Catheter Ablation for Atrial Fibrillation: Renal Function Benefit Only Makes Sense.

See Editorial Park et al.

Information within residency monthly evaluation forms at two institutions.

Periodic review of resident performance is an important aspect of residency training. Amongst allopathic residency programs, it is expected that the performance of resident physicians which can be grouped based on the ACGME core competencies, be assessed so as to allow for effective feedback and continuous improvement. Review of monthly evaluation forms for residents in the core ACGME programs at Marshall University and the University of Toledo demonstrated a wide spread in the number of Likert questions that faculty were asked to complete. This number ranged from a low of 7 in Surgery to a high of 65 in Psychiatry (both Marshall Programs). Correlation and network analysis were performed on these data. High degrees of correlations were noted between answers to questions (controlled for each resident) on these forms at both institutions. In other words, although evaluation scores varied tremendously amongst the different residents in all the programs studied, scores addressing different competencies tended to be very similar for the same resident, especially in some of the programs which were studied. Network analysis suggested that there were clusters of questions that produced essentially the same answer for a given resident, and these clusters were bigger in some of the different residency program assessment forms. This seemed to be more the rule in the residency programs with large numbers of Likert questions. The authors suggest that reducing the number of monthly questions used to address the core competencies in some programs may be possible without substantial loss of information.

Sexual dimorphism in obesity-related genes in the epicardial fat during aging.

Aging increases the risk of cardiovascular disease and metabolic syndrome. Alterations in epicardial fat play an important pathophysiological role in coronary artery disease and hypertension. We investigated the impact of normal aging on obesity-related genes in epicardial fat. Sex-specific changes in obesity-related genes with aging in epicardial fat (EF) were determined in young (6 months) and old (30/36 months) female and male, Fischer 344 × Brown Norway hybrid (FBN) rats, using a rat obesity RT2 PCR Array. Circulating sex hormone levels, body and heart weights were determined. Statistical significance was determined using two-tailed Student's t test and Pearson's correlation. Our results revealed sex-specific differences in obesity-related genes with aging. Dramatic changes in the expression profile of obesity-related genes in EF with aging in female, but not in male, FBN rats were observed. The older (30 months) female rats had more significant variations in the abundance of obesity-related genes in the EF compared to that seen in younger female rats or both age groups in male rats. A correlation of changes in obesity-related genes in EF to heart weights was observed in female rats, but not in male rats with aging. No correlation was observed to circulating sex hormone levels. Our findings indicate a dysfunctional EF in female rats with aging compared to male rats. These findings, with further functional validation, might help explain the sex differences in cardiovascular risk and mortality associated with aging observed in humans.

Curcumin nanoparticles attenuate cardiac remodeling due to pulmonary arterial hypertension.

Herein, we investigate whether curcumin nanoparticles (Cur NPs) are effective for the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension in Sprague Dawley rat. Echocardiography was performed at the start of the study and 28 days after MCT injection. Compared to MCT only animals, Cur NP administration was associated with reduced right ventricular (RV) wall thickness and a decreased right ventricle weight/body weight ratio. Cur NPs also attenuated MCT induced increase in RV mRNA expression of TNF-α and IL-1ß. These changes were also associated with decreased RV expression of nitrotyrosine, fibronectin and myosin heavy chain-ß.

Cerium oxide nanoparticles attenuate monocrotaline induced right ventricular hypertrophy following pulmonary arterial hypertension.

Cerium oxide (CeO2) nanoparticles have been posited to exhibit potent anti-oxidant activity which may allow for the use of these materials in biomedical applications. Herein, we investigate whether CeO2 nanoparticle administration can diminish right ventricular (RV) hypertrophy following four weeks of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Sprague Dawley rats were randomly divided into three groups: control, MCT only (60 mg/kg), or MCT + CeO2 nanoparticle treatment (60 mg/kg; 0.1 mg/kg). Compared to the control group, the RV weight to body weight ratio was 45% and 22% higher in the MCT and MCT + CeO2 groups, respectively (p < 0.05). Doppler echocardiography demonstrated that CeO2 nanoparticle treatment attenuated monocrotaline-induced changes in pulmonary flow and RV wall thickness. Paralleling these changes in cardiac function, CeO2 nanoparticle treatment also diminished MCT-induced increases in right ventricular (RV) cardiomyocyte cross sectional area, ß-myosin heavy chain, fibronectin expression, protein nitrosylation, protein carbonylation and cardiac superoxide levels. These changes with treatment were accompanied by a decrease in the ratio of Bax/Bcl2, diminished caspase-3 activation and reduction in serum inflammatory markers. Taken together, these data suggest that CeO2 nanoparticle administration may attenuate the hypertrophic response of the heart following PAH.

