Paul Malik

Can Carotid Bulb Plaque Assessment Rule Out Significant Coronary Artery Disease? A Comparison of Plaque Quantification by Two- and Three-Dimensional Ultrasound

BACKGROUND Screening tools for the detection of coronary artery disease (CAD) are of considerable interest in light of skyrocketing risk factors. Recent work suggests that carotid plaque has a relatively unexplored role in CAD risk prediction but has previously been limited by the difficulty in quantifying its irregular architecture using two-dimensional (2D) ultrasound. The aim of this study was to investigate the utility of a novel automated three-dimensional (3D) ultrasound-based carotid plaque volume quantification technique as a negative predictor of CAD. METHODS In this prospective study, 70 consecutive patients referred for coronary angiography underwent same-day 2D and 3D carotid ultrasound scans for the purpose of plaque quantification in the carotid bulbs. Two-dimensional plaque thickness was measured in its maximal value perpendicular to the vessel wall. Total 3D plaque volume was quantified using a stacked-contour method. Luminal narrowing of coronary arteries was analyzed using the established 16-segment model for coronary arteries to produce an overall angiographic score. Receiver operating characteristic curves, negative predictive value, and sensitivity of 2D and 3D plaque quantification relative to coronary angiography were determined. RESULTS The novel 3D carotid ultrasound method resulted in a higher negative predictive value and sensitivity relative to 2D carotid ultrasound at their optimal thresholds as determined by Youden indices of receiver operating characteristic curves. In particular, total 3D plaque volumes less than the threshold of 0.09 mL accurately predicted the absence of significant CAD in 93.3% of patients (98.0% sensitivity), whereas maximal 2D plaque thickness less than the threshold of 1.35 mm provided significantly lower negative predictability at 75% (93.9% sensitivity). CONCLUSIONS Using the determined threshold of 0.09 mL for plaque volumes, this feasibility study suggests that automated 3D ultrasound-based carotid plaque quantification may serve as an important clinical screening tool to help identify patients who are at low risk for significant CAD.

The impact of advanced Interatrial block on new-onset atrial fibrillation following TAVR procedure

Article history: Received 27 June 2016 Accepted 4 August 2016 Available online 04 August 2016 quickly becoming a go-to procedure for patients with AS who are deemed too high risk for a traditional AVR, and with a considerable incidence of new-onset AF following TAVR, the identification of advanced IAB as a predictor of new-onset AF would be of great value to clinicians managing this population. We conducted a retrospective study of patients who underwent a

