ROTTWEILER UpdateA NESTLÉ PURINA PUBLICATION DEDICATED TO ROTTWEILER ENTHUSIASTS VOLUME 14 | WINTER 2016

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SilverHill Rottweiler breeder Cathy Rubensis no stranger to subvalvular aortic stenosis(SAS), one of the most common congen-ital heart diseases in dogs.

“No matter how carefully I studypedigrees and try not to produce dogswith this heartbreaking disease, I can’tstop SAS,” says Rubens, of Apex, NorthCarolina. “After breeding six generationsof healthy cardiology-certified dogs, I amstill getting SAS. I made a European crossin the hopes that it would resolve theproblem, but it did not.”

The European sire that Rubens bred toher SilverHill female in 2014 produced alitter with two puppies affected with SAS.Subsequently, he was neutered. “Thepuppies started as mild cases but gotworse,” she says. “Both have a severeform of the disease.”

A breeder whose puppy buyers oftencome back years later for their secondRottweiler and then their third, Rubenstakes seriously producing healthy dogswith good temperaments and excellentconformation. More than 50 homebredshow champions, many having wonspecialty and all-breed shows, carry the SilverHill prefix.

Ruben’s first litter to have SAS wasborn in the 1980s. She kept the femalepuppy in the litter of five that had a mild

heart murmur. Although the Rottweilerlived a normal life and had a normal lifespan, not all dogs have a mild case. Thoseborn with severe SAS that do not receivetreatment live an average of 19 months.Many die before they are 4 ½ years oldeven with therapeutic cardiac treatment.

“The ability for mildly affected dogsto live a normal life means that many ofthem are never identified and thus neversee a veterinarian for their heart. Unfor-tunately, they may get bred and propagatethis disease within the breed,” says JoshuaStern, DVM, PhD, DACVIM-Cardiology,assistant professor at the University ofCalifornia-Davis. “SAS is an interestingdisease because of this wide variation.”

“This disease is heartbreaking forbreeders, owners and puppy buyers,”Rubens says. “I have cardiac auscultationtests performed on all my puppies at 6 weeks of age before they go to puppyhomes at 7 to 8 weeks old. Any puppydisplaying a SAS murmur is then echo -cardiogram tested. I also make sure mybreeding stock has been certified healthyfrom a cardiology standpoint.”

“What makes SAS so insidious is thattwo breeding partners can be tested andrated cardiac normal at 2 years of age yetpass the genetic mutation for the diseaseon to their offspring,” says Liz Wertz,past president of the Rottweiler HealthFoundation. “The offspring can be ratedcardiac normal yet carry the gene thatmay be expressed in future generations.”

ROTTWEILER Update

SAS Research inRottweilers MAY LEAD TO GENE MUTATION DISCOVERY & NEW THERAPY

Opposite page: SilverHill Rottweiler breederCathy Rubens with puppy “Ruth” (SilverHill’sHi Ho Silver) at 12 weeks of age.

“It is my dream that we willeventually know how this isinherited and have a test toidentify SAS and control thisterrible disease in Rottweilers.I believe that research willturn these results.”Cathy Rubens, breeder, SilverHill Rottweilers

Rubens with “Keeper” (Genworks Keeper),left, a 3 ½-year-old male who has helpedher reduce the incidence of heart murmursin litters he has sired, and puppy Ruth.

Winter 2016

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Winter 2016 ROTTWEILER Update

The inconsistent effect of SAS makesit a complicated, complex heart disease.Dogs with severe cases may not show signsof the disease until they die suddenly,accounting for why SAS is sometimescalled the silent killer.

Besides Rottweilers, breeds affectedby SAS include Newfoundlands, GoldenRetrievers, Bullmastiffs, Dogue de Bordeaux,Bouvier des Flandres, and Bull Terriers.A breakthrough came in 2013 when Dr. Stern and Kate Meurs, DVM, PhD,DACVIM-Cardiology, professor and as-sociate dean for research and graduatestudies at North Carolina State University,led the discovery of a gene mutation forSAS in Newfoundlands. (See “PICALMGene Mutation Linked to SAS in New-foundlands,” next page) Subsequently,a genetic test was developed for the dis-ease in this breed.

“I am looking at SAS in about six breedsin hopes that we can find the mutationthat causes it in these other breed pools,”Dr. Stern says. “In Golden Retrievers, wehave identified the chromosome wherethe mutation lies, but we need to con-tinue with whole genome sequencing.Goldens and Rottweilers do not appearto have the same mutation. In Rottweilers,we need to do additional gene mappingand whole genome sequencing.”