Age-associated alterations of cardiac structure and function in the female F344xBN rat heart.

The Fischer 344/NNiaHSD × Brown Norway/BiNia F1 (F344xBN) rat model exhibits an increased life span and fewer age-associated pathologies compared to commonly used Fischer 344 (F344). How aging may affect cardiac structure and function in these animals, has to our knowledge, not been investigated. Echocardiography was performed on female F344xBN rats at 6, 26, and 30 months of age using a Phillips 5500 Echocardiography system. Before sacrifice, electrocardiograms were measured in the female F344xBN in order to determine heart rhythm interval changes. Aging was associated with an increase in heart to body weight ratio, cardiomyocyte cross-sectional area, posterior wall thickening, and left ventricle chamber dilatation. Aging was associated with slight evidence of diastolic dysfunction. Alterations in heart rhythm intervals were associated with alterations in the spatial distribution of connexin 43. The incidence of arrhythmias was not different with age; however, valvular dysfunction was increased. These data suggest that aging in the female F344xBN rat heart is associated with changes in cardiac structure as well as function. Further investigation regarding other parameters of cardiac biochemistry and function is needed to better understand the normal compensated cardiovascular aging process in the female F344xBN.

The Effects of Aging on Indices of Oxidative Stress and Apoptosis in the Female Fischer 344/Nnia X Brown Norway/BiNia Rat Heart.

Oxidative-nitrosative stress may play a role in age-associated cardiovascular disease as implied by recent studies.However, limited research has been conducted using aged female rodent models. In this study, we examined hearts obtained from 6-, 26-, and 30-month old female Fischer 344/Nnia x Brown Norway/BiNia (F344xBN) rats in order to examine how aging affects levels of cardiac oxidative-nitrosative stress and apoptosis. Oxidative (superoxide anion and 4-HNE) and nitrosative (protein nitrosylation) stress markers were increased 180 ± 17 %, 110 ± 3 %, and 14 ± 2 %, respectively in 30-month hearts compared to the hearts of 6-month female rats. Coincident with these changes in oxidative-nitrosative stress, aging was also found to be associated with increases in the number of Tdt-mediated dUTP nick labeling (TUNEL)-positive cardiomyocytes, alterations in the Bax/Bcl-2 ratio, and elevated cleavage of caspase-3. Regression analysis demonstrates significant correlation in the age-associated changes markers of oxidative-nitrosative stress with changes in apoptotic signaling. The findings from this descriptive study imply that age-associated increases in mitochondrial-mediated apoptosis may be associated with the increase in oxidative-nitrosative stress in the aging F344xBN female heart.

Identification of genes contributing to cardiovascular disease in overweight and obese individuals from West Virginia.

Excess weight is a known risk factor for coronary artery disease (CAD) and a large percentage of overweight and obese individuals ultimately develop CAD. The objective of this study was to identify human genes associated with CAD in a subgroup of overweight and obese individuals using population-based association methods. Logistic regression analyses were used to test the association between single nucleotide polymorphisms (SNPs) in 34 candidate genes and the CAD phenotype with age, gender, and BMI as covariates. Two SNPs in the Apolipoprotein B (Apo B) gene [rs1042031 and rs1800479], one in the Cholesterol Ester Transfer Protein (CETP) gene [rs5880], and one in the Low Density Lipoprotein Receptor (LDLR) gene [rs2569538] met the 0.01 significance level for association with CAD. Based on these findings, we conclude that variants within the CETP and Apo B genes conferred susceptibility to CAD in overweight individuals and that a variant with the LDLR gene conferred susceptibility in an obese group.

The short-term consumption of a moderately high-fat diet alters nitric oxide bioavailability in lean female Zucker rats.

