5 Steps to prevent Heart Disease

Sunday, May 13, 2018

Statins save lives by it's anti-coagulation








Crestor 2017 Pleiotrophic effects

"Thanks to its non-cholesterol-lowering actions 
1-anti-inflammatory, 
2-antioxidant and 
3-antithrombotic

 represents a crucial tool for cardiovascular primary and secondary prevention.
 Moreover, recent data highlight rosuvastatin beneficial effects in several other fields"


Pleiotrophic effects of Niacin 2016

 "Moreover, niacin causes favorable changes to
 the qualitative composition of lipoprotein HDL. 

In addition to its pronounced hypolipidemic action, 
niacin exerts many other, non-hypolipidemic effects 

1- antioxidative, 

2-anti-inflammatory, 

3-anti-thrombotic, 

which favorably influence the development and progression of atherosclerosis.

 These effects are dependent on activation of the specific receptor HCA2.
 Recent results published by the two large clinical studies,
1- AIM-HIGH and 

2-HPS2-THRIVE,

 have led to the impugnation of niacin's role in future clinical practice. 

However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. 

This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.


Zetia pleiotropic effects 2017


CONCLUSIONS:

The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect compared with statin monotherapy.
 Owing to the emerging role of TNF-α in the pathogenesis of metabolic disorders, further investigations are required to unveil the translational relevance of this TNF-α-lowering effect.

Pleiotropic effect of PCSK9 2016


Treatment with statins is the standard of care for individuals at increased risk for cardiovascular disease and has been shown to significantly reduce cardiovascular events across a wide range of pretreatment low-density lipoprotein (LDL) cholesterol levels and cardiovascular risk.
 Further lowering of LDL cholesterol (LDL-C) by adding ezetimibe to statin provides incremental benefit, but event rates among such optimally treated patients remain high.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease that is secreted by the liver, binds to the LDL receptor, and directs the LDL receptor toward lysosomal degradation. 
Decreased availability of LDL receptors on the cell surface leads to decreased cellular LDL-C uptake and higher plasma LDL-C levels.
 The observation that PCSK9 loss-of-function mutations are associated with lifelong lower LDL-C levels and markedly decreased cardiovascular risk 
led to the development of monoclonal antibodies to PCSK9 that lower LDL-C by increasing LDL receptor expression on the cell surface and enhancing LDL-C clearance from plasma. 
These agents achieve LDL-C reductions of ≥50% to 60%, whether administered alone or in combination with a statin.1 Total LDL particle number, number of small and large LDL particles, and apoprotein B levels are similarly reduced.
Exploratory post hoc analyses of trial data with the 2 US Food and Drug Administration-approved agents (alirocumab and evolocumab) show reductions in cardiovascular events but await confirmation in large outcomes trials.
Investigations in animals and humans suggest that the impact of PCSK9 inhibition 
is not limited to reduction in LDL-C but also: 
1-lipoprotein metabolism,
 2-inflammation, 
3-thrombosis, and 
4-immune function.
Lp(a) (Lipoprotein (a)), an apoprotein B containing LDL-like particle with an apo(a) moiety attached, is believed to increase risk of cardiovascular events through
1- prothrombotic and 
2-proatherosclerotic mechanisms.
 Nicotinic acid (NIACIN), estrogens, and apheresis lower Lp(a) levels, but trials to date have not demonstrated cardiovascular event reduction with these measures.
 Large randomized trials specifically focused on individuals with high Lp(a) are lacking. 
PCSK9 inhibitors lower Lp(a) by as much as 30%
with greater absolute reductions in Lp(a) levels among individuals with the highest baseline levels of Lp(a).
 Proposed mechanisms include decreased synthesis of Lp(a) because of decreased apoprotein B availability and increased LDL receptor mediated Lp(a) clearance in the setting of low LDL-C levels. 
Notably, the lack of functional LDL receptors 
in homozygous familial hypercholesterolemia is not
 associated with lower efficacy of PCSK9 inhibitors on Lp(a) reduction.2
Triglyceride levels are associated with increased cardiovascular risk in
 population-based studies and among patients treated with high-intensity statins. 
Atherogenicity of triglyceride-rich lipoproteins has been demonstrated
 in vitro and in animal and human studies. 
Treatment with alirocumab and evolocumab has been shown to significantly reduce triglyceride-rich lipoproteins, possibly through enhanced clearance by LDL receptors and/or very low density lipoprotein receptors or by lowering production of triglyceride-rich lipoproteins.1 Effects on postprandial lipemia have been inconsistent.
PCSK9 (not the drug which is (PCSK9 inhibitor) serum levels are related to severity of coronary atherosclerosis and cardiovascular events independent of LDL-C levels.
 PCSK9 levels increase as a consequence of myocardial ischemia. 
PCSK9 is found in the arterial wall, exerts proinflammatory effects, and may relate to plaque composition and vulnerability.3 
A recent intravascular ultrasound study suggests that PCSK9 levels, independent of LDL-C levels or statin treatment, are correlated with necrotic core volume in nonculprit lesions assessed among patients with acute coronary syndrome.4
 Whether treatment with PCSK9 inhibitors could directly decrease plaque vulnerability and modify the course of acute coronary syndromes by modulating the systemic and arterial proinflammatory and prothrombotic environments is under investigation.
PCSK9 also appears to have a significant role in immune function, including antiviral and antimalarial properties.
 Concerns about increased susceptibility to hepatitis C infection in particular have not materialized in clinical trials to date. A recent study in mice suggested improved outcomes in septic shock with PCSK9 inhibition, believed to be mediated by enhanced removal of pathogen-related lipids through the LDL receptor mechanism. Retrospective analyses of outcomes among PCSK9 loss-of-function and gain-of-function gene carriers in 2 cohorts of patients with septic shock replicated these results, with better survival among carriers of loss-of-function gene variants and worse outcomes among those with gain-of-function variants.5


Monoclonal PCSK9 antibodies lower LDL-C and other atherogenic lipoproteins and seem to favorably affect the complex inflammatory and thrombotic mechanisms related to atherosclerosis progression and acute events. 
The potential effects on survival in sepsis are also intriguing.
 In the case of statins, pleiotropic effects appear to play at most a minor role in the observed cardiovascular benefits. 
Whether the pleiotropic effects of PCSK9 inhibitors will translate into morbidity and mortality benefits remains to be determined, and we do not know whether these effects differ between agents. 
The role of PCSK9 in extrahepatic tissues, in particular, is incompletely understood. 
Broad effects of PCSK9 inhibitors on multiple physiological systems come with concerns about the potential for unintended effects. To date, there has not been a significant safety signal in completed and ongoing trials of the available PCSK9 inhibitors, but ongoing surveillance will be essential as these agents are introduced to less-selected populations and used over extended time periods."


Pleiotrophic effects of statins. 2005

Statins for Deep Vein Thrombosis 

Statins anti-coagulant effect evidence not strong enough for indication 2017






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