Novel cyclooxygenase-catalyzed bioactive prostaglandin F2alpha from physiology to new principles in inflammation.
Medicinal research reviews
Prostaglandin F2alpha (PGF2alpha), a foremost stable vasoactive cyclooxygenase (COX)-catalyzed prostaglandin, regulates a number of key physiological functions such as luteolysis, ovarian function, luteal maintenance of pregnancy, and parturition as a constitutive part of ongoing reproductive processes of the body. It has recently been implicated in the regulation of intricate pathophysiological processes, such as acute and chronic inflammation, cardiovascular and rheumatic diseases. Since the discovery of a second isoform of COXs, it has been shown that PGF2alpha can be formed in vivo from arachidonic acid through both isoforms of COXs, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Being synthesized in various parts of the body, it metabolizes instantly to a number of rather inactive metabolites mainly in the lungs, liver, kidney, and efficiently excretes into the urine. 15-Keto-dihydro-PGF2alpha, a major stable metabolite of PGF2alpha that reflects in vivo PGF2alpha biosynthesis, is found in larger quantities than its parent compound in the circulation and urine in basal physiological conditions, with short-lived pulses during luteolysis, induced termination of pregnancy and parturition, and is increased in tissues and various body fluids during acute, sub-chronic, and severe chronic inflammation. Further, the close relationship of PGF2alpha with a number of risk factors for atherosclerosis indicates its major role in inflammation pathology. This review addresses multiple aspects of PGF2alpha in addition to its emerging role in physiology to inflammation.
Acute left ventricular dysfunction in the critically ill.
Chockalingam Anand,Mehra Ankit,Dorairajan Smrita,Dellsperger Kevin C
Acute left ventricular (LV) dysfunction is common in the critical care setting and more frequently affects the elderly and patients with comorbidities. Because of increased mortality and the potential for significant improvement with early revascularization, the practitioner must first consider acute coronary syndrome. However, variants of stress (takotsubo) cardiomyopathy may be more prevalent in ICU settings than previously recognized. Early diagnosis is important to direct treatment of complications of stress cardiomyopathy, such as dynamic LV outflow tract obstruction, heart failure, and arrhythmias. Global LV dysfunction occurs in the critically ill because of the cardio-depressant effect of inflammatory mediators and endotoxins in septic shock as well as direct catecholamine toxicity. Tachycardia, hypertension, and severe metabolic abnormalities can independently cause global LV dysfunction, which typically improves with addressing the precipitating factor. Routine troponin testing may help early detection of cardiac injury and biomarkers could have prognostic value independent of prior cardiac disease. Echocardiography is ideally suited to quantify LV dysfunction and determine its most likely cause. LV dysfunction suggests a worse prognosis, but with appropriate therapy outcomes can be optimized.
Prazosin in acute anthracyclene cardiomyopathy.
Carlon G C,Gee T,Kahn R C
A 32-year-old woman with a 14-month history of acute lymphoblastic leukemia received 300 mg/sq m of doxorubicin. Shortly after the last course of therapy, congestive failure developed that was attributed to anthracyclene cardiomyopathy. Three weeks later, an acute septic episode was complicated by hypotension and low cardiac output. Adequate blood pressure and cardiac output were restored with a combined intravenous infusion of dopamine hydrochloride and nitroglycerine. Within 24 hours, oral therapy with prazosin and digitalis was initiated, and two days later, the intravenous infusions could be discontinued. Acute anthracyclene cardiomyopathy can be successfully treated with a combination of oral inotropic and vasodilating agents.
CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)-mediated apoptosis.
Lee Y Y,Moujalled D,Doerflinger M,Gangoda L,Weston R,Rahimi A,de Alboran I,Herold M,Bouillet P,Xu Q,Gao X,Du X-J,Puthalakath H
Cell death and differentiation
Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases.
Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome: A Cautionary Case Report.
Radbel Jared,Narayanan Navaneeth,Bhatt Pinki J
Novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in Wuhan, China. Since then, COVID-19 has become a pandemic affecting more than 4.1 million people worldwide. Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH). Anti-cytokine therapy such as tocilizumab, an IL-6 receptor antagonist, is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking. We report two cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab. Both patients progressed to sHLH despite treatment with tocilizumab, and one developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS. These cases highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process.
An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction.
