VOLUME XXII No. 4 JULY-AUGUST 2018 PAGES 105-144 Rs. 1700/-­­­­ ISSN 0971-9172 RNI No. 66903/97 www.cimsasia­.com Cardiology

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NATIONAL EDITORIAL ADVISORY BOARD 'Wired' Medicine or 'Mired' Medicine 107 Arun K Purohit, Arun Malhotra, Ashok Seth, OP YADAVA Ashwin B Mehta, CN Manjunath, DS Gambhir, GS Sainani, Harshad R Gandhi, I Sathyamurthy, Jagdish Hiremath, JPS Sawhney, KK Talwar, K Srinath Reddy, KP Misra, ML Bhatia, Mohan Bhargava, MR Girinath, Mukul Misra, Nakul Sinha, PC Manoria, Peeyush Jain, Praveen Jain, Ramesh Arora, Ravi R Kasliwal, S Jalal, S Padmavati, Satyavan Sharma, SS Ramesh, Sunil Kumar Modi, Yatin Mehta, Yogesh Varma, R Aggarwala. REVIEW ARTICLE INTERNATIONAL EDITORIAL ADVISORY BOARD Andrew M Tonkin, Bhagwan Koirala, Carlos A Mestres, Aging Slowly, Living Longer and Future Chuen N Lee, David M Colquhoun, Davendra Mehta, Projections for Exponential Survival Enas A Enas, Gerald M Pohost, Glen Van Arsdell, Indranill Basu Ray, James B Peter, James F Benenati, and Longevity 109 Kanu Chatterjee, Noe A Babilonia, Pascal R Vouhe, VINOD NIKHRA Paul A Levine, Paul Simon, P K Shah, Prakash Deedwania, Salim Yusuf, Samin K Sharma, Sanjeev Saxena, Sanjiv Kaul, Yutaka Imoto.

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106 Cardiology Today VOL.XXII NO. 4 JULY-AUGUST 2018 EDITORIAL

‘Wired’ Medicine or ‘Mired’ Medicine

In this contemporary world of ours, which is totally wired and full of electro- magnetic vibrations, a scary thought crosses the mind, that with all the cardiac implants around, some of which life-sustaining, can there be a science fiction Frankenstein scenario of a fraudulently intended attempt at dysfunctioning someone’s device. With cardiac pacemakers, can someone from a distance remotely disable the cardiac pacemaker functions or alter its parameters or with an automatic implantable cardio-defibrillator reset the parameters with a view to harming the patient? Can a metallic cardiac valve leaflet motion be disabled and paralyzed by an ill intended magnetic field? Can in a patient with a left ventricular assist device or a total artificial heart, the programmers and drivers of the heart be disabled? All of these are scary thoughts but mundane ones and it behooves us to look at our checks and counter checks to prevent any such eventuality coming to fruition.

Is cardiac device hacking therefore a clinical problem? Certainly, it is not a moot question and is infact worthy of deliberation with due diligence. This issue was brought to the fore-front by a media scare which was created by a report in 2016 regarding hacking of the permanent pacemakers used by Abbott. Latter responded by producing a ‘Firm-ware’ patch for addressing the issue. The fix however was a bigger problem, than the original problem itself.

However, if a recent publication in the Journal of American College of Cardiology by Baranchuk et al1 is to be believed, then ‘it is a hypothetical scenario … with a just a soap-opera take on it’. Lending credence is the fact that till date not a single such case of hacking has been reported in human beings. However, according to Baranchuk et al1 a bigger possibility is of a hacker interfering with network of a hospital system, which communicates with the individual’s cardiac device and a clinical event may be missed by the over-seeing tracking authority in a hospital. Just as when the ACC statement allays a lot of concerns on this front, it also issues DR. OP YADAVA a caveat to the physicians, device manufacturers and the regulators to look into CEO and Chief Cardiac Surgeon National Heart Institute, these potential areas of concern going forwards. New Delhi

Cardiology Today VOL.XXII NO. 4 JULY-AUGUST 2018 107 Notwithstanding the preceding reassuring words of the ACC’s Electrophysiology section leadership group, the very fact that the human mind has conceived this idea and the pen written about it is proof enough that sooner or later such an event shall occur. Only debate … When? And the first such case may not be with a malevolent intent, but sheerly out of curiosity, and to satisfy man’s universal craving … me first.

God save the King !

REFERENCE 1. Baranchuk A, Refaat MM, Patton KK et al. Cyber security for cardiac implantable electronic devices, what should you know. J Am Coll Cardiol. Feb 2018. DOI:10.1016/j.jacc.2018.01.023

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Aging Slowly, Living Longer and Future Projections for Exponential Survival and Longevity Keywords zz aging VINOD NIKHRA zz metabolic dysfunction zz ROS zz longevity zz Abstract zz LIVING AND AGING: The phenomenon of aging is universal in the zz human brain project kingdom of living. With time, all living beings age. There have been zz CR immense developments in the scientific understanding of biology zz SIRT of aging and the changes that take place with aging at cellular and molecular levels. At the same time, the progress in healthcare and technology has made it possible to delay the aging process and bring about healthy aging. A longer life and aging slowly are mutually related. Healthy food, adequate physical activity and wholesome lifestyle keep the daily attrition-related damage at a minimum and can retard aging. With the progress of science and technology, there are futuristic visions of achieving significant longevity. LIFE-FORMS, LIFESPAN AND LONGEVITY: Under the socio-cultural layers, we human beings are biological life-forms and share the same fate like other members of the bio-spora. The lifespan of an organism is limited, though not fixed and goes through the phases of life - birth, maturity, aging and death. An organism’s lifespan is limited, and so is that of the human-being. The microscopic roundworm, Caenorhabditis elegans, has a lifespan of about 3 weeks, a mouse of about 3 years, bats of about 20 years, and humans can live for about 100 years. The plants live longer, many surviving to hundreds of years, still not showing changes related to aging. There is nothing inherent in anatomy or physiology that limits the lifespan. At the biological level, the root factors evolving the protective mechanism called the survival instinct, endorse that the evolution has prepared us for longevity, not the brevity. METABOLIC DYSFUNCTION, ROS AND DECAY: Aging may mean decay, as the repairing process falters and there is a failure to restore and rejuvenate body tissues. Aging is, thus, a collection of cumulative changes at the cellular and molecular levels occurring gradually. The reactive oxygen species (ROS) or free radical theory is fundamental to the understanding of aging. The uncontrolled metabolic dysfunction

Dr Vinod Nikhra is Senior Consultant (Physician) and the Teaching Faculty at Hindu Rao Hospital, Delhi

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is linked to accelerated aging. Thus, obesity is a disturbed metabolic state, having potential to cause metabolic syndrome, in which insulin resistance leads to diabetes, heart disease and other changes akin to aging related disorders. The life span has also been linked to metabolic rate and metabolic stability. GENETIC KEY AND CR: There are longevity clusters in population groups. The centenarians, in addition to being free of the negative genetic variations common in other human beings, have some positive mutations that increase the possibility of longer life span. The state of nutrition has a bearing on aging and the life span. The CR protects against disease, slows aging and prolongs life. With CR regimen, there is less free radical production, less mitochondrial mutation and less programmed cell deaths. The CR and CRAN reduce incidence of various diseases of aging such as cancer, heart disease, diabetes, osteoporosis, neurological decline and diseases such as Alzheimer's and Parkinson's, and improve the immune response. FUTURISTIC VISIONS OF SURVIVAL: The Life Extension Program (LEP) aims to increase the maximum lifespan beyond the current maximum for humans. It can be visualised to go through three steps - taking advantage of the existing knowledge for slowing aging like CR and CRAN; utilizing the advances in genetics and biotechnology; and using the future nanotechnology and artificial intelligence revolution to repair the mutation and other defect due to aging at molecular and cellular levels. The futuristic goal is, thus, to achieve and state of non-aging. A debatable aspect of LEP is cryonics, the practice of freezing a body at the time of clinical death with the aim of enabling eventual resuscitation back to life in the remote future. Another form of futuristic survival, quantum immortality, is to upload the mind like a computer software on to a new human-body-form generated by cloning, or onto a computer system and survive in a virtual environment. The initiative of the European Union, the Human Brain Project relates to this futuristic option and aims to scan and upload the human brain. CONCLUSION - QUEST FOR IMMORTALITY: A longer life is not separate from aging slowly, rather they are mutually related. With the scientific progress the futuristic visions of achieving significant longevity, if not immortality, seems quite possible. The eternal dream is on the verge of becoming a reality.

THE ESSENCE OF LIFE disease (CVD) and cerebrovascular surviving in their sixties and entering The phenomenon of aging is universal disease including stroke can be efficiently into the postretirement phase of life. in the kingdom of living. With time, managed leading to virtual freedom from With better health care and public health all living beings age. There have been their complications. This has led to an efforts, there is an increased average immense developments in scientific appreciable increase in life expectancy life expectancy in general and improved research and there has evolved a scientific and lifespan. The modern day high-tech survival rates in particular. There is a understanding of the biology of aging. interventions and revolutionized medicine significant reduction in chronic illness A vast body of knowledge can now and enable us to enjoy a good quality of and disability during the advanced years due to improved lifestyles and better explain the changes that take place with life (QOL) and maintain an optimal level healthcare, making it possible to slow aging at cellular and molecular levels. At of function well into the later years. The aging and living a longer and healthy life. the same time, the progress in healthcare Health is the prime instrument that lets us and technology makes it possible to delay enjoy life and the preservation of health LONGEVITY: THE ETERNAL DREAM aging process and bring about healthy associated with aging slowly, is the best Longer life and aging slowly are mutually aging. There are possibilities of being formula for longevity. related.3 The healthy food, adequate able to reverse the aging process as well The lifespan of organisms, including physical activity and wholesome lifestyle in near future.1 human beings, is not fixed but limited.2 As an organism, we go through the keep the daily attrition-related damage at phases of birth, maturation, youth, aging minimum and can retard aging. An optimal LIFE IN MODERN TIMES healthcare adds further. An individual’s We live in the unprecedented times. and death. Our physiological potential is life-course may appear unpredictable, but There is a boom of advances in every marred as we live through the life as a it is not. The genetic and environmental field, from the art to the science and biological-being and go on accumulating factors, both being of equal importance, technology including medical sciences. damage caused to body tissues due to disease processes and unhealthy lifestyles and behavioural patterns can successfully The incredible advances in the field resulting in an accelerated aging and predict the life expectancy. With the of medical science make it possible to premature death. But, there are some progress of science and technology, cure acute disorders and avoid untimely important emerging trends in the current there are futuristic visions of achieving demise. Chronic diseases like obesity, times. A good number of people are significant longevity, if not immortality. diabetes, hypertension, cardiovascular

110 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 The eternal dream of living a long life is The aging process is, thus, influenced by of years, still not showing changes on the verge of becoming a reality. 3 factors: the developmental damage related to aging. The simple organisms, People live life for different reasons. load, damaging effects of early life such as hydra, have an indefinite life But in essence, we live because the life situations, and adverse effects of chronic span, apparently free of an intrinsic gives us joy. Primarily, we are because we disease processes. The advances in . But, there is nothing inherent live. Life gone, there is no world for us. All hold promise to deal with the in anatomy or physiology that limits the things apart, living is itself the objective. damage. In the near future, the damages lifespan. The evolutionary process is not This is well demonstrated by all powerful can be corrected using gene technology, against longevity and the organisms are survival instinct pervading through the rejuvenative medication and futuristic programmed not to die but survive the bio-spora. Aging is just a temporal notion nanobiotechnology. The optimal adversities. Even the programmed cell and the life is never enough. The more healthcare and a careful and healthy death, an intrinsic phenomenon occurring you live, more you cherish, weaving a lifestyle, meanwhile, can help in slowing at cellular level called apoptosis, is a world for you. A world, in which you the aging process. mechanism meant to favour survival of want to live for forever. This is the prime the organism. At the biological level, the thing, the eternal dream. THE PLASICITY OF LIFESPAN root factors, which evolve the protective Life-Forms, Lifespan And Evolution mechanism called the survival instinct, PLAN FOR HEALTHY AGING Under the socio-cultural layers, we endorse the fact that the evolution has Further, aging process should not impact human beings are biological animals and prepared for longevity, not the brevity. the life force and need not disable a share the same fate like other members To stay alive is a basic instinctive drive, person. We should plan for a healthy of the bio-spora. The lifespan of an being a natural precondition for all other middle age and later years. Herein, comes organism is limited, though not fixed and activities. Today, a period of about 30,000 the concept of a healthy or successful goes through the phases of life - birth, days is the average human lifespan. For aging which can improve the QOL and maturity, aging and death. Reproduction, a centenarian, it is about 40,000 days. make longevity possible.4 There are whether sexual or asexual, allows new Long ago, the average life expectancy was certain issues, when we consider the aging organisms to replace the old ones. The less than 20 years or about 7,000 days. process. The first concerns the aging new organisms replacing in time the Two centuries back, the life expectancy in terms of length of time. The second older ones, adapt to the changes in the in 1796, was around 10,000 days which issue relates to the functional aspects of echosphere, allowing evolution to take doubled a century later. Thus, the human the aging. The Older adults may develop place. The advantageous changes are lifespan though finite, is not fixed. disability or incapacity for independent passed on to the next generation, the living as the result of damage load due to deleterious ones are eliminated along The Aging Process: Biology of Decay pre-existing diseases or due to the aging with the organism in due course of time. Whereas aging may mean decaying, as process itself. The third factor occurs Thus, goes on the evolution and life. the repairing process weakens, living at a more sublime level and involves Studies show that in the roundworm, C. means restoring and rejuvenating the behavioural attitudes and prejudices in elegans, a mutation of the genes involved body tissues.7 According to the Reliability the individuals themselves or prevalent in in the insulin-signaling pathway, namely theory, at some phase in life, the aging the society. A child, a youth or an older daf2 and daf16 genes can induce an up system falters, leading to failure unless adult all have equal right to survive and to 2-fold increase in life span.5 Several the cause is corrected or the faltering parts to look forward to a better living. There external, behavioural and internal factors are replaced.8 The aging process, thus, need not exist any prejudice against those including the environment, genes, sex and contributes to the age-related decline in older in age. The life force need not be reproduction, nutrition and food style, performance, productivity and health. diluted at any age. the accumulation of cellular attrition There are three main causes of decay: and damage, and the inherent ability to disease, trauma and aging. Looking at THE AGING PROCESS repair, influence aging process, life span the brighter side, a number of advances AT CELLULAR AND MOLECULAR and QOL during lifespan. The process of in healthcare have virtually nullified the LEVELS aging, though, begins much earlier before deterioration due to diseases, including In essence, the aging is a disorder of becoming apparent. both, infectious and non-infectious. Aging accumulated recurrent and chronic injury Organisms have different but limited is a collection of cumulative changes at at cellular and molecular levels.5 life spans. The microscopic roundworm, the cellular and molecular levels. It is The developmental damage load C. elegans, has a lifespan of about 3 not an event. Thus, we do not age all of a during early phases of life complicates weeks, a mouse of about 3 years, bats sudden, rather it comes gradually. Hence, further, having a bearing on the residual of about 20 years, and humans can live the aging is a process made of various functional capacity and the aging process. for about 100 years. The plants live components. As we, go on understanding longer, many surviving to hundreds the components of aging and developing

