Secondhand marijuana smoke more dangerous than tobacco.


With an increasing number of states legalizing medicinal and recreational marijuana, a new study has found that exposure to secondhand marijuana smoke is more damaging to blood vessels than breathing secondhand tobacco smoke.
© Cathal McNaughton

The study revealed that the blood flow in the arteries of rats that had inhaled secondhand marijuana smoke for one minute was less efficient for at least 90 minutes. Under a similar test for secondhand tobacco smoke, blood vessel impairment lasted only 30 minutes.

“While the effect is temporary for both cigarette and marijuana smoke, these temporary problems can turn into long-term problems if exposures occur often enough and may increase the chances of developing hardened and clogged arteries,” saidMatthew Springer, PhD, the study’s senior author and a professor of medicine at the University of California, San Francisco’s Division of Cardiology, in a released statement.

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Researchers also found that merely burning the plant material appears to cause impaired blood vessels, unlike chemicals like nicotine and tetrahydrocannabinol.

Researchers say the arteries of rats and humans are similar in how they respond to secondhand tobacco smoke.

The study on the health consequences of exposure to secondhand smoke from cannabis comes as three more states – California, Maine and Nevada – are due to vote on ballot initiatives on whether to legalize recreational marijuana this November.

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ABC News reported that one in six Americans now live in states where cannabis is legal.

“There is widespread belief that, unlike tobacco smoke, marijuana smoke is benign,” Springer said. “We in public health have been telling the public to avoid secondhand tobacco smoke for years. But we don’t tell them to avoid secondhand marijuana smoke, because until now we haven’t had evidence that it can be harmful.”

Is there such a thing as the “right diagnosis”? Review from the Diagnostic Error in Medicine conference 2016


As doctors, we probably already consider ourselves honorary members of the Society to Improve Diagnosis in Medicine (SIDM). It’s essentially part of our job description. But there is an option to become a fully paid up member. Founded in 2011 by US doctor Mark Graber, the SIDM is an international organisation that is dedicated to honouring all those who have been harmed by diagnostic error—aiming to create a “world where diagnosis is accurate, timely, and efficient.”

The society has hosted several international conferences on diagnostic error. June 2016 saw the first such conference to be hosted in Europe, with international healthcare colleagues travelling to the impressive Erasmus Medical Centre in Rotterdam, the Netherlands.

A hot topic of discussion was the recently published US Institute of Medicine landmark report on the problem of diagnostic error: Improving Diagnosis in HealthcareIt is sobering reading: 5% of US adults who seek outpatient care experience a diagnostic error each year and diagnostic error contributes to approximately 10% of patient deaths. It concludes that each of us is likely to experience one or more diagnostic errors in our lifetime.

The committee who produced the report also proposed a new definition for diagnostic error: “the failure to
• establish an accurate and timely explanation of the patient’s health problem(s) or
• communicate that explanation to the patient.”

They were explicit about their intentions to make this definition as patient centred as possible. And indeed it challenges the medical world’s concept of the “right diagnosis.”

No longer is it enough for doctors to spot the abnormality on the scan or make the correct interpretation of blood test results. If we don’t explain these results clearly to our patients in a way that they understand then we have got it wrong. We have made a diagnostic error.

The message is that diagnosis doesn’t end with a pat on the back because “we’ve got it right.” Apart from anything else, the diagnosis might not feel “right’ at all for the person sitting in front of us.

This is part of the ongoing identity shift for doctors from House style diagnosticians to person centred “holisticians,” who are concerned with patient experience rather than giving celebrated grand rounds presentations.

This new definition was largely welcomed at the conference. But for those involved in diagnostic error research, the broadened definition will pose an operational challenge that requires new study designs and outcome measures. The conference organisers committed to improving patient involvement in future to help identify what these desired outcomes might be.

Other interesting themes at the conference included the use of online tools to help aid diagnosis—particularly useful it seems in the case of rare diseases; the use of psychological theory to establish how individuals make diagnoses and where these thought processes might go wrong; and how system data, such as medical negligence databases, can help to identify where errors occur most frequently.

The research presented was varied and illuminating. One team in Switzerland explored why there is a high rate of change in individual patient diagnosis between admission and discharge. A British research group described how they are aiming to reduce “unclaimed” investigation results—tests that have been ordered, often in A&E or before a patient’s discharge, that are never checked or communicated back to patients, allowing potential diagnoses to go unnoticed. Another group is addressing the fact that a quarter of cancer diagnoses are made in emergency departments by seeing if there are missed opportunities for diagnosis in general practice.

Diagnostic certainty was discussed at length. It is rare that doctors can give a diagnosis to patients with 100% certainty. Could diagnostic error be exacerbated by overly confident assertions of the “correct” diagnosis? Might patients be less likely to question ongoing symptoms or return with their concerns if they’ve been inappropriately reassured?

Safety netting is one way of ensuring patients come back, but do we use it with patient wellbeing and safety in mind or as a way of absolving responsibility in case we’ve got it wrong?

Might being open and honest with patients, when we aren’t completely sure what’s going on, be the “right diagnosis”?

Early or Late Menopause Ups Risk for Type 2 Diabetes


Women who had their final menstrual period before age 45 or after 55 have a higher risk of developing type 2 diabetes (hazard ratio [HR], 1.04 and HR, 1.08, respectively, compared with those who had their final period between ages 46 and 55), new study results indicate.

The findings were published online July 27 in Menopause.

Erin S LeBlanc, MD, MPH, with Kaiser Permanente Center for Health Research, Portland, Oregon, and colleagues examined 124,379 women in the Women’s Health Initiative (WHI), a multicenter study launched in 1991 by the National Institutes of Health that looked at preventing disease in postmenopausal women.

Dr LeBlanc and colleagues also found that in related age-adjusted models, women with the shortest reproductive periods (less than 30 years) had a 37% greater risk of developing type 2 diabetes than those with reproductive periods of 36 to 40 years. Likewise, women with the longest reproductive span (more than 45 years) had a 23% higher risk than women with medium-length reproductive years.

Dr LeBlanc told Medscape Medical News the study suggests that lifetime estrogen exposure may play a role in whether a woman develops type 2 diabetes or not and that there may be a “sweet spot” where optimal estrogen exposure meets lowest risk for type 2 diabetes.

The research team had hypothesized that because endogenous estrogen has been known to have protective effects against developing diabetes, cardiovascular disease, and osteoporosis, those with shorter reproductive years would have less protection from diabetes.

Estrogen helps to preserve insulin secretion and stabilize glucose levels. Low estrogen negatively affects body-fat distribution and fat accumulation, important factors in type 2 diabetes risk.
The surprise was that the data showed those with the longest reproductive years also had a higher risk for type 2 diabetes. “I don’t have a good biological explanation for that,” Dr LeBlanc said.

Results Can Help Target Lifestyle Changes

Of course, there’s little women can do about age of menopause, given its strong genetic component, but those in the higher-risk groups can consider lifestyle changes, and clinicians, armed with this new information, can better counsel patients in the higher-risk groups.

“I don’t want women thinking this is something terrible and they’re doomed to get diabetes” if they are in the higher-risk groups, Dr LeBlanc said.

“The point of our study is to give women who have early menopause or late menopause another motivator for adopting a healthy lifestyle, because we know that a healthy lifestyle can substantially reduce a woman’s risk of developing diabetes.”

