The earliest archeological evidence for cat associations with humans has been dated to over 3,000–6,000 BC in Cyprus,^1-3 Egypt,⁴ and most recently, China⁵. Whether cats migrated to these different regions with trade and agriculture, or if regional wildcats were independently domesticated in different parts of the Old World remains an unresolved mystery. Since these early times, cats have continued their friendship with humans, having a symbiotic relationship - providing vermin control for humans, while gaining low energy expenditure for meals.^1,6-8 Hence, as soon as cats were somewhat tamed, they expanded and migrated around the world as man's constant but often inconspicuous companion. As trade and exploration opened new opportunities and resources for man, the cat too expanded its territory around the world.^9,10 However, like peoples that have formed ethnic groups and races, complete panmictic (random), worldwide breeding has not been possible for the cat, limited by natural boundaries, few founders, and sporadic migrations. Thus, mutations and allele frequencies do differ between cat populations, forming races and breeds, as like races and ethnic groups of humans. Genetic studies of worldwide feral populations and breeds have shed light into the population structure of domestic cats,¹¹ providing important clues to their genetic identity and genetic health management.

Genetic Structure of Cat Population

Genetic Races of Domestic Cats

The domestic cat likely derived from one or more subspecies of wildcat (Felis silvestris).¹² At least one domestication event for the cat was very likely to have been the Near East;¹³ however, independent domestications may be plausible due to the significant genetic distinction of cats in the Far East and the recent archeological find in China that associates cats with humans in an ancient agricultural site⁵. Different domestication events from many, and perhaps different, subspecies of wildcats implies high genetic diversity for the founding populations(s) of domestic cats, which should support health and the ability to adapt to different niches and physiological insults. Without archeological samples with sufficient DNA, only the present day populations of cats can be examined to evaluate genetic diversity and population differentiations. This genetic data can allow the potential extrapolation back to the number and different sites of cat domestication. However, regardless of the cat's ancient history, the extant, present-day feline populations are the concern of owners, breeders, and veterinarians.

World-wide cat populations have been genetically examined to define the differences that may be important for genetic-based health management.¹¹ Different genetic markers, such as mitochondrial DNA (mtDNA),¹⁴ short tandem repeats (STR, a.k.a. microsatellites),¹⁵ and single nucleotide polymorphisms (SNPs),¹⁶ all have different "genetic clocks" and examine different time points in domestic cat history and evolution^13,17. The combined analysis of these different markers then paints a picture of the present geographical demarcations and genetic distinction of cat populations. To date, several published studies have examined breeds but only one has extensively examined feral cat populations.¹¹ This previous study of feral cats has been expanded to include additional world-wide populations, refining the genetic races of feral cat populations. Figure 1 depicts groupings of cats based on genetic differentiation. Each color in the figure defines a grouping of cats. Groupings with the same color are genetically similar, as defined by the frequencies of the DNA variants that are tested across all the cats in the study populations. The DNA variants used for population studies are not supposed to be under any type of selection, thus are usually random DNA variants that are not important to health or how the cat looks. However, one can infer that other genetic variants, such as those causing specific phenotypes, diseases, or health concerns, would have similar frequencies in the genetically-like populations. Since the three different populations tested in Japan have similar allele frequencies and "cluster" as a common population, health concerns, such as the gangliosidosis, a rare genetic condition that has been documented in feral Japanese domestic shorthair cats,^18-20 should be more highly prioritized on a possible list of differentials for sick cats in the region. Cats from the UK have basically the same genetic composition as cats in the USA and Canada, due to their recent Old World to New World migrations in the past 500 years. Trade and colonization has broken the extensive, natural barrier of the Atlantic Ocean, thus cats in Australia, Kenya, and the Americas show the marks of the past from various European invasions and colonizations. Veterinarians in Australia need to be cognizant of health concerns documented in cats in both the USA and Europe, while cats in Italy seem to be a conglomerate of individuals from the Mediterranean and other regions of the world. However, cats in close proximity can have different genetic origins, such as the Iberian Peninsula and France. The Pyrenees mountain chain has apparently been an ecological barrier to cats, and like other species,²¹ cats of Portugal and Spain appear to be genetically different from the remaining European continental cats. Overall, twelve different groupings, clusters, or races of cats can be genetically defined from the various locations that have been sampled. Some island populations appear to have similar genetic signature to the mainland, such as Majorca and Iberia, while other island populations are more distinct, such as San Marcos, an island off the coast of California. Distinct island populations are likely unique when cat migrations are very limited or forbidden, such as the case of San Marcos, and the island is small and likely had limited founders to the population historically. Specific cats from several of the "races" have been extracted to develop our pedigreed fancy breeds.

Genetic Distinction of Domestic Cat Breeds

Breeds of cats act similar genetically to ethnic groups of humans. Previous studies have shown that cat breeds have been developed from Western European, Mediterranean, Arabian Sea, and Southeast Asian populations.¹¹ Ongoing studies may suggest that breeds like the Norwegian Forest cat can now be refined to more specific populations, such as the Northern European/Nordic race of cats. Thus, cat breeds will share health concerns and genetic traits in common with their races of origin. The same types of genetic analyses that were used to compare feral, randomly bred populations of cats have also been used to compare different cat breeds. Table 1 presents a listing of popular cat breeds. Over three dozen breeds have been genetically examined with the same genetic markers as the cat races. Approximately 24 breeds appear to be genetically distinct, while the remaining breeds are derived from a specific breed family, such as the Persian, the Siamese, or the Burmese families. These "parent" breeds have been bred to produce slightly different cat groups that are often declared a different breed, but are genetically different by perhaps only one genetic mutation. For example, the Persian family is composed of the Persian, Exotic, Selkirk Rex, Scottish Fold, and British Shorthair breeds.²² Exotics are different from Persians by having shorthair,²³ Selkirk Rex differ by having curly hair,²⁴ and Scottish Fold differ by having folded ears. Each difference is caused by a single gene mutation, which is not truly sufficient to affect the overall genetic constitution of the breed. Although the definition of cat breeds is arbitrary and of no major consequence, the health of the new and derived breeds can be significantly impacted by the individuals used to found and propagate the new breed. Selkirk Rex and Scottish Folds are new derivatives of Persians. Persians have historically been riddled with polycystic kidney disease.^25-33 Thus, each derivative breed should be monitoring the same health and genetic issues as found in the parent breed, such as PKD in the Persian derived breeds. Any breeds produced from Burmese need to be leery of craniofacial defects,^34,35 feline oral facial pain,^36,37 hypokalemia,³⁸ and diabetes^39,40. Breeds associated with Abyssinians should be cognizant of progressive retinal atrophies and pyruvate kinase deficiency.^41-43

Figure 1. Genetic structuring of world cat populations The figure presents individual cats and their contributions from different genetic groupings. Each cat with similar genetic contributions are clustered in the figure, producing the groups. After the analysis, the groups are labeled with the country of origin of each cat and the group depicted with a color. For example, the cats from Majorca are genetically similar to cats from Spain and Portugal, but different from other world populations. The cats in these countries do show some mixture with cats from different regions, but are significantly similar. Twelve groupings are significantly distinct, suggesting twelve worldwide races of cats. (Figure courtesy of R. Khan, University of California, Davis.)

Table 1. Genetic families of domestic cat breeds

*Modified from genetic studies based on 29 tetranucleotide short tandem repeat markers, 39 dinucleotide short tandem repeat markers, and unpublished data (LA Lyons). Siamese family includes Balinese, Havana Brown, Javanese, Colorpoint, Oriental.

References

1.  Vigne JD. The origins of animal domestication and husbandry: a major change in the history of humanity and the biosphere. C R Biol. 2011;334(3):171–181.

2.  Vigne JD, Briois F, Zazzo A, et al. First wave of cultivators spread to Cyprus at least 10,600 y ago. Proc Nat Acad Sci USA. 2012;109(22):8445–8449.

3.  Vigne JD, Guilaine J, Debue K, Haye L, Gerard P. Early taming of the cat in Cyprus. Science. 2004;304(5668):259.

4.  Malek J. In: The Cat in Ancient Egypt. Philadelphia, PA: University of Pennsylvania; 1993.

5.  Hu Y, Hu S, Wang W, et al. Earliest evidence for commensal processes of cat domestication. Proc Nat Acad Sci USA. 2014;111(1):116–120.

6.  Clutton-Brock J. In: A Natural History of Domesticated Mammals. London, UK: Cambridge University Press, British Museum; 1987.

7.  Driscoll CA, Clutton-Brock J, Kitchener AC, O'Brien SJ. The taming of the cat. Genetic and archaeological findings hint that wildcats became housecats earlier - and in a different place - than previously thought. Sci Am. 2009;300(6):68–75.

8.  Tresset A, Vigne JD. Last hunter-gatherers and first farmers of Europe. C R Biol. 2011;334(3):182–189.

9.  Todd NB. Cats and commerce. Sci Am. 1977;237:100–107.

10. Todd NB. An ecological, behavioral genetic model for the domestication of the cat. Carnivore. 1978;1:52–60.

11. Lipinski MJ, Froenicke L, Baysac KC, et al. The ascent of cat breeds: genetic evaluations of breeds and worldwide random-bred populations. Genomics. 2008;91(1):12–21.

12. Nowell K, Jackson P. Wild Cats Status Survey and Conservation Action Plan. Gland, Switzerland: IUCN; 1996.

13. Driscoll CA, Menotti-Raymond M, Roca AL, et al. The Near Eastern origin of cat domestication. Science. 2007;317(5837):519–523.

