Sometimes I really despair. A few days ago I heard on the radio one of the world leading, great South African medical academics state categorically that cholesterol has no relation to cardiovascular disease. This message was transmitted to perhaps hundreds of thousands listeners around Cape Town, South Africa and maybe the world.
Bearing in mind death and disability from cardiovascular disease is the world leader of destruction I was understandably concerned.
I had planned on moving straight ahead with “Optimal Medical Therapy” (OMT) in prevention of cardiovascular disease and in the aggressive management of those individuals who have already expressed the disease, but now I’m forced to provide a history lesson for OMT will not make sense if you are a “cholesterol sceptic”.
Actually the number of cholesterol sceptics across the world is high (just google this to be sure) and added to the “statin sceptics” we have the basis for a serious conspiracy theory. So please bear with me and take time (really take time) to read the following:
What we know about atherosclerosis – a 200 year adventure:
Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium.
It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immuno-inflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor play a critical role.
The earliest visible lesion in the development of atherosclerosis is the fatty streak. This comprises an area of intimal thickening composed of macrophages distended by lipid droplets (known as foam cells), lymphocytes, and smooth muscle cells. Plaques develop as a result of the accumulation of oxidised low-density lipoproteins (oxLDL) in the subendothelial space, followed by the diapedesis of leukocytes and formation of foam cells, proliferation of smooth muscle cells, and production of connective tissue. The landmark work of Seymour Glagov showed that the arterial wall can remodel itself in response to plaque growth by increasing its external diameter to accommodate the plaque without narrowing of the lumen. Thrombosis is the ultimate stage in the disease process that is responsible for clinically observable adverse events implicating coronary, cerebrovascular, and peripheral vascular beds. Studies indicate that in patients with atherothrombotic disease plaque formation is likely to be widespread throughout the vasculature, often affecting more than one vascular bed (systemic inflammatory disease).
More than 200 year historical perspective:
Even though atherosclerosis is reaching epidemic proportions nowadays, it is not in any way a disease specific to the modern times; it was already present in antiquity. Sir Marc Ruffer was able to identify in 1911 degenerative arterial changes suggestive of atherosclerosis in the left subclavian artery from an Egyptian mummy.
According to the historian J. O. Leibowitz, the Italian surgeon and anatomist Antonio Scarpa (1752-1832) was the first to present a pathological description of arterial wall degeneration in full detail. In his 1804 monograph on aneurysms, Scarpa opposed the view that a dilatation of the aorta was the intrinsic cause of an aneurysm leading to rupture. He emphasizes that “… especially the internal coat is subject, from slow internal cause, to an ulcerated and steatomatous (fatty) disorganization, as well as to a squamous and earthy rigidity and brittleness,” introducing the concept of an underlying metabolic disorder in the process of atherosclerosis, rather than the theory of inflammation that already prevailed at that time, the expression “heart abscess” being frequently used to describe heart pathology.
The term atheroma, derived from Greek and meaning “porridge,” was first proposed by Albrecht von Haller in 1755 to designate the degenerative process observed in the intima of arteries. London surgeon Joseph Hodgson (1788-1869) published in 1815 his Treatise on the Diseases of Arteries and Veins in which he claimed that inflammation was the underlying cause of atheromatous arteries. But thereafter, most of pathologists of the 19th century following Carl Rokitanski (1804-1878) abandoned the view that inflammation was an etiological factor and considered that atherosclerosis was a degenerative process, with intimal proliferation of connective tissue and calcification, best described by the term arteriosclerosis proposed in 1833 by French pathologist Jean Lobstein (1777-1835).
However, German pathologist Rudolf Virchow (1821-1902), a leading authority of his day in pathology and the greatest contributor to the notion of thrombosis, considered atheroma as a chronic inflammatory disease of the intima, that he called “chronic endarteritis deformans”. In his opinion, the accumulation of lipids was a late manifestation of atheroma. Finally, the Leipzig pathologist Marchand in 1904 first used the term atherosclerosis, which since has been widely adopted, instead of arteriosclerosis, to designate the degenerative process of the intimal layer of the arteries.
Until the beginning of the 20th century, the theories put forward to explain the pathogenesis of atherosclerosis remained purely descriptive and were based on the anatomical observation of human atherosclerotic vessels. A first revolution in the mechanistic assessment of atherosclerosis was initiated in 1908 when the Russian scientist Alexander Ignatowski showed that experimental atherosclerosis could be induced in rabbits by feeding them a diet of milk and egg yolk.
