The important role of autoimmunity in cardiovascular disease

Posted on December 28, 2011 by Dr. Jonathan

Summary: Inflammation of the blood vessels is the fundamental factor in cardiovascular diseases including heart attack and stroke. Vascular inflammation due to autoimmunity, a widespread phenomenon, is not encompassed by the ‘traditional’ metabolic risk factors. In the clinic the autoimmune components of vascular disease must be investigated and treated.

The authors of a paper published in the clinical journal Mædica observe:

“Inflammation plays a crucial role in atherogenesis either by local cellular mechanisms or humoral consequences…inflammation and endothelial dysfunction are triggered by cardiovascular risk factors: hypercholesterolemia, hypertension, smoking or diabetes. In other cases inflammation precedes atherosclerotic changes that occur in autoimmune diseases, as systemic lupus erythematosus and rheumatoid arthritis. In these diseases atherogenesis is mostly independent from conventional risk factors. Irrespective of its cause systemic inflammation is correlated with cardiovascular events.”

They also note:

“The pathogenic mechanisms of autoimmune disorders include an important localized or systemic inflammatory response. This may trigger as an “innocent bystander” reaction a peculiar type of endothelial injury that predisposes to atherogenesis. Many of these diseases are associated with early, accelerated atherosclerosis. This can also be due to concomitant presence of conventional risk factors, but is determined mainly by specific autoimmune and pro-inflammatory mechanisms or by specific medication (i.e. long term systemic corticosteroid use). In these cases atherosclerosis occurs in population subgroups traditionally protected from the atherosclerotic process, as young women that develop systemic lupus erythematosus. Atherothrombosis became the main cause of mortality in autoimmune disorders…Endothelial dysfunction found in early stages of athero genesis in autoimmune diseases is independent from traditional risk factors, depends only on the severity of systemic inflammation.”

As stated by the authors of a paper published in The Netherlands Journal of Medicine, autoimmune conditions such as rheumatoid arthritis and SLE have long been known to increase cardiovascular risk:

“Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis and spondyloarthritis, are associated with increased cardiovascular morbidity and mortality, independent of the established cardiovascular risk factors. The chronic inflammatory state, a hallmark of IMIDs, is considered to be a driving force for accelerated atherogenesis.”

They discuss autoimmunity and cardiovascular disease using as models RA, psoriatic arthritis and ankylosing spondyloarthritis, SLE and role of innate and adaptive immunity, concluding:

“Over the past two decades it has become increasingly clear that chronic inflammation is an independent risk factor for cardiovascular events, with an impact over and above established risk factors. Since IMIDs are protracted disorders, the focus on adequate cardiovascular prevention in these patients is long overdue. Pathophysiologically, chronic inflammation provides a direct link between IMIDs and accelerated atherogenesis.”

A fascinating review article, rich with references to other valuable citations, was published recently in the International Journal of Inflammation that expands on the role of oxidative stress in eliciting an autoimmune response that produces cardiovascular inflammation. The authors state:

“Recently, it has become clear that atherosclerosis is a chronic inflammatory disease in which inflammation and immune responses play a key role. Accelerated atherosclerosis has been reported in patients with autoimmune diseases, suggesting an involvement of autoimmune mechanisms in atherogenesis. Different self-antigens or modified self-molecules have been identified as target of humoral and cellular immune responses in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients, is the major event causing structural modification of proteins with consequent appearance of neoepitopes. Self-molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development.”

The authors acknowledge the role of infectious agents as instigators of autoimmune activity, but emphasize the role of modified self-antigens:

“Although infectious agents have been associated with the activation of immune mechanisms, evidence exist that the main antigenic targets in atherosclerosis are modified endogenous structures [12]. Atherosclerotic plaques express autoantigens that are targeted by both IgM and IgG. It is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful antigens [13, 14]. However, studies performed on hypercholesterolaemic mice deficient in different components of innate and adaptive immunity uniformly indicate that the net effect of immune activation is proatherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease.”

They go on to discuss the roles of oxidized LDL, heat shock proteins, Beta2-glycoprotein I (β2-GPI), and oxidized hemoglobin as oxidized agents that act as autoantigens eliciting an autoimmune response implicated in atherogenesis and cardiovascular disease, then conclude by stating:

“Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases…In addition to pro-inflammatory properties, self molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development…Modulation of the immune system could represent a useful approach to prevent and/or treat these diseases.”

