Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock

Investigators, Triumph; Alexander, John H.; Reynolds, Harmony R.; Stebbins, Amanda; Džavík, Vladimir; Harrington, Robert A.; Werf, Frans Van de; Hochman, Judith S.

doi:10.1001/jama.297.15.joc70035

Cited by 342 publications

(97 citation statements)

References 22 publications

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“…I had proposed a slightly extended Warburg effect which I would 38 like to call it as 'Warburg common pathogenesis model or Warburg differentiation dedifferentiation 39 effect', which has the potential to explain septic shock and sepsis associated multi-organ dysfunction 40 and many other major pathologies like SHT, PAH, CHF, DM, Asthma, ARDS, AKI implying most 41 of the diseases may have a common pathogenesis as the underlying mechanism. 42 Increased Nitric oxide (NO) in sepsis via iNOS or any respiratory poison in general irreversibly 43 inhibits the mitochondrial respiration and shifts the metabolic phenotype of the cell from oxidative 44 phosphorylation (OXPHOS) to glycolytic phenotype and the change in metabolic phenotype is 45 followed by the change in cell phenotype from the normal adult dynamic differentiation state to 46 irreversible dedifferentiation states -embryonic phenotype, synthetic / proliferative phenotype, and 47 cancer phenotype. This dedifferentiated state switching can be seen as the cells local survival 48 strategy in response to injuries, but returning to their primitive forms leads to disorder and ends in 49 global collapse of the organ systems and organism which requires order in terms of differentiation.…”

Section: Abstract: 36mentioning

confidence: 99%

“…198 Nitric oxide role in septic shock is an extensively researched area, reviewed in (43,44). An early 199 hypotension and late hypotension has been already shown in sepsis, initial phase is considered to be 200 due to increased eNOS activity and late hypotension is considered to be due to iNOS action (41, 201 42).Inhibition of iNOS has been tried as a treatment option for shock ,eventhough NOS inhibitors 202 were successful in animal studies, TRIUMPH trial conducted using nonspecific NOS inhibitor 203 tilarginine in cardiogenic shock in humans didn't showed beneficial effect, also it showed it may be 204 harmful (45). Many thought the reason for failure may be due to the nonspecific inhibition of NOS 205 and selective iNOS inhibition with eNOS restoration may be beneficial (46,47).…”

Section: Warburg Common Pathogenesis Model In Sepsis (Figure 2): 173mentioning

confidence: 99%

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Fundamental role of Warburg effect in various pathophysiological processes

Natesan¹

2017

Preprint

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Even though high NO via iNOS was involved in most of the pathologies including sepsis, any 56 substance that inhibits or uncouples the mitochondrial respiration can initiate this Warburg effect 57 and irreversible dedifferentiation. A mild and reversible Warburg differentiation dedifferentiation 58 effect may be necessary for normal functioning and the same effect in exaggerated and irreversible 59 way leading to irreversible dedifferentiation states may be the underlying mechanism in most of the 60 diseases including septic shock. 61 62 Keywords: Septic shock, Warburg effect, dedifferentiation, differentiation therapy, ascorbic acid, 63 adrenergic blockers, glycolysis. 64Abbreviations : systemic hypertension(SHT), pulmonary arterial hypertension (PAH),congestive 65 heart failure (CHF), acute kidney injury(AKI),acute respiratory distress syndrome(ARDS),diabetes 66 mellitus(DM),inducible nitric oxide synthase (iNOS) . 67 68 69 70 INTRODUCTION: 71This review article tries to show the fundamental role played by Warburg effect in most of the 72 pathologies. Warburg common pathogenesis model is proposed to show the common underlying 73 mechanism in most of the pathologies and septic shock was used as the base model. 74Sepsis is the harmful systemic response of the host to the infection (1). According to Lewis Thomas 75 the host's response to pathogen is more detrimental than the pathogen itself (2). Septic shock and 76 severe sepsis associated multi-organ dysfunction carries high mortality rate ~ 40 -70% (3,4). 77Septic shock is refractory to the vasopressors in most of the cases; this includes norepinephrine, the 78 primary drug used in reviving blood pressure in septic shock. Vascular hypo reactivity to various 79 vasopressors in septic shock has been studied extensively, many reviews are available (5,86). 80Irrespective of advances in this field, exact underlying mechanism behind septic shock is still a 81 mystery. Post mortem studies couldn't find the underlying cause in most of the cases, surprisingly 82 most of the organs looked normal (6).Lot of treatment options which were successful in animal 83 models were failed to show benefit in human studies, ranging from Nitric oxide Synthase (NOS) 84Inhibitors, Cyclooxygenase (COX) Inhibitors, endotoxin neutralizing proteins, TNF alpha 85 antagonists etc.., (3). Some of the recent promising directions include, counterintuitive use of 86 antihypertensive in septic shock -alpha2 adrenergic receptor agonists -clonidine (7-9), beta 87 blockers reviewed in (10, 11) -aimed to reduce the sympathetic hyper activation and hyper 88 metabolism associated with sepsis. Alpha2 AR antagonist also has been shown to improve survival 89 in sepsis animal model (12). Vitamin C has been used in sepsis reviewed in (13), Glycolysis 90 inhibitor shikonin (14), cytochrome C (15) and Caffeine (16). 91 Warburg common pathogenesis model has been proposed in this review article to explain the role of 92Warburg effect in most of the pathologies using septic shock as the base model. The model was 9...