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the means to correct them, we can look Metabolic Dysfunction, ROS and to the ability to resist free radical damage. ahead to win over the biological decay. Antioxidants The concept that mild stress might The free radical theory is fundamental to lead to health benefits is called hormesis.13 Attrition and Stress of Living the understanding of aging. Uncontrolled Plants given low doses of herbicide, for With life, there occurs exposure to metabolic dysfunction is linked to example, can actually become stronger continuous attrition and damage, and accelerated aging. Thus, obesity is and grow better. It is thought that Sirtuin- accumulation of wastes and toxins.9 There a disturbed metabolic state, having activating compounds (STACs) increase occur some alterations in the genome potential to cause metabolic syndrome, in lifespan because they are produced by due to inner causes like mitochondrial which insulin resistance leads to diabetes, plants when stressed or starving. Plants generation of free radicals and external CVD and other related disorders. The make these molecules to turn on their factors like cosmic radiations. Every life span has been linked to metabolic own protective sirtuin genes in order to time a cell divides, there is a potential rate. Metabolism generates ROS that defend themselves. Resveratrol is a plant 14 for error. Oxidative stress is also a can damage DNA and proteins. Animals extract of complex composition. Its use seems to mimic CR. Studies have proved potential source of damage at molecular that live fast, die young; because a high resveratrol’s role in yeast longevity. level. Free radicals are generated within metabolic rate produces large number of Feeding lab mice resveratrol suppresses mitochondria and have the potential to free radicals. According to this theory, the growth of implanted tumours. But, the alter the cellular material and internal long-lived animals should have high molecule is unstable and sensitive to light structures. These factors have been linked concentrations of antioxidant enzymes and air, having a short shelf-life. A high with aging process at the cellular level. in their tissues and low concentrations level of resveratrol is present in red wines. The cells possess a number of of free radicals. Another related theory The molecule, which is concentrated in systems for functional and structural states that metabolic stability is a better the skins of grapes, is highly insoluble maintenance and repair. In fact, the DNA- predictor of longevity than metabolic in water. Traditionally, wine is stored in repair capability correlates well with the rate. It proposes that an organism’s ability dark, light-proof bottles, corked to keep lifespan of a species. Also, there is a to maintain stable levels of free radicals is oxygen out. Resveratrol is thus preserved correlation between the ability to respond more important than how fast it produces 10 in red wines. to stress and life span. An increased them. Further, metabolic stability is stress resistance has been noted in more important than metabolic rate in long-lived genetic strains. Stem cells THE GENETIC KEY FOR LONGEVITY determining life span, and long-lived Molecular biology experiments with have a higher resilience than the organisms are more resistant to pathogens well-differentiated cells. Genes influence organisms such as yeast, nematodes, and other environmental stresses. the life span of organisms, the body fruit flies and mice have succeeded in The ROS or free radicals are appearance, structure and functioning increasing the life span by altering single highly energetic molecules. They are of inner organs. Studies also show that genes. The altered organisms age more chemically hyper-active and react with genes account for about 25 percent of slowly and live longer. Further, genetic molecules including DNA and cellular what determines the life span. manipulations causing these changes proteins, oxidizing and damaging them work through a common pathway across and giving rise to mutations and other Reproductive Issues many species endorsing that there is abnormalities leading them to become an evolutionary genetic program that Life birth, growth, reproduction, aging, 12 death and evolution through generations. dysfunctional. The antioxidants, on controls aging. the other hand, mop-up free radicals Studies show that unmated fruit flies live THE WORM-SIDE STORY: The tiny and help in reducing their damaging longer than those which mate. In females, nematodes, Caenorhabditis elegans, when effects. In the mice experimental studies, perhaps, the egg laying process imposes exposed to environmental stress during the antioxidant effect was obvious in a stress on survival. Also, species with their development, enter into a state akin increasing the longevity as well as in smaller litter sizes as compared to their to hibernation by modifying themselves preventing morbidity. Thus, by suitably into a spore like forms, called dauers. own body size tend to survive long. In the using antioxidants, it is possible to delay same species, the body size may influence They remain in this suspended condition or retard the underlying process of aging. for long periods, till the surroundings the aging and survival. The Aristocrat On the other hand, the pharmacological study – which compared the number of again become hospitable to growth. agents that reduce ROS concentrations This phenomenon is an indication that children and the age at which the mothers may even be harmful, because they could an organism can, as part of physiology, had their first child, and related these disturb the delicate balance necessary for regulate their life span. Further, altering values with the age at death, inferred that normal cell function. The accumulation the single gene - called daf-2 in C. elegans women who reached an older age and a of free-radical damage, thus, may be DNA, doubles the lifespan. Daf-2 appears higher life span delivered less children the key regulator of life span. Genetic to be a master control gene and modifies and at a later age.11 alterations in certain tissues may give rise

112 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 the functions of many other genes. These other genes act in various ways - some OXIDATIVE DAMAGE make anti-oxidant proteins that protect THEORY the cells from oxidative damage and other may protect the cells from getting DNA Damage Genome Stability infections by bacteria. The daf-2 also HORMESIS encodes an insulin receptor, which links HYPOTHESIS aging to another program, CR, that can extend life span in various organisms. Tissue THE MITOCHONDRIAL GENETIC Sress CALORIC MUTATIONS: The genetic mutations in RESTRICTION Insulin mitochondria, appear to trigger changes Signalling leading the cells to die and accelerate the aging process. By altering a gene called GLUCOSE-INSULIN polymerase-in mice, which functions Growth Hormone PATHWAYS as a spellchecker during the copying of mitochondrial DNA led them to age fast. IGF-1 Signalling Because the mitochondria also control GROWTH HORMONE: IGF-1 the natural process of cell death, called AXIS apoptosis, mistakes by the spell-checker Figure 1. Caloric Restriction and Longevity Circuits gene enhance apoptosis. As mitochondrial mutations accumulate, there are increased the CR regimen protects against disease mentally. There takes place a number cell deaths and appearance of the aging and slows aging (Figure 1). The animals of molecular changes in the brain due characteristics. on CR, have lower levels of circulating to exercise. It increases the production THE NEW ENGLAND blood glucose, insulin and triglycerides. of brain-derived neurotrophic factor CENTENARIAN PROJECT: The In this context, limiting fat, protein or (BDNF), which protects nerve cells Project underlines that there is a tendency carbohydrate, without accompanying CR, and increases the number of nerve cells toward longevity clusters in population does not increase the maximum lifespan. that are involved in various aspects 15 groups. In many centenarians’ families, It seems probable that CR is an effective of memory and cognition. But, losing longevity appears to be a dominant trait. way to prolong life by reducing the weight via increased caloric expenditure, Also, that one in 10,000 people alive amount of free radicals produced. There i.e. exercise, does not give the same today has longevity genes. Nevertheless, are less mitochondrial mutations and health benefits obtained by CR. The the clustering of genetic variations less programmed cell deaths. The effects reason lies in the free radical concept. among centenarians suggests that there of CR on lifespan, disease, and aging Reducing food intake with CR will may be one or two genes common processes are applicable to virtually all reduce oxidative damage. Exercise, in among long-lived individuals that have fact, contributes to increased free radical a much stronger influence than others. species. Human beings have the similar genes but An optimal CR reduces the incidence generation by burning food faster. But, vary from each other based on SNPs or of virtually all diseases of aging such these negative effects are more than offset single nucleotide polymorphisms. Some as cancer, CVD, diabetes, osteoporosis, by the health benefits of exercise, so that of these SNPs might increase the risk of auto-immune disorders, cognitive average lifespan is certainly increased hyperlipidaemia, CVD or Alzheimer’s decline and diseases such as Alzheimer's by exercise. But, exercise does not add disease. In addition to being free of the and Parkinson's diseases. CR extends anything to the maximum lifespan and negative genetic variations common in maximum and average life spans and fairly little to the average lifespan when other human beings, the centenarians improves disease resistance. Ingestion of there is already a . also have some positive mutations that fewer calories also alters fat deposition, The human brain begins to shrink 16 But, CR is not increase the possibility of longer life obesity, and hormones. in volume at about age 30, as a normal without certain adverse effects. There span. process of aging continues to lose volume occur hunger pangs, a decreased ability to until the end of life. Aerobic exercise handle stresses, such as cold temperatures CR AND CR WITH ADEQUATE slows down the loss of brain tissue in older or infection, osteoporosis and loss of NUTRITION adults. These effects are predominantly muscle mass, and loss of fertility. CALORIE RESTRICTION (CR) seen in three key areas of the brain: the The state of nutrition has a bearing on frontal, temporal and parietal regions. THE ROLE OF CR AND EXERCISE aging process and the life span. CR The frontal region regulates memory, Exercise helps, both physically and influences life expectancy. In general, planning, scheduling, decision-making,

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etc. The temporal region is related to Sir2 is believed to be the founding aging in muscle and fat, there appears memory and memory consolidation. The member, in evolutionary terms, of a to be a common oxidative pathway that parietal region is related to recall and family of genes known as sirtuins that becomes less efficient with age. navigation. are present in all complex life forms. Another gene has been identified that AGING PROCESS AND THEORIES OF THE LINKS BETWEEN SIRTUINS AND controls Sir2, a master regulator called, AGING CR PNC1. Stress turns on the PNC1 gene, Numerous studies and diverse There is a relationship between sirtuins, the activity of which turns on Sir2. observations have led to understanding insulin-signaling pathway and CR.17 The The STACs activate the sir2 protein. On of the phenomenon of aging. There are sirtuins are controlled by insulin and feeding these molecules to yeast cells, two main group of theories to explain another closely related hormone, insulin- roundworms and flies, the organisms the aging process: the systems theory like growth factor-1 (IGF-1). In mammals, live longer. These molecules act through (reliability theory) and those based on Sir2, and are ineffective when the gene there is SIRT1 gene (equivalent to Sir2 in the biological evolution. A synthesis of is deleted. The STACs have been found yeast) which rises when levels of insulin the two group of theories may seem an universally efficacious, even in humans. and IGF-1 fall, as they do in a calorie- attractive proposition. restricted organism. When sirtuins are THE RELIABILITY THEORY - triggered by STACs they don’t cause RESEARCH INTO THE AGING Considers aging as a set of processes, infertility, as occurs with CR. Thus, with PROCESS which contribute to the age-related RELATING LAB RESEARCH TO STACs we can get all the benefits of CR decline in performance, productivity HUMAN LONGEVITY without the trade-offs like infertility.18 and health, and ultimately death with the Intervention studies in lab animals The yeast is a single-celled fungus whose passage of time. Thus, the failure is an have led to understanding about types life span is defined by the number of times outcome, when the system deviates from of receptors and complex metabolic (on average 20-40) it can divide. Thus, the optimistically anticipated and desired pathways in mammals and humans. The reorganization of DNA over the course of behavior. The reliability theory predicts links between insulin signaling, CR, and the lifetime is limited. But when the cell’s that a system may deteriorate with age obesity could be centred on fat tissue. DNA is stabilized, both the average and even if it is built from non-aging elements Fat is known to make hormones called maximum lifespans increase. One of the with constant failure rate. The system's adipokines, which may act on other tissues redundancy for irreplaceable elements is proteins that stabilizes the chromosomes to alter longevity. Fat is also a source of responsible for the aging phenomenon. of a yeast cell, encoded by a gene of the molecules involved in oxidative stress, This theory allows to predict the age- same name, is called sir2. The Sir2 gene such as free radicals. Insulin signaling related failure kinetics for a given is activated when the yeast cells are has connections to diabetes and metabolic system and why mortality rates increase stressed. The Sir2 gene acts to stabilize syndrome. Calorie-restricted animals exponentially with age. Further, a living the chromosome, so the cells live longer also exhibit an altered metabolism. They organism may be formed with a high load (Figure 2). When an extra copy of Sir2 are slightly less efficient at converting of initial damage at birth or early-life gene was introduced into a yeast cell, food into energy but produce fewer free conditions and their lifespan and aging enabling to generate about twice as much radicals and less oxidative damage. In patterns may be sensitive to this initial sir2 protein and stabilizing the DNA, the human muscle, there is a decrease in damage load during early development. yeast lived about 30 percent longer. The oxidative metabolism with age. Given EVOLUTIONARY THEORIES sirtuins, thus, appear to be pro-survival these emerging connections among OF AGING - The major evolutionary molecules. diabetes, oxidative metabolism, and theories of aging include the mutation accumulation theory, the antagonistic Adiposity, Cytokine, IIS pleiotropy theory, the disposable soma 19 Signaling, Thyroid Hormone theory and theory of programmed death. Adiponectin The most viable evolutionary theories seem to be the mutation accumulation Activation of Longevity theory and the antagonistic pleiotropy CR SIRT1, PI3K/Akt signaling Promotion theory, though they are not mutually and Erk1/2) Signaling exclusive.

Activation of Stress Defense and PREDICTATORS OF LIFESPAN AND Survival Pathways / Attenuation LONGEVITY of Proinflammatory Mediators There is an unusual pattern of human lifespan inheritance. It has been Figure 2. CR and Longevity Promotion: SIRT and Other Players

114 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 discovered that there is no lifespan far future? This exercise will guide us in and are able to utilize experimental heritability, if parental lifespan is below warding off unreasonable expectations research, the life extension program a threshold age of 75-85 years and there from aging research; it will also help in (LEP) can be visualised to go through is a strong heritability of human lifespan consolidating our visions. A whole new three steps - Step One: Taking advantage if parents live longer lives. It has also generation of futurist visionaries believe of the existing knowledge for slowing been found that the early circumstances that it will be possible to maintain human aging like CR; Step Two: Utilizing the of human life, such as the month of birth, health at a youthful level for many extra advances in genetics and biotechnology; may have a profound effect 30 years later decades by healthy living, employing and Step Three: Using the future on the chances of survival. These findings new methods of anti-aging medicine and nanotechnology and artificial intelligence indicate that there may have been critical rejuvenation science. For the first time revolution, which may have the potential periods early in human development in human history, we have come close to to allow us to repair the mutations and understand, to slow down and probably that are particularly sensitive to seasonal other defects due to aging at molecular reverse the aging. variations in living conditions, such as and cellular levels. Further, the way to seasonal vitamin deficiencies or seasonal cure aging is to rejuvenate tissues, not THE MEANING OF LIFE EXTENSION exposure to pathogens, etc. Studies just to slow aging. Thus, the futuristic Life extension stands for an increase also show that paternal age at person's goal is to achieve rejuvenation and state in the maximum lifespan beyond the conception may be an important predictor of non-aging.24 current maximum lifespan for humans. of lifespan. This may be related to the THE SEVEN TYPES OF DAMAGE Exponential life extension can be defined mutation load or other genetic damage in WITH AGE: The first is cell loss. Certain as increase in life expectancy and life paternal sperm cells playing a significant tissues, like heart and brain, lose cells span by 50 per cent or more.22 For those role in determining the human lifespan.20 with aging and these cells are not naturally who regard aging as a disease, therapeutic Numerous studies demonstrate that replaced. The stem cell therapy can be methods to extend maximum lifespan manifestations of aging can be postponed used to restore the cells in these tissues. are anti-aging medicine. It was in 1970, or even reversed, and that lifespan can be Second, mutations in chromosomes the American Aging Association was significantly extended in experimental affect organ function and the life span formed under the initiative of Denham animals. Studies have found remarkable and can cause cancer. Targeted gene Harman, the originator of the free plasticity of aging and longevity and a therapy can be used to delete the telomere radical theory of aging. The bestselling elongation genes in particular tissues at significant potential for further extension book ‘Life Extension’ by Pearson risk of developing cancer. The third is the of human lifespan. On this basis we begin and Shaw popularized the phrase and mitochondrial mutations. Insertional gene to think of aging as a disease that can be emphasised antioxidant supplements. therapy can introduce modified versions cured, or at least be slowed down. In 1980, Saul Kent, the author of the of the 13 protein-coding mitochondrial book ‘The Life Extension Revolution’, genes into nuclear DNA, which will WHERE DO WE STAND? FUTURISTIC created the Life Extension Foundation, prevent accumulation of mutations in VISIONS OF LONGEVITY a non-profit organization. The Life the mitochondrial DNA. The fourth is In the current times, there has come a Extension Foundation later established, the senescent cells. Immune therapy growing interest for fitness and general the Alcor Life Extension Foundation, can be used to destroy senescent cells. health. People are looking forward for the largest cryonics organization. In Fifth, the extracellular cross-linking. It meaningful therapies, which can protect 1993 the American Academy of Anti- can be possible to design drugs that can health and preserve life. There is an Aging Medicine (A4M) was formed to break the cross links between long-lived increased awareness for fitness, longer create an anti-aging medical specialty molecules in the extra-cellular matrix, life and lasting health, and enthusiasm such as collagen and elastin. The sixth is distinct from geriatrics. The most recent for living a long life.21 The latter is the the extra cellular junk. This is important development in life extension has been driving force behind working for the in Alzheimer’s and Parkinson’s diseases the work of biogerontologist Aubrey life extension. The survival instinct is and other neurodegenerative disorders. de Grey, who proposes that the damage winning over the prejudices, fixations and A2E seems to be responsible for macular to macromolecules, cells, tissues and obstacles, and exciting changes are taking degeneration and malformed proteins in organs can be repaired by advanced place in the scientific world of gerontology, the brain are thought to be responsible nanobiotechnology.23 biotechnology and nanobiology which for Alzheimer’s disease. There is needed hold immense promise for slowing the a therapy which can slow down the THE VISIONS FOR FUTURE: aging and prolonging lifespan. accumulation and get rid of it as well. The PURSUING END OF AGING It is quite reasonable to take stock insertional by introducing As we are understanding the biological of the things, where do we stand and bacterial or fungal genes can break down principles of life and the aging process, what lies in store for us in the near and the damaging accumulated chemicals and

