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Platform for diagnosing long QT syndrome in horses - Step II: Identification of long QT syndrome

Periodic Reporting for period 1 - LQTS-HORSES (Platform for diagnosing long QT syndrome in horses - Step II: Identification of long QT syndrome)

Reporting period: 2015-10-01 to 2017-09-30

Recently sudden cardiac death (SCD) during exercise has received a lot of attention and has resulted in pre-participation screenings of human athletes in several countries. Among the reported diseases the screenings have also identified inherited rhythm disturbances as cause for cardiovascular incidences in at least 9% of the cases. Sudden death during exercise occurs also in horses, and 20-68% of such cases do not have structural lesions sufficient to account for death on necropsy and a cardiac origin is hypothesized.
Sudden deaths occurring during public events have a highly negative impact on the public perception about high performance sports, both in humans and in horses, and raise concerns about animal welfare especially in the racing industry. This bad publicity might affect the economy of the racing industry, an important economic factor for many European areas. Moreover, rider safety is also important in other equine disciplines and in leisure activities.
The inherited disturbances in the cardiac rhythm can be caused by mutations in ion channel encoding genes, resulting in altered expression of the channels or changes in their ability to conduct ions across the cell membrane. Drugs can also affect ion channel function. Several drugs have been withdrawn from the human drug market because of cardiac side effects and new drugs are tested for interactions with cardiac ion channels before release. But numerous drugs known in human medicine to induced cardiac arrhythmia are still widely used in veterinary medicine.
One of the known syndromes that is linked to an altered function of cardiac ion channels is the Long QT syndrome (LQTS). On the ECG it is recognized by an increased duration of the time interval between two deflections, namely the Q and T wave. Our objectives were to investigate whether LQTS exists in horses and whether this syndrome can explain some of the cases of SCD in horse.
In conclusion, we have found that the ion channels that account for approx. 80% of the LQTS cases in humans are functionally important for repolarisation in equine hearts, and we have verified that at least one equine drug results in a significant prolongation of the QT interval, suggesting that acquired LQTS exists in horses. But further investigations will have to show whether a prolonged QT interval in horses is associated with an increased risk of cardiac arrhythmia as in humans. But, our study raises the question about safety pharmacology in veterinarian medicine. Finally, our results suggest that there is a hereditary component of SCD in horses and that it is important to identify if certain genes can be linked to SCD. Overall, the impact of the project will increase animal welfare and rider safety, but also initiates studies on SCD, drug safety and on cardiac electrophysiology.
1) Acquired LQTS: we tested in vitro the effect of 3 commonly used drugs in equine medicine that where suspected to induce LQTS based on knowledge from human medicine and from case reports in horses. The drugs were Trimethoprim and Sulfadiazine, used as large spectrum antimicrobials, and Detomidine, a sedative agent. We expressed the equine K+ channel, Kv11.1 in Xenopus laevis oocytes and measured the currents by two-electrode voltage-clamp in presence and absence of the drugs. Only Trimethoprim showed an effect and reduced the initial current by 40%. We also developed series of voltage protocols that address the different gating parameters of the Kv11.1 current. In an in vivo experiment the 3 drugs were administered alone or in combination to healthy horses. Contrary to expectation Detomidine induced a significant prolongation of the QT intervals, whereas no effect was seen with the other drugs. We documented the possibility to induce an acquired LQTS in horses. However, the discrepancy between the in vitro and the in vivo experiments indicates that other ion channels than Kv11.1 might be involved in inducing the measured effect.

2) Inherited LQTS: we analysed the ECGs and the pedigree of a family of race horses. In 1 member of the family a significant prolongation of the QT intervals at rest was observed. During exercise the horse showed normal QT intervals and no signs of cardiovascular compromises. The analyses of ECGs at rest and during exercise form 1 relative and 1 brother revealed QT intervals in the upper range of normal QT intervals for horses. Blood samples were collected and will be analysed for genetic polymorphism. This is justified as many variants in K+ channel genes have been described in humans but not all have the same impact on surface ECG and on the probability to induce arrhythmias. This is the first description of a naturally occurring LQTS in horses. The family analysis suggests that in horses inherited LQTS is a polygenetic condition or has incomplete penetrance.

3) Genetic background of SCD: we analysed pedigree data from 26 horses with SCD. The group showed a higher inbreeding factor in comparison to the whole pedigree of the breed. This analysis together with the result from the previous family analysis is a strong indication for a genetic background of SCD and towards a possible inherited form of LQTS, as known form human athletes.

4) Exploitation and dissemination: Results have been disseminated through 5 international congresses and through 4 publications. They were presented to a large audience through participation at The Danish Research Festival in 2016 and 2017 and through a film portrait realised by the Office of Research & Innovation at the University of Copenhagen. Finally, the project strengthened the collaboration with our industrial partner and allowed to participate in the FAANG network (Functional Annotation of Animal Genomes-A coordinated international action to accelerate genome to phenome) promoting generation and dissemination of genetic knowledge on horses.
"The description of an acquired LQTS in horses will influence veterinary medicine as it should now be considered as differential diagnosis in cases of cardiovascular side effects during drug administration. It was also the starting point for screening other relevant drugs in equine medicine for interaction with Kv11.1 in collaboration with our industrial partner. Ideally the results from our project will be extended to other companion animals and will start a discussion about systematic screening for cardiovascular side effects related to interaction with Kv11.1 in veterinary medicine.
The results related to the inherited LQTS impact on the equine industry. The awareness for SCD and LQTS as differential diagnosis for SCD during exercise has been increased. In several countries the need for official registers and systematic investigations for SCD in horses during sport events are discussed and will hopefully been implemented.
Beyond veterinary science the results generated from the collaboration with the FAANG network will increase the amount of available genetic data for horses. Further, by identifying all ion channels expressed in the equine heart we will gain knowledge about basic electrophysiology of the equine heart and might be able to explain some of the physiological differences in the spread of the electrical activity through the heart seen among species.
Lastly, the project strengthened the collaboration within the Equine Cardiac Group at the University in Copenhagen and continued to solidify the ""platform for diagnosing LQTS in horses"" initiated in 2010.
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