For clinicians, this is another factor to add to the conversation on why it’s important to maintain a healthy weight, eat a balanced and nutritious diet, and increase exercise levels, she noted.

The authors add that previous work on this topic has had small sample sizes and lacked rigorous, prospective ascertainment of type 2 diabetes.

Strengths of this study include its large size, ability to more clearly characterize participants’ reproductive history, long follow-up, and prospective ascertainment of diabetes.

Other Factors Not Linked to Risk

The researchers examined several other factors, including number of previous pregnancies, age at first birth, whether menopause was surgical or natural, body mass index, and hormone therapy after menopause. But none of these factors had a statistically significant link to risk of developing type 2 diabetes.

Age at which periods started and irregular periods were also not statistically significant in risk for diabetes.

Study limitations included that women were asked to recall their age at start of menstruation, which could have resulted in measurement error. And because medically diagnosed diabetes was not available for all WHI women, the researchers relied on participants’ reports of diabetes.

“[H]owever, self-reports of ‘treated diabetes’ in WHI have been shown to be sufficiently accurate to allow use in epidemiologic studies such as this one,” they write.

The findings by Dr LeBlanc, et al, are aligned with those of a previous European study (Diabetes Care. 2013;36:1012-1019).

“In that nested, prospective case-cohort study of more than 8000 postmenopausal women followed for 11 years, there was a 6% increased risk of type 2 diabetes per standard deviation of lower reproductive lifespan in years,” the authors write.

But it still remains unknown how endogenous estrogen affects type 2 diabetes risk. Exploring that could lead to answers on how a woman could decrease diabetes risk as she ages, Dr LeBlanc and colleagues observe.

Further research could also test whether targeting women in these identified higher-risk groups could bring down the incidence of diabetes, Dr LeBlanc concluded.

Smell Test May Predict Memory Decline


The University of Pittsburgh Smell Identification Test (UPSIT) has potential as an inexpensive, noninvasive test to help diagnose Alzheimer’s disease, a new study shows.

In a study of older adults, both a low score on the UPSIT and positive amyloid beta (Aβ) status predicted memory decline.

“Reduced ability to identify odors has been seen in patients who are later diagnosed with Alzheimer’s disease at autopsy. And decreased odor identification is also seen in those with mild memory symptoms and those who develop Alzheimer’s disease dementia,” said William Kreisl, MD, from the Taub Institute and Columbia University Medical Center in New York City.

He presented the study at a press briefing here at the Alzheimer’s Association International Conference (AAIC) 2016.

Low-Cost Alternative to PET?

The investigators compared the predictive utility of odor identification impairment using the UPSIT with that of amyloid status, as determined by 11C-Pittsburgh Compound B (PIB) positron- emission tomography (PET) scanning or cerebrospinal fluid (CSF) analysis, in predicting memory decline.

Participants included 84 elderly adults from the Questionable Dementia II study who had either mild cognitive impairment (MCI) or normal memory at baseline. They had undergone either brain amyloid PET scanning or lumbar puncture at baseline and at a minimum of 6 months’ follow-up.
Amyloid positivity was defined as either CSF Aβ42 < 192 pg/mL or global PIB uptake > 1.5. Memory decline was defined as 1 standard deviation (SD) decrease over 4 years or 0.5 SD over 2 years on composite z-score from Logical Memory 1, Visual Reproduction, and Free and Cued Selective Reminding tests.

During follow-up, 67% of participants showed memory decline. After correcting for age, sex, and education, both amyloid positivity and a low UPSIT score (<35 of 40) significantly predicted memory decline, the researchers found.

Participants with a low UPSIT score were more than three times more likely to experience memory decline than those with a UPSIT score >35 (odds ratio, 3.95; P = .0192).

There also was “somewhat of a relationship between odor identification and beta-amyloid status in that those with a high UPSIT score tended to have lower amounts of amyloid on the PET scan,” Dr Kreisl said. “However, there was not perfect agreement between amyloid status and UPSIT score, so the two tests are not interchangeable,” he noted.

He also noted that the UPSIT did not predict decline as strongly in this study as has been seen in other studies. He suggested that this may due to the relatively younger age and higher educational status of the participants in the current study. The sample size was also relatively small, owing to the high cost of PET imaging.

“Despite these limitations, we conclude that UPSIT may be useful in evaluating patients who are concerned about their memory as a low-cost, noninvasive alternative to PET scan or spinal tap in assisting physicians in determining a patient’s risk of one day developing Alzheimer’s disease,” Dr Kreisl said.

Potential Biomarker

Briefing moderator Suzanne Craft, PhD, Wake Forest School of Medicine, Winston-Salem, North Carolina, said this study shows that “properties of smell can predict cognitive decline, and the ability to identify odors may be a very early sign or harbinger of future cognitive decline as well as the presence of Alzheimer’s pathology in terms of beta-amyloid, and further, that smell identification may be a correlate of beta-amyloid and has the potential to serve as a surrogate for the more expensive and invasive techniques, like amyloid imaging.”

Dr Craft, who is a member of the Alzheimer’s Association Medical and Scientific Advisory Council, said there is an “urgent need for biomarkers for Alzheimer’s disease that are simple and easily attainable, something similar to blood pressure.”

Problems with odor identification is one “very interesting” possibility, she said. “The sense of smell is supported by neurogenesis and is very strongly associated with memory, and it is thought by some that that connection might make it a very useful surrogate for what might be going on in the brain,” Dr Craft added.

FDA Approved: Toxic Decayed Meat Being Sold As “Fresh”


Many consumers are unaware that over 70% of beef and chicken in the United States and Canada is treated with poisonous carbon monoxide gas and the FDA allows it, despite the known public health risks.

A bill was introduced in Congress that would require the labeling of meat that has been treated with carbon monoxide but it was never enacted and the topic was swept under the rug entirely. [Bill: H.R. 3115 (110th) introduced on July 19, 2007; never enacted.

This practice makes meat appear and smell fresh even when contaminated with harmful bacteria such as Clostridium botulinum, Salmonella, Campylobacter, and E-coli 0157:H7.

Carbon monoxide makes meat appear fresher than it really is by reacting with the meat pigment myoglobin to create carboxymyoglobin. This bright red pigment masks the natural telltale signs of spoiled meat such as rank odors and slime. Meats containing carboxymyoglobin will appear red and fresh for days or even weeks beyond the point of spoiling.

Ironically, while it has allowed the used of carbon monoxide packaging, the FDA has also warned of the significant safety concern accompanying the use of reduced oxygen packaging (such as carbon monoxide packaging) stating that “the inhibition of the spoilage bacteria is significant because without these competing organisms, tell-tale signs signaling that the product is no longer fit for consumption will not occur.”

Cooking meat cannot eliminate the health problems that could occur when toxins are present, but not readily apparent, because of carbon monoxide. Even when contaminated meats are properly cooked, some toxins can survive.

grocmeat ft

The FDA’s acceptance of the GRAS (Generally Regarded As Safe) notifications for the use of carbon monoxide in fresh meat is illegal because it ignores existing Federal statutes and regulations. Precisely because of the potential for carbon monoxide to mask the appearance of spoilage and promote consumer deception, FDA regulations (Section 173.350) expressly prohibit the use of carbon monoxide in “fresh meat products.”