Nikolai N. Anichkov (1885-1964) demonstrated the role of cholesterol in the development of atherosclerosis. His classic experiments in 1913 paved the way to our current understanding of the role of cholesterol in cardiovascular disease. Anichkov’s research is often cited among the greatest discoveries of the 20th century.
Recognition of Anichkov’s Theory of Atherosclerosis:
Apparently, the only reference to Anichkov’s theory of atherosclerosis in the English-language medical literature before 1950 was a chapter written by Anichkov for the 1st edition of Cowdry’s Arteriosclerosis (1933). A similar chapter appeared in the 2nd edition of the book, published in 1967. Anichov’s work on coronary atherosclerosis was published in Circulation in 1964. However, worldwide recognition of Anichkov’s early experiments probably came in 1950 after publication of a paper by Dr. John Gofman and his associates in Science. Gofman began by emphasizing that it was Anichkov who first discovered that feeding cholesterol to rabbits promptly led to atherosclerosis. Using Anichkov’s technique, Gofman’s group had confirmed that Anichkov was correct. Then they did something that Anichkov could not have done in 1912-they developed and used a ultracentrifuge capable of rotating its tubes 40,000 times per minute. The hypercholesteremic serum samples of their cholesterol-fed rabbits were centrifuged and then sequestered into 2 distinct compartments. The 1st fraction was designated low-density lipoprotein (LDL) cholesterol, because it floated toward the surface of the serum sample. The 2nd fraction was deposited at the bottom and was designated high-density lipoprotein (HDL)cholesterol. Gofman’s group showed further that low-density lipoprotein cholesterol is responsible for the rapid progression of atherosclerosis in animals.
The next significant leap only came during the 1970s when Brown and Goldstein showed that the LDL receptor that they had discovered, a cell surface protein that binds LDL and removes them from blood is not involved in macrophage foam-cell formation and proposed that a macrophage receptor that recognized acetylated LDL plays a key role in this process.
Subsequently, during the 1980s, the central role of oxidised LDL cholesterol (oxLDL) in the pathogenesis of atherosclerosis was exposed by Daniel Steinberg and his group, and a number of scavenger receptors mediating their uptake by macrophages were identified. The model of the Watanabe heritable hyperlipidemic (WHHL) rabbit, introduced in 1980 was particularly useful in establishing the role of oxLDL in atherogenesis. A second revolution occurred at the beginning of the 1990s when mouse models of atherosclerosis, apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice, were derived by homologous recombination techniques. In contrast to the previous models, mice lacking functional apoE or LDLr genes were shown to develop widely distributed arterial lesions that progress from foam cell-rich fatty streaks to fibro-proliferative plaques with lipid/necrotic cores, typical of the spectrum of human lesions.
LDL-cholesterol and cardiovascular disease:
Evidence of the causative role of LDL-cholesterol in atherosclerosis is threefold: first, genetic mutations that impair receptor-mediated removal of LDL cholesterol from plasma cause fulminant atherosclerosis; second, animals with low LDL-cholesterol levels have no atherosclerosis, whereas increasing these levels experimentally leads to disease; and third, human populations with low LDL-cholesterol levels have minimal atherosclerosis, and the process increases in proportion to the level of LDL cholesterol in the blood.
A remarkable victory for patients with coronary artery disease came when the LDL-cholesterol pathway was delineated and the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), discovered by Akira Endo, was developed to lower LDL-cholesterol levels.
Brown and Goldstein’s discovery of the LDL-receptor pathway, for which they were awarded the 1985 Nobel Prize in Physiology or Medicine, provided a genetic cause for myocardial infarction in persons with familial hypercholesterolemia and introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors.
This last concept is one of the mechanism by which statins selectively lower LDL-cholesterol levels in plasma, reducing the risk of myocardial infarction and prolonging life, as shown in multiple, definitive clinical trials.
