study was to investigate the association between ACS and vascular remodeling in PA patients. Design and methods We prospectively enrolled 436 PA patients from October 2006 to November 2019. ACS (defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test) was detected in 23% of the PA patients. Propensity score matching (PSM) with age, sex, systolic and diastolic blood pressure was performed. The brachial-ankle pulse wave velocity (baPWV) was examined at baseline and 1 year after targeted treatment. Small arteries of periadrenal fat in 46 patients were stained with Picro Sirus red to quantify the severity of vascular fibrosis. Results After PSM, the PA patients with ACS had a significantly higher prevalence of diabetes mellitus, higher plasma aldosterone concentration and higher aldosterone-to-renin ratio. The baseline mean baPWV was also significantly higher in the PA patients with ACS. After multivariable regression analysis, the presence of ACS was a significant predictor of worse baseline mean baPWV (β: 235.745, 95% CI: 59.602–411.888, P = 0.010). In addition, the PA patients with ACS had worse vascular fibrosis (fibrosis area: 25.6 ± 8.4%) compared to those without ACS (fibrosis area: 19.8 ± 7.7%, P = 0.020). After 1 year of PA treatment, baPWV significantly improved in both groups. Conclusion The presence of ACS in PA patients is associated with worse arterial stiffness and vascular remodeling.

Simple Summary Primary aldosteronism (PA) is the most common form of secondary hypertension and induces various cardiovascular injuries. Aldosterone-producing adenoma (APA) is one of the major forms of PA. The occurrence of APA is closely correlated with somatic mutations, including KCNJ5. We described here the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of age, sex, and blood pressure status. We found KCNJ5 mutation carriers had similar arterial stiffness before surgery, but greater improvement of arterial stiffness after adrenalectomy compared with non-carriers. Hence, APA patients with KCNJ5 mutations had a greater improvement in arterial stiffness after adrenalectomy than those without mutations. Abstract Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were scheduled to undergo adrenalectomy. KCNJ5 gene sequencing of APA was performed. After propensity score matching (PSM) for age, sex, body mass index, blood pressure, number of hypertensive medications, and hypertension duration, there were 66 patients in each group with and without KCNJ5 mutations. The mutation carriers had a higher aldosterone level and lower log transformed brachial–ankle pulse wave velocity (baPWV) than the non-carriers before PSM, but no difference in log baPWV after PSM. One year after adrenalectomy, the mutation carriers had greater decreases in log plasma aldosterone concentration, log aldosterone–renin activity ratio, and log baPWV than the non-carriers after PSM. Only the mutation carriers had a significant decrease in log baPWV after surgery both before and after PSM. KCNJ5 mutations were not correlated with baseline baPWV after PSM but were significantly correlated with ∆baPWV after surgery both before and after PSM. Conclusively, APA patients with KCNJ5 mutations had a greater regression in arterial stiffness after adrenalectomy than those without mutations.

ObjectivesPatients with primary aldosteronism (PA) have cardiac remodeling due to hemodynamic and non-hemodynamic causes. However, component analysis of cardiac remodeling and reversal in PA patients is lacking. We investigated components of cardiac remodeling and reversal after adrenalectomy in patients with aldosterone-producing adenoma (APA).MethodsThis study prospectively enrolled 304 APA patients who received adrenalectomy and 271 with essential hypertension (EH). Clinical, biochemical and echocardiographic data were collected in both groups and 1 year after surgery in the APA patients. The hemodynamic and non-hemodynamic components of left ventricular (LV) remodeling were represented by predicted left ventricular mass index (LVMI) (pLVMI) and inappropriately excessive LVMI (ieLVMI, defined as LVMI-pLVMI).ResultsAfter propensity score matching, 213 APA and 213 EH patients were selected. APA patients had higher hemodynamic (pLVMI) and non-hemodynamic (ieLVMI) components of LV remodeling than EH patients. In multivariate analysis, baseline pLVMI was correlated with systolic blood pressure (SBP) and serum potassium, whereas ieLVMI was correlated with log plasma aldosterone concentration but not blood pressure. Post-operative echocardiography was available in 207 patents and showed significant decreases in both pLVMI and ieLVMI after adrenalectomy. In multivariate analysis, ΔpLVMI was correlated with SBP, ΔSBP, and pre-operative pLVMI, whereas ΔieLVMI was correlated with Δlog aldosterone-to-renin ratio (ARR) and pre-operative ieLVMI.ConclusionsThis study concluded that extensive cardiac remodeling in APA patients occurs through hemodynamic and non-hemodynamic causes. Adrenalectomy can improve both hemodynamic and non-hemodynamic components of LV remodeling. Regressions of pLVMI and ieLVMI were correlated with decreases in blood pressure and ARR, respectively.

