Heart disease
Cardiovascular diseases are considered the major cause of morbidity and mortality worldwide. They are the leading cause of death globally, taking an estimated 17.9 million lives each year.
In the UK, there are around 7.6 million people living with heart and circulatory diseases, and someone dies from the conditions every 8 minutes. More than half the population in the UK will be expected to contract a variation of these conditions over their lifetime. The ageing and growing population coupled with improved survival rates from heart and circulatory events could see these numbers rise further still.
Cardiovascular disease is an umbrella term for conditions affecting the heart or blood vessels. It includes everything from conditions that are inherited, to those that develop later. There are many different types of cardiovascular diseases, among which:
- Coronary heart disease, which occurs when the flow of oxygen-rich blood to the heart muscle is blocked or reduced.
- Strokes, where the blood supply to part of the brain is cut off, which can cause brain damage and possibly death, and transient ischaemic attacks similar to strokes but where the blood flow to the brain is only temporarily disrupted.
- Peripheral arterial disease, which occurs when there's a blockage in the arteries to the limbs, usually the legs.
- Aortic diseases, which are a group of conditions affecting the aorta, the largest blood vessel in the body, which carries blood from the heart to the rest of the body. One of most common aortic diseases is an aortic aneurysm, where the aorta becomes weakened and bulges outwards.
The exact cause of cardiovascular diseases isn't clear. Many risk factors tend to add up and increase the risk of developing the conditions. Around 80% of people with a cardiovascular disease has at least one other health condition. A healthy lifestyle, particularly daily exercise and not smoking, can go a long way to lowering the risk of contracting a cardiovascular disease or avoiding it from getting worse.
Animal models of heart disease
Over the past years, significant achievements have been made in the management of cardiovascular disease based on experimental animal models. The ability to develop preventative and ameliorative treatments, but also to advance our knowledge of cardiovascular disease, greatly depends on animal models that mimic human disease processes.
The ideal animal model of cardiovascular disease mimics the human condition metabolically and pathophysiologically, is large enough to permit physiological and metabolic studies, and develops end-stage disease comparable to those in humans. Unfortunately, given the complex multifactorial nature of cardiovascular diseases, no one species presents an exact simulation of the human disease.
Consequently there is no unique ideal animal model of the human cardiovascular system. As such, studies should not rely on a single animal model to address all questions. Animal models should be chosen according to the research objectives. Determining the best experimental model to be used requires therefore a number of decisions and compromises. Researchers are looking to obtain the optimal balance between the relevance of the data to the condition under investigation and the quantity and quality of data produced.
Small animal models
For the last 50 years or more, small animal models have been commonly used in basic and translational cardiovascular research. Small animal models such as mice may present many advantages over larger animals.
Small animal models – mostly rodents - have a short life span, so the investigators can follow the natural history of the disease at an accelerated pace. The development of genetically modified models, especially in mice as their genetic background is one of the most well-known to science, has allowed for the rapid establishment of proof-of-principle research linking genes and disease that can be later be extended into larger animal models.
However, the use of rodents has a few disadvantages as well. They are phylogenetically distant from humans which means some pathophysiological features of disease and their response to pharmacological treatments may not be reliable predictors for humans. Translational aspects and value of small animal models in the context of cardiovascular research must be interpreted with caution. Although rodents display some characteristics of human cardiac diseases, they typically do not recapitulate all.
Mice
For the past 25 years, the mouse has become the model organism of choice to study human heart disease. They have a short life span of around two years which allows for longitudinal studies. 99% of human genes have direct murine orthologs and mice are suitable for breeding of genetically modified individuals within a relatively short time because of their high breeding rate. The greatest benefit in using mouse models is the availability of a great number of relevant transgenic and knockout strains. In addition, cardiac physiological assessments have been facilitated greatly by newer technologies.
However, despite their widespread use, mice are one of the heart models farthest from human contractile function, mainly due to their small size and short lifespan. There is three orders of magnitude difference in heart size between mice and humans. The mouse is also characteristically resistant to cardiovascular disease, as such genetic mouse models are preferred. Translational aspects and the value of genetic mouse models must be interpreted with caution. They recapitulate some of the characteristics of the human cardiac phenotypes, but not all aspects of human cardiovascular disease.
Rat
Heart failure models were originally developed in rats. Recent technological advances in echocardiography, MRI, and micromanometer conductance catheters have greatly streamlined the assessment of cardiac function in rodents, removing a significant barrier to their use in heart failure research.
The rat and the mouse share many characteristics. However, spontaneous mutations in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, one of which spontaneously develops cardiovascular disease and ischemic lesions. Moreover, the development of suitable expertise to perform open-chest surgical procedures and invasive hemodynamic assessments in rats is far easier compared with that required for mice. Additionally, investigators are able to perform a greater number of postmortem histological or molecular biological analyses given the approximately 10-fold greater myocardial mass of rats compared with mice. For these reasons, the rat models have been the most widely and successfully used heart failure models in basic and translational research.