The LDL-Receptor Pathway and Treatment with LDL Cholesterol-Lowering Drugs, which Improves Cardiovascular Outcomes:
Statin therapy does not eliminate cardiovascular risk completely. Levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk, but despite considerable improvements in our understanding of HDL cholesterol and its metabolism, none of the pharmacologic agents that raise HDL cholesterol that have been tested so far have had a significant effect on cardiovascular morbidity and mortality. Ongoing clinical trials of agents that raise HDL-cholesterol levels and that have other antiinflammatory and antiatherosclerotic effects are currently under way.
The oxidised LDL theory:
Atherosclerosis clearly does not develop in any animal model without a significant level of plasma cholesterol, and the dominant role of serum cholesterol is also well established in humans.
While hypertension, diabetes, and smoking are factors that dramatically increase the risk of atherosclerosis, it is not rare to have clinically significant atherosclerosis in the absence of these risk factors. In contrast, below a certain level of total cholesterol (3.5 mmol/l), atherosclerosis is practically absent in human populations (this equates perfectly with Statin trials over the past few years demonstrating plaque regression at LDL levels ~ 1.8 mmol/l). Risk for atherosclerosis is well documented to gradually increases with increased plasma cholesterol levels.
Moreover, primary and secondary clinical trials have established the efficacy of lowering cholesterol with statins for prevention of cardiovascular disease without controversy (my next blog).
It is therefore tempting to hypothesize that the primary trigger of cytokine release in atherosclerosis has a link with cholesterol. Atherogenic cholesterol exists mainly in the form of LDL, which are the main culprit in atherosclerotic vessels. In fact, several lines of evidence support the hypothesis that oxidized lipids, including oxLDL, are the most likely triggering factors for cytokine production.
Quantitative analysis of atherosclerosis in fetal aorta showed that fatty streaks are already present at this early stage of life, lesions being more abundant in fetus from hypercholesterolemic mothers than from normocholesterolemic mothers. Interestingly, qualitative analysis of lesions depicted similar distribution of native LDL, oxLDL, and macrophages in lesions of offspring from both hypercholesterolemic and normocholesterolemic mothers. The presence of macrophages alone, without native LDL or oxLDL, or their association with native LDL, was almost never observed, and most of the lesions contained both oxLDL and macrophages. A few lesions with native LDL or oxLDL without macrophages were also present. This seminal study allows us to describe the exact chronology of events leading to fatty streak formation in humans, starting with native LDL uptake by the arterial intima, followed by LDL oxidation and, finally, monocyte recruitment after endothelial activation by oxLDL.
Oxidised LDL behaves as a potent inflammatory agent. In vivo administration of oxidised LDL to C57BL/6 mice causes rapid induction of circulating M-CSF and upregulation of genes coding for inflammatory cytokines as well as other inflammatory proteins in various tissues. OxLDL stimulates the expression of adhesion molecules. OxLDL has chemoattractant activity on monocytes, promotes their differentiation into macrophages, but inhibits their mobility. Binding of oxLDL to cells triggers the release of proinflammatory cytokines in macrophages. In addition, incubating human blood mononuclear cells with oxLDL results in T-lymphocyte activation, as assessed by increased expression of IL-2 receptors and HLA-DR antigens on T lymphocytes.
Oxidation of LDL generates many “neo-self determinants” that induce an active immune response and may challenge the regulatory pathways responsible for immune homeostasis. Both humoral and cellular immune responses can profoundly affect atherosclerotic development and progression.
The amount of lipid retained in macrophages depends on unregulated uptake of oxidised lipoproteins by scavenger receptors, as first identified by Brown and Goldstein, counterbalanced by degradation and efflux. Altogether these findings point to a role of oxLDL as a very early trigger of vascular inflammation. LDL accumulation and modification in the subendothelium trigger monocyte and lymphocyte recruitment. Thereafter, activated macrophages and lymphocytes secrete abundant amounts of cytokines that in turn can activate endothelial cells; smooth muscle cells and macrophages/lymphocytes to foster cytokine production, leading to a self-perpetuating inflammatory process that becomes less dependent on the presence of oxLDL. This might explain why oxLDL, while instrumental in triggering the early atherosclerotic events, are less critical in upholding the inflammatory environment. This might also explain in part the efficiency of antioxidant therapies in the prevention of atherosclerosis when these therapies are administered at the very beginning of the atherosclerotic process in animal models, but their failure to do so in most secondary or primary prevention clinical trials in humans, where treatment is administered at later stages of the disease when secondary inflammatory mediators become as important as the initial oxidative-related stimulus.
