Abstract-Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology. (Circ Res. 2003;93:388-398.)Key Words: nitric oxide Ⅲ contractile function Ⅲ cardiomyocytes Ⅲ endothelium Ⅲ heart failure A s the prototypical endothelium-derived relaxing factor, nitric oxide (NO) is a primary determinant of blood vessel tone and thrombogenicity. Applied to heart tissue, these functions alone largely justify the growing interest for NO as a regulator of cardiac function. However, the recognition that all three isoforms of nitric oxide synthase (NOS) are expressed in cardiomyocytes themselves has raised several intriguing questions regarding the signaling role of NO in the heart.The modulatory effects of NO on contractile function are undoubtedly complex. [1][2][3][4] Perhaps this is expected when one considers the versatility of NO biochemistry, the multiplicity of its intracellular targets (with sometimes opposite contractile influences), as well as the diversity of its cellular sources within the myocardium. However, subcellular targeting of NO, driven in a stimulus-specific manner, ensures coordinate regulation of cardiac function. Mouse models genetically deficient or overexpressing one or several of the three NOS isoforms helped to clarify the role of endogenously produced NO (versus exogenous NO from pharmacologic sources) in normal or diseased hearts despite several unanswered questions. In the following paragraphs, we attempt to revisit the major paradigms on the influence of NO on several parameters of cardiac contraction with the hindsight of recent knowledge from genetic or molecular characterization of NOS regulation. Cellular Regulation of NOSTwo major posttranslational modes of regulation of en...

Prognosis of hematologic malignancies does not predict intensive care unit or hospital mortality and almost reaches significance for 6-mo mortality (53%, 71%, and 84% rate for patients with good, intermediate, and poor prognosis, respectively, p =.058), but it determines long-term survival (p =.008). Intensive care unit, hospital, and 6-mo overall mortality rates were 38%, 61%, and 75%, respectively. Using multivariate analysis, intensive care unit mortality was best predicted on admission by respiratory failure and fungal infection, whereas hospital mortality was predicted by the number of organ failures, the bone marrow transplant status, and the presence of fungal infection. The Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II had no prognostic value, whereas the difference of the Multiple Organ Dysfunction Score between at the time of admission and at day 5 allowed quick prediction of hospital mortality. Diseases with the poorest 6-mo prognosis were acute myeloid leukemia and non-Hodgkin lymphoma. CONCLUSION The severity of the underlying hematologic malignancies does not influence intensive care unit or hospital mortality. Short-term prognosis is exclusively predicted by acute organ dysfunctions and by a pathogen's aggressiveness. Therefore, reluctance to admit patients with nonterminal hematologic malignancies to the intensive care unit based only on the prognosis of their underlying hematologic malignancy does not seem justified.

Background-Decreased heart rate variability (HRV) and increased blood pressure variability (BPV), determined in part by nitric oxide (NO)-dependent endothelial dysfunction, are correlated with adverse prognosis in cardiovascular diseases. We examined potential alterations in BPV and HRV in genetically dyslipidemic, apolipoprotein (apo) E Ϫ/Ϫ , and control mice and the effect of chronic statin treatment on these parameters in relation to their NO synthase (NOS)-modifying properties. Methods and Results-BP and HR were recorded in unrestrained, nonanesthetized mice with implanted telemetry devices with or without rosuvastatin. Cardiac and aortic expression of endothelial NOS and caveolin-1 were measured by immunoblotting. Both systolic BP and HR were elevated in apoE Ϫ/Ϫ mice, with abolition of their circadian cycles. Spectral analysis showed an increase in their systolic BPV in the very-low-frequency (ϩ17%) band and a decrease in HRV in the high-frequency (Ϫ57%) band, reflecting neurohumoral and autonomic dysfunction. Decreased sensitivity to acute injection of atropine or an NOS inhibitor indicated basal alterations in both parasympathetic and NOS regulatory systems in apoE Ϫ/Ϫ mice. Aortic caveolin-1 protein, an inhibitor of endothelial NOS, was also increased in these mice by 2.0-fold and correlated positively with systolic BPV in the very-low-frequency band. Rosuvastatin treatment corrected the hemodynamic and caveolin-1 expression changes despite persisting elevated plasma cholesterol levels. Conclusions-Rosuvastatin

