Corticosteroid wean after heart transplantation-Is there a risk for antibody formation?

BACKGROUND: Corticosteroid withdrawal after heart transplantation is limited to select immune-privileged patients but it is not known whether this predisposes patients to a higher risk for sensitization. METHODS: A total of 178 heart transplant recipients had panel-reactive antibody (PRA) measurements at transplant and every 6 months and were monitored for rejection with protocol endomyocardial biopsies. Corticosteroid withdrawal was initiated at 6 months post-transplant in select patients. RESULTS: Patients successfully weaned off prednisone (SPW; n=103) had lower PRA compared to those maintained on prednisone (MP; n=51) at pretransplant (34% vs 63%), 6 months (18% vs 49%), 12 months (19% vs 51%), and 18 months (15% vs 47%) after transplant (P<.05). Among 68 nonsensitized patients at transplant in the SPW group, seven (10%) developed de novo PRA at 12 months, compared to four of 19 (21%) of MP patients. Freedom from any treated rejection (97% vs 69% vs 67%), acute cellular rejection (100% vs 86% vs 71%), and antibody-mediated rejection (100% vs 88% vs 88%; all P≤.001) at 2 years was higher in SPW compared to MP and those who failed prednisone wean, respectively. CONCLUSION: Few patients successfully weaned off prednisone after heart transplant develop de novo circulating antibodies but are not at increased risk for developing rejection.

Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis.

INTRODUCTION: Heart transplant patients have risk factors that place them at higher risk for acute venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), than the general population. We assessed for rate of VTE and incidence of PE-related mortality among heart transplant patients. MATERIALS AND METHODS: A total of 1258 heart transplant patients were evaluated for the development of VTE. The diagnosis of DVT was made by Duplex ultrasonography, and PE was diagnosed by computerized tomography pulmonary angiography or ventilation-perfusion radionuclide scan. PE-related mortality was assessed at one yr, three yr, and five yr post-transplant. RESULTS: A total of 117 (9.3%) patients were diagnosed with DVT, including 65 of 117 (55.5%) with lower extremity DVT (LEDVT) and 52 of 117 (44.4%) with upper extremity DVT (UEDVT). A total of 24 (1.9%) patients experienced PE with seven (29.2%) resulting deaths. The rate of LEDVT and UEDVT was similar (55.5% vs. 44.4%); however, the incidence of PE was greater for those with LEDVT (23.1% vs. 7.7%; p = 0.04). Patients with PE had lower survival over the five-yr follow-up period compared to those with DVT only (67% vs. 81%; p = 0.51). CONCLUSION: Heart transplant patients have a high incidence of VTE despite current best practice, indicating a need for a more aggressive approach to thromboprophylaxis.

Rare Mycotic Aneurysm of the Mitral Valve without Aortic Valve Involvement.

Mycotic aneurysms can be a rare, but serious complication of infectious endocarditis. We report the case of a 20-year-old woman who presented with fever and malaise from streptococcal bacteremia and found to have vegetation on the anterior leaflet of the mitral valve. On follow-up visit, the patient was noted to have a mycotic aneurysm of the anterior mitral valve without aortic involvement. Her clinical course was complicated by mitral valve chordal rupture, severe mitral regurgitation, and dyspnea from severe mitral regurgitation for which she underwent successful surgical repair of the mitral valve.

Ultra-high sensitivity cardiac troponin-I concentration and left ventricular structure and function in women with ischemia and no obstructive coronary artery disease.

