José Luiz P. da Silva

Heart rate variability as predictor of mortality in sepsis: A prospective cohort study

Background Sepsis is a serious medical condition with increasing prevalence and high mortality. The role of the autonomic nervous system in pathophysiology of sepsis has been increasingly researched. The objective of this study is to evaluate the Heart rate variability (HRV) as a predictor of mortality in septic patients. Methods This was a prospective cohort of patients diagnosed with sepsis. Patient recruitment was carried out at ICU in tertiary university hospital between March 2012 and February 2014. Clinical data and laboratory exams were collected at admission. Each patient underwent a 20-minute Holter and a 24-hour Holter on the first day of enrollment. The primary outcome was the 28-day all-cause mortality. Results A total of 63 patients were included. Patients were categorized into nonsurvivor group (n = 16) or survivor group (n = 47) depending on this endpoint. Survivors were younger (48.6 years vs. 63.0 years), had better renal function and lower values in severity scores (APACHE II and SOFA) compared to nonsurvivors. In the 20-minute Holter, SDNN, Total Power, VLF Power, LF Power and LF/HF of nonsurvivors were significantly lower than those of survivors (p = <0.001, p = 0.003, p = 0.002, p = 0.006, p = 0.009 respectively). ROC curve of SDNN was built, showing area under the curve of 0.772 (0.638–0.906) for mortality. The value of 17ms was chosen as best SDNN cutoff to discriminate survivors and nonsurvivors. In the Cox proportional regression, adjusted for SOFA score and for APACHE II, a SDNN ≤ 17ms was associated with a greater risk of death, with hazard ratios of 6.3 (1.4–28.0; p = 0.015) and 5.5 (1,2–24,8; p = 0.027), respectively. The addition of the dichotomized SDNN to the SOFA model reduced AIC and increased the concordance statistic and the R2, indicating that predictive power of the SDNN + SOFA model is better than predictive power of SOFA only. Conclusions Several HRV parameters are reduced in nonsurviving septic patients. SDNN ≤17 is a risk factor for death in septic patients, even after adjusting for severity scores.

Amiodarone and Trypanosoma cruzi parasitemia in patients with Chagas disease.

