PLAC blood test for sudden cardiac arrest and stroke risk

Life Extension Foundation (LEF) unveiled a new blood test in an article in this month’s Life Extension Magazine (November 2008). Unlike cholesterol testing, which simply gives a measurement of high-density (HDL) and low-density (LDL) lipoprotein levels and provides little information about acute risk of stroke or heart attack, the PLAC® blood test “can accurately identify artherosclerotic plaque that is vulnerable to rupture,” essentially providing a direct assessment of sudden heart attack and stroke risk.

The PLAC® test, developed by diaDexus, Inc., provides this assessment by measuring levels of lipoprotein phospholipase A2 (Lp-PLA2), an enzyme that is directly involved in endothelial dysfunction leading to atherosclerosis (an inflammatory response of the blood vessel wall), plaque accumulation (build-up of lipid deposits inside blood vessels), and rupture (breaking loose of plaque which can then block a blood vessel, causing heart attack or stroke). The PLAC® test specifically measures Lp-PLA2 associated with oxidized LDL particles. In research studies, high levels of Lp-PLA2 have been determined to be highly specific for plaque inflammation: an elevated PLAC® test indicates an increased amount of inflamed atherosclerotic plaques and thus a higher risk of plaque rupture.

Because of the sensitivity and high specificity of the PLAC® test for such inflammation, the predictive value of the test for risk of cardiac arrest and/or stroke is higher than other markers for the prediction of acute events. Furthermore, the PLAC® test is inexpensive and convenient in comparison to CT and other imaging procedures since it involves only the collection of a blood sample.

In general, the PLAC® test is appropriate for those known to be at high risk for cardiovascular disease and stroke, and LEF recommends that it should be performed once a year in persons who are obese or are regular smokers, those with high blood pressure or cholesterol, type 2 diabetes, or a family history of stroke and coronary heart disease. The PLAC® test can be used to guide patient treatment options: from their article, the LEF panel “recommends that patients with high Lp-PLA2 levels be upgraded from moderate risk to high risk, or from high risk to very high risk. In these patients, a suitable goal is to lower LDL to 100 mg/dL in high-risk patients and to 70 mg/dL in very high-risk patients.”

The PLAC® test is currently the only blood test approved by the FDA to assess atherosclerotic risk for coronary heart disease and stroke. While this is useful for guiding patients in their use of known treatment options, it is not known whether lowering Lp-PLA2 itself will result in a reduction of this risk. A large study (IBIS-2 trial) is now underway to shed more light on this topic. In the meantime,  LEF claims that the PLAC® test is by far the most reliable, convenient, and inexpensive method for determining one’s risk of acute ischemic cardiovascular events and is undoubtedly a beneficial tool for helping patients to keep tabs on their risk level and to implement a more aggressive treatment strategy if indicated.

-=Get the PLAC® blood test=-

No disease in the brain of a 115-year old woman

In August 2008, Neurobiology of Aging published the interesting observations of den Dunnen, et al. of the post-mortem body of a 115 year old woman, which showed no evidence of atherosclerosis. Her brain was devoid of the amyloid plaques characteristic of Alzheimer’s disease and neural density was on par with healthy persons 60-80 year of age. Pre-mortem psychological testing of the woman at ages 112 and 115 found her cognitive abilities to be well above average, scoring better than the average healthy 60-75 year old. Indeed, the authors describe her repeatedly as “alert and attentive” and interpret their findings as follows:

“Our observations indicate that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable.”

This lack of pathophysiology and retention of mental abilities in old age is encouraging and should motivate us to take the best care of our bodies as possible, so that our latest years remain some of our best ones. However, it should be noted that while the woman’s Mini Mental State Examination (MMSE) score only dropped one point (from 27 to 26) from age 112 to 115, and her immediate recall ability and orientation did not deteriorate, she performed worse at age 115 at more complex tasks such as those testing working memory and mathematical calculation skills. In addition, though no amyloid deposits were found in her brain, the other hallmark of AD, neurofibrillary tangles, were observed in the medial temporal lobe, possibly indicating the very earliest stages of AD.