14. Grahn RA, Kurushima JD, Billings NC, et al. Feline non-repetitive mitochondrial DNA control region database for forensic evidence. Forensic Sci Int Genet. 2011;5(1):33–42.

15. Menotti-Raymond M, David VA, Pflueger SM, et al. Patterns of molecular genetic variation among cat breeds. Genomics. 2008;91(1):1–11.

16. Kurushima JD, Lipinski MJ, Gandolfi B, et al. Variation of cats under domestication: genetic assignment of domestic cats to breeds and worldwide random-bred populations. Animal Genet. 2013;44(3):311–324.

17. Driscoll CA, Menotti-Raymond M, Nelson G, Goldstein D, O'Brien SJ. Genomic microsatellites as evolutionary chronometers: a test in wild cats. Genome Res. 2002;12(3):414–423.

18. Hasegawa D, Yamato O, Kobayashi M, et al. Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat. J Feline Med Surg. 2007;9(3):232–237.

19. Uddin MM, Hossain MA, Rahman MM, et al. Identification of Bangladeshi domestic cats with GM1 gangliosidosis caused by the c.1448G>C mutation of the feline GLB1 gene: case study. J Vet Med Sci/Japan Soc Vet Sci. 2013;75(3):395–397.

20. Yamato O, Matsunaga S, Takata K, et al. GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats. Vet Rec. 2004;155(23):739–744.

21. Martin-Burriel I, Rodellar C, Canon J, et al. Genetic diversity, structure, and breed relationships in Iberian cattle. J Anim Sci. 2011;89(4):893–906.

22. Filler S, Alhaddad H, Gandolfi B, et al. Selkirk Rex: morphological and genetic characterization of a new cat breed. J Hered. 2012;103(5):727–733.

23. Kehler JS, David VA, Schaffer AA, et al. Four independent mutations in the feline fibroblast growth factor 5 gene determine the long-haired phenotype in domestic cats. J Hered. 2007;98(6):555–566.

24. Gandolfi B, Alhaddad H, Joslin SE, et al. A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats. Sci Rep. 2013;3:2000.

25. Barthez PY, Rivier P, Begon D. Prevalence of polycystic kidney disease in Persian and Persian related cats in France. J Feline Med Surg. 2003;5(6):345–347.

26. Beck C, Lavelle RB. Feline polycystic kidney disease in Persian and other cats: a prospective study using ultrasonography. Aust Vet J. 2001;79(3):181–184.

27. Biller DS, Chew DJ, DiBartola SP. Polycystic kidney disease in a family of Persian cats. J Am Vet Med Assoc. 1990;196(8):1288–1290.

28. Biller DS, DiBartola SP, Eaton KA, Pflueger S, Wellman ML, Radin MJ. Inheritance of polycystic kidney disease in Persian cats. J Hered. 1996;87(1):1–5.

29. Bogdanova N, Dworniczak B, Dragova D, et al. Genetic heterogeneity of polycystic kidney disease in Bulgaria. Hum Genet. 1995;95(6):645–650.

30. Bonazzi M, Volta A, Gnudi G, Bottarelli E, Gazzola M, Bertoni G. Prevalence of the polycystic kidney disease and renal and urinary bladder ultrasonographic abnormalities in Persian and Exotic Shorthair cats in Italy. J Feline Med Surg. 2007;9(5):387–391.

31. Domanjko-Petric A, Cernec D, Cotman M. Polycystic kidney disease: a review and occurrence in Slovenia with comparison between ultrasound and genetic testing. J Feline Med Surg. 2008;10(2):115–119.

32. Eaton KA, Biller DS, DiBartola SP, Radin MJ, Wellman ML. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Vet Pathol. 1997;34(2):117–126.

33. Lyons L, Biller D, Erdman C, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548–2555.

34. Zook BC. Encephalocele and other congenital craniofacial anomalies in Burmese cats. Vet Med/Small Anim Clin. 1983;78:695–701.

35. Noden DM, Evans HE. Inherited homeotic midfacial malformations in Burmese cats. J Craniofac Genet Dev Biol Suppl. 1986;2:249–266.

36. Rusbridge C, Heath S, Gunn-Moore DA, Knowler SP, Johnston N, McFadyen AK. Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases. J Feline Med Surg. 2010;12(6):498–508.

37. Heath S, Rusbridge C, Johnson N, Gunn-Moore D. Orofacial pain syndrome in cats. Vet Rec. 2001;149(21):660.

38. Gandolfi B, Gruffydd-Jones TJ, Malik R, et al. First WNK4-hypokalemia animal model identified by genome-wide association in Burmese cats. PloS One. 2012;7(12):e53173.

39. Rand JS, Bobbermien LM, Hendrikz JK, Copland M. Over representation of Burmese cats with diabetes mellitus. Aust Vet J. 1997;75(6):402–405.

40. O'Leary CA, Duffy DL, Gething MA, McGuckin C, Rand JS. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. New Zeal Vet J. 2013;61(6):354–358.

41. Menotti-Raymond M, Deckman K, David V, Myrkalo J, O'Brien S, Narfström K. Mutation discovered in a feline model of human congenital retinal blinding disease. Invest Ophthalmol Vis Sci. 2010;51(6):2852–2859.

42. Menotti-Raymond M, David VA, Schaffer AA, et al. Mutation in CEP290 discovered for cat model of human retinal degeneration. J Hered. 2007;98(3):211–220.

43. Grahn RA, Grahn JC, Penedo MC, Helps CR, Lyons LA. Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of domestic cats. BMC Vet Res. 2012;8(1):207.

Genetic testing is a key component to state-of-the-art healthcare. Since the 1960s, direct DNA mutation testing has been performed on newborn humans for rapid detection of inborn errors of metabolism. Each state in the USA and various countries world-wide tailor their now more extensive newborn DNA screening programs to detect the common mutations found in their regions most predominant ethnic groups. The same high standard of healthcare is available for companion animals, even cats, their breeds being analogous to human ethnic groups and races. Dozens of DNA mutations have been identified in cats that are pertinent to specific breeds. Because controlled breeding is routine and the norm in pedigreed cats, the potential for a higher standard of healthcare is even higher than humans, since genetic testing can be used to prevent the mating of individuals that produce unhealthy, undesired offspring. This presents the pertinent genetic mutations that should be monitored for their healthcare.

Simple Mutations for Simple Traits and Diseases

To date, over 40 genes conferring approximately 70 mutations have been documented to cause phenotypic, disease, or blood type variations in the domestic cat.^44,45 Since the presentation in this volume series in 2010,⁴⁶ twelve new genes causing cat phenotypes and health issues have been identified, implying 3–4 mutations are now being identified each year for cats. The genetically characterized diseases and health concerns for specific breeds is presented in Table 1. An additional mutation for retinal atrophy in the Abyssinian cat has been discovered,⁴¹ as well as genes conferring fur types, including hairless⁴⁷ and tabby patterns⁴⁸. The discovery of the hypokalemia mutation for Burmese cats reveals that a gene influencing overall potassium levels in cats can also influence blood pressure in humans.³⁸ By considering the breed relationships, genetic health concerns across cat populations can be inferred. Additional DNA mutations have been identified in domestic cats that are not of significant consequence to breeds. These additional mutations are presented in Table 2. These breed specific diseases should be monitored with populations and are available as commercial tests from a wealth of companies and veterinary programs around the world (Table 3). If similar conditions are suspected in cats, the publishing authors will generally consider testing for the known mutation as a non-commercial service and may continue analysis of the entire gene to determine if new mutations can be identified and causative for the conditions.

Many mutations that have been identified in domestic cats and their breeds control the phenotypes that often demarcate a breed and control the aesthetic value of our pets. Knowledge and understanding of the mode of inheritance and the effect of the phenotypic alleles can support cat health in an indirect manner, by population management. If breeders can be counselled on breeding schemes that will produce more of the color and fur type varieties and less that are undesired, less unwanted cats are produced. Less unwanted cats reduces cat overpopulation and the likelihood that individuals representing breeds will be relegated to animal shelters. In addition, if a breeder has more desired cats and less excess cats, more time, energy, and precious funds can be designated to the healthcare. Importantly, the reduction of cattery size inherently reduces stress and stress-associated health issues, such as upper respiratory diseases, urinary tract diseases, and feline infectious peritonitis. Thus, the correct genetic management of a simple coat color trait may indirectly improve the health of the entire cattery.

Several desired genetic mutations are associated with health concerns and are now documented. The mutations for taillessness have been identified.⁴⁹ Continued studies of the breed and other background genetics may now elucidate why some Manx have lameness, constipation, or incontinence as a secondary impact of improper vertebral development. The discovery of the tailless mutation has also revealed that Japanese Bobtail cats do not have mutations in the same gene and that the Pixie-Bob breed has Manx and Japanese Bobtail genetic contributions. Similarly, the genetic mutation for Scottish Fold has been identified but is yet to be published. Once this mutation is revealed, studies to understand the development of osteochondroplasia can be initiated.^50-53 In the future, the association of deafness and white should have similar revelations of the importance of genetic background and modifying genes.^51-53

Genetic testing can provide definitive answers for many health concerns and can predict risk for certain diseases. Personalized medicine is improving human healthcare and is becoming available for the domestic cat. Technology and competition will reduce the costs of genetic testing in cats, making it feasible to perform large batteries of genetic tests and eventually whole genome sequencing. Veterinarians will have more predictive powers for health concerns and will be able to implement proper interventions. As the genetic data becomes more readily available, veterinarians will be providing larger roles in healthcare management of individual cats and their populations. Genetic counselling is becoming a norm in veterinary medicine, bringing together the tests of the individual into consideration with the genetic diversity and health of the entire breed population. As humans continue to live longer and higher quality lives, so too will our furry companion felines.

