Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease

BACKGROUND: The prognostic value of cardiac troponins (cTn) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and chronic kidney disease (CKD) is debated. HYPOTHESIS: We tested the performance of cTnI and cTnT for risk stratification in patients with CKD and evaluated the prognostic significance of cTnI and cTnT elevations by their magnitude across the range of CKD severity. METHODS: We examined correlations among cTn elevation, CKD, and in-hospital mortality in 31,586 high-risk patients with NSTE ACS included in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative (CRUSADE). Cardiac tropinins I and T levels were categorized as ratios of each site's upper limit of normal (ULN) for myocardial necrosis: normal (cTn ratio < or =1 x ULN), mild (cTn ratio > 1-3 x ULN), and major (cTn ratio > 3 x ULN) elevation. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Stages of CKD were categorized as normal to mild (eGFR > 60 mL/min), moderate (eGFR 30-60 mL/min), or severe (eGFR < 30 mL/min). RESULTS: Mortality increased more steeply across CKD stages (2.0%-12.9%) than across cTn ratio categories (2.7%-5.4%). In normal or mild CKD, mortality was low regardless of cTn elevations. In moderate CKD, mortality increased incrementally with cTnI (3.3% versus 5.4% versus 7.4%) and cTnT (3.7% versus 5.3% versus 7.3%) elevation. Among severe CKD patients, only major cTn elevations further distinguished risk (cTnI: 10.1% versus 9.7% versus 14.6%; cTnT: 7.0% versus 5.7% versus 14.0%). CONCLUSIONS: In patients with CKD, cTnI and cTnT perform equally in differentiating short-term prognosis following NSTE ACS; however, the prognostic impact of cTn is dependent upon the degree of CKD severity.     

Neue β‑Laktam-Antibiotika und β‑Laktamase-Inhibitoren gegen multiresistente Gram-negative Erreger

Background

The worldwide spread of multidrug-resistant Gram-negative bacteria (MDR-GN) continues. Treatment options for infections caused by MDR-GN remain scarce and only few new substances are currently in clinical phase II/III studies or have already been granted market approval.

Objectives

To provide an overview about current data on new β?lactam antibiotics and β?lactamase inhibitor combinations, respectively. New macrolides, ketolides and aminoglycosides are not addressed.

Materials and methods

Selective literature research regarding published data on ceftazidim/avibactam, ceftolozan/tazobactam, imipenem/cilastatin?+?relebactam, meropenem/vaborbactam, aztreonam/avibactam and cefiderocol, as well as registered trials.

Results

The development of new antimicrobials for the treatment of MDR-GN infections offers new options for attending physicians. β?Lactamase producers are inhibited by these new substances, though with varying efficacy; however, there are still no adequate treatment options for metallo-β-lactamase (MBL) producers.

Conclusions

Clinical data are still indifferent and come from heterogeneous patient collectives. Direct comparisons with established treatment strategies, such as the “last-resort use” of polymyxins are hardly possible. Cases of early development of resistance have already been described. Finally, the importance of toxicity and optimal dosing—in organ failure or organ replacement procedures such as dialysis—remain unclear.

     

Additive value of low-dose dobutamine to technetium-99m sestamibi-gated single-photon emission computed tomography for prediction of wall motion improvement in patients undergoing coronary artery bypass graft

BACKGROUND: The two most useful methods for myocardial viability assessment are perfusion imaging and dobutamine echocardiography. HYPOTHESIS: The present study investigated the additive value of a new method, dobutamine technetium 99m (99mTc)-sestamibi-gated single-photon emission computed tomography (SPECT), which combines these two modalities, to the prediction of wall motion improvement after revascularization. METHODS: Fifty-five consecutive patients with ischemic cardiomyopathy, who were referred for viability evaluation, underwent resting and dobutamine (dose, 5-10 microkg/kg/min) gated SPECT with 99mTc-sestamibi. Of these patients, 36 underwent coronary artery bypass graft (CABG) within 1 month of the study and 32 had repeat resting gated SPECT within 1 year. Global and regional wall motion, wall thickness, and perfusion were simultaneously analyzed at rest and after dobutamine using the 20-segment model; the sestamibi uptake and wall motion response to dobutamine of each segment were rated quantitatively. Based on these findings, the segments were categorized as normal, viable, or nonviable. The predictive values for wall motion improvement were assessed by perfusion, using cutoffs of 50 and 60% of sestamibi uptake, and thereafter by the addition of dobutamine response in the segments that were rated nonviable. RESULTS: Of the 1,080 myocardial segments studied, 906 (84%) had abnormal wall motion and were analyzed for viability. Concordance between perfusion and wall motion response to dobutamine was 60% with the 50% cutoff of sestamibi uptake, and increased to 65% with the 60% sestamibi cutoff (p < 0.04). The respective predictive values of wall motion improvement using the 50 and 60% cutoff points were as follows: sensitivity 93 and 70%, respectively, (p < 0.01); specificity 59 and 86% (p < 0.001), respectively; accuracy 77% for both. The addition of the wall motion response to dobutamine to the assessment of the nonviable segments by perfusion (60% cutoff) increased the sensitivity from 70 to 85% (p = 0.001) and the negative predictive value from 70 to 81% (p = 0.009); the positive predictive value remained high (86 vs. 82%). No additive value of wall motion response to dobutamine was demonstrated for nonviable segments by perfusion with a 50% cutoff. CONCLUSION: Dobutamine sestamibi-gated SPECT is a feasible method for the analysis of myocardial perfusion, function, and contractile reserve of individual myocardial segments in patients with ischemic cardiomyopathy. Viability assessment based on a threshold of 60% uptake of sestamibi, with the addition of the wall motion response to dobutamine in the nonviable segments, seems to yield better predictive values for wall motion improvement after CABG.     

cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: role in vascular hypertrophy

Important output signals of the angiotensin subtype 1 receptor (AT1R) in vascular smooth muscle cells (VSMCs) are mediated by angiotensin II (Ang II)-stimulated transactivation of the epidermal growth factor receptor (EGF-R), which is critical for vascular hypertrophy. Ang II-induced EGF-R transactivation is mediated through cSrc, a proximal target of reactive oxygen species (ROS) derived from NAD(P)H oxidase (NOX) and is dependent on AT(1)R trafficking through caveolin1 (Cav1)-enriched lipid rafts. Underlying molecular mechanisms are incompletely understood. The nonreceptor tyrosine kinase, proto-oncogene cAbl is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1. We thus hypothesized that cAbl is important for ROS-, cSrc-, and Cav1-dependent growth-related AT1R signal transduction. Here we show that Ang II induces tyrosine phosphorylation of cAbl in rat VSMCs and mouse aorta, and that Ang II promotes association of cAbl with AT(1)R, both of which are Src-dependent. Pretreatment of rat VSMCs with the NOX inhibitor diphenylene iodonium or the antioxidants N-acetylcysteine or ebselen significantly inhibited Ang II-induced cAbl phosphorylation. Cell fractionation shows that both EGF-Rs and cAbl are found basally in Cav1-enriched membrane fractions. Knockdown of cAbl protein using small interference RNA inhibits Ang II-stimulated: (1) trafficking of AT1R into, and EGF-R out of, Cav1-enriched lipid rafts; (2) EGF-R transactivation; (3) appearance of the transactivated EGF-R and phospho-Cav1 at focal adhesions; and (4) vascular hypertrophy. These studies provide a novel role of cAbl in the spatial and temporal organization of growth-related AT1R signaling in VSMCs and suggest that cAbl may be generally important in signaling of G-protein coupled receptors.     

Familial recurring cardiac myxoma

A 34-year-old woman presented with her fourth occurrence of an atrial myxoma and a right lower lung field mass. Her surgical history was extensive. In addition to resection of three previous atrial myxomas, she had undergone resection of her adrenal glands as a teenager because of Cushing's syndrome, and a hysterectomy at age 26 revealed a myxoid leiomyoma. Family history was remarkable as a maternal uncle and daughter died from embolic complications of left atrial myxomas and her sister previously had a left atrial myxoma resected. The patient underwent uncomplicated removal of the myxoma, and resection of the lung mass revealed a granuloma. A review of typical and atypical aspects of cardiac myxomas is provided including a rare and recently described syndrome of familial cardiac myxoma associated with Cushing's syndrome, spotty skin pigmentation and other myxoid tumors.     

Reprogramming cells for transplantation

The field of tissue engineering, involving the reprogramming of stem cells or rejuvenation of specific differentiated cells, is emerging as a promising strategy to repair the damaged myocardium. The eventual goal is to be able to take a patient's own cells, expand them ex vivo, genetically engineer them to enhance specific properties, and then reintroduce them into the patient's heart to create a replacement tissue. Our review paper describes data that supports the potential of this strategy. This clinically relevant, combined strategy of genetic and tissue engineering could be of importance in treating elderly patients with massive myocardial damage, patients whose normal myogenic or angiogenic cells have been depleted or are inadequate in their growth potential, to prevent LV deterioration and heart failure.     

MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines

We analyzed for the first time the expression of chemokines in subpopulations of the murine immune system at the single-cell level. We demonstrate in vitro and in a model of murine listeriosis that macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, regulated on activation normal T cell expressed and secreted (RANTES), and activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin are cosecreted to a high degree with IFN-gamma by activated individual natural killer (NK), CD8(+) T, and CD4(+) T helper 1 (Th1) cells. Functionally, ATAC and the CC chemokines cooperate with IFN-gamma in the up-regulation of CD40, IL-12, and tumor necrosis factor-alpha, molecules playing a central role in the effector phase of macrophages. Our data indicate that (i) MIP-1alpha, MIP-1beta, RANTES, and ATAC are not only chemoattractants but also coactivators of macrophages, (ii) MIP-1alpha, MIP-1beta, RANTES, and ATAC constitute together with IFN-gamma a group of "type 1 cytokines," and (iii) these cytokines act together as a functional unit that is used by NK cells in the innate phase and then "handed over" to CD8(+) T cells in the antigen-specific phase of the immune defense, thus bridging the two components of a Th1 immune reaction.     

Müllerian inhibiting substance blocks the protein kinase A-induced expression of cytochrome p450 17alpha-hydroxylase/C(17-20) lyase mRNA in a mouse Leydig cell line independent of cAMP responsive element binding protein phosphorylation

Müllerian inhibiting substance (MIS) is produced by fetal Sertoli cells and causes regression of the Müllerian duct in male fetuses shortly after commitment of the bipotential embryonic gonad to testes differentiation. MIS is also produced by the Sertoli cells and granulosa cells of the adult gonads where it plays an important role in regulating steroidogenesis. We have previously shown that MIS can dramatically reduce testosterone synthesis in Leydig cells by inhibiting the expression of cytochrome P450 17alpha-hydroxylase/C(17-20) lyase (Cyp17) mRNA in vitro and in vivo. To characterize the signal transduction pathway used by MIS to control expression of endogenous Cyp17 in a mouse Leydig cell line, we demonstrate that MIS inhibits both LH- and cAMP-induced expression of Cyp17 at concentrations as low as 3.5 nM and for as long as 18 h. The induction of steroidogenic acute regulatory protein (StAR) mRNA by cAMP, however, was slightly increased by addition of MIS. Protein kinase A (PKA) inhibition with H-89 blocked Cyp17 mRNA induction, suggesting that MIS interferes with the PKA signal transduction pathway. Inhibition of Cyp17 induction was not seen with added U0126, and wortmannin inhibited the induction incompletely. In addition, phosphorylation of the cAMP responsive element binding protein (CREB) was not detected following 50 micro M cAMP exposure, a concentration sufficient for Cyp17 mRNA induction. Moreover, CREB phosphorylation, which was observed with addition of 500 micro M cAMP, was not inhibited by coincubation with MIS. Taken together, these results suggest that cAMP induces expression of Cyp17 by a PKA-mediated mechanism and that this induction, which is inhibited by MIS signal transduction, does not require CREB activity, and is distinct from that used to induce steroidogenic acute regulatory protein expression.     

Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta

Accumulation of extracellular matrix, fibrosis, is regarded to be one of the major manifestations of atherosclerosis. Collagen type I is the predominant matrix component in human atherosclerotic plaques. In this work we have demonstrated procollagen type I expressing cells (PCl-cells) and studied their localization in grossly normal human aorta and atherosclerotic lesions: initial lesions, fatty streaks, fibrolipid lesions (fibrolipid plaque, fibroatheroma), fibrotic lesions (fibrous plaque). PCl-cells were revealed immunocytochemically using SPI.D8 monoclonal antibody against human procollagen type I. We failed to detect PCl-cells in the areas of grossly normal aorta and media underlying atherosclerotic lesions. Positively stained cells were shown in the areas of initial lesions, fatty streaks, fibrolipid and fibrous plaques. The largest amount of PCl-cells was revealed in fatty streaks. These cells were predominantly localized in the preluminal proteoglycan-rich intimal sublayer. Intimal cells in grossly normal regions formed a common cellular network contacting each other with their processes. The cellular network is found to be partly disintegrated in atherosclerotic lesions, which leads to the appearance of isolated cells. The share of isolated PCl-cells localized outside the intimal cellular network was higher in advanced lesions than in the areas of early atherosclerotic lesions. In initial lesions most of PCl-cells were identified as smooth muscle cells using antibodies to smooth muscle -actin. In fatty streaks PCl-expressing smooth muscle cells were fewer in number. Much fewer cells double-stained with anti--actin and anti-PCI antibodies were found in fibrolipid and fibrous plaques. The proportion of these double stained cells was higher among total number of PCl-cells involved in the cellular network versus PCl-cells outside the network. The results of the study demonstrated that the most active de novo synthesis of interstitial collagen takes place in the regions of atherosclerotic lesions characterized by lipid deposition, which may lead to the further progression of atherosclerotic lesions.