[Organ transplantation during SARS-CoV-2 epidemic : the 2020-2021 Liege transplant Center experience]. / Face à la COVID-19. La transplantation d'organes en période de pandémie SARS-CoV-2 : l'expérience 2020-2021 du Centre liégeois de Transplantation.

The «Severe Acute Respiratory Syndrome coronavirus 2¼ (SARS-CoV-2) pandemic has disrupted medical care and intra-hospital organization during 2020, both in Belgium and throughout the world. Solid organ transplantation was not spared and in Belgium, the number of organ donors and transplants overall decreased by 20 % for livers and by 33 % for hearts between 2019 and 2020. The aim of this article is to summarize the experience acquired in 2020 and 2021 on the organizational and medical implications of the coronavirus disease 2019 (COVID-19) pandemic with regard to the care of patients transplanted or awaiting for organ transplants, and to draw conclusions both for the aftermath of COVID-19 but also for future pandemics. Vaccination against SARS-CoV-2 is highly recommended and particularly important in organ transplant recipients, even if the response rate is lower than in the non-transplanted population. A third injection is now advised in immunosuppressed patients.

La pandémie de «Severe Acute Respiratory Syndrome coronavirus 2¼ (SARS-CoV-2) a bouleversé les soins médicaux et l'organisation intra-hospitalière durant l'année 2020 en Belgique et dans le monde. La transplantation d'organes ne fut pas épargnée. En Belgique, le nombre de donneurs d'organes et de transplantations a globalement diminué de 20 % pour les foies et de 33 % pour les cœurs entre 2019 et 2020. Le but de cet article est de résumer l'expérience acquise en 2020 et 2021 sur les implications organisationnelles et médicales de la pandémie de «coronavirus disease 2019¼ (COVID-19) quant à la prise en charge des patients transplantés ou en attente de greffe d'organes, et d'en tirer les conclusions à la fois pour les suites de la COVID-19, mais aussi pour les éventuelles futures pandémies. La vaccination anti-SARS-CoV-2 est recommandée et particulièrement importante chez les patients transplantés d'organe, même si le taux de réponse est inférieur à la population non transplantée. Une troisième injection est conseillée chez les patients immunodéprimés.

[The first wave of COVID-19 in Intensive care]. / La première vague de la COVID-19 aux Soins intensifs, mars-mai 2020.

In December 2019, in Wuhan, a new human infectious pathology was born, COVID-19, consisting above all in pneumoniae, induced by the coronavirus named SARS-CoV-2 because of the respiratory distress it caused (SARS for severe acute respiratory syndrome, and CoV for Coronavirus). A real health and planetary crisis has appeared, much more substantial than that linked to SARS-CoV-1 in 2002-2004 and to MERS-CoV (Middle East Respiratory Syndrome Coronavirus) in 2012. In addition to respiratory damage that can be dramatic, this pathology is complicated by the frequency of cardiovascular, renal and coagulation diseases. Health care systems have had to adapt urgently, in the absence of hindsight from the pathology, and without effective therapeutic weapons. Through this review of the literature, we detail our local practices for the overall management of patients hospitalized in Intensive care.

En décembre 2019, à Wuhan, une nouvelle pathologie infectieuse humaine est née, le COVID-19, consistant avant tout en une pneumonie, induite par le coronavirus nommé SARS-CoV-2 en lien avec l'intensité de la détresse respiratoire qu'il entraîne (SARS pour syndrome respiratoire aigu sévère, et CoV pour coronavirus). Une véritable crise sanitaire et planétaire est apparue, bien plus conséquente que celle liée au SARS-CoV-1 en 2002-2004 et au MERS-CoV (Middle East Respiratory Syndrome Coronavirus) en 2012. Outre une atteinte respiratoire pouvant être dramatique, cette pathologie est complexifiée par la fréquence des atteintes cardiovasculaires, rénales et de la coagulation. Les systèmes de soins de santé ont dû s'adapter urgemment, en l'absence de recul face à la pathologie, et sans armes thérapeutiques efficaces. Au travers de cette revue de la littérature, nous détaillons nos pratiques locales pour la prise en charge globale des patients hospitalisés aux Soins intensifs.

[Deceased organ donation in 2020]. / Le don d'organes en 2020.

