Summary: Although antibiotics are commonly used to treat sinusitis though there has been no reliable evidence to support this practice. A recent study shows that in most cases they do not really benefit.

A study just published in The Journal of the American Medical Association finally seeks to answer the question “do antibiotics really help treat acute sinusitis”? The authors state:

“Evidence to support antibiotic treatment for acute rhinosinusitis is limited, yet antibiotics are commonly used.”

They randomized 166 adults with acute sinusitis to receive either a 10 day course of amoxicillin or placebo in order to…

“…determine the incremental effect of amoxicillin treatment over symptomatic treatments for adults with clinically diagnosed acute rhinosinusitis.”

All patients received a supply of symptomatic treatments for pain, fever, cough, and nasal congestion to use as needed. As a metric they used the Sinonasal Outcome Test, changes in sinus symptoms and overall functional state, relapse, satisfaction and adverse effects of treatment. How did the outcomes compare?

“The mean change in Sinonasal Outcome Test-16 scores was not significantly different between groups on day 3 (decrease of 0.59 in the amoxicillin group and 0.54 in the control group; mean difference between groups of 0.03) and on day 10 (mean difference between groups of 0.01), but differed at day 7 favoring amoxicillin (mean difference between groups of 0.19). There was no statistically significant difference in reported symptom improvement at day 3 (37% for amoxicillin group vs 34% for control group) or at day 10 (78% vs 80%, respectively), whereas at day 7 more participants treated with amoxicillin reported symptom improvement (74% vs 56%, respectively). No between-group differences were found for any other secondary outcomes. No serious adverse events occurred.”

The authors state in their conclusion:

“Among patients with acute rhinosinusitis, a 10-day course of amoxicillin compared with placebo did not reduce symptoms at day 3 of treatment…There is now a considerable body of evidence from clinical trials conducted in the primary care setting that antibiotics provide little if any benefit for patients with clinically diagnosed acute rhinosinusitis.”

Guidelines recently released here and in the U.K. suggest ‘watchful waiting’. The CDC currently recommends treating only severe cases with antibiotics. Jay Piccirillo, MD, of Washington University in St. Louis, one of the study’s authors, stated in The JAMA Report:

“It provides further evidence for what we’ve really suspected for a long time — that in the management of patients with acute sinusitis, antibiotics do not convey any additional benefit.”

While antibiotics don’t help most cases of sinusitis (which are viral), there are of course interventions that do support the body’s intrinsic resources.

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Summary: Cognitive decline begins early in life with accelerated neurodegeneration. Take realistic steps now to protect brain health.

A study just published in The Lancet offers evidence that cognitive decline starts becoming apparent as early as age 45. The authors set out to…

“…estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline.”

They assessed 5,198 men and 2,192 women, aged 45-70 at the beginning of cognitive testing in 1997-9 for memory, reasoning, vocabulary, and phonemic and semantic fluency three times over 10 years. Their data confirm an early loss of cognitive function:

“All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test×100, in reasoning was −3.6% in those aged 45-49 at baseline and −9.6% in those aged 65-70. In women, the corresponding decline was −3.6% and −7.4%.”

A strategy to protect brain health begins with finding out the individual’s specific needs according to the biological basics. Fundamentals that apply equally to adults are listed in the Parents’ Guide To Brain Health. The authors conclude with the important observation:

“Cognitive decline is already evident in middle age (age 45-49).”

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Summary: Care must be taken when considering iodine supplementation because it can provoke latent thyroid autoimmunity resulting in hypothyroidism.

A noteworthy study just published in The American Journal of Clinical Nutrition adds more evidence that iodine supplementation, even in small amounts, can produce hypothyroidism. The authors state:

“The beneficial health effects associated with Universal Salt Iodization are well known. Yet, little is known about the possible adverse health effects in people with high iodine intake and the safe daily intake upper limit in the Chinese population…The objective of this study was to explore the safe upper level of total daily iodine intake among adults in China.”

They examined 256 adults with apparently normal thyroid function in a 4 week double-blind, placebo-controlled, randomized controlled trial. The subjects were randomly assigned to 12 different levels of iodine supplementation ranging from 0 to 2000 micrograms per day (2000 μg = 2 milligrams). Iodine from both supplements and diet was taken into consideration. They were then evaluated for thyroid function, thyroid size, and urinary iodine. The outcome was striking for what would seem to be a modest amount:

“The mean iodine intake from the diets and salt intake of the participants were 105 ± 25 and 258 ± 101 μg/d, respectively. In comparison with the placebo group, all iodide-supplemented groups responded with significant increases in median urinary iodine concentrations and in thyroid-stimulating hormone concentration. Thyroid volume decreased after 4 wk in the high-iodine intervention groups (1500–2000 μg). Subclinical hypothyroidism appeared in the groups that received 400 μg I (5%) and 500–2000 μg I (15–47%).”