BackgroundPrimary aldosteronism (PA) is a common cause of secondary hypertension and associated with higher incidence of new-onset atrial fibrillation (NOAF). However, the effects of surgical or medical therapies on preventing NOAF in PA patents remain unclear. The aim of this meta-analysis study was to assess the risk of NOAF among PA patients receiving mineralocorticoid receptor antagonist (MRA) treatment, PA patients receiving adrenalectomy, and patients with essential hypertension.MethodsWe performed the meta-analysis of the randomized or observational studies that investigated the incidence rate of NOAF in PA patients receiving MRA treatment versus PA patients receiving adrenalectomy from database inception until December 01, 2020 which were identified from PubMed, Embase, and Cochrane Library.ResultsA total of 172 related studies were reviewed, of which three fulfilled the inclusion criteria, including a total of 2,705 PA patients. The results of meta-analysis demonstrated a higher incidence of NOAF among the PA patients receiving MRA treatment compared to the PA patients receiving adrenalectomy (pooled odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.76–4.57 in the random effects model, I2 = 0%). The pooled OR for the PA patients receiving MRA treatment compared to the patients with essential hypertension was 1.91 (95% CI: 1.11–3.28). The pooled OR for the PA patients receiving adrenalectomy compared to the patients with essential hypertension was 0.70 (95% CI: 0.28–1.79).ConclusionCompared to the essential hypertension patients and the PA patients receiving adrenalectomy, the patients with PA receiving MRA treatment had a higher risk of NOAF.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42021222022.

Elevated serum aldosterone promotes arterial hypertension, cardiac hypertrophy, and diastolic dysfunction. However, the effect of elevated aldosterone levels on cardiac mitochondria remains unclear. We used primary cultures of mouse cardiomyocytes to determine whether aldosterone has direct effects on cardiomyocyte mitochondria, and aldosterone-infused mice as a preclinical model to evaluate the impact of aldosterone in vivo. We show that aldosterone suppressed mtDNA copy number and SOD2 expression via the mineralocorticoid receptor (MR)-dependent regulation of NADPH oxidase 2 (NOX2) and generation of reactive oxygen species (ROS) in primary mouse cardiomyocytes. Aldosterone suppressed cardiac mitochondria adenosine triphosphate production, which was rescued by N-acetylcysteine. Aldosterone infusion for 4 weeks in mice suppressed the number of cardiac mitochondria, mtDNA copy number, and SOD2 protein expression. MR blockade by eplerenone or the administration of N-acetylcysteine prevented aldosterone-induced cardiac mitochondrial damage in vivo. Similarly, patients with primary aldosteronism had a lower plasma leukocyte mtDNA copy number. Plasma leukocyte mtDNA copy number was positively correlated with 24-hour urinary aldosterone level and left ventricular mass index. In conclusion, aldosterone suppresses cardiac mitochondria in vivo and directly via MR activation of ROS pathways.

The aim of this study was to update the information on internationally acceptable standards and clinical practice recommendations for the management of patients with primary aldosteronism (PA). The Taiwan Society of Aldosteronism (TSA) Task Force acknowledged the novel issues of PA and reached a group consensus on PA in Taiwan by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. Unilateral adrenalectomy is the preferred treatment for patients with aldosterone-producing adenoma (APA). For medical treatment with mineralocorticoid receptor antagonists (MRAs), spironolactone is the first-line treatment, and eplerenone is a reasonable alternative in PA patients intolerant or contraindicated to spironolactone. The dose of MRAs can be titrated according to plasma renin activity (PRA). For screening PA-related comorbidities, we suggest albuminuria to predict a post-treatment decline in renal function, echocardiography as cardiac evaluation, bone mineral density scan for osteoporosis, and obstructive sleep apnea. In tissue and genetic surveys, we suggest immunohistochemical staining and somatic mutation screening for post-operative adrenal specimens in APA patients. With this consensus, we hope to update the information on PA for clinical physicians to facilitate better identification, management and treatment of patients with PA.