Hungry for life

Atherosclerosis, reduced insulin sensitivity, hypertension, aortic stenosis: these are some of the many conditions that comprise the penultimate disease that afflicts us all. Life is that disease; it has absolute mortality and no cure. The existential angst imbued in this idea is not meant to be depressing; it is merely meant to illuminate an often forgotten, yet ever-present, adversary. For if life is the disease, aging is the weapon it uses to fell its victim. In this light, health care practitioners do not directly address the master disease itself, but only its consequences. Intuitively, we all appreciate the temporal dichotomies of aging. A ‘good 85-year-old’ may be accepted for bypass surgery, yet a ‘frail 85-year-old’ may be denied, despite having similar comorbidities. We sanitize and label the discrimination as experience or clinical judgement, but what makes the two patients so different? Is it all genetics, in that they were destined to arrive at this state of health at this point in time, or is there more to the story? How do we even begin to understand and ‘treat’ aging? The first randomized controlled clinical trials would only be published in our children’s lifetimes! However, a beginning dawns in observations made from long-lived societies and animal data. The common link seems to be a calorie-restricted diet, such as the one consumed by the residents of Okinawa. This Japanese island is home to one of the highest numbers of centenarians on earth (40 times more than on any other Japanese island). Residents not only enjoy an exceptional quantity of life, but also an extraordinary quality of life by having a delayed onset of heart disease and many types of cancer. There are also tantalizing clues from animal experiments. By consuming 30% to 50% fewer calories, a white rat extends its average life span from 23 to 33 months and its maximum life span from 33 to 47 months, a guppy extends its average life span from 33 to 46 months and its maximum life span from 54 to 59 months, and a Bowl and Doily Spider extends its average life span from 50 to 90 days and its maximum life span from 100 to 139 days. Investigators have ruled out the confounder of variable dietary composition as the cause of longevity. Rodents that are fed limited quantities of specific dietary constituents (protein, carbohydrate and fat) without caloric restriction, or ones that have diets supplemented with multivitamins, antioxidants or specific types of fat, do not have an increase in life span. Primate data, although encouraging, are not yet definitive. Early work suggests that calorie-restricted monkeys have lower body temperature, blood pressure, glucose and insulin levels, but whether these surrogate markers translate into longevity is yet to be determined. It is important to qualify what is meant by calorie restriction as a means to longevity. The most significant is that nutrition is not compromised; intake of essential amino acids, vitamins, minerals and fats is preserved. It is for this reason that studies of calorie restriction and longevity cannot be undertaken in poverty-stricken societies, in which both nutritional and caloric intakes are reduced. Similarly, calorie restriction must also be distinguished from the eating disorder of anorexia, which is characterized by poor nutrition. Furthermore, the focus of anorexia is weight loss and a negative self-image. Although weight loss is frequently associated with caloric restriction, it is not the prime focus, and practitioners concentrate positively on health rather than appearance. If caloric restriction is truly the fountain of youth, it offers some insight into the mechanisms of aging. Contemporary views deal primarily with cellular metabolism and respiration. Caloric restriction is thought to limit the generation of free radicals, which damage cellular mitochondria and reduce their efficiency. A more tantalizing mechanism comes from genetic studies. Although several candidate genes controlling aging have been studied, the best known and studied is the silent information regulator 2 (Sir2) gene. Sir2 has been found in organisms such as yeast, worms, rodents and humans. It prevents the transcription of certain seemingly redundant genes that lead to the production of ribosomal DNA (ultimately to undergo ribosomal translation). Sir2 prevents the accumulation of ribosomal DNA copies seen with each cell division. Therefore, the cell does not have to expend energy in translating these proteins. Adding one copy of Sir2 to yeast increases its life span by 30%. The link to caloric restriction was established by finding that it increased the activity of nicotinamide adenine dinucleotide (NAD) and reduced the activity of NADH (the reduced form of NAD). A reduced NAD to NADH ratio profoundly increases the activity of Sir2. Studies on Sir2 have challenged the notion of caloric restriction being merely a slowing of metabolism, with a resultant reduction in accumulation of toxic products. Instead, caloric restriction is seen as a low-grade biological stressor that shifts the balance from cellular apoptosis to repair and regeneration through the activity of Sir2. Not surprisingly, there has been considerable effort in developing drugs that mimic calorie restriction. One potential candidate is 2-deoxy-D-glucose, which blocks the uptake of glucose into the cells and reduces ATP synthesis. However, it has an extremely narrow therapeutic window and a low toxicity threshold. Another drug, known as resveratrol, also holds promise. This small molecule is found in some plants, as well as in red wine, of all things! Giving this molecule to yeast, worms and flies extends their life spans by 30% without the need for caloric restriction. It is thought that resveratrol activates Sir2. An added benefit to the drug is the avoidance of reduced fertility, which is a side effect of caloric restriction. An excellent series of papers further detailing caloric restriction and longevity is found in a recent publication of Scientific American Reports (1). While the idea of calorie restriction has existed for over 70 years, it is not surprising to see why it has not caught on, given the difficulties with changing human behaviour. It is not suitable for everyone, including children and women who are or may become pregnant. Nonetheless, it provides invaluable lessons on the importance of a high-value diet. Whether intermittent fasting provides similar benefits to caloric restriction remains to be seen. If nothing else, it shows us that longevity is not a place we seek to be, but rather a journey shaped by the decisions we make every day of our lives. Selected sites Wikipedia The Okinawa Centenarian Study The Calorie Restriction Society