An excellent paper published in the journal Nature Reviews Rheumatology (formerly Nature Clinical Practice Rheumatology) discusses the mechanisms of atherosclerosis in autoimmune diseases. The authors note:

“Many components of the immune system are involved in the pathologic processes underlying the development of atherosclerosis: macrophages that develop into foam cells; T cells; autoantibodies; autoantigens that are components of vessel walls and cholesterol particles; and cytokines that are secreted by cells within atherosclerotic plaques, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IL-10, tumor-necrosis factor, interferon-gamma and platelet-derived growth factor.”

They note evidence for the role of cellular immunity…

“Several autoimmune diseases are characterized as being TYPE 1 T HELPER (TH1) CELL-mediated or TYPE 2 T HELPER (TH2) CELL-mediated conditions. A study in which ApoE-/- mice were treated with pentoxifylline (an inhibitor of the TH1 differentiation pathway) for 12 weeks suggested that atherosclerosis is a TH1-mediated process.”

And the participation of humoral immunity is characterized by antibodies to oxidized LDL cholesterol and to heat-shock proteins (HSPs):

“Oxidized LDL (oxLDL) is the type of LDL cholesterol most likely to be taken up by macrophages that develop into foam cells. Increased levels of anti-oxLDL antibodies have been detected in patients with early-onset peripheral vascular disease, severe carotid atherosclerosis, and angiographically verified coronary artery disease (CAD). In addition, raised levels of oxLDL antibodies were found to be predictive of progression of carotid atherosclerosis, MI, and death…it was found that individuals with atherosclerosis had significantly higher levels of anti-HSP65 antibodies than controls.”

It has long been known that antiphospholipid antibodies (aPL) and anticardiolipin antibodies (aCL) can be associated with cardiovascular disease, and the authors discuss their relation to arterial intima–media thickness (IMT, pathological thickening of the blood vessel wall). They conclude:

“The complex involvement of the immune system in the pathogenesis of atherosclerosis is most evident in patients with autoimmune diseases, but is also important in the general population. Immunomodulation of atherosclerosis carries great potential for future human therapies…

Autoimmune rheumatic diseases are characterized by enhanced atherosclerosis, which leads to cardiovascular disease

Some forms of atherosclerosis can be detected at the preclinical stage

Both cellular and humoral components of the immune system are involved in the pathogenesis of atherosclerosis

Classical and nonclassical risk factors for atherosclerosis are associated with accelerated atherosclerosis in autoimmune rheumatic diseases

Atherosclerosis can be immunomodulated in experimental models in various ways, which include induction of immune tolerance”

The authors of a paper published in the journal Stroke observe that inflammation plays the critical role in arterial plaque destabilization:

“Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder.”

Expanding on this…

“…a complex endothelial dysfunction induced by elevated and modified low-density lipoproteins (LDL), free radicals, infectious microorganisms, shear stress, hypertension, toxins after smoking or combinations of these and other factors leads to a compensatory inflammatory response. Endothelial dysfunction is characterized by decreased nitric oxide synthesis, local oxidation of circulating lipoproteins and their entry into the vessel wall. Intracellular reactive oxygen species similarly induced by the multiple atherosclerosis risk factors lead to enhanced oxidative stress in vascular cells and further activate intracellular signaling molecules involved in gene expression. Upregulation of cell adhesion molecules facilitates adherence of leukocytes to the dysfunctional endothelium and their subsequent transmigration into the vessel wall. As outlined in this review, the evolving inflammatory reaction is instrumental in the initiation of atherosclerotic plaques and their destabilization.”

The authors summarize the stream of events leading to plaque rupture:

“Inflammation plays an important role in the progression of atherosclerosis and ICA plaque destabilization converting a chronic process into an acute disorder with ensuing thrombo-embolism. During atherosclerosis, T cells and macrophages infiltrate the vessel wall triggered by endothelial dysfunction, and locally interact in a synergistic manner. Autoreactive T cells recognize oxLDL, HSP and shared microbial antigens by molecular mimicry and locally release proinflammatory cytokines. Macrophages on stimulation by T-cell-derived cytokines and transformation into foam cells after uptake of oxLDL secrete MMP predisposing the plaques to subsequent rupture. Plaque-associated macrophages, moreover, are an important cellular source of TF. On plaque rupture TF-rich plaque material gets in contact with the circulation and activates the extrinsic coagulation pathway…Vaccination against modified LDL and HSP can slow development of atherosclerotic plaques. Current therapeutics effective in preventing atherosclerosis and stroke such as statins, ASS [aspirin] and renin-angiotensin system inhibitors may exert part of their effects by modulating inflammatory responses in the vessel wall.”