Background Primary aldosteronism ( PA ) is associated with higher atrial fibrillation prevalence and other cardiovascular complications. However, the effect of target treatment to prevent new‐onset atrial fibrillation ( NOAF ) remains unclear. This study investigated incidence of NOAF under different treatment strategies in patients with PA. Methods and Results We analyzed longitudinal data for patients with PA without atrial fibrillation history from 1997 to 2009 within the National Health Insurance Research Database in Taiwan. Patients with essential hypertension matched by propensity score were enrolled as controls. The primary outcome measurement was NOAF , and secondary outcome measurements were mortality, major cardiac and cardiac/cerebrovascular events, and a combined end point of NOAF and mortality. We identified 2202 patients with PA (534 adrenalectomy, 1668 mineralocorticoid receptor antagonist [MRA] therapy) and 8808 essential hypertension controls with mean follow‐up of 4.4 years. In primary outcome measurement, patients with PA who underwent adrenalectomy had a lower incidence of NOAF (adjusted hazard ratio; 0.28, P =0.011) than controls. In contrast, the patients with PA who received MRA therapy had comparable risk of NOAF (adjusted hazard ratio, 1.20; P =0.224). In secondary outcome measurement, patients with PA who underwent adrenalectomy had a lower rate of mortality and combined end point of NOAF and mortality than controls. Patients with PA who received MRA therapy had a higher risk of mortality, major cardiac and cardiac/cerebrovascular events, and combined NOAF with mortality than the essential hypertension controls. Conclusions Compared with patients with essential hypertension, patients with PA who underwent adrenalectomy had a lower incidence of NOAF . However, this finding was not observed in patients with PA who received MRA therapy with a lower dose. Differences between the 2 strategies may reduce with a higher dose of MRA therapy.

BACKGROUND Primary aldosteronism is associated with a higher incidence of left ventricular (LV) hypertrophy and diastolic dysfunction than essential hypertension. However, systolic function via endocardial measurements is similar between patients with primary aldosteronism and essential hypertension. Speckle-tracking echocardiography is a sensitive tool which can detect subclinical impairments in systolic function. The aim of this study was to investigate aldosterone-induced subclinical impairments in systolic function. METHODS We prospectively enrolled patients with primary aldosteronism and essential hypertension and analyzed their clinical data, biochemical data, and echocardiographic parameters, including myocardial strain [global longitudinal strain (GLS)]. RESULTS Thirty-six patients with primary aldosteronism and 31 patients with essential hypertension were enrolled for analysis. The patients with primary aldosteronism had significantly lower serum potassium levels, lower plasma renin activity, higher aldosterone-to-renin ratio (ARR), and higher 24-h urinary aldosterone levels than patients with essential hypertension. With regards to echocardiographic parameters, the patients with primary aldosteronism had a thicker ventricular wall and higher LV mass index than those with essential hypertension. Most importantly, we found significant degradation of GLS in the patients with primary aldosteronism compared with those with essential hypertension (-17.84 ± 2.36 vs. -20.13 ± 2.32, P

// Chi-Sheng Hung 1 , Xue-Ming Wu 2 , Ching-Way Chen 3 , Ying-Hsien Chen 1 , Vin-Cent Wu 1 , Che-Wei Liao 4 , Yi-Yao Chang 5 , Ruh-Fang Yen 6 , Ching-Chu Lu 6 , Mao-Yuan M. Su 7 , Kao-Lang Liu 7 , Chin-Chen Chang 7 , Li-Yu Daisy Liu 8 , Kwan-Dun Wu 1 , Yen-Hung Lin 1 and the TAIPAI Study Group 1 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan 3 Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan 4 Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan 5 Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan 6 Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 7 Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 8 Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan Correspondence to: Yen-Hung Lin, email: austinr34@gmail.com Keywords: primary aldosteronism, salt intake, left ventricular mass, TAIPAI Received: December 08, 2016 Accepted: April 05, 2017 Published: April 28, 2017 ABSTRACT Salt intake is highly associated with cardiac structure in patients with primary aldosteronism (PA). We investigated the association among dietary salt intake, aldosterone and left ventricular mass in patients with PA. We enrolled 158 patients with PA and 158 patients with essential hypertension. We measured 24-hour urinary sodium (UNa) and aldosterone (UAldo) level and echocardiography parameters. In patients with PA, the UAldo level was positively correlated with left ventricular mass index (LVMI; r=0.231, p=0.007). The UNa level was not linearly correlated with left ventricular structural parameters in patients with PA. To test if UNa has a non-linear relationship with LVMI among patients with PA, we categorized the participants according to the tertile of UNa (low, median, and high tertile). PA patients with medium tertile of UNa had significant lower LVMI than the other two groups (LVMI: 144.1 ± 42.9, 121.1 ± 33.4, and 136.7 ± 32.8 g/m2, from the lowest to the highest tertile of Una; analysis of variance p=0.006, post-hoc p