Table 1. Common commercialized DNA tests for diseases in domestic cats and breeds

‡ Mode of inheritance of the non-wild type variant
§ Long fur variants are more or less common depending on the breed.
Not all transcripts for a given gene may have been discovered or well documented in the cat, mutations presented as interpreted from original publication.

Table 2. Uncommon mutations for inherited domestic cat diseases†

† The presented conditions are not prevalent in breeds or populations but may have been established into research colonies.
‡ Not all transcripts for a given gene may have been discovered or well documented in the cat, mutations presented as interpreted from original publication.
*A variety of mutations have been identified, yet unpublished for porphyrias in domestic cats. Contact PennGen at the University of Pennsylvania for additional information.

Table 3. Domestic cat DNA testing laboratories

† Tests reference to those listed in Table 1. If a laboratory offers only one or two test, those tests are listed. PKD and the HCMs are the most popular cat tests offerings.
‡ PennGen also offers tests for diseases in Table 2 that are not of concern to the cat breeds or cat population in general.

References

1.  Vigne JD. The origins of animal domestication and husbandry: a major change in the history of humanity and the biosphere. C R Biol. 2011;334(3):171–181.

2.  Vigne JD, Briois F, Zazzo A, et al. First wave of cultivators spread to Cyprus at least 10,600 y ago. Proc Nat Acad Sci USA. 2012;109(22):8445–8449.

3.  Vigne JD, Guilaine J, Debue K, Haye L, Gerard P. Early taming of the cat in Cyprus. Science. 2004;304(5668):259.

4.  Malek J. In: The Cat in Ancient Egypt. Philadelphia, PA: University of Pennsylvania; 1993.

5.  Hu Y, Hu S, Wang W, et al. Earliest evidence for commensal processes of cat domestication. Proc Nat Acad Sci USA. 2014;111(1):116–120.

6.  Clutton-Brock J. In: A Natural History of Domesticated Mammals. London, UK: Cambridge University Press, British Museum; 1987.

7.  Driscoll CA, Clutton-Brock J, Kitchener AC, O'Brien SJ. The taming of the cat. Genetic and archaeological findings hint that wildcats became housecats earlier - and in a different place - than previously thought. Sci Am. 2009;300(6):68–75.

8.  Tresset A, Vigne JD. Last hunter-gatherers and first farmers of Europe. C R Biol. 2011;334(3):182–189.

9.  Todd NB. Cats and commerce. Sci Am. 1977;237:100–107.

10. Todd NB. An ecological, behavioral genetic model for the domestication of the cat. Carnivore. 1978;1:52–60.

11. Lipinski MJ, Froenicke L, Baysac KC, et al. The ascent of cat breeds: genetic evaluations of breeds and worldwide random-bred populations. Genomics. 2008;91(1):12–21.

12. Nowell K, Jackson P. Wild Cats Status Survey and Conservation Action Plan. Gland, Switzerland: IUCN; 1996.

13. Driscoll CA, Menotti-Raymond M, Roca AL, et al. The Near Eastern origin of cat domestication. Science. 2007;317(5837):519–523.

14. Grahn RA, Kurushima JD, Billings NC, et al. Feline non-repetitive mitochondrial DNA control region database for forensic evidence. Forensic Sci Int Genet. 2011;5(1):33–42.

15. Menotti-Raymond M, David VA, Pflueger SM, et al. Patterns of molecular genetic variation among cat breeds. Genomics. 2008;91(1):1–11.

16. Kurushima JD, Lipinski MJ, Gandolfi B, et al. Variation of cats under domestication: genetic assignment of domestic cats to breeds and worldwide random-bred populations. Animal Genet. 2013;44(3):311–324.

17. Driscoll CA, Menotti-Raymond M, Nelson G, Goldstein D, O'Brien SJ. Genomic microsatellites as evolutionary chronometers: a test in wild cats. Genome Res. 2002;12(3):414–423.

18. Hasegawa D, Yamato O, Kobayashi M, et al. Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat. J Feline Med Surg. 2007;9(3):232–237.

19. Uddin MM, Hossain MA, Rahman MM, et al. Identification of Bangladeshi domestic cats with GM1 gangliosidosis caused by the c.1448G>C mutation of the feline GLB1 gene: case study. J Vet Med Sci/Japan Soc Vet Sci. 2013;75(3):395–397.

20. Yamato O, Matsunaga S, Takata K, et al. GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats. Vet Rec. 2004;155(23):739–744.

21. Martin-Burriel I, Rodellar C, Canon J, et al. Genetic diversity, structure, and breed relationships in Iberian cattle. J Anim Sci. 2011;89(4):893–906.

22. Filler S, Alhaddad H, Gandolfi B, et al. Selkirk Rex: morphological and genetic characterization of a new cat breed. J Hered. 2012;103(5):727–733.

23. Kehler JS, David VA, Schaffer AA, et al. Four independent mutations in the feline fibroblast growth factor 5 gene determine the long-haired phenotype in domestic cats. J Hered. 2007;98(6):555–566.

24. Gandolfi B, Alhaddad H, Joslin SE, et al. A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats. Sci Rep. 2013;3:2000.

25. Barthez PY, Rivier P, Begon D. Prevalence of polycystic kidney disease in Persian and Persian related cats in France. J Feline Med Surg. 2003;5(6):345–347.

26. Beck C, Lavelle RB. Feline polycystic kidney disease in Persian and other cats: a prospective study using ultrasonography. Aust Vet J. 2001;79(3):181–184.

27. Biller DS, Chew DJ, DiBartola SP. Polycystic kidney disease in a family of Persian cats. J Am Vet Med Assoc. 1990;196(8):1288–1290.

28. Biller DS, DiBartola SP, Eaton KA, Pflueger S, Wellman ML, Radin MJ. Inheritance of polycystic kidney disease in Persian cats. J Hered. 1996;87(1):1–5.

29. Bogdanova N, Dworniczak B, Dragova D, et al. Genetic heterogeneity of polycystic kidney disease in Bulgaria. Hum Genet. 1995;95(6):645–650.

30. Bonazzi M, Volta A, Gnudi G, Bottarelli E, Gazzola M, Bertoni G. Prevalence of the polycystic kidney disease and renal and urinary bladder ultrasonographic abnormalities in Persian and Exotic Shorthair cats in Italy. J Feline Med Surg. 2007;9(5):387–391.

31. Domanjko-Petric A, Cernec D, Cotman M. Polycystic kidney disease: a review and occurrence in Slovenia with comparison between ultrasound and genetic testing. J Feline Med Surg. 2008;10(2):115–119.

32. Eaton KA, Biller DS, DiBartola SP, Radin MJ, Wellman ML. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Vet Pathol. 1997;34(2):117–126.

33. Lyons L, Biller D, Erdman C, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548–2555.

34. Zook BC. Encephalocele and other congenital craniofacial anomalies in Burmese cats. Vet Med/Small Anim Clin. 1983;78:695–701.

35. Noden DM, Evans HE. Inherited homeotic midfacial malformations in Burmese cats. J Craniofac Genet Dev Biol Suppl. 1986;2:249–266.

36. Rusbridge C, Heath S, Gunn-Moore DA, Knowler SP, Johnston N, McFadyen AK. Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases. J Feline Med Surg. 2010;12(6):498–508.

37. Heath S, Rusbridge C, Johnson N, Gunn-Moore D. Orofacial pain syndrome in cats. Vet Rec. 2001;149(21):660.

38. Gandolfi B, Gruffydd-Jones TJ, Malik R, et al. First WNK4-hypokalemia animal model identified by genome-wide association in Burmese cats. PloS One. 2012;7(12):e53173.

39. Rand JS, Bobbermien LM, Hendrikz JK, Copland M. Over representation of Burmese cats with diabetes mellitus. Aust Vet J. 1997;75(6):402–405.

40. O'Leary CA, Duffy DL, Gething MA, McGuckin C, Rand JS. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. New Zeal Vet J. 2013;61(6):354–358.

41. Menotti-Raymond M, Deckman K, David V, Myrkalo J, O'Brien S, Narfström K. Mutation discovered in a feline model of human congenital retinal blinding disease. Invest Ophthalmol Vis Sci. 2010;51(6):2852–2859.

42. Menotti-Raymond M, David VA, Schaffer AA, et al. Mutation in CEP290 discovered for cat model of human retinal degeneration. J Hered. 2007;98(3):211–220.

43. Grahn RA, Grahn JC, Penedo MC, Helps CR, Lyons LA. Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of domestic cats. BMC Vet Res. 2012;8(1):207.

44. Lyons LA. Feline genetics: clinical applications and genetic testing. Top Companion Anim Med. 2010;25(4):203–212.

45. Lyons LA. Genetic testing in domestic cats. Mol Cell Probes. 2012;26(6):224–230.

46. Lyons LA. Genetic testing in domestic cats. In: August JR, ed. Consultations in Feline Medicine. Vol 6. St. Louis, MO: Saunders Elsevier; 2010.

