Presence Of Cardiac Risk Factors Research Articles

Left ventricular shape index and eccentricity index assessed by gated PET/CT. Promising parameters for detection of left ventricular remodelling

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Groningen/University Medical Center Groningen. Background Left ventricular (LV) remodelling has been described as the pathway that precedes heart failure. This process consists of changes in the shape, size, volume and function of the left ventricle; all of this directly associated to increased risk of major adverse cardiac events (MACEs). Different parameters are used to evaluate cardiac geometry in multiple cardiac imaging modalities. In nuclear medicine, LV geometry can be studied through shape index (SI) and eccentricity index (EI). These values examine the degree of sphericity (SI) and elongation (EI) of the left ventricle. However, in cardiac perfusion PET/CT, the LV remodelling has not been extensively studied with SI and EI values, and their role is yet to be elucidated. Purpose This project aim to describe the role of SI and EI values in patients examined by gated 13N-ammonia PET/CT in ischemic and infarction scenario. Methods We retrospectively randomly selected 140 patients referred to 13N-ammonia PET/CT between 2016 and 2022 for suspected or diagnosed CAD. The patients were classified in 4 groups of 35 patients according to the presence and burden of ischemia or infarction: normal=0% of scar burden and ischemic burden; mild ischemia=5–10% of ischemic burden; moderate-severe ischemia≥10% of ischemic burden and infarction≥5% of scar burden. We collected the information regarding myocardial flows (myocardial blood flow (MBF) at rest, hyperaemic MBF at stress and coronary flow reserve (CFR)) and left ventricular geometry (SI end-diastolic at rest and stress, SI end-systolic at rest and stress, and EI at rest and stress). All the variables were automatically processed with QPS/QGS software. We performed a multicomparison analysis for the mentioned variables with One way ANOVA variance and Dunnett’s Test as Post Hoc, stablishing as the control the infarction group. Results The study population consisted of 35.7% women, all patients over 36 years old, with no significant differences between groups regarding the presence of cardiac risk factors. The control group showed important changes in all SI and EI when compared to the rest of the groups. With a maximum change of 0.090 observed in SI end-systolic stress in the mild ischemia group, and a minimum change of −0.041 in EI rest in the moderate-severe ischemia group. Control subjects had statistically significant higher values of SI end-diastolic rest (p<0.001) and stress (p = 0.005), end-systolic rest (p = 0.001)and stress (p<0.001) and statistically significant lower values of EI rest (p<0.001) and stress (p<0.001) when compared with all the other groups. Additionally, all SI and EI values in stress follow a linear change proportional to the degree of myocardial extend (Figure 1 and 2). Conclusions(s) SI and EI by 13N-ammonia PET/CT are variables that seem clinically relevant for the early detection of LV remodeling. However, there is still research to do for establishing cut-off values and evaluating the prediction of MACEs.

Prognostic value of coronary artery calcium score in hospitalized COVID - 19 patients

