The cardiomiopatia hypertrophic (HCM) is a disease autosomica dominant, whose prevalence has been estimated at approximately 0.2% (1 in 500), being probably the cardiovascular disease inherited most common and the most frequent cause of sudden death. It is a heart disease primary, in which the property is diagnosed basica, it is the hypertrophy of the left ventricle without ventricular dilatation, in the absence of any other disease of the heart or systemic (hypertension, valve disease, etc.), that store the hipertrófia of the myocardium. Up to the present, have been identified more than 200 mutations in 11 genes that encode proteins of the sarcomero explains Dr. Carlos San Roman of the Ramón y Cajal Hospital in Madrid; the gene for the heavy chain of the beta-cardiac myosin (MYH7), the gene for the heavy chain of the alpha-cardiac myosin (MYH6), the gene for cardiac troponin T (TNNT2), the gene for cardiac troponin I (TNNI3), the gene for cardiac troponin C, cardiac (TNNC1); the gene of the alpha-tropomyosin (TPM1), the gene for protein C enlazadora cardiac myosin (MYBPC3), and the chain genes essential light (MYL3) and regulatory (MYL2) of myosin. It has also been identified mutations in the genes for cardiac alpha-actin (ACTC), and titin (TTN).
Heart bisecionado of a Maine Coon kitten with HCM severe (weight of the heart, 35 g). The section has passed through the centers of both muscles papillary severely hypertrophied, which have caused the obstruccion midventricular sistolica . The left atrium moderate enlarged shelters a thrombus large (left half).
Section cross section of a heart of a cat, the Maine Coon HCM severe (weight of the heart, 37 g). The myocardium has experienced contraction in post-mortem resulting in the obliteracion of the cavity of the LV. The muscles papillary hypertrophied can be seen as a mass of pink light from the tissue that covers two third internal wall of the LV.
Models of genetically modified animals developed for the study of genes and causal mutations in hypertrophic cardiomyopathy.
MYBPC-3
Mutations in the gene of the MyBP-C heart are responsible for approximately 15% of cases of hypertrophic cardiomyopathy family. We have described a large number of mutations (> 31), the majority of which result in mutations instead of cutting and splicing, insertions and deletions , which produce proteins truncated. Most of the truncations occur in terminal domain COOH, which contains a place of union for myosin, being this a few times if and other not the place of union for titin. Interestingly, the presentation of the disease does not occur until the fifth to sixth decade of life, and is characterized by a late start of the cardiomiopatia hypertrophic family, incomplete penetrance, and a profile clinico relatively benign , which contrasts with other mutations genetic disorders sarcomericas more malignant. Due to these features, the changes patologicos longitudinal linked to the disease in patients with alterations in the MyBP-C are difficult to obtain.
Mutations in the gene of the MyBP-C heart in your most produce a protein truncated , and the transgenic approach is a good tool to investigate the pathological effects of these mutations, which occur in the fifth or sixth decade of life, due to the possibility of studying the severity and progression of the disease and its relationship with the levels of expression of the protein. Since it has been postulated the haplo-insufficiency functional as one of the probable mechanisms of production of the phenotype, since the same could not be found in biopsies from patients , we constructed two models of mice transgenic. The first model replacement approximately half of the MyBP-C heart with a protein lacking the domains to bind to the myosin and titin . The truncated protein was coded was stable, but could not be incorporated efficiently in the sarcomero, what sugeria that the protein did not act as a “peptide-toxic”. Abnormalities fisiopatologicas and structural mice were related to the dose, and illustrated the structural consequences caused by the insufficient incorporation of MyBP-C functional in the assembly sarcomerico and/or by the incorporation of the polipeptido aberrado. The dysgenesis sarcomerica was prevalent, indicating that they are necessary normal amounts of the protein to the structural integrity of the sarcomeros of cardiomyocytes. The minor phenotype developed by mice reproduces the clinical phenotype relatively benign that is observed in certain mutations. However, it has been postulated that this phenotype can vary depending on the mutation. To test this hypothesis, we generated a second transgenic mouse model that expressed in the heart, a mutant form of the MyBP-C that lacks the place of the union of the myosin . According to what is expected for this mutation, only found a modest state of the protein, which is consistent with the data obtained from biopsies of human in which the protein mutated could not be detected. Despite the normal levels of the protein endogena, significant changes were observed in the structure and ultra-structure of the heart. The mechanics of the fiber was altered, observandose a decrease in the speed of shortening, the shortening maximo and in the force maxima relative. This model supports the concept of “peptide-toxic” protein mutated.