47. Gandolfi B, Outerbridge C, Beresford L, et al. The naked truth: Sphynx and Devon Rex cat breed mutations in KRT71. Mamm Genome. 2010;21(9–10):509–15.

48. Kaelin CB, Xu X, Hong LZ, et al. Specifying and sustaining pigmentation patterns in domestic and wild cats. Science. 2012;337(6101):1536–1541.

49. Buckingham KJ, McMillin MJ, Brassil MM, et al. Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats. Mamm Genome. 2013;24(9–10):400–408.

50. Malik R, Allan G, Howlett C, et al. Osteochondrodysplasia in Scottish fold cats. Aust Vet J. 1999;77(2):85–92.

51. Bamber RC. Correlation between white coat colour, blue eyes, and deafness in cats. J Genet. 1933;27:407–413.

52. Wilson TG, Kane F. Congenital deafness in white cats. Acta Otolaryngol. 1959;50(3–4):269–275; discussion 275–267.

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74. Muldoon LL, Neuwelt EA, Pagel MA, Weiss DL. Characterization of the molecular defect in a feline model for type II GM2-gangliosidosis (Sandhoff disease). Am J Pathol. 1994;144(5):1109–1118.

75. Martin DR, Cox NR, Morrison NE, et al. Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis. Acta Neuropathol. 2005;110(5):443–450.

76. Meurs KM, Norgard MM, Ederer MM, Hendrix KP, Kittleson MD. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics. 2007;90(2):261–264.

77. Lettice LA, Hill AE, Devenney PS, Hill RE. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet. 2008;17(7):978–985.

78. Lyons LA, Biller DS, Erdman CA, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548–2555.

79. Fyfe JC, Menotti-Raymond M, David VA, et al. An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival. Genome Res. 2006;16(9):1084–1090.

80. Owens SL, Downey ME, Pressler BM, Birkenheuer AJ, Chandler DW, Scott-Moncrieff JC. Congenital adrenal hyperplasia associated with mutation in an 11beta-hydroxylase-like gene in a cat. J Vet Intern Med. 2012;26(5):1221–1226.

81. Berg T, Tollersrud OK, Walkley SU, Siegel D, Nilssen O. Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats. Biochem J. 1997;328(Pt 3):863–870.

82. Mazrier H, Van Hoeven M, Wang P, et al. Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease. J Hered. 2003;94(5):363–373.

83. He X, Li CM, Simonaro CM, et al. Identification and characterization of the molecular lesion causing mucopolysaccharidosis type I in cats. Mol Genet Metab. 1999;67(2):106–112.

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Incidence of Heart Disease in the Cat

Many healthy, normal cats have systolic heart murmurs. Echocardiography is the best method to assess cardiac structure and function and determine whether the murmur is related to important underlying disease. Gallop rhythms are not normal and can be detected in 15% of cats with cardiomyopathy.

Heart Disease vs. Heart Failure

Occult cardiomyopathy refers to myocardial disease without a history of failure. Because heart failure is a syndrome and not a disease, there is no single test that reliably identifies the failing heart.

Cardiac Morbidity and Mortality

More than 95% of cardiac morbidity and mortality is caused by cardiomyopathy (myocardial disease). While the majority of affected cats appear to remain asymptomatic for life, the proportion that develops morbidity has not been identified. Diastolic heart failure is the most common cause of heart failure.

Diastolic Dysfunction

This principal pathophysiologic consequence results from a wide range of phenotypically heterogeneous myocardial disorders - most commonly hypertrophy (HCM) and restrictive (RCM) cardiomyopathy.

Diastolic Heart Failure

When alterations in diastolic function lead to increased left ventricular filling pressure and mean left atrial pressure, CHF may result. Diastolic heart failure is present when pulmonary edema occurs in the setting of abnormal diastolic function and relatively normal systolic function. It is the most common condition associated with acute CHF in the cat.

Systolic Dysfunction

This may represent an end-stage consequence of HCM in some cases, while in others it results from infarction, inflammation, or unknown causes. Segmental or global myocardial thinning and/or dysfunction is best detected by echocardiography. Taurine deficiency is now rare.

Test for Discriminating Cardiac vs. Respiratory Cause of Dyspnea

Biomarkers: Echocardiography, the gold standard to assess cardiac structure and function, has limited availability and requires trained personnel. Recent studies have reported high sensitivity and specificity using the cardiac biomarker, NT-proBNP, as an adjunct test to help differentiate cardiac vs. non-cardiac causes of respiratory distress. Moreover, assessment of NT-proBNP concentration in combination with conventional evaluation significantly improves accuracy of this test.

The Role of Genetics and Feline Heart Disease

Feline HCM is inherited in Maine Coon, Sphynx, Ragdoll, Siberian and Norwegian Forest cat breeds, and is suspected in the Persian, American shorthair, and others. Genetic mutation testing for HCM is relatively simple and can utilize DNA obtained from an oral swab to test for mutations found predominantly in the Main Coon cat and Ragdoll cat. The absence of a detectible mutation does not mean that the cat will never develop HCM.

Goals for Managing Heart Disease

The Asymptomatic Cat

There is currently no evidence that treatment of asymptomatic cats prevents disease progression, reduces risk factors, or affects morbidity and mortality. Nevertheless, certain factors appear to increase risk of cardiovascular morbidity.

Potential Cardiovascular Risk Factors

In certain circumstances, abnormalities of myocardial structure or function might promote adverse outcome, thereby providing raison d'être for pharmacologic intervention. The following may warrant therapy, although efficacy remains to be proven.

Myocardial infarction might justify use of ACE inhibitors and/or beta-blockers. Rationale for ACEI therapy is based upon the potential of these agents to favorably influence ventricular remodeling and reduce mortality in people and in experimental animals. Rationale for beta-adrenergic blockers include reduction of infarct size, myocardial oxygen utilization, and reduced mortality.

Tachyarrhythmia. Rapid tachyarrhythmias can reduce cardiac filling, promote ischemia, and result in hemodynamic instability. Sustained tachyarrhythmias are usually associated with myocardial disease with attendant cardiac remodeling (myocyte necrosis, fibrosis, inflammation, and interstitial matrix changes).

Massive left ventricular hypertrophy (severe HCM). Cats with greatly increased left ventricular mass (maximal diastolic septal or left ventricular wall thickness > 8 mm) may be at increased risk for cardiovascular events.

Spontaneous echo contrast ("smoke"). Spontaneous echo contrast is associated with blood stasis. This finding is considered to presage thrombosis and is associated with increased thromboembolic risk. It should therefore warrant antiplatelet drugs (aspirin, Plavix) and perhaps more aggressive therapies.

"Malignant" familial history of sudden death (high-risk genotype). Pedigrees may be identified with a documented heritable pattern of HCM with severe morbidity and mortality (e.g., Maine coon cats, others).

Myocardial failure. In some HCM cats, LV contractility is reduced (e.g., fractional shortening, 23–29%; LV end-systolic dimension, 12–15 mm) from acute or chronic myocardial infarction, myocarditis, and other causes of LV remodeling. Therapies include oral taurine supplementation, ACE inhibitors to counteract neurohormonal activation and reduce remodeling.

Dynamic LV outflow tract obstruction. When HCM is associated with systolic anterior motion (SAM) of the mitral valve, the obstructive form of HCM is present. While this carries increased risk in humans, limited veterinary literature is mixed as to whether it promotes cardiac morbidity.

Arrhythmic right ventricular cardiomyopathy (arrhythmic cardiomyopathy). Cats with advanced structural lesions (e.g., severe RV dilation, ventricular tachycardia) may be at risk for CHF. ACE inhibitors and potentially antiarrhythmics (sotalol) should be considered.

Restrictive LV filling (diastolic dysfunction). Cats who develop restrictive diastolic filling (detected via Doppler echocardiography) are at increased risk of morbidity and death.

Managing Diastolic Heart Failure

Acute CHF (pulmonary edema) treatment goals include cardiac stabilization and rapid resolution of edema. Diuretics with supplemental O₂ represent the cornerstone for emergency management. Intravenous furosemide causes peak diuresis within 15–30 minutes by inhibiting renal sodium tubular reabsorption or its accompanying anions. This reduces vascular volume, decreasing LV filling pressures (i.e., cardiac preload), and pulmonary congestion. Resolution of pulmonary edema may be enhanced by application of transdermal 2% nitroglycerin ointment, ¼ to ½ inch q6h. To reduce nitrate tolerance, alternate 12 h with and 12 h without nitroglycerine therapy. Supplemental oxygen (40–60% O₂-enriched inspired gas) may improve pulmonary gas exchange. Dehydration, azotemia, and hypokalemia result from over-diuresis, so it is important to reduce the dosage or frequency of administration as soon as signs improve.

Chronic CHF. Long-term therapy is individualized to maintain a congestion-free state; prevent arterial thromboembolism; halt, slow, or reverse myocardial dysfunction (theoretically); promote enhanced quality of life; and prolong survival. Treatable and contributory diseases should be identified and managed (e.g., systemic hypertension, hyperthyroidism, and anemia). Therapy for each case must ultimately be individualized.

Furosemide is gradually decreased to the lowest effective dosage. Some cats remain stable on 1–2 mg/kg PO given daily or every other day. The author prefers to combine furosemide with long-term ACE inhibitor therapy (enalapril, 0.5 mg/kg daily) so long as renal function is normal. There is no evidence that beta blockers are effective. Some clinicians may add pimobendan, 0.625–1.25 mg per os q12h, although indications and efficacy for this therapy remain to be demonstrated.

