Combined Computed Tomography Angiography-Computed Tomography Perfusion in the Identification and Prognostic Assessment of Myocardial Bridging from the CORE320 Study: 5-Year Follow-Up.

Our objective is to use computed tomography angiography (CTA) and computed tomography perfusion (CTP) to identify the ischemic significance of myocardial bridging (MB). We also seek to determine the long-term prognostication of MB in the presence or absence of obstructive coronary artery disease (CAD). The CORE320, a prospective, multicenter study including 381 patients with known or suspected CAD clinically referred for invasive coronary angiography who underwent combined (CTA-CTP) and single-photon emission computed tomography before conventional coronary angiography. The incidence of MB was identified in 135 patients (35.4%) with 93.9% identified in the left anterior descending artery. MB were divided as partially encased versus fully encased. There was no difference in ischemia identified between partially encased MB and fully encased MB (37 [40%] vs 25 [35%], p = 0.54]. Ischemia was identified at similar rates in partially versus fully encased MB by single-photon emission computed tomography at (8 [9%] vs 8 [11%], p = 0.57] and CTP (34 [37%] vs 21 [30%], p = 0.33]. There was no difference in the primary outcome of 5-year outcome of combined incidence of myocardial infarction or death. The restricted mean survival time in patients with CTA with <50% stenosis with or without a MB was 4.906 years (95% confidence interval 4.759 to 5.000) and 4.891 years (95% confidence interval 4.718 to 5.000), respectively (p = 0.824). Cardiac computed tomography perfusion imaging can assess both anatomic and functional significance of myocardial bridging with diagnostic accuracy similar to current standard imaging. Furthermore, 5-year cardiovascular events were not different with the presence of MB in both obstructive and non-obstructive CAD.

The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

The severity of individual menopausal symptoms, cardiovascular disease, and all-cause mortality in the Women's Health Initiative Observational Cohort.

OBJECTIVE: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality. METHODS: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality. RESULTS: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality. CONCLUSION: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.

Postoperative Myocardial Injury and Outcomes in Liver and Kidney Transplant Patients.

BACKGROUND/PURPOSE: Myocardial injury after noncardiac surgery (MINS) is associated with major adverse cardiac events (MACE), but its significance post-liver and post-kidney transplantation is not well-defined. METHODS/MATERIALS: We retrospectively studied consecutive patients undergoing single-organ liver or kidney transplantation at a large tertiary transplant center. Liver and kidney transplant patients with troponins drawn within 30 days of transplantation were included. The primary exposure was MINS, defined as troponin elevation above the 99th percentile of the upper reference limit within 30 days of transplantation. The primary outcome was MACE, defined as death, myocardial infarction, revascularization, stroke, or heart failure hospitalization. RESULTS: Overall, 112 patients were included: 58 (51.7%) were liver transplant recipients, and 54 (48.3%) were kidney transplant recipients. Patients with MINS were significantly older (mean age 59 vs. 54 years, p = 0.01) and more likely to have diabetes (35% vs. 17%, p = 0.03). Other baseline characteristics were similar. Sixteen patients (14.2%) developed MACE, including 11 (9.8%) with 1-year MACE. MINS patients were significantly more likely to develop 1-year MACE (adjusted hazard ratio, 10.4; 95% confidence interval, 1.8-198). Kaplan-Meier cumulative MACE was significantly higher in the MINS group (p = 0.03). CONCLUSIONS: Liver and kidney transplant recipients with MINS are significantly more likely to develop 1-year MACE compared to those without MINS. Future prospective studies are needed to further delineate the cardiac risk and outcomes in transplanted patients.

Association of Major Dietary Protein Sources With All-Cause and Cause-Specific Mortality: Prospective Cohort Study.

