L-NMMA (a Nitric Oxide Synthase Inhibitor) is Effective in the Treatment of Cardiogenic Shock

Cotter, Gad; Kaluski, Edo; Blatt, Alex; Milovanov, Olga; Moshkovitz, Yaron; Salah, Ahmed; Alon, Daniela; Michovitz, Yoav; Metzger, Michael; Vered, Zvi; Golik, Ahuva

doi:10.1161/01.cir.101.12.1358

Cited by 123 publications

(63 citation statements)

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“…53 Indeed, preliminary studies in patients with refractory cardiogenic shock have shown improved hemodynamic status and survival with N G -monomethyl-L-arginine, a nitric oxide synthase inhibitor. 54 Considering their likely role in plaque destabilization and in vascular and myocardial remodeling, MMPs represent another potential therapeutic target. Inhibitors of MMPs are currently being investigated in acute MI, although it is unlikely that chronic, broad-spectrum MMP inhibitors will have a favorable tolerability profile.…”

Section: Treatment Of the Acs: Perspective On The Futurementioning

confidence: 99%

Pathophysiology of Coronary Artery Disease

2005

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Abstract-During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events. Key Words: atherogenesis Ⅲ inflammation Ⅲ ischemia Ⅲ plaque Ⅲ acute coronary syndromes D uring the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. As patients with CAD generally present with either chronic or acute manifestations, this discussion will consider in turn these distinct modes of presentation. The Pathophysiology of Chronic CAD Lesion FormationPreviously considered a cholesterol storage disease, we currently understand atherogenesis as a complex interaction of risk factors including cells of the artery wall and the blood and molecular messages that they exchange. A useful organizing theme, which emerged first from laboratory studies and has now gained currency in the clinic, accords inflammation a major role in all stages of atherogenesis. 1 Inflammation also participates in the local, myocardial, and systemic complications of atherosclerosis.When the arterial endothelium encounters certain bacterial products or risk factors as diverse as dyslipidemia, vasoconstrictor hormones inculpated in hypertension, the products of glycoxidation associated with hyperglycemia, or proinflammatory cytokines derived from excess adipose tissue, these cells augment the expression of adhesion molecules tha...

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Section: Treatment Of the Acs: Perspective On The Futurementioning

confidence: 99%

Pathophysiology of Coronary Artery Disease

2005

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“…11 Some preliminary clinical studies suggest that these hemodynamic effects may increase survival and decrease the need for support with intra-aortic balloon pumps and mechanical ventilation. 4,12,13 Despite evidence that NOS and NO play a role in CS, little is known about the levels of the NOS substrate arginine and its metabolites. Arginine availability may limit NO synthesis, particularly in cells expressing iNOS.…”

Section: Clinical Perspective P 2324mentioning

confidence: 99%

Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction

et al. 2007

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Background-It is unclear whether abnormalities of arginine and nitric oxide metabolism are related to hemodynamic dysfunction and mortality in patients with cardiogenic shock (CS) after acute myocardial infarction. Methods and Results-Plasma metabolites reflecting arginine bioavailability, nitric oxide metabolism, and protein oxidation were analyzed by mass spectrometry in patients with CS (nϭ79) and age-and gender-matched patients with coronary artery disease and normal left ventricular function (nϭ79). CS patients had higher levels of asymmetric dimethylarginine (ADMA; PϽ0.0001), symmetric dimethylarginine (PϽ0.0001), monomethylarginine (Pϭ0.0003), nitrotyrosine (PϽ0.0001), and bromotyrosine (PϽ0.0001) and lower levels of arginine (PϽ0.0001), ratio of arginine to ornithine (Pϭ0.03), and ratio of arginine to ornithine plus citrulline) (Pϭ0.0003). CS patients with elevated ADMA levels were 3.5-fold (95% confidence interval, 1.4 to 11.3; Pϭ0.02) more likely to die in 30 days than patients with low ADMA levels. ADMA remained the only independent predictor of mortality on multiple logistic regression analysis. In patients with normal renal function, symmetric dimethylarginine levels inversely correlated with mean arterial pressure and systemic vascular resistance, whereas levels of ADMA correlated with pulmonary capillary wedge pressure and both systolic and diastolic pulmonary artery pressures. Despite dramatic elevations, levels of protein oxidation products did not predict hemodynamic dysfunction or mortality in CS patients. Conclusions-CS is characterized by an arginine-deficient and highly specific pro-oxidant state, with elevated levels of methylated arginine derivatives, including endogenous nitric oxide synthase inhibitors. Levels of methylated arginine derivatives strongly correlate with hemodynamic dysfunction. Among all clinical and laboratory parameters monitored, ADMA levels were the strongest independent predictor of 30-day mortality.

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“…Pathophysiological observations and hemodynamic end-point studies suggested that a novel nitric oxide synthase Dauerman Death, Shock, and Aortic Stenosis 1443 inhibitor, tilarginine, would clearly be superior to standard therapy for patients with acute myocardial infarction complicated by cardiogenic shock. 8 When an international, multicenter, mortality-driven trial was performed, the surrogate end points proved useless, and tilarginine had no effect on mortality. 9 Similarly, the superiority of TAVR seems clear retrospectively, but the benefit was much less clear to patients and investigators during the trial.…”

Section: Interventional Cardiology Trials and Deathmentioning

confidence: 99%