Heart Disease: 
A primary cause of death

Heart Disease: 
A primary cause of death

Dr Catrin Rutland BSc PGCHE MSc MMedSci PhD SFHEA FAS

Heart disease is one of the primary causes of death throughout the world in both humans and animals. Research at The School of Veterinary Medicine and Science, University of Nottingham is dedicated to understanding differing types of cardiovascular disease in order to prevent, manage, treat and cure heart disorders. Cardiovascular disease is observed in many animals from dogs through to apes. We also translate our research into understanding related human disorders. Our approach combines the expertise from a number of medical and scientific professionals. We combine valuable work and expertise from veterinary clinicians such as cardiologists, pathologists, first opinion veterinarians, surgeons and anaesthetists with that from scientists in fields such as genetics, molecular and cellular biology, epidemiology, bioinformatics and protein biology.

Cardiomyopathy research programme

The Nottingham Canine Health Genomics team is directed by Dr Catrin Rutland, Professor Malcolm Cobb, Professor Nigel Mongan and Dr Mark Dunning. Their research brings together the expertise of cardiovascular and small animal clinicians with scientific disciplines including genetics, bioinformatics, histology and cell biology in order to comprehensively study heart disease. We have collected many thousands of canine samples, matched with clinical and owner reported data, which in turn enable us to gain valuable insights into the disorders. The group study a number of illnesses but their work into cardiomyopathy has advanced the field of veterinary genetics, whilst also having significant impact and highlighting areas of importance in humans and other animals. Cardiomyopathies affect up to 50% of animals in some breeds. It frequently significantly shortens lifespan and affects lifestyle and is therefore a very serious problem. Our genome analysis work has resulted in a predictive disease model and in the discovery of a multiple genetic associations for cardiomyopathy. We have also highlighted likely candidate genes, shown clinical similarities and differences between species and breeds and shown histopathological comparisons across differing species [1-3- 1. Simpson, S., et al., PeerJ, 2015. 3: p. e842. / 2. Simpson, S., et al., Int J Genomics, 2015. 2015: p. 204823. / 3. Simpson, S., et al., Biomed Res Int, 2016. 2016: p. 6374082.]. We have also published links between prognosis, age of onset, sex and associations with other cardiac disorders such as atrial fibrillation. The work on cardiomyopathy is not only being carried out in dogs, other mammals feature heavily too [4- 4. Simpson, S., et al., Vet Sci, 2017. 4(1).]. Work on this problem in cats has looked at congestive heart failure in relation to the safety and efficacy of present treatment options available lead by Professor Malcolm Cobb [5 – 5. James, R., et al., Journal of Veterinary Cardiology, 2018. 20(1): p. 1-12.].

Ape heart project

Research within the school also looks into cardiovascular problems in more exotic animals. The Ape Heart Project is an excellent example of some of the work being undertaken. Professor Kate White and Dr Kerstin Baiker from the School of Veterinary Medicine and Science are working closely with other experts within the school and across Europe in the fields of zoological, comparative medicine and cardiology to form a European taskforce. Endorsed by the European Association of Zoos and Aquaria (EAZA) Great Ape Taxon Advisory Group (TAG), The Ape Heart Project; led by Twycross Zoo, is a pan-European collaborative initiative aimed at enhancing current understanding about all aspects (epidemiology, pathology and clinical) of great ape cardiovascular disease [6-8 – 6. Strong, V., et al., Journal of Zoo and Wildlife Medicine, 2017. 48(2): p. 277-286. / 7. Strong, V.J., et al., Journal of Zoo and Wildlife Medicine, 2016. 47(3): p. 697-710. / 8. Strong, V.J., et al., International Zoo Yearbook, 2018. 52: p. 1-11.].

Heart disease is often reported as a significant cause of death among captive great apes (chimpanzees, bonobos, gorillas and orangutans). However, our understanding about the condition and consequently our abilities to treat and prevent it are limited. In particular, very little work has been done looking at the European population of apes. Twycross Zoo and The University of Nottingham are leading the way in this exciting project which will help us to provide even better care for all captive great apes across Europe.

Congenital portosystemic shunts

Another key area of research within the School of Veterinary Medicine and Science is based around congenital portosystemic shunts in cats and dogs lead by Professor Rob White. Congenital portosystemic shunts (CPSSs) are vascular anomalies that divert portal blood directly into the systemic circulation, bypassing the liver parenchyma. The absence of a normal hepatic portal circulation has two important consequences; 1) impaired hepatic development and function, and 2) direct systemic effects of toxins, nutrients, hormones and other factors that originate from the splanchnic area. CPSSs have been described with frequency in the dog and cats but are only occasionally reported in humans. CPSSs commonly occur as single vessels that may have either an intrahepatic (20-33%) or extrahepatic (66-80%) localisation. Extrahepatic CPSSs mainly occur in small-sized dog breeds, whereas intrahepatic CPSSs often occur in larger dog breeds.