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proteins, including oxidized cholesterol future.28 However, it may come at a price POSITIVE PROJECTIONS FOR causing atherosclerosis. The seventh, is to and there are fears associated with the EXTENDED LIFE keep alive or preserved till the technology extended life. Life extension is the natural progression is practically available. Until molecular zz The Tithonus Option: of curing diseases by treatment repair technologies are available, good Today, the majority of people living in and preventing the effects of aging health practices, nutritional supplements, the developed countries can expect to live altogether.30 The human life is sacred and CR and organ transplantation, and well into their seventies. Even so, the final should be cherished and preserved. The cryopreservation after death are the best years are usually marked by impaired extended life spans will bring positive hopes. health and often senile dementia. There effects on society of a host of people is a fear that anti-aging technology may with the wisdom of 150 years of life THE CONCEPT OF IMMORTALITY present us with the extended lifespan and the youthful vitality, which has been Immortality or eternal life is the concept but limited improvement in QOL. The called the Gursky option, so named after existing for a potentially infinite length nightmare, that we will live longer, but in Ian McDonald's novel, ‘The Days of of time. The ideas of immortality exist bad health and mental deterioration, has Solomon Gursky’, where the inventions since time immemorial in mythological been called Tithonus option - immortal allow humans to stave off disease and tales. The modern sci-fi writers have also life with sub-functional brain or eternal improve their bodies. The issue of woven immortal worlds in their fiction. dementia. overpopulation should not be feared as In more recent times, people have had The three possible futuristic outcomes with spread of benefits of technology, their dead bodies cryopreserved in the may seem probable: The first, we will live education, and women’s rights, fertility hope that advances in medical science and die as we do today. There may accrue rates will decline. Life extension will will allow them to be unfrozen, cured, no benefit of aging research. The second not place a burden on health care but and restored to health at some point in the possibility, called the Tithonus option, is will itself be associated with good health future.25 that the technology will give extended and disability limitation. Older adults There are three main causes of death: lifespan but will not be able to reduce with extended life will be economically aging, disease and trauma. The hardest prevalence of dementia and debility. The productive members of society.31 Delayed cause of death to overcome is trauma. In third possibility is that technology will the postulated future world where aging be able to repair the damage done to our aging will lead to various social changes. will be correctable and diseases will be tissues with age, including neurons, thus The age stratification in the society will triumphed over, a trauma would still granting us longevity with good quality disappear, and along with it, many of our kill, unless technology advances to such of life. current social mores. The new ideas and zz Life on Support Systems: 32 extent that a body can automatically heal new possibilities will evolve. In intensive care units, it is commonly itself after a severe trauma (technological seen that for the critically ill patients, immortality), as it heals for the smaller CRYONICS AND BEYOND: more and more invasive procedures are ones. CRYOFREEZING FOR THE FUTURE performed to save the life and more and An interesting possibility involves Cryonics is the practice of freezing a body more of vital functions are taken over by uploading the mind like a computer at the time of clinical death with the aim bio-machines. The person is considered software on to a new human-body- of enabling eventual resuscitation back to living till the brain functions. It is an form generated by cloning, or simply life in the remote future. Cryonics offers artificially prolonged life on support uploading human consciousness onto a bridge to the future33 and a speculative systems, amounting to a nightmare of a computer system, and survive in life support technology that seeks to proportion of the Tithonus option: a long a virtual environment.26 Quantum preserve human life in a state that will be life with zero quality of life. immortality is the name for this kind of viable and treatable by future medicine.34 While genetic engineering and speculation.27 The important aspects of Further, modern cryonics is based on current practical scientific thinking about nanotechnology may help in extending the life significantly, it does not follow that a more sophisticated understanding immortality are human cloning, cryonics of death called ‘information-theoretic and nanotechnology. These projections future technology will be able to repair all wear-and-tear on the brain and other death’. In the past, death was defined lead us to notions of immortality or an as cardiac arrest and the current unending existence. body organs. If the future technology cannot repair all microscopic injuries, the medical definition of death is based Tithonus option will result. Considering on the cessation of electrical activity DARKER-SIDE OF LIFE EXTENSION a poor-quality-of-life better than no life, in the cerebral cortex. A person is dead It appears that with the advancements in we may fall in the trap, finally accepting according to the information theoretic medical science, genetics, biotechnology Tithonus option. People may regard it criterion if their memories, personality, and nanoscience, a true extension of better than cryopreservation in hope of a hopes, dreams, etc. have been destroyed human lifespan will come in the near novel treatment in the remote future.29 in the information theoretic sense, and the

116 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 structures in the brain that encode memory then the body is further cooled gradually whole body to ‘neuro-preservation’ and personality have been so disrupted to -130°C. Anti-freeze compounds are (i.e. head-only cryopreservation), on that it is no longer possible to recover then injected to stop cells being damaged. the assumption that the rest of the body them. The information-theoretic death is Finally the body is placed in a container could be regrown and reconstructed with ‘absolutely irreversible death’ in when which is lowered into a tank of liquid nanotechnology. The main goal now is to the structures in the brain that encode nitrogen at -196°C. The body or body preserve the information contained in the memory and personality have been so parts, for instance brain, are cryopreserved structure of the brain, on which memory disrupted that it is no longer possible to in liquid nitrogen contained in the Dewar and personal identity depends, and the recover them, and the destruction of the flask, which is custom-designed to available scientific and medical evidence brain has occurred to such an extent that contain four whole-body patients and six suggests that the mechanical structure any information it may have ever held is cryopreserved heads with brains inside, of the brain is wholly responsible for irrevocably lost for all eternity.35 immersed in liquid nitrogen at -196°C. It personal identity and memories. The The cryo-preserved bodies, not is an insulated container which consumes chemical brain preservation can be viewed irreversibly dead as per the understanding no electric power. Liquid nitrogen is as a life-saving medical procedure. It of information-theoretic death, are kept added periodically to replace the small allows the brain to be preserved for a long indefinitely preserved in a thermos-type amount that evaporates. period and in the future, the information container filled with liquid nitrogen until Newer forms of cryonics use a process in a chemically preserved brain may be the cryo-preservation damage would be 36 called vitrification. Vitrification employs able to be decoded and emulated in a possibly reversed at some time in future low temperatures and cryoprotectants to computer. Recent advances indicate this when the advanced state of science will turn tissue into a glass-like state where may soon be a real possibility. Damage allow the cause of the fatal disease to decay is extremely slow. It is also possible caused by freezing and fracturing is be cured and negate of the damage to to develop hybrid procedures involving the body because of the aging process. thought to be potentially repairable in the elements of both cryonics and chemical distant future, using nanotechnology. The The support for cryopreservation is brain preservation.37 based on debatable projections of future main limitation of current cryonics is that technologies and of their ability to enable it is uncertain whether the information in HEAD (NEURO-) Vs. WHOLE-BODY molecular-level repair of tissues and the brain is truly preserved. Nonetheless, CROPRESERVATION there is indirect evidence that cryonics organs. During the 1980s, the cryonics as currently practiced may preserve the corporations shifted emphasis from CRYOPRESERVATION: THE FROZEN LIFE The cryopreservation process must Legal death declared, process to begin in 2-15 min. begin immediately after legal death is The body packed with ice, and declared as the individual organs remain Injected with chemicals to stop clotting biologically alive for some time, and vitrification, particularly of the brain, is possible. The legal death is a declaration Body taken to cryonics facility. by medical personnel that there is nothing Cooled to just over freezing point. more can be done to save the patient. But, Blood replaced with Solutions to preserve organs the declaration of legal death does not mean that life has suddenly ended - death is a gradual process, not a sudden event. Acting immediately, the body is suitable Another solution injected to stop ice crystal for cryopreservation or the preservation formation in organs and tissues. of the brain is possible. Cryonicists try The body cooled to - 130 degree C to minimize ischemic and reperfusion injury by beginning cardiopulmonary support and cooling as soon as possible after pronouncement of death (Figure 3). The body placed in a container. The container put in a tank of liquid nitrogen The body is cooled to just above 0°C and at temperature - 196 degree C. the blood is replaced with a preservant and a solution is injected to stop ice Figure 3. Cryopreservation in action crystals formation in organs and tissues,

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information in the brain which could be had their bodies preserved in cryogenic detrimental to rational scientific behavior. recovered. chambers after death in the hope to be Thinking rationally, it is unlikely that The hypothesis of chemical brain revived in the future. The experts at something like a pill or potion, can preservation as life extension was the (CI), Michigan reverse the changes and dysfunction proposed by Drexler in 198738 and have claimed that cryonically bringing associated with aging. At the same time, Olson in 1988. The systematic brain someone back to life should definitely the progress in healthcare and technology lesion studies have shown that the brain be doable in 100 years or sooner. The has made possible to slow aging. Further, is completely responsible for the mind CI has about 160 patients frozen in there are possibilities of being able to and the identity is defined by anatomy: specialised tanks of liquid nitrogen at its reverse the aging process. that is, brain connectivity. Our memories headquarters and has almost 2,000 people The possibility of a lengthy-healthy life and personalities are captured in the signed up to be frozen after they die.46 is alluring. As the life expectancy at synaptic and dendritic connections in the Two main US cryonics organisations are birth rises and there is taking place an brain, referred to as the connectome.39,40 Alcor at Arizona, and the CI at Michigan. improvement in average and maximum The information theory of death and A Russian body KrioRus and Alcor's lifespan, the possibility of living life understanding of the connectome European laboratory in Portugal are the more than never before seems logical. imply that death does not occur until the information in the connectome is two facilities outside the US to offer the Science gives visions; technology irreversibly lost.41,42 Chemical brain service. Aside from Trans Time, the other makes the visions possible. The future preservation is not currently an option, three cryonics organizations in the world technology appears to offer us visions but it is extremely likely that within a few which are storing human patients in liquid that rival the dreams of myth and legend. 47 years, whole brain preservation protocols nitrogen are the Alcor Life Extension As per the Arthur C. Clarke's Third Law with strong scientific support in favour Foundation (founded in 1972 by Fred - ‘any sufficiently advanced technology of connectome preservation will be and Linda Chamberlain), the Cryonics is indistinguishable from magic’. One available. When this happens, chemical Institute (founded in 1976 by Robert of these magical dreams is that of brain preservation can be viewed as a Ettinger), and KrioRus (located near exponential life extension. life-saving medical procedure. Moscow in Russia, founded in 2006). In the distant future, technology may Cryopreservation arrangements can THE LIFE BEAUTIFUL advance to the state where the information be expensive, currently ranging from An ideal body weight is desirable. of an individual’s brain design can be $35,000 at the Cryonics Institute to Doing something new helps the brain. extracted from his or her preserved $200,000 at Alcor. KrioRus' charges Research shows that most people lose brain and the complete connectome to $37,600 for the procedure. But, even over 20 percent of their muscle mass by be obtained from preserved brains. The assuming perfect cryopreservation age 70, leading to infirmity. People can next key piece of technology in making techniques, many scientists still regard reverse this aspect of aging by regular chemical brain preservation a life-saving the eventual revival as a long shot. It is exercising. Reducing stress and adopting procedure is whole brain emulation being claimed that cryonics may replace coping mechanisms is important. Taking (WBE). WBE involves replicating the traditional burials and cremations in a walk, praying, meditating or having informational structure of the brain in the next few decades, leading to Cryo- lunch with a friend, are some of the software that could then be run in a Parlours in place of Funeral Parlours. stress-busting measures. People, who computer. Knowledge of the connectome build the stress-busting habits into their should allow for a complete emulation CONCLUSION: FROM AGING daily routine, benefit much. Finally, of brain function, and the technologies SLOWLY TO EXPONENTIAL LIFE finding life interesting is a primal desire, for mapping the connectome and for EXTENSION AND IMMORTALITY 43 which encourages you to live and go on WBE have been advancing rapidly. The CLARKE’S THIRD LAW discovering the multiple facets of life on development of WBE and the computer The aging is universal in the kingdom the Earth and beyond. technology to implement it is now an of living. We find people aging; we initiative of the European Union known ourselves age and grow older. There has as the Human Brain Project,44 which aims evolved a whole novel understanding of REGENERATIVE MEDICINE Apart from CR, regenerative medicine to develop a complete emulation of a the biology of aging. Aging is a complex is the next concrete step for achieving mouse brain and later that for the human process and affects virtually all organs of longevity. The most promising in brain. The Human Brain Project aims to the body. A vast body of knowledge can regenerative medicine is therapeutic scan and upload a significant portion of now explain the changes that take place 45 cloning. A new organ can be grown for the human brain. with aging at molecular and cellular level. transplantation using one’s own cells. But, irrational hopes from technology The process would involve transferring CRYONICS: THE FACTS move us away from terra-ferma and are Around 350 people worldwide have the nucleus from a cell to an enucleated

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Published online first February 25. doi:10.1136/ we lose our health and fitness and pass doi 10.1155/2012/646354. medethics-2015-102715. through an abridged life. Scientifically 13. Mattson MP. 2008. Hormesis Defined. Ageing Res Rev. 34. Merkle R. Lecture at the Farquhar College of Arts and speaking, longer life is not separate from 7:1; 1–7, doi: 10.1016/j.arr.2007.08.007. Sciences Division of Math, Science, and Technology, Nova 14. Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. South-Eastern University. Merkle discussed "Life, Death, aging slowly, rather they are mutually 2017. The therapeutic potential of resveratrol: a review and Cryonics" on Thursday, October 2, 2008. related. With the scientific progress the of clinical trials. Npj Precision Oncology, vol 1, Article 35. Whetstine L, Streat S, Darwin M, Crippen D. 2005. Pro/ number: 35. con ethics debate: When is dead really dead? Critical futuristic visions of achieving significant 15. Sebastiani P, Perls TT. 2012. The Genetics of Care 9: 538–42. longevity, if not immortality seems quite Extreme Longevity: Lessons from the New England 36. Pichugin Y, Fahy G, Morin R. 2006. Cryopreservation of possible. The eternal dream is on the Centenarian Study, Front Genet. 3: 277, doi: 10.3389/ rat hippocampal slices by vitrification. Cryobiology 52: fgene.2012.00277. 228–40. verge of becoming a reality. 16. Masoro EJ. 2000. There takes place an improvement in 37. McIntyre RL, Fahy GM. 2015. Aldehyde-stabilized the immune response, as well. restriction and aging: an cryopreservation. Cryobiology.71:3; 448-58 update. Experimental Gerontology 35; 299–305. 38. Drexler KE. 1987. Engines of creation: The coming FOOTNOTES 17. Guarente, L. 2000. Sir2 links chromatin silencing, era of nanotechnology. London: Anchor. ISBN: 978- 1. Affiliation – Senior Chief Medical metabolism, and aging. Genes Dev. 14, 1021–26. 0385199735. Officer and Consultant, Department 18. Guarente L. 2013. Calorie restriction and sirtuins 39. Sporns O, Tononi G, Kötter R. 2005. The human revisited. Genes Dev. 27:19; 2072–85. doi: 10.1101/ connectome: A structural description of the human brain. of Medicine, Hindu Rao Hospital and gad.227439.113. PLoS Computational Biology 1:4; e42. NDMC Medical College, New Delhi, 19. ScientificWorldJournal. 2002 Feb 7;2:339-56. 40. Dubnau HK, Oyibo H, Zhan G, et al. 2012. Sequencing India. Email: [email protected] Evolutionary theories of aging and longevity. Gavrilov the connectome. PLoS Biology 10:10; e1001411. LA, Gavrilova NS. Article?id=10.1371. 2. Disclosures – None. 20. Palmore EB. 1982. Predictors of the Longevity Difference: 41. Seung HS. 2011. Towards functional connectomics. 3. The Figures 1-3 in this Review Article A 25-Year Follow-Up. The Gerontologist, Vol 22:6, 513– Nature 471:170–72. 18, https://doi.org/10.1093/geront/22.6.513. 42. Seung HS. 2013. Connectome: How the brain’s wiring are subject to Copyright by Dr Vinod 21. Marshall J. 2006. Life extension research: an analysis of makes us who we are. New York: Houghton Mifflin Nikhra. contemporary biological theories and ethical issues. Med Harcourt. Health Care Philos. 9:1;87-96. 43. Eth D, Foust J, Whale B. 2013. The prospects of whole 22. Cerullo MA. 2016. The Ethics of Exponential Life brain emulation within the next half-century. Journal of REFERENCES Extension through Brain Preservation. Journal of Artificial General Intelligence, 4:3; 130-52. 1. Johnson SC, Rabinovitch PS, Kaeberlein M. 2013. mTOR Evolution and Technology, 26:1, 94-105. 44. Human Brain Project. n.d. Human Brain Project website. is a key modulator of ageing and age-related disease. 23. de Grey A. 2003. ‘The foreseeability of real anti-aging https://www.humanbrainproject.eu. Nature. 2013 Jan 17;493(7432):338-45. doi: 10.1038/ medicine: focusing the debate’. Exp. Gerontology 38:9; 45. Human Brain Project SP2. n.d. Human Brain nature11861. 927-34. Project Strategic Human Brain Data. https://www. 2. Petralia RS, Mattson MP, and Yao PJ. 2014. Aging and 24. Norman A, Reedy C. 2017. An End to Aging: Can Science humanbrainproject.eu/strategic-human-brain-data. longevity in the simplest animals and the quest for Allow Humans to Become Immortal? Future Society. 46. Harry Pettit, Mail Online 15 January 2018. http://www. immortality. Ageing Res Rev. 0: 66–82. Futurism, accessed https://futurism.com/1-evergreen-an- dailymail.co.uk/sciencetech/article-5270257/Cryogenics- 3. Tosato M, Zamboni V, Ferrini A, Cesari M. 2017. The end-to-aging-heres-how-were-fighting-death on 10 July corpses-brought-10-years.html. aging process and potential interventions to extend life 2018. 47. Arthur C. Clarke. 2000. Profiles of the Future: An expectancy. Clin Interv Aging. 2(3): 401–12. 25. Ben B. 2000. Immortality: How Science Is Extending Your Inquiry into the Limits of the Possible. ISBN-13: 978- 4. Strawbridge WJ, Wallhagen MI, Cohen RD. 2002. Life Span-and Changing the World. Avon: New York ISBN 1898801214. Publisher: Phoenix, The Orion Publishing Successful Aging and Well-Being: Self-Rated Compared 0-380-79318-0. Group Ltd.