While brain disease at 100 may not be inevitable, and we will certainly enjoy our healthy lives as long as we have them, ultimately even the healthiest supercentenarians succumb to the progression of aging and its entourage of aging-related diseases. Cracking the mystery of aging will require multiple approaches, and studies of the oldest-lived among us provide clues as to which lines of inquiry are the best leads to follow.

Revitalize aging feet

My mother, being a decidedly well put-together woman, impressed upon me the importance of self-care from an early age. She was obsessed with skin maintenance and especially careful to instruct me in hand and foot care. I was given my first bottle of moisturizer at the age of fourteen (“I heard your skin starts losing its elasticity at that age”) and vividly recall sharing in an invigorating bi-weekly foot soak and pedicure. Later on, after developing severely fallen arches (aka “flat feet”) and enduring the pain associated with that condition, foot care became an especially important part of my self-care routine and I have since become somewhat of a foot care proselytizer.

As such, I was delighted to see an article entitled “Revitalize Aging Feet: The Importance of Proactive Foot Care” in the latest issue of Life Extension Magazine. This article, by Dr. Gary Goldfaden, begins with a spiel that I also frequently employ, alerting readers to the fact that the feet are the most overworked and undercared for part of the human body. For these reasons, our feet are particularly susceptible to injury, fatigue, infection, and skin aging –more so as we age and they lose their protective fat cushioning and have been exposed to a lifetime of ultraviolet radiation.

But, as with most things related to the body, an ounce of prevention is worth a pound of cure. Preventative foot care can not only make your feet look better, it can also lessen pain and muscle fatigue, which ultimately makes your entire body feel better.

As Dr. Goldfaden points out, many commercial foot creams consist primarily of water, which only serves to “plump up” the skin, thus smoothing out wrinkles, for as long as the water remains. Additionally, many of these products also contain oils that can actually increase free-radical oxidation and accelerate skin aging! Fortunately, there are some natural products that can significantly improve the look and condition of the feet.

Essential oils such as eucalyptus and menthol are a great place to start. Eucalyptis oil contains a compound called 1,8-cineole, which helps facilitate the production of skin lipids (ceramides), an important factor in retaining moisture in the skin. Eucalyptus oil also serves to protect feet from microorganisms that cause odor and infection, and acts as a natural analgesic for soothing achy joints and muscles. Menthol is also an effective pain reliever, and has the added benefit of providing a cooling sensation which is very refreshing for tired feet. Both eucalyptus oil and menthol also have beneficial effects on foot circulation, increasing blood flow to the feet and promoting the delivery of oxygen and nutrients to the deepest layers of the skin.

Also discussed is tea extract, which is rich in anti-oxidants which can protect feet from oxidative stress and inflammation. Other properties of antioxidant tea blends, such as their vitamin C activity, are also believed to contribute to improved skin tone and structure by strengthening connective tissues. Squalene, found in olive oil, is a natural emollient that hydrates and nourishes tissue while also providing anti-oxidant effects and inhibiting the proliferation of microorganisms. Coconut oil has an abundance of medium chain triglycerides that are “almost identical to the medium chain fatty acids found in human sebum” and is also a proven antibacterial, antiviral, and antifungal agent. Last, but not least, shea butter is touted for its abundance of vitamin E, a powerful antioxidant that is known for its ability to diminish wrinkles and smooth skin tone. I have personally found that buying vitamin E oil from a pharmacy is also very cost effective and works wonders to keep my feet looking and feeling soft and supple.

While the LEF article is timely and full of good advice, I was somewhat disappointed that it did not discuss other aspects of preventative and therapeutic foot care such as wearing appropriately supportive shoes, inserts and orthotics, visiting a specialist in case of foot disorders such as flat feet or neuromas, and the benefits of massage and reflexology. Expect to see a follow-up at this blog covering these topics in the near future.