Value-added nutrition

At its most basic level, the content of physician-patient interactions can be broken down into disease-specific and health maintenance information. Clinicians, by virtue of training focusing on diagnostics and therapeutics, are experts in the care of the sick, but arguably weak in the care of the healthy. Health maintenance, or preventive care, has typically been regarded as the domain of public health and a patient responsibility. Nonetheless, patients expect physicians, as curators of life, to excel in both. A cornerstone of health maintenance is diet. With certain disease conditions excluded, notably diabetes, the bulk of dietary advice revolves around caloric reduction for the purposes of weight loss and a tacit reference to Canada’s food guide. Industry has effectively exploited this gap by targeting a host of products with purported benefits beyond the conventional item in the form of value-added foods. So-called nutraceuticals, a derivation of the terms ‘nutrition’ and ‘pharmaceuticals’, are foods that claim to have added benefits to human health. Such products, also known as functional foods, are to be distinguished from organic products, fortified products, genetically modified products and supplements. Milk high in fibre, orange juice with calcium and bread enriched with omega-3 fatty acids are examples of nutraceuticals. Indeed, these are some relatively mundane manipulations. More exotic examples include oil extracted from Antarctic krill, read ‘whale food’, for the purposes of treating arthritis and dyslipidemia. A trip to the local grocery store will demonstrate the prolific nature of these products. Estimates of global consumption of nutraceuticals range from

Won't or don't: studying medication adherence.

70 to

The axiom of Rose

250 billion annually. Canada makes up 3% of this market. Furthermore, the nutraceutical industry is growing at a rate of 7% to 10%, whereas the conventional food industry is growing at 2% to 3% annually. Regardless of personal sentiments on these products – be they innovation or misrepresentation – it is this very proliferation that forces physicians to take notice, because all patients are consumers and many consumers will at some time become patients. However, it is difficult to restrain the inner skeptic when one learns of these products in the financial pages of a newspaper rather than in reputable medical journals. From a medical perspective, many questions remain. For example, what is the influence of nutraceuticals on conventional pharmaceuticals? Are pharmacokinetic and pharmacodynamic properties altered? This is particularly important for medications with a narrow therapeutic window such as digoxin and warfarin. Also, what of the importance of concomitant nutrients? For example, a woman who curtails milk intake in favour of calcium-enriched orange juice may actually increase her risk of fracture by virtue of a reduction in vitamin D intake. Indeed, marketing efforts to date have stressed the importance of calcium in bone health with little attention paid to vitamin D, making this scenario eminently plausible. Central to the proliferation of functional foods is the health claims made on food labels. This is a highly controversial area, and it is not surprising that countries in the developed world have different regulations. In fact, not only can the wording of the claim vary, but also the number of claims per product and the strength of the science behind the claim. Canada is the most restrictive, at five claims allowed per product. The United States will allow up to 18 different claims (and soon up to 30), whereas Japan will soon allow 400. Loopholes can also be exploited by the industry to give a false impression of the health benefits of foods. For example, in 1999, Kellogg’s functional foods division introduced a line of 21 items known as Ensemble in the United States. These items included cereals, frozen entrees, baked snacks and cookies. The foods contained psyllium husk and whole oats, which are known to lower cholesterol. Packaging for the items stated, “Great tasting food made with a natural soluble fibre that actively works to promote heart health”. However, the overall fat and caloric items of some of these items made them anything but heart healthy. This so-called structure/function claim is one loophole that allows manufacturers to make a claim based on a few ingredients rather than the whole food item. Fortunately, the Ensemble line was eliminated soon after it was introduced due to poor sales. If nutraceuticals were to be held to the same level of scientific rigour and scrutiny as pharmaceuticals, many, if not most, would be doomed to fail. Critics of the scientific purist raise economic arguments. While much of the developed world, including the United States, Japan and the European Union, are moving to a less restrictive environment in labelling, Canada maintains its oppressive and stifling regulations. In fact, some countries have a fast-tracking system of approval for novel nutraceuticals such as the GRAS (generally recognized as safe) system in the United States. Industry has long argued that, at the very least, most functional foods do no harm to the vast majority of the population, and the international competitive equality gained by Canadian companies justifies a more liberal regulatory environment. The industry is not composed of just private companies. Partnerships have been established between private companies and major Canadian universities, as well as the Canadian Institutes of Health Research, all to find the next form of bottled water. Selected sites on nutraceuticals Wikipedia Sibbald B. Health Canada leery as US “nutraceutical” movement prepares to move north. CMAJ 1999;161:742. Agriculture and Agri-food Canada The Globe and Mail Neptune Technologies & Bioressources Inc. Center for Science in the Public Interest Helium