To determine whether short-term consumption of a moderately high-fat diet (MHFD) affects nitric oxide (NO) production, the concentration of stable NO metabolites (NOx) in urine and plasma of rats fed a MHFD (15.6 %g fat) or control diet (4.5 %g fat) was measured weekly for 4 weeks. Plasma and urine NOx levels were significantly depressed in the MHFD group by week 1 and remained so for the duration of the study. Decreased NO bioavailability may result from a decrease in NO production or the scavenging of NO by reactive oxygen species (ROS). Because endothelial NOS (eNOS) is the major contributor to NO production and circulating levels of NOx, eNOS expression was measured in several tissues. At week 1, there was a MHFD-associated decrease in eNOS expression in the liver. Subsequently, eNOS expression declined in the heart and kidney medulla of MHFD-fed rats at weeks 3 and 4, respectively. The expression of eNOS in the kidney cortex and adipose tissue did not change. These results suggest that a MHFD alters eNOS expression in a time-dependent and tissue-specific manner. In the liver, NOS activity and tissue levels of NOx and nitrotyrosine were measured. Nitrotyrosine levels were used as an indirect measure of the NO scavenged by ROS. There was a decrease in NOS activity, suggesting that the low levels of hepatic NOx were due, in part, to a decrease in NO production. In addition, there was a dramatic increase in nitrotyrosine formation, suggesting that the decline in hepatic NOx was also due to an increased interaction of NO with ROS. Tyrosine nitration commonly has detrimental effects on proteins. The decrease in NO and increase in protein nitration could potentially have adverse effects on tissue function.

The dangers of gathering data: surgeon-specific outcomes revisited.

The accuracy of risk adjustment is important in developing surgeon profiles. As surgeon profiles are obtained from observational, nonrandomized data, we hypothesized that selection bias exists in how patients are matched with surgeons and that this bias might influence surgeon profiles. We used the Society of Thoracic Surgeons risk model to calculate observed to expected (O/E) mortality ratios for each of six cardiac surgeons at a single institution. Propensity scores evaluated selection bias that might influence development of risk-adjusted mortality profiles. Six surgeons (four high and two low O/E ratios) performed 2298 coronary artery bypass grafting (CABG) operations over 4 years. Multivariate predictors of operative mortality included preoperative shock, advanced age, and renal dysfunction, but not the surgeon performing CABG. When patients were stratified into quartiles based on the propensity score for operative death, 83% of operative deaths (50 of 60) were in the highest risk quartile. There were significant differences in the number of high-risk patients operated upon by each surgeon. One surgeon had significantly more patients in the highest risk quartile and two surgeons had significantly less patients in the highest risk quartile (p < 0.05 by chi-square). Our results show that high-risk patients are preferentially shunted to certain surgeons, and away from others, for unexplained (and unmeasured) reasons. Subtle unmeasured factors undoubtedly influence how cardiac surgery patients are matched with surgeons. Problems may arise when applying national database benchmarks to local situations because of this unmeasured selection bias.

Deferasirox decreases age-associated iron accumulation in the aging F344XBN rat heart and liver.

It is thought that aging in rats and humans is associated with increases in iron accumulation and cell apoptosis. Here, we examine the relationship between cardiac iron levels and apoptosis in aged F344XBN rats that had been treated with an oral iron chelator (Deferasirox; 100 mg/kg body weight) on alternate days for 6 months. Compared to adult animals (6 month), cardiac iron (+72%), liver iron (+87%), ferritin light chain (+59%), divalent metal transporter-1 (+56%) and the number of TdT-mediated dUTP nick end labeling (TUNEL) positive cells (4.3 fold increase) were higher in 33-month-old animals (P < 0.05). Deferasirox treatment decreased cardiac iron levels by 37% (P < 0.05), and this was associated with decreases in the number of TUNEL-positive cells. Age-associated increases in cell death were coupled with increases in Bax to Bcl-2 ratio, and the amount of Bad, full-length caspase-3, and cleaved caspase-3. Deferasirox treatment decreased the Bax to Bcl-2 ratio by 17% (P < 0.05) and the amount of Bad, full-length caspase-3, cleaved caspase-3 (19 kDa), and cleaved caspase-3 (17 kDa) by 41, 16, 22, and 37%, respectively (P < 0.05). Taken together, these data suggest that deferasirox may be effective in diminishing age-associated iron accumulation and cardiac apoptosis in the F344XBN rat model.

Possible molecular mechanisms underlying age-related cardiomyocyte apoptosis in the F344XBN rat heart.