Recent developments in the treatment of Alzheimer's

The full text of the Life Extension Foundation magazine article (August 2008) describing the use of Enbrel for the treatment of Alzheimer’s disease and announcing LEF’s new Enbrel trial, is now available. As previously discussed, Enbrel (entanercept) has been shown to provide immediate benefits in Alzheimer’s patients, improving memory performance and less frustration and agitation within minutes of treatment.

The more recent publication (pdf document) of additional data from the same patients in the previously reported six month Phase II trial adds further evidence to these results, specifically noting a rapid improvement in the verbal fluency of patients undergoing weekly perispinal Enbrel injections. Additionally, case studies of two more patients are given in the text of the report, and a stronger case for carrying out larger scale studies (including Phase III clinical trials) is made.

A blog post at Al Fin reports on other promising Alzheimer’s treatments such as the drug Rember, which “appears to target ‘Tau tangles’ in the portion of the brain most active in memory formation.”

TNF-alpha modulation in Alzheimer's patients

More than a decade of basic research and clinical evidence now implicates inflammatory processes in the pathogenesis of Alzheimer’s disease (AD). TNF-alpha is a pro-inflammatory cytokine, also known as the “master regulator” of the immune response, and is the key initiator of immune-related inflammation in the brain. Much evidence has linked excess TNF-alpha to the development of AD, including the demonstration of 25-fold elevated levels of TNF-alpha in the cerebrospinal fluid of AD patients and the finding that beta-amyloid (the main constituent of the amyloid plaques found in the brains of AD patients) stimulates the secretion of TNF-alpha, which in turn induces beta-amyloid production in a vicious positive-feedback loop. This beta-amyloid-induced neuroimflammation has been shown to result in neurotoxicity and to upregulate other inflammatory mediators in the brain, including interleukin (IL)-1 beta, IL-6, and nitric oxide.

To examine the effect of downregulating this inflammatory process, a group of researchers performed a 6 month pilot study in 2006 to determine the effect of modulating TNF-alpha in AD patients using the specific anti-inflammatory agent entanercept (Enbrel). Enbrel selectively inhibits the biologic activity of TNF-alpha by binding to TNF-alpha and preventing its interaction with cell-surface TNF receptors.  Entanercept is already FDA approved for the treatment of such diseases as rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Fifteen patients with mild to severe AD were evaluated before treatment began and once a month thereafter for six months using three standard measures of cognition: the AD Assessment Scale-Cognitive subscale (ADAS-Cog), the Severe Impairment Battery (SIB), and the Mini-Mental State Examination (MMSE). Treatment consisted of a total dose of 25 to 50 mg of Enbrel in sterile water per week via interspinous injection. This injection between two cervical vertebrae is hypothesized to improve flow of the drug to the central nervous system (CNS). All patients in this pilot study improved significantly on all assessments of cognitive ability, which is particularly amazing given the cognitive decline that would normally be expected of an AD patient over the course of six months.

As mentioned, this pilot study was approved to evaluate patients only at monthly intervals. However, during this six-month study and over the course of their clinical experience since the pilot study, the researchers noted “an unexpected and largely unprecedented clinical phenomenon… a noticeable clinical improvement within minutes of perispinal entanercept administration.” To validate these observations, the researchers performed a case study in 2008 in which a patient with severe AD was evaluated prior to, ten minutes after, two hours after, and one week after Enbrel administration.

Prior to treatment the patient had been unable to recall his birthday, his father’s occupation, or the names of any of the physicians treating him. He was not oriented to the calendar date, day of the week, year, place, city, or state. Ten minutes after receiving an injection of Enbrel, the patient correctly identified the state as California and his demeanor was observed to be calmer and more attentive. His responses to questions were less effortful, as well.