This is striking in that even 400 micrograms, only 0.4 milligrams, provoked subclinical hypothyroidism in a significant percentage of patients. This is why I published an earlier post regarding the need for care in the use of iodine for radiation protection, to say nothing of the inappropriate supplementation of large amounts of iodine without due care. In this study the highest intervention group which was still only 2 mg per day had noticeable thyroid shrinkage. The authors conclude:

“This study showed that subclinical hypothyroidism appeared in the participants who took the 400-μg I supplement, which provided a total iodine intake of ∼800 μg/d. Thus, we caution against a total daily iodine intake that exceeds 800 μg/d [0.8 milligrams] in China and recommend further research to determine a safe daily upper limit.”

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Summary: Borderline levels of TSH (thyroid stimulating hormone) still within the reference ranges typically printed in laboratory reports can indicate low thyroid function (and predict hyperthyroid on the other end of the scale). A thorough assessment of the more than two dozen patterns of thyroid dysfunction is necessary for an accurate diagnosis.

Clinicians and patients may often be misled by TSH levels that appear normal, but experienced practitioners know that they can mask the presence thyroid disorders. Because hypothyroidism affects function globally, a study just published in the Journal of Clinical Endocrinology & Metabolism that practitioners in all specialties should be vigilant. The authors state:

“Serum TSH in the upper part of the reference range may sometimes be a response to autoimmune thyroiditis in early stage and may therefore predict future hypothyroidism. Conversely, relatively low serum TSH could predict future hyperthyroidism…The objective of the study was to assess TSH within the reference range and subsequent risk of hypothyroidism and hyperthyroidism.”

The authors examined 10,083 women and 5,023 men without previous thyroid disease who had a baseline TSH of 0.20–4.5 mU/liter for the predictive probabilities of developing hypothyroidism or hyperthyroidism according to categories of baseline TSH during follow-up 11 years later. Their data drew a strong result:

“During 11 yr of follow-up, 3.5% of women and 1.3% of men developed hypothyroidism, and 1.1% of women and 0.6% of men developed hyperthyroidism. In both sexes, the baseline TSH was positively associated with the risk of subsequent hypothyroidism. The risk increased gradually from TSH of 0.50–1.4 mU/liter [women, 1.1%; men, 0.3%] to a TSH of 4.0–4.5 mU/liter (women, 31.5%; men, 14.7%). The risk of hyperthyroidism was higher in women with a baseline TSH of 0.20–0.49 mU/liter (3.9%) than in women with a TSH of 0.50–0.99 mU/liter (1.4%) or higher (∼1.0%).”

Too many patients with thyroid dysfunction fall between the cracks of routine care. This evidence strongly supports the importance of a complete assessment of thyroid function when these disorders, especially autoimmune thyroid disease, are suspected. The authors conclude:

“TSH within the reference range is positively and strongly associated with the risk of future hypothyroidism. TSH at the lower limit of the reference range may be associated with an increased risk of hyperthyroidism.”

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Summary: the hormonal and menstrual irregularities, metabolic dysfunction and adverse cardiovascular changes of PCOS (polycystic ovary syndrome) can be effectively treated with the right dietary and lifestyle interventions according to two recent studies. This is not surprising considering that excessive levels of insulin promote the development of ovarian cysts.

A study recently published in The Journal of Clinical Endocrinology & Metabolism offers excellent evidence that the metabolic and cardiovascular irregularities of PCOS respond well to the appropriate lifestyle changes. The authors state:

“Polycystic ovarian syndrome (PCOS) is associated with cardiovascular risk factors (CRF). Lifestyle intervention is regarded as therapy of choice even if studies in adolescent girls with PCOS are scarce…Our objective was to analyze the impact of lifestyle intervention on menses irregularities, hyperandrogenemia, CRF, and intima-media thickness (IMT) in adolescent girls with PCOS.”

They examined 59 obese girls with PCOS aged 12–18 years for menstrual irregularities,IMT (thickening of the inner layer of the arteries), waist circumference, blood pressure, fasting lipids, insulin, glucose, testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and SHBG (sex hormone binding globulin) before and after a one year intervention of nutrition education, exercise training, and behavior therapy. The results were instructive:

“In contrast to the 33 girls without weight loss, the 26 girls reducing their body mass index during the lifestyle intervention (by a mean of −3.9 kg/m2) improved most CRF and decreased their IMT (by a mean of −0.01 cm). Testosterone concentrations decreased (by a mean of −0.3 nmol/liter) and SHBG concentrations increased (by a mean of +8 ng/ml) significantly in girls with weight loss in contrast to girls with increasing weight. The prevalence of amenorrhea (−42%) and oligoamenorrhea (−19%) decreased in the girls with weight loss. The changes in insulin in the 1-yr follow-up were significantly correlated to changes in testosterone and SHBG.”