Abstract Funding Acknowledgements Type of funding sources: None. Background The association of known cardiovascular risk factors with poor prognosis of coronavirus disease 2019 (COVID-19) has been recently emphasized (1). Coronary artery calcium (CAC) score is considered a risk modifier in primary prevention of cardiovascular disease and has shown to improve cardiovascular risk prediction in addition to classical risk factors (2). Purpose We hypothesized that the absence of CAC might have an additional predictive value for an improved cardiovascular outcome of hospitalized COVID-19 patients. Methods We prospectively included 310 consecutive hospitalized patients with COVID-19. Thirty patients with a history of coronary artery disease were excluded. Low dose non - contrast chest computed tomography (CT) was performed in all patients at admission. Visual assessment of CAC in every coronary artery was obtained by using an ordinal scoring of 0, 1, 2 or 3 corresponding to absent, mild, moderate or severe CAC score. A total score was calculated by summing the score of each vessel, which was further categorized as 0 (undetectable), 1-3 (mild), 4-5 (moderate) and ≥ 6 (severe). (Figure 1). Demographics, medical history, clinical characteristics, laboratory findings, imaging data, in-hospital treatment, and outcomes were retrospectively analyzed. A composite endpoint of major adverse cardiovascular events (MACE) was defined as all - cause mortality, heart failure, acute coronary syndrome, atrial fibrillation and stroke. Results Two hundred eighty patients (63.2 ± 16.7 years old, 57.5% male) were included in the analysis. One hundred thirty one (46.7%) patients had a CAC score of 0. MACE rate was 21.8% (61 patients). Multivariable logistic regression showed that the absence of CAC was inversely associated with MACE (OR 0.209, 95% CI 0.052–0.833, p = 0.027), with a negative predictive value of 84.5% (sensitivity 72%, specificity 55%), independent of age, risk factors or disease severity (Figure 2). Conclusion The absence of CAC had a high negative predictive value for MACE in patients hospitalized with COVID-19, independent of the presence of cardiac risk factors or disease severity. These findings reinforce the idea that the assessment of CAC could be a useful marker for risk stratification and management of COVID - 19 patients. Future directions should focus on the implementation of CAC score into mid - term and long - term follow - up of this particular population, to provide a more precise and earlier estimation of cardiovascular risk. Abstract Figure. Abstract Figure.

Prognostic value of coronary artery calcium score in hospitalized COVID-19 patients

Abstract Background The association between known cardiovascular risk factors and poor prognosis of patients diagnosed with coronavirus disease 2019 (COVID-19) has been recently emphasized (1). Coronary artery calcium (CAC) score assessed by computed tomography (CT) is considered a risk modifier in primary prevention of cardiovascular disease and has shown to improve cardiovascular risk prediction in addition to classical risk factors (2). Purpose We hypothesized that the absence of CAC might have an additional predictive value for an improved cardiovascular outcome of hospitalized COVID-19 patients. Methods We prospectively included 310 consecutive hospitalized patients with COVID-19. Thirty patients with a history of coronary artery disease were excluded.Low dose non-contrast chest CT was performed in all patients at admission. Visual assessment of CAC in every coronary artery was obtained by using an ordinal scoring of 0, 1, 2 or 3 corresponding to absent, mild, moderate or severe CAC score. A total score was calculated by summing the score of each vessel, which was further categorized as 0 (undetectable), 1–3 (mild), 4–5 (moderate) and ≥6 (severe). (Figure 1). Demographics, medical history, clinical characteristics, laboratory findings, imaging data, in–hospital treatment and outcomes were retrospectively analyzed. A composite endpoint of major adverse cardiovascular events (MACE) was defined as all-cause mortality and cardiovascular events (heart failure, myocarditis, arrhythmia, acute coronary syndrome, stroke, pulmonary embolism). Results Two-hundred eighty patients (63.2±16.7 years old, 57.5% male) were included in the analysis. One hundred thirty one (46.7%) patients had a CAC score of zero. MACE-rate was 24.2% (68 patients). Multivariate logistic regression showed that the absence of CAC was inversely associated with MACE (OR 0.264, 95% 0.071–0.981, p=0.047), with a negative predictive value (NPV) of 81.4%, sensitivity 70%, specificity 55%, independent of age, risk factors or disease severity (Table 1). Conclusion The absence of CAC translated into a low risk for MACE in COVID-19 patients, even in the presence of cardiac risk factors, which reinforces the idea that the assessment of CAC score in COVID-19 patients could be a useful marker for patients risk stratification and management. Future directions should focus on the implementation of CAC score into mid-term and long-term follow-up of this particular population, to provide a more precise and earlier estimation of cardiovascular risk Funding Acknowledgement Type of funding sources: None. Figure 1Table 1

Prognostic Value of Coronary Artery Calcium Score in Hospitalized COVID-19 Patients.