Chagas disease (ChD) is a main cause of cardiopathy in Latin America, causing thousands of deaths each year.(1) Amiodarone has been widely used as antiarrhythmic drug to prevent recurrences of malignant ventricular arrhythmias in patients with ChD. Although the antiarrhythmic effects of amiodarone are well known, there are some evidences that it also has anti-Trypanosoma cruzi activity,(2) disrupting Ca2+ homeostasis and blocking oxidosqualenecyclase enzyme in T. cruzi, causing ultrastructural damage.(3) Nevertheless, data showing antiparasitic effects of amiodarone in human are lacking, with only one case report demonstrating decrease in parasite load after amiodarone use.(4) We evaluated whether patients in use of amiodarone have lower parasite load than matched infected subjects, employing a recently developed target-capture real-time PCR assay that can detect as few as one parasite per 20mL of processed blood(5), in a previously described cohort of Chagas disease subjects studied by the National Heart, Lung and Blood Institute (NHLBI) Retrovirus Epidemiological Donor Study-II (REDS-II).(6-8) The REDS-II cohort of ChD subjects included 499 T. cruzi seropositive subjects recruited among blood donors and 101 patients previously diagnosed as Chagas cardiomyopathy from the Heart Institute of the University of Sao Paulo. From 2008 to 2010, recruited individuals were submitted to a questionnaire and medical evaluation, resting 12-lead, echocardiogram and blood draw for NT-proBNP and PCR measurements.(7, 8) Soronegative donors used as the control group in the original study were excluded from this analysis. Resting 12-lead ECGs were recorded using General Electric MAC 1200 electrocardiograph (GE Healthcare, Waukesha, WI). ECGs were analyzed electronically and classified by Minnesota code criteria by a central ECG laboratory (EPICARE, Wake Forest University, Winston-Salem, NC). NT-proBNP levels in plasma were measured using VITROS System (Ortho Clinical Diagnostics, Raritan, NJ, US).(7) Echocardiograms were performed using a Sequoia 512 ultrasound instrument (Acuson, Mountain View, CA, USA) or a GE Vivid3 (GE Healthcare, Waukesha, WI). Cardiac measurements were performed according to the guidelines of the American Society of Echocardiography. All measurements were analyzed offline at the Cardiovascular Branch, Echocardiography Laboratory, NHLBI/NIH, Bethesda, Maryland, US.(6) Chagas cardiomyopathy was recognized by the presence of a predefined set of abnormalities in clinical examination, echocardiogram or ECG measurements, according to the evaluation of an expert panel, as detailed elsewhere.(6) Twenty milliliters of whole blood were collected for quantitative, real-time PCR. Aliquots were frozen in Brazil at -20°C until shipped to the US REDS-II Central Laboratory on dry ice, followed by maintenance at -70°C. Subsequently, PCR assays were performed by amplification of kinetoplastminicircle DNA sequences of T. cruzi.(9) We recognized ChD subjects in use of amiodarone among the whole cohort and used a new matching method, Genetic Matching (GenMatch), to select a comparison group of ChD patients with similar characteristics in order to allow the evaluation of the effect of amiodarone on parasitemia presence and intensity. GenMatch is a method of multivariate matching that uses an evolutionary search algorithm to determine the weight each covariate is given, in order to maximize the balance in the distribution of baseline characteristics between both groups.(10) In the entire cohort, there were 37 patients using amiodarone. These patients were matched in a 1:1 ratio by age, gender, years of exposure to Chagas disease, New York Heart Association (NYHA) Functional class, definite cardiomyopathy, use of β-blockers, angiotensin converter enzyme (ACE) inhibitors or angiotensin-receptorblockers, QRS duration, major and minor ECG abnormalities, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVED), segmental wall-motion abnormality, left ventricular lateral and septal E/e′ ratio, and NT_proBNP levels (table 1). Balance was measured with standardized mean difference; a difference of 10% was taken to indicate meaningful imbalance. All the statistical analyses were conducted using R (Version 3.0.1). Table 1 Patients characteristics before and after Genetic Matching This study protocol follows the 1975 Declaration of Helsinki and was approved by the Brazilian National Ethics Committee (CONEP# 1312∕2006). Written informed consent was obtained from all subjects. The mean daily dose of amiodarone was 205mg ± 54mg. In unmatched analysis, patients on amiodarone treatment used more frequently β-blocker and ACE inhibitors or angiotensin-receptor blockers and showed more frequently left ventricular dysfunction and dilatation in the echocardiographic study, as well ECG abnormalities. After GenMatch, the baseline characteristics became similar in both groups, except for gender and NT_proBNP levels (table 1). The qualitative analysis of PCR showed positive results in 86% patients on amiodarone treatment and in 58% control patients. After matching, PCR was positive in 69% of paired control subjects (p = 0.13), demonstrating no difference between both groups. T. cruzi DNA concentrations in blood were higher in patients on amiodarone treatment (1.3 parasite/20 mL vs 0.7 parasite/20 mL), but after GenMatch, quantitative analysis yielded similar results (1.3 parasites/20 mL vs 1.0 parasites/20 mL; p=0.63), also showing no statistical difference between patients treated or not with amiodarone. Ventricular arrhythmia is a frequent and ominous finding in ChD patients(1) and the presence of parasitemia in chronic infected patients is related to the disease severity and may have prognostic importance.(9) Thus, a double effect of amiodarone, both as antiarrhythmic and anti-parasite drug, would be highly desirable and could affect favorably the natural history of Chagas cardiomyopathy. Although there are some experimental evidences of this anti-T.cruzi activity of amiodarone, our cohort did not show difference nor in qualitative PCR, neither in parasite load in patients using this drug, even after balancing baseline differences between groups in potential confounding factors. This study has several limitations. First, this study was a retrospective analysis of data from REDS-II study and it was not designed for this purpose. Second, matching technics were necessary to balance both populations and even in well balanced populations hidden bias can be present. Third, the number of patients using amiodarone is relatively small and there was limited information about duration of therapy. In conclusion, using a well validated PCR assay to measure parasitic load in blood stream of ChD patients, we could not demonstrate lower levels of T. cruzi parasitemia in habitual users of amiodarone, as compared to a matched sample of ChD subjects.

