O167 Addition of Simvastatin to Standard Treatment Improves Survival After Variceal Bleeding in Patients With Cirrhosis. A Double-Blind Randomized Trial (Nct01095185)

Abraldes, J.G.; Villanueva, C.; Aracil, Carlos Ferre; Turnés, Juan; Hernandez-Guerra, Manuel; Genescà, Joan; Navascués, C.A.; Castellote, José; Calleja, J.L.; Albillos, A.; Bosch, J.

doi:10.1016/s0168-8278(14)61462-8

Cited by 15 publications

(15 citation statements)

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“…Statins may further improve liver fibrogenesis in cirrhosis [38]. Preliminary results from a double-blind randomized controlled trial suggest a survival benefit in advanced stages when simvastatin is administered on top of currently available treatments [95]. The possibility of improving portal hypertension by modifying the microbioma, endotoxaemia, and its consequences is also close to clinical application.…”

Section: Areas For the Future And New Avenues For Researchmentioning

confidence: 99%

Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments

Bosch

Groszmann

Shah

2015

Journal of Hepatology

208

187

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Summary Among the common complication of cirrhosis portal hypertension witnessed a major improvement of prognosis during the past decades. Principally due to the introduction of rational treatments based on new pathophysiological paradigms (concepts of thought) developed in the 1980s. The best example being the use of non-selective beta-blockers and of vasopressin analogs, somatostatin, and its analogs. Further refinement in the knowledge of the molecular mechanisms involved in the regulation of both the splanchnic and hepatic circulation has led to the emergence of new treatments, which are based on evidence that show not only structural but also vasoactive components increase the hepatic vascular resistance, as well as of angiogenesis. This knowledge and future improvements will most likely result in more effective treatment of portal hypertension and effective prevention of its complications in early stages.

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Section: Areas For the Future And New Avenues For Researchmentioning

confidence: 99%

Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments

Bosch

Groszmann

Shah

2015

Journal of Hepatology

208

187

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“…3 Underlying mechanisms of recently described therapeutic strategies to improve the microvascular dysfunction of cirrhotic livers. AA arachidonic acid pathway, BH 4 tetrahydrobiopterin, DDAH dimethylarginine-dimethylaminohydrolase, eNOS endothelial nitric oxide synthase, HSC hepatic stellate cells, KLF2 kruppel-like factor 2, LSEC liver sinusoidal endothelial cells, NF-kB nuclear factor kappalight-chain-enhancer of activated B cells, NO nitric oxide, Nrf2 nuclear factor (erythroid-derived 2)-like 2, OA obeticholic acid, ROS radical oxygen species, TGFb transforming growth factor beta, VEGF vascular endothelial growth factor Hepatol Int effective in improving portal hypertension [68], and more recently, the protective effects of long-term simvastatin administration against portal hypertensionderived complications have also been proved [69].…”

Section: Arachidonic Acid-derived Vasoconstriction Can Bementioning

confidence: 99%

New cellular and molecular targets for the treatment of portal hypertension

et al. 2015

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Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.

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“…Finally, the cirrhotic LSEC phenotype can be efficiently improved by administering statins, especially simvastatin, which upregulate the expression and activity of the transcription factor KLF2 conferring a vasoprotective phenotype to the hepatic endothelium [26,47,55,56]. Remarkably, in a randomized controlled trial, simvastatin has been demonstrated to be effective in improving portal hypertension [57] and, more recently, the protective effects of long-term simvastatin administration against portal hypertension-derived complications have also been proven [58]. …”

Section: Rational Basis Of Therapymentioning

confidence: 99%

Pathophysiology and a Rational Basis of Therapy

Gracia‐Sancho

Maeso‐Díaz

Bosch

2015

Dig Dis

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Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A₂, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to b...

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O167 Addition of Simvastatin to Standard Treatment Improves Survival After Variceal Bleeding in Patients With Cirrhosis. A Double-Blind Randomized Trial (Nct01095185)

Cited by 15 publications

References 0 publications

Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments

Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments

New cellular and molecular targets for the treatment of portal hypertension

Pathophysiology and a Rational Basis of Therapy

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