Zebrafish
The zebrafish is an interesting model organism because it can regenerate its heart tissue even in the presence of scarring produced by ventricular injury or amputation. Unlike mammals, they can repair and rebuild tissue lost to injury or disease.
Human and adult mouse hearts scar permanently. Their heart muscle cells are unable to divide and reconstitute new muscle. If the heart is damaged, it stays damaged. However, if part of the zebrafish’s ventricle is cut off, it will completely regenerate within two months without any scarring. Remaining heart cells, called cardiomyocytes, can de-differentiate and proliferate to replace the lost cardiac tissue.
Insights in zebrafish can find applications in mice but also help identify cellular or molecular mechanisms that can be genetically manipulated in mice at a later stage. Findings in zebrafish can be applied in mice before tests in humans. This reduces the number of mice used in research but also refines the experiments the mice are used for.
Long term the hope is that human heart tissue can be modified to be regenerative.
Rabbit
Rabbits develop cardiovascular disease when fed high-cholesterol diets but there are no rabbit models of metabolic syndrome. Importantly, the rabbit myocardium shares more similarities with human myocardium than small rodent myocardium; therefore, rabbit genetic models, albeit expensive, can be used as a steppingstone to determine whether a particular study can be extended to humans and larger animal models. They are an attractive alternative to larger animal models for cardiac research.
However, differences between rabbit and human myocardium remain, which might lead to different reactions in rabbits and humans. For example, rabbits might not serve as the best animal model for studying the effects of exercise on the cardiovascular system mainly because their heart rate reserve is much less than that in humans and large animal models, such as canines.
Cat
Spontaneous cardiac diseases similar or identical to those in humans are extremely common in cats. However, they are rarely used as models of human cardiac disease because of the restrictions on using cats in research, and the practical difficulties of keeping large numbers of cats in laboratory conditions.
Hypertrophic cardiomyopathy (HCM) is currently the most common heart disease in cats, that suffer from similar symptoms to humans, and its incidence appears to be increasing. In particular, the Maine Coon, has a genetic mutation that makes the breed prone to suffer from HCM. However, it is highly likely that other causes (genetic or not) are also responsible for the disease in the Maine Coon. Individuals of this breed can be used as relevant animal models to study the development and pathophysiology of HCM in the context of veterinary follow-ups.
Large animal models
For research aimed at clinical translation, it is imperative that initial results from rodent studies be confirmed in a large animal model whose heart more closely resembles that of a human. Differences between laboratory animals and humans are decreased as the body/heart weight of the model approaches that of humans so typically this would be a pig or dog.
However, the use of larger animals in research is more problematic, due to ethical reasons first, but also practically due to housing and cost considerations. Moreover, spontaneous models are harder to generate in large animals, less suited for genetic modifications. Most animal studies involve the sudden occlusion of a coronary artery in what was previously healthy tissue, very different for the complex and progressive pathological development in humans.
It is important to keep in mind that, although a larger animal model is more expensive (the daily housing fees of large animals are 30 to 90 times more expensive than those of mice) and difficult to manipulate, its genetic, structural, functional, and even disease similarities to humans make it often more interesting for clinical translation of discoveries. Moreover, because of their size, they often allow cardiac functions and responses to be assessed in the intact animal.
Dogs
Canine and human hearts share many characteristics on both the organ and cellular levels. Canine heart rate, body weight, and heart weight are more comparable to humans than the that of mice, rats, and rabbits.
The size of the dog heart also allows almost all in vivo techniques used on human hearts to be utilized in canines.
Historically dog research was vital in the creation of the pacemaker but today the use of dogs in research is heavily controlled and necessary approval is not given out lightly.
Dogs in medical research into heart function
Pigs
Pig hearts are similar to human hearts in organ size, coronary anatomy, immunology, and physiology. As such, swine often stand out as the most attractive model for pre-clinical protocols.
Pigs are often used as alternatives to dogs. In general, it is thought that the young human heart may be somewhat “pig-like” whereas the older heart with ischemic heart disease may be more “dog-like”.
Recently, modified pigs have provided hearts for transplant trials in primates and humans.
Sheep
Sheep also share similarities to the human heart. The resting heart rate in sheep (60–120 bpm) is similar to humans (60–75 bpm). This is also true for the systolic (~90–115 mmHg) and diastolic (~100 mmHg) pressure in sheep and humans (120 mmHg and 80 mmHg, respectively). At cellular and molecular levels, sheep heart muscle molecules resemble humans. In terms of functionality, the contractile and relaxation kinetics of sheep cardiomyocytes are also similar to human heart cells.
Sheep serve as a good pre-clinical animal model for cardiovascular research and several sheep models of heart disease have been reported.