At the 2-hour post-evaluation, the patient was able to recall the name of his evaluator and was able to identify the month, day of the week, place, and name the state of California. He was slightly off on the calendar date and year, but “appeared more aware of his deficient performance.” The patient’s scores on all mental tests also improved dramatically. These improvements were maintained over the course of a week, whereupon he was evaluated again before receiving his next Enbrel dose. The patient continued to receive a weekly dose of Enbrel for a total of 5 weeks and was re-evaluated at 7 weeks (fourteen days after his last dose). His improvement in all areas of cognitive performance was marked and significant.

An important consideration when treating a patient with Enbrel, however, is that it is immunosupressive and as such leaves the patient at high risk of morbidity if they acquire an infection. This is especially important in late-stage Alzheimer’s patients, who are generally elderly, frequently visit hospitals/treatment centers, and live in community environments, making them particularly susceptible to community-acquired infection.

Following up on the publication of these unprecedented findings, the Life Extension Foundation recently published a review of both Enbrel pilot studies and the initial results of their own pilot study involving a 91-year-old female AD patient with severe cognitive deficits, who has also shown marked improvement in cognitive ability. The Life Extension Foundation is now eager to “launch an expanded study with the objective of measuring the long-term effects of weekly Enbrel injections plus nutrients that help suppress the production of excess TNF-alpha.” These trials are aimed at treating early-stage AD patients, and weekly Enbrel injections will be given in the Fort Lauderdale area.

To inquire about enrolling in this new study, contact the Life Extension Foundation.

Gary Taubes and bias in nutrition science

In a recent blog post, Overcoming Bias reports that Gary Taubes, who has written much to further the idea that refined carbohydrates are a stronger contributing factor to overweight and “diseases of civilization” than dietary fat and cholesterol, has compiled his thoughts on the subject in a major 600-page work called Good Calories, Bad Calories.

Why is Taubes so interested in bias?  For several decades, it has been the conventional wisdom that dietary fat (and especially saturated fat) contributes to obesity, heart disease, and cancer.  Judging from Taubes’ exhaustive research — indeed, I’d be surprised if any other book examined bias within a particular scientific field in such detail — the conventional wisdom was based on unreliable and slender evidence that, once established and institutionalized in government funding, set a pattern of confirmation bias by which further research was judged (or ignored).

Related: The Entitled to an Opinion blog on bad cholesterol and political correctness.

Insurance against death through cryonics

Let’s face it: we’re all (still) getting older, and aging leads to death. This is a major reason for cryonics’ existence — to preserve ourselves, usually in an aged, diseased, and/or deteriorated state, until medical science is capable of curing our ailments and prolonging our lives. Because many people (especially young cryonics supporters) tend to think that they will benefit from radical life extension therapies in their own lifetime, some choose to forgo making early cryonics arrangements. As discussed in a recent post, even if aging is ended or reversed there will remain a non-trivial risk of death by accident or other fatal incidents. Others who support cryonics but endlessly put off making their own arrangements also take an enormous risk in securing their own cryopreservations. It is important to be an activist for your own cause, too, after all.

That most people do acquire the financial means and/or appropriate insurance coverage to make arrangements as soon as they determine that they want to be cryopreserved is a cornerstone upon which cryonics providers rely to operate as efficiently as possible. The fact is that life insurance is easiest and cheapest to obtain when you are young and healthy. In an age where people nonchalantly dole out hundreds of dollars a month for their cell phone usage, life insurance coverage that will pay out the required amounts for your cryopreservation upon legal death is a trivial payment (on the order of $20-80/mo for a healthy young adult). Even if you are not totally sure yet whether you want to be cryopreserved, obtaining insurance at a young age that can provide for your cryopreservation is a wise move. Arriving on the doorstep of a cryonics provider as a “last minute case” is not advisable, since these are often the most demanding and controversial cases, and are also frequently subject to family interference.

