Pedro V. Staziaki

Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance ImagingCLINICAL PERSPECTIVE

Background—Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice. Methods and Results—This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001). Conclusions—Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.

HIV Infection and Heart Failure Outcomes in Women

There is a 2.5-fold increased risk of incident heart failure (HF) among women living with human immunodeficiency virus (HIV) (WLWHIV) [(1)][1]. Whether HF outcomes differ by HIV status among women has not been established. Leveraging data from a large, current and established U.S. health care system

Neuroprotective effect of omega-3 polyunsaturated fatty acids in the 6-OHDA model of Parkinson's disease is mediated by a reduction of inducible nitric oxide synthase

Objective: Parkinsons disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. Methods: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. Results: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. Discussion: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD. GRAPHICAL ABSTRACT

Fish Oil has Beneficial Effects on Behavior Impairment and Oxidative Stress in Rats Subjected to a Hepatic Encephalopathy Model

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver failure, in which there is injury to brain cells, particularly neurons and glia. Brain cells and their function are greatly influenced by omega-3 polyunsaturated fatty acids, essential components of cell membrane phospholipids in the brain that are crucial to normal function. This study assessed the effect of chronic fish oil (FO) supplementation (rich in omega-3 polyunsaturated fatty acids) on behavior and oxidative stress of Wistar rats subjected to HE due to a liver failure caused by thioacetamide (TAA) intoxication. The FO supplementation started in an early phase of brain development, that is, at the 21st day of life, and extended to the 122th day of life. The results indicated that cognitive function, specifically spatial memory, was markedly affected in the group that received TAA. Most notably, the ill effects caused by TAA administration were counteracted by FO supplementation. In addition to behavioral improvements, FO also promoted reduction in levels of thiobarbituric acid-reactive substances and superoxide dismutase activity in hippocampus and cerebral cortex. In summary, FO protected against spatial memory deficits and oxidative stress caused by HE in rats subjected to liver lesion due to TAA intoxication. Further studies are necessary to understand the mechanism underlying FO behaviors in rats subjected to encephalopathy.

Hepatoblastoma com aspecto sólido e multicístico simulando hamartoma mesenquimal: achados anatomopatológicos e de imagem

A 29-day-old infant was evaluated at our center for a hepatic mass found during gestation. Ultrasound revealed a heterogeneous lesion which comprised three anechoic areas with hypoechoic debris and a predominantly hyperechoic central region with signs of vascularization on Doppler imaging (Figure 1A). Computed tomography showed a large bulging mass with three clearly defined cystic components with heterogeneous contrast enhancement of peripheral solid nodules (Figure 1B). The cystic component suggested a diagnosis of mesenchymal hamartoma. However, a highly elevated level of alpha-fetoprotein led to the diagnosis of hepatoblastoma, which tends to present as a solid lesion. An ultrasound-guided biopsy confirmed a mixed epithelial/mesenchymal hepatoblastoma (Figures 1C and 1D). Liver tumors are not uncommon in adults. Hepatoblastoma is the most common primary hepatic malignancy in children, accounting for nearly 80% of all malignant liver tumors. Hepatoblastoma usually presents as an incidental finding of an asymptomatic abdominal mass in children under 5 years of age. On ultrasound, hepatoblastomas appear as predominantly solid masses that are hyperechoic relative to the adjacent liver, although hypoechoic fibrotic septa can also be seen. Epithelial hepatoblastomas may appear homogeneous, whereas mixed epithelial/mesenchymal tumors are heterogeneous (due to osteoid, cartilaginous, and fibrous components) and frequently contain echogenic calcifications with acoustic shadowing and anechoic foci representing hemorrhage or necrosis. The appearance of hepatoblastoma on computed tomography is that of a well-defined mass with regular borders that is hypoattenuating in comparison with the adjacent hepatic parenchyma. The tumor commonly displays diffuse heterogeneous contrast enhancement. Approximately half of all hepatoblastomas appear lobulated or septated, especially on contrast-enhanced images. In the case presented here, the imaging findings indicated a different entity. The predominantly cystic appearance of the tumor was consistent with a cystic liver tumor, namely mesenchymal hamartoma. Mesenchymal hamartomas, which typically occur in children under 2 years of age, present as a large solitary neoplasm with variable amounts of solid and cystic components on ultrasound or computed tomography. Our conclusion is that we should be aware of this rare mostly cystic presentation of hepatoblastoma, should we encounter cystic hepatic lesions in children under 3 years of age with elevated alpha-fetoprotein levels.

Medical Registry Data Collection Efficiency: A Crossover Study Comparing Web-Based Electronic Data Capture and a Standard Spreadsheet.