Non-Human Primates
Non-human primate models have the advantage of being very similar to humans, physiologically, metabolically, biochemically and genetically.
Notably, a primate model of heart failure closely mimics the cardiomyopathic process observed in humans. Unlike existing heart failure models, it allows for continuous study during progressive stages of heart failure, including myocardial ischemia, progressive left ventricular remodeling and end-stage congestive heart failure.
Despite these advantages advantage, there is a relative scarcity of non-human primate models used in the study of cardiac diseases.
Heart repair and regeneration
To date, there are no cell-based models or any in vitro studies that can reproduce actual organ regeneration response in a 3D-multicellular context. However, some animals are capable of such feat.
Zebrafish are renowned for their regenerative abilities. They can repair heart damage throughout their life by the replication of existing heart cells, called cardiomyocytes. Though most mammals can replace a small number of heart cells, this isn’t enough to mend the damage of a heart attack for example. Adult mammals can’t repair heart damage. However, newborn mice can regenerate their own heart tissue following heart damage, suggesting there is a narrow time window in mammals after which the heart loses its regenerative abilities.
It seems mammals have the same ability as fish to self-repair, but only for a short time after birth. It is hoped that the research could lead to ways to restart the regenerative capacity of the heart in human adults. Such treatments would be vital in treating patients after a heart attack. Researchers are now looking for genes that could be linked to heart regeneration. They are also screening for medicines that could reawaken the mechanisms in adult hearts.
Stem cells and heart repair
In the same effort to restore cells to their previous health after damage, scientists have focused of stem cells. Stem cells can be found in the epicardium (layer surrounding the heart) of adult mouse hearts.
Stem cells have been shown to restore cardiac muscle back to its condition before a heart attack. Research in mice, rats and zebrafish mostly have helped determine molecules involved in heart cell death but also regeneration. Stimulating these molecules, or stem cells resident in the heart, could limit damage to the heart muscle.
To improve heart cell repair, researchers have developed a patch. Immature heart cells from newborn rats placed onto a biodegradable 'scaffold' exposed to chemicals which encouraged cells growth helped form a network of blood vessels and muscle fibres in the abdomens of rats. Full integration, where the patch was able to synchronise its beat with the surround tissue, was seen within a month of grafting the rat's heart.
Gene therapy to repair hearts
Scientist managed to repair damaged heart tissue in mice using gene therapy. They had identified three genes, collectively called GMT, that direct the development of heart muscle in the embryo. Turning these genes on in cultured fibroblasts, could create muscle cells
The technology was the first to turn non-beating heart cells into beating ones in a living animal. To achieve the same effect in a whole living animal the researchers injected a modified virus carrying the GMT genes into the hearts of mice that had been surgically induced under anaesthesia to have a heart attack. The virus delivered the genes into the cells where they were activated, turning the fibroblasts into heart muscle cells. Genetic and molecular tests confirmed to transformation.
This shows that in principle, gene therapy could be used to improve heart function in people who have suffered a heart attack.
Pig to human heart transplant
On 7 January 2022, for the first time ever, a pig heart was transplanted into a human. Xenotransplantations – animal to human transplants – are technically demanding on many levels. Surgeons have been attempting to put baboon and chimpanzee organs into humans since at least the 1960s. In 1984, a human infant even received a heart from a baboon but she died 21 days after the transplant.
Primates fell out of favour in the 1990s as potential organ donors because the risk of viral infections was deemed too great. Not just any heart from any animal can be harvested and transplanted into humans, or it would have been done decades ago. The organ has to be a similar size to that of a human and that is what brought pigs into the research spotlight.
Full story : https://www.understandinganimalresearch.org.uk/news/how-did-we-get-to-pig-hearts-in-humans
Computer models predict heart treatment
Scientists have developed a computer model that predicts the effect of anti-arrhythmic medicines on the heart. The model gives the same results as experiments conducted on humans and animals.
Contraction of the heart is tightly regulated by electrical impulses generated by heart cells. Irregular heartbeat, or arrhythmia, occurs when these impulses get out of synchrony. Anti-arrhythmic medicines act on cell membranes to control the flow of ions across the membranes which cause the electrical currents. However, the wrong dose can often make symptoms worse or cause sudden death. Thorough testing on animals is therefore essential to ensure safety.
In the computer model, scientists used equations to represent the opening and closing of channels in cell membranes that allow ions to flow from one side to the other, generating impulses. Researchers can then input a medicine and dose and the model will predict what effect it has on the heart as a whole. In the future, this model could reduce the number of animal experiments needed when developing new medicines.
In another development, a team of UC Davis Health scientists has developed a predictive model that translates cardiac research findings across different animal species into human-specific insights. The researchers presented a set of translators for mapping the electric activity of mouse, rabbit, and human cardiac cells.
Last edited: 27 October 2022 09:27