The success of solid organ transplantation induced an increased need for grafts and the necessary registration of transplant candidates on long waiting lists. Many patients die while waiting for transplantation, even in Belgium where the donation rates have been high these last years. In order to fight this lack of donor organs, the transplant centers widened donation criteria for brain dead donors, including older age and potential transmissible diseases. In addition, programs of donation after circulation death have been developed, first for kidneys, then for livers and recently for the hearts. Organ donation after euthanasia is also regularly performed in Belgium. All these policies lead to the fact that organ donation rates stay high in Belgium, and particularly in the Liege region, but efforts are still ahead if we aim to reduce waiting list mortalities.

Le succès des transplantations a entraîné un besoin important en organes et la nécessité d'inscrire les patients candidats à la greffe sur de longues listes d'attente. De trop nombreux patients meurent avant d'avoir pu bénéficier de la transplantation, malgré le fait que la Belgique soit un des pays du monde où le taux de prélèvement est, proportionnellement, le plus élevé. Afin de lutter contre ce manque d'organes, les centres de transplantation ont élargi les critères de prélèvement des donneurs en mort cérébrale, tant au niveau de leur âge qu'au niveau de certaines maladies potentiellement transmissibles. De plus, des programmes de prélèvement à partir de donneurs en mort circulatoire ont également été développés avec succès, d'abord pour les reins et le foie, plus récemment pour le coeur. Les prélèvements d'organes sont également réalisables après euthanasie. L'ensemble de ces politiques fait que le taux de prélèvement d'organes après décès reste élevé en Belgique, et particulièrement dans la région liégeoise, mais des efforts doivent encore être réalisés si l'on veut encore réduire la mortalité en liste d'attente.

[Acute respiratory distress syndrome]. / Le syndrome de détresse respiratoire aiguë.

Since its first description in 1967, a lot of progress has been made in understanding the pathophysiology, diagnosis and management of acute respiratory distress syndrome (ARDS). This nosological entity is based on the appearance of a diffuse alveolar damage associating pulmonary epithelial barrier disruption with an alveolar filling, both responsible of profound hypoxemia and important morbi-mortality. Nowadays, ARDS remains a frequent syndrome, associated with various etiologies. Diagnosis is based on the occurrence of acute hypoxic respiratory failure not explained by cardiac insufficiency or volume overload, within 7 days after a recognized risk factor, and in the presence of bilateral pulmonary opacities not fully explained by effusions, atelectasis or nodules on the chest radiography. Survivors present an increased risk of developing cognitive decline, depression, post-traumatic stress, and typical ICU related side-effects such as polyneuropathy and sarcopenia. In this context and not withstanding significant recent progress in the field of mechanical ventilation and extra-corporeal respiratory assistance, early diagnosis remains essential to identify patients with ARDS in order to offer them the most appropriate therapy.

Depuis sa première description en 1967, des progrès majeurs ont été réalisés dans la compréhension de la physiopathologie, le diagnostic et la prise en charge du syndrome de détresse respiratoire aiguë (SDRA). Cette entité nosologique repose sur l'apparition d'un dommage alvéolaire diffus associant une rupture de la barrière épithéliale pulmonaire avec un comblement alvéolaire à l'origine d'une hypoxémie profonde. De nos jours, le SDRA reste un syndrome fréquent, grevé d'une mortalité élevée, et prenant source dans de multiples situations pathologiques. Le diagnostic du SDRA repose sur l'apparition d'une insuffisance respiratoire aiguë hypoxique non expliquée par une insuffisance cardiaque ou une surcharge volémique, dans un délai de 7 jours suivant l'apparition d'un facteur de risque reconnu, en présence d'opacités pulmonaires bilatérales non complètement expliquées par des épanchements, des atélectasies ou des nodules. Les survivants sont à haut risque de développer un déclin cognitif, une dépression, ou un stress post-traumatique en plus des effets secondaires classiques d'une longue hospitalisation en unité de soins intensifs que sont la polyneuropathie ou la sarcopénie. Dans ce contexte, et en dépit de progrès importants dans le domaine de la ventilation mécanique et de l'assistance respiratoire par circulation extra-corporelle, il reste primordial d'identifier précocement les patients souffrant de SDRA afin de leur proposer la thérapeutique la plus appropriée dès les premiers signes cliniques.

[Pulmonary tumour thrombotic microangiopathy associated with a gastric adenocarcinoma]. / Microangiopathie thrombotique tumorale pulmonaire associée à un adénocarcinome gastrique.

