Abstract Purpose The aim of this study was to evaluate echocardiography-based indices of myocardial function and markers of vascular inflammation and endothelial dysfunction in the early phases of ...severe sepsis. Material and Methods Forty-five adult patients (67% women; age 51 ± 18 years; Acute Physiology and Chronic Health Disease Classification System II score, 23 ± 7) admitted to the intensive care unit up to 24 hours after fulfilling criteria for severe sepsis or septic shock were studied. Clinical, laboratorial (endothelin 1 ET1, vascular cellular adhesion molecule 1), and echocardiographic data were collected within the first 24 hours and again 72 hours and 7 days after admission. Results Intrahospital mortality was 33% (15 deaths). Left ventricular (LV) dysfunction (LV ejection fraction <55%) was identified in 15 (33%) patients, whereas right ventricular (RV) dysfunction (RV tissue Doppler peak systolic velocity RV-Sm <12 cm/s) was present in 14 (30%) patients. LogET1 was increased in patients with LV dysfunction (2.3 ± 0.6 vs 1.8 ± 0.4 pg/mL; P = .01) and RV dysfunction (2.5 ± 0.5 vs 1.8 ± 0.4 pg/mL; P < .001) and had negative correlations with LV ejection fraction ( r = −0.50; P = .002) and RV-Sm ( r = −0.67; P < .001). Left ventricular end-diastolic diameter, RV-Sm, and diastolic dysfunction were able to discriminate survivors from nonsurvivors, and the combination of these parameters identified groups of very low and high risk. Conclusion Both LV and RV systolic dysfunctions are prevalent in severe sepsis, being directly associated with markers of endothelial dysfunction. Left ventricular nondilation, RV dysfunction, and diastolic dysfunction seem related to poor prognosis in this scenario.
Advances in diagnosis and treatment of cancer has improved survival but resulted in increased cardiotoxic effects. The decrease in left ventricular ejection fraction (EF), one of the pillars of ...diagnosis of cardiotoxicity, seems to be a late process in the evolution of the disease, so 123I-metaiodobenzylguanidine (MIBG) cardiac imaging has been proposed to detect early cardiac impairment. The aim of this systematic review was to evaluate the performance of MIBG cardiac scan in this scenario.
A systematic search was conducted in five international databases comparing MIBG parameters with EF for evaluation of cardiotoxicity. Twelve studies were included and separated in three groups. First, studies evaluating patients with established cardiotoxicity, in which EF was reduced and MIBG parameters were abnormal. Second, studies analyzing patients during or after treatment compared to controls, with MIBG parameters significantly different between groups in most studies, even when EF remained normal. Finally, studies analyzing anthracycline (ATC) dose-related changes, with alteration in MIBG parameters occurring even when EF was preserved.
Although studies had high methodological variability, cardiac sympathetic innervation imaging seems to be a promising tool for assessing early cardiotoxicity. Further studies are needed to analyze its diagnostic value in this scenario.
Abstract
Aims
Although loop diuretics are widely used to treat heart failure (HF), there is scarce contemporary data to guide diuretic adjustments in the outpatient setting.
Methods and results
In a ...prospective, randomized and double-blind protocol, we tested the safety and tolerability of withdrawing low-dose furosemide in stable HF outpatients at 11 HF clinics in Brazil. The trial had two blindly adjudicated co-primary outcomes: (i) symptoms assessment quantified as the area under the curve (AUC) of a dyspnoea score on a visual-analogue scale evaluated at 4 time-points (baseline, Day 15, Day 45, and Day 90) and (ii) the proportion of patients maintained without diuretic reuse during follow-up. We enrolled 188 patients (25% females; 59 ± 13 years old; left ventricular ejection fraction = 32 ± 8%) that were randomized to furosemide withdrawal (n = 95) or maintenance (n = 93). For the first co-primary endpoint, no significant difference in patients’ assessment of dyspnoea was observed in the comparison of furosemide withdrawal with continuous administration median AUC 1875 (interquartile range, IQR 383–3360) and 1541 (IQR 474–3124), respectively; P = 0.94. For the second co-primary endpoint, 70 patients (75.3%) in the withdrawal group and 77 patients (83.7%) in the maintenance group were free of furosemide reuse during follow-up (odds ratio for additional furosemide use with withdrawal 1.69, 95% confidence interval 0.82–3.49; P = 0.16). Heart failure-related events (hospitalizations, emergency room visits, and deaths) were infrequent and similar between groups (P = 1.0).
Conclusions
Diuretic withdrawal did not result in neither increased self-perception of dyspnoea nor increased need of furosemide reuse. Diuretic discontinuation may deserve consideration in stable outpatients with no signs of fluid retention receiving optimal medical therapy.
ClinicalTrials.gov Identifier
NCT02689180.