Background Primary aldosteronism is the most common cause of secondary hypertension and is associated with left ventricular hypertrophy. However, whether aldosterone excess is responsible for left ventricular (LV) diastolic dysfunction is unknown. Methods and Results We prospectively enrolled 129 patients with aldosterone‐producing adenoma and 120 patients with essential hypertension, and analyzed their clinical, biochemical, and echocardiographic data, including tissue Doppler images. The patients with aldosterone‐producing adenoma were reevaluated 1 year after adrenalectomy. After propensity score matching, there were 105 patients in each group. The patients with aldosterone‐producing adenoma had worse diastolic function than the patients with essential hypertension, as reflected by lower e′ ( P P =0.003). Multivariate analysis showed that LV diastolic function was significantly correlated with age ( P P P =0.002), systolic blood pressure ( P =0.004), creatinine ( P =0.008), and log‐transformed aldosterone‐renin ratio ( P =0.003). After adrenalectomy, the patients with aldosterone‐producing adenoma had significant improvements in LV diastolic function as reflected by an increase in e′ ( P =0.003) and decrease in E/e′ ( P =0.002). The change in E/e′ was independently correlated with baseline E/e′ ( P P =0.006). Conclusions The patients with primary aldosteronism had worse LV diastolic function than the patients with essential hypertension after propensity score matching, and this could be reversed after adrenalectomy, suggesting that aldosterone excess may induce LV diastolic dysfunction.

Background Cardiac fibrosis (CF) plays a critical role in the pathogenesis of heart failure (HF), predisposing to contractile dysfunction, myocardial stiffness and life-threatening arrhythmias. Early detection and intervention of myocardial fibrosis, therefore, can delay or prevent the progression of HF. Current diagnostic and treatment options for CF, however, are very limited. Purpose To test the hypothesis that circulating lncRNA expression signature can be a sensitive biomarker to diagnose and correlate with the extent of CF in human heart. Methods Plasma RNA samples from healthy control (n=23) and from patients with diffuse myocardial fibrosis documented by cardiac magnetic resonance (T1 mapping technique, n=16) were analyzed by RNA sequencing (RNASeq), followed by differential expression, gene ontology/pathway and receiver operating characteristic (ROC) curve analyses. Results RNASeq revealed that 439 mRNAs were differentially expressed in the plasma from patients with CF, compared to that from controls. Gene ontology analyses showed significant enrichment of these CF-linked genes in cytoskeleton organization, innate immune response, and MAPK-Erk signaling, cellular processes known to contribute to the development of CF. Further analyses showed that 84 plasma lncRNAs were dysregulated in patients with CF; 5 of the lncRNAs (ENSGehz746.10420265401.1, ENSGehz746.10420229124.6, ENSGehz746.10420281376.1, ENSGehz746.10420273275.1 and ENSGehz746.10420179818.13) showed concordant changes with their cis-mRNA (UBB, VIM, BCL2L1, PPP3R1 and PCBP1). Hierarchical clustering analyses demonstrated that the expression signature of plasma lncRNAs could distinguish patients with CF from control patients (classification accuracy 87%). The expression levels of plasma lncRNAs ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1, in particular, were markedly downregulated in patients with myocardial fibrosis. ROC curve analyses showed that low expression levels of ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1 were highly sensitive and specific to detect the presence of CF in human heart (AUC 0.9 for both lncRNAs, Figure). LncRNA Predicts Cardiac Fibrosis Conclusions The present study revealed a circulating transcriptome signature that reflects the pathogenesis of CF. The expression profiles of circulating lncRNAs discriminated between patients with and without interstitial myocardial fibrosis. LncRNAs ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1, in particular, are novel biomarkers with potential to facilitate clinical diagnosis of myocardial fibrosis.