Aims: Women are disproportionally impacted by ischemia and no obstructive coronary artery disease (INOCA), and such women are at increased risk of developing heart failure with preserved ejection fraction (HFpEF), however the mechanisms linking these conditions remain poorly understood. The aim of this study was to determine whether ultra-high sensitivity cardiac troponin I (u-hscTnI), an indicator of cardiomyocyte injury, is associated with abnormalities in myocardial perfusion and left ventricular (LV) structure and function in women with INOCA. Methods: 327 women with INOCA enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent vasodilator stress cardiac magnetic resonance imaging (CMRI) and u-hscTnI measurements (Simoa HD-1 Analyzer, Quanterix Corporation). Multivariable linear regression was used to evaluate associations between u-hscTnI concentrations and myocardial perfusion (MPRI), LV mass index and feature-tracking derived strain measures of LV function. Results: u-hscTnI concentrations were quantifiable in 100% of the cohort and ranged from 0.004 to 79.6 pg/mL. In adjusted models, u-hscTnI was associated with LV mass index (+2.03; 95% CI 1.17, 2.89; p < 0.01) and early diastolic radial strain rate (SR) (+0.13; 95% CI 0.01, 0.25; p = 0.03), early diastolic circumferential SR (-0.04; 95% CI -0.08, 0.002; p = 0.06) and early diastolic longitudinal SR (-0.03; 95% CI -0.07, 0.002; p = 0.06). u-hscTnI was not associated with MPRI (p = 0.39) in adjusted models. Conclusion: Together, these findings support cardiomyocyte injury as a putative pathway towards adverse LV remodeling and dysfunction; however, further research is needed to define the specific mechanism(s) driving myocellular injury in INOCA.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

AIMS: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. METHODS AND RESULTS: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007). CONCLUSION: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Maladaptive left ventricular remodeling in women: An analysis from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study.

BACKGROUND: Women represent approximately half of heart failure hospitalizations and are disproportionately affected by heart failure with preserved ejection fraction (HFpEF). Women with signs and symptoms of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD) often have elevated left ventricular end-diastolic pressure (LVEDP). However, isolated elevated LVEDP in the absence of coronary microvascular dysfunction (CMD) is not understood. METHODS: Among 244 women with signs and symptoms of ischemia, no obstructive CAD, and preserved LVEF who underwent invasive coronary reactivity testing (CRT), 43 (18%) women had no evidence of CMD. LVEDP was measured at time of CRT, and left ventricular (LV) volumes and mass were assessed by cardiac magnetic resonance (CMR) imaging. RESULTS: Of the 43 women without CMD, 24 (56%) had elevated LVEDP [mean 18 mm Hg (SD = 3)] compared to 19 (44%) with normal LVEDP [11 mm Hg (SD = 3)]. The elevated LVEDP group had a comparatively higher systolic and diastolic blood pressure, lower LV end-diastolic volume index (EDVI), and higher mass-to-volume ratio. Other functional parameters were not significantly different. CONCLUSIONS: Among women with signs and symptoms of ischemia without obstructive CAD, absence of CMD, and preserved LVEF, isolated elevated LVEDP is associated with a significantly higher systolic and diastolic blood pressure, higher LV mass-to-volume ratio and lower LV EDVI. These results suggest these women have maladaptive remodeling to blood pressure. Given the relatively high prevalence of HFpEF in women, these hypothesis-generating results suggest that further study of ventricular remodeling is warranted.

Carotid artery distensibility and hormone therapy and menopause: the Los Angeles Atherosclerosis Study.