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Section: Abstract: 36mentioning

confidence: 99%

Section: Warburg Common Pathogenesis Model In Sepsis (Figure 2): 173mentioning

confidence: 99%

Fundamental role of Warburg effect in various pathophysiological processes

Natesan¹

2017

Preprint

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“…However, with advances in coronary reperfusion techniques over the past few decades, especially with the introduction of primary percutaneous percutaneous coronary intervention, the mortality rate has improved to below 50% 4,[6][7][8][9][10][11][12] . The trend toward better outcomes may also be due to greatly awareness of the need for timely treatment, improvements in the medical care of haemodynamically unstable patients as well as the use of mechanical support devices, though this has not yet been clearly demonstrated.…”

Section: Incidence and Prognosis Of Cardiogenic Shockmentioning

confidence: 99%

Primary Angioplasty For Patients in Cardiogenic Shock: Optimal Management

Joseph¹,

Patterson²,

Arri³

et al. 2016

Interventional Cardiology Review

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Abstract:Cardiogenic shock complicates approximately 5-10% of all myocardial infarction and remains the most common cause of death amongst these patients. Over the past few decades, the mortality associated with cardiogenic shock has improved with the introduction of early revascularization although there is limited data in patients with triple-vessel disease and left main stem disease. In more recent years, there have been a number of advances in the mechanical circulatory support devices that can help improve the haemodynamics of patients in cardiogenic shock. Despite these advances, together with progress in the use of inotropes and vasopressors, cardiogenic shock remains associated with a high morbidity and mortality. This review will outline the management of cardiogenic shock complicating acute myocardial infarction with major focus on revascularization techniques and the use of mechanical circulatory support devices.

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“…5 However, with advances in coronary reperfusion techniques over the past few decades, especially with the introduction of primary percutaneous coronary intervention (PCI), the mortality rate has improved to below 50 %. 4,[6][7][8][9][10][11][12] The trend towards better outcomes may also be due to greater awareness of the need for timely treatment, improvements in the medical care of haemodynamically unstable patients as well as the use of mechanical support devices, although this has not yet been clearly demonstrated.Despite this high mortality rate, it is important to note that patients with cardiogenic shock who survive to discharge have a long-term outcome similar to that of patients without cardiogenic shock, with a good functional outcome at 1 year. 13,14 This highlights the importance of improving the chance of early survival among patients in cardiogenic shock.…”

mentioning

confidence: 99%

Primary Angioplasty For Patients in Cardiogenic Shock: Optimal Management

Joseph¹,

Patterson²,

Arri³

et al. 2016

Interventional Cardiology Review

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CoronaryCardiogenic shock is a clinical condition of inadequate end-organ perfusion due to cardiac dysfunction (see Table 1). It most commonly occurs in the setting of acute MI with left ventricular failure (~80 % cases), 1,2 but can also be caused by right ventricular infarction or late mechanical complications, such as acute mitral regurgitation or ventricular rupture (septal or free wall). Non-infarct-related cardiogenic shock is comparatively rare, and may result from decompensated valvular heart disease and arrhythmias, to name a few mechanisms.The pathophysiology of cardiogenic shock is complex. Myocardial ischaemia induces marked depression of myocardial contractility, this sets into motion a downward spiral of reduced cardiac output and hypotension, which in turn drives further myocardial ischaemia. Incidence and Prognosis of Cardiogenic ShockCardiogenic shock complicates 5-10 % of acute MI cases, and despite advances in acute care there remains the same incidence (~60,000-70,000 patients per year in Europe). 2,4 Historically, MI complicated by cardiogenic shock was associated with a mortality rate of 80-90 %. 5 However, with advances in coronary reperfusion techniques over the past few decades, especially with the introduction of primary percutaneous coronary intervention (PCI), the mortality rate has improved to below 50 %. 4,[6][7][8][9][10][11][12] The trend towards better outcomes may also be due to greater awareness of the need for timely treatment, improvements in the medical care of haemodynamically unstable patients as well as the use of mechanical support devices, although this has not yet been clearly demonstrated.Despite this high mortality rate, it is important to note that patients with cardiogenic shock who survive to discharge have a long-term outcome similar to that of patients without cardiogenic shock, with a good functional outcome at 1 year. 13,14 This highlights the importance of improving the chance of early survival among patients in cardiogenic shock. Management Myocardial ReperfusionThere is evidence that the high mortality rates associated with cardiogenic shock have improved over time. 7,9,11,15,16 This benefit is thought to be due to increased use of coronary revascularisation strategies, which, by restoring flow to the ischaemic myocardium, can limit infarct size as well as interrupt the downward spiral that characterises cardiogenic shock. 7,9,15 As such, the cornerstone of the management of cardiogenic shock complicating acute MI is prompt revascularisation, as highlighted in AbstractCardiogenic shock complicates approximately 5-10 % of all MI events and remains the most common cause of death among MI cases. Over the past few decades, the mortality rate associated with cardiogenic shock has decreased with the introduction of early revascularisation, although there are limited data for patients with triple-vessel disease and left main stem disease. In more recent years, there have been a number of advances in the mechanical circulatory support devices that can help improv...

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Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock

Cited by 342 publications

References 22 publications

Fundamental role of Warburg effect in various pathophysiological processes

Fundamental role of Warburg effect in various pathophysiological processes

Primary Angioplasty For Patients in Cardiogenic Shock: Optimal Management

Primary Angioplasty For Patients in Cardiogenic Shock: Optimal Management

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