Background: The association of known cardiovascular risk factors with poor prognosis of coronavirus disease 2019 (COVID-19) has been recently emphasized. Coronary artery calcium (CAC) score is considered a risk modifier in the primary prevention of cardiovascular disease. We hypothesized that the absence of CAC might have an additional predictive value for an improved cardiovascular outcome of hospitalized COVID-19 patients.Materials and methods: We prospectively included 310 consecutive hospitalized patients with COVID-19. Thirty patients with history of coronary artery disease were excluded. Chest computed tomography (CT) was performed in all patients. Demographics, medical history, clinical characteristics, laboratory findings, imaging data, in-hospital treatment, and outcomes were retrospectively analyzed. A composite endpoint of major adverse cardiovascular events (MACE) was defined.Results: Two hundred eighty patients (63.2 ± 16.7 years old, 57.5% male) were included in the analysis. 46.7% patients had a CAC score of 0. MACE rate was 21.8% (61 patients). The absence of CAC was inversely associated with MACE (OR 0.209, 95% CI 0.052–0.833, p = 0.027), with a negative predictive value of 84.5%.Conclusion: The absence of CAC had a high negative predictive value for MACE in patients hospitalized with COVID-19, even in the presence of cardiac risk factors. A semi-qualitative assessment of CAC is a simple, reproducible, and non-invasive measure that may be useful to identify COVID-19 patients at a low risk for developing cardiovascular complications.

Biomarker-Based Preoperative Risk Stratification for Patients Undergoing Non-Cardiac Surgery.

Perioperative morbidity and mortality remains a substantial problem and is strongly associated with patients’ cardiac comorbidities. Guidelines for the cardiovascular assessment and management of patients at risk of cardiac issues while undergoing non-cardiac surgery are traditionally based on the exclusion of active or unstable cardiac conditions, determination of the risk of surgery, the functional capacity of the patient, and the presence of cardiac risk factors. In the last two decades, strong evidence showed an association between cardiac biomarkers and adverse cardiac events, with newer guidelines incorporating this knowledge. This review describes a biomarker-based risk-stratification pathway and discusses potential treatment strategies for patients suffering from postoperative myocardial injury or infarction.

Impact of disease state on arrhythmic event detection by action potential modelling in cardiac safety pharmacology

IntroductionThe use of in silico cardiac action potential simulations is one of the pillars of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) currently under evaluation designed to detect more accurately proarrhythmic liabilities of new drug candidate. In order to take into account the variability of clinical situations, we propose to improve this method by studying the impact of various disease states on arrhythmic events induced by 30 torsadogenic or non-torsadogenic compounds. MethodIn silico modelling was done on the human myocytes using the Dutta revised O'Hara-Rudy algorithm. Results were analysed using a new metric based on the compound IC50s against the seven cardiac ionic currents considered to be the most important by the CiPA initiative (IKr, IKs, INa, INaL, IK1, Ito, ICaL) and the minimal rate of action potential voltage decrease calculated at the early-afterdepolarization (EAD) take-off membrane voltage (Vmin). ResultsThe specific threshold at which each torsadogenic compounds induced EAD, was exacerbated by the presence of cardiac risk factors ranked as follows: congestive heart failure > hypertrophic cardiomyopathy > cardiac pause > no risk factor. Non-torsadogenic compounds induced no EAD even in the presence of cardiac risk factors. DiscussionThe present study highlighted the impact of pre-existing cardiovascular disease on arrhythmic event detection suggesting that disease state modelling may need to be incorporated in order to fully realize the goal of the CiPA paradigm in a more accurate predictability of proarrhythmic liabilities of new drug candidate.

Controversies in diagnosis and management of community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a common condition; however, it appears to be overdiagnosed. Diagnosing CAP too frequently may be adding to the problems of overuse of antibiotics, such as bacterial resistance in the community and greater costs and complications in individuals. Data support that most patients with non-severe CAP can be treated for 3-5 days; however, most patients with CAP are receiving much longer courses of therapy. Macrolides such as azithromycin have the potential to prolong the QT interval, although large population studies show that this does not appear to result in excess cardiac mortality. CAP is associated with an increase in a variety of cardiac complications, most notably infarctions and worsening cardiac failure, so clinicians should be vigilant for signs and symptoms of these complications, particularly in patients with a history of ischaemic cardiac disease or the presence of cardiac risk factors. Cardiac risk factors should be assessed and managed in patients with CAP over 40 years of age, although there are yet to be data to show that this approach reduces deaths. Corticosteroids may have a slight effect on reducing deaths in patients with severe CAP, but this must be balanced against the significant potential for side effects.

