Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure

Böhm, M.; Kirchmayr, Rita; Gierschik, Peter; Erdmann, E

doi:10.1016/0300-9572(95)99859-9

Cited by 16 publications

(19 citation statements)

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“…Increased expression of Gi␣ proteins was also observed in human diseased heart and in numerous animal models of heart failure. [37][38][39][40][41][42] These data suggest that elevated Gi␣ signaling and negative regulation of PKA in heart is a common feature associated with the onset of heart failure. However, most of the studies focused on the Gi␣2 and Gi␣3 subunits.…”

Section: Discussionmentioning

confidence: 89%

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

et al. 2007

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Background-Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear. Methods and Results-Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf-mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca 2ϩ defects, and loss of protein kinase A-dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G␣ inhibiting subunit 1 (Gi␣1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals. Conclusions-These data suggest that selective induction of G␣ inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy. Key Words: hypertrophy Ⅲ cardiomyopathy Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ signal transduction H ypertrophic cardiomyopathy is the most common form of heart disease caused by genetic mutations of cardiac proteins, whereas left ventricular hypertrophy can be caused by mechanical overload associated with hypertension and valvular disease. Both may be characterized by myocyte hypertrophy, interstitial fibrosis, and induction of fetal gene expression. [1][2][3][4] Both the genetic and acquired forms of cardiac hypertrophy are risk factors for sudden cardiac death associated with electrophysiological remodeling and resultant cardiac arrhythmias. [5][6][7][8] Investigation of the underlying mechanisms of these manifestations has been the main focus of the field in recent years. Clinical Perspective p 605Ventricular arrhythmias are the most common cause of sudden cardiac death in hypertrophic cardiomyopathy and other cardiac diseases, including heart failure. 9 -11 Abnormal conduction and heterogeneous action potential propagation are the main causes of reentrant arrhythmias in ischemic hearts. In contrast, triggered arrhythmias caused by early or delayed afterdepolarizations are thought to be a major cause of ventricular arrhythmias in nonischemic cardiomyopathies. 12 Although prolonged action potential duration (APD), repressed outward K ϩ currents, and increased sodium...

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Section: Discussionmentioning

confidence: 89%

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

et al. 2007

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“…Importantly, there seems to be significant disruption of the myocardial signal transduction following β-adrenoceptor stimulation. Endotoxemic rabbits displayed decreased levels of stimulatory G-proteins (90), and septic rats exhibited increased expression of inhibitory G-protein (91), which was also reported in the myocardium of human nonsurvivors of septic shock (92). These events are likely to decrease the activity of the adenylyl cyclase, resulting in decreased intracellular levels of cyclic adenosine monophosphate (cAMP), paralyzing the cardiomyocyte.…”

Section: β-Adrenergic Receptorsmentioning

confidence: 89%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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“…Early sepsis is characterized by high levels of circulating catecholamines [20,60,61] that derive from the autonomous nervous system, the gut [62], lymphocytes [63,64] macrophages [65] and neutrophils [66,67]. A major mechanism of sepsis-induced cardiac dysfunction is the attenuation of the adrenergic response at the cardiomyocyte level due to down-regulation of β-adrenergic receptors [68,69] and depression of post-receptor signaling pathways [70][71][72][73]. These changes are mediated by cytokines [74,75] and nitric oxide [76,77].…”

Section: Underlying Mechanismsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure

Cited by 16 publications

References 0 publications

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

Molecular Events in the Cardiomyopathy of Sepsis

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

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