Background Dietary recommendations regarding protein intake have been focused on the amount of protein. However, such recommendations without considering specific protein sources may be simplistic and insufficient. Methods and Results We included 102 521 postmenopausal women enrolled in the Women's Health Initiative between 1993 and 1998, and followed them through February 2017. During 1 876 205 person-years of follow-up, 25 976 deaths occurred. Comparing the highest with the lowest quintile, plant protein intake was inversely associated with all-cause mortality (hazard ratio [HR], 0.91 [0.86, 0.96]), cardiovascular disease mortality (HR, 0.88 [0.79, 0.97]), and dementia mortality (HR, 0.79 [0.67, 0.94]). Among major protein sources, comparing the highest with the lowest quintile of consumption, processed red meat (HR, 1.06 [1.01, 1.10]) or eggs (HR, 1.14 [1.10, 1.19]) was associated with higher risk of all-cause mortality. Unprocessed red meat (HR, 1.12 [1.02, 1.23]), eggs (HR, 1.24 [1.14, 1.34]), or dairy products (HR, 1.11 [1.02, 1.22]) was associated with higher risk of cardiovascular disease mortality. Egg consumption was associated with higher risk of cancer mortality (HR, 1.10 [1.02, 1.19]). Processed red meat consumption was associated with higher risk of dementia mortality (HR, 1.20 [1.05, 1.32]), while consumption of poultry (HR, 0.85 [0.75, 0.97]) or eggs (HR, 0.86 [0.75, 0.98]) was associated with lower risk of dementia mortality. In substitution analysis, substituting of animal protein with plant protein was associated with a lower risk of all-cause mortality, cardiovascular disease mortality, and dementia mortality, and substitution of total red meat, eggs, or dairy products with nuts was associated with a lower risk of all-cause mortality. Conclusions Different dietary protein sources have varying associations with all-cause mortality, cardiovascular disease mortality, and dementia mortality. Our findings support the need for consideration of protein sources in future dietary guidelines.

Association of Adverse Pregnancy Outcomes With Risk of Atherosclerotic Cardiovascular Disease in Postmenopausal Women.

Importance: Atherosclerotic cardiovascular disease (ASCVD) may have unique risk factors in women. Most women have a history of pregnancy; common adverse pregnancy outcomes (APOs) appear to be associated with ASCVD, but prior studies have limitations. Objective: To assess whether APOs are associated with increased ASCVD risk independently of traditional risk factors. Design, Setting, and Participants: The APO history among participants in the Women's Health Initiative, a large multiethnic cohort of postmenopausal women, was assessed. The associations of 5 self-reported APOs (gestational diabetes, hypertensive disorders of pregnancy, low birth weight [ie, birth weight less than 2.49 kg], high birth weight [ie, birth weight greater than 4.08 kg], and preterm delivery by 3 weeks or more) with ASCVD were analyzed, adjusting for traditional ASCVD risk factors. Data were collected and analyzed in 2017. Exposures: APOs (gestational diabetes, hypertensive disorders of pregnancy, low birth weight, high birth weight, and preterm delivery). Main Outcomes and Measures: Adjudicated ASCVD. Results: A total of 48 113 Women's Health Initiative participants responded to the survey; the median (interquartile range) age at time of enrollment was 60.0 (55.0-64.0) years. A total of 13 482 participants (28.8%) reported 1 or more APOs. Atherosclerotic cardiovascular disease was more frequent in women who reported an APO compared with those without APOs (1028 of 13 482 [7.6%] vs 1758 of 30 522 [5.8%]). Each APO, analyzed separately, was significantly associated with ASCVD, and gestational diabetes, hypertensive disorders of pregnancy, low birth weight, and preterm delivery remained significant after adjustment for traditional ASCVD risk factors. When all APOs were analyzed together, hypertensive disorders of pregnancy (odds ratio, 1.27; 95% CI, 1.15-1.40) and low birth weight (odds ratio, 1.12; 95% CI, 1.00-1.26) remained independently associated with ASCVD. All findings were materially unchanged by additional adjustment for parity, body mass index, and socioeconomic factors. Conclusions and Relevance: In this large multiethnic cohort of women, hypertensive disorders of pregnancy and low birth weight were independently associated with ASCVD after adjustment for risk factors and other APOs.

Social Support, Social Network Size, Social Strain, Stressful Life Events, and Coronary Heart Disease in Women With Type 2 Diabetes: A Cohort Study Based on the Women's Health Initiative.

OBJECTIVE: We studied associations between social support, social network size, social strain, or stressful life events and risk of coronary heart disease (CHD) in postmenopausal women with type 2 diabetes. RESEARCH DESIGN AND METHODS: From the Women's Health Initiative, 5,262 postmenopausal women with type 2 diabetes at baseline were included. Cox proportional hazards regression models adjusted for demographics, depressive symptoms, anthropometric variables, and lifestyle factors were used to examine associations between social factors and CHD. RESULTS: A total of 672 case subjects with CHD were observed during an average 12.79 (SD 6.29) years of follow-up. There was a significant linear trend toward higher risk of CHD as the number of stressful life events increased (P for trend = 0.01; hazard ratio [HR] [95% CI] for the third and fourth quartiles compared with first quartile: 1.27 [1.03-1.56] and 1.30 [1.04-1.64]). Being married or in an intimate relationship was related to decreased risk of CHD (HR 0.82 [95% CI 0.69-0.97]). CONCLUSIONS: Among postmenopausal women with type 2 diabetes, higher levels of stressful life events were associated with higher risk of CHD. Experience of stressful life events might be considered as a risk factor for CHD among women with type 2 diabetes.