Managing Systolic Heart Failure

Historically, myocardial failure was synonymous with taurine-deficient, reversible, dilated cardiomyopathy. This condition was nearly eliminated in the late 1980s after pet food companies reformulated diets to increase taurine content. Presently, idiopathic dilated is still detected. Many cases present with pulmonary edema or with edema and effusions; hypothermia is common; cardiogenic shock develops in some instances.

Acute management includes administration of dobutamine (2–5 mcg per kilogram per minute constant-rate infusion), judicious furosemide administration (often constant-rate infusion), ACE inhibitor administration (enalapril, benazepril, 0.5 mg/kg q24h), pimobendan (1.25 mg q12h), physical removal of effusion, and generalized supportive measures including supplemental O₂, preserving electrolyte balance and renal function. Supplemental feeding via nasoesophageal tube can help treat protracted anorexia. Chronic management includes reduction of furosemide to the lowest effective dose; adding spironolactone (6.25 mg q24h); ACEI; and pimobendan. Long-term prognosis is guarded.

Recurrent CHF

Diuretic resistance may occur as heart failure progresses, and recurrent CHF is likely to benefit from IV furosemide which has higher bioavailability. A second diuretic (e.g., thiazide - 5 to 10 mg daily or every other day, or spironolactone - 6.25–12.5 mg daily) is reserved for diuretic resistance. It is prudent to assess creatinine, electrolytes and blood pressure routinely.

Thromboembolism

Antiplatelet aggregating therapy may be considered when severe left atrial enlargement is present, when spontaneous echo contrast is evident in the LA or LAV, or when cats have had previous thromboembolic episodes. Aspirin can be administered, 20 mg every three days. Clopidogrel (Plavix) is a new potent antiplatelet agent that has been shown to be superior to aspirin to prevent recurrent thrombosis (1/4 of a 75-mg tab q24h).

Low molecular-weight heparin drugs can be added when cats have thromboembolic complications. Two particular agents, enoxaparin (Lovenox) and dalteparin (Fragmin), have received the most attention. Fragmin (100 U/kg q12–24h SQ) or enoxaparin (1 mg/kg q12h SQ) have been used relatively safely. Administration rates of every 6 to 8 hours are ideal but are generally impractical for long-term administration.

Overall medical management must include evaluation of renal function and electrolytes. Hyperkalemia can occur acutely as a result of reperfusion injury. Continuous ECG monitoring is valuable during the first days of hospitalization to detect arrhythmias and alterations in the P-QRS-T wave related to hyperkalemia. Periodic evaluation of BUN and electrolytes is useful. Abdominal ultrasound examination can sometimes be helpful by identifying the location and extent of thrombosis and detecting renal involvement.

Indicators of a Relatively Favorable Prognosis - Arterial TE

Favorable signs:

1.  Resolution of CHF and/or control of serious arrhythmias

2.  Lack of LA/LV thrombi or spontaneous echo contrast

3.  Reestablished appetite

4.  Relatively normal BUN/creatinine/electrolytes

5.  Return of limb viability

6.  Return of femoral arterial pulses and pink nail beds

7.  Lack of self-mutilation

Indicators of a Grave Prognosis - Arterial TE

Grave prognosis:

1.  Refractory CHF or malignant arrhythmias

2.  Acute hyperkalemia

3.  Declining limb viability; failure of these muscles to soften 48–72 hours after presentation, distal limb necrosis

4.  Multiorgan/multisystemic embolization

5.  History of previous embolic episodes

6.  LA/LV thrombus or spontaneous echo contrast

7.  Rising creatinine

8.  Disseminated intravascular coagulation

9.  Unresponsive hypothermia

10.  Severe LA enlargement

11.  Tachyarrhythmia

Sarcomeric Gene Mutations in Humans with HCM

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterized by myocardial wall thickening (almost always confined to the left ventricle). In humans, HCM is a genetic disease and is usually inherited in an autosomal dominant pattern. The first mutation (in the β-myosin heavy chain gene [β-MHC]) responsible for HCM in humans was identified in 1989, and since then, over 600 mutations in 10 genes that encode for sarcomeric proteins have been identified in human families with HCM.¹ They include the β-myosin heavy chain, α-tropomyosin, cardiac troponins I, C, and T, myosin binding protein C, essential and regulatory light chains, titin, and actin genes. The genes with the most mutations described and the ones that most commonly produce disease are the β-MHC and cardiac myosin binding protein C (MYBPC3) genes, which account for roughly 60% of the mutations identified, and for 60% of HCM cases. It is now known that sarcomeric gene mutations actually cause HCM since several mutations that have been identified in human families with HCM have been placed in transgenic mice and the disease reproduced (at least partially), thus fulfilling Koch's postulates.²

Mutations in the MYBPC3 gene in humans with HCM were first identified in 1995 and it was the fourth causal gene to be identified.³ To date, approximately 200 mutations in MYBPC3 that cause HCM have been identified in humans. Compared with mutations in β-MHC, a larger number of the MYBPC3 mutations are associated with a more benign clinical course (later average age at onset of symptoms and a lower incidence of sudden death). Nonetheless, MYBPC3 mutations are a significant cause of morbidity and mortality for millions of people worldwide. For instance, a single MYBPC3 founder mutation found in people in South Asia (India, Pakistan, Sri Lanka, Indonesia and Malaysia; close to 5% of this population and upwards of 40 million people) makes them up to 7 times more at risk for development of cardiac dysfunction and heart failure than normal individuals. Typically, individuals affected with this mutation are free of HCM through the third decade of life but 90% of older individuals eventually develop cardiac complications.

The majority of MYBPC3 mutations are splice site donor/acceptor or other insertion/deletion mutations that are predicted to lead to reading frame shifts, premature stop codons, and truncated proteins. However, approximately 40% of the mutations in MYBPC3 are due to point mutations (single base pair changes resulting in single amino acid substitutions). When compared to truncation/frame shift/splice variants, point mutations more commonly result in a more benign clinical course although there are those that produce severe disease.

The functional pathophysiology of missense mutations in MYBPC3 is not yet fully known, but potentially they can alter cMyBP-C structure, disrupt cardiac myosin binding C (cMyBP-C) protein function or alter interactions with other proteins.³ Missense mutations could result in so-called haploinsufficiency where one allele is rendered nonfunctional, resulting in only half the protein product being produced, and so in sarcomere dysfunction, as can occur with truncation mutations. Alternatively, a protein that is produced by a mutated gene can be so altered that it is lysed within the cell before it ever is incorporated into a sarcomere. A missense mutation can also just result in a dysfunctional protein that is incorporated into a sarcomere. For example, the N775K mutation in humans allows the C5 domain of the protein to unfold rendering it dysfunctional. In other instances a mutation alters the ability of the protein (cMyBP-C) to interact with other proteins. For example, domains C7 to C10 anchor cMyBP-C to myosin and titin and disruptions of this interaction could impair the function of cMyBP-C. Lastly, missense mutations can result in a dominant-negative effect where an altered protein produced by a mutated gene has a detrimental effect on the normal protein.

The manner by which HCM is produced by sarcomeric mutations is relatively unknown and still controversial. One theory is that the abnormal protein produced by a mutated gene results in dysfunctional sarcomeres through any of the means discussed in the previous paragraph. Those dysfunctional sarcomeres contract poorly and this either forces functional sarcomeres to bear a larger work load (if, for example half of the sarcomeres are rendered dysfunctional) or all of the sarcomeres together can do less work (generate less force; if, for example, all of the sarcomeres are working at 50% capacity). The myocardium then has to compensate by replacing the dysfunctional sarcomeres with additional functional ones or has to add in more dysfunctional sarcomeres to help carry the load. The net result is that the myocardium adds in new sarcomeres within myocytes resulting in the cells growing wider. Because myocytes make up a large part of the heart muscle, the thicker myocytes result in the wall of the left ventricle increasing in thickness.

Familial Feline HCM

The first "family" of cats with an inherited form of HCM was identified in a research colony of Maine coon cats in 1992 and first reported in 1999.⁴ The disease appeared to be inherited as a simple autosomal dominant trait in this breed with 100% penetrance (all cats affected with HCM). However, this colony was particularly inbred and, so, genetic modifying factors were probably uniform and a number of cats were probably homozygous for the subsequently identified mutation. In Maine coon cats in the real world, it is now known that the disease is not 100% penetrant. Two lines of evidence support this. First, it is known that when an affected cat is identified (proband) that it is possible that neither parent may have echocardiographic evidence of the disease. Secondly, Maine Coon cats screened for the identified mutation and for HCM often have the mutation but no HCM, especially when the screening clinic includes only young cats.

The disease has been reproduced in Maine coon cats in the original research colony by mating affected to unaffected and affected to affected cats as well as by breeding affected Maine coon male cats to domestic shorthair female cats. The fact that HCM can be produced in offspring from mating a Maine Coon cat with HCM to a normal domestic shorthair cat proves that the disease is inherited as an autosomal dominant trait. The course of the disease can be accelerated by mating affected to affected cats, probably because cats that are homozygous for the mutation are produced. Penetrance is age related and the disease is progressive over months to years. In many affected Maine coon cats in the research colony, HCM is not apparent during the first year of life but becomes apparent by 2 years of age in males. Females tend to get the disease later, with many manifesting the disease by 3–4 years of age but some not showing evidence of HCM until 6 or 7 years of age and, others not until 10 and 13 years of age (most recently identified in two cats with the identified mutation in the research colony). When both parents have HCM, an affected Maine coon kitten may have echocardiographic evidence of the disease as early as 6 months of age and have severe disease by one year of age, whether male or female. Again, these are assumed to be cats that are homozygous for the subsequently identified mutation.