 

The FDA has evaluated the issue of carbon monoxide use in meat products on at least three separate occasions yet they claim carbon monoxide is still GRAS.

 

Regulations of the U.S. Department of Agriculture’s Food Safety and Inspection Service (FSIS) also prohibit the introduction of ingredients in fresh meat that function to conceal damage or inferiority, or to give the appearance the product is better or of greater value.

Because of these safety concerns, many countries have banned the use of carbon monoxide in certain foods. The European Union prohibited the use of carbon monoxide in meat and tuna after the European Commission’s Scientific Committee on Food concluded: “The stable cherry-color can last beyond the microbial shelf life of the meat and thus mask spoilage.” Canada, Japan and Singapore have similarly banned the use of carbon monoxide in tuna.

In addition to the public health concern regarding foodborne illness, Prevent Disease reports:

Carbon monoxide (often referred to as CO) is a colorless, odorless, tasteless gas, one measly oxygen molecule away from the carbon dioxide we all exhale. But that one molecule makes a big difference in that it does very, very bad things to the human body at very, very low concentrations.

CO is toxic because it sticks to hemoglobin, a molecule in blood that usually carries oxygen, even better than oxygen can.

When people are exposed to higher levels of CO, the gas takes the place of oxygen in the bloodstream and wreaks havoc. Milder exposures mean headaches, confusion, and tiredness. Higher exposures mean unconsciousness and death, and even those who survive CO poisoning can suffer serious long-term neurological consequences.

Intelligent people have one thing in common


According to a few different studies, intelligent people are more likely to be nocturnal than people with lower IQ scores. In a study run on young Americans, results showed that intelligent individuals went to bed later on weeknights and weekends than their less intelligent counterparts.

In “Study Magazine,” Satoshi Kanazawa, a psychologist at the London School Of Economics And Political Science, reported that IQ average and sleeping patterns are most definitely related, proving that those who play under the moon are, indeed, more intelligent human beings.

The data supports the notion that all night owls feel: the only real time for living is after everyone’s gone to bed.

Intelligent people have one thing in common

Stats

Very Dull (IQ < 75)
Weekday: 11:41 pm -7:20 am
Weekend: 12:35 am -10:09 pm

Normal (90 < IQ < 110)
Weekday: 12:10 am -7:32 am
Weekend: 1:13 am -10:14 am

Very Bright (IQ > 125)
Weekday: 12:29 am -7:52 am
Weekend: 1:44 am -11:07 am

Are you a night owl and you think there is a correlation?

Florida regulators approve hike in some cancer-causing toxic substances in state water


A hydraulic fracturing site in South Montrose, Pa. Also known as fracking, it stimulates gas production by injecting wells with high volumes of chemical-laced water to free up pockets of natural gas below. A Florida panel voted Tuesday to relax standards on dozens of chemicals in the state's water, including benzene, a toxic byproduct of fracking. (Photo by Spencer Platt/Getty Images)

A hydraulic fracturing site in South Montrose, Pa. Also known as fracking, it stimulates gas production by injecting wells with high volumes of chemical-laced water to free up pockets of natural gas below. A Florida panel voted Tuesday to relax standards on dozens of chemicals in the state’s water, including benzene, a toxic byproduct of fracking.

TALLAHASSEE — Florida regulators voted to approve new water quality standards Tuesday that will increase the amount of cancer-causing toxic substances allowed in state rivers and streams under a plan that officials say will protect more Floridians than current standards.

The Environmental Regulation Commission voted 3-2 to approve a proposal drafted by state regulators that would impose new standards on 39 chemicals not currently regulated by the state and revise the regulations on 43 other toxics, most of which are carcinogens.

“We have not updated these parameters since 1992. It is more good than harm,” said Cari Roth, a Tallahassee lawyer who represents developers on the commission and serves as its chair. “The practical effect is, it is not going to increase the amount of toxins going into our waters.”

But the proposal, based on a one-of-a-kind scientific method developed by the Florida Department of Environmental Protection and nicknamed “Monte Carlo,” is being vigorously criticized by environmental groups. They warn the new standard will allow polluters to dump dangerous amounts of chemicals in high concentrations into Florida waters before they trigger the limits of the new rule, and allow Florida to adhere to standards that are weaker than federal guidelines.

“Monte Carlo gambling with our children’s safety is unacceptable,” said Marty Baum of Indian Riverkeeper, an environmental group based in Indian River County.

Under the proposal, the acceptable levels of toxics will be increased for more than two dozen known carcinogens and decreased for 13 currently regulated chemicals. DEP, however, touted the part of the plan that will impose new rules on 39 other chemicals that are not currently regulated, including two carcinogens.

“The department has left no stone unturned to develop science-based and legally defensible criteria,” said Tom Frick, director of the DEP division of environmental management and restoration, at the daylong meeting.

The federal Environmental Protection Agency must now approve the rules, which are required under the federal Clean Water Act, before they take effect. After the narrow vote, several members of Florida’s congressional delegation sent a letter to the head of the EPA, voicing their concerns and asking for a public comment period for them to carefully evaluate each proposed human health criteria “to ensure the utmost protection for our population, environment, and economy.”

Linda Young, executive director of Clean Water Network, which led the opposition to the rule, said her group will urge EPA to reject the rule but, if it is approved, “then absolutely we will file suit,” she said.

DEP aggressively defended its proposal, saying it has been developing the criteria for more than a decade and was forced to develop a consistent model that could be defended in court. Drew Bartlett, assistant secretary at DEP, said one of the most frequent questions is why the state can’t retain the current levels relating to carcinogens while adopting new levels for all the other compounds.

“What would be wrong with keeping the current levels?” he said. “We’re charged with implementing state law and federal law, and those two laws don’t make room for not basing the criteria on a scientific process because they have to be based on logic and facts.”

Agency officials also defended the use of the Monte Carlo scientific method — also known as “probabilistic analysis” — saying it is more responsive to Florida variables by shielding people who consume large amounts of fish from the buildup of dangerous toxics.

The approach creates thousands of variables to calculate the health effects of being exposed to a lifetime of toxic chemicals by taking into consideration average body weight, drinking water consumption rate, fish and shellfish consumption rate, and the fat content of fish — important because fat absorbs most of the toxics in seafood.

During the hearing, more than three dozen people representing the Miccosukee Tribe, the Conservancy of Southwest Florida, Broward County, Martin County, Physicians for Social Responsibility and others raised concerns. Many of them argued that 80 percent to 90 percent less protective for most chemicals than the federal EPA recommendations.

“We want this to happen but we’d like this to happen in a way that is actually going to protect human health in Florida,” said Linda Young, executive director of the Florida Clean Water Network.

Commissioner Adam Gelber of Miami, a senior scientist who represents science and technical interests on the commission, opposed the rule. He commended the department but said he was not confident that the information was based on Florida data.

“I fear there is a fatal flaw,” Gelber said. He questioned the decision by DEP to increase the allowed levels of benzene, a known carcinogen.

DEP initially proposed raising the standard from 1.18 parts per billion in Florida’s drinking water sources to 3 parts per billion but, after public outcry, the agency revised its criteria and reduced the level to 2 parts per billion. The federal standard is 1.14 parts per billion.

“If we went back and adjusted the models, how would the other criteria drop?” he asked. “… It would appear to me there are some tweaks in the system that could be made across the board.”