Niederbichler Andreas D,Hoesel Laszlo M,Westfall Margaret V,Gao Hongwei,Ipaktchi Kyros R,Sun Lei,Zetoune Firas S,Su Grace L,Arbabi Saman,Sarma J Vidya,Wang Stewart C,Hemmila Mark R,Ward Peter A
The Journal of experimental medicine
Defective cardiac function during sepsis has been referred to as "cardiomyopathy of sepsis." It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a-C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance.
Impact of Right Ventricular Dysfunction on Short- and Long-Term Mortality in Sepsis: A Meta-Analysis of 1,373 Patients.
Vallabhajosyula Saraschandra,Shankar Aditi,Vojjini Rahul,Cheungpasitporn Wisit,Sundaragiri Pranathi R,DuBrock Hilary M,Sekiguchi Hiroshi,Frantz Robert P,Cajigas Hector R,Kane Garvan C,Oh Jae K
BACKGROUND:Right ventricular (RV) dysfunction in sepsis and septic shock has been infrequently studied and has uncertain prognostic significance. RESEARCH QUESTION:Does RV function impact mortality in sepsis and septic shock? STUDY DESIGN AND METHODS:We reviewed the published literature from January 1999 to April 2020 for studies evaluating adult patients with sepsis and septic shock. Study definition of RV dysfunction was used to classify patients. The primary outcome was all-cause mortality divided into short-term mortality (ICU stay, hospital stay, or mortality ≤30 days) and long-term mortality (>30 days). Effect estimates from the individual studies were extracted and combined, using the random-effects, generic inverse variance method of DerSimonian and Laird. RESULTS:Ten studies, 1,373 patients, were included; RV dysfunction was noted in 477 (34.7%). RV dysfunction was variably classified as decreased RV systolic motion, high RV/left ventricular ratio and decreased RV ejection fraction. Septic shock, ARDS, and mechanical ventilation were noted in 82.0%, 27.5%, and 78.4% of the population, respectively. Patients with RV dysfunction had lower rates of mechanical ventilation (71.9% vs 81.9%; P < .001), higher rates of acute hemodialysis (38.1% vs 22.4%; P = .04), but comparable rates of septic shock and ARDS. Studies showed moderate (I = 58%) and low (I = 49%) heterogeneity for short-term and long-term mortality, respectively. RV dysfunction was associated with higher short-term (pooled OR, 2.42; 95%CI, 1.52-3.85; P = .0002) (10 studies) and long-term (pooled OR, 2.26; 95%CI, 1.29-3.95; P = .004) (4 studies) mortality. INTERPRETATION:In this meta-analysis of observational studies, RV dysfunction was associated with higher short-term and long-term mortality in sepsis and septic shock.
Cardiac Dysfunction After Neurologic Injury: What Do We Know and Where Are We Going?
Krishnamoorthy Vijay,Mackensen G Burkhard,Gibbons Edward F,Vavilala Monica S
Recent literature has implicated severe neurologic injuries, such as aneurysmal subarachnoid hemorrhage, as a cause of cardiac dysfunction, impaired hemodynamic function, and poor outcomes. Mechanistic links between the brain and the heart have been explored in detail over the past several decades, and catecholamine excess, neuroendocrine dysfunction, and unchecked inflammation all likely contribute to the pathophysiologic process. Although cardiac dysfunction has also been described in other disease paradigms, including septic shock and thermal injury, there is likely a common underlying pathophysiology. In this review, we will examine the pathophysiology of cardiac dysfunction after neurologic injury, discuss the evidence surrounding cardiac dysfunction after different neurologic injuries, and suggest future research goals to gain knowledge and improve outcomes in this patient population.
Right Ventricular Dysfunction in Early Sepsis and Septic Shock.