Unfortunately, there are situations in which persons who have been dedicated to cryonics for many years fall upon hard times or are otherwise disposed of the ability to maintain their cryonics arrangements. For these legitimate cases, a plea for help can be raised when presented with adequate information concerning the person, their involvement in cryonics, and the nature of the circumstances leading to their disability to provide funding for cryopreservation. Of course, those who are already disabled or terminally ill before hearing about cryonics make up a good proportion of these legitimate claims, as well.

However, some of these “pleas for help” are not infrequently issued to the general cryonics populace at large via cryonics-specific Internet message forums, with little to no circumstantial information provided to assess the validity of the request. Such requests leave a lot to be desired in terms of properly addressing the need of the person desiring assistance, and devalue the importance of acquiring and maintaining cryonics arrangements throughout life, so they are not dependent upon others when bad times finally do befall them.

Looking forward, the last thing cryonics providers need are multiple series of last-minute cases and daily fundraising appeals when the “Singularity” turned out not to be as near as some people might have thought….

Cerebral blood flow during and after cardiac arrest

As discussed in a previous post, perfusion of the brain following long-term (>5 min) ischemia has been shown to be significantly compromised, particularly in subcortical regions. An interesting recent article by Ristagno, et. al in Resuscitation (May 2008) has added new data to the equation, using some of the most advanced technologies available for measuring cerebral microvascular blood flow.

To briefly summarize the experiment, pigs were subjected to 3 minutes of untreated ventricular fibrillation followed by 4 minutes of cardiopulmonary resuscitation and subsequent defibrillation. Blood flow in large (>20 micrometers) and small (<20 micrometers) cerebral vessels was measured during and after CPR by direct visualization using orthogonal polarization spectral imaging (OPS) together with cortical-tissue partial pressure of carbon dioxide.

Though prior studies implied a dissociation between microcirculatory flow and macrocirculation during CPR, Ristagno, et. al found “a close relationship between microvascular flows and the macrocirculation during cardiac arrest, during CPR and following return of spontaneous circulation (ROSC).” Interestingly, they also noted that cerebral blood flow was reduced, but did not stop, for more than 2 minutes after cardiac arrest, most likely due to residual compliance in the arterial circuit. After ROSC, flow progressively increased back to normal (pre-arrest) values within 3 minutes.

Importantly, the researchers also noted that cerebral cortical-tissue partial pressure of carbon dioxide (a measure of the severity of cerebral ischemia) increased progressively througout CPR, providing evidence for the fact that the pressure and flow generated during chest compressions “may minimise but do not reverse the magnitude of the brain ischaemia which preceded the start of CPR.”

Though many investigations, such as the previously reported study by Fischer & Ames reported no-reflow or hypoperfusion following ischemia, these authors observed no such phenomena, possibly because of the short duration of cardiac arrest. Indeed, they ultimately conclude that “a 3-min interval of ischaemia was therefore probably not long enough to induce alterations in blood flow during reperfusion.” Also of importance is the fact that OPS technology limits visualization of microvessels to within 1mm of the cortical surface. However, this paper still gives us better insight into the immediate effects of cardiac arrest, cardiopulmonary resuscitation, and reperfusion on microcirculatory flow in the brain.

Soft nanotechnology

Ever since humans imagined the ability to deliberately manipulate matter on the atomic scale, they have glimpsed the boundless possibilities of the science of nanotechnology. And for almost as long, they have disputed whether molecular machines should be built using a “hard” (physical engineering) or “soft” (biology-based) approach. On his blog, Richard Jones, author of the book Soft Machines, discusses some of the more intricate details and debates in molecular nanotechnology.

In a recent post, Jones delves into the issue of what lessons nanotechnology should take away from biological systems: should we view cell biology as the penultimate achievement in nanotechnology, or can we improve upon the slap-dash, trial-and-error approach of evolution by making rational choices in materials? In his words:

The engineers’ view, if I can put it that way, is that nature shows what can be achieved with random design methods and a palette of unsuitable materials allocated by the accidents of history. If you take this point of view, it seems obvious that it should be fairly straightforward to make nanoscale machines whose performance vastly exceeds that of biology, by making rational choices of materials, rather than making do with what the accidents of evolution have provided, and by using the design principles we’ve learnt in macroscopic engineering.