Higher Lipophilic Index Indicates Higher Risk of Coronary Heart Disease in Postmenopausal Women.

Fatty acids (FAs) are essential components of cell membranes and play an integral role in membrane fluidity. The lipophilic index [LI, defined as the sum of the products between FA levels and melting points (°C), divided by the total amount of FA: [Formula: see text]] is thought to reflect membrane and lipoprotein fluidity and may be associated with the risk of coronary heart disease (CHD). Therefore, we examined the associations of dietary and plasma phospholipid (PL) LI with CHD risk among postmenopausal women. We determined dietary LI for the cohort with completed baseline food frequency questionnaires and free of prevalent cardiovascular diseases in the Women's Health Initiative (WHI) observational study (N = 85,563). We additionally determined plasma PL LI in a matched case-control study (N = 2428) nested within the WHI observational cohort study. Cox proportional hazard regression and multivariable conditional logistic regression were used to calculate HRs/ORs for CHD risk between quartiles of LI after adjusting for potential sources of confounding and selection bias. Higher dietary LI in the cohort study and plasma PL LI in the case-control study were significantly associated with increased risk of CHD: HR = 1.18 (95% CI 1.07-1.31, P for trend <0.01) and OR = 1.76 (95% CI 1.33-2.33, P for trend <0.01) comparing extreme quartiles and adjusting for potential confounders. These associations still persisted after adjusting for the polyunsaturated to saturated fat ratio. Our study indicated that higher LI based on either dietary or plasma measurements, representing higher FA lipophilicity, was associated with elevated risk of CHD among postmenopausal women.

The lower the achieved blood pressure goal the better.

PURPOSE OF REVIEW: Hypertension is the eminent risk factor for renal and cardiovascular disease (CVD). Its management is a topic of public health priority. As either too high or too low blood pressure (BP) levels can have detrimental effects on health, optimal targets for BP continue to be controversial. The current manuscript will review relevant data published over the last year that add to this topic of controversy. RECENT FINDINGS: Recent studies confirm increased CVD-related risk with increasing SBP levels more than 140  mmHg among patients with hypertension and CVD as well as those over the age of 60 years. A SBP target less than 140  mmHg conveyed lessened risk of CVD-related events. There is some evidence suggesting that the ideal BP target lies between 120 and 140  mmHg. SUMMARY: Recent data support a target SBP of less than 140  mmHg among patients with hypertension or CVD, and achievement of this target might benefit those older than 60 years of age as well. Treating to SBPs below 120  mmHg may not result in further benefit. Data from randomized controlled trials specifically addressing the question whether lower BPs are associated with better outcomes are needed to further define ideal BP-target goals.

Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1α activation: a novel aspect of angiogenesis in atherosclerosis.

Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1α in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1α activation in monocyte-macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1α and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte-macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1α and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1α inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1α inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1α and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1α and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1α pathway.

An update on menopausal hormone replacement therapy in women and cardiovascular disease.

PURPOSE OF REVIEW: This review presents the available evidence for effects of menopausal hormone replacement therapy (MHT), more specifically estrogen, and selective estrogen receptor modulators on the cardiovascular system with a focus on randomized controlled trials (RCTs) published since 2010. RECENT FINDINGS: In contrast to early observational studies, the Women's Health Initiative, the largest randomized controlled trial of MHT in generally healthy women, suggested harmful cardiovascular effects. Subsequent subanalyses of the Women's Health Initiative and other studies suggest the cardiovascular effects of MHT may vary by age and time since menopause, giving rise to a 'timing hypothesis'. Recent trials have looked at this issue by evaluating surrogate markers of cardiovascular disease (CVD) or CVD events adjudicated as secondary outcomes in RCTs and show a reduction in events with MHT. SUMMARY: Athough the data overall do not support the use of MHT or selective estrogen receptor modulator for primary prevention of CVD, evidence is accumulating that careful use of MHT for perimenopausal symptoms may not carry CVD harm. This review highlights some of the strengths and weaknesses of these recent reports. Ongoing studies of MHT will shed more light on the interaction between age or time after menopause and the vascular effects of MHT.

Preeclampsia and hypertensive disease in pregnancy: their contributions to cardiovascular risk.