Estimated glomerular filtration rate (eGFR) is an important topic in patients with primary aldosteronism (PA). However, the relationship between left ventricular structure and eGFR is unclear. We conducted a prospective, observational, and cross-sectional study to analyze 168 patients with PA and 168 propensity score-matched patients with essential hypertension (EH) as the control group, matched by age, gender, and systolic blood pressure. In the patients with PA, the eGFR was not correlated with left ventricular mass index (LVMI; r=−0.065, p=0.404), while in the patients with EH, the eGFR was negatively correlated with LVMI (r=−0.309, p2, from the lowest to highest tertile of eGFR; analysis of covariance p=0.032). The medium tertile of eGFR is associated with lowest LVMI. Patients with PA with high and low eGFR were associated with higher LVMI. The findings implied that the reasons for an increased LVMI in patients with PA may be different to those in patients with EH.

Macrophages play an important role in aldosterone-induced myocardial fibrosis, in which the first key steps are macrophage recruitment and infiltration. We hypothesized that IL-6 may be a key mediator of aldosterone-induced macrophage recruitment and infiltration. To test this hypothesis, we designed cell studies with a human monocytic cell line THP-1 that with monocyte/macrophage functions to explore the signaling pathway of aldosterone-induced macrophage infiltration, and further investigated the phenomenon and consequent pathway in aldosterone-infused mice studies. The results showed that aldosterone induced the expression of IL-6 via mineralocorticoid receptors, and enhanced THP-1 cell migration and infiltration. Further experiments using a protease array and siRNA revealed that expressions of MMP-1 and MMP-9 were associated with aldosterone-induced macrophage infiltration. In addition, aldosterone-induced MMP-1 and MMP-9 expressions were mediated via cyclooxygenase-II and prostaglandin E2/EP-2 and EP-4 receptors. In aldosterone-infused mice, mRNA expressions of MMP-1, MMP-9 and COX-2 in peripheral blood monocytic cells were significantly increased. Moreover, the number of mouse macrophage-restricted F4/80 protein-positive cells in the myocardium was significantly higher in the aldosterone-infused mice compared with control mice. The increase in F4/80-positive cells in the myocardium was suppressed in the aldosterone-infused mice with the aldosterone antagonist eplerenone or anti-IL-6 antibody treatment. In conclusion, interleukin-6 played an important role in aldosterone-induced macrophage recruitment and infiltration in the myocardium.

Primary aldosteronism has been associated with myocardial fibrosis, and is the most common cause of secondary hypertension. We previously showed that aldosterone can induce the secretion of galectin-3. The aim of this study was to investigate the association between myocardial fibrosis and plasma galectin-3 level in patients with primary aldosteronism. We prospectively analyzed 11 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008, and 17 patients with essential hypertension as controls. Levels of plasma galectin-3 were determined in both groups, and both groups underwent echocardiography with cyclic variations of integrated backscatter (CVIBS) to characterize tissue initially and 1 year after surgery in the APA group. Diastolic blood pressure, concentration of plasma aldosterone and aldosterone-renin ratio were significantly higher, and serum potassium level and plasma renin activity significantly lower in the APA group compared to the controls. In addition, left ventricular mass index was significantly higher and CVIBS significantly lower in the APA group (7.3±2.0 vs 9.2±1.7 dB, p=0.015). Furthermore, the concentration of plasma galectin-3 was significantly higher in the APA group (2.1±0.9 vs 1.1±0.6 ng/mL, p=0.005) compared to the controls. CVIBS was correlated to plasma galectin-3 level. In the APA group, CVIBS increased significantly (7.3±2.0 to 9.2±2.4 dB, p=0.032) and plasma galectin-3 decreased (2.1±0.9 to 1.2±0.6, p=0.049) 1 year postadrenalectomy. The patients with APA had increased myocardial fibrosis, and this was associated with a higher plasma galectin-3 level. Both increased myocardial fibrosis and plasma galectin-3 level recovered at least partially after adrenalectomy. Trial registration number 200611031R; Results.