It is noteworthy that atherosclerotic plaques do not regress, or regress very slowly, in cholesterol-fed rabbits following short-term withdrawal of cholesterol feeding and normalization of cholesterol plasma levels. It is only after a prolonged cholesterol withdrawal period that decrease in plaque size, together with reduced vascular inflammation and plaque stabilization, is observed. This has recently been reproduced in patients with documented coronary atherosclerosis plaque treated with high dose Rousuvastatin (CRESTOR) 40mg/d or Atorvastatin (LIPITOR) 80mg/d. Reducing serum LDL ~1.6-1.8 mmol/l caused progressive plaque regression over 2 years. There are a multitude of trials over the past decade in humans, that aggressive lipid lowering treatment using statins has been shown to be very effective in limiting plaque development and reducing plaque progression and rupture.
The cytokine network is incredibly complicated & may thus serve as a final common proinflammatory pathway regardless of the initiating event and provides a supplemental therapeutic target, especially in late stages of the disease.
Inducers of cytokine production in atherosclerosis:
According to the classical view of inflammation, cytokines are produced by cells of the innate immune system (monocytes, neutrophils, NKT cells) in response to microbial infection, toxic reagents, trauma, antibodies, or immune complexes.
An etiologic role for infectious agents in atherosclerosis, especially Chlamydia pneumoniae and cytomegalovirus (CMV), has been repeatedly evoked since the first seroepidemiologic evidence of an association of the chlamydia TWAR strain with acute myocardial infarction and chronic coronary disease was reported in 1988. However, the most recent clinical trials, including Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD), Azithromycin in Acute Coronary Syndrome (AZACS), Antibiotic Therapy After Acute Myocardial Infarction (ANTIBIO), Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), and Azithromycin and Coronary Events Study (ACES), assessing the potential benefits of antibiotic therapy with the goal of targeting Chlamydia pneumoniae showed no effect of treatment in patients with CAD. Moreover, experimental studies showed that infection is not necessary for initiation or progression of atherosclerosis in apoE-deficient mice. Atherosclerosis develops identically in germ-free animals and in animals raised with ambient levels of microbial challenge.
One must therefore conclude that pathogens do not serve as etiologic agents for atherosclerosis, even though one cannot rule out a role in disease exacerbation. Several reports indicate that inoculation of atherosclerosis-prone mice with high doses of C. pneumoniae fosters atherosclerosis. Yet, the atherogenic effect of C. pneumoniae requires elevated serum cholesterol levels.
Once inflammation has been triggered and cytokine release is initiated at the onset of atherosclerotic lesion development, a number of factors that are found in the atherosclerotic plaque can participate in maintaining and amplifying cytokine production.
OxLDL is a major autoantigen involved in atherosclerosis, and both oxLDL and anti-oxLDL antibodies are present in atherosclerotic lesions. Immune complexes consisting of oxLDL and anti-oxLDL may be ingested by macrophages leading to their activation and subsequent release of inflammatory cytokines, oxygen-activated radicals, and metalloproteinase.
Defective clearance of apoptotic cells:
Intrinsic defects in the clearance of apoptotic cells are associated with spontaneous and persistent tissue inflammation and autoimmunity. This may be due to reduced production of immunoregulatory cytokines due to defective phagocytosis and/or to the immunogenic and proinflammatory potential of the unremoved apoptotic cells.
With regard to atherosclerotic plaques, it has been shown that apoptotic microparticles accumulate in the lipid core, most likely as a result of reduced capacities of clearance of apoptotic cells by foam macrophages that are in an oxidant-rich environment. Defect in the clearance of apoptotic cells/microparticles may promote and perpetuate proinflammatory cytokine production.
Microparticles (MPs) are plasma membrane-derived vesicles shed from the plasma membrane of stimulated or apoptotic cells. They are now acknowledged as cellular effectors involved in fundamental physiological processes including intercellular communication, hemostasis, and immunity. MPs are ideal links between inflammation, thrombosis, and atherosclerosis. MPs express a number of proinflammatory and prothrombogenic molecules and could play an important role in the dissemination of these factors to sites remote from the site of their production.
MPs are abundantly present in the lipid core of human atherosclerotic plaques where they are responsible for tissue factor activation and may contribute to plaque inflammation. MPs also circulate at high levels in the peripheral blood of patients with acute coronary syndromes and are suggested to play an important role in endothelial dysfunction in addition to their potential role as carriers of blood-borne tissue factor, involved in blood thrombogenicity.