Environmentalists say they are suspicious that DEP has increased the levels of benzene, which is found in the wastewater of oil and gas hydraulic fracturing operations, in an effort to pave the way for fracking in Florida.

DEP officials, however, said that the science of benzene has changed in recent years resulting in the higher limits.

Also voting against the proposal was Commissioner Joe Joyce of Gainesville, who represents agricultural interests on the commission. He also raised questions about the unexplained rise in benzene levels and asked Bartlett if there was “any correlation between this rule and benzene and fracking?”

“We don’t see a connection between this rule and fracking,” Bartlett responded. The the audience jeered.

Commissioner Craig Varn, a lawyer from Tallahassee who was the DEP general counsel a year ago, supported the rule, saying the decision came down to whether was going to accept the new modeling method or not.

“I’m erring on the side of human health,” he said. “Is it perfect? No.”

In an interview with the Times/Herald, Varn said he could not recall being involved in the development of the rule while he was general counsel.

Broward County’s top environmental scientist was among those who urged the commission to reject the new rule, warning that it will lead to dangerous concentrations of chemicals that may not be detected by testing.

DEP’s documents acknowledge that permits can be allowed to require companies to meet the water quality standard in a water body after the discharge has passed through what is known as “mixing zones,” thereby allowing for dilution and diffusion of the pollution beyond the point of discharge before it’s tested, said Jennifer Jurado, director of Broward County environmental planning and community resilience division.

By contrast, she said, Broward County water quality criteria imposes a stricter standard, imposing water quality testing at the end of the pipe where the chemicals are discharged into a water body.

“So there is a lot of flexibility, depending on how they choose to apply the standard, that creates an exposure,” she said.

The commission was scolded for not having its full complement of members while agreeing to reschedule the vote on the controversial rules from September to July.

As the commission was about to take a vote, John Moran, who identified himself as a graduate student from Stanford University, walked to the dais and sat in an open chair.

“The governor has spat on our decision process by keeping these seats vacant for over a year,” he said. DEP security escorted him out, and the commission voted.

Higher osteoprotegerin levels associated with foot ulcer in type 1 diabetes


In patients with type 1 diabetes, higher levels of the glycoprotein osteoprotegerin are associated with development of a foot ulcer, independent of other well-known risk factors, according to recent findings.

“Diabetic foot ulcers are a frequent, disabling and costly occurrence; however, it is a complication often overlooked in terms of research,” Emilie Hein Zobel, MD, of the Steno Diabetes Center in Gentofte, Denmark, and colleagues wrote. “To the best of our knowledge, we are the first to show an association between higher levels of [osteoprotegerin] and development of foot ulcer in type 1 diabetes, independent of other risk factors. This might be attributed to the role of [osteoprotegerin] both in peripheral vascular disease and neuropathy; the two major factors contributing to foot ulcer.”

In a prospective cohort study, Zobel and colleagues analyzed data from 573 adults with longstanding type 1 diabetes and persistent normoalbuminuria (n = 176) or type 1 diabetes and diabetic nephropathy (n = 397), recruited from the Steno Diabetes Center between 1993 and 2002. Participants provided blood samples; researchers measured serum cholesterol, HbA1c, urinary albumin excretion rate, serum creatinine level and estimated glomerular filtration rate. Researchers assessed participants for the presence of foot ulcer, Charcot foot, amputation, foot pulse and claudication at baseline and from patient record information; baseline information on lower limb vascular surgery was not available. Peripheral sensory neuropathy was evaluated at baseline and follow-up.

Participants with foot complications were excluded when analyzing the association between osteoprotegerin and development of foot complications. At baseline, 23 participants had a foot ulcer; three had Charcot foot; 14 had a lower limb amputation or vascular surgery; 31 had absent foot pulse and 198 had neuropathy. Of the remaining patients, 153 developed foot ulcer; 14 developed Charcot foot; 53 underwent amputation or vascular surgery during median follow-up time of 12.7 years.

In models adjusted for age, sex, nephropathy status, smoking status, HbA1c, systolic blood pressure, serum cholesterol, high sensitivity C-reactive protein, eGFR and presence of neuropathy or claudication at baseline, researchers found that higher osteoprotegerin level was associated with development of foot ulcer (HR = 1.75; 95% CI, 1.04-2.97). Other independent risk factors for development of foot ulcer included neuropathy at baseline (HR = 1.98; 95% CI, 1.17-3.37); nephropathy (HR = 2.05; 95% CI, 1.14-3.7) and male sex (HR = 1.36; 95% CI, 1.59-1.01).

Researchers also found that higher osteoprotegerin was associated with development of a combined endpoint of Charcot foot, amputation, vascular surgery and foot ulcer after adjustment for age and sex (P = .001), but any association was lost after adjustment for other factors.

“Measuring [osteoprotegerin] is relatively uncomplicated and inexpensive,” the researchers wrote. “Our findings, and previous studies, illustrate that this biomarker may also be helpful in the risk assessment for foot complications, and in particular for foot ulcers in type 1 diabetic persons. However, our findings need to be validated and further studies are needed to establish cutoff values and to document the added value to currently available strategies before using [osteoprotegerin] in screening.” – by Regina Schaffer

Dementia Drugs Increase Survival, Save Money


For patients with Alzheimer’s disease (AD), early treatment with currently recommended medications may prolong survival and save healthcare dollars, compared with nontreatment, according to a longitudinal retrospective study.

“The arguments for early treatment are myriad, but this study shows greater survival and less all-cause healthcare costs among those receiving treatment for dementia,” Christopher M. Black, MPH, from Merck Research Laboratories, said in a statement.

“These results indicate that choosing not to treat, or even a delay in starting treatment, may lead to less favorable results. Early diagnosis and time to treatment should be a priority for policy makers, physicians, and the public,” Black noted.

He presented the study findings at a press briefing here at the Alzheimer’s Association International Conference (AAIC) 2016.

Positive Economic, Patient Impact

Few studies have assessed the effects of existing antidementia drug therapies on the economy and mortality in comparison with no treatment in patients in the United States who have been newly diagnosed with Alzheimer’s disease, Black explained.

To investigate, the study team identified 6553 incident cases of Alzheimer’s disease from Medicare fee-for-service claims data over a 2-year period. Three quarters of the patients were women. They were categorized as being either treated and nontreated on the basis of whether they were prescribed an existing AD drug after diagnosis. The patients were followed until death, disenrollment, or the end of the study period.
Common first treatments for those patients receiving treatment were donepezil (multiple brands, 66.8%), memantine (Namenda, Forest Labs, 18.5%), rivastigmine (Excelon, Novartis, 12.5%), and galantamine (Razadyne, Janssen, 2.0%).

Compared with treated patients, untreated patients were generally older and had more comorbid conditions. In addition, the unadjusted death rate during the study period was higher for patients receiving treatment than for untreated patients.

In a propensity score-matched cohort of 694 treated and 694 untreated patients, survival was better for the treated patients (hazard ratio, 0.72; P = .0079), and they had fewer hospice visits (0.04 vs 0.09; P = .0001) and lower monthly all-cause costs ($2207 vs $2349, P = .3037) in comparison with untreated patients.

For all patients, average healthcare costs more than tripled in the first month after an AD diagnosis. But patients receiving Alzheimer’s medication had lower overall health carecosts in the month they were diagnosed compared with those who did not receive a treatment ($5535 vs $6711).