The authors of a review article published in Clinical and Developmental Immunology consider epigenetic mechanisms involved in autoimmune cardiovascular risk. They state:

“Autoimmune diseases (AIDs) have been associated with accelerated atherosclerosis (AT) leading to increased cardio- and cerebrovascular disease risk…many new genes and signalling pathways involved in autoimmunity…have been further detected. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Epigenetic regulatory mechanisms comprise DNA methylation, histone modifications, and microRNA activity, all of which act upon gene and protein expression levels. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development.

In other words, environmental factors that modulate gene expression play a role in ‘turning on’ autoimmunity that promotes heart attacks and strokes. As the authors note:

“It is widely known that AIDs are the result of interaction between predisposing genetic factors, deregulation of the immune system, and environmental triggering factors.”

Of great importance is that these factors can be modified:

“Moreover, epigenetic changes may be reversed. A remarkable example of disease in which epigenetic abnormalities and patterns of inheritance are extremely complex is SLE. The high incidence of twin pairs in which SLE develops in only one of the siblings supports the notion that environmental factors and their involvement in epigenetic modifications could affect the onset of disease.”

And there seem to be differences of autoimmune expression depending on the disease and the individual:

“Significant evidence has shown that there is heterogeneity in the characteristics of vasculopathies underlying different autoimmune diseases such as APS, SLE, RA, and pSS. It has been also shown a relevant heterogeneity with respect to inflammatory risk factors. The data presented in this revision further indicated that epigenetic mechanisms also seem to influence inflammation and cardiovascular disease in those autoimmune conditions.”

The authors of a paper published in Zeitschrift für Rheumatologie (Journal of Rheumatology) note that EULAR (the European League Against Rheumatism) recommends aggressive cardiovascular risk factor management for rheumatoid arthritis, which would be reasonable extrapolate to other autoimmune diseases:

“Beyond the traditional CV risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Numerous studies have shown that atherosclerosis is not a passive process characterized by accumulation of lipids in the vessel walls, but rather represents active inflammation of the vasculature…According to the recently published EULAR recommendations for CV risk screening and management in patients with inflammatory arthritis, annual CV risk assessment is recommended for all patients with RA. Any CV risk factors identified should be optimally managed. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower CV risk.”

Stroke in young women, particularly in the absence of ‘traditional’ risk factors such as elevated cholesterol, hypertension, metabolic syndrome and obesity, etc. is a great concern. In a paper published recently in the Canadian Journal of Neurological Sciences the authors state:

“In women ages 15-45 years, an additional set of risk factors are important in the pathogenesis of ischemic stroke. Some of these pertain strictly to women, and relate to exogenous hormones and pregnancy. Various other conditions are more common in women, which include migraine with aura, selected vascular disorders and autoimmune conditions. These differences do have implications for management in both the primary and secondary prevention of stroke in this age group.”

Of interest to clinicians is another paper in the same journal drawing attention to the role of the cytokine transforming growth factor-β (TGF-β) in vascular inflammation. The authors investigated polymorphisms of the TGF-β gene in ischemic stroke:

“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cerebrovascular complications. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with a central role in inflammation. To investigate whether polymorphisms of the TGF-β1 gene can modify the risk of ischemic stroke (IS) in Chinese population, we conduct this hospital-based, case-control study.”

They determined the transforming growth factor-β1 genotype in 450 Chinese patients (306 male and 144 female) with ischemic stroke compared to 450 control subjects (326 male and 124 female).

“Subjects carrying 869TT were susceptible to IS (odds ratio [OR] =1.58). Further analysis of IS data partitioned by gender revealed the female-specific association with 869T/C (OR=2.64).”

While the 869TT genotype of the TGF-β1 gene increased the risk of stroke for both sexes, the increase in risk for stroke was 264% for females.