Models transgene of the MyHC illustrate some of the important points concerning the usefulness of the overall approach. In the first place, an animal model of rodent small, it can faithfully reproduce the elements of the pathology of human. In the second place, the rate is relatively rapid with which these models can be generated to demonstrate the diversity of the pathophysiological mechanisms that can result in HSCS, which are involved different mutations of the same gene (MYBPC3). Due to the limited number of investigations that can be performed in humans, the models raton provide a unique opportunity to discover pathogenic processes that evolve gradually over the life of the animal .
It has generated a model of raton transgenico “knockout” with the purpose of evaluating the function of the MyHC and understand the mechanism of production of HSCS product of mutations in the gene MYBPC3 . The authors have produced strains of mice with loss of MyHC, the product of a deletion of exons 3 to 10 of the MyHC endogenous cardiac. Mice heterozygous for the mutation (+/-) were indistinguishable from the normal (+/+), whereas those homozygous for the mutation (-/-) showed cardiac hypertrophy important. Evaluation of echocardiographic mice showed a decrease of important indices of function sistolica and diastolic blood pressure in the homozygotes for the mutation. Calcium sensitivity was reduced in mice homozygotes but not in heterozygotes. These results establish that the MyHC is not essential for cardiac development, but the absence of MyHC gives as a result a deep hipertrófia heart and a function contraáctil defective.
SOME GENES INVOLVED IN HCM
| GENE | PROTEIN | NOTE |
| MYH7 | beta-MyHC | Hipertrófia common |
| MYL2 | MLC2s/v | Obstruction of the outflow tract of the left ventricle |
| MYL3 | MLC1s/v | Obstruction of the outflow tract of the left ventricle |
| TNNT2 | cTnT | Sudden death |
| TNNI3 | cTn1 | Hypertrophic apical |
| TPM1 | alpha-TM | Hipertrófia variable and sudden death |
| MYBPC3 | cMyBP-C | Late-onset |
| ACTC | alpha-actin | High penetrance |
GENETIC TESTING IN THE MAINE COON
The first gene discovered to the HCM in the Maine Coon was in the year 2005 by Kittleson and Kate Meurs, this gene is the MyBPC-3) and the first mutation found is the (A3P1).For the completion of the test , it is enough with a sample of blood or saliva of the cat.We have three possible outcomes of the test.Our Maine Coon can be :
Negative:you don't have any copies of the mutation (A3P1)
Parent heterozygous: Has a copy of the mutation (A3P1)
Homozygosity mapping:you Have two copies of the mutation (A3P1)
The cat is negative it does not transmit any mutation to their offspring,the parent heterozygous forward it to 50% and the homozygosity of the transimitirá to 100%.We must clarify that both cats positive as well as negative may OR MAY NOT DEVELOP HCM.
Immunoblot was performed to confirm the identification of the proteins are abnormal. Lanes 1 and 3 contain samples of the myocardium of the normal cats, lane 2 contains a sample of the myocardium of an affected cat (the parent heterozygous). The genotypes of the cats are shown below the lanes as G/G (normal cat) and C/G (parent heterozygous affected).
Analysis of proteins of the myocardium in cats affected and normal cats.We observed that the protein MyBPC and the Myomesina were reduced in cats affected.
RECOMMENDATIONS FOR JEROLL S BELL ( Clinical Associate Professor of Genetics )
“My recommendations regarding the counseling genetic and management, genetics of the disease is based on two premises ,in the first place, I agree that you should avoid breeding affected individuals, but on the other hand it must be to maintain the quality and diversity of the breed.The recommendation is to cross cats affected with normal cats.We must keep in mind that this is just a mutation discovered by the HCM and not all positive cats develop HCM, or die of cardiac arrest.We must take into account the problems that may be caused to the race if all breeders castran to its positive.This is only the first gene ,but there will be many others.If these genetic tests,are used only for the removal of cats from breeding,then there will be no cat to breed, because everyone will have a defective gene.
I am not a fan of breeding with all of the positive cats, but prudence suggests that some cats affected high-quality ,you don't have a family history,which may be used for the rearing and go selecting .This is only a test testable and quality of breeding lines must continue to maintain the diversity of the race.”