Collaborative efforts to advance Stern’sSAS research are being developed bythe Rottweiler Health Foundation andAmerican Bullmastiff Association withsupport from the AKC Canine HealthFoundation. Rottweiler clubs that havepledged to support the research includethe Colonial Rottweiler Club, RottweilerClub of Alaska, Sierra Rottweiler Owners,and Southwestern Rottweiler Club ofSan Diego.

“SAS is a common congenital diseasein Rotweilers,” Wertz explains. “In the lastdecade, with the American RottweilerClub requiring cardiac health tests forCHIC (Canine Health Information Center)certification, we have seen some declinein the number of cases. Unfortunately,those numbers are skewed as many casesgo unreported.”

DNA samples from affected Rottweilersand control dogs are needed for the research,as well as three-generation pedigrees andechocardiogram reports. A jump start oncollecting Rottweiler DNA samples, pedi-grees and clinical information was begunin 2003 by Dr. Meurs when she was at TheOhio State University.

Dr. Stern, who completed his veteri-nary cardiology residency working withDr. Meurs, says, “We believe that this nextresearch step involving whole genomesequencing will result in the developmentof a genetic test for SAS in Rottweilers,and hopefully uncover more informationabout how SAS forms in the heart. We alsoare studying why SAS is less severe in somedogs while causing severe signs in others.”

Understanding SASSubvalvular aortic stenosis is the for-

mation of an abnormal ring or ridge oftissue (stenosis) below the aortic valvein the heart. This lesion restricts bloodflow from the heart into the aorta and thusreduces blood flow out of the heart to thebody. The extra tissue causes the heart towork harder to pump blood to the body.

The first sign that a dog has SAS maybe a collapse, fainting spell, irregularheart rate, or even sudden death. Somedogs may cough or have shortness ofbreath. Veterinarians may discover thedisease when they detect a heart murmurfrom blood being pumped turbulently overthe stenosis and then conduct furtherdiagnostic tests.

“The gold standard for diagnosing SASis a necropsy showing the subvalvular

ridge or ring,” Dr. Stern says. “In dogssuspected of having SAS, the most impor-tant test is echocardiography (cardiacultrasound of the heart and blood vessels)to identify elevated aortic flow velocitiesand/or subvalvular lesions. Even echo -cardiography is not perfect as there is arange of aortic flow velocity values thatare inconclusive. Some dogs in this rangethat we termed equivocal for SAS aretruly normal dogs while others have verymild disease.

“Echocardiography is the only way todetermine if a dog is truly abnormal,” hesays. “You cannot overestimate aorticvelocity, as a truly abnormal result in acalm dog should be taken seriously. Dogsthat are clear for SAS by auscultation(stethoscope examination) alone maynot be good enough. Soft murmurs maybe difficult to hear in excitable dogs.Furthermore, excitement alone can gen-erate heart murmurs that are indistin-guishable from SAS, a common findingin many breeds that suffer from SAS suchas Golden Retrievers and Rottweilers.”

Although rare, SAS can occur in chil-dren. Their treatment may involve surgicalremoval of the ridge or ring below theaortic valve. In dogs, such a surgicalprocedure has not increased survival,plus few veterinary hospitals offer openheart surgery for dogs. Medical manage-ment with beta blockers may help delaythe onset of more severe disease, suchas sudden death and congestive heartfailure, in dogs with SAS.

The Future of SAS ResearchUnderstanding the genetics that cause

SAS may one day lead to a direct DNAtest to help Rottweiler breeders reducedisease incidence. It also may lead to newdrug therapies to target affected genes.

“If we knew that upregulating ordownregulating a gene with a mutationwould help dogs with SAS, that wouldbe brilliant,” Dr. Stern says. “Pharmaco-genetics, the study of how genetic dif-ferences can affect individual responsesto drug therapies, offer hope as well. I’dlove to be able to know from the outset

which drugs are going to work. Geneticscan help us do that. I think it is a waveof the future.”

Breeders face tough decisions in choos-ing which dogs to breed. Trying to per-petuate the best qualities of their dogswhile avoiding producing puppies withSAS and those that carry the SAS geneor genes can be challenging.

As Rubens says, “It is my dream thatwe will eventually know how this is inherited and have a test to identify SAS and control this terrible disease in Rottweilers. I believe that researchwill turn these results.” �

An echocardiogram shows subvalvularaortic stenosis (SAS), the most commoncongenital heart disease in dogs. The >mark between the left ventricle (LV) andaorta (AO) points to the bright subvalvularridge that is characteristic of SAS.

PICALM Gene Mutation Linked to SAS in NewfoundlandsTen years after research began, a gene mutation for subvalvular aortic stenosis(SAS) in Newfoundlands was discovered. The welcome news came none toosoon, as Newfoundlands are the most overrepresented breed affected by thepotentially fatal heart disease.