These results illuminate the role of insulin resistance and its association with obesity and PCOS. The authors conclude:

“Weight loss due to lifestyle intervention is effective to treat menses irregularities, normalize androgens, and improve CRF and IMT in obese adolescent girls with PCOS.”

These results add savor to another study published shortly afterward in The American Journal of Clinical Nutrition that offers evidence for the most effective protein/carbohydrate ratio for PCOS. The authors state:

“Some evidence has suggested that a diet with a higher ratio of protein to carbohydrates has metabolic advantages in the treatment of polycystic ovary syndrome (PCOS)…The objective of this study was to compare the effect of a high-protein (HP) diet to a standard-protein (SP) diet in women with PCOS.”

They assigned 57 PCOS women to either a high protein (HP) diet (>40% of energy from protein and 30% of energy from fat) or a standard protein (SP) diet (<15% of energy from protein and 30% of energy from fat). Both diets were without caloric restriction, but dietary counseling was given monthly. At baseline and 3 and 6 mo, They took anthropometric measurements and collected blood samples at the beginning and after 3 and 6 months. The results support the replacement of carbohydrates with protein for women with PCOS:

“The HP diet produced a greater weight loss (mean: 4.4 kg) and body fat loss (mean: 4.3 kg) than the SP diet after 6 mo. Waist circumference was reduced more by the HP diet than by the SP diet. The HP diet produced greater decreases in glucose than did the SP diet, which persisted after adjustment for weight changes. There were no differences in testosterone, sex hormone–binding globulin, and blood lipids between the groups after 6 mo. However, adjustment for weight changes led to significantly lower testosterone concentrations in the SP-diet group than in the HP-diet group.”

Considering that PCOS is driven by elevated insulin levels associated with insulin resistance the authors’ conclusion offers sound guidance:

“Replacement of carbohydrates with protein in ad libitum diets improves weight loss and improves glucose metabolism by an effect that seems to be independent of the weight loss and, thus, seems to offer an improved dietary treatment of PCOS women.”

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Summary: the stress of oxygen starvation that occurs with sleep disordered breathing (sleep apnea and hypopnea) contributes to metabolic syndrome and high blood pressure. CPAP (continuous positive airway pressure) can help .

I have been finding that people coming to our practice who have been struggling with the depredations of metabolic syndrome including overweight, hypertension, elevated lipids and HgbA1c, etc. have not been evaluated for sleep disordered breathing. A study recently published in The New England Journal of Medicine offers evidence that treatment for sleep apnea can provide significant benefit. The authors state:

“Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components…In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between.”

They measured anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance, fasting blood lipids, glycated hemoglobin, carotid intima–media thickness, and visceral fat before and after the real and sham CPAP interventions. Their data showed a worthwhile effect:

“A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg), serum total cholesterol (13.3 mg per deciliter), non–high-density lipoprotein cholesterol (13.3 mg per deciliter), low-density lipoprotein cholesterol (9.6 mg per deciliter), triglycerides (18.7 mg per deciliter), and glycated hemoglobin (0.2%). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP).”

Clinicians should not fail to consider the possibility of sleep disordered breathing when managing hypertension, overweight and other components of metabolic syndrome. Do you snore or wake in the morning unrefreshed and fall asleep inappropriately during the day? If so, a screening may be appropriate. The authors conclude:

“In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities.”

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Summary: cholesterol plays critical roles in cell membranes and steroid hormone production. This study associates low LDL cholesterol with worse cognitive performance. As expected, the effect is amplified by inflammation. Care should be taken to apply a balanced approach to cholesterol lowering therapies.

A truly fascinating study was just published in the journal Neurobiology of Aging investigating lipoproteins and loss of cognitive function. The authors state:

“The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation.”

They collected biological and cognitive data on 1003 persons ≥ 65 years of age over 6 years of follow-up, measuring cognition with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). High HDL was associiated with better memory performance, but their data seem to suggest the importance of sufficient LDL cholesterol in brain neuronal membranes:

“We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed.”

Not at all surprisingly they found that inflammation compounds the adverse effects of low LDL:

“Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance.”