Factors associated with compliance to AHA/ACC performance measures in a myocardial infarction system of care in Brazil

Objective To evaluate compliance with American Heart Association/American College of Cardiology (AHA/ACC) performance measures for adults with acute myocardial infarction (AMI) and to investigate the factors associated with compliance, in an AMI System of Care in Brazil. Design Observational longitudinal study. Setting A high-complexity University Hospital, part of the AMI System of Care implemented in Belo Horizonte, Brazil, in 2010. Participants Of note, 1129 patients with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) admitted to a single center over 36 months (between 2011 and 2014). Main Outcome Measures Compliance with 13 pre-specified AHA/ACC AMI performance measures was evaluated for patients with AMI, observing exclusion criteria and appropriate numerators and denominators. Median compliance was calculated and variables independently associated with compliance rates were evaluated. Results Median age was 60 (51/68) years, 67.7% male, 69.8% presented with STEMI and hospital mortality was 8.7%. Median compliance with performance measures was 83% (75/88). Among patients with STEMI, 56% received reperfusion therapy. Overall, 67.3% of patients complied with ≥80% of quality measures. Factors independently associated with better compliance were later date of presentation (semester), likely reflecting ongoing training (OR = 1.19, 95% CI: 1.10-1.28, P < 0.001), male gender (OR = 1.33, 95% CI: 1.00-1.76, P < 0.046), Killip I/II on admission (OR = 1.95, 95% CI: 1.36-2.80, P < 0.001) and diagnosis of NSTEMI (OR = 5.0, 95% CI: 3.51-7.11, P < 0.001). Conclusion Compliance with AHA/ACC AMI performance measures remains below target in Brazil, but the time trends observed suggest improvement. Continuing education, reduction of system delays and prioritizing high-risk groups are needed to optimize AMI systems of care and improve patient outcomes.

The effects of weight and waist change on the risk of long-term mortality in older adults- The Bambuí (Brazil) Cohort Study of Aging

ObjectiveWe aimed to investigate the risk of long-term mortality associated with weight and waist circumference (WC) change among older adults, particularly the overweight and obese ones.DesignCohort Study.SettingThe Bambuí (Brazil) Cohort Study of Aging.ParticipantsCommunity-dwelling elderly (n=1138).MeasurementsWeight and WC were reassessed three years after baseline. Mortality risk associated with a 5% weight/WC loss and gain was compared to that of weight/WC stability by Cox models adjusted for clinical, behavioral and social known risk factors for death (age, gender, BMI, smoking, diabetes, total cholesterol, hypertension, Chagas disease, major electrocardiographic changes, physical activity, B-type natriuretic peptide, C-reactive protein, creatinine, education and household income).ResultsFemale sex was predominant (718; 63.1%). Mean age was 68 (6.7) years. Weight stability (696; 61.1%) was more common than weight loss (251; 22.1%) or gain (191; 16.8%). WC remained stable in 422 (37.3%), decreased in 418 (37.0%) and increased in 291 (25.7%) participants. There were 334 (29.3%) deaths over a median follow-up time of 8.0 (6.4-8.0) years from weight/WC reassessment. Weight loss (HR 1.69; 95% CI 1.30-2.21) and gain (HR 1.37; 95% CI 1.01-1.85) were associated with increased mortality, except in those who were physically active in which weight gain was associated with decreased mortality. Results were similar for participants who were overweight/ obese or with abdominal obesity at baseline (HR 1.41; 95%CI 1.02-1.97 and HR 2.01; 95%CI 1.29-3.12, for weight loss and gain, respectively). WC change was not significantly associated with mortality.ConclusionAlthough weight loss has been recommended for adults with excessive weight regardless of age, weight change might be detrimental in older adults. Rather than weight loss, clinical interventions should target healthy lifestyle behaviors that contribute to weight stability, particularly physical activity in overweight and obese older adults.

Net atrioventricular compliance is an independent predictor of cardiovascular death in mitral stenosis