In 2005, Dr. Kate Meurs identified the first gene mutation responsible for HCM in Maine Coon cats from our research colony.⁵ This mutation is in exon 3 of MYBPC3. The exact location is codon 31 of the gene where a single point base pair (missense) mutation changes alanine to proline in the encoded protein (A31P). This region of the gene is highly conserved across species and the resultant amino acid change results in a change in the computed protein structure. Several studies have now shown that this mutation is only found in Maine Coon cats (not in other purebred cats). Prevalence of the mutation across continents is generally in the 30–40% range (highly prevalent).

In 2007, a mutation in the same gene (MYBPC3) was identified in Ragdoll cats with HCM (R820W).⁶ This mutation is at a completely different location on the gene, but it again occurs in a highly conserved region. Ragdoll cats have long been known to have a particularly malignant form of the disease where they often die before reaching one year of age.

Several studies have now been done to look at the penetrance of the A31P mutation in Maine Coon cats (to determine what percent of cats with the mutation have HCM). To date, these have all been done as part of echocardiographic clinics to screen for HCM. Unfortunately, this type of study is inherently biased since the cats being screened are chosen by the breeder, not the investigator. This has resulted in populations of younger and female-predominant cats.

The first study looked at a group of Maine Coon cats during a screening clinic and correlated the genetic findings with echocardiographic findings.⁷ The investigators found that many Maine Coon cats with the A31P mutation did not have echocardiographic evidence of HCM, and a few cats without the A31P mutation had HCM. The veiled conclusion by the authors was that the A31P mutation might not be causal and that genetic testing for the mutation in this breed may not be warranted. However, what was shown instead is that the penetrance of this mutation is relatively low, at least in young cats, which is not surprising since most MYBPC3 mutations in humans have a low and an age-related penetrance. They also showed that there appears to be at least one more cause of HCM in this breed. This has been apparent in the colony at UC Davis for a number of years.

Another study made observations on the echocardiographic appearance of hearts from Maine coon cats with the A31P MYBPC3 mutation.⁸ In this study, echocardiography was performed on 96 Maine coon cats presented for screening for HCM. Both two-dimensional and tissue Doppler imaging echocardiography were performed. Cats had to have an LV wall thickness greater than 6 mm to make the diagnosis of HCM. Of the 96 cats, 44 of the cats had the A31P mutation (38 were heterozygous and 6 were homozygous). Unfortunately, 45 of the 96 cats were less than 2 years of age and so too young to have evidence of HCM if they were heterozygous. These young cats probably should have been excluded from analysis if they were heterozygous. Of the 38 heterozygous cats, four had clear evidence of at least moderate HCM. However, only 10 of the 34 heterozygous cats that did not have HCM were over 4 years of age. Of the 44 cats that had the mutation, 13 were male and 31 were female. This produced an additional bias, since female Maine coon cats get HCM at a later age and get less severe disease. Still, this study clearly suggests that the A31P mutation is not nearly 100% penetrant in Maine coon cats when a cat is heterozygous for the mutation (11% in this study). As expected, homozygous cats appear to be a different story. Of the 6 cats that were homozygous for the A31P MYBPC3 mutation in this same study, 4 had clear echocardiographic evidence of HCM and the other two had abnormal diastolic function as assessed by TDI, an abnormality previously shown to be present in cats that go on to develop HCM. Consequently, it appears that all 6 of these cats had HCM, which once again proves the mutation to be causal. Two cats in this study without the known mutation also had HCM. This once again documents that there is at least one more cause of HCM in Maine coon cats. Lastly, some of the cats heterozygous for the A31P mutation had evidence of regional diastolic dysfunction, showing that their myocardium was not normal even when they had no evidence of hypertrophy.

The most recent study into this subject looked at 332 cats.⁹ They similarly showed that penetrance for Maine Coon cats heterozygous for the mutation is low (6%), that most but not all cats homozygous for the mutation get HCM (penetrance is high) and that most of the Maine Coon cats that get severe HCM prior to 6 years of age do so because they are homozygous for the mutation. The prevalence of HCM was 6%. Eighteen cats were homozygous and 89 cats were heterozygous for the mutation. The odds ratio for having HCM for homozygous cats was 21.6 (95% confidence interval 7–66). Overall, 50% of the cats that were homozygous for the mutation had HCM. Only two cats over four years were homozygous and both had HCM.

The previously referenced studies have only made a preliminary attempt to look at penetrance of the A31P mutation in Maine coon cats that are heterozygous for the A31P mutation. What really needs to be done is a longitudinal study looking at the same mutated cats until they are at least 10 years of age to tell what the true penetrance is for heterozygous cats rather than looking at a group of cats once at one point in time.

We are currently examining the cellular effects of this mutation and have preliminary evidence to show clear abnormalities produced by this mutation (e.g., myocardium from cats homozygous for the A31P mutation has no myosin binding protein C). Our preliminary findings clearly show that the A31P mutation causes intracellular derangement. It has also been shown that the mutated protein in cats with the A31P mutation is incorporated into the sarcomere, even in cats homozygous for the mutation.³ This means the mutation does not result in haploinsufficiency.

There are currently several labs that test for the A31P MYBPC3 mutation in Maine Coon cats (one in the USA and at least two in Europe). This service has been set up so that breeders can try to rid their breed of this mutation and the HCM caused by this mutation. Many breeders have been reluctant to do testing and even more reluctant not to breed mutated cats. To be fair, the method of dealing with this problem is controversial (discussed below). In Dr. Meurs' lab, approximately 35% of the DNA samples submitted have had the mutation.¹⁰

Concern has been expressed about what would happen if all of these cats were removed from the breeding pool. The concern has to do with decreasing the size of the gene pool and so producing more recessive traits in this breed. In other words, if 35% of the cats could no longer be bred, the remaining cats would have to make up the breeding pool and by shrinking that pool, the breed may be worse off because of increased inbreeding. The author's counter to that argument is as follows. Breeders commonly only use around 10% of cats in a purebred population for breeding. That means they already exclude 90% of cats from being bred. So if we recommend that they don't breed any cat with a mutation, it means we're recommending that they not use 35% of 10% or 3.5% of the entire population. Yes, that does mean that 35% of the cats they would normally breed (the good-looking 10%) would be no longer eligible for breeding. But it also means that they could still use the 65% of the cats they normally don't breed (the less than good-looking 90%) to breed. What would they sacrifice? Maybe their breed wouldn't be quite as visually attractive as before - but it also might be healthier without the mutation. Of course, getting breeders to breed cats they don't think look quite as good as some others is probably an impossible task. So one recommendation has been made that if a cat is heterozygous for the A31P mutation and it is very good looking, it can be bred once. Its kittens then should be tested for the mutation and only those without should be bred. The question then comes, what do you do with the mutant kittens that have been produced in this process? And this recommendation was first made 3 years ago, meaning breeders have had plenty of time to do this and should no longer be relying on this method.

Lastly, it should be mentioned that the Ragdoll mutation (R820W) has also now been identified in humans. In humans, it also produces HCM but can also produce left ventricular noncompaction in some individuals. Another mutational variant affecting the same codon (R820Q) also produces HCM and one that progresses to the so-called burnout phase (i.e., DCM) more frequently. The A31P mutation has not been identified in humans.

References

1.  Tian T, Liu Y, Zhou X, Song L. Progress in the molecular genetics of hypertrophic cardiomyopathy: a mini-review. Gerontology. 2013;59(3):199–205.

2.  Bonne G, Carrier L, Bercovici J, Cruaud C, Richard P, Hainque B, et al. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet. 1995;11:438–440.

3.  Harris SP, Lyons RG, Bezold KL. In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament. Circ Res. 2011;108(6):751–764.

4.  Kittleson MD, Meurs KM, Munro MJ, Kittleson JA, Liu SK, Pion PD, et al. Familial hypertrophic cardiomyopathy in Maine Coon cats: an animal model of human disease. Circulation. 1999;99:3172–3180.

5.  Meurs KM, Sanchez X, David RM, Bowles NE, Towbin JA, Reiser PJ, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet. 2005;14:3587–3593.

6.  Meurs KM, Norgard MM, Ederer MM, Hendrix KP, Kittleson MD. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics. 2007;90:261–264.

7.  Wess G, Schinner C, Weber K, Hartmann K. Genetic Association of the A31P and A74T polymorphism in the MYBPC3 gene and hypertrophic cardiomyopathy in Maine Coon Cats. J Vet Intern Med. 2008;22:717.

8.  Carlos Sampedrano C, Chetboul V, Mary J, Tissier R, Abitbol M, Serres F, et al. Prospective echocardiographic and tissue Doppler imaging screening of a population of Maine Coon Cats Tested for the A31P mutation in the myosin-binding protein C gene: a specific analysis of the heterozygous status. J Vet Intern Med. 2009;23:91–99.

9.  Godiksen MT, Granstrom S, Koch J, Christiansen M. Hypertrophic cardiomyopathy in young Maine Coon cats caused by the p.A31P cMyBP-C mutation - the clinical significance of having the mutation. Acta Vet Scand. 2011;53:7.