Lanspa Michael J,Cirulis Meghan M,Wiley Brandon M,Olsen Troy D,Wilson Emily L,Beesley Sarah J,Brown Samuel M,Hirshberg Eliotte L,Grissom Colin K
BACKGROUND:Sepsis is a frequently lethal state, commonly associated with left ventricular (LV) dysfunction. Right ventricular (RV) dysfunction in sepsis is less well understood. RESEARCH QUESTION:In septic patients, how common is RV dysfunction, and is it associated with worse outcomes? STUDY DESIGN AND METHODS:We measured echocardiographic parameters on critically ill patients with severe sepsis or septic shock within the first 24 hours of ICU admission. We defined RV dysfunction as fractional area change (FAC) less than 35% or tricuspid annulus systolic plane excursion (TAPSE) less than 1.6 cm. We defined LV systolic dysfunction as ejection fraction (EF) less than 45% or longitudinal strain greater than -19%. Using logistic regression, we assessed the relationship between 28-day mortality and presence of RV dysfunction and LV systolic dysfunction, controlling for receipt of vasopressors, receipt of fluid, mechanical ventilation, and the acute physiology and chronic health evaluation (APACHE II) score. RESULTS:We studied 393 patients. RV and LV dysfunction were common (48% and 63%, respectively). Mean echocardiographic values were: RV end-diastolic area, 22.4 ± 7.0 cm; RV end-systolic area, 14.2 ± 6.0 cm; RV FAC, 38 ± 11%; TAPSE, 1.8 ± .06 cm; RV longitudinal strain, -15.3 ± 6.5%; LV EF, 60% ± 14%; LV longitudinal strain, -16.5% ± 6.0%. Patients with RV dysfunction had higher 28-day mortality (31% vs 16%, P = .001). In our multivariable regression model, RV dysfunction was associated with increased mortality (OR, 3.4; CI, 1.7-6.8; P = .001), and LV systolic dysfunction was not (OR, 0.63; CI, 0.3 -1.2; P = .32) INTERPRETATION: Right ventricular dysfunction is present in nearly half of studied septic patients and is associated with over threefold higher 28-day mortality.
The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.
Martin Lukas,Derwall Matthias,Al Zoubi Sura,Zechendorf Elisabeth,Reuter Daniel A,Thiemermann Chris,Schuerholz Tobias
Septic cardiomyopathy is a key feature of sepsis-associated cardiovascular failure. Despite the lack of consistent diagnostic criteria, patients typically exhibit ventricular dilatation, reduced ventricular contractility, and/or both right and left ventricular dysfunction with a reduced response to volume infusion. Although there is solid evidence that the presence of septic cardiomyopathy is a relevant contributor to organ dysfunction and an important factor in the already complicated therapeutic management of patients with sepsis, there are still several questions to be asked: Which factors/mechanisms cause a cardiac dysfunction associated with sepsis? How do we diagnose septic cardiomyopathy? How do we treat septic cardiomyopathy? How does septic cardiomyopathy influence the long-term outcome of the patient? Each of these questions is interrelated, and the answers require a profound understanding of the underlying pathophysiology that involves a complex mix of systemic factors and molecular, metabolic, and structural changes of the cardiomyocyte. The afterload-related cardiac performance, together with speckle-tracking echocardiography, could provide methods to improve the diagnostic accuracy and guide therapeutic strategies in patients with septic cardiomyopathy. Because there are no specific/causal therapeutics for the treatment of septic cardiomyopathy, the current guidelines for the treatment of septic shock represent the cornerstone of septic cardiomyopathy therapy. This review provides an up-to-date overview of the current understanding of the pathophysiology, summarizes the evidence of currently available diagnostic tools and treatment options, and highlights the importance of further urgently needed studies aimed at improving diagnosis and investigating novel therapeutic targets for septic cardiomyopathy.
Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion.
Gurevitch J,Frolkis I,Yuhas Y,Paz Y,Matsa M,Mohr R,Yakirevich V
Journal of the American College of Cardiology
OBJECTIVES:The purpose of this study was to examine whether tumor necrosis factor-alpha (TNF-alpha) is released directly from the ischemic myocardium undergoing reperfusion. BACKGROUND:Tumor necrosis factor-alpha is a protein hormone produced by systemic leukocytes (primarily by activated macrophages). It has been implicated as a systemic mediator in the development of septic shock and other pathologic conditions. Serum TNF-alpha has also been detected in a variety of cardiac disease states and after myocardial ischemia-reperfusion injury. METHODS:Nine isolated rat hearts undergoing 30 min of perfusion, followed by warm cardioplegic arrest, 1 h of global ischemia and 30 min of reperfusion, were investigated using the modified Langendorff model. RESULTS:Significant amounts of TNF-alpha (752 +/- 212 pmol/ml) were detected in the effluent during the first minute of reperfusion. Tumor necrosis factor-alpha levels correlated with postischemic deterioration in peak systolic pressures (r = 0.7882, p = 0.012), dP/dt max (r = 0.6795, p = 0.044), time-pressure integral (r = 0.7661, p = 0.0016) and postischemic creatine kinase levels (r = 0.8367, p = 0.005). The deterioration in coronary flow, however, was inversely correlated with TNF-alpha levels (r = -0.7581, p = 0.018). CONCLUSIONS:To our knowledge, this study is the first to suggest that the isolated rat myocardium synthesizes and releases TNF-alpha in response to ischemia and reperfusion, which directly correlates with the postischemic deterioration in myocardial mechanical performance and the amount of cellular necrosis.