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Current Management of Acute Heart failure

Keywords MOHAN BHARGAVA, MOHIT M BHAGWATI, PRACHAL BHARGAVA zz acute heart failure zz decompensated geart failure zz acute hypertensive failure zz cardiogenic shock zz vasodilators Abstract zz vasopressins Acute Heart failure (AHF) can be defined as the new onset (sudden or zz inotropes gradual) or recurrence of symptoms and signs of HF which requires zz beta blockers urgent therapy and results in hospitalization. It is one of the most common causes of emergency visits and ICU admissions. The annual incidence of HF in India is 491,600–1.8 million. Acute heart failure should be suspected in patients who present to the hospital with complaints of sudden or gradual onset dyspnea, edema or chest discomfort. Initial diagnosis of AHF should be based on a history , prior cardiac history and potential precipitating factors, as well as on the assessment of signs/symptoms of congestion and/or hypoperfusion by physical examination and further confirmed by appropriate additional investigations such as ECG, Chest X-ray, laboratory assessment (with specific biomarkers) and Echocardiography. Risk stratification can serve as important clinical tool in identifying high risk patients. Due to the high risk of mortality and re-hospitalization in the first 3 months after discharge, a risk stratification for post discharge events is necessary. There are well-defined criteria for ICU/CCU admission. Treatment of AHF is a complex multi-step process involving various goals at different levels of care including emergency care, hospital management, pre- discharge planning and post-discharge management and prevention of re-hospitalization. AHF continues to be a challenge for physicians across the globe and a systematic plan based management shall help us overcome this challenge with less difficulty.

INTRODUCTION which requires urgent therapy and results Acute heart failure (AHF) can be defined in hospitalization. It is one of the most as the new onset (sudden or gradual) or common causes of emergency visits and recurrence of symptoms and signs of HF intensive care unit (ICU) admissions. In

Dr. Mohan Bhargava is Principal Consultant and Interventional Cardiologist, Dr Mohit Bhagwati is 3rd yr SR, at Max Superspeciality Hospital, Saket, New Delhi & Dr Prachal Bhargava is Masters in Emergency Medicine 3rd yr SR, Aster CMI Hospital Bangalore

120 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 US, 4 million patients are hospitalized every year with a diagnosis of heart failure (HF), and AHF contributes to more than 7 million hospital days every year.1 In India, the prevalence of heart failure is estimated to range from 1.3 to 4.6 million, with an annual incidence of 491,600–1.8 million.2 In Trivandrum heart failure registry, one out of three patients was admitted with AHF at least once in one year after recruitment to the registry.3 AHF can be the first presentation or it can be due acute decompensation of chronic heart failure. Ischemic heart disease and acute valve insufficieny are one of the most common primary caused while infection, uncontrolled hypertension, rhythm disturbances or non-adherence with drugs/diet are the most common triggers for sudden decompensation.

DIAGNOSIS OF ACUTE HEART FAILURE Acute heart failure should be suspected in patients who present to the hospital with complaints of sudden or gradual onset dyspnea, edema or chest discomfort. Initial diagnosis of AHF should be based on a history , prior cardiac history and potential precipitating factors, as well as on the assessment of signs/symptoms of congestion and/or hypoperfusion Fig 1: Initial management of acute heart failure by physical examination and further confirmed by appropriate additional perfused without congestion). This therapy in the initial phase and carries 4-6 investigations such as ECG, Chest X-ray, classification may be helpful to guide prognostic information. However, the laboratory assessment (with specific biomarkers) and Echocardiography. Table 1: Signs and symptoms of acute heart failure Usually signs and symptoms of AHF Symptoms Signs reflect fluid overload (pulmonary Due to Volume Dyspnea (Exertional dyspnea, Fine crackles, pleural effusion congestion and/or peripheral odema) or, overload orthopnea, paroxysmal less often, reduced cardiac output with nocturnal dyspnea) peripheral hypoperfusion (Table 1). Foot and leg discomfort Pedal edema Clinical classification of AHF is based on Abdominal bloating, early Ascitis, increased weight, positive bedside physical examination on basis of satiety, anorexia hepatojugular reflux the presence of clinical symptoms/signs Due to Fatigue Cold extremities of congestion (‘wet’ vs. ‘dry’ if present vs. Hypoperfusion absent) and/or peripheral hypoperfusion Altered mental status, daytime Pallor, hypotension (‘cold’ vs. ‘warm’ if present vs. absent). drowsiness, confusion The combination of these options thus Dizziness, presyncope, Narrow pulse pressure divides AHF into four groups: warm and or syncope wet (well perfused and congested) — most commonly present; cold and wet Other Depression Orthostatic hypotension (hypoperfused and congested); cold and (hypovolemia) dry (hypoperfused without congestion); Sleep disturbances S4 and warm and dry (compensated, well Palpitation Systolic/diastolic murmurs

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sensitivity and specificity of clinical signs HF. New-onset or de novo HF amounts are the important counter regulatory and symptoms are often not satisfactory, to about 20% of hospitalizations for hormones in HF with vasodilatory so careful clinical evaluation needs to be AHF.8 Majority of AHF are sudden effects. They play an important role in followed by certain investigations like decompensation of chronic heart failure. the differential diagnosis of patients Chest Xray, ECG, 2D Echocardioraphy, (Table 2). These patients usually have a presenting in the emergency department and blood investigations including less dramatic clinical presentation, since (ED) with dyspnea and are strongly natriuretic peptides and renal function the chronic nature of the disorder has recommended by clinical practice test. The initial evaluation of the allowed for recruitment of compensatory guidelines.10,11 The negative predictive patient with acute HF should focus mechanisms and usually these patients are value of natriuretic peptides is greater on establishing a definitive diagnosis already being treated with neurohormonal than the positive predictive value, so of AHF as rapidly and efficiently as antagonists and loop diuretics, such it can be used as a good rule out test in possible, initiating emergency treatment that neurohormonal activation may be the emergency department (thresholds: for potentially life-threatening conditions less profound but diuretic resistance BNP <100 pg/mL, NT-proBNP <300 (e.g., shock, respiratory failure, is more common. Acute hypertension pg/mL). Cardiac troponin is frequently identifying and addressing any relevant of reactive type is also associated with elevated in patients presenting with AHF, clinical triggers or other conditions AHF, these patients are more likely to and elevated levels are associated with requiring specific treatment (e.g., ACS, have sudden onset of symptoms. Frank worse in-hospital and post-discharge acute pulmonary embolism), risk pulmonary edema with evident rales outcomes. Apart from natriuretic peptides stratifying the patient in order to triage and florid congestion on chest x-ray film and troponins, the following laboratory patient to appropriate level of care (e.g., is much more common in this group of assessments should be performed at ICU, telemetry unit, observation unit) and patients, likely related to difference in LV admission in all patients with AHF: blood defining the clinical profile of the patient compliance, acuity of pressure changes, urea nitrogen (BUN) (or urea), creatinine, (based on blood pressure, volume status, and pulmonary lymphatic capacity, electrolytes (sodium, potassium), liver and renal function) in order to rapidly however this group tends to respond well function tests, thyroid-stimulating implement the most appropriate therapy. to therapy and have lower in-hospital hormone (TSH), glucose and complete European Society of Cardiology, in its mortality.8 Other less common causes of blood count; D-dimer is indicated 2016 guidelines of Acute and Chronic heart failure are isolated right HF or high in patients with a suspicion of acute heart failure recommends the following output HF. pulmonary embolism.7 Creatinine, BUN approach to initial management of acute Apart from classical signs and and electrolytes should be measured heart failure (Figure 1).7 symptoms, certain investigations are every 1–2 days while in the hospital routinely indicated to aid in diagnosis of and before discharge from the hospital. AHF can be classified on the basis of the Acute heart failure. Cardiac biomarkers Pre-discharge assessment of NPs may presence or absence of a prior history of of heart failure like BNP and NT-proBNP be considered for prognostic evaluation.

Table 2: Classification of acute heart failure9 Clinical Symptom Triggers Signs and Clinical Course Classification Onset Symptoms Assessment

Decompensated Usually Noncomplicance, ischemia, Perpherial edems, SEP: variable Variable, high rehospitalization heart failure gradual Infections orthopnea, dyspnea CXR: often clear despite rate exertion elevated filling pressure Acute Usually Hypertension, atrial Dyspnea (often severe) SBP: high High acuity, but patient often hypertensive sudden arrhythmias, tachypnea, tachycardia (>180/100mmHg) responds quickly to therapy failure ACS rales common CXR with pulmonary with vasodilators, noninvasive edema ventilation. Hypoxemia common

Cardiogenic Variable Progression of advanced HF End-organ hypo- SBP: low or low normal High inpatient mortality Shock or major myocardial insuit perfusion; Oliguria, LV function usually Poor prognosis unless readily (e.g., large AMI, acute confusion, cool severely depressed reversible cause or mechanical myocarditis) extremities RV dysfunction support, transplanation common Laboratory evidence of end-organ dysfunction (renal, hepatic)

122 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 Invasive haemodynamic evaluation with a pulmonary artery catheter is not indicated routinely for the diagnosis of AHF. Chest Xray, ECG and 2d Echocardiography is indicated in all patients presenting with acute heart failure. 2D Echo should be done urgently in patients who are hemodynamically unstable.

RISK STRATIFICATION Risk stratification can serve as important clinical tool in identifying high risk patients. Data from ADHERE Registry has been used to develop a classification and regression tree (CART) analysis to identify the best predictors of in- hospital mortality.12 They identified elevated BUN, lower SBP, and higher serum creatinine at admission to be the best predictors of in-hospital mortality. As there is a substantial risk of mortality or re hospitalization in the first 60 to 90 days after discharge in AHF patients, a risk stratification for post discharge events should also be done. Systolic BP has been found to be an important predictor of outcomes. There was a relatively monotonic relationship between blood pressure and mortality across the spectrum of blood pressure in the OPTIMISE HF registry.13 Apart from SBP, BUN and Natriuretic peptides Figure 2: Clinical classification of AHF patients and their management are independent predictors of outcome in patients of AHF.14,15 All patients who 2. Hospital Management of HF and inhaled oxygen should present with AHF to the emergency 3. Pre-discharge planning be provided to all patients who have department should be preferably admitted 4. Post-discharge management and hypoxemia (SpO2<90). However, routine in the hospital. The criteria for ICU/CCU prevention of rehospitalisation oxygen administration is not indicated admission include any of the following:16 in patients without hypoxemia and zz need for intubation (or already Phase I- Emergency care has shown to have adverse effects like intubated) The initial goals of emergency care after vasoconstriction.17 Special care is needed zz signs/symptoms of hypoperfusion making a precise clinical diagnosis of in COPD patients where oxygen can be z z oxygen saturation (SpO2) <90% heart failure are to treat life threatening detrimental. Non-invasive ventilation (despite supplemental oxygen) abnormalities, provide urgent symptom in form of NIPPV (non-invasive zz use of accessory muscles for relief, establish etiology and precipitating positive pressure ventilation) and CPAP breathing, respiratory rate >25/min factors of AHF and transfer the patient (continuous positive airway pressure) zz heart rate <40 or >130 bpm, SBP in ward or intensive care unit for further has been found effective in controlling <90 mmHg. management. Patients should be classified dyspnea, heart rate and acidosis in on the basis of congestion and perfusion patients who have cardiogenic pulmonary TREATMENT OF ACUTE HEART and initial treatment should be started edema.18 Endotracheal intubation and FAILURE (Figure 2). mechanical ventilation is indicated if Treatment of AHF is a complex multi- Dyspnea is the most common here is a contradiction to non-invasive step process involving various goals at symptom in patients with AHF and ventilation (NIV) or if the patient is different level of care and can be divided immediate treatment should be provided unable to tolerate NIV. Morphine may into four phases : to all patients to relieve dyspnea. Pulse be useful in patients with anxiety, 1. Emergency Care oxymetry shouId be done in all patients however it should not be routinely used

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Vasodilators can be used as first-line therapy in combination with diuretics in the management of AHF patients to improve congestive symptoms, in the absence of hypotension.22 They decrease preload by venodilatation and decrease afterload by arterial dilatation, in addition increase stroke volume. Despite theoretical benefit, no robust evidence is there which prove their mortality benefit.23 These should be used with caution in patients who are preload or afterload dependent (e.g., severe diastolic dysfunction, aortic stenosis, mitral stenosis, coronary artery disease (CAD), since these drugs may cause severe hypotension. (Table 3) The inotropic drugs are inodilators (inotropic drugs with vasodilatory properties), increase cardiac output through cAMP-mediated inotropy and Figure 3: Effect of Door to Furosemide time on In hospital mortality in AHF reduce pulmonary capillary wedge pressure (PCWP) through vasodilation. as it increases the likelihood of invasive creatinine at 72 hours with administration (Table 4). However, use of inotropes is ventilation, ICU admission and mortality. by bolus compared to infusion or with the associated with slight risk in in-hospital Intravenous Loop Diuretics are the low- versus high-dose strategy.20 Thiazide and long term mortality.24,25 Inotropes most frequently used initial treatment diuretics, metolazone and natriuretic should be reserved for patients with strategy in AHF and are cornerstone of doses of mineralocorticoid receptors can a severe reduction in cardiac output the management of patients presenting be added to loop diuretics to augment the resulting in compromised vital organ with AHF and congestion. In addition to effect or to overcome diuretic resistance.21 increased renal salt and water excretion, diuretics have some vasodilatory effect. Table 3: Commonly used Vasodilators in Acute Heart Failure Drugs Dose Adverse Effects Others However, In patients with AHF and Nitroglycerine Start with10–20 µg/min, Hypotension, headache Tolerance on signs of hypoperfusion, diuretics should increase up to 200 µg/min continuous use be avoided before adequate perfusion is Isosorbide dinitrate Start with 1 mg/h, Hypotension, Tolerance on attained. Time to first administration of increase up to 10 mg/h headache continuous use diuretic after entering the emergency, Sodium Nitroprusside Start with 0.3 µg/kg/min Hypotension, Light sensitive i.e., door to furosemide time (D2F time) and increase up to isocyanate toxicity should be less than 60 minutes and early 5 µg/kg/min treatment with intravenous loop diuretics Nesiritide Bolus 2 µg/kg + Hypotension is associated with lower in-hospital infusion 0.01 µg/kg/min mortality in patients presenting at the ED for AHF (Figure 3).19 IV loop diuretics should be given in doses between 1 and Table 4: Inotropes and Vasopressors used in AHF 2.5 times the patient's oral loop diuretic Drug Dose dose for those receiving chronic diuretic Noradrenaline 0.2-1 mcg/kg/min therapy. However for newly diagnosed Adrenaline 1mg IV bolus every 2-3 minutes for resuscitation patients 20-40 mg of Furosemide or 10-20 or 0.05-0.5 mcg/kg/min mg of Torsemide should be administered. Dopamine 3-5 mcg/kg/min for inotropic action, DOSE, a randomized double-blind >5mcg/kg/min for vasopressor action study, prospectively compared diuretic Dobutamine 2-20 mcg/kg/min strategies in AHF and found that there Levosimendan 12mcg/kg iv bolus over 10 minutes, was no significant difference in either 0.1 mcg/kg/min(0.05-2 mcg/kg/min) of the co-primary endpoints of global Milrinone 25-75 mcg/kg iv bolus over 10-20 minutes, assessment of symptoms and change in 0.375-0.75mcg/kg/min