Cells present in the atherosclerotic plaque can produce reactive oxygen species (ROS) such as O2-, H2O2, and ·OH in response to activation by a number of molecular actors of atherosclerosis, including cytokines (TNF, IL-1), growth factors (PDGF), vasoactive peptides (angiotensin II), platelet-derived products (thrombin, serotonin), and mechanical factors (cyclic stretch, laminar and oscillatory shear stress). Major sources of ROS include normal products of mitochondrial respiration, NADPH oxidases, NO synthases, cyclooxygenases, lipoxygenases, cytochrome P-450 monooxygenase, and xanthine oxidase. These enzymes are all expressed in the atherosclerotic plaque, but evidence suggests that NADPH oxidase-like activity appears to be the major contributing enzymatic source of ROS in the vascular wall, generating superoxide anion in endothelial and smooth muscle cells.
A large body of evidence indicates that angiotensin II (ANG II) has significant proinflammatory activity in the vascular wall, inducing the production of ROS, inflammatory cytokines, and adhesion molecules.
The proinflammatory effects of ANG II are generally considered to be Angiotensin Receptor 1 dependent and may explain why clinical studies with Angiotensin II Inhibitors (ACE-I) and Angiotensin AT1 Receptor Blocker therapy reduce the morbidity and mortality when used in patients with vascular disease.
Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the vessel wall especially in diabetes but also in euglycemia, in the latter case driven by oxidant stress. AGEs may exert their pathogenic effects by engaging cellular binding sites/receptors. The interaction of AGEs with macrophages has been shown to activate macrophages leading to the induction of PDGF, insulin-like growth factor (IGF)-I, and proinflammatory cytokines, such as IL-1 and TNF.
Blood flow-induced shear stress has long been recognized as critically important in atherogenesis. Atherosclerotic lesions preferentially develop in areas of disturbed or oscillatory flows, including arterial bifurcations, branch ostia, and curvatures. The vascular endothelium is extremely sensitive to changes in blood flow; in vitro experiments suggest that physiological levels of shear stress are anti-inflammatory and antiadhesive, while low or oscillatory shear stress promotes oxidative and inflammatory transformations in EC, with enhanced monocyte adhesion, VCAM-1, ICAM-1, and E-selectin expression.
This would support our myriad of clinical trials in the of treatment of HYPERTENSION with reduced target organ damage.
Epidemiological investigations clearly pointed out that hypertension is a powerful cardiovascular risk factor. Besides being associated with exaggerated atherosclerosis, elevated blood pressure levels have been found to be highly predictive of atherosclerosis-associated cardiovascular events, including ischemic coronary disease, stroke, and peripheral arterial disease. In human subjects, carotid artery intima-media thickness, measured with high-resolution B-mode ultrasound, is highly correlated with blood pressure levels and accurately reflects cardiovascular risk.
Experimental studies have demonstrated that hypertension increases the rate of atherosclerotic plaque development particularly in the setting of LDL-C > 1.8. The atherosclerotic plaques of hypertensive animals with high ANG II showed signs of instability.
Several mechanisms can account for hypertension-induced atherosclerosis. Pressure-induced stretch of the vessel wall increases endothelial permeability to LDL and accentuates LDL accumulation in the intima, which is central to the atherogenic process. In addition, hypertension may promote or aggravate vascular inflammation.
A large body of evidence links obesity with accelerated atherosclerosis. Adipose tissue is an active endocrine and paracrine organ that releases a large number of cytokines and bioactive mediators, designated adipokines. These products influence not only body weight homeostasis but also inflammation, coagulation, and fibrinolysis, which ultimately affects atherosclerosis and its clinical complications. Adipokines with proinflammatory activities include TNF, IL-6, plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, leptin, and resistin. Increased production of these proteins by adipose tissue in obesity is likely to raise circulating levels of acute-phase proteins and inflammatory cytokines leading to a state of chronic low-grade inflammation that characterizes the obese.
Leptin, which shares structural and functional similarities with the IL-6 family of cytokines, enhances the production of TNF, IL-6, and IL-12 from LPS-stimulated monocytes/macrophages. Leptin also plays an important role in the regulation of adaptive immunity.