The authors of an interesting paper published recently in the Endocrine Journal investigate the association of chronic inflammation in autoimmune thyroiditis with endothelial (vascular) dysfunction:

“Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism.”

They evaluated 37 patients with subclinical hypothyroidism (29 women, 8 men) in comparison to 23 healthy volunteers (19 women, 4 men) for endothelial dysfunction as measured by brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). They also measured serum TNF-alpha, interleukin-6, and hs-CRP, and estimated insulin resistance by HOMA score. The data make paint an interesting picture:

“There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls…The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group.”

The vascular inflammation associated with autoimmune thyroiditis stands out in high relief against a background of normal traditional risk factors like BMI, waist circumference and insulin resistance. The authors conclude:

“Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors.”

Finally, in the journal Circulation Research the authors of a commentary on a study just published in the Journal of Clinical Investigation ask the question “Is Atherosclerosis an Allergic Disease?“:

“A new report in the Journal of Clinical Investigation adds to the ever-increasing evidence that immunological mechanisms play an important role in atherogenesis. These new observations suggest involvement of IgE and its FcϵR1α receptor in the promotion of atherosclerosis, and specifically in plaque instability and clinical events.”

They further note, importantly…

“In addition, aside from conditions in which there are generalized increases in IgE levels, such as parasitic infections and hyper-IgE syndromes, elevated IgE levels usually reflect allergic-type immune responses.”

This is one mechanism by which food and other allergies contribute to the inflammation of cardiovascular disease. The authors conclude:

“The report by Wang et al and other reports describing the potential importance of mast cells to CVD have provided a compelling case to study the role of IgE in inflammatory conditions such as atherosclerosis. It adds to the growing evidence of the importance of immune function in atherogenesis and in particular of the role that immunoglobulins play, both through antigen-specific interactions and antigen-independent regulatory roles.”

Bottom line: In clinical management of cardiovascular disease the autoimmune components should be investigated and addressed with a rational treatment strategy.

Stroke risk is greater with both higher and lower than normal blood pressure

Posted on December 15, 2011 by Dr. Jonathan

Summary: lower than normal blood pressure results from underlying causes that need investigation and treatment. These underlying factors can increase the risk of stroke comparable to higher than normal blood pressure.

An important study recently published in the JAMA (The Journal of the American Medical Association) offers evidence that lower than normal blood pressure is a risk factor for stroke comparable to blood pressure that is higher than normal. The authors state:

“Recurrent stroke prevention guidelines suggest that larger reductions in systolic blood pressure (SBP) are positively associated with a greater reduction in the risk of recurrent stroke and define an SBP level of less than 120 mm Hg as normal. However, the association of SBP maintained at such levels with risk of vascular events after a recent ischemic stroke is unclear.”

So they set out to…

“…assess the association of maintaining low-normal vs high-normal SBP levels with risk of recurrent stroke.”

They examined two and a half years of data for 20,330 patients from 35 countries who had recently had an ischemic stroke. Patients were categorized based on their average systolic blood pressure as very low–normal (<120 mm Hg), low-normal (120-<130 mm Hg), high-normal (130-<140 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg). Their primary outcome measure was a stroke of any kind, and the secondary outcome was a composite of stroke, heart attack, or death from any other vascular cause. What did the data show?

“The recurrent stroke rates were 8.0% for the very low–normal SBP level group, 7.2% for the low-normal SBP group, 6.8% for the high-normal SBP group, 8.7% for the high SBP group, and 14.1% for the very high SBP group. Compared with patients in the high-normal SBP group, the risk of the primary outcome was higher for patients in the very low–normal SBP group (adjusted hazard ratio [AHR], 1.29), in the high SBP group (AHR, 1.23), and in the very high SBP group (AHR, 2.08). Compared with patients in the high-normal SBP group, the risk of secondary outcome was higher for patients in the very low–normal SBP group (AHR, 1.31), in the low-normal SBP group (AHR, 1.16), in the high SBP group (AHR, 1.24), and in the very high SBP group (AHR, 1.94).”

In other words, while the very high systolic blood pressure was the worst for both primary and secondary outcomes, the very low-normal group was the ‘runner up’ for both recurrent stroke (29%) and the secondary outcomes of heart attack or death from other vascular causes (31%). The authors conclude:

“Among patients with recent non–cardioembolic ischemic stroke, SBP levels during follow-up in the very low–normal (<120 mm Hg), high (140-<150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke.”