124 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 perfusion, which occurs most often in significant benefit of ultrafiltration over renal function, especially when RAAS hypotensive AHF. They should not be diretics.33-34 The use of ultrafiltration inhibitors are introduced. Evaluation for used in the setting of hypovolemia or is limited to patients with refractory myocardial ischemia may be needed if other potentially correctable factors volume overload, oliguria unresponsive there is suspicion of ischemia as a trigger of shock. If beta-blockade is thought to fluid resuscitation measures, severe of decompensation. Dietary sodium to be contributing to hypoperfusion, hyperkalemia (K+ >6.5 ), severe acidosis restriction (2 g daily) and fluid restriction levosimendan is preferable over (pH <7.2), serum urea level >150 mg/ (2 L daily) may be useful to help treat dobutamine to reverse the effect of beta- dL and serum creatinine >3.4 mg/dL. congestion, however its role is not yet blockade.26 Levosimendan is not suitable Intra-aortic balloon pump is not indicated certain.35 Thromboembolism prophylaxis for treatment of patients with hypotension routinely, however ventricular assist should be given as per guidelines in (SBP <85 mmHg) or cardiogenic devices and other mechanical supports case of prolonged immobility. Invasive shock unless in combination with other may be used as a bridge to decision in hemodynamic monitoring is not indicated inotropes or vasopressors.27 Vasopressors refractory cardiogenic shock.7 routinely, however intra-arterial blood like adrenaline, noradrenaline and pressure monitoring can be done in dopamine are used raise blood pressure PHASE II- HOSPITAL MANAGEMENT hypotensive patients. and redistribute blood to the vital organs. The goals of in hospital management after If the patient of AHF has been However, they also increase LV afterload. providing acute treatment and stabilizing admitted due to acute decompensation of Among them, norepinephrine has fewer hemodynamics, volume status, initiate or chronic heart failure, every attempt should side effects and lower mortality associated optimize chronic HF therapy. Etiology be made to continue disease modifying with it and remains inotrope of choice.28 of AHF should be identified and all guideline based oral therapy. In the other co-morbidities must be addressed. absence of hemodynamic instability or OTHER PHARMACOLOGICAL Standard hemodynamic monitoring of contraindications, beta-blocker therapy MEASURES heart rate, blood pressure, respiratory should be continued in patients already Digoxin rapidly improves hemodynamics rate and oxygen saturation should be on beta blockers during the admission for without increasing heart rate or decreasing done in all patients. Patients should AHF, unless significant hypotension or BP by its positive inotropic action. be weighed daily and accurate fluid cardiogenic shock are present. Patients However it is mostly indicated in patients balance chart including intake output who had beta blocker withdrawn had with AF and rapid ventricular rate (>110 measurement should be done in all higher in-hospital mortality, short-term bpm) and given in boluses of 0.25–0.5 patients. Laboratory monitoring should mortality, and combined short-term mg intravenously. Due to various drug- include daily analysis of electrolytes and rehospitalization.36 RAAS inhibitors can drug interactions and toxicity, it is not 38 recommended routinely.29 Digoxin is now Table 5 : Criteria for Hospital discharge in Acute Heart failure only used as reserve drug in patients not Recommended in all AHF patients  Exacerbating factors addressed. responding to other therapy. Vasopressin  Near optimal volume status observed. antagonists such as tolvaptan block the  Transition from intravenous to oral diuretic action of arginine vasopressin (AVP) at the successfully completed. V2 receptor in renal tubules. It promotes  Patient and family education completed, aquauresis. It can be used to treat patients including clear discharge instructions with volume overload and resistant  LVEF documented hyponatraemia.30 However, studies of  Smoking cessation counseling initiated short-term therapy when compared  Near optimal pharmacologic therapy achieved, to placebo in AHF did not show any including ACE inhibitor and beta blocker (for benefit.31 Thromboembolism prophylaxis patients with reduced LVEF), or intolerance with heparin or another anticoagulant is documented recommended only if there is an indication  Follow-up clinic visit scheduled, usually for 7-10 days like acute coronary syndrome, acute Should be considered for patients  Oral medication regimen stable for 24 hours pulmonary embolism, atrial fibrillation with advanced HF or recurrent  No intravenous vasodilator or inotropic or if the patient is on existing treatment admissions for HF agent for 24 hours with oral anticoagulants. Ultrafiltration  Ambulation before discharge to assess functional using renal replacement therapy has a capacity after therapy theoretical advantage over diuretics of  Plans for post discharge management removing isotonic fluid without causing (scale present in home, visiting nurse or telephone neurohormonal activation.32 However, follow up generally no longer than 3 days after various studies comparing loop diuretics discharge) and ultrafiltration failed to show any  Referral for disease management, if available

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AHF results in a substantial clinical Table 6: Starting dose and target doses of drugs in Guideline directed medical worsening of patients.39 Therefore patients therapy.42 discharged from the hospital require post Drugs Starting dose Target dose discharge support with a care plan, early Beta Blockers physician follow-up and patient-centered Bisoprolol 1.25 mg once daily 10 mg once daily discharge instructions about diet, Carvedilol 3.125 mg twice daily 25 mg twice daily for weight <85 kg exercise and adherence to medication. and 50 mg twice daily for weight > 85 kg This care plan includes up-titration of Metoprolol succinate 12.5–25 mg/d 200 mg daily guideline directed medical therapy with ARNI regular monitoring, need and timing of Sacubitril/valsartan 24/26 mg–49/51 mg 97/103 mg twice daily device therapy if required and education twice daily for lifestyle management. All details ACE inhibitor regarding medication, dietary sodium Captopril 6.25 mg thrice daily 50 mg thrice daily restriction, and recommended activity Enalapril 2.5 mg twice daily 10–20 mg twice daily level should be provided in detail. Early Lisinopril 2.5–5 mg daily 20–40 mg daily follow up prevents re hospitalization and Ramipril 1.25 mg daily 10 mg daily should be scheduled within 7 to 10 days ARB after discharge, or even earlier in high Candesartan 4–8 mg daily 32 mg daily risk patients.40 Alcohol moderation and Losartan 25–50 mg daily 150 mg daily smoking cessation should be advised Valsartan 40 mg twice daily 160 mg twice daily and a regular monitoring of body weight, Aldosterone antagonists electrolytes and renal function should Eplerenone 25 mg daily 50 mg daily be done. All disease modifying drugs Spironolactone 12.5–25 mg daily 25–50 mg daily should be escalated to maximum possible Vasodilators doses to achieve maximal benefit. (Table Fixed-dose 20 mg/37.5 mg 2 tabs thrice daily 6) Early initiatation and upgradation combination (one tab) of GDMT has shown to decrease post isosorbide dinitrate thrice daily discharge outcomes more than any /hydralazine other factor.41 All other co-morbidities Ivabradine 2.5–5 mg twice daily Maximum dose should also be given importance while Titrate to heart 7.5 mg twice daily evaluating a multi-disciplinary approach Rate 50–60 bpm to treat heart failure. be temporarily stopped if worsening renal is associated with a high risk for re- MECHANICAL CIRCULATORY failure necessitates their discontinuation. hospitalization.37 Evaluation of functional DEVICES IN AHF In case of HF with reduced ejection capacity with simple maneuvers such as Some patients of AHF may not respond fraction (HFrEF) diagnosed de novo, all climbing one flight of stairs or walking to medical therapy alone and may attempts should be made to initiate oral down the corridor should be done before require intra-aortic balloon pump guideline directed medical therapy inside discharge. Observation for a period of 24 support or Impella device support prior the hospital. hours after discontinuation of vasoactive to revascularization, while some patients or inotropic support is ideal, but shorter would require ECMO (extra corporeal periods may suffice for patients whose PHASE III- PRE DISCHARGE membrane oxygenation) or LVAD symptoms have significantly improved PLANNING (left ventricular assist device) which is The goals of pre-discharge planning in a and who tolerate weaning of intravenous lifesaving, or in some patients they may patient admitted with AHF comprises of support well. be used as bridge to heart transplant.43-46 preparing and evaluating the readiness for (Figure 4). discharge, initiation of guideline directed PHASE IV- POST DISCHARGE medical therapy, address the side effects MANAGEMENT AND PREVENTION FUTURE DIRECTIONS of medication and worsening of renal OF RE HOSPITALIZATION AHF continues to be the biggest problem function with optimal management and A robust post-discharge care plan should for cardiologists across the globe, several optimizing therapy in order to prevent be implemented in all AHF patients as the therapies tried so far target symptoms, early re-hospitalization (Table 5). All natural history of AHF is characterized the syndrome. However, various studies attempts should be made to achieve dry by relatively low in-hospital mortality are being carried out targeting the weight of the patient before discharge as but a high rate of recurrent post discharge pathophysiology of the syndrome. The persistent clinical congestion at discharge events. Recurrent hospitalizations for concept of “One therapy fits all” doesn’t

126 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 10. Knebel F, Schimke I, Pliet K,et al . NT-ProBNP in acute Medical therapy heart failure: correlation with invasively measured Inotropic support Vasopressor support hemodynamic parameters during recompensation. J Card Fluids Fail. 2005 ;11(5):S38-41 Ventilatory support 11. Maisel AS, Krishnaswamy P, Nowak RM, et al: Rapid Age Revascularization measurement of B-type natriuretic peptide in the Comorbidities emergency diagnosis of heart failure. N Engl J Med 2002; Neurological function Patient unstable Patient stable 347:161-16 12. Fonarow GC, Adams KF, Abraham WT, et al: for the Adhere Scientific Advisory Committee. Risk stratification LVAD support Weaning for in-hospital mortality in acutely decompensated heart No cardiac Cardiac function Cardiac function failure: classification and regression tree analysis. JAMA function 2005; 293: 572-580 recovers recovery recovers 13. Gheorghiade M, Abraham WT, Albert NM, et al: Systolic blood pressure at admission, clinical characteristics, Weaning Assess neurology/ Standard therapy and outcomes in patients hospitalized with acute heart end organ function failure. JAMA 2006; 296: pp. 2217-2226 Normal 14. Filippatos G, Rossi J, Lloyd-Jones DM, et al: Prognostic Impaired neurological value of blood urea nitrogen in patients hospitalized neurological function with worsening heart failure: insights from the Acute and function Chronic Therapeutic Impact of a Vasopressin Antagonist Weaning Consider surgical in Chronic Heart Failure (ACTIV in CHF) study. J Card Fail LVAD/BiVAD 2007; 13: 360-364 Age, Age, 15. Kociol RD, Horton JR, Fonarow GC, et al: Admission, comorbidities comorbidities discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Destination therapy Heart Initiate Lifesaving Treatment in Hospitalized Patients with transplantation Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Figure 4: Algorithm for use of Ventricular assist device16 Circ Heart Fail 2011; 4: 628-636 16. Mebazaa A , Yilmaz MB, Levy P, Ponikowski P, Peacock hold true for AHF due to heterogeneity challenge for physicians across the globe WF, Laribi S, Ristic AD, Lambrinou E, Masip J, Riley JP, McDonagh T, Mueller C, DeFilippi C, Harjola V-P, Thiele H, of the disease. Current research on and a systematic plan based management Piepoli MF, Metra M, Maggioni A, McMurray J, Dickstein natriuretic peptides like urodilation and shall make us overcome this challenge K, Damman K, Seferovic PM, Ruschitzka F, Leite-Moreira soluble guanylate cyclase activators like with less difficulty. AF, Bellou A, Anker SD, Filippatos G. Recommendations on pre-hospital and early hospital management of acute cinaciguat are promising and further heart failure: a consensus paper from the HFA of the ESC, large trials are required to prove their REFERENCES the European Society of Emergency Medicine and the benefit.47-48 More and more intensive 1. Mozaffarian D, Benjamin EJ, Go AS, et al: Heart disease Society of Academic Emergency Medicine. Eur J Heart Fail and stroke statistics—2016 update: a report from the 2015;17:544–558 device-based management of refractory American Heart Association. Circulation 2016; 133: pp. 17. Sepehrvand N, and Ezekowitz JA: Oxygen therapy in cardiogenic shock is being studied to e38-e60 patients with acute heart failure: friend or foe? JACC save the most sick fraction of AHF 2. Huffman MD, Prabhakaran D. Heart failure: Epidemiology Heart Fail 2016; 4: 783-790 and prevention in India. Natl Med J India 2010;23:283-8 18. Gray A, Goodacre S, Newby DE, et al: Noninvasive patients by providing them circulatory 3. Harikrishnan S, Sanjay G, Agarwal A, Kumar NP,et al. ventilation in acute cardiogenic pulmonary edema. N support. Guideline-based management One-year mortality outcomes and hospital readmissions Engl J Med 2008; 359:142-151 of HF continues to be the cornerstone of of patients admitted with acute heart failure: Data from 19. Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, Okumura T,Kida K, Mizuno A, Oishi S, Inuzuka HF management till we get some robust the Trivandrum Heart Failure Registry in Kerala, India. Am Heart J. 2017 ;189:193-199 Y, Akiyama E, Matsukawa R, Kato K, Suzuki S,Naruke T, evidence. 4. Ponikowski P, Jankowska EA. Pathogenesis and clinical Yoshioka K, Miyoshi T, Baba Y, Yamamoto M, Murai K, presentation of acute heart failure. Rev Esp Cardiol (Engl Mizutani K, Yoshida K, Kitai T. Time-to-Furosemide Treatment and Mortality in Patients Hospitalized CONCLUSION Ed) 2015;68:331–337. 5. Nohria A, Tsang SW, Fang JC,et al. Clinical assessment With Acute Heart Failure. J Am Coll Cardiol. 2017 AHF remains one of the most common identifies hemodynamic profiles that predict outcomes in 27;69(25):3042-3051. doi:10.1016/j.jacc.2017.04.042. causes of emergency department visits, patients admitted with heart failure. J Am Coll Cardiol PubMed PMID: 28641794. 20. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, especially in the elderly population. It 2003;41:1797–1804 6. Stevenson LW. Design of therapy for advanced heart Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili is not only a difficult disease to manage, failure. Eur J Heart Fail 2005; 7:323–331 EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, but carries a high in-hospital and 30 day 7. Ponikowski P, Voors AA, Anker SD, et al: 2016 ESC Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM; NHLBI Heart Guidelines for the diagnosis and treatment of acute and mortality. AHF patients require prompt Failure Clinical Research Network. Diuretic strategies chronic heart failure. The Task Force for the Diagnosis in patients with acute decompensated heart failure. N diagnosis and quick risk stratification and Treatment of Acute and Chronic Heart Failure of the Engl J Med. 2011 Mar 3;364(9):797-805. doi: 10.1056/ and should be managed in an aggressive European Society of Cardiology (ESC). Developed with NEJMoa1005419. PubMed PMID: 21366472; PubMed the special contribution of the Heart Failure Association manner with diuretics, vasodilators, Central PMCID: PMC3412356 (HFA) of the ESC. Eur Heart J 2016; 37: 2129-2200 inotropes, oxygen and positive pressure 21. Mentz RJ , Kjeldsen K, Rossi GP, Voors AA, Cleland JGF, 8. Nieminen MS, Brutsaert D, Dickstein K, et al: EuroHeart ventilation. Patients should be stabilized Anker SD, Gheorghiade M, Fiuzat M, Rossignol P, Zannad Failure Survey II (EHFS II): a survey on hospitalized acute F, Pitt B, O'Connor C, Felker GM. Decongestion in acute and disease-modifying guideline-directed heart failure patients: description of population. Eur heart failure. Eur J Heart Fail 2014;16:471–482 medical therapy of HF should be initiated Heart J 2006; 27: 2725-2736 22. Singh A, Laribi S, Teerlink JR, Mebazaa A. Agents with 9. Felker GM, Teerlink JR: Diagnosis and Management before discharge in all patients to prevent vasodilator properties in acute heart failure. 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23. Ho EC, Parker JD, Austin PC, et al: Impact of nitrate use 33. Patarroyo M, Wehbe E, Hanna M, et al: Cardiorenal for patients hospitalized with heart failure. JAMA 2007; on survival in acute heart failure: a propensity-matched outcomes after slow continuous ultrafiltration therapy in 297: -70 analysis. J Am Heart Assoc 2016; 5: refractory patients with advanced decompensated heart 42. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/ AHA/ 24. Mebazaa A, Parissis J, Porcher R, et al: Short-term failure. J Am Coll Cardiol 2012; 60:1906-1912 HFSA focused update on new pharmacological therapy survival by treatment among patients hospitalized with 34. Costanzo MR, Negoianu D, Jaski BE, et al: Aquapheresis for heart failure: an update of the 2013 ACCF/ AHA acute heart failure: the global ALARM-HF registry using versus intravenous diuretics and hospitalizations for guideline for the management of heart failure: a report propensity scoring methods. Intensive Care Med 2011; heart failure. JACC Heart Fail 2016; 4:95-105 of the American College of Cardiology/American Heart 37: pp. 290-301 35. Aliti G, Rabelo ER, Clausell N, et al: Aggressive fluid and Association Task Force on Clinical Practice Guidelines 25. Felker GM, Benza RL, Chandler AB, et al: Heart failure sodium restriction in acute decompensated heart failure: and the Heart Failure Society of America. J Am Coll etiology and response to milrinone in decompensated a randomized clinical trial. JAMA Intern Med 2013; Cardiol. 2016;68:1476–88 heart failure: results from the OPTIME-CHF study. J Am 173:1058-1064 43. Mizuno M, Sato N, Kajimoto K, Sakata Y, Minami Y, Coll Cardiol 2003; 41: pp. 997-1003 36. Prins KW, Neill JM, Tyler JO, et al: Effects of beta-blocker Munakata R, Hagiwara N,Takano T; Acute Decompensated 26. Mebazaa A , Nieminen MS, Filippatos GS, Cleland JG, withdrawal in acute decompensated heart failure: a Heart Failure Syndromes [ATTEND] investigators.Intra- Salon JE, Thakkar R, Padley RJ, Huang B, Cohen-Solal A. systematic review and meta-analysis. JACC Heart Fail aortic balloon counterpulsation for acute decompensated Levosimendan vs. dobutamine: outcomes for acute heart 2015; 3:647-653 heart failure. Int J Cardiol. 2014 Oct 20;176(3):1444-6. failure patients on β-blockers in SURVIVE. Eur J Heart 37. Ambrosy AP, Pang PS, Khan S, et al: Clinical course and doi: 10.1016/j.ijcard.2014.08.154. Epub 2014 Sep 2. Fail 2009;11:304–311 predictive value of congestion during hospitalization in PubMed PMID: 25223815 27. Gong B , Li Z, Yat Wong PC. Levosimendan treatment for patients admitted for worsening signs and symptoms of 44. Hall SA, Uriel N, Carey SA, Edens M, Gong G, Esposito M, heart failure: a systematic review and meta-analysis. J heart failure with reduced ejection fraction: findings from O'Kelly R, Annamalai S, Aghili N, Adatya S, Kapur NK. Use Cardiothorac Vasc Anesth 2015;29:1415–25 the EVEREST trial. Eur Heart J 2013; 34: 835-843 of a percutaneous temporary circulatory support device 28. De Backer D , Biston P, Devriendt J, Madl C, Chochrad D, 38. Heart Failure Society of America, Lindenfeld J, Albert as a bridge to decision during acute decompensation of Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, advanced heart failure. J Heart Lung Transplant. 2018 J-L. Comparison of dopamine and norepinephrine in the Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Jan;37(1):100-106. doi:10.1016/j.healun.2017.09.020. treatment of shock. N Engl J Med 2010;362:779–789 Stevenson WG, Tang WH, Teerlink JR, Walsh MN. HFSA Epub 2017 Sep 30. PubMed PMID: 29056460 29. Gheorghiade M, and Braunwald E: Reconsidering the 2010 Comprehensive Heart Failure Practice Guideline. 45. Dangers L, Bréchot N, Schmidt M, Lebreton G, Hékimian role for digoxin in the management of acute heart failure J Card Fail. 2010 ; 16 (6):e1-194. doi:10.1016/j. G, Nieszkowska A, Besset S, Trouillet JL, Chastre J, syndromes. JAMA 2009; 302: 2146-2147 cardfail.2010.04.004. PubMed PMID: 20610207 Leprince P, Combes A, Luyt CE. Extracorporeal Membrane 30. Gheorghiade M , Konstam MA, Burnett JC, Grinfeld L, 39. O'Connor CM, Miller AB, Blair JE, et al: Causes of death Oxygenation for Acute Decompensated Heart Failure. Crit Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook and rehospitalization in patients hospitalized with Care Med. 2017 Aug;45(8):1359-1366. doi: 10.1097/ T, Ouyang J, Zimmer C, Orlandi C, Efficacy of Vasopressin worsening heart failure and reduced left ventricular CCM.0000000000002485. PubMed PMID: 28471885 Antagonism in Heart Failure Outcome Study With ejection fraction: results from Efficacy of Vasopressin 46. Tallaj J.A., Pamboukian S.V., Bourge R.C. (2008) Role Tolvaptan (EVEREST) Investigators. Short-term clinical Antagonism in Heart Failure Outcome Study with of Left Ventricular Assist Devices in Acute Heart Failure effects of tolvaptan, an oral vasopressin antagonist, Tolvaptan (EVEREST) program. Am Heart J 2010; 159: Syndrome and the Future of the Replacement Heart. In: in patients hospitalized for heart failure: the EVEREST 841-849 e1 Mebazaa A., Gheorghiade M., Zannad F.M., Parrillo J.E. Clinical Status Trials. JAMA 2007;297:1332–1343 40. Hernandez AF, Greiner MA, Fonarow GC, et al: (eds) Acute Heart Failure. Springer, London 31. Felker GM, Mentz RJ, Cole R, et al: Efficacy and safety Relationship between early physician follow-up and 47. Packer M, O’Connor C, McMurray JJ, et al. Effect of of tolvaptan in patients hospitalized with acute heart 30-day readmission among Medicare beneficiaries ularitide on cardiovascular mortality in acute heart failure. J Am Coll Cardiol 2017; 69:1399-1416 hospitalized for heart failure. JAMA 2010; 303: 1716- failure. N Engl J Med. 2017;376:1956–1964 32. Felker GM, and Mentz RJ: Diuretics and ultrafiltration in 1722 48. Erdmann E, Semigran MJ, Nieminen MS, et al. Cinaciguat, acute decompensated heart failure. J Am Coll Cardiol 41. Fonarow GC, Abraham WT, Albert NM, et al: Association a soluble guanylate cyclase activator, unloads the heart 2012; 59: 2145-2153 between performance measures and clinical outcomes but also causes hypotension in acute decompensated heart failure. Eur Heart J. 2013;34:57–67.