Following the month of diagnosis, healthcare costs decreased, but the average cost per patient per month remained considerably higher than baseline. The biggest driver of cost was inpatient care, which made up 30% of the total expenditures for both treated and untreated patients.

The study also showed that only 35% of patients were prescribed an antidementia drug after their diagnosis.

“The new results support that early Alzheimer’s treatment ― even with today’s first-generation therapies ― has significant potential to benefit the person with the disease, and the economy,” said Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, in a conference statement.

“Today, Alzheimer’s is incurable and progressive, and some assume that treating dementia is an unjustified cost drain on our healthcare system, but this study presents compelling arguments for prescribing the standard of care,” she added.

In an interview with Medscape Medical News, Dr Carrillo said this is an important study because “right now, we think of standard of care as not as effective as we’d like, and some people actually question whether Alzheimer’s treatments are effective at all in their loved one. This study, along with others in the past that have shown delayed institutionalization with treatment, shows that there is some benefit to current standard of care.”

This study, she added, shows that “treatment actually can make a difference in mortality. It’s important for neurologists to know this because there is some sense of nihilism in the field in general with standard of care.”

Inflammatory Cytokines in Atherosclerosis: Current Therapeutic Approaches


Abstract

The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.

Introduction

Atherosclerosis is considered to be a chronic inflammatory disease[1] and scientific interest has focussed on the role of cytokines as possible therapeutic agents for atherosclerosis, as cytokines are known to orchestrate the complex inflammatory response within the atherosclerotic plaque. Indeed, cytokines are produced by and act (often synergistically) on almost all cells involved in the pathogenesis of atherosclerosis, participating in all steps of the process, from the early endothelial dysfunction to the late formation and disruption of a vulnerable plaque.[2]

Throughout the years multiple therapeutic approaches in the cardiovascular field, i.e. statins and anti-hypertensive agents, have shown their ability to modify immunological and inflammatory responses in parallel to their principal effects as cholesterol-lowering agents or blood pressure reduction.[3]Moreover, novel agents directed against specific targets in the inflammatory cascade are now also being applied in clinical settings.[4] Interest in this novel therapeutic field is expanding rapidly, as demonstrated by the large number of ongoing clinical trials involving this kind of agents. As our knowledge regarding the role of cytokines in atherogenesis expands, newer approaches come to light and many show promising results in the fight against atherosclerosis. The goal of this review is to describe the actions and effects of anti-inflammatory agents, highlight available data on their clinical significance, and provide further insight regarding their future prospects.

Cytokines and Atherosclerosis

In the context of atherosclerosis, cytokines can be classified broadly as pro- or anti-atherogenic, depending on their effects on the formation and progression of the atherosclerotic plaque (Figure 1).

Figure 1.

Pro- and anti-atherogenic cytokines. Cytokines can be divided into two groups depending on whether they promote or suppress atherogenesis. Notably, there are also cytokines such as interleukin-2 and interleukin-17 whose exact role in atherogenesis has not been fully elucidated. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-α,β,γ, interferon-α, -β, and -γ; IL, interleukin (e.g. IL-1β, interleukin-1β); MCP-1, monocyte chemoattractant protein-1; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α.

Pro-atherogenic Cytokines

Pro-atherogenic cytokines such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6 are secreted by macrophages, lymphocytes, natural killer cells, and vascular smooth muscle cells.[2] Tumour necrosis factor-α and IL-1 signalling is mainly mediated by the p38 mitogen-activated protein kinase (p38MAPK)/nuclear factor kappa-light-chain-enhancer of the activated B-cell (NF-κ) pathway,[5] and this affects almost all cells involved in atherogenesis by promoting the expression of cytokines, adhesion molecules, and the migration and mitogenesis of vascular smooth muscle and endothelial cells.[2]

The actions of pro-atherogenic cytokines can be better appreciated based on experimental studies with hyperlipidaemic mouse models. For example, TNF-α−/−, apolipoprotein E (ApoE)−/− double knockout mice showed decreased atherogenesis, endothelial adhesiveness, and inflammatory markers when compared with controls.[6] Similar conclusions were drawn when ApoE−/− mice were treated with a recombinant soluble TNF-αp55 receptor that acted as decoy to inhibit TNF-α activity.[7] In humans, TNF-α promotes the interaction between circulating leucocytes and the endothelium through up-regulation of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1).[8]

Interleukin-6 actions on the other hand are mediated by the IL-6 receptor and a signal transducing protein called gp130, which result in activation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 and 3.[9] In studies with ApoE-deficient mice, recombinant IL-6 injections exacerbated the progression of atherosclerosis.[10] Clinical studies have further revealed that IL-6 serum levels are increased in unstable angina patients and are considered an independent risk factor for coronary artery disease (CAD).[2,11]

Anti-atherogenic Cytokines

Contrary to TNF-α, IL-1, and IL-6, several other cytokines appear to act in a protective manner against the formation of atherosclerotic plaques. For example, transforming growth factor-β (TGF-β) is closely associated with T-regulatory (Treg) cells, a distinct subset of T lymphocytes with known immunomodulatory activity. It is known that part of the immunomodulatory activity of Treg cells is mediated by the secretion of anti-inflammatory and atheroprotective cytokines including TGF-β, IL-10, and IL-35.[12] As far as IL-10 is concerned, it appears to possess multiple anti-atherogenic activities including but not limited to down-regulation of TNF-α production[13] and intercellular adhesion molecule 1 (ICAM-1) expression on endothelial cells.[14]

Even though a detailed presentation of the role of all cytokines goes beyond the scope of this review, it is crucial to keep in mind that cytokine actions are extremely complex. This issue represents an enormous challenge when developing and testing novel cytokine-related treatments, a problem that will become more evident as we discuss the potential risks and benefits of newer therapeutic approaches.

The Emerging Role of Cytokine-related Treatment

Established Clinical Approaches in Humans

The first steps towards the development of anti-inflammatory treatments in atherosclerosis were accomplished while studying patients with chronic inflammatory and autoimmune diseases, such as psoriasis or rheumatoid arthritis. It has long been known that these conditions are associated with an increased risk of atherosclerosis similar to that of diabetes mellitus[15] and a more severe presentation of adverse cardiovascular events.[16,17] In addition, treatment with methotrexate or biological agents in rheumatoid arthritis protects against atherosclerosis,[18] whereas anti-TNF-α therapy is also associated with a reduced risk for all cardiovascular events.[19]

In general, anti-inflammatory approaches in atherosclerosis can be divided into two major categories. The first includes conventional drugs with broad-based anti-inflammatory properties such as statins, aspirin, methotrexate, and colchicine, which can additionally affect the inflammatory cascade. The second group includes anti-inflammatory drugs designed to inhibit specific mediators and cytokines in the inflammatory pathway (Table 1 and Figure 2). Several ongoing and completed clinical trials testing the effects of these interventions in humans are summarized in Table 2 and Table 3.

Cytokine-related therapeutic approaches in atherosclerosis. In the context of atherosclerosis, several methods have been studied to modify the inflammatory cascade. 1. Broad-based immunomodulatory agents. 2. Blockade of pro-inflammatory cytokines. 3. Delivery of anti-inflammatory cytokines with adenovirus vectors or liposomes. 4. Induction of regulatory T cells. 5. In vivo transfection with oligonucleotides. IL, interleukin; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cell.