Abstract Objectives To evaluate whether changes in hydration status (reflecting fluid retention) would be detected by bioelectrical impedance vector analysis (BIVA) and phase angle during ...hospitalization for acute decompensated heart failure (ADHF) and after clinical stabilization. Methods Patients admitted to ADHF were evaluated at admission, discharge and after clinical stabilization (3 mo after discharge) for dyspnea, weight, brain natriuretic peptide, bioelectrical impedance resistance, reactance, and phase angle. Generalized estimating equations and chi-square detected variations among the three time points of evaluation. Results Were included 57 patients: Mean age was 61 ± 13 y, 65% were male, LVEF was 25 ± 8%. During hospitalization there were improvements in clinical parameters and increase in resistance/height (from 250 ± 72 to 302 ± 59 Ohms/m, P < 0.001), reactance/height (from 24 ± 10 to 31 ± 9 Ohms/m, P < 0.001), and phase angle (from 5.3 ± 1.6 to 6 ± 1.6°, P = 0.007). From discharge to chronic stability, both clinical and BIVA parameters remained stable. At admission, 61% of patients had significant congestion by BIVA, and they lost more weight and had higher improvement in dyspnea during hospitalization ( P < 0.05). At discharge, more patients were in the upper half of the graph (characterizing some degree of dehydration) while at chronic stability normal hydration status was more prevalent ( P < 0.001). Conclusions BIVA and phase angle were able to detect significant changes in hydration status during ADHF, which paralleled the clinical course of recompensation, both acutely and chronically. The classification of congestion by BIVA at admission identified patients with more pronounced changes in weight and dyspnea during compensation.
MicroRNAs (miRs) are a class of small non-coding RNAs that regulate gene expression. Studies of transgenic mouse models have indicated that deregulation of a single miR can induce pathological ...cardiac hypertrophy and cardiac failure. The roles of miRs in the genesis of physiological left ventricular hypertrophy (LVH), however, are not well understood.
To evaluate the global miR expression in an experimental model of exercise-induced LVH.
Male Balb/c mice were divided into sedentary (SED) and exercise (EXE) groups. Voluntary exercise was performed on an odometer-monitored metal wheels for 35 days. Various tests were performed after 7 and 35 days of training, including a transthoracic echocardiography, a maximal exercise test, a miR microarray (miRBase v.16) and qRT-PCR analysis.
The ratio between the left ventricular weight and body weight was increased by 7% in the EXE group at day 7 (p<0.01) and by 11% at day 35 of training (p<0.001). After 7 days of training, the microarray identified 35 miRs that were differentially expressed between the two groups: 20 were up-regulated and 15 were down-regulated in the EXE group compared with the SED group (p = 0.01). At day 35 of training, 25 miRs were differentially expressed: 15 were up-regulated and 10 were decreased in the EXE animals compared with the SED animals (p<0.01). The qRT-PCR analysis demonstrated an increase in miR-150 levels after 35 days and a decrease in miR-26b, miR-27a and miR-143 after 7 days of voluntary exercise.
We have identified new miRs that can modulate physiological cardiac hypertrophy, particularly miR-26b, -150, -27a and -143. Our data also indicate that previously established regulatory gene pathways involved in pathological LVH are not changed in physiological LVH.
Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. ...Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.
Circulating levels of matrix metalloproteinase-2 (MMP-2) predict mortality and hospital admission in heart failure (HF) patients. However, the role of MMP-2 gene polymorphisms in the susceptibility ...and prognosis of HF remains elusive. In this study, 308 HF outpatients (216 Caucasian- and 92 African-Brazilians) and 333 healthy subjects (256 Caucasian- and 77 African-Brazilians) were genotyped for the -1575G>A (rs243866), -1059G>A (rs17859821), and -790G>T (rs243864) polymorphisms in the MMP-2 gene. Polymorphisms were analyzed individually and in combination (haplotype), and positive associations were adjusted for clinical covariates. Although allele frequencies were similar in HF patients and controls in both ethnic groups, homozygotes for the minor alleles were not found among African-Brazilian patients. After a median follow-up of 5.3 years, 124 patients (40.3%) died (54.8% of them for HF). In Caucasian-Brazilians, the TT genotype of the -790G>T polymorphism was associated with a decreased risk of HF-related death as compared with GT genotype (hazard ratio HR = 0.512, 95% confidence interval CI 0.285-0.920). However, this association was lost after adjusting for clinical covariates (HR = 0.703, 95% CI 0.365-1.353). Haplotype analysis revealed similar findings, as patients homozygous for the -1575G/-1059G/-790T haplotype had a lower rate of HF-related death than those with any other haplotype combination (12.9% versus 28.5%, respectively; P = 0.010). Again, this association did not remain after adjusting for clinical covariates (HR = 0.521, 95% CI 0.248-1.093). Our study does not exclude the possibility that polymorphisms in MMP-2 gene, particularly the -790G>T polymorphism, might be related to HF prognosis. However, due to the limitations of the study, our findings need to be confirmed in further larger studies.
MicroRNAs (miRs) regulate processes involved in both cardiac remodeling and obesity. We investigated if the expression of selected miRs in patients with heart failure (HF) is influenced by the ...presence of obesity.