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Non Cardiac Surgery – How to ‘Clear’ a Patient ?

PC MANORIA*, PANKAJ MANORIA**, NIDHI MISHRA***

Keywords Abstract zz functional capacity Worldwide around 20 million people undergo non-cardiac surgery zz preoperative cardiac testing annually, of which a large proportion are geriatric patients. Mortality zz electrocardiogram from surgery increases with age, and cardiovascular complications are zz left ventricular function the most common cause of death. Cardiac complications after non- zz anticoagulants cardiac surgery depend on procedure-related risk, patient-related risk zz statins and functional capacity (FC). Perioperative cardiac morbidity evaluation can be assessed using the revised cardiac risk index. It is reasonable to perform a 12-lead electrocardiogram (ECG) preoperatively in patients with known Coronary Artery Disease (CAD), peripheral arterial disease, significant arrhythmia, cerebrovascular disease, or other structural heart disease, except in case of low-risk procedure. In patients with unknown cause of dyspnea or in patients with HF with worsening dyspnea or any change in clinical status, it is reasonable to assess left ventricular (LV) function preoperatively by echocardiography. Assessment of functional capacity by exercise stress testing is useful only if it will change management. In patients in whom functional capacity is not known, cardiopulmonary testing may be considered prior to elevated- risk noncardiac surgery. Preoperative revascularization for noncardiac surgery is recommended only when it is indicated as per guidelines for acute coronary syndrome (ACS). In patients undergoing surgery, the benefit of continuation of anticoagulants should be weighed against risk of bleeding procedure. Management of anticoagulant use is also crucial. A careful evaluation of the patient taking into consideration the procedure related risk, the patient related risk and functional capacity coupled with use of appropriate drugs and necessary precautions paves the way for minimizing cardiovascular morbidity and mortality in the peri-operative period and also shorten the hospital stay.

Worldwide, it is estimated that around the morality is higher (about 5%). 20 million people undergo noncardiac Cardiovascular complications are the surgery annually.1 One-third of surgeries most common cause of death.2,3 All deaths are performed in geriatric population. The in the first 48 hours are due to cardiac overall mortality is 1-5%; in individuals causes like heart failure (HF), acute <65 years the average mortality is 1% coronary syndrome. The deaths from 48 whereas in individuals above 65 years hours to 6 weeks are usually due to a non

Dr. P.C. Manoria is Director, Dr. Pankaj Manoria is Chief Intervention Cardiologist at Manoria Heart & Critical Care Hospital, Bhopal and Dr. Nidhi Mishra is Asst. Professor, Deptt. of Biochemistry, Mahaveer Institute of Medical Sciences, Bhopal

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cardiac causes like Pneumonia, Sepsis, FUNCTIONAL CAPACITY It is reasonable to perform a 12-lead Pulmonary Embolism, Renal Failure etc. It is an important test in preoperative electrocardiogram (ECG) preoperatively Pre-operative evaluation is of paramount cardiac risk assessment and is measured in patients with known Coronary Artery importance as appropriate preventive in metabolic equivalents (METs). Disease (CAD), peripheral arterial disease, and therapeutic strategies may decrease Exercise testing provides an objective significant arrhythmia, cerebrovascular cardiovascular (CV) morbidity and assessment of FC but without this it can disease, or other structural heart disease, mortality and shorten the hospital stay. be estimated from the ability to perform except for those patients who are going for low-risk procedure. Routine use of The main purpose of peri-operative activities in daily life (Table 3). evaluation is to get familiar with the preoperative 12-lead ECG is not useful Poor functional capacity is following basic questions. and is not recommended. A 12- lead ECG associated with an increased incidence zz What are the underlying risk factors gives important prognostic information of post operative cardiac events. When which the patient is having prior to in patients with known CAD related to functional capacity is good, the prognosis non-cardiac surgery? short-term and long term morbidity and is excellent even in presence of stable zz What is the anticipated patient related mortality. It also provides a baseline that IHD or risk factors. risk? can be compared postoperatively if any Peri-operative cardiac morbidity risk zz What is the proper preoperative change in the clinical status of the patient evaluation: This is commonly assessed treatment to reduce the anticipated occurs. An interval of 1 to 3 months is by Revised Cardiac Risk Index. risk during surgery and steps to be considered to be an acceptable interval taken in the post operative period to Revised cardiac risk index: The between the scheduled noncardiac reduce morbidity and mortality revised cardiac risk index (4,5) is a surgery and obtaining a 12-lead ECG; The cardiac complications after non- simple tool that has been validated to however, optimal timing is unknown. cardiac surgery depends on 3 factors: assess the peri-operative risk of major 1. Procedure related risk. cardiac events. The variables of this score ASSESSMENT OF LEFT VENTRICULAR 2. Patient related risk. are shown in Table 4 and single point FUNCTION 3. Functional capacity (FC). is assigned to every risk factor present. In patients with unknown cause of dyspnea The risk of cardiac arrest, or death 30 or in patients with HF with worsening PROCEDURE RELATED RISK days after surgery are shown in Table dyspnea or any change in clinical status, The surgical risk for cardiac events 5. Patients having zero or only one risk it is reasonable to assess left ventricular depends on the type of procedure being factor have a low risk of major adverse (LV) function preoperatively by carried out. High risk procedures have cardiac events (MACE), whereas those echocardiography. Reassessment of LV a mortality of 5%, intermediate risk with 2 or more risk factors have elevated function can be considered in clinically procedures 1-5% and low risk procedures risk. stable patients, if it was done more than <1% (Table 1) a year ago. However, routine evaluation ANCILLARY PREOPERATIVE of LV function is not recommended 6 PATIENT RELATED RISK CARDIAC TESTING- preoperatively. There is an association The patient related risk depends on the RECOMMENDATIONS documented in literature between reduced underlying disease as shown in Table 2. 12- Lead electrocardiogram LV systolic function and peri-operative

Table 1: Procedure related risk High (5%) Intermediate (1-5%) Low (<1%) Emergent major operations (elderly) *Carotid endarterectomy Endoscopic procedures Aortic & other major vascular surgery Head and neck surgery Superficial procedure Peripheral vascular surgery *Intraperitoneal, Intrathoracic surgery Cataract surgery Anticipated prolonged surgical procedures Orthopedic surgery Breast surgery Prostate surgery Dental Pulmonary, renal/liver transplant. Gynecology, urologic-minor

Table 2: Patient related risk Major Intermediate Minor ACS Prior Myocardial infarction Advanced age Decompensated HF Mild angina Abnormal ECG Significant Arrhythmias Compensated HF Rhythm other than sinus Severe VHD* Stenotic lesions like AS, MS Diabetes Mellitus Past stroke Poor FC Renal insufficiency Uncontrolled hypertension *VHD : Valvular Heart Disease, AS: Aortic Stenosis, MS:Mitral Stenosis

130 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 echocardiogram or pharmacologic stress Table 3: Assessment of functional capacity myocardial perfusion imaging (Table 6), Severity Assessment only if it changes further management. Poor Unable to climb a flight of stairs (< 4 METs) However routine screening is not Moderate Climbing flight of stairs (4-7 METs) recommended in patients going for low Good Participation in moderate recreational activities (>7 METs) risk noncardiac surgery.8 Very Good Participation in strenuous sports, swimming (> 10 METs) There is a lack of randomized controlled trials (RCTs) on the use of Table 4: Revised cardiac risk index variables2 preoperative stress testing. Evidence is Variables Pts based on large number of studies which Hx of IHD 1 have shown that the presence of moderate Hx of CHF 1 to large areas of myocardial ischemia, Hx of CVD 1 predicts increased peri-operative MI Insulin for diabetes 1 and/or death. Also if a patient has a normal Serum creatinine >2.0 mg/dL 1 study, it has a high negative predictive High-risk surgery 1 value for peri-operative MI and/or cardiac death. Also, fixed defects seen Table 5: Assessment of cardiac events in preoperative period based on RCRI points on myocardial perfusion imaging (MPI) Total RCRI points Risk of MI, cardiac arrest, or have a low peri-operative predictive death 30 days after surgery value for cardiac events compared with 0 0.4% (95% CI: 0.1-0.8) normal MPI, but have an increased risk 1 1.0% (95% CI: 0.5-1.4) of long term events, likely related to the 4 2 2.4% (95% CI: 1.3-3.5) presence of underlying CAD. Stress ≥3 5.4% (95% CI :2.8-7.9) echocardiography appears to be slightly superior in predicting postoperative complications, more so in patients with surgery, it reasonable to proceed for cardiac events compared to nongated postoperative HF. Greatest risk is seen surgery without any further stress testing. MPI with thallium. However, there is in patients with left ventricular ejection Routine screening with noninvasive a lack of RCTs for such comparison. It fraction (LVEF) of <35% at rest. There are stress testing is not recommended.7 should be noted that these do not address very little data on assessment of diastolic evaluation of patients scheduled for liver dysfunction preoperatively. However, it CARDIOPULMONARY TESTING or kidney transplantation that has its own is recommended to perform LV function In patients in whom functional capacity specific set of guidelines. in patients who are candidates for is not known, cardiopulmonary testing In ambulatory patients, exercise potential solid organ transplantation as may be considered prior to elevated-risk electrocardiography can provide per transplantation specific guidelines. noncardiac surgery. useful information related to any Many studies have shown that underlying ischemia and functional EXERCISE STRESS TESTING a low anaerobic threshold predicts status. This is at times combined with In patients undergoing elevated risk peri-operative cardiac complications either echocardiography or MPI. procedure with unknown or poor and postoperative death. The proposed However, in patients who have ECGs that functional capacity (<4 METs), it is discriminative anaerobic threshold ranges limit interpretation (like LV hypertrophy, left bundle branch block, etc.), imaging reasonable to assess the functional between 9 and 11 mL O2/kg/min. capacity by exercise stress testing, with either echocardiography or MPI only if it will change management. In PHARMACOLOGICAL TESTING should be pursued. In patients having patients with excellent exercise tolerance In patients who have poor functional left bundle branch block who undergo (>10 METs) or those with moderate capacity scheduled for elevated-risk exercise MPI, septal perfusion defects to good exercise tolerance (>4 METs) noncardiac surgery, it is reasonable to are seen, which are not related to CAD scheduled for elevated risk noncardiac evaluate with either dobutamine stress and decrease the specificity of the study.

Table 6: Recommendations for non cardiac surgery in patients who have undergone coronary interventions Recommendations COR LOE Elective noncardiac surgery should not be performed within 14 days of balloon angioplasty in patients in III Harm C whom aspirin will need to be discontinued perioperatively. Elective noncardiac surgery should not be performed within 30 days after BMS implantation or within III Harm B 6-12 months after DES implantation in patients in whom DAPT will need to be discontinued perioperatively. Elective non cardiac surgery after DES implantation may be considered after 180 days if the risk of further IIb B delay is greater than the expected risks of ischemia and stent thrombosis.

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6 weeks after stent implantation.11,12 Table 7 : Use of antiplatelet drugs in patients requiring early surgery after coronary In case dual anitplatelet therapy (DAPT) intervention. has to be discontinued for urgent or BLEEDING RISK emergent surgery, such a decision should Low Intermediate High be individualized, weighing the risk and Cataract, Oral GI Surgeries, Intracranial, Prostate, aortic ENT, benefit. dental surgery Cholecystectomy, Posterior segment surgery Appendicetomy etc. The recommendations for non cardiac surgery in patients who have undergone Continue aspirin Stop clopidogrel Stop aspirin and and clopidogrel and clopidogrel continue aspirin and bridge with cangrelor: 0.75 mg/kg/min balloon angioplasty or stenting with or tirofiban: 0.1 mg/kg min. If renal dys- BMS/DES are outlined in Table No 7. function, decrease dose to 0.05 mg/ kg If surgery is to be performed in BMS and start 24-48 hrs. after last dose and implantation before 30 days or DES continue till 4-8 hrs. before surgery implantation before 6-12 months, then the strategy for using antiplatelet drugs Hence, in such cases, pharmacological coronary revascularization to reduce depends on the bleeding risk of the patient stress testing is preferred with adenosine, peri-operative cardiac events in as outlined in Table 8. dipyridamole, or regadenoson. In patients noncardiac surgery is not recommended.10 In such subset of patients, the surgeon with valvular heart disease or pulmonary There are no prospective RCTs supporting should be encouraged to operate on hypertension, an echocardiographic stress either coronary artery bypass grafting aspirin at least in patients with low or test is preferred as it provides clinically (CABG) or percutaneous coronary intermediate bleeding risk. important information.4 intervention (PCI) to decrease intra- operative or postoperative cardiac events ANTICOAGULANT THERAPY CORONARY ANGIOGRAPHY as part of peri-operative management In patients undergoing surgery, the There is insufficient data to recommend for noncardiac surgery. However, benefit of continuation of anticoagulants routine use of coronary angiography patients with ACS prior to noncardiac should be weighed against risk of preoperatively for noncardiac surgery should be managed according bleeding procedure. Low bleeding surgical procedures (excluding to guideline-directed therapy for ACS. risk surgeries, like, cataract surgery or patients undergoing kidney or liver In those who are scheduled for time- minor dermatological surgeries, do not transplantation). There is also very little sensitive noncardiac surgery, balloon predispose to prolonged bleeding, and in information regarding the significance angioplasty or bare-metal stent (BMS) such cases, anticoagulant therapy can be of coronary computed tomographic (CT) placement is preferred for management. continued.13 angiography and calcium scoring due to There are no studies on the limited data.9 Elective noncardiac surgery in prevention of peri-operative myocardial patients with prior PCI—Timing ischemia or MI by anticoagulants in Peri-operative Medical Therapy and and recommendations peri-operative period for noncardiac Interventions-Recommendations Non cardiac surgery in the early period surgeries. Depending on the location of Coronary revascularization following BMS/DES implantation is the prosthetic valve along with associated Preoperative revascularization for problematic because withdrawal of risk factors for thromboembolism (which noncardiac surgery is recommended only antiplatelet drugs is associated with include the presence of atrial fibrillation when it is indicated as per guidelines for (AF), previous thromboembolism, LV the risk of stent thrombosis, the highest acute coronary syndrome (ACS). Routine dysfunction, hypercoagulable condition, risk of which occurs in the first 4 to