Statins. Statins are traditionally known for their hypolipidaemic effects but have also been shown to act in an immunomodulatory manner. This is believed to be due to decreased production of isoprenoid intermediates that are responsible for the post-translational modification of small GTPases. In other words, statins are able to modify intracellular inflammatory pathways.[3]

Indeed, several statins have been shown to antagonize the effects of inflammatory cytokines (Figure 3). For example, simvastatin appears to neutralize the pro-inflammatory and pro-atherogenic actions of TNF-α through inhibition of the TNF-α-induced expression of VCAM-1 and suppression of thrombomodulin and endothelial nitric oxide synthase.[20] Atorvastatin improves vascular nitric oxide bioavailability and decreases the post-glucose loading levels of TNF-α.[21] In addition, statins have been shown to affect the production of cytokines by leucocytes[43] down-regulating the production of pro-inflammatory IL-1 and up-regulating the anti-inflammatory cytokine IL-10.[44,45] Interestingly, recent studies have shown that the reduction of C-reactive protein (CRP) levels with statin treatment is independent from the reduction in LDL cholesterol levels.[46]

Examples of cytokine-related statin effects in the microenvironment of an atherosclerotic plaque. Statins have been shown to antagonize the effects of inflammatory cytokines. For example, simvastatin neutralizes the pro-atherogenic actions of tumour necrosis factor-α through inhibition of the tumour necrosis factor-α-induced expression of vascular cell adhesion molecule 1 and suppression of thrombomodulin, whereas atorvastatin improves vascular nitric oxide bioavailability. Simvastatin can potently down-regulate the production of known pro-inflammatory cytokines such as interleukin-1 while also up-regulating the expression of anti-inflammatory cytokines such as interleukin-10. Finally, simvastatin is also able to counteract the combined pro-proliferative effects of tumour necrosis factor-α and interleukin-18 on aortic smooth muscle cells. IL, interleukin; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.

It is therefore generally accepted that statins exert pleiotropic actions and affect a variety of parameters associated with atherosclerosis. Early administration of low-dose atorvastatin in patients with ST-elevation myocardial infarction (SEMI) can even improve the clinical outcome by down-regulating endothelial activation and inflammation.[47] Recently, the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) has reported the beneficial effects of rosuvastatin in contrast-induced nephropathy caused in subjects with ST elevation myocardial infraction.[48] Since inflammation promotes endothelial dysfunction and vulnerability of kidney vessels, this action may be mediated by anti-inflammatory effects of statins, as it was recently proposed.[49]

In regard to clinical applicability, several studies have revealed that an inflammatory-based treatment approach may be useful. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a 5-year randomized trial that included 5742 subjects without CAD, it was shown that lovastatin prevented ACS especially in the high CRP group despite a favourable lipid profile. Indeed, lovastatin reduced CRP levels by 15%, and it was effective to reduce cardiovascular events even in patients with favourable lipid profile at baseline but with increased CRP levels. Importantly, it was found that the number needed to treat to prevent one event in this category of patients with CRP levels >0.16 mg/dL was 48.[50] In line with this evidence, the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)—one of the most important large-scale randomized control studies, which included 17 802 apparently healthy individuals randomized to either rosuvastatin 20 mg/day or placebo with follow-up for a median of 1.9 years—demonstrated that in subjects with CRP levels >2 mg/L, even with low LDL cholesterol levels, rosuvastatin treatment can decrease adverse cardiovascular events.[51] Notably, the greatest benefit is observed in patients in whom rosuvastatin treatment decreases not only LDL levels <70 mg/dL but also CRP levels <1 mg/L (79% reduction in the event rate compared with subjects in the placebo arm or 0.24 events per 100 persons compared with 1.11 events per 100 persons, respectively).[52] This is in accordance with several studies which show that the beneficial effects of statins cannot and should not be solely attributed to their lipid-lowering effects but are also related to their ability to dampen inflammation or improve endothelial[53] and arterial wall function[54] through lipid-independent mechanisms.[3]

Aspirin. Aspirin inhibits cyclooxygenase irreversibly and suppresses the production of prostaglandins and thromboxanes.[55] Therefore, it acts not only as an antiplatelet agent but also as an anti-inflammatory one. In murine models of atherosclerosis, low-dose aspirin improves vascular inflammation and plaque stability.[56] Recent data in ApoE-deficient mice support the hypothesis that aspirin can also reduce fractalkine levels (fractalkine acts both as a chemokine and as an adhesion molecule) and improve the severity of atherosclerotic lesions.[57] Recently, it was also documented in humans that low-dose aspirin treatment reduces chemerin (a peptide chemoattractant for macrophages and an adipokine-regulating adipocyte differentiation and metabolism) secretion by adipocytes through reduction of pro-inflammatory cytokine secretion by macrophages.[58] Aspirin further protects human endothelial function in the presence of inflammation[59] and decreases the plasma levels of several inflammatory cytokines and markers such as IL-6, CRP, and monocyte colony-stimulating factor (M-CSF) in patients with stable angina.[60] Interestingly, the use of aspirin as a primary prevention therapy is associated with a reduction in the development of myocardial infarction, which appears to be directly related to CRP levels, raising the possibility that the anti-inflammatory properties of aspirin may be as important as its anti-thrombotic effects.[61] Moreover, in primary prevention, aspirin can improve arterial stiffness even after 2 weeks of low dose (160 mg/day).[62] However, we have to notice that the exact anti-atherosclerotic effect of aspirin cannot be determined as reports support the notion that aspirin can reduce hypertriglyceridaemia, cholesterol, and free fatty acid production[63] but also increases lipid peroxidation.[64] Indeed, the exact benefit of aspirin in chronic CAD has recently been questioned by the results of the CONFIRM study (Coronary CT Angiography EvaluatioN for Clinical Outcomes study). In this multicentre international registry, 5712 individuals with normal coronary arteries and 4706 individuals with non-obstructive CAD were followed up for a median of 27.2 months, and aspirin use, contrary to statins, was not associated with mortality benefit in patients with non-obstructive CAD irrespective of the status of the plaque.[65] Similarly, data from the prevention of progression of arterial disease and diabetes (POPADAD) trial have shown that even in patients with diabetes mellitus and asymptomatic peripheral arterial disease aspirin did not reduce the rate of cardiovascular events.[66] Moreover, in 1884 recipients of low-dose aspirin with chronic kidney disease paired with 1884 non-recipients, the incidence of atherosclerotic events was significantly higher in the aspirin users.[67] It would be interesting to study the effects of aspirin in groups with elevated vs. low levels of circulating inflammatory markers.
Methotrexate. Methotrexate is an antimetabolite drug that acts by inhibiting the metabolism of folic acid. Its anti-inflammatory actions, however, may also be attributed to an increase in adenosine levels.[68] In fact, methotrexate treatment reduces the size of experimentally induced myocardial infarction probably via adenosine release which not only reduces inflammation but also improves coronary flow in the culprit lesion.[69] In addition, previous studies have shown that methotrexate can further modulate the expression of ICAM-1, E-selectin, VCAM-1,[22] and IL-6.[23]