Objectives Rheumatic mitral stenosis (MS) is a progressive disease, and risk of death may persist despite relief of the obstruction. Net atrioventricular compliance (Cn) modulates the overall haemodynamic burden of the MS and may be useful in predicting cardiovascular death after percutaneous mitral valvuloplasty (PMV). Methods A total of 427 patients (mean age 50±16 years, 84% female) with severe MS undergoing PMV were enrolled. Doppler-derived Cn was estimated at baseline using a previously validated equation. The primary endpoint was late cardiovascular death, and the secondary endpoint was a composite of all-cause mortality, mitral valve (MV) replacement or repeat PMV over a median follow-up of 31 months (IQR: 7.8–49.2 months). Results At baseline, 209 patients (49%) were in New York Heart Association (NYHA) functional class III or IV. During follow-up, 49 patients died (41 cardiovascular deaths), 50 underwent MV replacement and 12 required repeat PMV, with an overall incidence of cardiac mortality and adverse events of 4.1 deaths and 11.1 events per 100 patient-years, respectively. Low baseline Cn was a strong predictor of both cardiac death (adjusted HR 0.70, 95% CI 0.49 to 0.86) and composite endpoint (adjusted HR 0.81, 95% CI 0.67 to 0.91) after adjusting for clinical factors, baseline pulmonary artery pressure, tricuspid regurgitation severity, right ventricular function and immediate procedural haemodynamic data. The inclusion of Cn in a model with conventional parameters resulted in improvement in 5-year cardiovascular mortality risk prediction. Conclusions Baseline Cn is a strong predictor of cardiovascular death in patients with MS undergoing PMV, independent of other prognostic markers of decreased survival in MS, including baseline patient characteristics and postprocedural data. Cn assessment therefore has potential value in evaluation of cardiovascular mortality risk in the setting of MS.

Impact of left atrial compliance improvement on functional status after percutaneous mitral valvuloplasty

Conventional hemodynamic parameters may not accurately predict symptomatic improvement after percutaneous mitral valvuloplasty (PMV). Changes in left heart chamber compliance following adequate relief o0066 mitral stenosis (MS) may be useful in determining functional capacity after PMV. This study aims to determine the acute effects of PMV on compliance of the left heart and whether its changes relate to the patients functional capacity.

Evaluation of accuracy of IHI Trigger Tool in identifying adverse drug events: a prospective observational study

Adverse drug events (ADEs) can seriously compromise the safety and quality of care provided to hospitalized patients, requiring the adoption of accurate methods to monitor them. We sought to prospectively evaluate the accuracy of the triggers proposed by the Institute for Healthcare Improvement (IHI) for identifying ADEs.

Association between Microvolt T-Wave Alternans and Malignant Ventricular Arrhythmias in Chagas Disease

Background Sudden cardiac death is the most frequent death mechanism in Chagas disease, responsible for 55% to 65% of the deaths of patients with chronic Chagas cardiomyopathy (CCC). The most often involved electrophysiological mechanisms are ventricular tachycardia and ventricular fibrillation. The implantable cardioverter defibrillator (ICD) has a beneficial role in preventing sudden death due to malignant ventricular arrhythmias, and, thus the correct identification of patients at risk is required. The association of microvolt T-wave alternans (MTWA) with the appearance of ventricular arrhythmias has been assessed in different heart diseases. The role of MTWA is mostly unknown in patients with CCC. Objectives To evaluate the association between MTWA and the occurrence of malignant ventricular arrhythmias in patients with CCC. Method This is a case-control study including patients with CCC and ICD, with history of malignant ventricular arrhythmias (case group), and patients with CCC and no history of those arrhythmias (control group). The MTWA test results were classified as negative and non-negative (positive and indeterminate). The significance level adopted was a = 0.05. Results We recruited 96 patients, 45 cases (46.8%) and 51 controls (53.1%). The MTWA test was non-negative in 36/45 cases (80%) and 15/51 controls (29.4%) [OR = 9.60 (95%CI: 3.41 - 27.93)]. After adjustment for known confounding factors in a logistic regression model, the non-negative result continued to be associated with malignant ventricular arrhythmias [OR = 5.17 (95%CI: 1.05 - 25.51)]. Conclusion Patients with CCC and history of malignant ventricular arrhythmias more often have a non-negative MTWA test as compared to patients with no history of arrhythmia.

Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy

Background Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied. Objective To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy. Methods Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time. Results Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity. Conclusion In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Marginal models for the association structure of hierarchical binary responses

ABSTRACT Clustered binary responses are often found in ecological studies. Data analysis may include modeling the marginal probability response. However, when the association is the main scientific focus, modeling the correlation structure between pairs of responses is the key part of the analysis. Second-order generalized estimating equations (GEE) are established in the literature. Some of them are more efficient in computational terms, especially facing large clusters. Alternating logistic regression (ALR) and orthogonalized residual (ORTH) GEE methods are presented and compared in this paper. Simulation results show a slightly superiority of ALR over ORTH. Marginal probabilities and odds ratios are also estimated and compared in a real ecological study involving a three-level hierarchical clustering. ALR and ORTH models are useful for modeling complex association structure with large cluster sizes.