We report the case of a 67 years old patient with a history of gastric adenocarcinoma who died in a context of severe dyspnea and whose autopsy will confirm the diagnosis of a Pulmonary Tumor Thrombotic Microangiopathy (PTTM). PTTM is a fatal pulmonary complication associated to multiple cancers. It starts with an acute or subacute respiratory failure quickly evolving towards fatal thrombo-embolic pulmonary hypertension and right heart failure. Pre-mortem diagnosis is difficult and not frequent because the pathology is rare, the underlying neoplastic disease is not always known, clinical and radiological signs are not specific and progression is fast. When made soon enough, PTTM diagnosis avoids useless and sometimes harmful medication. In some cases, an improvement of patient's symptoms and comfort is observed. Some studies described several months of extended survival.

Nous rapportons le cas d'un patient de 67 ans avec un antécédent d'adénocarcinome gastrique décédé dans un contexte de dyspnée majeure et dont l'autopsie confirmera la présence d'une microangiopathie thrombotique tumorale pulmonaire (Pulmonary Tumor Thrombotic Microangiopathy - PTTM). La PTTM est une complication pulmonaire fatale associée à de multiples cancers. Elle se présente par une insuffisance respiratoire d'installation aiguë ou subaiguë, évoluant rapidement vers une hypertension thrombo-embolique pulmonaire et une insuffisance cardiaque droite fatales. Le diagnostic ante-mortem est difficile et rarement posé car la pathologie est rare. L'affection néoplasique sous-jacente n'est pas toujours connue, les signes cliniques et radiologiques sont peu spécifiques et son évolution est rapide. Réalisé à temps, le diagnostic permet, néanmoins, d'éviter une médication inefficace et parfois délétère. Dans certains cas, on observe une amélioration des symptômes et de l'inconfort du patient et, parfois, une survie prolongée de quelques mois.

Measurement of pleural pressure swings with a fluid-filled esophageal catheter vs pulmonary artery occlusion pressure.

PURPOSE: Pleural pressure measured with esophageal balloon catheters (Peso) can guide ventilator management and help with the interpretation of hemodynamic measurements, but these catheters are not readily available or easy to use. We tested the utility of an inexpensive, fluid-filled esophageal catheter (Peso) by comparing respiratory-induced changes in pulmonary artery occlusion (Ppao), central venous (CVP), and Peso pressures. METHODS: We studied 30 patients undergoing elective cardiac surgery who had pulmonary artery and esophageal catheters in place. Proper placement was confirmed by chest compression with airway occlusion. Measurements were made during pressure-regulated volume control (VC) and pressure support (PS) ventilation. RESULTS: The fluid-filled esophageal catheter provided a high-quality signal. During VC and PS, change in Ppao (∆Ppao) was greater than ∆Peso (bias = -2 mm Hg) indicating an inspiratory increase in cardiac filling. During VC, ∆CVP bias was 0 indicating no change in right heart filling, but during PS, CVP fell less than Peso indicating an inspiratory increase in filling. Peso measurements detected activation of expiratory muscles, development of non-west zone 3 lung conditions during inspiration, and ventilator-triggered inspiratory efforts. CONCLUSIONS: A fluid-filled esophageal catheter provides a high-quality, easily accessible, and inexpensive measure of change in pleural pressure and provided insights into patient-ventilator interactions.

Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.

BACKGROUND: The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository. METHODS/DESIGN: Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject. DISCUSSION: Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk. TRIAL REGISTRATION: The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.

DNA copy number aberrations in small-cell lung cancer reveal activation of the focal adhesion pathway.

Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer in its clinical behavior, with a 5-year overall survival as low as 5%. Despite years of research in the field, molecular determinants of SCLC behavior are still poorly understood, and this deficiency has translated into an absence of specific diagnostics and targeted therapeutics. We hypothesized that tumor DNA copy number alterations would allow the identification of molecular pathways involved in SCLC progression. Array comparative genomic hybridization was performed on DNA extracted from 46 formalin-fixed paraffin-embedded SCLC tissue specimens. Genomic profiling of tumor and sex-matched control DNA allowed the identification of 70 regions of copy number gain and 55 regions of copy number loss. Using molecular pathway analysis, we found a strong enrichment in these regions of copy number alterations for 11 genes associated with the focal adhesion pathway. We verified these findings at the genomic, gene expression and protein level. Focal Adhesion Kinase (FAK), one of the central genes represented in this pathway, was commonly expressed in SCLC tumors and constitutively phosphorylated in SCLC cell lines. Those were poorly adherent to most substrates but not to laminin-322. Inhibition of FAK phosphorylation at Tyr(397) by a small-molecule inhibitor, PF-573,228, induced a dose-dependent decrease of adhesion and an increase of spreading in SCLC cell lines on laminin-322. Cells that tended to spread also showed a decrease in focal adhesions, as demonstrated by a decreased vinculin expression. These results support the concept that pathway analysis of genes in regions of copy number alterations may uncover molecular mechanisms of disease progression and demonstrate a new role of FAK and associated adhesion pathways in SCLC. Further investigations of FAK at the functional level may lead to a better understanding of SCLC progression and may have therapeutic implications.

[Extracorporeal membrane oxygenation (ECMO) in ICU patients suffering from cardiogenic shock, refractory hypoxemia or cardiac arrest]. / L'ECMO (extracorporeal membrane oxygenation) aux soins intensifs: intérêt chez le patient en choc cardiogénique réfractaire, en hypoxémie réfractaire ou en arrêt cardiaque.

ExtraCorporeal Membrane Oxygenation (ECMO) is a cardiopulmonary assistance device able to support patients in cardiac arrest, refractory cardiogenic shock or refractory hypoxemia otherwise sentenced to death. Recent technical progresses, early indication decision, bedside multidisciplinary implant, specific complications screening and echocardiographic weaning testing are crucial points to allow success of this exceptional technique.

High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications.

During the last decade, high-throughput technologies including genomic, epigenomic, transcriptomic and proteomic have been applied to further our understanding of the molecular pathogenesis of this heterogeneous disease, and to develop strategies that aim to improve the management of patients with lung cancer. Ultimately, these approaches should lead to sensitive, specific and noninvasive methods for early diagnosis, and facilitate the prediction of response to therapy and outcome, as well as the identification of potential novel therapeutic targets. Genomic studies were the first to move this field forward by providing novel insights into the molecular biology of lung cancer and by generating candidate biomarkers of disease progression. Lung carcinogenesis is driven by genetic and epigenetic alterations that cause aberrant gene function; however, the challenge remains to pinpoint the key regulatory control mechanisms and to distinguish driver from passenger alterations that may have a small but additive effect on cancer development. Epigenetic regulation by DNA methylation and histone modifications modulate chromatin structure and, in turn, either activate or silence gene expression. Proteomic approaches critically complement these molecular studies, as the phenotype of a cancer cell is determined by proteins and cannot be predicted by genomics or transcriptomics alone. The present article focuses on the technological platforms available and some proposed clinical applications. We illustrate herein how the "-omics" have revolutionised our approach to lung cancer biology and hold promise for personalised management of lung cancer.

[Clinical case of the month. Spontaneous pneumopericardium after sternal dehiscence]. / Pneumopéricarde dans les suites d'une déhiscence de sternum.

We report a case of pneumopericardium occuring after cardiac surgery. Pneumopericardium is a rare condition; trauma is the most frequent etiology. Nontraumatic causes include fistulae in relationship with the bronchial tree or oesophagus and intrapericardial gazeous production due to bacterial pericarditis. Pericardiocentesis is indicated in case of air tamponade and local infection.

Churg Strauss Syndrome masquerading septic shock.

Systemic inflammatory response syndrome (SIRS) can be related to acute inflammatory conditions that can be sometimes missed and inappropriately managed as severe infections. We report a case of Churg Strauss Syndrome (CSS), presenting as septic shock with acute onset of fever and multiple organ failure including pulmonary involvement with severe hypoxemia, hypotension requiring vasoactive support and acute renal failure. Antibiotics were discontinued and intravenous steroids allowed a rapid clinical improvement in close relationship with the fall in circulating eosinophils count.

[Predicting prognosis in post-anoxic coma]. / Comment prédire l'évolution du coma post-anoxique?

Most patients who remain comatose for a few hours after a period of global cerebral ischemia have a poor prognosis. Early identification of these patients is desirable to reduce uncertainty about treatment and non-treatment decisions, and to improve relationships with the family. The absence of pupillary light response and corneal reflexes, absent or stereotyped extension motor response to noxious stimulation (3 days after insult); myoclonus status epilepticus; absence of cortical N20 response on somatosensory evoked potential studies; generalised suppression or burst-suppression EEG and serum neuron-specific enolase above 33 microg/L (sampled 1-3 days after insult) have been shown to predict poor outcome. We here propose an algorithm to help intensive care physicians' clinical decision making in post-anoxic coma.