Toxic shock syndrome due to group C streptococci. A case report.
Natoli S,Fimiani C,Faglieri N,Laurenzi L,Calamaro A,Frasca A M,Arcuri E
Intensive care medicine
BACKGROUND:Streptococcal toxic shock-like syndrome is a life-threatening illness which is on the increase. In early reports, only group A beta-hemolytic streptococcus was associated with the disease, but recent evidence indicates non-A streptococci groups are also involved. OBSERVATIONS:We describe the first reported case of streptococcal toxic shock-like syndrome caused by a group C strain in Italy. Prior to the disease, the patient, a 46-year-old man, had been in good health and had only a 3-day history of sore throat, low grade fever, vomiting, diarrhea, and myalgia before admission. Initially, diagnosis was based only on clinical evidence: shock, multiorgan failure, profound hypothermia, and no apparent signs of infection. Toxic cardiomyopathy was also present. RESULTS:Positive throat swab and blood culture confirmed a "definite case" following established criteria. Anamnesis showed a diagnosis of monoclonal gammopathy. Antibiotic treatment was begun immediately on admission of the patient, who was discharged 20 days later in good health. CONCLUSIONS:This case illustrates how an early diagnosis and prompt antibiotic therapy can determine a more favorable outcome.
Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related.
van Obbergh L,Vallieres Y,Blaise G
Journal of hepatology
BACKGROUND/AIMS:Although the cardiac output is increased in liver cirrhosis, some degree of cardiac failure could coexist as suggested by human investigations showing cardiac enlargement in cirrhosis and by animal studies describing a limited response to fluid loading in the cirrhotic rat. Endotoxemia induces similar hemodynamic changes during the septic shock. This septic cardiomyopathy has been attributed to an increased secretion of nitric oxide by the myocytes. In this study, we aimed to verify if cirrhotic cardiomyopathy was present in the rat with biliary cirrhosis, and if it could be related to abnormal nitric oxide secretion. METHODS:We therefore compared the coronary pressure, the systolic ventricular pressure and the peak rate of rise of the left ventricular pressure obtained from isolated hearts perfused with a modified Langendorff apparatus in control rats and in cirrhotic rats obtained by bile duct ligation. The variations occurring after inhibition of nitric oxide synthesis by the addition of NG monomethyl-L-arginine (10(-6)M) to the perfusing Krebs-Ringer solution were also studied in both groups. RESULTS:We found that the coronary pressure and the contractility of the cirrhotic hearts decreased significantly when compared to the controls. Inhibition of the nitric oxide synthesis increased those values significantly when the hearts were obtained from cirrhotic animals. This was not observed in the control group. CONCLUSIONS:Our data suggest that the cardiac modifications induced by the cirrhosis in the studied parameters are related to nitric oxide.
Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure: their relation to lesion site and beta-adrenergic receptor therapy.
Fukuchi M,Hussain S N,Giaid A
BACKGROUND:Recent reports have suggested that excessive amounts of endogenous NO may contribute to the myocardial dysfunction and injury in heart failure. In the present report, we investigate the cellular expression and activity of endothelial (eNOS) and inducible (iNOS) NO synthase in failing human hearts with special reference to the underlying lesion and drug therapy. METHODS AND RESULTS:Myocardial tissues were obtained from 28 failing human hearts with various pathogeneses and 4 nonfailing hearts as controls. Only weak or focal expression of both eNOS and iNOS was seen in ventricles of nonfailing hearts. In failing hearts, immunoreactivity and hybridization signals for eNOS were increased only in cardiac myocytes of subendocardial areas. Signals for iNOS in cardiac myocytes were consistently seen in heart failure of various pathogeneses and were apparent in both infarcted and noninfarcted regions of ischemic cardiomyopathy. Apparent signals for iNOS were also seen in infiltrating macrophages in infarcted regions of ischemic cardiomyopathy, myocarditis, and septic hearts. The expression of eNOS but not iNOS in the myocytes was intimately associated with beta-adrenergic therapy before the operation, being more abundant in patients on beta-blockers compared with diminished presence in patients on beta-agonists. In contrast to immunohistochemical data, iNOS activity was more variable than constitutive NOS activity and correlated significantly with the density of infiltrating macrophages. CONCLUSIONS:These results suggest that whereas increased eNOS and/or iNOS expression in failing cardiac myocytes may in general contribute to myocardial dysfunction, myocyte injury or death associated with inflammatory lesions may be caused in part by abundant iNOS expression within infiltrating macrophages rather than cardiac myocytes.
Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure.
Wong S C,Fukuchi M,Melnyk P,Rodger I,Giaid A
BACKGROUND:Chronic heart failure is associated with induction of secondary inflammatory mediators, including prostanoids. The latter exert diverse functional and morphological effects on cardiac myocytes. Induction of cyclooxygenase (COX), the enzyme responsible for generating prostanoids, requires activation of nuclear factor-kappaB (NF-kappaB). The aim of the present study was to determine the expression of COX-2 and activation of NF-kappaB in the failing human heart. METHODS AND RESULTS:Myocardial tissue from 27 patients with end-stage heart failure (various etiologies: ischemic heart disease, n=16; idiopathic dilated cardiomyopathy, n=10; and valvular heart disease, n=1), 2 septic patients, and 8 normal control subjects was immunostained with antisera to COX-2 and NF-kappaB. Western blotting was performed and showed high anti-COX-2 antibody specificity and the presence of COX-2 protein in the sample tissues. In situ hybridization and immunohistochemistry showed little or no expression of COX-2 and NF-kappaB in the control hearts. In contrast, there was abundant expression of COX-2 mRNA and protein in myocytes and inflammatory cells in areas of fibrotic scar compared with regions of normal morphology in all cases of heart failure, except the cases with sepsis, which showed an abundance of COX-2 throughout the myocardium. Sites of NF-kappaB activation were associated with those of COX-2 expression. CONCLUSIONS:We demonstrate induction of COX-2 and activation of NF-kappaB in the myocardium of failing human hearts. Induction of both molecules appears to be associated with the presence of inflammation and scar formation.
Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death.
Mungrue Imran N,Gros Robert,You Xiaomang,Pirani Asif,Azad Azar,Csont Tamas,Schulz Richard,Butany Jagdish,Stewart Duncan J,Husain Mansoor
The Journal of clinical investigation
Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.
Septic endocarditis and indwelling pulmonary artery catheters.
Greene J F,Fitzwater J E,Clemmer T P
A pulmonary artery catheter removed from a man with idiopathic cardiomyopathy yielded Staphylococcus aureus in culture, as did blood and sputum. Septic endocarditis of the right side of the heart was found at autopsy. A review of 438 autopsy reports in which an indwelling pulmonary catheter had been used and of another 493 reports preceding its use at our medical center suggests no association between the use of indwelling catheters in the right side of the heart and endocarditis in the left, although there is a risk of thrombotic endocardial vegetation formation in the right side of the heart, with possible infection or embolization.
Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.
Larche Jérome,Lancel Steve,Hassoun Sidi Mohamed,Favory Raphael,Decoster Brigitte,Marchetti Philippe,Chopin Claude,Neviere Remi
Journal of the American College of Cardiology
OBJECTIVES:The purpose of this study was to test whether mitochondrial dysfunction is causative of sepsis sequelae, a mouse model of peritonitis sepsis induced by cecal ligation and perforation. Inhibition of mitochondrial permeability transition was achieved by means of pharmacological drugs and overexpression of the antiapoptotic protein B-cell leukemia (Bcl)-2. BACKGROUND:Sepsis is the leading cause of death in critically ill patients and the predominant cause of multiple organ failure. Although precise mechanisms by which sepsis leads to multiple organ dysfunction are unknown, growing evidence suggests that perturbations of key mitochondrial functions, including adenosine triphosphate production, Ca2+ homeostasis, oxygen-derived free radical production, and permeability transition, might be involved in sepsis pathophysiology. METHODS:Heart and lung functions were evaluated respectively by means of isolated heart preparation, bronchoalveolar lavage fluid protein concentration, lung wet/dry weight ratio, lung homogenate myeloperoxidase activity, and histopathologic grading. Respiratory fluxes, calcium uptake, and membrane potential were evaluated in isolated heart mitochondria. RESULTS:Peritonitis sepsis induced multiple organ dysfunction, mitochondrial abnormalities, and increased mortality rate, which were reduced by pharmacological inhibition of mitochondrial transition by cyclosporine derivatives and mitochondrial Bcl-2 overexpression. CONCLUSIONS:Our study provides strong evidence that mitochondrial permeability transition plays a critical role in septic organ dysfunction. These studies demonstrate that mitochondrial dysfunction in sepsis is causative rather than epiphenomenal and relevant in terms of vital organ function and outcome. Regarding the critical role of heart failure in the pathophysiology of septic shock, our study also indicates a potentially new therapeutic approach for treatment of sepsis syndrome.
Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha.
Bryant D,Becker L,Richardson J,Shelton J,Franco F,Peshock R,Thompson M,Giroir B
BACKGROUND:Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-alpha secretion is, at least in part, cardiac myocytes. METHODS AND RESULTS:To determine the consequences of TNF-alpha production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-alpha coding sequence was driven by the murine alpha-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis. CONCLUSIONS:This is the first report detailing the effects of tissue-specific production of TNF-alpha by cardiac myocytes in vivo. These findings indicate that production of TNF-alpha by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.
A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.
Parrillo J E,Burch C,Shelhamer J H,Parker M M,Natanson C,Schuette W
The Journal of clinical investigation
We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.
Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis.
Ziegler Tilman,Horstkotte Jan,Schwab Claudia,Pfetsch Vanessa,Weinmann Karolina,Dietzel Steffen,Rohwedder Ina,Hinkel Rabea,Gross Lisa,Lee Seungmin,Hu Junhao,Soehnlein Oliver,Franz Wolfgang M,Sperandio Markus,Pohl Ulrich,Thomas Markus,Weber Christian,Augustin Hellmut G,Fässler Reinhard,Deutsch Urban,Kupatt Christian
The Journal of clinical investigation
Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.
Characterization of membrane N-glycan binding sites of lysozyme for cardiac depression in sepsis.
Jacobs Hans,Mink Steven N,Duke Krika,Bose Deepak,Cheng Zhao-Qin,Howlett Susan,Ferrier Gregory R,Light R Bruce
Intensive care medicine
PURPOSE:In sepsis, reversible myocardial depression has been ascribed to the release of mediators of inflammation. We previously found that lysozyme released from leukocytes from the spleen and other organs mediated myocardial depression in an Escherichia coli model of septic shock in dogs. We hypothesize that lysozyme binds to or cleaves a cardiac surface membrane N-glycoprotein to cause depression. The objectives of the present study were: 1) to determine whether the binding of lysozyme is reversible; 2) to assess the N-glycan structure to which lysozyme binds; 3) to examine whether nonenzymatic proteins, termed lectins, with a binding specificity similar to that of lysozyme could also cause depression; and 4) to assess whether the membrane to which lysozyme binds is affected by the enzymes protease type XIV and collagenase A, that are used to prepare single cell myocyte experiments. METHODS:We measured isometric contraction in a right ventricular trabecular preparation. RESULTS:We found that lysozyme binds in a reversible manner to the Man beta(1-4) GlcNAc beta(1-4)GlcNAc moiety in the tri-mannosyl core structure of high mannose/hybrid and tri-antennary carbohydrate classes where GlcNAc is N-acetylglucosamine and Man is mannose. Lectins with a specificity similar to that of lysozyme also caused depression, and lysozyme's depressant activity was eliminated by protease type XIV and collagenase A. CONCLUSIONS:These results indicate that lysozyme reversibly binds to a membrane glycoprotein to cause myocardial depression in sepsis. We further localize its binding site to a variant of the chitotriose structure in the tri-mannosyl core of the membrane glycoprotein.
Venoarterial extracorporeal membrane oxygenation to rescue sepsis-induced cardiogenic shock: a retrospective, multicentre, international cohort study.