Microcredit and health

Hypertension is a quizzical disease. It inflicts a high disease burden in that it is highly prevalent and leads to considerable multisystem morbidity and mortality. Although hypertension is a chronic disease, it is by and large easily diagnosed and monitored. Multiple therapies that have been shown to reduce morbidity and mortality are available. Yet despite the human suffering, economic toll from the disease and available treatment, it remains poorly controlled worldwide. The most common cause of refractory hypertension is the lack of patient adherence to medications. Formerly known as ‘medication compliance’, the term has largely fallen out of favour because it implies a passive acceptance of the physician’s directives and removes the responsibility for partnership in care. Preferred terminology includes ‘adherence’, ‘persistence’ and ‘patient concordance’. A ‘poorly compliant’ patient also becomes stigmatized by health care providers and may be denied therapies required in the future course of the disease. The global pandemic of chronic illness and consequences of poor patient adherence have been recognized by the World Health Organization. Central to the issue is the understanding that nonadherence stems not only from patient factors, but also from physician-based factors and the health care system. Only after this is understood can physicians move away from ‘blaming the patient’ and toward designing interventions to improve adherence. However, even before strategies for improving adherence can be considered, it is important to detect and measure it. Loosely defined, adherence is the extent to which a patient takes a prescribed medication. Although this most often ranges between 0% and 100%, some patients may actually take more than the prescribed dose. Satisfactory medication adherence varies according to the disease studied and, ultimately, on the ability to achieve cure or persistent control. For HIV antiretroviral therapy, adherence must exceed 95% to reduce viral replication and prevent drug resistance. For hypertension, 80% has been advocated to achieve control (1). Modes to detect poor adherence are imperfect. Self-reporting frequently underestimates rates of adherence. Pill counts are prone to patient manipulation. Even directly observed therapy, an approach long used in the treatment of tuberculosis, can be inaccurate if patients hide pills in their mouth. Measuring drug metabolites in blood is fraught with error because patients can simply take the medication only when they are due to be tested. This is known as ‘white coat adherence’. Detection must be combined with prediction in enhancing rates of adherence. Major predictors include some readily identifiable ones familiar to most clinicians. These include depression, cognitive impairment, complexity of treatment regimen, side effects and cost. Other predictors that are not as apparent and do not receive the same consideration are the patient’s lack of belief in the benefit of treatment, lack of insight into illness, missed appointments, poor follow-up arrangements and a poor physician-patient relationship. Indeed, the very diagnosis of hypertension may provoke a denial response if it is perceived as an economic or social threat through loss of job or loss of sexual potency. Preventing poor adherence by ensuring adequate follow-up and addressing patient concerns and barriers are the ultimate goals. Rectifying the problem requires a non-judgemental disposition by the health care provider. All stakeholders have the responsibility and unique talents to enhance adherence. These individuals include pharmacists, family members and community support services. Medication nonadherence is nonselective and may also apply to comorbidities such as hyperlipidemia and the need for lifestyle modification. Recognizing and targeting poor adherence in one area may yield great benefits in the global disease burden.

A gathering of the dying

Geoffrey Rose was not a Grand Master of the Priory of Scion, but rather a well-known British epidemiologist and author of The Strategy of Preventive Medicine (1). His book frames our understanding of the concept of risk. Clinicians constantly estimate risk when faced with an individual patient and act on that determination. When a statin is prescribed to an obese patient who smokes, he or she is being treated for risk, not actual disease. Strategies to mitigate risk are divided into two types – primary and secondary prevention – depending on the absence or presence of clinically evident disease, respectively. This is a simplistic framework that reduces the continuity of risk to a dichotomy. Risk factors such as hypertension and serum cholesterol are continuously distributed, with the incidence of disease following suit. Designations such as ‘hyperlipidemic’ and ‘hypertensive’, while logistically convenient, are artificial and ignore the influence of smaller degrees of cholesterol or blood pressure elevation. Rose sought to change the paradigm of risk factor modification by treating the whole population rather than high-risk individuals exclusively. According to Rose (1), “a large number of people at small risk may give rise to more cases than a small number of people at high risk”. As such, a small reduction in cholesterol in the overall population would yield fewer deaths from vascular disease than a large reduction of cholesterol in high-risk individuals. The high-risk approach will only flatten out the right-hand side of the bell curve of disease. Another example is the reduction of the average speed of all motorists to prevent accidents rather than just targeting those that speed excessively. The key assumption of this hypothesis is that risk is

Wealth of nations is health of nations.