10. Fries R, Heaney AM, Meurs KM. Prevalence of the myosin-binding protein C mutation in Maine Coon cats. J Vet Intern Med. 2008;22:893–896.

Genetic Counselling in Veterinary Medicine

Once a DNA test is obtained on a cat, this is where the story and the communications should begin. The client and the veterinarian need to recognize that the current DNA tests for cats do not predict severity of disease. In the case of polycystic kidney disease (PKD), many cats can have mild presentations of cysts throughout their lives, never succumbing to renal failure, and dying of other causes. However, some cats develop end-stage renal disease within a few years and have an early death. A second example is hypertrophic cardiomyopathy (HCM) in Maine Coon cats.⁶⁰ The genetic mutation is known, it clearly confers risk - but the extent of the risk is nebulous.⁶¹ Thus, genetic tests should be used as a tool for the veterinarian and the owner, supporting the overall picture of a given cat's healthcare. In the case of PKD, ultrasound and/or creatinine levels should be used to monitor disease progression in PKD positive cats. Ultrasound monitoring remains the standard for HCM testing, although early detection biomarkers are being explored. DNA never replaces, but should always enhance, interactions between the client and the veterinarian.

Veterinarians are expected to obtain, understand, and interpret DNA results and provide this "genetic counselling." However, since a majority of the cat population and cliental does not represent fancy breed cats, breeders are not generally the largest portion of clients in a standard veterinary practice and genetic testing in random bred cats is minimal. But what pertains to cats, certainly pertains to dogs, and the use of genetics for "marker-assisted selection" on the farm is also becoming a standard practice. Genetic testing for marbling of meat, milk fat, and milk production and even "speed" for horse racing are genetic tests currently on the market to be considered by the farmer. Farmers have considered genetics regarding their crop seed selection for decades, now it also pertains to their livestock and companion animal farm workers - the cat and dog.

For the past 10–15 years, many veterinarians have received formal training in genetics within their veterinary curriculum in the USA. Minimally, different modes of inheritance are reviewed and younger veterinarians should be able to provide minimal genetic counselling as a result. The mode of inheritance, (autosomal versus sex-linked, recessive, dominant) incomplete penetrance, variable expression, age of onset, and risk are terms the modern veterinarian should know and understand. Directed versus non-directed counselling is also a concept that should be considered. Most veterinarians want to provide "directed" counselling - your cat has PKD - then you should alter it and never breed the cat again. Directed counselling is extremely taboo in human medicine, and if the "big picture" is considered in veterinary medicine, directed counselling should also be very non-standard in animal genetic counselling as well. The "big picture" not only pertains to the cat itself, but the breed population and the livelihood of the breeder. As determined by sequencing of thousands of humans, each individual, human or cat, has several severe mutations in their genome that should render them unfit! We yet do not understand how all the ~ 21,000 genes of the body interact, thus, explaining terms like "incomplete penetrance" and "variable expression." Cats have a PKD or HCM mutation - definitely - but we cannot predict their overall health because of the interaction of thousands of other genes in the body, which are designed to be redundant and maintain our fitness. Thus, in genetic counselling, one should consider all the good things as well as the bad things that a cat has to determine future breeding and population management. Certainly the present health condition of the cat should be the utmost concern; however, this cat's nature, reproductive success, resistance to other health problems, as well as their aesthetic qualities need to be considered. By understanding the mode of inheritance, diseases can be slowly removed from populations, importantly to not cause other bottlenecks and other inbreeding concerns.

References

60. Meurs KM, Sanchez X, David RM, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet. 2005;14(23):3587–3593.

61. Longeri M, Ferrari P, Knafelz P, et al. Myosin-binding protein C DNA variants in domestic cats (A31P, A74T, R820W) and their association with hypertrophic cardiomyopathy. J Vet Intern Med. 2013;27(2):275–285.

Treatment of Cats With No Clinical Signs (Nothing Works)

There currently is no evidence that any drug alters the natural history of HCM in cats until they are in heart failure. Diltiazem, atenolol, and ACE inhibitors are commonly administered to cats with mild to severe HCM that are not in heart failure on an empirical basis. Studies by the author have shown that ramipril, an ACE inhibitor, and spironolactone have no beneficial effects on HCM prior to the onset of heart failure (do not work),¹ resulting in left ventricular (LV(2)"container-title":"J Vet Intern Med,""page":"335-41,""volume":"22,""archive_ cation":"18346145,""abstract":"BACKGROUND: Myocardial fibrosis occurs in cats with hypertrophic cardiomyopathy (HCM In addition, spironolactone produced severe skin lesions in some cats. Atenolol does not decrease circulating NT-proBNP or troponin in cats with HCM prior to the onset of heart failure.³ In a recent study, atenolol also did not prolong survival in cats with preclinical HCM when compared to cats that were not on atenolol.⁴

Treatment of Cats in Heart Failure Due to HCM (Some Things Work)

Cats that present in heart failure primarily have clinical signs referable to pulmonary edema and/or pleural effusion. Consequently, therapy is generally aimed at decreasing left atrial and pulmonary venous pressures in these cats and physically removing the effusion. In some cats with severe heart failure, clinical evidence of hypoperfusion (low-output heart failure) may also be apparent. The signs may be manifested primarily as cold extremities. Pulmonary edema is primarily treated with diuretics (almost exclusively with furosemide) acutely and chronically and an ACE enzyme inhibitor chronically, although recent evidence suggests that ACE inhibition may not be that helpful in prolonging survival in cats with HCM. Diltiazem and beta adrenergic blockers, usually atenolol, have been commonly used as adjunctive agents. Recent evidence suggests that diltiazem is not helpful in prolonging survival in cats with heart failure due to severe HCM and that atenolol may actually shorten survival time. Pleurocentesis is most effective for treating cats with severe pleural effusion. However, furosemide is often helpful at slowing effusion re-accumulation.

Acute Therapy

Cats that present with respiratory distress suspected of having heart failure secondary to HCM need to be placed in an oxygen enriched environment. If possible, the cat should be initially evaluated by doing a cursory physical examination, taking care not to stress the patient during this or any other procedure, since stress exacerbates dyspnea and arrhythmias and often leads to death. Most, but not all, cats with severe HCM that are in heart failure will have a heart murmur, and many will have a gallop sound (gallop rhythm). A butterfly catheter should be used to perform thoracentesis on both sides of the chest to look for pleural effusion as soon as possible. Generally, this should be done with the cat in a sternal position so that it does not become stressed during the procedure. Clipping of the hair is not needed. If fluid is identified, it should be removed. If none is identified, a lateral thoracic radiograph to identify pulmonary edema may be taken with the veterinarian present to ensure that the cat is not stressed.

Furosemide (Works)

Furosemide should initially be administered IV or IM to the cat in severe respiratory distress. Cats that can tolerate an intravenous injection may benefit from the more rapid onset of action (within 5 minutes of an IV injection vs. 30 minutes for an IM injection). The initial furosemide dose to a cat in distress should generally be in the 2 to 4 mg/kg range IM or IV. This dose may be repeated within 1 hour to 2 h. Dosing must be reduced sharply once the respiratory rate starts to decrease to avoid severe dehydration.

High-dose parenteral furosemide therapy commonly produces electrolyte disturbances and dehydration in cats. Cats with severe heart failure that require intensive therapy are often precarious. They may be presented dehydrated and electrolyte-depleted because of anorexia. They may remain anorexic, and consequently dehydrated and depleted of electrolytes once the edema and/or the effusion are lessened. Judicious intravenous or subcutaneous fluid administration may be required to improve these cats clinically. Overzealous fluid administration will result in the return of CHF. If fluid administration is required, the furosemide administration must be discontinued for that time.

Nitroglycerin (Probably Does Not Work)

Nitroglycerin cream may be beneficial in cats with severe edema formation secondary to feline cardiomyopathy. However, no studies have examined any effects of this drug in this species and its efficacy is suspect. Nitroglycerin is certainly safe and some benefit may occur with its administration in some cats. Consequently, 1/8" to 1/4" of a 2% cream may be administered to the inside of an ear every 4 to 6 h for the first 24 h as long as furosemide is being administered concomitantly. One should never rely on nitroglycerin to produce a beneficial effect. Nitroglycerin tolerance develops rapidly in other species and probably does so in the cat. Consequently, prolonged administration is probably of even lesser benefit.

Once drug administration is complete, the cat should be left to rest quietly in an oxygen enriched environment. Care should be taken not to distress the cat. A baseline measurement of the respiratory rate and assessment of respiratory character should be taken when the cat is resting. This should be followed at 30-minute intervals and furosemide administration continued until the respiratory rate starts to decrease (a consistent decrease of the respiratory rate from 70 to 90 breaths/minute into the 50 to 60 breaths/minute range is a general guide) and/or the character of the cat's respiratory effort improves. When this occurs, the furosemide dose and dosage frequency should be curtailed sharply.

Sedation or Anesthesia

In some cats, sedation with acepromazine (0.04 to 0.1 mg/kg subQ) may help by producing anxiolysis. Oxymorphone (0.04 to 0.1 mg/kg q6h IM, IV, or subQ) or butorphanol tartrate (0.08 mg/kg IV or 0.36 mg/kg q4h subQ) may be used but are secondary choices, because they can produce respiratory depression.

In some cats with fulminant heart failure, anesthesia, intubation, and ventilation are required to control the respiratory failure. This can be lifesaving in some cats.