Bréchot Nicolas,Hajage David,Kimmoun Antoine,Demiselle Julien,Agerstrand Cara,Montero Santiago,Schmidt Matthieu,Luyt Charles-Edouard,Lebreton Guillaume,Hékimian Guillaume,Flecher Erwan,Zogheib Elie,Levy Bruno,Slutsky Arthur S,Brodie Daniel,Asfar Pierre,Combes Alain,
Lancet (London, England)
BACKGROUND:Patients with sepsis-induced cardiomyopathy with cardiogenic shock have a high mortality. This study assessed venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for sepsis-induced cardiogenic shock refractory to conventional treatments. METHODS:In this retrospective, multicentre, international cohort study, we compared outcomes of 82 patients (aged ≥18 years) with septic shock who received VA-ECMO at five academic ECMO centres, with 130 controls (not receiving ECMO) obtained from three large databases of septic shock. All patients had severe myocardial dysfunction (cardiac index 3 L/min per m or less or left ventricular ejection fraction [LVEF] 35% or less) and severe haemodynamic compromise (inotrope score at least 75 μg/kg per min or lactic acidaemia at least 4 mmol/L) at time of inclusion. The primary endpoint was survival at 90 days. A propensity score-weighted analysis was done to control for confounders. FINDINGS:At baseline, patients treated with VA-ECMO had more severe myocardial dysfunction (mean cardiac index 1·5 L/min per mvs 2·2 L/min per m, LVEF 17% vs 27%), more severe haemodynamic impairment (inotrope score 279 μg/kg per min vs 145 μg/kg per min, lactataemia 8·9 mmol/L vs 6·5 mmol/L), and more severe organ failure (Sequential Organ Failure Assessment score 17 vs 13) than did controls, with p<0·0001 for each comparison. Survival at 90 days for patients treated with VA-ECMO was significantly higher than for controls (60% vs 25%, risk ratio [RR] for mortality 0·54, 95% CI [0·40-0·70]; p<0·0001). After propensity score weighting, ECMO remained associated with improved survival (51% vs 14%, adjusted RR for mortality 0·57, 95% CI [0·35-0·93]; p=0·0029). Lactate and catecholamine clearance were also significantly enhanced in patients treated with ECMO. Among the 49 survivors treated with ECMO, 32 who had been treated at the largest centre reported satisfactory Short Form-36 evaluated health-related quality of life at 1-year follow-up. INTERPRETATION:Patients with severe sepsis-induced cardiogenic shock treated with VA-ECMO had a large and significant improvement in survival compared with controls not receiving ECMO. However, despite the careful propensity-weighted analysis, we cannot rule out unmeasured confounders. FUNDING:None.
The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts.
Behrends Matthias,Peters Jürgen
Intensive care medicine
OBJECTIVE:Sepsis-evoked myocardial dysfunction is possibly due to decreased myofilament calcium sensitivity, and a calcium sensitizer may thus specifically improve contractility in sepsis by enhancing myofilament calcium sensitivity. We examined whether the calcium sensitizer levosimendan mitigates myocardial dysfunction and improves contractility in hearts isolated from endotoxin-treated guinea pigs. DESIGN AND SETTING:Prospective, controlled, randomized animal study in a university research laboratory. SUBJECTS:Guinea pig hearts isolated 4 h (n=10) or 18 h (n=8) following E. coli LPS (4 mg/kg i.p.) and hearts from sham-treated controls (n=11 and n=6). INTERVENTIONS:Isolated hearts were perfused at constant aortic pressure [Krebs-Henseleit buffer, heart rate: 300/min, left ventricular (LV) diastolic pressure: 6-8 mmHg], and LV developed pressure (LVd P) and LVd P/d t were continuously assessed. Levosimendan was added to the perfusate in incremental concentrations (0.03, 0.1, 0.3 microM). MEASUREMENTS AND RESULTS:Endotoxin resulted in a significant decrease in LVd P by 20+/-6% and 43+/-8%, in +LVd P/d t by 16+/-5% and 44+/-7%, and in -LVd P/d t by 27+/-8% and 47+/-8% after 4 and 18 h, respectively. In septic hearts levosimendan increased LV function concentration-dependently by 32+/-4% (LVd P), 33+/-5% (+LVd P/d t), and 37+/-7% (-LVd P/d t) 4 h and by 31+/-6% (LVd P), 33+/-6% (+LVd P/d t), and 32+/-7% (-LVd P/d t) 18 h after LPS. However, levosimendan increased myocardial function similarly in control hearts. CONCLUSIONS:While the calcium sensitizer levosimendan markedly improved LV contractility in hearts from both endotoxic and sham animals, it failed to specifically abolish endotoxin-evoked myocardial dysfunction. Thus, decreased calcium sensitivity either does not play a major role in endotoxin-evoked cardiomyopathy or the location of its pathomechanism differs from levosimendan's site of action.
Part 6: Pediatric Basic Life Support and Pediatric Advanced Life Support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.
de Caen Allan R,Maconochie Ian K,Aickin Richard,Atkins Dianne L,Biarent Dominique,Guerguerian Anne-Marie,Kleinman Monica E,Kloeck David A,Meaney Peter A,Nadkarni Vinay M,Ng Kee-Chong,Nuthall Gabrielle,Reis Amelia G,Shimizu Naoki,Tibballs James,Veliz Pintos Remigio,
Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function.