In this case–control study, we compared plasma levels of miR-21, -130b, -221, -423-5p, and the -221/-130b ratio in 57 age- and gender-matched subjects: 40 HF patients (20 obese HF and 20 lean HF) and 17 lean healthy controls. Body composition was estimated by bioelectrical impedance analysis. MiRs were measured by quantitative reverse transcription-PCR. Bioinformatics analysis was performed based on miRs findings to predict their putative targets and investigate their biological function.
HF was associated with increased miR-423-5p levels in both lean and obese patients (P<0.05 vs. controls) without differences between HF groups. MiR-130b levels were reduced in obese HF patients compared with HF lean (P=0.036) and controls (P=0.025). MiR-221 levels were non-significantly increased in obese HF patients. MiR-21 levels were not different among the groups. MiR-221/-130b ratio was increased in obese HF patients, and was positively associated with body fat percentage (r=0.43; P=0.002), body mass index (r=0.44; P=0.002), and waist circumference (r=0.40; P=0.020). Computational prediction of target genes followed by functional enrichment analysis indicated a relevant role of miR-130b and miR-221 in modulating the expression of genes associated to cardiovascular and endocrine diseases, and suggested their influence in important signaling mechanisms and in numerous processes related to the circulatory and endocrine systems.
In HF patients, the presence of obesity is associated with a differential expression of selected miRs and the miR-221/-130b ratio had significant correlations with adiposity parameters. Computational target prediction analysis identified several interrelated pathways targeted by miR-130b and miR-221 with a known relationship with endocrine and cardiovascular diseases, representing potential mechanisms to be further validated.
•In HF patients, obesity is associated with altered expression of miR-130b and miR-221.•The ratio miR-221/-130b has positive correlation with adiposity parameters.•Predicted miR targets are highly enriched in cardiovascular and endocrine diseases.•Bioinformatics analysis reveals that these miRs modulate important signaling pathways.
The aim of this study was to evaluate the effectiveness of a diuretic adjustment algorithm (DAA) in maintaining clinical stability and reducing HF readmissions using telemonitoring technologies.
...Randomized clinical trial of patients with an indication for furosemide dose adjustment during routine outpatient visits. In the intervention group (IG), the diuretic dose was adjusted according to the DAA and the patients received telephone calls for 30 days. In the control group (CG), the diuretic dose was adjusted by a physician at baseline only. Co-primary outcomes were hospital readmission and/or emergency department visits due to decompensated HF within 90 days, and a 2-point change in the Clinical Congestion Score and/or a deterioration in New York Heart Association functional class within 30 days.
A total of 206 patients were included. Most patients were male (
=119; 58%), with a mean age of 62 (SD 13) years. Four patients (2%) in the IG and 14 (7%) in the CG were hospitalized for HF (odds ratio (OR) 0.31 (0.10-0.91);
=0.04). Multivariate analysis showed a reduction of 67% in readmissions and/or emergency department visits due to decompensated HF in the IG compared with the CG (95% CI 0.13-0.88;
=0.027). Regarding the combined outcome of HF readmission and/or emergency department visits or clinical instability, the IG had 20% fewer events than the CG within 30 days (IG:
=48 (23%), CG:
=70 (34%); OR 0.80 (0.63-0.93);
=0.03).
Using DAA improved the combined outcome in these outpatients, with favorable and significant results that included a reduction in HF admissions and in clinical instability. (NCT02068937).
Epithelial to mesenchymal transition (EMT) is reportedly an important transition in cancer progression in which the underlying cellular changes have been identified mainly using in vitro models. In ...this study, we examined the expression pattern of EMT markers in vivo and determined the occurrence and clinical significance of these events in a series of bladder carcinomas.
Eight hundred and twenty-five tumor samples from 572 bladder cancer patients were assembled in 10 tissue microarrays. Paraffin sections from each tissue microarray were subjected to antigen retrieval and processed by immunohistochemistry for the expression of E-cadherin, plakoglobin, beta-catenin, N-cadherin, and vimentin.
Pathologic expression of E-cadherin, beta-catenin, plakoglobin, and vimentin were associated with the clinicopathologic variables of grade and stage with only the cytoplasmic localization of plakoglobin found associated with lymph node status. Associations between the aforementioned markers were found significant as determined by the Spearman correlation coefficient with N-cadherin showing no associations in this analysis. In univariate survival analysis involving patients who underwent cystectomy, the reduction or loss of plakoglobin significantly influenced overall survival (P = 0.02) in which the median time to death was 2 years compared with 4 years when a normal level of plakoglobin was recorded. When the analysis was done for cancer-specific survival, low levels of both plakoglobin (P = 0.02) and beta-catenin (P = 0.02) significantly influenced survival.
The putative markers of EMT defined within a panel of bladder carcinoma cell lines were recorded in vivo, frequently associated with tumors of high grade and stage. Although multivariate analysis showed no significant influence of the EMT biomarkers on survival, alterations associated with plakoglobin were identified as significant prognostic features in these tumors.
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