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Eosinophilia-Associated Coronary Artery Vasospasm in Patients with Aspirin-Exacerbated Respiratory Disease

Some patients with aspirin-exacerbated respiratory disease (AERD) and eosinophilia report angina-type chest pain that occurs at rest and responds to corticosteroid therapy. The frequency of eosinophilia-associated coronary artery vasospasm in patients with AERD, a disease characterized by blood and respiratory tissue eosinophilia, however, is unknown. The objective of this study was to understand the cause of the chest pain described above and determine the most appropriate treatment for it. A chart review of 153 patients with AERD who are followed at Brigham and Women's Hospital was performed. Patients who reported any type of chest pain were assessed for the presence of cardiac risk factors, eosinophilia, and response of chest pain to a variety of treatments. Two patients with AERD and eosinophilia who had recurrent chest pain due to suspected vasospasm are described in detail, and 8 other cases are also summarized. Of the 153 patients reviewed, 10 had a history of chest pain concerning for ischemia. Of the 10 patients with chest pain, 8 had undergone aspirin desensitization and initiated high-dose aspirin therapy; of these, 6 reported an increase in the frequency or severity of chest pain while on high-dose aspirin with improvement after aspirin discontinuation or dose reduction. Many patients had traditional cardiac risk factors, but none had any evidence of coronary atherosclerosis; almost all had significant eosinophilia. Their chest pain did not improve with typical antianginal treatments but did respond to corticosteroid therapy. Although uncommon, patients with AERD can develop eosinophilia-associated coronary artery vasospasm, which is occasionally worsened by high-dose aspirin. Patients with AERD who present with symptoms of ischemic chest pain should be screened for eosinophilia, as early treatment with corticosteroids can be life-saving.

Eosinophilia-Associated Coronary Artery Vasospasm in Patients with Aspirin-Exacerbated Respiratory Disease

Eosinophilia is known to be associated with coronary artery vasoconstriction that does not respond to conventional vasodilator treatment but does respond to eosinophil-suppressing treatment. The prevalence of eosinophilia-associated coronary vasospasm in patients with aspirin-exacerbated respiratory disease (AERD), an inflammatory disease characterized by blood and respiratory tissue eosinophilia, is unknown. We observed that some patients with AERD report angina-type chest pain that responds to corticosteroid therapy. We sought to understand the cause of and determine the most appropriate treatment for such chest pain. A retrospective chart review of patients with AERD followed at Brigham and Women’s Hospital was performed. Patients who reported chest pain were assessed for presence of cardiac risk factors, eosinophilia, and chest pain response to conventional and unconventional treatments. One hundred fifty three patients were reviewed; 10 had a history of angina-like chest pain. Eight of the 10 patients had undergone aspirin desensitization and initiated high-dose aspirin; of those, 6 reported an increase in the frequency or severity of chest pain while on high-dose aspirin with improvement after aspirin discontinuation or dose reduction. Most patients had no traditional cardiac risk factors but did have significant eosinophilia. Their chest pain did not improve with typical anti-anginal treatments but did respond to corticosteroid therapy. Though uncommon, patients with AERD can develop eosinophilia-associated coronary artery vasospasm, which is occasionally worsened by high-dose aspirin. AERD patients who present with chest pain, particularly if they are on high-dose aspirin, should be screened for eosinophilia as early treatment with corticosteroids could be life saving.