The modulatory role of endothelial nitric oxide synthase (eNOS) on heart contraction, relaxation and rate is examined in light of recent studies using genetic deletion or overexpression in mice under specific conditions. Unstressed eNOS‐/‐ hearts in basal conditions exhibit a normal inotropic and lusitropic function, with either decreased or unchanged heart rate. Under stimulation with catecholamines, eNOS‐/‐ mice predominantly show a potentiation in their β‐adrenergic inotropic and lusitropic responsiveness. A similar phenotype is observed in β3‐adrenoceptor deficient mice, pointing to a key role of this receptor subtype for eNOS coupling. The effect of eNOS on the muscarinic cholinergic modulation of cardiac function probably operates in conjunction with other NO‐independent mechanisms, the persistence of which may explain the apparent dispensability of this isoform for the effect of acetylcholine in some eNOS‐/‐ mouse strains. eNOS‐/‐ hearts submitted to short term ischaemia‐reperfusion exhibit variable alterations in systolic and diastolic function and infarct size, while those submitted to myocardial infarction present a worsened ventricular remodelling, increased 1 month mortality and loss of benefit from ACE inhibitor or angiotensin II type I receptor antagonist therapy. Although non‐conditional eNOS gene deletion may engender phenotypic adaptations (e.g. ventricular hypertrophy resulting from chronic hypertension, or upregulation of the other NOS isoforms) potentially confounding the interpretation of comparative studies, the use of eNOS‐/‐ mice has undoubtedly advanced (and will probably continue to improve) our understanding of the complex role of eNOS (in conjunction with the other NOSs) in the regulation of cardiac function. The challenge is now to confirm the emerging paradigms in human cardiac physiology and hopefully translate them into therapy.

No abstract

Subglottic secretion suctioning resulted in a significant reduction of ventilator-associated pneumonia prevalence associated with a significant decrease in antibiotic use. By contrast, ventilator-associated condition occurrence did not differ between groups and appeared more related to other medical features than ventilator-associated pneumonia.

BACKGROUND: Heart transplantation (HT) from donation after circulatory death (DCD) has yet to achieve wide clinical application despite the encouraging resultsreported recently. In this study we describe 2 cases of successful adult DCD HT performed at our institution using an original protocol. METHODS: Our local abdominal DCD protocol was updated to allow DCD heart procurement, and was accepted by the institutional ethics committee. The main features of the protocol include: pre-mortem insertion of peripheral venoarterial extracorporeal membrane oxygenation cannulas; thoracoabdominal normothermic regional perfusion (NRP) by clamping the 3 aortic arch vessels to exclude cerebral circulation; and in-situ heart resuscitation. The retrieved hearts were directly transplanted into recipients located in an adjoining operating room. RESULTS: The procurement warm ischemic time was 25 minutes for the first donor, and 26 minutes for the second donor. The cold ischemic time was 16 minutes for the first recipient and 17 minutes for the second recipient. The suture time was 30 minutes for the first recipient, and 53 minutes for the second recipient. Both recipients were easily weaned off cardiopulmonary bypass in sinus rhythm and inotropic support. Post-operative evaluation of cardiac function was excellent and the patients were subsequently discharged home. CONCLUSIONS: Transplantation of hearts from DCD donors is now a clinical reality.NRP is a useful tool for resuscitation, reperfusion, and preservation of transplanted hearts. It also offers the opportunity to assess the function and viability of organs before transplantation. However,due to ethical issues, some may object to ante-mortem intervention.

Background-In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium. Methods and Results-We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the ␣-myosin heavy chain promoter (NOS3-TG