The effect of aldosterone on vascular smooth muscle cell function is still unclear. One method to measure vascular smooth muscle cell function is endothelial-independent vascular dilation, for which the key factor is sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA).Our objective was to investigate the effect of aldosterone on vascular smooth muscle cell function and SERCA regulation.We prospectively analyzed 35 patients with primary aldosteronism (PA; 32 patients with aldosterone-producing adenoma and three patients with idiopathic hyperaldosteronism) and 30 patients with essential hypertension (EH) who were enrolled as the control group. Flow and nitrate-mediated dilation were performed in both groups and 1 year after adrenalectomy in the patients with aldosterone-producing adenoma. In addition, we investigated the effect of aldosterone on SERCA regulation in human aortic smooth muscle cells.This study took place in an academic clinical research center.Participants included 35 patients with PA and 30 patients with EH.Adrenalectomy was undertaken in patients with aldosterone-producing adenoma.The PA patients had significantly lower flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) values than the patients with EH (FMD: 13 ± 6 vs 16 ± 4; NMD: 16 ± 6 vs 19 ± 5; both P.05). FMD/NMD were significantly correlated with log 24 hour-urine aldosterone (FMD: r = -0.287, P = .048; NMD: r = -0.402, P = .005) but not blood pressure. The impaired FMD and NMD values were significantly restored 1 year after adrenalectomy (FMD: 11 ± 4 to 19 ± 7; NMD: 15 ± 6 to 21 ± 6; both P.01). Under confocal microscopy, aldosterone was shown to suppress the expression of SERCA2a of human aortic smooth muscle cells. Aldosterone significantly suppressed the expression of SERCA2a from 10(-8) M in mRNA and protein levels. This suppression was through down-regulation of mineralocorticoid receptor dependent mitochondrial transcription factors A and B2.Aldosterone impairs vascular smooth muscle cell function and suppresses SERCA 2a expression.

Background Primary aldosteronism (PA) is one of the major etiologies for secondary hypertension featuring more prominent left ventricular hypertrophy. The purpose of the study was to investigate the predictive factors of left ventricular mass index (LVMI) regression in patients with PA after adrenalectomy. Methods We prospectively analyzed 30 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from October 2006 to September 2008. Echocardiography was performed preoperation and 1 year after operation. Results Thirty patients with aldosterone-producing adenoma undergoing adrenalectomy were enrolled. In a 1-year follow-up, LVMI decreased significantly by an average of 18.6%. Net LVMI decrease (ΔLVMI) was associated with preoperative LVMI, preoperative serum potassium level, baseline systolic blood pressure (SBP), baseline diastolic blood pressure, net SBP decrease (ΔSBP), net diastolic blood pressure decrease, preoperative/postoperative change of log-transformed plasma aldosterone concentration, preoperative/postoperative change of log-transformed plasma renin activity, and preoperative/postoperative change of serum potassium level (Δserum potassium level). In a multiple regression analysis, preoperative LVMI (β = −0.287, P = 0.049), ΔSBP (β = 0.518, P = 0.01), and Δserum potassium level (β = −20.471, P = 0.014) were significantly correlated with ΔLVMI. Conclusions The LVMI in patients with PA regressed significantly after adrenalectomy. Preoperative LVMI, ΔSBP, and Δserum potassium levels are independent factors associated with the degree of LVMI regression.

Background: Glomerular hyperfiltration has been recently noticed as an important issue in primary aldosteronism (PA) patients. However, its effect on the cardiovascular system remains unknown. Methods: We prospectively analyzed 47 PA patients including 11 PA patients with estimated glomerular filtration rate (eGFR) > 130 ml/min per 1.73 m2 (group 1), and 36 PA patients with eGFR 90-110 ml/min per 1.73 m2 (group 2). Fourteen essential hypertension (EH) patients with eGFR 90-110 ml/min per 1.73 m2 were included as the control group (group 3). Echocardiography including left ventricular mass index (LVMI) measurement and tissue Doppler imaging (TDI) was performed. Predicted left ventricular mass (LVM) was calculated. Inappropriate LVM was defined as an excess of > 35% from the predicted value. Results: The value of LVMI decreased significantly in order from groups 1 to 3 (group 1>2>3). While group 2 had a significantly higher percentage of inappropriate LVM than group 3, the percentage of inappropriate LVM were comparable in groups 1 and 2. Group 1 had a higher mitral E velocity, E/A ratio than that of group 2. In the TDI study, the E/E' ratio also decreased significantly in order from groups 1 to 3 (group 1>2>3). Group 2 had lower E' than that of group 3, although the E' of group 1 and 2 were comparable. Conclusions: Although PA patients with glomerular hyperfiltration were associated with higher LVMI, higher mitral E velocity, higher E/E' ratio, they had comparable E' with PA patients with normal GFR. This phenomenon may be explained by higher intravascular volume in this patient group.