Interestingly, studies have proved that low-dose methotrexate can decrease the cardiovascular risk of patients with chronic inflammatory disease. In patients with rheumatoid arthritis, methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality.[40] Similar results were also described by van Halm et al. in a case–control study.[70] However, some studies did not confirm the protective role of methotrexate in the incidence of cardiovascular events in rheumatoid arthritis patients.[71] Therefore, further studies have now been designed to test this hypothesis. For example, the Cardiovascular Inflammation Reduction Trial (CIRT) aims to enrol 7000 individual to test the role of methotrexate in the medical management of stable CAD patients with persistent elevation of high-sensitivity CRP,[72] while the TETHYS trial aims to evaluate its value in reducing infarct size when administered within the first 6 h of admission for ST-elevation myocardial infraction.[73] Furthermore, a recently announced CIRT sub-study aims to evaluate the effects of methotrexate in arterial inflammation (as seen on PET-CT scanning) in patients with prior MI or multi-vessel CAD (NCT02576067). It is difficult, however, to definitely conclude that the beneficial effect of methotrexate in cardiovascular incidence is solely due to its anti-inflammatory properties. Studies have recently documented that methotrexate modifies lipid levels increasing both HDL and LDL cholesterol and affects macrophage cholesterol handling opposing foam cell formation.[74]

Colchicine. Evidence for the ability of colchicine to modify cytokine levels is based on patients with familiar Mediterranean fever. In this condition, modification of the inflammatory cascade with colchicine not only reduces symptoms of the disease but also decreases the risk for ischaemic heart disease.[75] In addition, a retrospective cross-sectional study concluded that long-term treatment of gout with low-dose colchicine decreased not only CRP levels but also the incidence of myocardial infraction.[76] Furthermore, Nidorf and Thompson showed that colchicine, in addition to aspirin and high-dose atorvastatin treatment, can significantly lower high-sensitivity CRP in patients with stable CAD.[24] Finally, in the Low-Dose Colchicine (LoDoCo) trial—a prospective, randomized, observer blinded endpoint design study of 532 subject—addition of colchicine 0.5 mg/day to aspirin and/or clopidogrel and statins in CAD patients resulted in lower incidence (5.3%) of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischaemic stroke vs. the placebo group (16%).[39] Currently, several ongoing trials aim to evaluate the potential benefit of colchicine in improving cardiovascular indices and prognosis in patients with CAD as summarized in Table 2 and Table 3.

Corticosteroids. A few reports that examined intermediate atherosclerotic markers such as arterial stiffness as assessed by pulse wave velocity have shown that the use of corticosteroids can act beneficially in some chronic inflammatory disorders such as polymyalgia rheumatic.[77] However, corticosteroids in the setting of acute myocardial infarction have failed to demonstrate significant mortality benefit, as shown in one meta-analysis of randomized control trials.[41] In addition, long-term use of corticosteroids in rheumatoid arthritis patients is associated with a significantly higher incidence of acute myocardial infarction.[78]

Specific Target-based Anti-inflammatory Treatment

Blockade of Pro-inflammatory and Delivery of Anti-inflammatory Cytokines. As described in the previous section, the prophylactic effect of broad-based anti-inflammatory treatments is currently limited to statins and aspirin. Nevertheless, especially for aspirin, its value in primary prevention is equivocal while for methotrexate, colchicine, and corticosteroids results are not definitive. Therefore, several novel strategies have been developed to more specifically antagonize the actions of pro-inflammatory cytokines, the most important being the administration of soluble decoy receptors, direct receptor antagonists (e.g. endogenous IL-1Ra), and monoclonal antibodies (Table 4).

Anti-tumour Necrosis Factor-α Treatment: Several anti-TNF agents (infliximab, etanercept, adalimumab, golimumab, and certolizumab) have been introduced recently against inflammatory and autoimmune diseases.[85]

Interestingly, spare pre-clinical data have shown that anti-TNF treatment can favourably affect atherosclerosis. Recently, in a model that reproduced in vivo interactions between leucocytes and endothelial cells, anti-TNF treatment diminished leucocyte-endothelial interactions induced by inflammatory stimuli.[86] It is currently known that treatment with anti-TNF agents can improve endothelial function and arterial wall properties in patients with autoimmune diseases, such as psoriasis.[27] Moreover, it has been reported that inhibition of TNF-α in rheumatoid arthritis can increase circulating endothelial progenitor cells concurrently with a proportional decrease of disease activity[79] and decrease serum asymmetric dimethyl arginine levels.[26]

Clinical studies have revealed that anti-TNF-α therapies in patients with ankylosing spondylitis improve subclinical atherosclerosis and aortic stiffness when compared with placebo controls.[87] A meta-analysis published in 2011 showed that anti-TNF-α treatment in rheumatoid arthritis is associated with a lower risk for all cardiovascular events.[19] Nevertheless, we have to take into consideration that studies with these agents in patients with chronic heart failure have failed to improve patient outcome.[88] Unfortunately, there are currently no ongoing trials evaluating the exact health or mortality benefit of anti-TNF-α agents in a large cohort of healthy or CAD patients and studies so far have been limited to rheumatological patients.

Interleukin-1β Inhibition: Canakinumab is a monoclonal human antibody that binds to human IL-1β, blocking its interaction with its receptor. Interleukin-1β has so far been used in the treatment of rare hereditary IL-1β-driven disorders, such as Muckle–Wells syndrome. Treatment of such cryopyrin-associated periodic syndromes and rheumatoid arthritis with canakinumab produces a rapid and sustained inhibition of the acute phase response resulting in a substantial reduction in CRP levels.[89,90]

Previously, studies have shown that IL-1-deficient mice show decreased atherosclerosis.[91] Moreover, in an atherosclerotic mouse model, inhibition of IL-1 orients tissue macrophages to an anti-inflammatory phenotype and atherosclerotic lesions are therefore reduced.[92]

Furthermore, canakinumab has been shown to effectively reduce glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels in male patients with well-controlled diabetes mellitus and high cardiovascular risk.[28] However, a definite cardiovascular event or survival benefit has not been demonstrated yet but is currently investigated by the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), which focusses on post-myocardial patients with persistent elevation of high-sensitivity CRP.[83]

Another approach used to modify IL-1 activity is by enhancing the activity of IL-1Ra, which in turn negatively regulates IL-1 signalling. For example, anakinra, a human IL-1Ra, can block the biological activity of IL-1 in rheumatoid arthritis patients by competitively inhibiting the binding of IL-1 to the IL-1-type receptor and also reduces IL-6 and endothelin-1 levels with a parallel increase in flow-mediated dilation, coronary flow reserve, and aortic dispensability.[84] In the MRC-ILA-HEART study, subcutaneous IL-1Ra administration for 14 days in non-SEMI (NSTEMI) patients resulted in lower CRP and IL-6 levels at the end of the treatment; however, a higher rate of MACE was observed after the treatment (HR 3.39, 95% CI 1.10–10.4, P = 0.023).[29] The VCU-ART 2 (Virginia Commonwealth University Anakinra Remodeling Trial) study showed that anakinra given for 2 weeks post-STEMI has a neutral effect on recurrent ischaemic events but may lower new heart failure incidence or mortality at 1 year (HR 0.16, 95% CI 0.03–0.76, P = 0.008),[38] a finding that will be further evaluated by the more recent VCU-ART-3 trial (NCT01950299).