OBJECTIVE: Observational studies have suggested that arterial distensibility decreases during menopause; however, its relationship with hormone therapy use remains controversial. We prospectively studied distensibility and hormone therapy use at different menopause stages. METHODS: One hundred sixty-one women (aged between 42 and 61 y) without cardiovascular disease underwent carotid artery measurements by ultrasound to calculate distensibility index at baseline and 3 years later. Menopause stage was classified at each visit as premenopausal, perimenopausal, and postmenopausal. Across 3 years of prospective observation, women were classified as remaining premenopausal, remaining postmenopausal, or transitioning (defined as change from premenopausal to perimenopausal, from premenopausal to postmenopausal, from perimenopausal to perimenopausal, or from perimenopausal to postmenopausal). RESULTS: Distensibility declined across time at all menopause stages (P < 0.0001). Compared with postmenopausal women, premenopausal and transitioning/no hormone therapy women had more than twice the decline in distensibility index (P = 0.06 and P = 0.016, respectively), whereas transitioning/hormone therapy women did not differ in distensibility decline (P = 0.28). In a multivariate model, change in systolic blood pressure (P < 0.0001) and change in pulse pressure (P = 0.004) were independent predictors of distensibility index change and served as effect modulators. In an adjusted model, women in the premenopausal and transitioning/no hormone therapy groups had a significantly faster decline in distensibility index (P = 0.002 and P = 0.001, respectively) compared with postmenopausal women, whereas the transitioning/hormone therapy group did not (P = 0.21). CONCLUSIONS: These findings confirm that the menopausal transition is associated with reduced vascular compliance. Hormone therapy is associated with better arterial distensibility only during the menopausal transition. Additional prospective studies are needed to confirm these findings and to determine whether hormone therapy use beyond the menopausal transition is related to distensibility.

Chronic inflammatory disorders and accelerated atherosclerosis: chronic kidney disease.

Increasing evidence points to the fact that plasma HDL cholesterol levels do not always accurately predict HDL function including reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of our innate immune system. HDL is anti inflammatory in healthy individuals in the absence of systemic oxidative stress and inflammation. In those with chronic illnesses such as renal failure however, HDL may become dysfunctional and actually promote inflammation. HDL may be thought of as a shuttle whose size can be estimated by HDL cholesterol levels. The content of the shuttle however, is what determines the anti inflammatory potential of HDL and can change from one, supporting reverse cholesterol transport to one that is less efficient in carrying out this function. Chronic kidney disease (CKD), and inflammatory disorder, is associated with development of accelerated atherosclerosis and premature death from coronary artery disease (CAD). Patients with CKD present with dyslipidemia, oxidative stress and systemic inflammation. Among the abnormalities in lipid metabolism in these patients is reduced levels and protective capacity of HDL. Recent studies have shown that HDL from patients with end stage renal disease is not capable of preventing LDL oxidation and that it induces monocyte migration in artery wall model systems. Treatment of plasma from these patients, with an HDL mimetic peptide improved the anti inflammatory properties of patient's HDL and made LDL more resistant to oxidative modification. Animal models of kidney disease also had proinflammatory HDL and treatment with the peptide mimetic improved markers of inflammation and anti inflammatory capacity of HDL. Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies.

Time-resolved single-step protease activity quantification using nanoplasmonic resonator sensors.

Protease activity measurement has broad application in drug screening, diagnosis and disease staging, and molecular profiling. However, conventional immunopeptidemetric assays (IMPA) exhibit low fluorescence signal-to-noise ratios, preventing reliable measurements at lower concentrations in the clinically important picomolar to nanomolar range. Here, we demonstrated a highly sensitive measurement of protease activity using a nanoplasmonic resonator (NPR). NPRs enhance Raman signals by 6.1 x 10(10) times in a highly reproducible manner, enabling fast detection of proteolytically active prostate-specific antigen (paPSA) activities in real-time, at a sensitivity level of 6 pM (0.2 ng/mL) with a dynamic range of 3 orders of magnitude. Experiments on extracellular fluid (ECF) from the paPSA-positive cells demonstrate specific detection in a complex biofluid background. This method offers a fast, sensitive, accurate, and one-step approach to detect the proteases' activities in very small sample volumes.

Cellular effect of high doses of silica-coated quantum dot profiled with high throughput gene expression analysis and high content cellomics measurements.