Sepsis is associated with an upregulation of functional beta3 adrenoceptors in the myocardium.

OBJECTIVE: To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression. METHODS AND RESULTS: beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice. CONCLUSIONS: beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.

[Aspergillus pericarditis with cardiac tamponade and haemophagocytic syndrome: a non-classical case of immunodeficiency]. / Péricardite aspergillaire avec tamponnade cardiaque et syndrome hémophagocytaire: un cas non classique d'immunodéficience.

We report the case of a 31-year-old woman who died in a context of haemophagocytic syndrome with multiple opportunist infections:viral, mycobacterial and fungal. To our knowledge, this is the tenth case of invasive aspergillosis manifested by an aspergillus pericarditis with cardiac tamponade. Search for HIV infection, neoplasia, haematological malignancies was negative. In addition, the patient carried on a nonviral, non-ethylic cirrhosis, the etiology of which remained unknow. We will particularly develop the aspergillus pericarditis with cardiac tamponade and the haemophagocytic syndrome.

Restoration of TGF-beta signalling reduces tumorigenicity in human lung cancer cells.

Members of the transforming growth factor-beta (TGF-beta) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-beta-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (TbetaRII) expression. In this study, we investigated the expression pattern of TbetaRII in human lung cancer tissues by RT-PCR and Western blot analyses. We observed downregulation of TbetaRII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT-PCR. Western blot analyses with tumour lysates showed reduced expression of TbetaRII in 77% cases. We also determined the effect of TbetaRII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-beta due to lack of TbetaRII expression. Stable expression of TbetaRII in these cells restored TGF-beta-mediated effects including Smad2/3 and Smad4 complex formation, TGF-beta-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing TbetaRII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-beta signalling in TbetaRII null cells by stable expression of TbetaRII can reverse malignant behaviour of cells and loss of TbetaRII expression may be involved in lung tumour progression.

Cloned fusion product from a rare t(15;19)(q13.2;p13.1) inhibit S phase in vitro.

BACKGROUND: Somatically acquired chromosomal translocation is a common mechanism of oncogene activation in many haematopoietic tumours and sarcomas. However, very few recurrent chromosomal translocations have been reported in more common epithelial tumours such as lung carcinomas. METHODS: We established a cell line HCC2429 from an aggressive, metastatic lung cancer arising in a young, non-smoking woman, demonstrating a t(15;19)(q13.2;p13.1). The breakpoints on chromosomes 15 and 19 were cloned using long distance inverse PCR and we determined by RT-PCR that the translocation results in a novel fusion transcript in which the 3' end Brd4 on chromosome 19p is fused to the 5' end of NUT on chromosome 15q. RESULTS: In total, 128 lung cancer tissues were screened using fluorescent in situ hybridisation, but none of the tumours screened demonstrated t(15;19), suggesting that this translocation is not commonly found in lung cancer. Consistent with previous literature, ectopic expression of wild type Brd4 was shown to inhibit G(1) to S progression. However, we also found that the Brd4-NUT fusion augments the inhibition of progression to S phase compared with wild type Brd4. CONCLUSION: Alteration in cell cycle kinetics is important in tumorigenesis, although the exact role of Brd4-NUT fusion protein in the pathogenesis of lung cancers remains unclear and need to be further elucidated.

Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis.

Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. To date, 3 distinct NOS isoforms have been identified: neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3). Biochemically, NOS consists of a flavin-containing reductase domain, a heme-containing oxygenase domain, and regulatory sites. NOS catalyse an overall 5-electron oxidation of one Nomega-atom of the guanidino group of L-arginine to form NO and L-citrulline. NO exerts a plethora of biological effects in the cardiovascular system. The basal formation of NO in mitochondria by a mitochondrial NOS seems to be one of the main regulators of cellular respiration, mitochondrial transmembrane potential, and transmembrane proton gradient. This review focuses on recent advances in the understanding of the role of enzyme and enzyme-independent NO formation, regulation of NO bioactivity, new aspects of NO on cardiac function and morphology, and the clinical impact and perspectives of these recent advances in our knowledge on NO-related pathways.