Physics describes four known forces – strong nuclear force, electromagnetism, weak nuclear force and gravitation. The modern holy grail of physics is to link these forces in a single ‘field’ described through the language of mathematics, which is known as the unified field theory or universal theory. As a matter of analogy, I offer four forces that describe humanity – nature (or genetics), nurture (upbringing, or collective sum of experiences), health (physical stability used to improve individual station) and economics (insofar as misdistribution of wealth creates misdistribution of opportunity). The interplay of these four forces may be used to understand everything from acts of kindness to genocide. Some degree of unification is readily apparent, yet some linkages may not be readily apparent. The union of health and economics is an important one. In general, the rich have better quality and quantity of life than the poor. Is this because of improved living conditions, better education and access to health care for the rich, or is it because those who are healthy are able to accumulate wealth? The question lies at the heart of how best to deliver health care to the poor. Traditional delivery in the form of medicine and surgery is end-stage. To truly deliver health care to the poor is to deliver wealth-generating power. As arbiters of health, physicians have the power to influence this social imperative. Poverty is the greatest and most difficult problem faced by this and every other generation thus far. It is a problem that has the power to influence everyone, because poverty or extreme economic disproportion is frequently the root cause of many cases of social unrest. Racial or religious disgruntlement only lights the fuse. Controlling the problem of poverty will require a myriad of complementary solutions. One such solution can be found in the work of 2006 Nobel Laureate, Muhammad Yunus, on microcredit. The idea of microcredit is to give small, graduated loans to individuals or groups who cannot offer any collateral and do not have a credit history. Traditional banks have shied away from these groups because they are deemed to be at excessive risk of default on the loan, and also because of the excessive costs in monitoring and enforcing the transactions. As such, the poor fall victim to loan sharks and become enmeshed in a debt trap. Microcredit, while delivered with a socially beneficial conscience, is not charity, and allows the poor to become self-sustaining and develop a credit history for entry into the middle class. While Yunus did not invent the idea of microcredit, he did demonstrate its successes and develop its practical abilities, and his receipt of the Nobel Peace Prize has certainly popularized it. In the 1970s, Yunus found a number of people in one particular village in Bangladesh indebted to a local loan shark for a total of US

Income and Outcome

27. He gave these individuals the small sum and was moved by the extraordinary effect it had. He also recognized the economic value of the poor. In his own words, “giving the poor access to credit allows them to immediately put into practice the skills they already know – to weave, husk rice paddy, raise cows, peddle a rickshaw. And the cash they earn is then a tool, a key that unlocks a host of other abilities and allows them to explore their own potential”. At first glance, it would seem that microcredit is ideally designed for those just under the poverty line or those with ability but no capital to carry it out. Not so. Through Yunus’s painstaking work with beggars, he was able to reach the poorest of the poor by employing them as personal shoppers or door-to-door salesmen! Another added benefit to microcredit is that lending is done preferentially to women. In developing nations, where men typically control money, this policy promotes sex equality by providing women with economic power and the ability to engage in the development of the community. The policy, however, is borne of practical reasons rather than social justice. Experience has shown that women, in general, spend their money on improving their family and children, and are more likely to spend it on improving their business, while men spend more on themselves. However, microfinance is not a panacea for poverty itself and has many detractors. Critics argue that it is a kinder, gentler form of loan sharking. The high interest rates necessary to maintain its economic viability and pressure to make the payments has forced borrowers to sell household goods and land, and forego food; it has even resulted in suicides. Ensuring that the borrowers are truly poor (ie, without access to traditional financial services) and that the loan is truly used to generate income are other major problems. It is clear that microfinance cannot be used in isolation, but must be instituted with other more traditional poverty alleviation initiatives, such as provision of food aid, basic health services and security. Its principles have proven to be so powerful in practice that it is also being applied to poverty in developed nations. If we return to the problem of social unrest lying on the powder keg of poverty, we see that there is another ingredient in the mix – idleness. Poverty combined with idleness breeds contempt. Microfinance, by providing gainful self-employment, is one attempt to address both of these factors. It is noteworthy that Yunus, a trained economist, was awarded the Nobel Prize not for economics, but for peace. Selected sites Wikipedia CSA Illumina – Discovery Guide Grameen The New York Times YouTube