Aims An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. Methods and results In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kB pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion. Conclusions IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.

Background: Galectin-3 (Gal-3) shows the ability of survival prediction in heart failure (HF) patients. However, Gal-3 is strongly associated with serum markers of cardiac extracellular matrix (ECM) turnover. The aim of this study is to compare the impact of Gal-3 and serum markers of cardiac ECM turnover on prognostic prediction of chronic systolic HF patients. Methods: Serum Gal-3, brain natriuretic peptide (BNP), extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2, 9 (MMP-2, 9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. Cox regression analysis was used for survival analysis. Results: A total of 105 (81 male) patients were enrolled. During 980±346 days follow-up, 17 patients died and 36 episodes of HF admission happened. Mortality of these patients was significantly associated with the log PIIINP (β= 15.380; P=0.042), log TIMP-1(β= 44.530; P=0.003), log MMP-2 (β= 554.336; P

The purpose of this study was to assess the effects of 12 weeks of atorvastatin treatment on myocardial fibrosis in patients with hypertension with atherosclerosis. 15 statin-naïve participants (11 males; mean age 67±10 years) with atherosclerosis were given atorvastatin (40 mg/day) for 12 weeks and underwent echocardiography including ultrasonic tissue characterization by cyclic variation of integrated backscatter (CVIBS). Serum galectin-3 and fibrosis markers including aminoterminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also analyzed. After 12 weeks of atorvastatin (40 mg/day) treatment, serum total cholesterol and low-density lipoprotein cholesterol decreased significantly (204±31 to 140±24 mg/dL and 133±26 to 69±17 ng/mL, respectively, both pTrial registration number NTC00172419; results.

Primary aldosteronism not only results in hypertension but also stiffer arteries. The time course and factors predicting the reversal of arterial stiffness after treatment are unclear. We prospectively enrolled 102 patients with aldosterone-producing adenoma (APA) from March 2006 to January 2012. We measured the pulse wave velocity (PWV) between brachial-ankle (baPWV) and heart-ankle (haPWV) before, 6 and 12 months after their adrenalectomy. After treatment, the PWV decreased significantly during the first 6 months (both p 0-6mo) and baseline baPWV were significantly associated with the decrease in baPWV at 6 months (ΔbaPWV0-6mo). The associated factors of the change in haPWV at 6 months (ΔhaPWV0-6mo) were baseline haPWV, ΔDBP0-6mo and change in log-transformed plasma renin activity. Our result suggested that reversal of arterial stiffness in APA patients occurred early after adrenalectomy and determined by baseline vascular condition, hemodynamic factors, and humoral factors.

Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.

OBJECTIVE To test if collagen markers are associated with aldosterone-induced diastolic dysfunction. BACKGROUND Although primary aldosteronism is associated with more prominent cardiac remodeling and diastolic dysfunction, the reversibility of diastolic function is unclear. In addition, there is no known biomarker associated with aldosterone-induced diastolic dysfunction. METHODS We enrolled 27 patients with aldosterone-producing adenoma (APA) preparing for adrenalectomy, and 27 patients with essential hypertension prospectively from October 2006 to March 2010 at a tertiary referral center. Plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured, and echocardiography including tissue Doppler images was performed in both groups and 1 year after receiving adrenalectomy in the APA group. RESULTS The baseline plasma TIMP-1 level (88.4 ± 38.7 vs. 63.6 ± 32.5 ng/ml; P = 0.014), left ventricular mass index (LVMI), and E/E' ratio (11.5 ± 2.9 vs. 9.0 ± 2.1; P