Abstract 18537: Aortic Valve Repair Improves Mid-term Outcomes versus Replacement for Aortic Insufficiency: A Propensity Matched Study

Objectives: Aortic valve (AV) repair has emerged as a feasible and attractive alternative to AV replacement in patients with aortic insufficiency (AI). However, little data exists comparing outcomes following repair versus replacement. We performed a single-center comparative study in patients undergoing AV repair or replacement for AI. Methods: Patients undergoing AV replacement (n=263) or repair (n=153) for AI between 2000 and 2014 were included. Patients ineligible for both repair and replacement surgeries and patients lacking perioperative data were excluded (n=155). To adjust for baseline differences, non-parsimonious logistic regression models were used to generate propensity scores. A 1:1 greedy matching algorithm was used to create 70 propensity matched pairs. Peri-operative and long-term clinical and echocardiographic outcomes were assessed, focusing on survival and valve-related events, and analyzed using Kaplan-Meier techniques. Primary endpoints included late mortality, myocardial infarction, stroke, and AV reoperation. Total follow-up exceeded 1100 patient-years in the entire cohort and 800 patient-years in the matched cohort. Results: The matched pairs were similar in baseline attributes including age (57±14 vs. 56±15, p=0.75), sex (Female: 17% vs. 25%, p=0.22), incidence of LV dysfunction (27% vs. 24%, p=0.38), severe AI (67% vs. 74%, p=0.42) and presence of cardiac risk factors. Replacements consisted of 53% mechanical, 41% bioprosthetic, and 6% homograft valves. Repairs included 61% valve-sparing root replacements, 70% cusp repairs with 43% bicuspid AVs. In hospital mortality (1% vs. 4%, repair vs. replacement, p=0.62) and perioperative outcomes were similar between groups. Four-year survival was 97±2% and 87±4% in repair vs. replacement groups (p=0.11). A total of 5 vs. 17 valve-related events occurred in repair vs. replacement groups. Freedom from primary endpoints at 4 years was 97±2% and 82±8% in the repair vs. replacement groups (p=0.03). Conclusions: In a propensity matched cohort, AV repair for AI was associated with a mid-term reduction in death and serious valve related complications compared to AV replacement. AV repair should be considered, when technically feasible, as the preferred treatment of AI.

Recipient Criteria Predictive of Graft Failure in Kidney Transplantation.

Several classifications systems have been developed to predict outcomes of kidney transplantation based on donor variables. This study aims to identify kidney transplant recipient variables that would predict graft outcome irrespective of donor characteristics. All U.S. kidney transplant recipients between October 25,1999 and January 1, 2007 were reviewed. Cox proportional hazards regression was used to model time until graft failure. Death-censored and nondeath-censored graft survival models were generated for recipients of live and deceased donor organs. Recipient age, gender, body mass index (BMI), presence of cardiac risk factors, peripheral vascular disease, pulmonary disease, diabetes, cerebrovascular disease, history of malignancy, hepatitis B core antibody, hepatitis C infection, dialysis status, panel-reactive antibodies (PRA), geographic region, educational level, and prior kidney transplant were evaluated in all kidney transplant recipients. Among the 88,284 adult transplant recipients the following groups had increased risk of graft failure: younger and older recipients, increasing PRA (hazard ratio [HR],1.03-1.06], increasing BMI (HR, 1.04-1.62), previous kidney transplant (HR, 1.17-1.26), dialysis at the time of transplantation (HR, 1.39-1.51), hepatitis C infection (HR, 1.41-1.63), and educational level (HR, 1.05-1.42). Predictive criteria based on recipient characteristics could guide organ allocation, risk stratification, and patient expectations in planning kidney transplantation.