Table 8: Peri-operative beta blocker therapy Recommendations COR LOE bB should be continued in patients undergoing surgery who have been on it chronically. I BSR It is reasonable for the management of bB after surgery to be guided by clinical circumstances, independent IIa BSR of when the agent was started. In patients with intermediate –or high-risk myocardial ischemia noted in preoperative risk stratification tests, IIb CSR it may be reasonable to begin peri-operative bB. In patients with 3 or more RCRI risk factors (.e.g diabetes mellitus, HF, CAD, renal insufficiency, IIb BSR cerebrovascular accident), it may be reasonable to begin bB before surgery. In patients with a compelling long-term indication for beta blocker therapy but no other RCRI risk factors, IIb BSR initiating beta blockers in the periopreative setting as an approach to reduce periopreative risk is of uncertain benefit. In patients in whom beta-blocker therapy is initiated, it may be reasonable to begin peri-operative beta blockers IIb BSR long enough in advance to assess safety and tolerability, preferably more than 1 day before surgery. bB therapy should not be started on the day of surgery. III BSR

132 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 or older generation prosthetic aortic bleeding or with mild renal insufficiency prevention of cardiac events in peri- valve), patients on vitamin K antagonist (creatinine clearance 50-80 mL/min). operative period. (VKA) may or may not require bridging Due to the rapid offset and onset, with either unfractionated heparin or low bridging anticoagulation is not required Calcium channel blockers molecular-weight heparin. in patients on newer oral anticoagulants. There is limited data on the efficacy In patient having a mechanical This is reserved only for patients of calcium channel blockers in peri- mitral valve, bridging anticoagulation with a very high risk of postoperative operative therapy for patients undergoing is appropriate with interruption of thromboembolism and requires extended noncardiac surgery. Most of the benefits anticoagulation in peri-operative period interruption of such as in cases where shown are attributed to diltiazem. regardless of the presence or absence of oral diet is restricted for some time (e.g., There was no decrease in the incidence risk factors of thromboembolism. Same intestinal surgeries). It should be resumed of myocardial ischemia with the use is true for patients with mechanical aortic when homeostasis is achieved. Caution of dihydropyridines and verapamil. It valve with one or more risk factors of should be exercised in patients with high should be kept in mind that verapamil 13 thromboembolism. risk of bleeding as onset of action is rapid and diltiazem can worsen and even Bridging anticoagulation is (within 2-3 hours). Resuming dabigatran precipitate HF in patients with decreased recommended in the time period when can be delayed in patients with high risk ejection fraction (EF) and/or clinical then international normalized ratio (INR) of bleeding or it can be administered in a HF. More studies are needed to make is subtherapeutic preoperatively. lower dose for the first 2 to 3 days. specific recommendations regarding Patients with atrial fibrillation (AF) Activated partial thromboplastin time peri-operative use of calcium channel who are managed with VKA therapy for dabigatran can be monitored; levels blockers. and are at low risk of thromboembolism close to control levels suggest a low (CHA2DS2-VASc score of 0 to 1) or those serum concentration of these agents. Angiotensin-Converting Enzyme who are back to normal sinus rhythm, Inhibitors undergoing surgery with increased risk REVERSAL OF VKAS It is reasonable to continue angiotensin- of bleeding, holding VKA therapy for In case emergent reversal of converting enzyme (ACE) inhibitors 1 week to allow normalization of INR anticoagulation is required for VKA, or angiotensin blockers (ARBs) without bridging anticoagulation is vitamin K is not recommended because perioperatively. If they are held before, it acceptable. VKA therapy is then resumed the effect is not predictable and not is reasonable to restart as soon as possible once homeostasis is achieved.14,15 immediate. This can even delay the return postoperatively.19 In patients who have high risk to therapeutic level of anticoagulation of thromboembolism (prior strokes, when VKAs are restarted. Intravenous nitroglycerin mechanical valves, CHA2DS2-VASc Fresh frozen plasma or prothombin Use of intravenous nitroglycerin score >2), bridging anticoagulation is complex concentrates are recommended prophylactically to prevent myocardial preferred once VKA therapy is withheld in patients with mechanical prosthetic ischemia has shown to be ineffective in and INR is subtherapeutic. valves receiving VKA therapy where patients undergoing noncardiac surgery. homeostasis has to maintained in case DIRECT ORAL ANTICOAGULANTS of uncontrollable bleeding or in a patient In patients on direct thrombin inhibitors requiring emergent noncardiac surgery.13 PREOPERATIVE EVALUATION IN (e.g., dabigatran) undergoing noncardiac SPECIFIC PATIENT POPULATION- surgery with normal renal function, b-blocker therapy GENERAL CONSIDERATIONS anticoagulation can be discontinued The use of beta blocker (bB) in peri- Age 48 to 72 hours before the procedure. operative period17 is outlined in Table 9. Age plays an important role in determining In those with mildly impaired renal MACE as there is an increased prevalence of cerebrovascular disease, diabetes function (with creatinine clearance of 50- Statin therapy 80 mL/min), this can be withheld 4 to 5 Peri-operative statins therapy for mellitus, and other medical condition as days prior to procedure. Longer duration noncardiac surgery should be continued in age increase. may be required in case of severe renal patients taking them. It is also reasonable insufficiency (creatinine clearance of to initiate statin therapy in those going Coronary artery disease <50 mL/min).16 for vascular surgery. Statins may also Cardiac morbidity during and/ or after For patients on oral direct factor be considered in patients scheduled noncardiac surgery depends on how it Xa inhibitors having normal renal for elevated risk procedure who have is defined. These can just be elevation function undergoing elective procedures, clinical indications for initiation of statin in cardiac biomarkers alone or may anticoagulation can be stopped 48 hours therapy.18 involve typical symptoms and signs prior to the scheduled noncardiac elective of ischemia. There is an association surgery. Prolonged discontinuation can Alpha-2 agonist of prior cardiovascular (CAD) events be exercised in patients with high risk of Alpha-2 agonists are not useful in with MACE after noncardiac surgery.20

Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 133 REVIEW ARTICLE

A study by Livhits, et al., showed that increase in cardiac complications or any 5. Ford MK, Beattie WS, Wijeysundera DN. Systematic review: prediction of peri- operative cardiac complications the rate of postoperative MI decreased increased risk of nonfatal MI or cardiac and mortality by the revised cardiac risk index. Ann Intern significantly with increase in time from death in patients seen to have frequent Med 2010;152:26–35. 6. Rohde LE, Polanczyk CA, Goldman L, Cook EF, Lee RT, prior MI and date of procedure. It also ventricular premature beats, couplets or Lee TH. Usefulness of transthoracic echocardiography as showed an improved 30-day mortality. nonsustained ventricular tachycardia, a tool for risk stratification of patients undergoing major noncardiac surgery. Am J Cardiol 2001;87:505–9. This suggests that a noncardiac surgery and couplets in peri-operative period 7. Eagle K A, Coley CM, Newell JB, et al. Combining clinical should be performed after at least for noncardiac surgery.22,23 Patients who and thallium data optimizes preoperative assessment of develop such arrhythmias may require cardiac risk before major vascular surgery. Ann Intern 2 months of MI in the absence of coronary Med 1989;110:859–66. intervention. Risk of MACE depends on referral to a cardiologist for further 8. Das MK, Pellikka PA, Mahoney DW, et al. Assessment the type of coronary intervention at the evaluation. Atrial fibrillation (AF) of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll time of MI prior to surgery. A recent MI is very common, especially in older Cardiol 2000;35:1647–53. (occurring within 6 months of noncardiac patients. Patients with preoperative AF 9. Ahn JH, Park JR, Min JH, et al. Risk stratification using computed tomography coronar y angiography in patients surgery) is also an independent risk factor who are asymptomatic and stable do undergoing intermediate-risk noncardiac surgery. J Am of peri-operative stroke, associated with not require any changes in their medical Coll Cardiol 2013;61:661–8. 10. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery an increase in peri-operative mortality of management, apart from adjustment of revascularization before elective major vascular surgery. 8-fold. anticoagulation, in the peri-operative N Engl J Med 2004;351:2795–804. 11. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. period. There is potential, however, of Catastrophic outcomes of noncardiac surgery soon after Heart failure peri-operative formation of left atrial coronary stenting. J Am Coll Cardiol 2000;35:1288–94. 12. Tokushige A, Shiomi H, Morimoto T, et al. Incidence and Active HF or patients with history of thrombus in patients with persistent AF, outcome of surgical procedures after coronary bare- HF are at a higher risk of peri-operative undergoing thoracic surgeries or other metal and drug-eluting stent implantation: a report noncardiac surgeries involving physical from the CREDO-Kyoto PCI/CABG registry cohort-2. Circ complications, based on data from Cardiovasc Interv 2012;5:237–46. many studies. One such study involved manipulation of the heart. 13. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ ACC guideline for the management of patients with population-based data analysis of valvular heart disease: a report of the American College 38047 patients. This study showed that CONCLUSION of Cardiology/American Heart Association Task Force on Clearing a cardiac patient for non-cardiac Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. compared with 30-day postoperative 14. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ mortality rate in patients with CAD surgery is a common issue in our day to HRS guideline for the management of patients with (2.9%) risk was higher in patients with practice. Cardiovascular complications atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force non ischemic HF (9.3%) and ischemic HF like heart failure and acute coronary on practice guidelines and the Heart Rhythm Society. (9.2%) An LVEF <35% in the absence of syndrome are the commonest cause of Circulation 2014;130:e199–267. 15. Douketis JD, Spyropoulos AC, Kaatz S, et al. peri- symptoms, itself is an independent risk death in first 48 hours while mortality operative Bridging Anticoagulation in Patients with Atrial factor for peri-operative morbidity and from 48 hours to 6 weeks is usually Fibrillation. N Engl J Med 2015;373:823–33. 16. Schulman S, Carrier M, Lee AY, et al. peri-operative mortality in patients undergoing elevated- due to a non-cardiac complication like Management of Dabigatran: A Prospective Cohort Study. risk noncardiac surgery.21 Studies in pneumonia, sepsis, pulmonary embolism, Circulation 2015;132:167–73. renal failure etc. A careful evaluation 17. Wijeysundera DN, Duncan D, Nkonde-Price C, et al. patients having symptomatic diastolic peri-operative beta blockade in noncardiac surgery: dysfunction, with and without systolic of the patient taking into consideration a systematic review for the 2014 ACC/AHA guideline the procedure related risk, the patient on peri-operative cardiovascular evaluation and dysfunction, has also been shown to be management of patients undergoing noncardiac surgery: associated with higher incidence rate of related risk and functional capacity a report of the American College of Cardiology/American coupled with use of appropriate drugs and Heart Association Task Force on practice guidelines. J Am MACE, high rates of postoperative HF, Coll Cardiol 2014;64:2406–25. and prolonged length of hospital stay. necessary precautions paves the way for 18. Lindenauer PK, Pekow P, Wang K, Gutierrez B, minimizing cardiovascular morbidity and Benjamin EM. Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA Peri-operative arrhythmias mortality in the peri-operative period and 2004;291:2092–9. also shorten the hospital stay. 19. Rosenman DJ, McDonald FS, Ebbert JO, Erwin PJ, LaBella It is important to seek underlying M, Montori V M. Clinical consequences of withholding cause of any arrhythmia that occurs versus administering renin-angiotensin- aldosterone in the peri-operative period as it REFERENCES system antagonists in the preoperative period. J Hosp 1. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation Med 2008; 3:319–25. can be precipitated by underlying and prospective validation of a simple index for 20. Livhits M, Ko CY, Leonardi MJ, Zingmond DS, Gibbons cardiopulmonary disease, ischemia, prediction of cardiac risk of major noncardiac surgery. MM, de Virgilio C. Risk of surgery following recent Circulation 1999;100:1043–9. myocardial infarction. Ann Surg 2011;253: 857–64. drug toxicity, metabolic derangements, 2. Weiser TG, Regenbogen SE, Thompson KD, et al. An 21. Healy KO, Waksmonski CA, Altman RK, Stetson PD, etc. These can alter outcomes in patients estimation of the global volume of surgery: a modelling Reyentovich A, Maurer MS. peri-operative outcome and strategy based on available data. Lancet 2008;372:139– long-term mortality for heart failure patients undergoing undergoing noncardiac surgery. Specific 44. intermediate- and high-risk noncardiac surgery: impact recommendations related to peri- 3. Bakker EJ, Ravensbergen NJ, Poldermans D. peri- of left ventricular ejection fraction. Congest Heart Fail operative cardiac evaluation, monitoring, and risk 2010;16:45–9. operative arrhythmias cannot be provided reduction strategies in noncardiac surgery patients. Curr 22. Mahla E, Rotman B, Rehak P, et al. peri-operative due to the limited number of studies to Opin Crit Care 2011;17:409–15. ventricular dysrhythmias in patients with structural heart 4. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 disease undergoing noncardiac surgery. Anesth Analg determine surgical risk in such cases. Few ACC/AHA guideline on peri-operative cardiovascular 1998;86:16–21. studies have shown supraventricular and evaluation and management of patients under-going 23. O’Kelly B, Browner WS, Massie B, Tubau J, Ngo L, Mangano noncardiac surgery: a report of the American College of DT. Ventricular arrhythmias in patients undergoing ventricular arrhythmias to have low risk of Cardiology/ American Heart Association Task Force on noncardiac surgery. The Study of peri-operative Ischemia peri-operative cardiac events. There is no practice guidelines. J Am Coll Cardiol 2014;64:e77–137. Research Group. JAMA 1992;268:217–21.

134 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 ECG OF THE MONTH

T Wave Inversion

Keywords SR MITTAL zz acute abdomen zz cardiomyopathy zz cerebrovascular accidents Abstract zz coronary artery disease T wave inversion can be primary or secondary. T wave inversion zz electrocardiography without any associated QRS changes are called primary. T wave zz pericardial diseases inversion secondary to depolarization abnormalities (QRS changes) zz T wave are called secondary. Primary T wave inversion can be as benign as persistent juvenile pattern or early repolarization variant. Anxiety, hyperventilation, meals and upright posture can produce transient benign T wave inversions. Acute abdominal disorders, hypothyroidism, hypokalemia and cerebrovascular accidents can produce T wave inversion even in persons without history or clinical signs of heart disease. Transmural or nontransmural myocardial infarction are common cause of deep symmetrical T wave inversion.

Biphasic or inverted T waves in leads V1 to V4 in a case of angina suggests tight occlusion of proximal left anterior descending coronary artery. Common cardiac causes of T wave inversion include mitral valve prolapse, recent Stokes-Adams attack, post-tachycardia T wave inversion, pericardial constriction and cardiomyopathies.

INVERTED T WAVES [A] NORMAL VARIANTS (c) Hyperventilation (a) Persistent Juvenile Pattern Changes may normalise on exercise. T wave inversion in right precordial leads is common in children but in some (d) Orthostatic Variation persons it may persist in adulthood. It T wave is inverted on assumption is more common in women. T wave is of upright posture. It usually affects

inverted in leads V1 to V4 (Figure 1). T inferior leads. it is common in asthenic

wave depth usually decreases from V1 to individuals.

V4. (e) Post Prandial (b) Anxiety Changes may normalize on exercise. (f) Pregnancy

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 135 ECG OF THE MONTH

detected even on detailed evaluation. It is common in females.1,2 Such T wave changes without any underlying disease per se do not imply a poor prognosis.

(h) Early repolarization variant Prominent, biphasic T wave inversion with ST segment elevation (Figure 2) is 3 seen in leads V1 to V4. It is usually seen in athletes. Exercise normalizes T wave inversion.

[B] NON CARDIAC CAUSES (a) Acute Abdominal Disorders Pancreatitis (Figure 3), Cholecystitis (Figure 4), Peritonitis.

(b) Endocrine Disorders (i) Hypothyroidism There is generalized diminution of Figre 2. Electrocardiogram from a case of amplitude or shallow inversion of T wave. Figure 1. Electrocardiogram from a case early repolarization variant showing mild Sinus bradycardia and low voltage QRS ST segment elevation with shallow T wave of persistent juvenile pattern showing T are other findings. inversion (arrows) in leads V3 to V5. wave inversion (arrows) in leads V1 to V4. except lead aVR. This may occur in (ii) Hypoadrenalism (g) Idiopathic Global T Wave several conditions including myocardial (iii) Hypopituitarism Inversion ischemia, CNS disorders, myocarditis, (iv) Pheochromocytoma apical hypertrophic cardiomyopathy, Global T wave inversion means inversion cardiac tumors and pheochromyocytoma. (c) Electrolyte Abnormalities of T wave in all the standard leads It is called idiopathic when no cause is Hypokalemia Flattening or inversion of T wave is associated with ST segment depression, increased prominence of ‘u’ wave and prolongation of QTc interval

Figure 3. Electrocardiogram from a case of acute pancreatitis showing T wave inversion

(arrows) in leads I, aVL, V3 to V6.