Resistin is another adipokine with potent inflammatory activities. Resistin seems to be expressed at much higher levels in mononuclear leukocytes, macrophages, and bone marrow cells than in human adipose cells. Taken together, these data indicate that leptin and resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis.
On the contrary, adiponectin exerts potent anti-inflammatory properties. It inhibits TNF-induced expression of adhesion molecules in vascular EC blocks lipid accumulation in macrophages, and suppresses the expression of class A scavenger receptors. Adiponectin also upregulates the expression of IL-10 in human monocyte-derived macrophages and increases TIMP-1 expression through IL-10 induction. Plasma adiponectin levels are reduced in patients with CAD, and overexpression of adiponectin in apoE-/- mice inhibits the progression of atherosclerosis, an effect that appears to be mediated by adiponectin-induced IL-10 production.
Cytokines and cardiovascular risk:
Once produced, cytokines are rapidly trapped by neighboring cells via their high-affinity receptors. Accordingly, measuring the levels of circulating cytokines is not necessarily a perfect surrogate end point reflecting the actual activity of the cytokine. Nevertheless, a variety of plasma inflammatory markers have been shown to well predict future cardiovascular risk. They can be useful for risk stratification and also to identify those patients who might benefit from targeted interventional therapy. Of these markers, ultra sensitive C-Reactive Protein (us-CRP), an acute-phase protein, has been the most extensively studied, and there is now robust evidence from primary prevention cohorts and among patients presenting with an acute coronary that elevated us-CRP levels predict future cardiovascular event. The production of us-CRP occurs almost exclusively in the liver by the hepatocytes as part of the acute phase response upon stimulation by IL-6, and to a lesser degree by TNF and IL-1, originating at the site of inflammation. CRP activates the classical complement cascade and mediates phagocytosis. In the 1990s, Berk, Weintraub, and Alexander showed that plasma CRP levels are elevated in patients with “active” CAD compared with those with stable CAD. In 1994, Attilio Maseri and his group established a link between CRP elevation and cardiovascular events in patients with unstable angina (UA). In the late 1990s, several studies linked elevated ultra-sensitivity CRP (us-CRP) levels with future cardiovascular events in different populations. Of importance us-CRP is relatively cheap and easy to measure as part of a persons “risk stratification”.
It is believed that classical cardiovascular risk factors including LDL cholesterol, hypertension, smoking, and diabetes can instigate the vascular release of proinflammatory cytokines and subsequent promotion of low-grade inflammation. These proinflammatory cytokines increase serum levels of CRP, supporting the concept that CRP acts as an integrator for many inflammatory stimuli, which in association with plasma LDL-cholesterol levels can predict the cardiovascular risk. Of potential clinical interest, the combination of an inflammatory marker (CRP, SAA, sICAM-1, or IL-6) with lipid testing improved upon risk prediction based on lipid testing alone. Thus lipid and inflammatory parameters appear to be assessing different biological pathways that carry separate prognostic value. In support of this hypothesis, the PROVE-IT-TIMI 22 study recently established that the risk of recurrent myocardial infarction (MI) or death from coronary causes among patients with acute myocardial syndromes (ACS) is best predicted by the combination of LDL cholesterol and CRP levels.
Furthermore the landmark JUPITER study published in 2008 showed in HEALTHY middle age males and females identified by high us-CRP (average us-CRP 4.3 mg/L) but normal LDL (the average LDL was 2.7 mmol/l) benefit from CRESTOR 20 mg/d in reducing the time to the first vascular event (over a very short trial period average under 2 years). Interestingly in people whose LDL was reduced to < 1.8 and us-CRP reduced to < 1.0 the risk reduction was > 70% for vascular events.
1 Timothy 2:7
“Have nothing to do with godless myths and old wives’ tales; rather, train yourself to be godly. 8 For physical training is of some value, but godliness has value for all things, holding promise for both the present life and the life to come. 9 This is a trustworthy saying that deserves full acceptance. 10 That is why we labour and strive, because we have put our hope in the living God, who is the Saviour of all people, and especially of those who believe”.
Ultimately you are allowed to choose what you believe, as we have been given God’s grace of “Spiritual Freedom” and freedom of choice.
In my next BLOG I will start the daunting task of outlining “Optimal Medical Therapy”.