Sex and the CT: An Evolving Story of the Heart

Sex and the CT: An Evolving Story of the Heart

Sensitive Troponin I Assay in Patients With Suspected Acute Coronary Syndrome

To the Editor: Dr Mills and colleagues demonstrated a significant reduction in myocardial infarction (MI) and death in patients with suspected acute coronary syndrome (ACS) through use of a lower-threshold troponin assay. One surprising finding was a modest increase in use of recommended therapies in patients with plasma troponin concentrations of 0.05 to 0.19 ng/mL during the implementation phase, which would be expected to result in reduced events. In fact, revascularization rates were stable despite more than a doubling in coronary angiography. Aspirin, -blocker, and angiotensin-converting enzyme inhibitor use did not differ between the phases. Although more statins were prescribed at discharge in the implementation phase, a similar difference was present on admission, suggesting possible baseline differences between these nonrandomized samples. The most striking difference was in clopidogrel use, 31% in the validation phase vs 61% in the implementation phase. If the outcome difference between the 2 groups was driven by clopidogrel, this would be a substantially greater benefit than demonstrated in prior studies. For example, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed a 2.1% absolute risk reduction in death from cardiovascular causes, nonfatal MI, or stroke over 12 months (9.3% in clopidogrel group vs 11.4% in placebo group) for patients with ACS without ST-segment elevation compared with an 18% difference in death or recurrent MI at 12 months (39% in validation cohort vs 21% in implementation cohort) in the report by Mills et al. Determination of the rates of clopidogrel use in patients who did or did not have an event would be interesting. In addition, other than the presence of cardiac risk factors and interventions, little is known about the population. Given the high overall mortality rates and low rates of revascularization despite angiography, many patients may have had noncardiac medical issues, and the results may be due to higher attention to underlying coronary artery disease in a population with comorbid illnesses. This is supported by the low rates of use of recommended therapies. For instance, only 47% of validation phase patients with peak troponin concentrations of 0.05 to 0.19 ng/mL were taking a -blocker at discharge when 69% of these patients carried a diagnosis of ischemic heart disease prior to admission. It would be useful to know the number of patients who underwent stress testing, the percentage diagnosed with ischemic heart disease, other discharge diagnoses, and creatinine levels as alternate explanations for elevated troponin levels. Jeffrey D. Clough, MD, MBA Seth S. Martin, MD Matthew W. Cope, MD

Präoperatives Vorgehen bei elektiven, nicht-kardiochirurgischen Eingriffen – Erweiterte Maßnahmen bei kardialen Risikopatienten

Preoperative differentiated cardiac clarification may be necessary in case of patients suffering from known or suspected cardiovascular diseases. Such clarification should be effected well before surgery. This preparatory investigation should include pharmacological and interventional aspects as well as any necessary examinations or re-programming of therapeutic implants such as pacemakers or implantable cardiovert defibrillators (ICD) or if necessary co-ordination. Decision for or against extended preoperative diagnosis depends on four factors: presence of an acute symptomatic cardiac disease, presence of cardiac risk factors in the patient, the patient's capacity to cope with stress factors and the cardiac risk of surgery. By means of transparent and definite interdisciplinary agreement it should be possible to arrive at a mutual consent on the situation of cardiac risk patients while avoiding unnecessary preoperative examinations. This shortens preoperative procedures and finally also cuts down the overall cost.

Prevalence of Fat Deposition Within the Right Ventricular Myocardium in Asymptomatic Young Patients Without Ventricular Arrhythmias

Variable amounts of intramyocardial fat can be found within the right ventricular muscle fibers. We aimed to determine the prevalence of intramyocardial fat deposition within the right ventricle (RV) in asymptomatic patients aged 40 years and younger who underwent imaging of the heart for coronary artery disease screening. Retrospective review of 540 consecutive patients aged 40 years or younger referred for coronary calcium scoring. The images were reviewed by 2 dedicated cardiac radiologists, and the following specific observations were made: presence or absence of macroscopic fat in the RV by location, RV size as normal or enlarged, and presence of additional foci of fat deposition in the visualized thorax. The clinical data were reviewed from the patients' medical record, and the following information was recorded: age, sex, body mass index, and the presence of cardiac risk factors. The electrocardiographic examinations were reviewed as well. The study cohort included 398 males (73%) and 142 females (27%), with a mean age of 36.2+/-4.3 years and a range of 12 to 40 years. Sixty-two patients (11.5%) had macroscopic fatty deposition of the RV myocardium. Fatty replacement of the free wall of the RV is common, occurring in up to 11% of asymptomatic patients younger than 40 years of age undergoing cardiac screening examinations. No statistically significant association with cardiac risk factors or body mass index was found.