More women than men die each year of cardiovascular disease, which remains the leading cause of death in the United States. Sex-specific factors, including pregnancy-related disorders, should be considered when assessing cardiovascular (CV) risk in women. Hypertensive disorders of pregnancy have been associated with CV risk later in life and may identify women in whom earlier primary prevention may reduce their risk. This article reviews the physiologic changes in blood pressure during pregnancy, current definitions of hypertensive diseases of pregnancy and preeclampsia, and postulated pathophysiologic mechanisms leading to preeclampsia that might contribute to later CV risk. Also summarized are studies providing evidence on the association between hypertensive diseases of pregnancy and future CV risk.

A stepwise approach to the visual interpretation of CT-based myocardial perfusion.

Cardiovascular anatomic and functional testing have been longstanding and key components of cardiac risk assessment. As part of that strategy, CT-based imaging has made steady progress, with coronary computed tomography angiography (CTA) now established as the most sensitive noninvasive strategy for assessment of significant coronary artery disease. Myocardial CT perfusion imaging (CTP), as the functional equivalent of coronary CTA, is being tested in currently ongoing multicenter trials and is proposed to enhance the accuracy of coronary CTA alone. However, unlike coronary CTA that has published guidelines for interpretation and is rapidly gaining applicability in the noninvasive risk assessment paradigms, myocardial CTP is rapidly evolving, and guidance on a standard approach to its interpretation is lacking. In this article we describe a practical stepwise approach for interpretation of myocardial CTP that should add to the clinical applicability of this modality. These steps include (1) coronary CTA interpretation for potentially obstructive atherosclerosis, (2) reconstruction and preprocessing of myocardial CTP images, (3) image quality assessment and the identification of potentially confounding artifacts, (4) rest and stress image interpretation for enhancement patterns and areas of hypoattenuation, and (5) correlation of coronary anatomy and myocardial perfusion deficits. This systematic review uses already published methods from multiple clinical studies and is intended for general usage, independent of the platform used for image acquisition.

The significance of transient ischemic dilation in the setting of otherwise normal SPECT radionuclide myocardial perfusion images.

BACKGROUND: Transient ischemic dilation (TID) in the setting of an abnormal SPECT radionuclide myocardial perfusion imaging (MPI) study is considered a marker of severe and extensive coronary artery disease (CAD). However, the clinical significance of TID and its association with CAD in patients with an otherwise normal MPI study is unclear. METHODS: From a database of patients who underwent MPI over a 9-year period, 96 without known cardiac history who had normal image perfusion patterns, and who underwent coronary angiography within 6 months, were identified. TID quantitative values were derived. To adjust for varying stress and image protocols, a TID index based on published threshold values was derived for each patient, with >1 considered as TID. We examined the relationship of TID to the presence/extent of CAD, and to a CAD prognostic index. TID was also correlated with patient survival. To address referral bias, survival in a separate cohort of 3,691 patients with a normal perfusion MPI who did not undergo angiography in the 6-month interval was correlated with the presence and severity of TID. RESULTS: For 28 (29.2%) patients with normal MPI perfusion patterns but with TID, there was no increased incidence of CAD, multivessel or left main disease, or a higher prognostic index compared with no TID. In addition, there was no increased mortality associated with TID in both the angiography cohort and in the patients who did not undergo immediate angiography. CONCLUSIONS: TID in patients with an otherwise normal SPECT MPI study does not increase the likelihood of CAD, its extent or severity, and is not associated with worsened patient survival.

CT perfusion: ready for prime time.

Advancements in computed tomography (CT) technology have revolutionized clinical practice, particularly regarding the noninvasive assessment of coronary artery disease (CAD). The versatility of cardiac CT has rendered multiple applications including assessment of cardiac structure and function, myocardial viability, and coronary anatomy. The merits of cardiac computed tomography angiography (CTA) have been proven for the detection, and particularly the exclusion, of CAD. However, CTA becomes limited in the presence of significant CAD. Its inability to consistently identify lesion-associated ischemia may necessitate additional radionuclide myocardial perfusion imaging. Myocardial computed tomography perfusion imaging (CTP) has emerged as a useful and convenient method to immediately assess myocardial ischemia. In this review, we discuss the current state of CTP including available technology, its performance to date from current literature, and future challenges to this field.

Quantitative and qualitative analysis and interpretation of CT perfusion imaging.