It’s important for both clinicians and patients to understand that lower than normal blood pressure is an indicator that things ‘under the surface’ are not working as they should. For example, autoimmune disorders that are Th1 dominant can be associated with lower adrenocortical activity due to the effect on the brain’s paraventricular nucleus—while promoting vascular inflammation.

Patients with psoriasis are at increased risk for vascular disease

Posted on November 25, 2011 by Dr. Jonathan

Summary: People with psoriasis are at increased risk for vascular disease. They require more aggressive screening and treatment.

A study published in the Journal of General Internal Medicine alerts us to pay special attention to vascular risk factors for those with psoriasis.The authors note:

“Psoriasis afflicts 2-3% of the world’s population. Affected patients commonly have risk factors for cardiovascular disease (CVD). In addition, psoriasis is independently associated with CVD and mortality.”

They set out to…

“…determine which CVD risk factors are associated with psoriasis independent of confounders, whether psoriasis is associated with CVD independent of CVD risk factors, and whether there is increased mortality among patients with psoriasis.”

90 studies out of 2,303 met the inclusion criteria for the authors’ review. The data led to this conclusion:

“Patients with psoriasis demonstrate a higher prevalence of cardiovascular risk factors and appear to be at increased risk for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. This increase in vascular disease may be independent of shared risk factors and may contribute to the increase in all-cause mortality….Physicians should screen for and aggressively treat modifiable risk factors for CVD in patients with psoriasis.”

These findings are not surprising considering the fundamental role of inflammation and autoimmune component of cardiovascular disease. Searching earlier posts for cardiovascular disease (search box above) will yield further evidence on this topic.

Women can reduce sudden cardiac death with basic lifestyle practices

Posted on August 11, 2011 by Dr. Jonathan

It doesn’t hurt to have a reminder of the power of lifestyle factors to reduce chronic disease such as this study just published in JAMA (the Journal of the American Medical Association) in which the authors correlated several of them to the risk of sudden cardiac death. As they note, sudden death is often the first sign of heart disease:

“Sudden cardiac death (SCD) accounts for more than half of all cardiac deaths; the majority of SCD events occur as the first manifestation of heart disease, especially among women. Primary preventive strategies are needed to reduce SCD incidence.”

Sudden cardiac death means dying within an hour of the onset of symptoms. For their purpose they defined a “healthy lifestyle” as not smoking, having a body mass index (BMI) of less than 25, exercising for 30 minutes per day or longer, and to exceed 40% of the alternate Mediterranean diet score (defined as a high intake of vegetables, fruits, nuts, legumes, whole versus refined grains, fish and moderate alcohol. What did the data show?

“All 4 low-risk lifestyle factors were significantly and independently associated with a lower risk of SCD. The absolute risks of SCD were 22 cases/100 000 person-years among women with 0 low-risk factors, 17 cases/100 000 person-years with 1 low-risk factor, 18 cases/100 000 person-years with 2 low-risk factors, 13 cases/100 000 person-years with 3 low-risk factors, and 16 cases/100 000 person-years with 4 low-risk factors. Compared with women with 0 low-risk factors, the multivariable relative risk of SCD was 0.54 for women with 1 low-risk factor, 0.41 for 2 low-risk factors, 0.33 for 3 low-risk factors, and 0.08 for 4 low-risk factors. The proportion of SCD attributable to smoking, inactivity, overweight, and poor diet was 81%. Among women without clinically diagnosed coronary heart disease, the percentage of population attributable risk was 79%.”

Considering that the benefits of diet and exercise can be further enhanced by customization according to functional metabolic-genomic assessment needs and more effective time-saving interval training respectively, it is likely that even these significant percentages can be further improved. The authors conclude:

“Adherence to a low-risk lifestyle is associated with a low risk of SCD.”

Sugar turns LDL cholesterol “ultra-bad”

Posted on June 19, 2011 by Dr. Jonathan

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

“MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

“MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”

Borderline anemia increases risk of death in coronary disease

Posted on June 12, 2011 by Dr. Jonathan

Earlier posts have offered evidence for the need to take even slightly low levels of hemoglobin very seriously. Now a research article just published in PLoS Medicine (Public Library of Science) reports that borderline anemia makes coronary artery disease significantly more lethal. The authors note:

“Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries…Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.”