Molecular mechanisms underlying pharmacological stimulation of eNOS expression and eNOS activity

Endothelium-derived nitric oxide (NO) generated by endothelial NO synthase (eNOS) is a key regulator of endothelial function. Vascular NO induces vasodilation, inhibits platelet aggregation and adhesion, prevents oxidative modification of LDL cholesterol, limits vascular smooth-muscle-cell proliferation, and decreases the expression of proinflammatory genes that promote the development of atherosclerosis. In the presence of cardiac risk factors or cardiovascular disease, endothelial function is impaired. A growing amount of evidence indicates that oxidative stress – an imbalance between endogenous reactive oxygen species (ROS) and antioxidants in favor of the former – contributes markedly to endothelial dysfunction. A crucial aspect of endothelial dysfunction is the reduced bioactivity of NO. A dominant mechanism reducing bioavailability of vascular NO relates to its rapid oxidative inactivation by the ROS superoxide anion. In addition, evidence indicates that persisting oxidative stress renders eNOS dysfunctional, such that it ceases to produce NO and produces superoxide instead. In recent years, we have identified a number of compounds that can revert these events and improve the bioavailability of NO [1-3]. Below we describe the effects of trans-resveratrol as an example. Trans-resveratrol, a naturally occurring phytoalexin found in grapes and wine, is likely to contribute to the potential of red wine in preventing human cardiovascular disease. We have published previously, that resveratrol upregulates eNOS expression and enhances eNOS activity [5,4]). In addition to its (moderate) direct antioxidant effect, we have found that resveratrol regulates gene expression of pro- and antioxidative enzymes in the cardiovascular system. Resveratrol is an activator of sirtuin 1 (SIRT1) [6], a NAD+-dependent histone deacetylase. SIRT1 facilitates the formation of heterochromatin, the more tightly packed form of chromatin associated with histone hypoacetylation and gene repression. Multiple non-histone targets have also been described for SIRT1. These include some transcription factors or cofactors such as the tumor suppressor p53, the forkhead box class O (FOXO) transcription factors, nuclear factor κB (NF-κB), and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) [7]. Recent studies point to SIRT1 as a key regulator of angiogenesis, vascular tone and endothelial function. Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol resulted in a concentration- and time-dependent upregulation of superoxide dismutases (SOD)1, 2 and 3. SIRT1 inhibition with sirtinol or knockdown of SIRT1 by sRNAi markedly reduced the upregulation of SOD1 and 2 with little effect on SOD3. Also glutathione peroxidase 1 (GPx1) and catalase were upregulated by resveratrol. Sirtinol and SIRT1 knockdown prevented the effect on GPx1, but had no significant effect on the enhancement of catalase. The same resveratrol regimen downregulated the expression of NADPH oxidase Nox4, which occurred independently of SIRT1. (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) is an essential cofactor of eNOS. BH4 is sensitive to oxidation and diminished in oxidative stress. BH4 is synthesized from guanosine 5'-triphosphate (GTP) via a de novo pathway by the rate-limiting enzyme GTP cyclohydrolase I (GCH1). Treatment of EA.hy 926 cells with resveratrol enhanced the expression of GCH1, which was reversed by sirtinol or knockdown of SIRT1 by siRNA. Atherosclerotic apolipoprotein E knockout (ApoE-KO) mice were treated with resveratrol (30 or 100 mg/kg/day for 7 days via gavage). Resveratrol treatment significantly reduced the levels of superoxide in the heart, which was associated with an upregulation of SOD1-3, GPx1, and catalase. In parallel, mRNA expression of NADPH oxidase subunits Nox2 and Nox4 were reduced. Resveratrol also inhibited the translocation of p47phox and Rac1 and decreased the activity of the NADPH oxidase complex in heart membrane fractions. The cardiac content of malondialdehyde, an indicator of lipid peroxidation and a biomarker for oxidative stress, was reduced by resveratrol treatment. Resveratrol also reduced 3-nitrotyrosine levels in the heart. ApoE-KO mice are an animal model of oxidative stress, and eNOS was found in an uncoupled state, producing superoxide instead of NO. This was probably due to a relative deficiency of BH4. Treatment of ApoE-KO mice with resveratrol enhanced the expression of GCH1 and significantly increased BH4 levels in the heart. This was associated with reduced superoxide production by eNOS. These data demonstrate that resveratrol protects against vascular oxidative stress in vitro and in vivo, by changing the expression pattern of pro- and antioxidative genes in an advantageous manner. The data also indicate that many of these effects are mediated by SIRT1, thereby identifying SIRT1 as a key regulator of cardiovascular oxidative stress.