The slow process of discovery involved a committed effort by the Newfound-land Club of America and researchers. The research is still ongoing as the teamcontinues to search for modifying genes and other possible causative mutations.

Veterinary cardiologist Dr. Joshua Stern of the University of California-Davisled the research that identified a causative gene mutation. A three-nucleotideexonic insertion in the phosphatidylinositol-binding clathrin assembly protein(PICALM) was associated with the development of SAS in U.S. Newfoundlands.A whole genome analysis screening thousands of genes from 93 Newfoundlandsand 180 control dogs of 30 breeds led to the discovery in 2013.

A pedigree analysis of a family of 45 Newfoundlands supported an autosomaldominant pattern of inheritance. This means that only one parent must carry thePICALM gene mutation for offspring to inherit the disease, and not all dogs carryingthe mutation will develop SAS. A direct DNA test is now available to help breedersidentify Newfoundlands that carry the SAS gene mutation.

“Now that we know one gene that is responsible for SAS and more about whichproteins are involved, we can move forward to consider novel therapies that mayhelp treat this devastating condition,” Dr. Stern says. “Finding the mutation is great,but understanding how it does what it does is really important because eventuallywe’d like to develop novel treatment options for dogs that are severely affected. Wecontinue our work in Newfoundland SAS as this is a complex disease and it appearsthat there is at least one other gene responsible for this disease in the breed.”

Rottweiler Owners MayParticipate in SAS StudyBreeders and owners of normal andaffected Rottweilers may take part inthe subvalvular aortic stenosis researchunderway at the University of California-Davis. Led by Dr. Joshua Stern, the goalof the study is to identify the mutationthat causes the cardiac disease inthe breed.

To participate in the research, pleasecontact Dr. Stern at jstern@ucdavis.edu.He will provide enrollment forms anddetails about submitting:• A three-generation pedigree• Blood sample in EDTA (ethylenedi-

amine tetraacetic acid, an antico-agulant)

• Echocardiography report with aortic flow velocity information

Ruth and Keeper walk with Rubens.

Purina thanks Liz Wertz, past presidentof the Rottweiler Health Foundation, forhelping us to identify this topic for theRottweiler Update.

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Since it began in 2002, the Purina Parent Club Partnership (PPCP) Program hasraised more than $3.07 million to support canine health research funded by theAKC Canine Health Foundation. Rottweiler enthusiasts who are members ofPurina Pro Club and who have designated Rottweiler as their breed of dog andsubmitted weight circles from qualifying Purina brand dog foods have contributedto the $69,173 given directly to the American Rottweiler Club through PPCP since2002. An annual donation based on the value of the submitted weight circles issplit between the parent club’s Donor Advised Fund at the Foundation for caninehealth research and the parent club for education, research and rescue efforts.

PPCP Raises More Than $3 Million for Canine Health Research

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The No. 1 all-breed show dog in the country in 2015, the German ShepherdDog “Rumor,” also tallied the most points to win the Purina Pro PlanChampions Cup. Among her prizes, Multi-BIS/Multi-BISS GCH Lockenhaus’

Rumor Has It V Kenlyn received $10,000 and an original oil painting byaccomplished canine artist Linda Draper. The 4-year-old female, who washandled by breeder-owner Kent Boyles of Edgerton, Wisconsin, won 175Bests of Breed, 154 Herding Group Firsts, 93 Bests in Show, and 33 ReserveBests in Show in 2015.

GCH Lockenhaus’ Rumor Has It V Kenlyn, the No. 1 all-breed show dog in 2015, winsthe Purina Pro Plan Champions Cup.

Want to Reach the Editor?Have comments about the Rottweiler Update? Send them to: Barbara Fawver, Editor, Nestlé Purina PetCare, 2T CheckerboardSquare, St. Louis, MO 63164 or via email at editor@purina.nestle.com.

Looking to Reprint?Purina Pro Club Update articles may be reprinted provided the article is used in its entirety and in a positive manner. To requestpermission to reprint an article, please contact the editor at: editor@purina.nestle.com. Reprints should include the followingattribution: Used with permission from the Purina Pro Club Update newsletter, Nestlé Purina PetCare Company.

‘Rumor’ Wins 2015 Purina Pro Plan Champions Cup

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Ann Viklund of Purina, center, presents the 2015 PPCP donation to Dr. Diane Brown, CEO,and Dr. Duane Butherus, chair, of the AKC Canine Health Foundation.

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Purina Pro Plan Introduces BRIGHT MIND for Adult Dogs