They examined the data for 20,131 with stable angina and another 14,171 who had survived a first heart attack for an average of 3.2 years, correlating outcomes with hemoglobin values. Their findings are very important for clinicians and patients, who should inquire about their hemoglobin values, to bear in mind:

“For men with MI, the threshold value was 13.5 g/dl; the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI.”

In other words, hemoglobin below 13.5 g/dl in men and slightly lower in women doubled the risk of death. The authors conclude:

“There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here.“

Those who have had a heart attack should never take a NSAID

Posted on May 30, 2011 by Dr. Jonathan

Many people who have suffered a heart attack may be advised to take a non-steroidal anti-inflammatory drug (NSAID, such as ibuprofen, Advil, Motrin, Aleve, Celebrex and others*) for a variety of reasons, but a nation-wide cohort study just published in the journal Circulation reports that taking an NSAID can significantly increase their risk of death and they should never do so even for short periods. The authors set the stage for their study:

“Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI).”

They examined data for all Danish patients ≥30 years of age who had a first-time MI during 1997 to 2006 along with their subsequent NSAID use for risk of death and recurrent heart according to duration of NSAID treatment. What did the data show?

“Of the 83,677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI at the beginning of the treatment, and the risk persisted throughout the treatment course. Analyses of individual NSAIDs showed that the traditional NSAID diclofenac [Voltaren] was associated with the highest risk.”

This study is an alarm that should be clearly heard by clinicians and any heart attack survivors who self-medicate with over-the-counter preparations. Practitioners should also not fail to consider a corollary implication: what about patients who, though they have not yet suffered an MI, have significant heart attack risk factors such as elevated Lp-PLA2? Fortunately there are alternatives to NSAID use for chronic inflammation. The authors conclude:

“Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.”

*including Nuprin, Naproxen, Relafen, Tolectin, etc.

The highest amounts of calcium intake increase the risk of fracture

Posted on May 28, 2011 by Dr. Jonathan

Patients are often surprised to learn that osteoporosis is not a calcium deficiency disorder but rather a failure to maintain the microarchitecture of the bone of which the protein matrix is a critical component. Moreover, earlier posts on magnesium and calcium have document the pro-inflammatory potential of calcium supplementation. Now fascinating research just published in the British Medical Journal offers evidence that calcium above the lowest quintile does not improve the risk of fracture of any type, while the highest levels actually increase the risk of fracture. The authors set out to…

“……investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.”

They note that confusion regarding the issue of calcium requirements has been…

“…reflected by the wide range of daily calcium recommendations for individuals older than 50 years: at present 700 mg in the UK, 800 mg in Scandinavia, 1200 mg in the United States, and 1300 mg in Australia and New Zealand.”

The authors investigated 61,433 women born between 1914 and 1948 for 19 years for correlations between dietary intake of calcium and fractures of any type, hip fractures, and osteoporosis. They took into consideration vitamin D consumption, hormonal status, and other pertinent biological and lifestyle factors including physical activity. Perhaps not surprisingly in light of other evidence that has emerged recently about calcium, their data challenges the conventional wisdom:

“These findings show an association between a low habitual dietary calcium intake (lowest quintile) and an increased risk of fractures and of osteoporosis. Above this base level, we observed only minor differences in risk. The rate of hip fracture was even increased in those with high dietary calcium intakes.“

In others, amounts higher than the lowest level of calcium intake adequate to avoid gross insufficiency and compromised bone micoarchitecture there were not only no significant benefits, the highest levels of intake increased fracture risk. The authors comment:

“The present results may reflect a situation when a moderate intake of calcium* combined with adequate intake of other micronutrients is sufficient to meet the structural and functional demands of the skeleton. High levels of intake did not further decrease the rate of fracture, and might even increase the rate of hip fractures…Moreover, use of supplemental calcium has been associated with higher rates of hip fracture both in a cohort study and in randomised controlled trials…Furthermore, high calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density.”

*Their data indicate that a total dietary intake of 700 mg of calcium per day is sufficient to prevent fracture and osteoporosis. The authors conclude:

“Incremental increases in calcium intake above the level corresponding to the first quintile of our female population were not associated with a further reduction of osteoporotic fracture rate.”