Figure 5. Electrocardiogram from a case of hypokalemia showing T wave inversions Figure 4. Electrocardiogram from a case of acute cholecystitis showing shallow T wave (arrows), prominent U wave (*) and

inversion in leads V3 to V5 (arrows). prolonged QTc.

136 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 Figure 7. Electrocardiogram from a case of evolved anterior myocardial infarction.

Figure 6. Electrocardiogram from a case clinical signs of primary heart disease. of anterior myocardial infarction showing Widening and inversion of T waves in initial inversion of terminal part of T wave. precordial leads is accompanied by QTc prolongation and brandycardia. Exact Figure 8. Electrocardiogram from a case (Figure 5). Concomitant hypomagne- mechanism is not clear. of non ST elevation anterior myocardial semia also affects the ECG. Therefore, Autonomic neural stimulation from infarction showing shallow symmetrical T wave inversion in leads aVL, V to V (ar- ECG findings, therefore, may not exactly 3 6 the hypothalamus or elevated levels of rows). correlate with serum potassium levels. catecholamines could be responsible for first to become inverted followed by the ECG changes. (d) Acute Pulmonary Embolism the middle and initial portion (Figure 6).9 T waves may be very deep (Figure T wave is inverted in leads III, aVF and (f) Following Truncal Vagotomy, V to V . Right bundle branch block may 7) but may decrease or even normalize 1 4 Radical Neck Dissection and with time.1 Opposite leads may show be present. Bilateral Carotid Endarterectomy8 prominent T wave 1. Negative T wave in leads II, III and aVF may produce (e) Cerebrovascular Injury [C] CARDIAC CAUSES 4,5 6 prominent T wave in leads I and aVL Stroke , intracranial bleed and (a) Myocardial Infarction 7 and vice versa. Failure of reperfusion subarachnoid hemorrhage are associated (i) Evolved phase of transmural infarc- with electrocardiographic changes even tion. in those patients who have no history or Terminal portion of the T wave is the

Figure 10. Electrocardiogram showing

Figure 9. Electrocardiogram from a case of non ST elevation inferior myocardial infarction inverted T waves in leads V1 to V4 without showing symmetrical T wave inversion in leads III. Q wave or ST elevation (Wellens’ sign)

Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 137 ECG OF THE MONTH

In patients with chronic stable an- gina, it may predict clinically signifi- cant mid LAD lesion.12,13

(b) Mitral valve prolapse. T wave may show shallow inversion in

leads II, III, aVF, V5 and V6 (Figure 12).

(c) Following a Recent Stokes- Adams Attack T wave is broad. QTc is prolonged (Figure 13). There is high degree atrio-ventricular block.

(d) Post- tachycardia T wave Inversion ST segment depression may be associated with T wave inversion following reversal of supraventricular or ventricular tachycardia (Figure 14). Changes may persist for hours to days.

(e) Rate Dependent T wave inversion Tachycardia dependent T wave inversion (Figure 15) may be seen in presence of myocardial ischemia. Bradycardia Figure 11. Electrocardiogram showing T Figure 12. Electrocardiogram from a case wave inversion in lead aVL with reciprocal dependent T wave inversion (Figure 16). of mitral valve prolapse showing T wave prominent T waves in leads II, III, aVF. may be seen in setting of prolonged QT inversion in leads II, III, aVF and V to V . 3 6 syndrome.

(f) Pericardial Effusion/ constriction Diffuse low voltage or shallow inversion of T wave is associated with low voltage QRS complex (Figure 17). There are no reciprocal changes. Depth of inversion of T wave correlates with the degree of peri- cardial adherence to the myocardium and underlying myocardial damage.

(g) Hypertrophic Cardiomyopathy Tall QRS are accompanied by diffuse deep T wave inversion14 (Figure 18, 19). Normal QRS with diffuse unexplained T Figure 13. Electrocardiogram from a case of complete A-V block with history of Stokes- wave inversion should also raise suspicion Adams attack showing deep T wave inversion in lead V . 4 of hypertrophic cardiomyopathy.

may result in failure of inversion of T biphasic or inverted T waves in (h) Other Cardiomyopathies and wave. leads V1 to V4 without Q wave or Myocarditis (ii) Subendocardial infarction (Non ST significant ST segment elevation ST depression and T wave inversion are (Figure 10) suggest tight occlusion elevation acute coronary syndrome). common in leads V4 to V6 (Figure 20). T wave inversion is usually symmetric of proximal left anterior descending Abnormal Q waves, slow progression or but is usually not deep. coronary artery.10,11 Precordial R wave non progression of r wave and deep S progression may be normal. (iii) Wellens sign wave in leads V2 and V3 can be other find- In a case of acute coronary syndrome, (iv) T wave inversion in aVL (Figure 11). ings.

138 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 Figure 14. Electrocardiogram during supraventricular tachycardia (A) and after Figure 15. Electrocardiogram from a case conversion to sinus rhythm (B) showing of Wenkebach A-V block showing T wave post tachycardia T wave inversion. inversion following short R-R cycle in lead V3 (arrow).

Figure 16. Electrocardiogram from a case of atrial fibrillation with right bundle branch block showing T wave inversion in cycles following longer pause (arrow).

Figure 17. Electrocardiogram from a case of pericardial constriction showing low QRS voltage and diffuse shallow T wave inversion.

Figure 19. Electrocardiogram from another Figure 18. Electrocardiogram from a case of hypertrophic cardiomyopathy showing tall case of hypertrophic cardiomyopathy QRS with diffuse deep T wave inversion. showing tall QRS with diffuse deep T wave inversion. (k) Secondary T wave Abnormalities depression with T wave inversion. These (i) Arrhythmogenic Right changes are secondary to depolarization Ventricular Cardiomyopathy Intraventricular conduction defects like abnormalities. In the context of left T wave inversion is common in leads V fascicular blocks, bundle branch block 1 ventricular hypertrophy, these changes and V . (Figure 21), pre-excitation, ventricular 2 suggest increased cardiovascular risk.15,16 ectopics, paced beats and ventricular T wave is directed away from later portion (j) Myocardial Tumors hypertrophy (Figure 22) are associated of the QRS complex. In these conditions, with down sloping ST segment if the direction of T wave is similar to

Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 139 ECG OF THE MONTH

Figure 22. Electrocardiogram from a case of left ventricular hypertrophy showing secondary T wave inversion in leads III, Figure 20. Electrocardiogram from a case of congestive cardiomyopathy showing diffuse T aVF, V4 to V6. wave inversion, non-progression of r in leads V1 to V4 and deep S waves in leads V2 and V3.

REFERENCES nonspecific finding or a sign for left anterior descending 1. De Luna B, Goldwasser D, Fid M, Bayes Genis A. Surface artery lesion ? J Emerg Med 2014;46:165-70. electrocardiography. In Fuster V, Walsh RA, Harrington 14. Levis J. ECG Diagnosis : Apical hypertrophic cardiomyo- RA (eds) Hurst’s The Heart. Mc Graw Hill, New York; pathy. Perm J 2013;17:84. 2011:307-70. 15. Larsen CT, Dahlin J, Blackburn H, et al. Prevalence and 2. Walder LA, Spodick DH et al. Global T wave inversion. prognosis of electrocardiographic left ventricular hyper- Long term follow up. J Am Coll Cardiol 1993;21:1652. trophy, ST segment depression and negative T wave. The 3. Uberoi A, Jain N, Froelicher V et al. Early repolarization Copenhagen city heart study. Eur Heart J 2002;23:315- in an ambulatory clinical population. Circulation 2011; 24. 124:2208-14. 16. Okin PM, Devereux RB, Nieminen MS. Electrocardio- 4. Togha M, Sharifpour A, Ashraf H et al. Electrocardio- graphic strain pattern and prediction of cardiovascular graphic abnormalities in acute cerebrovascular events in morbidity and mortality in hypertensive patients. Hyper- patient with / without cardiovascular disease. Ann Indian tension 2004;44:48-54. Acad Neurol 2013;16:66–71. 17. Kernohan RJ. Post – paroxysmal tachycardia syndrome. 5. Murthy SB. Shah S, Venkatasubba Rao CP, et al. Clinical Br Heart J 1969;31:803-6. characteristics of myocardial stunning in acute stroke. J 18. Kolb JC. Cardiac memory – persistent T wave changes Clin Neurosci 2014;21:1279-52. after ventricular pacing. J Emerg Med 2002;23:191-7. 6. Qaga AY, Suleiman A, Alsumrain M et al. Electrocardio- graphic abnormalities in patients presenting with intrac- ranial parenchymal hemorrhage. Acta Cardiol 2012;67: 635-9. 7. Chatterjee S. ECG changes in subarachnoid hemorrhage: A Synoposis. Neth Heart J 2011;19:31-4. 8. Mirvis DM, Goldberger AL. Electrocardiography. In Mann DL, Zipes DP, Libby P, Bonow RO (eds). Braunwald’s Heart Disease. Elsevier, Philadelphia; 2015:114-52. 9. Wagner GS, Lim TH. Myocardial infarction. In Wagner Figure 21. Electrocardiogram from a case GS(ed). Marriott’s Practical Electrocardiography, Wolters of left bundle branch block showing Kluwer, Philadelphia; 2001:178-207. secondary T wave inversion in leads I, aVL, 10. De Zwaan C, Bar FW, Wellens HJ. Characteristic electro- cardiographic pattern indicating a critical stenosis high V and V . 5 6 in left anterior descending coronary artery in patients ad- mitted because of impending myocardial infarction. Am the terminal part of QRS, it is abnormal Heart J 1982;103:730-6. and suggests myocardial disease. If the 11. Htut Oo SZMW, Khalighi K, Kodali A, May C, Aung TT, Snyder R. Ominous T wave inversions: Wellens’ syndrome intraventricular conduction, defect is revisited. J Community Hosp Intern Med Perspect 2016; intermittent, T wave changes may persist 6 : 10.3402/Jchimp. V6.32011. for hours or days after normalization of 12. Farhan HL, Hassan KS, Al Belushi A, et al. Diagnostic val- ue of electrocardiographic T wave inversion in lead aVL ventricular depolarization. Such changes in diagnosing coronary artery disease in patients with have been termed as “Memory T wave” chronic stable angina. Oman Med J 2010;25:124-7. changes.8,17,18 13. Hassen GW1, Costea A2, Smith T et al. The neglected lead on electrocardiogram: T wave inversion in lead aVL,

140 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 MCQs T Wave Inversion Q1. In children T waves may be Q8. Exercise can normalize T wave Q15. Acute pulmonary embolism normally inverted in leads inversion produced by produces T wave inversion in (A) I, aVL (A) Anxiety leads (B) V , V (B) Hyperventilation (A) III, aVF 5 6 (B) V to V (C) V to V (C) Early repolarization variant 1 4 1 4 (C) I & aVL (D) V7 to V9 (D) Myocardial ischemia (D) V5 & V6 Q2. Transient non-ischemic T wave Q9. Which of the following inversion can occur during conditions can produce T wave Q16. T wave inversion can be seen in (A) Anxiety inversion (A) Stroke (B) Hyperventilation (A) Acute pancreatitis (B) Intracranial bleed (C) Assumption of upright posture (B) Cholelithiasis (C) Subarachnoid hemorrhage (D) All (C) Renal colic (D) Subdural hematoma (D) Nephrotic syndrome Q3. Non-ischemic T wave inversion Q17. Hypothalamic bleed can produce can be seen in Q10. Which of the following (A) Widening of T wave (A) Post-prandial period conditions can produce T wave (B) QTc prolongation (B) Pregnancy inversion (C) Tachycardia (C) Exercise (A) Acute cholecystitis (D) All (D) Fasting (B) Acute peritonitis (C) Hyperthyroidism Q18. Which of the following can Q4. Global T wave inversion can be (D) Acute gastritis produce T wave inversion seen in (A) Truncal vagotomy (A) Cerebrovascular accidents Q11. Low voltage QRS, sinus (B) Radical neck dissection (B) Cardiac tumors bradycardia and generalized (C) Bilateral carotid endarterectomy (C) Pheochromocytoma diminution of T waves suggests (D) None (D) None (A) Cardiac tamponade (B) Cor-pulmonale Q19. In ST elevation myocardial Q5. Global T wave inversion is not (C) Myxoedema infarction, which portion of seen in (D) All T wave is the first to become (A) Myocardial ischemia inverted (B) Myocarditis Q12. T wave inversion with (A) Initial (C) Dilated cardiomyopathy prolongation of QTc interval is (B) Middle (D) Left bundle branch block seen in (C) Terminal (A) Hypokalemia Q6. Early repolarization variant (B) Cerebrovascular injury Q20. In a case of acute coronary produces changes in leads (C) Recent Stokes-Adams attack syndrome inverted T waves in leads V to V suggests tight (A) II, III, aVF (D) All 1 4 occlusion of proximal (B) V5 & V6 (C) V to V Q13. T wave inversion is seen in (A) LAD 2 4 (B) LCX (D) V7 to V9 (A) Hyperkalemia (B) Hypomagnesemia (C) RCA Q7. Early repolarization variant (C) Hypocalcemia (D) Left main coronary artery produces (D) Hyponatremia (A) ST segment elevation Q21. In a case of ST elevation (B) Biphasic T waves Q14. Hypokalemia produces myocardial infarction, T wave (C) Deep symmetrical T wave (A) Flattening of T wave inversion suggest inversion (B) ST segment depression (A) Successful reperfusion (D) Q waves (C) Prominence of U wave (B) Failure of reperfusion (D) Shortening of QTc interval (C) Ongoing ischemia (D) Infarction in opposite leads

Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 141 ECG OF THE MONTH PICTORIAL CME

Q22. In patients with chronic stable Q26. Combination of sinus (A) Fascicular blocks angina, T inversion in lead aVL tachycardia, low voltage QRS (B) Pre-excitation suggest occlusion of and diffuse shallow T wave (C) Paced beats (A) Proximal LAD inversion should suggest (D) None (B) Mid LAD (A) Gross pericardial effusion (C) Proximal D1 (B) Pericardial constriction Q30. In secondary T wave (D) Proximal major obtuse marginal (C) Myxoedema abnormalities, T wave are (D) Cor pulmonale directed Q23. Mitral valve prolapse can (A) Away from later portion of QRS produce T wave inversion in Q27. Combination of tall QRS, (B) Towards the later portion of QRS leads horizontal ST segment, diffuse (C) Away from the initial portion of (A) I and aVL deep T wave inversion, absence QRS (B) II, III and aVF of Q wave and any sequential (D) Towards the initial portion of QRS (C) V1 to V3 change on repeated ECG should

(D) V5, V6 suggest (A) Hypertrophic cardiomyopathy Q31. Secondary T wave directed Q24. Broad inverted T waves, QTc (B) Myocardial infarction towards later portion of QRS prolongation and high degree (C) Myocarditis suggests A-V block suggest (D) Cardiomyopathy (A) Non specific change (A) Severe hypokalemia (B) Myocardial damage (B) Hypothalamic bleed Q28. Arrhythmogenic right (C) Early repolarization (C) Recent Stokes- Adam’s attack ventricular dysplasia produces T (D) Electrolyte imbalance (D) Severe hypothyroidism wave inversion in leads

(A) V1, V2 Q32. Persistent T wave inversion after

Q25. Post tachycardia T wave (B) V5, V6 recovery from transient paced inversion suggests (C) I, aVL rhythm suggests (A) Non specific change (D) II, III, aVF (A) Myocardial ischemia (B) Myocardial ischemia (B) Myocardial infarction (C) Myocardial infarction Q29. Secondary T wave abnormalities (C) Memory T wave

(D) Electrolyte imbalance are seen in (D) Hypokalemia

A, B, C, (19) C, (20) A, (21) A, (22) B, (23) B, D, (24) C, (25) A, (26) A, B, (27) A, (28) A, (29) A, B, C, (30) A, (31) B, (32) C. C. (32) B, (31) A, (30) C, B, A, (29) A, (28) A, (27) B, A, (26) A, (25) C, (24) D, B, (23) B, (22) A, (21) A, (20) C, (19) C, B, A, Answers:(1) C, (2) D, (3) A, B (4) A, B, C (5) D, (6) C, (7) A, B, (8) A, B, C, (9) A, (10) A, B, (11) C, (12) D, (13) B, (14) A, B, C, (15)A, B, (16) A, B, C, (17) A, B, (18) (18) B, A, (17) C, B, A, (16) B, (15)A, C, B, A, (14) B, (13) D, (12) C, (11) B, A, (10) A, (9) C, B, A, (8) B, A, (7) C, (6) D, (5) C B, A, (4) B A, (3) D, (2) C, Answers:(1)

142 Cardiology Today VOL. XXII NO. 4 JULY-AUGUST 2018 PICTORIAL CME

Giant Ramus Artery

MONIKA MAHESHWARI

Congenital coronary anomalies are rare. Recently one such case of giant ramus artery was encountered by us (Figure 1, 2) and is picturised herein mimicking double left anterior descend- ing coronary artery.

Figure 1: Left Coronary Angiogram (RAO: Figure 2. Left Coronary Angiogram (RAO: 29.7° Caudal: 27.6° view) showing giant 2.1° Caudal: 28.8° view) showing giant ramus artery simulating double left ramus artery anterior descending coronary artery.

Dr. Monika Maheshwari is Professor at Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

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