And since high triglycerides are commonly provoked by the high insulin levels due to insulin resistance which also have deleterious effects on the brain…

“Also, high triglycerides were associated with lower memory performance in those with high inflammation.”

The authors conclude by suggesting that HDL, LDL and inflammatory indicators can be used as predictors of poor cognitive function:

“Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.”

This compels us to use caution and see the ‘big picture’ when designing strategies to manage lipids—care should be taken to not suppress LDL cholesterol to too low a level.

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Summary: Magnesium, important for the human body for many reasons, can help with hot flashes due to menopause and treatment for breast and prostate cancer.

Hot flashes occur during the onset of menopause as abrupt changes in estrogen levels elicit vasomotor reactions through the hypothalamus, and they can also occur as estrogen levels are suppressed by chemotherapy in breast cancer treatment. A study recently published in the journal Supportive Care in Cancer presents evidence that magnesium helps to reduce menopausal hot flashes in breast cancer patients.

The authors derived a hot flash score from frequency and severity of hot flashes in breast cancer patients who had been experiencing at least 14 hot flashes a week, before and after taking 400 mg of magnesium oxide 400 mg for 4 weeks. The study subjects were allowed to increase the dose to 800 mg if needed. The results were impressive…

“The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 to 27.7, a 41.4% reduction… Hot flash score was reduced from 109.8, a 50.4% reduction. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial.”

These results are welcome because magnesium, the fourth most abundant mineral in the human body plays a vital role in hundreds of important pathways and is frequently subject to depletion. It is the ‘calming mineral’. The patients whose hot flashes were reduced likely obtained other benefits. The authors conclude:

“Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal.”

These findings are echoed in another report published in the Journal of Clinical Oncology. The author states:

“Hot flashes are common with natural menopause or induced estrogen deficiency from chemotherapy, tamoxifen, raloxifene, or the aromatase inhibitors. As many as 90% of perimenopausal women have hot flashes, and 40% of survivors of breast cancer rate their hot flashes rate the effect as “quite a bit” to “severe”.”

He notes that the common medications for hot flashes…

“…have potential adverse effects. Antidepressants can cause mental, emotional, and physical adverse effects. Megestrol acetate and medroxyprogesterone acetate, while effective, can potentially cause fluid retention, premenstrual symptoms, and deep vein thrombosis.”

He goes on to report clinical experience consonant with the previous study:

“Recently I saw two patients with breast cancer who volunteered that when they began magnesium supplements for reasons other than hot flashes, their hot flashes diminished within 24 hours and had not returned. In each case, the person was not expecting any relief from magnesium, so placebo effect is unlikely.”

It should be noted that men undergoing hormone blockade therapy for prostate cancer can also suffer from hot flashes. The potential benefits of magnesium apply to them too.

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Summary: A recent study analyzing ten individual trials offers evidence that probiotics (beneficial flora such as Lactobacillus, Bifidus and other species) help prevent acute upper respiratory tract infections.

A study published recently by The Cochrane Library examined the potential for probiotics taken as supplements to ward off upper respiratory tract infections. The authors state:

“Probiotics may improve a person’s health by regulating their immune function. Some studies show that probiotic strains can prevent respiratory infections…Acute upper respiratory tract infections (URTIs) include the common cold, inflammation of the trachea and larynx with symptoms including fever, cough, pain and headaches…Some live micro-organisms can confer a health benefit to the patient when administered in adequate amounts. Lactic acid bacteria and bifidobacteria are the most common types of probiotics… However, no evidence of the benefits of probiotics for acute upper respiratory tract infections (URTIs) and related potential adverse effects has been published. “

So they set out to assess the effectiveness and safety of probiotics for preventing acute upper respiratory tract infections by examining a range of international randomised controlled trials (RCTs) that compare probiotics with placebo. What did the data show?

“We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI: at least one episode: odds ratio (OR) 0.58; at least three episodes: OR 0.53…and reduced antibiotic prescription rates for acute URTIs: OR 0.67…Side effects of probiotics were minor and gastrointestinal symptoms were the most common.”

As the ability to research the vast human microbiome and its vital interactions with an individual’s unique resident flora for immune and metabolic modulation continue emerge, we are slowly gaining more insight into how to use probiotics to benefit health in many ways. This and other studies offer compelling evidence that we can benefit by ‘exercising’ our immune system and modulating the genetic expression of our stable resident flora with appropriate probiotic administration in key foods and supplements. The authors conclude:

“Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTIs, the rate ratio of episodes of acute URTI and reducing antibiotic use. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs.”

Lab tests that examine microbial DNA in the stool help to know which strain of beneficial flora and when.

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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.

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