Considering that chronic inflammation can be a primary factor in causing loss of the protein ‘scaffolding’ of bone responsible for strength, resilience, and the matrix to which minerals attach, these findings invoke recollection of the recent evidence that calcium supplementation can increase the inflammation of cardiovascular disease. In case you missed it, a recent research paper published in the British Medical Journal follows up on earlier reports of this association. The authors’ intent was…

“To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.”

The examined the data from a randomised, placebo controlled trial of calcium alone or with vitamin D in 36,282 postmenopausal women over seven years for myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke. The data told an interesting story:

“In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events…Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).”

Clinicians and patients need to appreciate that inflammation, a fundamental causal factor in both osteoporosis and cardiovascular disease, can be made worse by calcium supplements. The authors conclude:

“Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.“

As insulin goes up so does the danger of arterial plaques

Posted on April 15, 2011 by Dr. Jonathan

Most readers of these posts, practitioner and layperson alike, have probably long been aware of the role of insulin resistance in cardiovascular disease, chronic inflammation and cancer as described in last week’s New York Times article. A fascinating study that adds to the mountain of scientific evidence was just published in the Public Library of Science (PLoS One) in which the authors show that higher insulin levels are associated with the unstable form of carotid artery plaque:

“The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric 14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques.”

The authors dissected the cores of carotid plaques from 29 patients with carotid stenosis and analyzed them for 14C. Their findings are fascinating:

“The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5–15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels…plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages…Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation.”

As readers here know, a heart attack or stroke occurs when a vulnerable plaque ruptures and blocks a smaller vessel downstream. These investigators show that unstable plaque is associated with higher insulin levels. Intervening to reduce insulin resistance is one of the most important things that clinicians and patients can do for a host of conditions. The authors conclude:

“Our results show, for the first time, that plaque age, as judge[d] by relative incorporation of 14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.”

Regarding laboratory testing to determine the presence of inflamed vulnerable plaque, see the earlier post on Lp-PLA2.

Less mortality and cardiovascular risk with metformin than other diabetes drugs

Posted on April 11, 2011 by Dr. Jonathan

It’s by far best to prevent type 2 diabetes by acting on the earliest signs of metabolic syndrome with appropriate lifestyle changes and evidence-based support for genetic and epigenetic needs based on objective laboratory data. All too often, however, this isn’t accomplished and the case advances to type 2 diabetes as insulin resistance mounts and insulin production can no longer compensate. When we enter the realm of pharmaceuticals for T2DM there are choices. A huge study just published in the European Heart Journal offers valuable evidence that metformin is associated with much less risk of cardiovascular disease and all-cause mortality. The authors state:

“The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.”

The authors examined the data for all Danish residents over 20 years old who starting taking an a single-agent insulin secretagogue (medication that provokes the secretion of insulin, ISs) or metformin between 1997 and 2006, a total of 107,806 subjects. They were followed for up to 9 years (3.3 years on average) for all-cause mortality, cardiovascular mortality, and the combination of myocardial infarction (MI), stroke, and cardiovascular mortality. This was correlated with the use of individual ISs. What did their data show?

“Compared with metformin, glimepiride: 1.32, glibenclamide: 1.19, glipizide: 1.27, and tolbutamide: 1.28 were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30, glibenclamide: 1.47, glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47. Results for gliclazide and repaglinide and were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.”

In other words, for example, patients (who had never had a heart attack) taking glimepiride had a 32% increased chance of dying compared with taking metformin. The authors conclude by stating:

“Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.”

This outcome is not unexpected when we consider that, in addition to suppressing hepatic glucose production, metformin acts to increase insulin receptor sensitivity. The authors of an editorial published in the same journal comment on the gravity of this study:

“While this is not the first study to evaluate outcomes with these drug classes comparatively, the observations are among the most robust published based on the very large sample of patients with drug choices largely free of selection bias, sufficient numbers of events ascertained to yield substantial statistical power to analyse outcomes for each insulin secretagogue individually, with additional stratification by history of previous myocardial infarction.”

Important: metformin is known to interfere with vitamin B12 absorption (see previous posts). Patients should be followed carefully for indications of suboptimal vitamin B12 levels, preferably by urine or serum methylmalonic acid assays.