The opposite view stresses that evolution is an extremely effective way of searching parameter space, and that in consequence is that we should assume that biological design solutions are likely to be close to optimal for the environment for which they’ve evolved. Where these design solutions seem odd from our point of view, their unfamiliarity is to be ascribed to the different ways in which physics works at the nanoscale. At its most extreme, this view regards biological nanotechnology, not just as the existence proof for nanotechnology, but as an upper limit on its capabilities.

Ultimately, argues Jones, nanotechnology has a lot to learn from biological systems — but that doesn’t preclude the possibility of improving upon it, either. He cites the emerging science of synthetic biology as a field that is using a sensible engineering approach to the development of biological nanodevices such as molecular motors, and wonders if this approach may ultimately lead to a biomemetic nanotechnology.

The right lessons for nanotechnology to learn from biology might not always be the obvious ones, but there’s no doubting their importance. Can the traffic ever go the other way – will there be lessons for biology to learn from nanotechnology? It seems inevitable that the enterprise of doing engineering with nanoscale biological components must lead to a deeper understanding of molecular biophysics. I wonder, though, whether there might not be some deeper consequences. What separates the two extreme positions on the relevance of biology to nanotechnology is a difference in opinion on the issue of the degree to which our biology is optimal, and whether there could be other, fundamentally different kinds of biology, possibly optimised for a different set of environmental parameters. It may well be a vain expectation to imagine that a wholly synthetic nanotechnology could ever match the performance of cell biology, but even considering the possibility represents a valuable broadening of our horizons.

In a more recent post, Jones announces the upcoming Soft Nanotechnology meeting in London next year.

A forthcoming conference in London will be discussing the “soft” approach to nanotechnology. The meeting – Faraday Discussion 143 – Soft Nanotechnology – is organised by the UK’s Royal Society of Chemistry, and follows a rather unusual format. Selected participants in the meeting submit a full research paper, which is peer reviewed and circulated, before the meeting, to all the attendees. The meeting itself concentrates on a detailed discussion of the papers, rather than a simple presentation of the results.

Cerebral ischemia and impairment of circulation

Cryopreservation of the brain depends on the removal of blood from the brain’s vasculature and its replacement with cryoprotective solutions in order to prevent ice crystal formation (freezing) during cooling (i.e., facilitate vitrification). Ultimately, the success of a good cryoprotectant is limited by perfusability of the brain, or the ability of cryoprotective solutions to penetrate all areas and cells of the brain via the cerebral vessels. Long periods of global cerebral ischemia detrimentally affect reperfusion of the cerebral vessels, thereby significantly degrading perfusability of the brain. Many possible causes for post-ischemic impaired perfusion have been hypothesized in the past, including swelling of the endothelial cells that make up the inside lining of blood vessels. However, a landmark 1972 paper by Fischer & Ames provided evidence implicating changes in the blood itself as the probable reason for post-ischemic reductions in perfusability of the brain.

Ames, et al. had already demonstrated impaired reperfusion in rabbits after cerebral circulatory arrest followed by infusion of a suspension of carbon black and examination of coronal brain sections. Brains undergoing less than five minutes of arrest perfused well and were evenly stained by carbon black ink. Ischemia in excess of five minutes resulted in patchy white areas where perfusion was impaired and blood vessels did not fill with ink. In an extension of this work, Fischer and Ames investigated the effects of perfusion pressure, anticoagulation, and hemodilution on post-ischemic perfusability.