Quantum dots (Qdots) are now used extensively for labeling in biomedical research, and this use is predicted to grow because of their many advantages over alternative labeling methods. Uncoated Qdots made of core/shell CdSe/ZnS are toxic to cells because of the release of Cd2+ ions into the cellular environment. This problem has been partially overcome by coating Qdots with polymers, poly(ethylene glycol) (PEG), or other inert molecules. The most promising coating to date, for reducing toxicity, appears to be PEG. When PEG-coated silanized Qdots (PEG-silane-Qdots) are used to treat cells, toxicity is not observed, even at dosages above 10-20 nM, a concentration inducing death when cells are treated with polymer or mercaptoacid coated Qdots. Because of the importance of Qdots in current and future biomedical and clinical applications, we believe it is essential to more completely understand and verify this negative global response from cells treated with PEG-silane-Qdots. Consequently, we examined the molecular and cellular response of cells treated with two different dosages of PEG-silane-Qdots. Human fibroblasts were exposed to 8 and 80 nM of these Qdots, and both phenotypic as well as whole genome expression measurements were made. PEG-silane-Qdots did not induce any statistically significant cell cycle changes and minimal apoptosis/necrosis in lung fibroblasts (IMR-90) as measured by high content image analysis, regardless of the treatment dosage. A slight increase in apoptosis/necrosis was observed in treated human skin fibroblasts (HSF-42) at both the low and the high dosages. We performed genome-wide expression array analysis of HSF-42 exposed to doses 8 and 80 nM to link the global cell response to a molecular and genetic phenotype. We used a gene array containing approximately 22,000 total probe sets, containing 18,400 probe sets from known genes. Only approximately 50 genes (approximately 0.2% of all the genes tested) exhibited a statistically significant change in expression level of greater than 2-fold. Genes activated in treated cells included those involved in carbohydrate binding, intracellular vesicle formation, and cellular response to stress. Conversely, PEG-silane-Qdots induce a down-regulation of genes involved in controlling the M-phase progression of mitosis, spindle formation, and cytokinesis. Promoter analysis of these results reveals that expression changes may be attributed to the down-regulation of FOXM and BHLB2 transcription factors. Remarkably, PEG-silane-Qdots, unlike carbon nanotubes, do not activate genes indicative of a strong immune and inflammatory response or heavy-metal-related toxicity. The experimental evidence shows that CdSe/ZnS Qdots, if appropriately protected, induce negligible toxicity to the model cell system studied here, even when exposed to high dosages. This study indicates that PEG-coated silanized Qdots pose minimal impact to cells and are a very promising alternative to uncoated Qdots.

Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast.

The increasing use of nanotechnology in consumer products and medical applications underlies the importance of understanding its potential toxic effects to people and the environment. Although both fullerene and carbon nanotubes have been demonstrated to accumulate to cytotoxic levels within organs of various animal models and cell types and carbon nanomaterials have been exploited for cancer therapies, the molecular and cellular mechanisms for cytotoxicity of this class of nanomaterial are not yet fully apparent. To address this question, we have performed whole genome expression array analysis and high content image analysis based phenotypic measurements on human skin fibroblast cell populations exposed to multiwall carbon nano-onions (MWCNOs) and multiwall carbon nanotubes (MWCNTs). Here we demonstrate that exposing cells to MWCNOs and MWCNTs at cytotoxic doses induces cell cycle arrest and increases apoptosis/necrosis. Expression array analysis indicates that multiple cellular pathways are perturbed after exposure to these nanomaterials at these doses, with material-specific toxigenomic profiles observed. Moreover, there are also distinct qualitative and quantitative differences in gene expression profiles, with each material at different dosage levels (6 and 0.6 microg/mL for MWCNO and 0.6 and 0.06 microg/mL for MWCNT). MWCNO and MWCNT exposure activates genes involved in cellular transport, metabolism, cell cycle regulation, and stress response. MWCNTs induce genes indicative of a strong immune and inflammatory response within skin fibroblasts, while MWCNO changes are concentrated in genes induced in response to external stimuli. Promoter analysis of the microarray results demonstrate that interferon and p38/ERK-MAPK cascades are critical pathway components in the induced signal transduction contributing to the more adverse effects observed upon exposure to MWCNTs as compared to MWCNOs.