Introduction: Hypokalemia in primary aldosteronism (PA) patients correlates with higher levels of cardiovascular events and altered left ventricular geometry. However, the influence of aldosterone on microvascular endothelial function and the effect of hypokalemia on the vascular structure still remain unclear. Objectives: We investigated the peripheral arterial functions, including the endothelial function of microvasculature and arterial stiffness in PA and essential hypertension (EH) patients, and the correlation between hypokalemia and peripheral arterial function among PA patients. Methods: Twenty patients diagnosed as EH and 37 patients with PA were enrolled in this study. Reactive hyperemia index (RHI) and the augmentation index (AI) were obtained by non-invasive peripheral arterial tonometry. Results: Twenty EH patients and a total of 37 PA patients, including 21 patients with normokalemia and 16 patients with hypokalemia, were enrolled and divided into groups 1, 2 and 3 respectively. PA patients had significantly higher AI ( p =0.024) but not RHI than EH patients. RHI showed no difference between groups 1, 2 and 3. Group 3 had higher AI than either group 1 or group 2. In the whole study population, serum potassium level, after multivariate regression analysis testing, was the only factor associated with AI (ß= −0.102; p =0.002). In PA patients, serum potassium level was the only significant factor correlated with AI. (r= −0.458; p =0.004) Conclusions: PA patients had higher arterial stiffness but comparable microvascular endothelial function to EH patients. Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in PA patients.

Context Patients with primary aldosteronism are associated with increased myocardial fibrosis. Galectin-3 is one of the most important mediators between macrophage activation and myocardial fibrosis. Objective To investigate whether aldosterone induces galectin-3 secretion in vitro and in vivo. Methods and Results We investigated the possible molecular mechanism of aldosterone-induced galectin-3 secretion in macrophage cell lines (THP-1 and RAW 264.7 cells). Aldosterone induced galectin-3 secretion through mineralocorticoid receptors via the PI3K/Akt and NF-κB transcription signaling pathways. In addition, aldosterone-induced galectin-3 expression enhanced fibrosis-related factor expression in fibroblasts. We observed that galectin-3 mRNA from peripheral blood mononuclear cells and serum galectin-3 levels were both significantly increased in mice implanted with aldosterone pellets on days 7 and 14. We then conducted a prospective preliminary clinical study to investigate the association between aldosterone and galectin-3. Patients with aldosterone-producing adenoma had a significantly higher plasma galectin-3 level than patients with essential hypertension. One year after adrenalectomy, the plasma galectin-3 level had decreased significantly in the patients with aldosterone-producing adenoma. Conclusion This study demonstrated that aldosterone could induce galectin-3 secretion in vitro and in vivo.

Objective. Primary aldosteronism (PA) is associated with inappropriate left ventricular hypertrophy (LVH) in relation to a given gender and body size. There is no ideal parameter to predict the presence of LVH or inappropriate LVH in patients with PA. We investigate the performance of 24-hour urinary aldosterone level, plasma renin activity and aldosterone-to-renin ratio on this task.Methods. We performed echocardiography in 106 patients with PA and 31 subjects with essential hypertension (EH) in a tertiary teaching hospital. Plasma renin activity, aldosterone concentration, and 24-hour urinary aldosterone level were measured.Results. Only 24-hour urinary aldosterone was correlated with left ventricular mass index (LVMI) and excess LVMI among these parameters. The multivariate analysis revealed the urinary aldosterone level as an independent predictor for LVMI and excess LVMI. Analyzing the ability of urinary aldosterone, plasma aldosterone concentration, and plasma aldosterone-to-renin ratio to identify the presence of LVH (ROC AUC = 0.701, 0.568, 0.656, resp.) and the presence of inappropriate LV mass index (defined as measured LVMI in predicting LVMI ratio >135%) (ROC area under curve = 0.61, 0.43, 0.493, resp.) revealed the better performance of 24-hour urinary aldosterone.Conclusions. In conclusion, 24-hour urinary aldosterone level performed better to predict the presence of LVH and inappropriate LVMI in patients with PA.

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Nosocomial infections caused by Acinetobacter baumannii have increased in recent years. Isolates of multidrug-resistant A. baumannii (MDRAB) have been recovered in Taiwan since 1999. The characteristics of 55 patients with MDRAB bacteraemia infections occurring between January 2003 and February 2005 were analysed retrospectively. The overall 30-day mortality rate was 49%. The portal of entry was identified in 80% of patients, with the respiratory tract being implicated most frequently. Among the different antimicrobial regimens prescribed, the combination of a carbapenem and ampicillin-sulbactam was associated with a better outcome than the combination of a carbapenem and amikacin, or a carbapenem alone.