In their experiment, the researchers induced cerebral circulatory arrest in rabbits and then perfused the head and neck with carbon black immediately following various ischemic periods. The perfusion solution was introduced to the cerebral circulation from a reservoir placed above the rabbit and through tubing that was inserted into and secured in the ascending aorta. Perfusion pressure may thus be modulated by varying the height of the reservoir above the animal. In some animals, acute hemodilution was achieved by rapid infusion (50 ml/kg) of saline into the femoral vein for moderate hemodilution or by a combination of saline administration and blood removal for extreme hemodilution prior to ischemia and carbon black infusion. A series of animals were also anticoagulated by giving heparin (500 units/kg) intravenously 15 minutes prior to ischemia. Brains were then removed and diffusion fixed in 10% formalin, allowing coronal sections of the brain to be examined macroscopically.

Brains from 5 groups of animals were studied:

Group 1: 4.5 minutes’ ischemia, reservoir at 28 cm above the heart (two animals), 40 cm (two animals), and 110 cm (two animals).

Group 2: 15 minutes’ ischemia, reservoir at 70 cm (six animals), 110 cm (eight animals), and 170 cm (seven animals).

Group 3: 30 minutes’ ischemia, reservoir at 170 cm (six animals).

Group 4: Hemodilution, 15 minutes’ ischemia, reservoir at 70 cm, hematocrit (HCT) 21 to 32 (five animals); HCT 4 to 13 (six animals).

Group 5: Heparin, 15 minutes’ ischemia, reservoir at 70 cm (six animals).

As previously observed, “animals with 4.5 minutes of ischemia failed to demonstrate impaired cerebral reperfusion even with perfusion pressures as low as 28 cm of water, all brains being completely and evenly black.” However, significant impairment of perfusion was observed after 15 minutes of ischemia. The effect was greatest in the thalamus and brain stem, while cerebral cortex remained adequately perfused after 15 minutes of ischemia at all levels of perfusion pressure. White (non-perfused) areas were significantly greater after 30 minutes of ischemia than after 15 minutes at comparable pressures and in all areas examined (including cortex). Hemodilution greatly improved reperfusion after 15 minutes of ischemia, but no difference between anticoagulated animals and controls was observed.

The authors speculate that blood viscosity, rather than clotting or cellular swelling, was the most probable cause of impaired reperfusion following ischemia. They further noted that “improved postischemic cerebral circulation has also been noted to follow the infusion of hyperosmolar agents,” which they speculated was also due to reducing blood viscosity. Red cell aggregation during blood stasis was assumed to be a major contributing factor to the increase in viscosity, and differences in vascular resistance throughout the brain manifesting as differences in circulatory impairment were thought to underlie the observation of impairment of discrete, macroscopic regions of the brain — particularly subcortical regions.

The results of Fisher et al. support rapid restoration of perfusion pressure (mechanical cardiopulmonary support) after cardiac arrest in cryonics patients, and hemodilution with agents like Dextran-40. It is harder to reconcile with the emphasis in cryonics to administer fibrinolytics and anticoagulants to eliminate and prevent blood clotting. The results of Fisher et al. are also at odds with those of Böttiger et al., who found that activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Perhaps these findings can be reconciled if we allow for the possibility that cardiac arrest and cerebral ischemia induce formation of (micro)thrombi, but that these are not clinically significant, or at least do not affect reperfusion as greatly as other blood abnormalities such as red cell aggregation. And perhaps the formation of thrombi in small cerebral vessels can adversely affect cryoprotectant perfusion without being visible by gross examination. Formation of large clots may still be a problem after longer periods of circulatory arrest. Tisherman et al. have observed large vessel blood clots in rats and dogs after normothermic cardiac arrest of more than 20 minutes. Finally, cryonics patients may present with existing blood clotting problems as a result of (septic) shock.

Although the emphasis on antithrombotic therapy to maintain circulatory patency in cryonics patients seems to be warranted, more emphasis on other factors that affect cerebral (micro) circulation in cryonics patients seems desirable. As the work of Fisher et al. indicates, hypertension and hemodilution during cardiopulmonary support may be just as, if not more, important. The relationship between in vivo stasis of blood circulation and coagulation remains elusive and could benefit from more research.