Background Electronic medical records and electronic data capture (EDC) have changed data collection in clinical and translational research. However, spreadsheet programs, such as Microsoft Excel, are still used as data repository to record and organize patient data for research. Objective The objective of this study is to assess the efficiency of EDC as against a standard spreadsheet in regards to time to collect data and data accuracy, measured in number of errors after adjudication. Methods This was a crossover study comparing the time to collect data in minutes between EDC and a spreadsheet. The EDC tool used was Research Electronic Data Capture (REDCap), whereas the spreadsheet was Microsoft Excel. The data collected was part of a registry of patients who underwent coronary computed tomography angiography in the emergency setting. Two data collectors with the same experience went over the same patients and collected relevant data on a case report form identical to the one used in our Emergency Department (ED) registry. Data collection tool was switched after the patient that represented half the cohort. For this, the patient cohort was exactly 30 days of our ED coronary Computed Tomography Angiography registry and the point of crossover was determined beforehand to be 15 days. We measured the number of patients admitted, and time to collect data. Accuracy was defined as absence of blank fields and errors, and was assessed by comparing data between data collectors and counting every time the data differed. Statistical analysis was made using paired t -test. Results The study included 61 patients (122 observations) and 55 variables. The crossover occurred after the 30th patient. Mean time to collect data using EDC in minutes was 6.2±2.3, whereas using Excel was 8.0±2.0 (P <.001), a difference of 1.8 minutes between both means (22%). The cohort was evenly distributed with 3 admissions in the first half of the crossover and 4 in the second half. We saw 2 (<0.1%) continuous variable typos in the spreadsheet that a single data collector made. There were no blank fields. The data collection tools showed no differences in accuracy of data on comparison. Conclusions Data collection for our registry with an EDC tool was faster than using a spreadsheet, which in turn allowed more efficient follow-up of cases.

Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer

Background and Purpose Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA. Methods From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors. Results The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01). Conclusions Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.

Human Papillomavirus Status and the Risk of Cerebrovascular Events Following Radiation Therapy for Head and Neck Cancer

Background Radiation therapy (RT) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events (CVEs; stroke or transient ischemic attack). Human papillomavirus (HPV) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVEs after RT is unknown. Methods and Results Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV. The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVEs was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59±12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV‐positive and ‐negative patients. Over a median follow‐up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV‐positive patients compared with the HPV‐negative patients (2.6% versus 0.9%, P=0.002). In a multivariable model, HPV‐positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5–13.2; P=0.008). Conclusions In this study, HPV‐positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer.

Identification of coronary artery calcification can optimize risk stratification in patients with acute chest pain

BACKGROUND The number of patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) is substantial. We tested whether identification of coronary artery calcium (CAC) can improve the negative predictive value (NPV) of clinical risk assessment for ACS in patients with acute chest pain. METHODS AND RESULTS We included 826 consecutive patients (mean age: 53±11years; 42% female) without known coronary artery disease (CAD) or initially elevated serum biomarkers, whom underwent non-contrast CT, to assess the CAC score, and CT angiography (CTA), to detect coronary stenosis. We analyzed the diagnostic performance of CAC and the Thrombolysis In Myocardial Infarction (TIMI) risk score for our primary outcomes (ACS and obstructive CAD). No CAC was found in 54% (n=444) of all patients, 63% (n=524) had a TIMI score of 0 and 40% (n=328) had both. The prevalence of obstructive CAD was 16% for ≥50% stenosis and 8.7% for ≥70% stenosis. The incidence of ACS was 7.9%, (MI=11, UAP=54). The NPV of CAC=0 was 99.5% for ACS. The NPV of a combination of TIMI score=0 and no CAC was 89% for any CAD (any plaque or stenosis) and 99.7% for ≥50% stenosis. A 100% NPV was found for ≥70% stenosis and ACS, correctly identifying 328 (40%) patients. CONCLUSIONS The exclusion of CAC, in combination with clinical risk assessment, has high clinical value in patients with acute chest pain, as it identifies patients at low risk for ACS and obstructive CAD more accurately as compared to clinical risk assessment alone.

Presence, Characteristics, and Prognostic Associations of Carotid Plaque Among People Living With HIVCLINICAL PERSPECTIVE

Background— Data from broad populations have established associations between incidental carotid plaque and vascular events. Among people living with HIV (PLWHIV), the risk of vascular events is increased; however, whether incidental carotid plaque is increased and there is an association between incidental carotid plaque, plaque characteristics, and vascular events among PLWHIV is unclear. Methods and Results— Data from the multi-institutional Research Patient Data Registry were used. Presence and characteristics (high-risk plaque, including spotty calcification and low attenuation) of carotid plaque by computerized tomography among PLWHIV without known vascular disease were described. Data were compared with uninfected controls similar in age, sex, and cardiovascular risk factors, including diabetes mellitus, hyperlipidemia, and cigarette smoking to cases. Primary outcome was an atherosclerotic cardiovascular disease event, and secondary outcome was ischemic stroke. Cohort consisted of 209 PLWHIV (45±10 years, 72% male) and 168 controls. Using computerized tomography, PLWHIV without vascular disease had higher rates of any carotid plaque (34% versus 25%; P=0.04), noncalcified (18% versus 5%; P<0.001) and high-risk plaque (25% versus 16%; P=0.03). Over a follow-up of 3 years, 19 atherosclerotic cardiovascular disease events (9 strokes) occurred. Carotid plaque was independently associated with a 3-fold increase in atherosclerotic cardiovascular disease events among PLWHIV (hazard ratio, 2.91; confidence interval, 1.10–7.7, P=0.03) and a 4-fold increased risk of stroke (hazard ratio, 4.43; confidence interval, 1.17–16.70; P=0.02); high-risk plaque was associated with a 3-fold increased risk of atherosclerotic cardiovascular disease events and a 4-fold increased risk of stroke. Conclusions— There is an increase in incidental carotid plaque, noncalcified plaque, and high-risk plaque among PLWHIV, and the presence and characteristics of carotid plaque are associated with subsequent vascular events.