Chronic Therapy

Many aspects of chronic therapy of HCM are controversial. All therapy is palliative and ultimately futile in most cases. Furosemide is the only drug that has a clearly beneficial effect chronically on survival in cats with HCM.

Pleurocentesis (Works)

Many cats with HCM are dyspneic because of pleural effusion that reaccumulates despite appropriate medical therapy. These cats need periodic pleurocentesis as outlined above in the section on DCM.

Furosemide (Works)

In cats with CHF due to HCM, furosemide administration, once initiated, should usually be maintained for the rest of the cat's life. In a few cases, furosemide can be discontinued gradually once the cat has been stabilized. This usually only occurs in a cat that has had a precipitating stressful event.

As for DCM, the maintenance dose of furosemide in cats usually ranges from 6.25 once a day to 12.5 mg PO q8h, although the dose may be increased further if the cat is not responding to a conventional dose. We have administered higher doses (up to 37.5 mg q12h) than commonly recommended to a few cats with severe heart failure without identifying severe consequences, as long as the cats were eating and drinking. Cats on high-dose furosemide therapy are commonly mildly dehydrated and mildly to moderately azotemic. However, they often continue to maintain a reasonable quality of life.

The furosemide dose needs to be titrated carefully in each patient. The owner should be taught how to count the resting respiratory rate at home and instructed to keep a daily written log of the respiratory rate as outlined above under DCM. This is highly beneficial for making decisions regarding dosage adjustment in individual patients.

ACE Inhibitors (May Be of Some Benefit)

The use of ACE inhibitors in cats with HCM is relatively recent because veterinarians shared the fears of their human medical counterparts that they might worsen SAM. Over the past 10 years, it has become obvious to veterinary cardiologists that ACE inhibitors do not worsen the clinical signs referable to HCM. Many have believed and one study has suggested that ACE inhibitors improve the quality and quantity of life of cats with HCM. Evidence from an unpublished placebo-controlled and blinded clinical trial suggests that enalapril produces little to no benefit when compared to furosemide alone in cats with heart failure due to HCM. However, this study also included cats with unclassified (restrictive) cardiomyopathy and both cats with and without SAM. Subgroup analysis failed to change the conclusions of the study but the subgroups were small. Consequently, this author recommends we continue to use an ACE inhibitor in cats in heart failure due to HCM at a dose of 1.25 to 2.5 mg PO q24h.

Diltiazem (Questionable Efficacy)

In cats with severe HCM that have or have had evidence of CHF, diltiazem or a beta adrenergic blocking agent are often administered. Both provide symptomatic benefit in human patients. Their utility in cats with HCM is controversial, although there is little doubt that neither drug produces dramatic benefits. Diltiazem, however, appears to produce no harm. Diltiazem is a calcium channel blocker previously reported to produce beneficial effects in cats with HCM when dosed at 7.5 mg q8h.⁵ Beneficial effects that have been reported include lessened edema formation and decreased wall thickness in some cats. In the author's experience, only a few cats appear to experience a clinically significant decrease in wall thickness, and it is impossible to tell if this is due to drug effect or time. Rarely does it appear clinically that diltiazem controls CHF on its own or helps control pulmonary edema or pleural effusion when added on to furosemide therapy. Diltiazem does improve the early diastolic relaxation abnormalities seen in feline HCM. Whether this helps decrease diastolic intraventricular pressure and so decrease edema formation is unknown. Theoretically it should have little benefit in the resting cat with a slow heart rate. Slower myocardial relaxation during rapid heart rates may not allow the myocardium enough time to relax, resulting in increased diastolic intraventricular pressure. Consequently, diltiazem may help protect a cat that undergoes a stressful event. Incomplete relaxation and decreased compliance, however, are more plausible explanations for increased diastolic pressure due to diastolic dysfunction in feline HCM. In humans, diltiazem does not change left ventricular chamber stiffness and so does not alter passive diastolic function. Diltiazem decreases SAM, but beta blockers generally produce a greater decrease in the amount of SAM. Recent evidence suggests that diltiazem has no effect on survival time in cats with severe HCM and heart failure. Consequently, there currently appears to be no ethical mandate for its use in cats with heart failure due to HCM and it would appear that many veterinary cardiologists have abandoned its use.

In addition to its regular formulation (30-mg tablets in the USA), diltiazem is supplied as slow-release (long-acting) products. Cardizem CD is supplied as 180-mg capsules that contain hundreds of small capsules. The larger capsule can be opened and a number of the smaller capsules divided into groups of four (45 mg each) and placed in smaller gelatin capsules for administration. One capsule is then administered q24h. Dilacor XR capsules can be opened to yield 2, 3, or 4 60-mg tablets. This drug is dosed at 30 mg per cat PO q12h and produces a significant decrease in heart rate and blood pressure in cats with HCM for 12 to 14 h.

Beta-Adrenergic Receptor Blockers (Work to Reduce SAM)

Beta blockers are primarily used to reduce SAM and heart rate in cats with HCM. However, at this stage beta blockers should probably be reserved for cats with severe SAM at rest or with tachyarrhythmias and not routinely administered to the affected population as a whole, since a recent study has suggested that atenolol shortens the survival of cats with diastolic dysfunction, including cats with HCM. Beta blockade is questionable for SAM and tachycardia observed in a clinical situation anyway. Cats spend 85% of their life asleep, and sleep probably reduces sympathetic activity better than a beta-adrenergic blocking drug. Consequently, many cats with mild to moderate SAM in a veterinary clinic probably have no or milder SAM at home and the same can be said for tachycardia. Beta blockers are effective for reducing SAM. Two unpublished studies have examined the effects of esmolol, a short-acting β₁-adrenergic blocking drug, in cats with HCM and obstruction to left ventricular outflow due to SAM and shown a reduction in the pressure gradient across the outflow tract. In both studies, the degree of outflow tract obstruction decreased and the heart rate slowed and in one esmolol was more effective than diltiazem.

Atenolol is a specific β₁-adrenergic blocking drug that needs to be administered twice a day, usually at a total dose of 6.25 to 12.5 mg PO q12h.⁶ "container-title":"Am J Vet Res,""page":"1050-3,""volume":"57,""source":"NLM,""archive_ location":"8807020,""abstract":"OBJECTIVES: To determine the pharmacokinetics of atenolol (AT

In cats, atenolol has a half-life of 3.5 h. When administered to cats at a dose of 3 mg/kg, atenolol attenuates the increase in heart rate produced by isoproterenol for 12, but not for 24, h.

Pimobendan

In theory, pimobendan, due its potent positive inotropic effects in other species, should be contraindicated in cats with HCM. One retrospective study, however, used pimobendan in 68 cats with HCM and recorded no untoward effects.⁷ However, in another study, pimobendan to a cat with systolic anterior motion of the mitral valve resulted in hypotension.⁸

A survey of veterinary cardiologists/residents regarding their use of pimobendan in cats with cardiomyopathy was recently performed by the author. Results show:

1.  Most do not use PB in cats with HCM unless they have myocardial dysfunction or are refractory to conventional heart failure therapy.

2.  In cats with HCM refractory to conventional heart failure therapy, around 50% use it only if SAM is not present and 50% use it regardless of whether it's present or not.

3.  Almost all use pimobendan in cats with HCM and myocardial failure, DCM, and UCM/RCM when the cat is in heart failure.

4.  In cats with HCM, around 50 to 60% think more than 50% of cats have a clinical response to pimobendan.

5.  (VIN editor: Step 5 was missing from the original text.)

6.  Approximately half had the impression that cats with HCM and DCM lived longer. Only around one-third thought cats with UCM/RCM lived longer.

7.  Most use a dose of 0.25 to 0.3 mg/kg BID.

References

1.  MacDonald KA, Kittleson MD, Larson RF, Kass P, Klose T, Wisner ER. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in Maine Coon cats with familial hypertrophic cardiomyopathy without heart failure. J Vet Intern Med. 2006;20:1093–1105.

2.  MacDonald KA, Kittleson MD, Kass PH, White SD. Effect of spironolactone on diastolic function and left ventricular mass in Maine Coon cats with familial hypertrophic cardiomyopathy. J Vet Intern Med. 2008;22:335–341.

3.  Jung SW, Kittleson MD. The effect of atenolol on NT-proBNP and troponin in asymptomatic cats with severe left ventricular hypertrophy because of hypertrophic cardiomyopathy: a pilot study. J Vet Intern Med. 2011;25:1044–1049.

4.  Schober KE, Zientek J, Li X, Fuentes VL, Bonagura JD. Effect of treatment with atenolol on 5-year survival in cats with preclinical (asymptomatic) hypertrophic cardiomyopathy. J Vet Cardiol. 2013;15(2):93–104.

5.  Bright JM, Golden AL, Gompf RE, Walker MA, Toal RL. Evaluation of the calcium channel-blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Intern Med. 1991;5:272–282.

6.  Quinones M, Dyer DC, Ware WA, Mehvar R. Pharmacokinetics of atenolol in clinically normal cats. Am J Vet Res. 1996;57:1050–1053.

7.  Macgregor JM, Rush JE, Laste NJ, Malakoff RL, Cunningham SM, Aronow N, et al. Use of pimobendan in 170 cats (2006–2010). J Vet Cardiol. 2011;13:251–260.

8.  Gordon SG, Saunders AB, Roland RM, Winter RL, Drourr L, Achen SE, et al. Effect of oral administration of pimobendan in cats with heart failure. J Am Vet Med Assoc. 2012;241:89–94.