Intereleukin-6 Inhibition: Potential strategies using anti-IL-6 therapies have not been as widely tested as in the case of TNF-α or IL-1. Tocilizumab is a monoclonal antibody that blocks both membrane-bound and circulating IL-6 receptor. Randomized trials in patients with rheumatoid arthritis have shown that tocilizumab increases total, HDL, and LDL cholesterol and triglyceride levels.[93] Moreover, it results in improved endothelial function and decreased aortic stiffness.[30] Currently, several ongoing studies investigate the role of tocilizumabin in NSEMI (NCT01491074, Phase 2 trial) and in comparison to etanercept in patients with rheumatoid arthritis and cardiovascular risk factors (NCT01331837, Phase 4 trial).

Anti-interleukin-12/23p40 and Anti-interleukin-17 Agents: Monoclonal antibodies that are targeted against the shared p40 subunit of IL-12 and IL-23 have recently been introduced in the treatment of psoriasis. These cytokines mediate the function of Th17 cells, a distinct subset of T cells that have been identified as a pro-atherogenic group of leucocytes within the atherosclerotic plaque.[94] Despite these pro-atherogenic effects, a recent meta-analysis concluded that treatment with such agents (ustekinumab and briakinumab) may even increase the risk for major adverse cardiovascular events when compared with placebo.[42] Brodalumab (an IL-17 receptor A antagonist), ixekizumab, and secukinumab (IL-17A antagonists), also used in psoriasis, are potential antagonists of atherosclerosis, given the pro-inflammatory nature of IL-17.[95] Interleukin-17 inhibition attenuates atherosclerosis in animals,[96] but clinical studies in humans are not available to date.

Anti-P-selectin Agents: P-selectin, a cell adhesion molecule that organizes endothelial cell and platelet interactions, plays a role in leucocyte activation, formation of thrombi, and neointimal formation. The SELECT ACS study in 544 patients with NSTEMI showed that inclacumab—a recombinant monoclonal antibody against P-selectin—decreases the myocardial damage.[97] However, the SELECT CABG study, a Phase 2 trial, which is planning to test the efficacy of inclacumab in saphenous vein graft disease, has not yet been published.

Targeting Post-ischaemic Reperfusion Injury. Re-establishment of coronary perfusion after an acute ischaemic event causes the so-called reperfusion injury, which is attributed to oxidative stress, accumulation of reactive oxygen species, and ultimately diminished mitochondrial ability to produce energy in the form of ATP.[98] Bendavia is an intravenously administered mitochondrial targeting peptide that has been shown to reduce myocardial infarct size and attenuate coronary no-reflow in experimental models when given before reperfusion.[99] Therefore, the EMBRACE STEMI study enrolled 300 patients with first anterior STEMI to test whether Bendavia is superior to placebo for the reduction of myocardial infarction size.[100] The first preliminary reports of this study have recently been announced and have shown that Bendavia infusion is safe although it did not achieve a significant reduction in the infarct size. However, future trials are planning to test if higher doses can be beneficial in patients with systolic heart failure (NCT02388464 and NCT02388529).

Experimental Approaches in Animal Models. Future directions concerning the targeted modification of the inflammatory cascade can be derived from experimental models. However, the extrapolation of animal outcomes to human patients is not straightforward as significant differences exist in the pathophysiology of atherosclerosis between different species.[101]

Delivery of Anti-inflammatory Cytokines. Delivery of anti-inflammatory cytokines for therapeutic purposes has been attempted in experimental animal models with promising results. It is now possible to locally deliver anti-inflammatory cytokines to specific atherosclerosis sites via adenoviruses. Such is the case of IL-19 which is an anti-inflammatory cytokine that promotes the Th2 anti-inflammatory cell phenotype.[31] Furthermore, a recently developed method exploits stealth liposomes that are coupled with IL-10 and act to specifically and reliably transfer the atheroprotective cytokine to the desired site in atherosclerotic plaques.[32] It is obvious that these methods may have unknown risks, and studies on safety and efficacy are warranted before they can be applied in humans.

Targeting Intracellular Signaling: Certain studies have succeeded in limiting atherosclerosis by manipulating intracellular signalling in animal models. For example, an oligonucleotide that acted as a decoy binding site for NF-κB succeeded in preventing intimal hyperplasia following balloon angioplasty.[33] An adenovirus-expressed suppressor of cytokine signalling 3 has also been successful in limiting inflammation though not in a model of atherosclerosis,[102] and similar efforts have been done trying to block JAK3 signalling.[103] However, given the ubiquitous nature of these molecules (especially NF-κ), it is important to guarantee that treatment does not interfere with normal processes in order to minimize adverse effects.

Promoting the Actions of T-regulatory Cells: Administration of anti-CD3 antibodies in mice with progressed atherosclerosis managed to suppress atherogenesis and was linked to up-regulated TGF-β and Foxp3 expression in lymphoid organs.[34,104] In addition, oral calcitriol administration to hyperlipidaemic mice blocked atherosclerosis possibly by inducing the expansion of T-regulatory cells,[105] whereas local delivery of IL-2 suppressed atherogenesis in already existing lesions through the same mechanism.[35]

Unanswered Questions and Future Directions

The immune and inflammatory networks are complex and not fully understood at present, and even though our knowledge regarding the basic mechanisms of action of cytokines in humans is constantly expanding, there are still no absolute data on the benefit of targeted anti-inflammatory therapy in atherosclerosis. Notably, as demonstrated by the MRC-ILA-HEART study[36] and other direct and indirect anti-inflammatory strategies such as with anti-IL-12/23 antibodies,[42] corticosteroids,[41] aspirin[65] and COX-2 inhibitors,[106] targeted and broad-based anti-inflammatory treatments may even lead to an increased rate of adverse cardiovascular events in some cases. Indeed, our experience shows that several drugs with promising results in animals fail to demonstrate similar efficacy in humans, such as Bendavia in the recent EMBRACE STEMI trial.[100]

Nevertheless, other studies have shown significant benefit for such anti-inflammatory strategies. Overall, there seems to be a significant gap between our detailed understanding of cytokine actions and the benefit of such targeted interventions. This could be explained by the complex actions of a huge number of cytokines that are involved in atherogenesis as well as by the lack of large-scale clinical trials that can provide reliable data on the efficacy of these strategies.

Therefore, modulation of cytokines poses a therapeutic dilemma and the risks and benefits of inflammation suppression must be weighed before treatment. Particularly in regard to the newer biological agents, observations are limited mostly to rheumatological patients, and small-scale clinical trials and evidence regarding health and survival benefit are lacking in some cases (e.g. TNF inhibitors). Interestingly, there are currently several such clinical trials that are taking place (most notably the CANTOS, CIRT, and Entracte trials) whose results are eagerly awaited and may shape the future of atherosclerosis management and treatment.

Conclusion

Atherosclerosis is considered an inflammatory disease, and the significant role of cytokines in the initiation and maintenance of a pro-inflammatory state is well established. In recent years, novel therapeutic approaches capable of modulating cytokine production or their actions have been tested or are under investigation. Indeed, broad-based immunomodulatory therapies or specific molecules against inflammatory cytokines are now under investigation for the treatment of high-risk atherosclerotic subjects generating new hopes for the future. However, so far, there are no definitive data on the benefit of targeted anti-inflammatory therapy in atherosclerosis and therefore further studies are needed. Hopefully, in the next few years, we are going to have new data that will provide answers and guidance for our next steps in the fight against atherosclerosis and coronary heart disease.