Effect of Chronic Beta-Blocker Use on Stroke After Noncardiac Surgery

The incidence of postoperative stroke ranges from 0.08% to 0.7% in noncardiac surgery. Recently, the PeriOperative ISchemic Evaluation (POISE) study reported an incidence of postoperative stroke of 1% in patients scheduled for noncardiac surgery when beta blockers were initiated immediately before surgery. To assess the association between chronic beta-blocker use and postoperative stroke in noncardiac surgery, we undertook a case-control study among 186,779 patients who underwent noncardiac surgery from 2000 to 2008 at the Erasmus Medical Centre. Patients who were undergoing intracerebral surgery or carotid surgery or who had head and/or carotid trauma were excluded. The case subjects were 34 patients (0.02%) who had experienced a stroke within 30 days after surgery. Of the remaining patients, 2 controls were selected for each case and were stratified according to calendar year, type of surgery, and age. For cases and controls, information was obtained regarding beta-blocker use before surgery, the presence of cardiac risk factors, and the use of other cardiovascular medication. The use of beta blockers was as common in the cases as in the controls (29% vs 29%; p = 1.0). The adjusted odds ratio for postoperative stroke among beta-blocker users compared with nonusers was 0.4 (95% confidence interval 0.1 to 1.5). Similar results were obtained in the subgroups of patients stratified according to the use of cardiovascular therapy and the presence of cardiac risk factors. In conclusion, the present case-control study has shown no increased risk of postoperative stroke in patients taking chronic beta-blocker therapy.

Fluoropyrimidine-associated cardiotoxicity: revisited

Background: The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. Patients and methods: We performed a literature review (1969 – 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. Results: Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m2/day (36%), 751 – 999 (16%), 1,000 (26%), 1,001 – 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died. Conclusions: Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.

Clinical impact of routine serial multigated acquisition scans (MUGA) in patients with relapsed ovarian cancer exposed to pegylated liposomal doxorubicin (PLD)

5589 Background: Ovarian cancer patients are a difficult to treat population as most of them have been previously treated by a combination of chemotherapeutic agents and at least a platinum and taxane based regimen. Several studies have suggested that pegylated liposomal doxorubicin (PLD) administered at cumulative dose of less than 550 mg/m2 appears to be effective and with reduced risk of cardiotoxicity. Although the cumulative dose in these patients typically has been <240 mg/m2, cardiac function monitoring by serial MUGA scans are routinely employed. The practice of continued monitoring should be weighed against the cost-benefit ratio and should be re- evaluated. Method: A retrospective chart review was performed in our institution from 1985–2006. Patients who were included in the study were women from 30–85 years of age with relapsed ovarian cancer and have been treated with PLD. Age, stage, performance status, previous exposure to anthracycline therapy, presence of cardiac risk factors, and cumulative doses were analyzed against determination of LVEF through serial MUGA scans. Statistical analysis was performed using SAS 9.1 (Cary, NC). Descriptive statistics were used to characterize patient demographics and the fisher exact test utilized for crosstab analysis. Results: 61 patients met the inclusion criteria. This population has received a median of 2 chemotherapy regimens prior to initiation of PLD. 13% of the patients enrolled have received prior doxorubicin therapy and 16% have cardiac risk factors. The cumulative dose of PLD delivered range from 40–732 mg/m2 with a median dose of 200 mg/m2. Serial MUGA scans were obtained only in 21% of the population. Of these, no patients experienced clinical evidence of heart failure and no patients experienced a decline in LVEF of < 50% nor a > than 10% reduction in their baseline values. Conclusions: The patient population in this study represents the majority of patients with relapsed ovarian cancer. The clinical impact of monitoring serial MUGA scans in patients exposed to PLD with cumulative doses less than 550mg/m2 seems to be superfluous and guidelines recommending its use should be reconsidered. No significant financial relationships to disclose.