Despite advances in treatment, age-related cardiac dysfunction still remains a leading cause of cardiovascular death. Recent data have suggested that increases in cardiomyocyte apoptosis may be involved in the pathological remodeling of heart. Here, we examine the effects of aging on cardiomyocyte apoptosis in 6-, 30-, and 36-month-old Fischer344 x Brown Norway F1 hybrid rats (F344XBN). Compared with 6-month hearts, aged hearts exhibited increased TdT-mediated dUTP nick end labeling-positive nuclei, caspase-3 activation, caspase-dependent cleavage of alpha-fodrin and diminished phosphorylation of protein kinase B/Akt (Thr 308). These age-dependent increases in cardiomyocyte apoptosis were associated with alterations in the composition of the cardiac dystrophin glycoprotein complex and elevated cytoplasmic IgG and albumin immunoreactivity. Immunohistochemical analysis confirmed these data and demonstrated qualitative differences in localization of dystrophin-glycoprotein complex (DGC) molecules with aging. Taken together, these data suggest that aging-related increases in cardiac apoptotic activity model may be due, at least in part, to age-associated changes in DGC structure.

Acetaminophen combinations protect against iron-induced cardiac damage in gerbils.

This study tested if acetaminophen, N-methyl-D-glucamine dithiocarbamate (NMGDTC), deferoxamine, and combinations of these agents reduce excess iron content, prevent iron-induced pathology, reduce cardiac arrhythmias, and reduce mortality in iron-overloaded gerbils. Eight groups of 16 gerbils received iron dextran injections (ferric hydroxide dextran complex, 120 mg/kg, ip) or saline solution (controls) twice/wk for 8 wk. The 8 groups were treated every Monday, Wednesday, and Friday with one of the following: saline control, acetaminophen, 150 mg/kg, ip), acetaminophen (150 mg/kg, po), deferoxamine, 83 mg/kg, ip), NMGDTC (200 mg/kg, ip), or combinations of acetaminophen (75 mg/kg) with deferoxamine (42 mg/kg, each ip, separately) or acetaminophen (75 mg/kg) with NMGDTC (100 mg/kg, each ip, separately). The treatments were given 4 hr after each iron injection on days when both iron administration and treatment occurred during iron overloading (8 wk) and were continued 4 wk thereafter. Echocardiography (ECHO) was used to evaluate iron-induced cardiac changes and detect arrhythmias. Acetaminophen and NMGDTC, or combinations thereof, reduced cardiac and hepatic excess iron content as measured by inductively coupled plasma atomic emission spectrometry (ICP-AES). Acetaminophen was effective whether administered po or ip. Acetaminophen treatment had a positive inotropic effect on cardiac function. Acetaminophen-deferoxamine combination conferred equal cardioprotection as acetaminophen or deferoxamine alone, was equally able to remove hepatic iron, and was superior to either acetaminophen or deferoxamine in removing cardiac iron from iron-overloaded gerbils. Acetaminophen-NMGDTC combination was also effective in removing cardiac and hepatic iron and protecting against iron-induced cardiac damage. ECHO evaluation of iron-overloaded, untreated gerbils demonstrated a high incidence of cardiac arrhythmias, usually PVCs (10/16 = 63%), and mortality prior to completion of the experiment (4/16 = 25%). All treatments except deferoxamine, alone, reduced the incidence of cardiac arrhythmias and deaths. All treatments reduced iron-induced increases in hepatic and cardiac weights. This study demonstrates injection alternates that are equally or more effective than deferoxamine injections and shows oral acetaminophen to be effective in treatment of iron-overload and associated cardiac complications.

Aging influences multiple indices of oxidative stress in the heart of the Fischer 344/NNia x Brown Norway/BiNia rat.

We report the influence of aging on multiple markers of oxidative-nitrosative stress in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd x Brown Norway/BiNia (F344/NXBN) rats. Compared to adult (6-month) hearts, indices of oxidative (superoxide anion [O2*-], 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were 34.1 +/- 28.1%, 186 +/- 28.1% and 94 +/- 5.8% higher, respectively, in 36-month hearts and these findings were highly correlated with increases in left ventricular wall thickness (r > 0.669; r > 0.710 and P < 0.01, respectively). Regression analysis showed that increases in cardiac oxidative-nitrosative stress with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in transcriptional (NF-kappaB) activities, signaling (mitogen-activated protein kinases along with Src), apoptotic (Bcl-2, Traf-2), and cellular stress (HSPs). These results suggest that the aging F344/NXBN heart may be highly suited for unraveling the molecular events that lead to age-associated alterations in cardiac oxidative stress.

A moderately high fat diet promotes salt-sensitive hypertension in obese zucker rats by impairing nitric oxide production.

The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NO(x)) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NO(x) excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NO(x) excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge.