Coronary artery disease (CAD) remains the leading cause of death in the United States. Rest and stress myocardial perfusion imaging has an important role in the non-invasive risk stratification of patients with CAD. However, diagnostic accuracies have been limited, which has led to the development of several myocardial perfusion imaging techniques. Among them, myocardial computed tomography perfusion imaging (CTP) is especially interesting as it has the unique capability of providing anatomic- as well as coronary stenosis-related functional data when combined with computed tomography angiography (CTA). The primary aim of this article is to review the qualitative, semi-quantitative, and quantitative analysis approaches to CTP imaging. In doing so, we will describe the image data required for each analysis and discuss the advantages and disadvantages of each approach.

Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model.

OBJECTIVES: The role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. BACKGROUND: Doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially life-threatening cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through free-radical injury. METHODS: Male Sprague Dawley rats fed iron-rich chow (n = 8) and regular chow (n = 8) were treated with DOX or saline (4 animals in each arm). Cardiotoxicity was assessed using mortality, weight changes, Tc-99m annexin-V imaging, histopathology, and immunohistochemistry. RESULTS: Animals fed iron-rich chow showed significantly higher DOX cardiotoxicity as evidenced by greater weight loss (107 +/- 14 g vs. 55 +/- 10 g weight loss, p < 0.05), higher annexin uptake (0.14 +/- 0.01% vs. 0.08 +/- 0.01% injected dose/g of myocardium, p < 0.05), more severe myocyte injury on electron microscopy, and significantly higher cleaved caspase-3 staining compared with regular chow fed rats given DOX. Feeding iron-rich chow alone did not result in any cardiotoxicity. CONCLUSIONS: Dietary iron loading resulted in a substantially increased DOX cardiotoxicity in rats. Body iron stores as well as its bioavailability in tissue may be important independent predictors of susceptibility to DOX cardiotoxicity in man. Further clinical studies are warranted.

Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study.

AIMS: Endothelial dysfunction, platelet hyperactivity, and inflammation play a crucial role in atherogenesis. A growing body of evidence suggests that inhibition of the thromboxane A2 (TxA2 or TP) receptor may improve endothelial function and reduce the inflammatory component of atherosclerosis in addition to its demonstrated antiplatelet activity. Consequently, we sought to assess the effect of a novel TP receptor antagonist S18886, on atherosclerotic lesion progression and composition by serial non-invasive magnetic resonance imaging (MRI). METHODS AND RESULTS: S18886 was compared with control in an experimental model of established aortic atherosclerosis in New Zealand White rabbits (n=10). The animals underwent MRI of the abdominal aorta at the time of randomization and at the end of treatment. Subsequently, animals were euthanized and specimens were stained for histopathology and immunohistochemistry with anti-alpha-actin antibodies for vascular smooth muscle cells (VSMC), anti-RAM-11 for macrophages, anti-caspase-3 for apoptotic cells, anti-MMP-1 for metalloproteinases, and anti-endothelin-1 (ET-1) as a marker of endothelial dysfunction. MRI analysis revealed a significant reduction in total vessel area (TVA) and vessel wall area (VWA) in the S18886 group (P<0.05). Immunostaining analysis showed a significant decrease in RAM-11, caspase-3, MMP-1, ET-1 and an increase in alpha-actin in the treated group (P<0.05 vs. control). CONCLUSION: Inhibition of the TP receptor by S18886 causes a regression of advanced atherosclerotic plaques. In addition, the reduction in the markers for macrophages, apoptotic cells, metalloproteinases, and endothelin-1 and the increase in VSMC, suggests that S18886 may not only halt the progression of atherosclerosis, but also transform lesions towards a more stable phenotype. The possibility of combining antithrombotic and antiatherosclerotic activity by means of the administration of TP inhibitors deserves further investigation in a clinical setting.

Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.

BACKGROUND: The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. METHODS AND RESULTS: Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01). CONCLUSIONS: VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.

Update in atherothrombotic disease.

Crucial advances in our understanding of the pathogenesis of atherothrombosis, defined as atherosclerosis and its thrombotic complications, have been achieved during the past two decades. The historical hypothesis of pathogenesis ("lipid accumulation") has evolved to integrate several factors contributing to the initiation and evolution of this complex disease. Endothelial dysfunction is considered to be the earliest event in atherogenesis. Inflammation and apoptosis play critical roles in its progression and onset. Tissue factor is postulated to be a central actor in determining plaque thrombogenicity. A hyperreactive state of the blood ("vulnerable blood") may be responsible for one-third of all the acute coronary syndromes. This review will discuss emerging concepts in the pathogenesis of and therapeutic approaches to atherothrombotic disease.