Recently, the most common extrahepatic CPSSs which involve the azygos, left colic, left gastric, right gastric, left phrenic and splenic veins were independently described in detail using computed tomography angiography (CTA), intra-operative mesenteric portovenography and gross anatomical findings [9-12 – 9. White, R.N., et al., J Small Anim Pract, 2013. 54(9): p. 459-67. / 10. White, R.N., et al., J Small Anim Pract, 2015. 56(7): p. 430-40. / 11. White, R.N., et al., J Small Anim Pract, 2016. 57(1): p. 28-32. / 12. White, R.N., et al., J Small Anim Pract, 2016. 57(5): p. 247-54.]. These studies concluded that there was consistency of morphology for these five most common shunt types and that with each type, the site of communication between the shunt and the systemic circulation was highly consistent and anatomically well-defined. In a further recent study it was concluded that in dogs four consistent shunt types (spleno-caval, left gastro-phrenic, left gastro-azygos and those involving the right gastric vein) were responsible for 94% of shunts reported in the species, whereas, in cats three consistent shunt types (spleno-caval, left gastro-phrenic and left gastro-caval) were responsible for 92% of extrahepatic shunts reported [13 – 13. White, R.N., et al., J Small Anim Pract, 2017. 58(12): p. 669-677.].

Intrahepatic shunts are divided in left, central or right divisional shunts, depending on their localisation, draining in most instances into the intrahepatic or post hepatic vena cava. Previous studies have confirmed that in both dogs and cats the most common of the intrahepatic CPSSs results from failure of the ductus venosus to close after birth (persistent ductus venosus) [14, 15 – 14. White, R.N., et al., Veterinary Record, 2000. 146(15): p. 425-429. / 15. White, R.N., et al., J Feline Med Surg, 2001. 3(4): p. 229-33. / ]. The anatomical descriptions and classifications of both extrahepatic and intrahepatic CPSSs are important with regards to what is the recognised as the preferred therapeutic management of the condition; that is, the surgical closure of the anomalous shunting vessel [16 – 16. White, R.N., et al., Vet Rec, 1996. 139(13): p. 314-7.].

Platelet activity determination and development of anti-platelet drugs.

Dr Mark Dunning and a group of platelet biologists from the Queens Medical Centre have developed a test for dogs that is also used in humans which looks at how active platelets are in the circulation [17 – 17. Dunning, M., et al., Journal of Veterinary Internal Medicine, 2018. 32(1): p. 119-127.]. This is important as in certain types of heart disease in cats and dogs blood clots can occur. This test is unique in that it can be performed on blood taken from the patient and stored for up to 20 days. This is a major breakthrough as currently platelet activity testing must be conducted on fresh blood samples within just a few hours. Platelet activities can therefore be monitored from general veterinary practices, enabling them to predict which animals may form clots and whether their platelet activity is sufficiently suppressed by anti-platelet drugs, thus reducing their chances of forming clots. Further work is underway in cats and primates looking at whether the test can be applied to samples from these species in addition to dogs.

Human Heart Disease

It may seem unusual for a Veterinary School to undertake research into human disorders, but the School has a very strong comparative medicine team. For example Dr Catrin Rutland has studied cardiomyopathies in several animals and this often informs the work in humans and vice versa. Her work includes searching for mutations in the human genome which cause not only cardiomyopathies but also septal and ventricular defects. This research helps us to understand not only the mechanisms behind heart disease but also to further the genetic tests available in order to establish whether a patient has cardiomyopathies/heart defects prior to onset of clinical manifestations and to understand the complications observed during heart development. This work has used a number of complimentary techniques including genetic knockdown, cell culture, histology and protein analysis and includes collaborators from across the medical School but also with researchers throughout the world. Primarily the work has concentrated on the myosin and TBX5 genes and proteins and their involvement with cardiovascular morphology, contraction and electrical signalling pathways [18-21 – 18. Rutland, C.S., et al., Development, 2011. 138(18): p. 3955-66. / 19. England, J., et al., J Mol Cell Cardiol, 2017. 106: p. 1-13. / 20. Ghosh, T.K., et al., J Mol Cell Cardiol, 2018. 114: p. 185-198. / 21. Rutland, C., et al., J Anat, 2009. 214(6): p. 905-15.].

The School of Veterinary Medicine and Science strives to support veterinary professionals throughout the world by undertaking research into cardiovascular disease. We work together with owners, veterinary professionals and scientists in order to further the knowledge known about each disorder. Using cutting edge technology in state-or-the-art laboratories, we are able to improve the well-being of animals and people through world-leading innovative research.

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