Drosatos Konstantinos,Pollak Nina M,Pol Christine J,Ntziachristos Panagiotis,Willecke Florian,Valenti Mesele-Christina,Trent Chad M,Hu Yunying,Guo Shaodong,Aifantis Iannis,Goldberg Ira J
RATIONALE:Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown. OBJECTIVE:To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara. METHODS AND RESULTS:We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels. CONCLUSIONS:Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.
Elevation of troponin I in sepsis and septic shock.
Ammann P,Fehr T,Minder E I,Günter C,Bertel O
Intensive care medicine
OBJECTIVE:To detect myocardial damage in severe systemic inflammation by cTnI measurements in patients without acute coronary syndromes. DESIGN:Prospective case control study. SETTING:Tertiary referral center. PARTICIPANTS:Twenty patients with sepsis, septic shock, and systemic inflammatory response syndrome (SIRS) were examined and compared to controls without coronary artery disease or myocarditis. MEASUREMENTS AND RESULTS:cTnI levels were assessed in patients with SIRS, sepsis, and septic shock. Eight patients (two female/six male) suffered from septic shock, nine (three female/six male) from sepsis without shock, and three (three male) from SIRS. Seventeen patients (85%) showed elevated cTnI (median 0.57 microg/l; 0.17-15.4), whereas no patient in the control group showed elevated cTnI (P < 0.0001). Six patients (30%),--three with septic shock and three with sepsis--died during hospitalization, five of them with elevated cTnI. Four out of five autopsies showed normal coronary arteries. Coronary angiography, autopsy, and stress echocardiography ruled out significant coronary artery disease in ten cTnI-positive patients (59%). In 41 % of cTnI-positive patients, Streptococcus pneumoniae could be cultured, whereas no cTnI-negative or control patient showed signs of infection due to S. pneumoniae. CONCLUSION:Cardiac troponin I was elevated in 85% of patients with sepsis, septic shock or SIRS in our study. A high percentage showed infection caused by S. pneumoniae. In what way microorganisms cause cTnI elevations is not yet understood.
Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide.
Mebazaa A,De Keulenaer G W,Paqueron X,Andries L J,Ratajczak P,Lanone S,Frelin C,Longrois D,Payen D,Brutsaert D L,Sys S U
BACKGROUND:In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits. METHODS AND RESULTS:Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2-related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482+/-14 versus 420+/-14 ms in the saline-treated group, P<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (P<0.01). CONCLUSIONS:Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.
Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.
Pathan Nazima,Hemingway Cheryl A,Alizadeh Ash A,Stephens Alick C,Boldrick Jennifer C,Oragui Emmanuelle E,McCabe Colm,Welch Steven B,Whitney Adeline,O'Gara Peter,Nadel Simon,Relman David A,Harding Sian E,Levin Michael
Lancet (London, England)
BACKGROUND:Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS:We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS:We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION:Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.
Novel therapies for septic shock over the past 4 decades.
Suffredini Anthony F,Munford Robert S
Infections that result in shock and organ failure are a major public health problem worldwide. Severe sepsis and septic shock affect patients of all ages and often complicate chronic diseases. They are the major causes of death in critical care units and contribute substantially to hospital inpatient costs. Translating the scientific advances of the last 4 decades into clinical practice has been challenging. Despite many attempts to develop new therapies, the basic elements of treatment have not changed since the 1960s. In this Grand Rounds, we summarize the results of the clinical trials conducted during the last 4 decades, discuss some lessons learned, and suggest possible directions for future investigation.
Pathophysiology of sepsis-induced cardiomyopathy.
Hollenberg Steven M,Singer Mervyn
Nature reviews. Cardiology
Sepsis is the life-threatening organ dysfunction caused by a dysregulated host response to infection and is the leading cause of death in intensive care units. Cardiac dysfunction caused by sepsis, usually termed sepsis-induced cardiomyopathy, is common and has long been a subject of interest. In this Review, we explore the definition, epidemiology, diagnosis and pathophysiology of septic cardiomyopathy, with an emphasis on how best to interpret this condition in the clinical context. Advances in diagnostic techniques have increased the sensitivity of detection of myocardial abnormalities but have posed challenges in linking those abnormalities to therapeutic strategies and relevant clinical outcomes. Sophisticated methodologies have elucidated various pathophysiological mechanisms but the extent to which these are adaptive responses is yet to be definitively answered. Although the indications for monitoring and treating septic cardiomyopathy are clinical and directed towards restoring tissue perfusion, a better understanding of the course and implications of septic cardiomyopathy can help to optimize interventions and improve clinical outcomes.