Recommendation from Jens Hagstrom,DVM PhD, Diplomate ECVIM-CA (Cardiology) Professor Internal Medicine
“In the summer of 2007 has been found another mutation to the gene MyBPC-3 in the Maine Coon this mutation is the (A74T) found by the team of Jorgen Koch.
The cardiomopatía hypertrophic affects felines in general, regardless of their race, today we are researching mutations for the different races.
In the last conference held in Dianamrca talked about studies that are being carried out with British Shorthair and the Ragdolls ,the latter has already been discovered as a mutation of which can be to test, this is the MYBPC3 Gene (R820W).
The concept of a gene and a disease is elegant, but incomplete. A mutation in a single gene can make many other genes to start or stop doing it.
Today, the most reliable method to detect HCM is through ECHOCARDIOGRAM DOPPLER,this method also we can give three different results:
NORMAL:Indicates that at the time of the ultrasound, the heart of the cat is normal and can be used to breed.
EQUIVOCAL:Indicates that there is a thickness abnormal at the walls,but in that time has not yet developed HCM, if a cat is young, less than two years is not recommended to use it to raise,even after repeated test to ensure that it does not develop HCM but if the cat is older than two years ,you will be required to perform checks every 6 months,it is important that you make before any mounts, and always cross this cat with a cat that has an ultrasound of the normal.
HCM:Indicates that the cat is sick and should not be used for breeding under no circumstances.”
PARAMETERS IN DIFFERENT RACES
| Parameters | Maine Coon | European | Sphynx |
| Normal/HCM | Normal/HCM | Normal/HCM | |
| LVWDd(mm) | 4.3+/-0.62 >6 | 4.1+/-0.7 >6 | 4.6+/-0.5 >5.5 |
| IVSDd(mm) | 4.0+/-0.7 >6 | 4.2+/-0.7 >6 | 4.3+/-0.8 >5.5 |
| LVIDd(mm) | 18.5+/-2.1 <12 | 5.0+/-2.0 >10 | 16.3+/-3.0 >11 |
| Weight(Kg) | 5.5/8 kg | 4.7/6kg | 3.3/4kg |
LVWDd : free Wall of the left ventricle in diastole.
IVSDd :intraventricular Septum in diastole,which means ,
the extent of the septum between the two ventricles,the septum
it is the wall that separates the left ventricle from the right.
LVIDd: internal Diameter of the ventricle internal,is measured
in diastole, and then in systole.
NATRIURETIC PEPTIDES
The plasma concentration of atrial natriuretic peptide and brain natriuretic peptide are markers biofisiológicos important and of great sensitivity to the damage left ventricular in patients with symptomatic heart failure as asymptomatic. Brain natriuretic peptide has shown higher sensitivity than the atrial and a prognostic value of dysfunction ventricular independent of the ejection fraction. makes them a useful tool in the area clinic to supplement or to differentiate from other diseases non-cardiac. As many times radiographically or with an electrocardiogram could be no doubt whether or not there is heart disease.It has been observed that in patients with congestive heart failure, mitral regurgitation, gastroesophageal dirofilaria, the levels of ANP are kept high so that they can be measured in blood. Also, the PNC is used as an excellent discriminator of dyspnea by pathology cardiac and non-cardiac.In the united States is using the PNA and in France, the PNC with satisfactory results.There is a test approved by the Federeal Drug Administration,through a simple and practical examination of blood for clinical trial in patients with first-admission to identify quickly people with a high likelihood of heart disease basic.
Oulu, Finland: Natriuretic peptides retained their prognostic value in the era of the agents beta-blockers. Elevated levels of brain natriuretic peptide are associated with risk of sudden cardiac death after a myocardial infarction independently of clinical variables and the fraction of the expulsion of the left ventricle.
Today are referred to three types of peptides natriureticos in and to the human heart: the ANP, BNP and CNP.The CNP, has not been found in animals.
Hospital Ramón y Cajal de Madrid http://www.monografias.com/trabajos16/peptidos-natriureticos/peptidos-natriureticos.shtml http://www.ammvepe.com/articulos/peptidos.html http://www.revespcardiol.org/cgi-bin/wdbcgi.exe/cardio/mrevista_cardio.fulltext?pident=13059721 http://hmg.oxfordjournals.org/cgi/content/full/14/23/3587 http://www.mcbfa.org/healthfiles.html http://www2.scielo.org.ve/scielo.php http://www.chatterie-du-potemkine.ch/HCM2.htm
English 
Español