Uniaxial stretch-induced regulation of mitogen-activated protein kinase, Akt and p70 S6 kinase in the ageing Fischer 344 x Brown Norway rat aorta.

The effects of ageing on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signalling molecules that may be of particular importance in mediating numerous cellular responses, including control of cell growth, differentiation and adaptation, are the proteins associated with the mitogen-activated protein kinase (MAPK) signalling systems. The MAPKs, in conjunction with the p70 S6k signalling cascade, have emerged as critical components for regulating numerous mechanotransduction-related cellular responses. Here we investigate the ability of uniaxial stretch to activate the MAPK and p70 S6k pathways in adult (6-month-old), aged (30-month-old) and very aged (36-month-old) Fischer 344/NNiaHSd x Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signal-regulated kinase (Erk) 1/2, p38- and c-Jun NH(2)-terminal kinase (Jnk)-MAPKs showed differential expression and activation between these proteins with age. An acute 15 min interval of 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of Erk1/2, p38- and Jnk-MAPK. However, ageing altered uniaxial induced p70 S6k pathway signalling. These observations confirm previous data demonstrating that MAPK proteins are mechanically regulated and also suggest that p70 S6k signalling expression and activation are controlled differently with ageing. Taken together, these data may help to explain, in part, the age-related changes in vascular morphology, function and response to injury.

Acetaminophen protects against iron-induced cardiac damage in gerbils.

There are few effective agents that safely remove excess iron from iron-overloaded individuals. Our goal was to evaluate the iron-removing effectiveness of acetaminophen given ip or orally in the gerbil iron-overload model. Male gerbils were divided into 5 groups: saline controls, iron-overloaded controls, iron-overloaded treated with ip acetaminophen, iron-overloaded treated with oral acetaminophen, and iron-overloaded treated with ipdeferoxamine. Iron dextran was injected iptwice/wk for 8 wk. Acetaminophen and deferoxamine treatments were given on Mondays, Wednesdays, and Fridays during the same 8 wk and continued for 4 wk after completion of iron-overloading. Echocardiograms were performed after completion of the iron-overloading and drug treatments. Liver and cardiac iron contents were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Iron-overloaded controls had 232-fold and 16-fold increases in liver and cardiac iron content, respectively, compared to saline controls. In iron-overloaded controls, echocardiography showed cardiac hypertrophy, right and left ventricular distension, significant reduction in left ventricular ejection fraction (-22%), and fractional shortening (-31%) during systole. Treatments with acetaminophen (ip or oral) or deferoxamine (ip) were equally effective in reducing cardiac iron content and in preventing cardiac structural and functional changes. Both agents also significantly reduced excess hepatic iron content, although acetaminophen was less effective than deferoxamine. The results suggest that acetaminophen may be useful for treatment of iron-induced pathology.

Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats.

Aging is associated with left ventricular hypertrophy, dilatation, and fibrosis of the heart. The Fischer 344/Brown Norway F1 (F344/BNF1) rat is recommended for age-related studies by the National Institutes on Aging because this hybrid rat lives longer and has a lower rate of pathological conditions than inbred rats. However, little is known about age-associated changes in cardiac and aortic function and structure in this model. This study evaluated age-related cardiac changes in male F344/BNF1 rats using ECHO, gross, and microscopic examinations. Rats aged 6-, 30-, and 36-mo were anesthetized and two-dimensional ECHO measurements, two-dimensional guided M-mode, Doppler M-mode, and other recordings from parasternal long- and short-axis views were obtained using a Phillips 5500 ECHO system with a 12 megahertz transducer. Hearts and aortas from sacrificed rats were evaluated grossly and microscopically. The ECHO studies revealed persistent cardiac arrhythmias (chiefly PVCs) in 72% (13/18) of 36-mo rats, 10% (1/10) of 30-mo rats, and none in 6-mo rats (0/16). Gross and microscopic studies showed left ventricular (LV) dilatation, borderline to mild hypertrophy, and areas of fibrosis that were common in 36-mo rats, less evident in 30-mo rats, and absent in 6-mo rats. Aging was associated with mild to moderate decreases of LV diastolic and systolic function. Thus, male F344/BN F1 rats demonstrated progressive age-related (a) decline in cardiac function (diastolic and systolic indices), (b) LV structural changes (chamber dimensions, volumes, and wall thicknesses), and (c) persistent arrhythmias. These changes are consistent with those in humans. The noninvasive ECHO technique offers a means to monitor serial age-related cardiac failure and therapeutic responses in the same rats over designated time intervals.