WO2012154452A1 - Stratification, thérapies, traitement ciblé et prévention des tachyarrhythmies ventriculaires - Google Patents

Stratification, thérapies, traitement ciblé et prévention des tachyarrhythmies ventriculaires Download PDF

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WO2012154452A1
WO2012154452A1 PCT/US2012/036004 US2012036004W WO2012154452A1 WO 2012154452 A1 WO2012154452 A1 WO 2012154452A1 US 2012036004 W US2012036004 W US 2012036004W WO 2012154452 A1 WO2012154452 A1 WO 2012154452A1
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mutations
syndrome
long
patients
channel
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Arthur J. Moss
Ilan Goldenberg
Jin OUCHI
Coeli Maria BASTOS LOPES
Alon Eli Bar SHESHET
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University Of Rochester
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • This invention relates generally to systems and methods for risk stratification, therapies, targeted treatments and prevention of cardiac disorders, and more specifically to Systems And Methods For Risk Stratification, Therapies, Targeted Treatment And Prevention of Life- Threatening Ventricular Tachyarrhythmias And Sudden Cardiac- Death For Patients With Congenital Type- 1 Long QT Syndrome (LQT1 ),
  • LQTS Congenital long-QT syndromes
  • LQTS type- 3 LQT
  • Patients with LQTl have increased risk for life-threatening ventricular tachyarrhythmias and sudden cardiac death during sympathetic activation, associated predominantly with exercise activity or swimming. Accordingly, current guidelines recommend non-specific treatment wit beta-blocker therapy in. LQTS patients. Despite this, however, there are still a considerable number of LQTl patients who experience life-threatening ventricular tachyarrhythmias during beta-blocker therapy. Furthermore, despite multiple attempts for risk stratification studies in long QT syndrome, currently there is limited ability to identify LQTS patients who will not respond to beta-blocker therapy .
  • C-loop mutations can be used to distinguish between LQTl women with a high or low risk of sudden death.
  • Systems And Methods for identifying and reducing the risk of life-threatening ventricular tachyarrhythmias and sudden 5 cardiac death tor patients with congenital type-1 long QT Syndrome comprising an instrument for genetic testing of LQTl syndrome and a treatment construct using data from genetic testing for therapy of LQTl syndrome.
  • Figure I is a diagram depicting frequency and location of mutations in the CNQ1 Potassium Channel from a study of 860 subjects;
  • Figure 2 is a graph of Kaplan-Meier estimates of cumulative probability of a life threatening cardiac event by mutation location and type;
  • Figure 3 is a bar graph depicting risk of life threatening cardiac events by mutation location, and beta blocker treatment;
  • Figure 4 depicts regulation of LOT.! mutant channels by PKA;
  • Figure 5 is a diagram depicting risk stratification for A.CA or SCD in LQTS patients
  • Figure 6 is a diagram depicting risk, stratification for ACA or SCD in LQl ' l patients according t the presen i invention ;
  • Figure 7 is a diagram depicting methods of targeted treatment of the present invention.
  • Figure 8 is a diagram depicting data sources used for treatment, constructs of the present invention.
  • Figure 9 is a diagram depicting a method of determining LQT1 patient responders and non- responders to beta blocker therapy:
  • Figure 10 is a diagram depicting a method of determining LQTI patients at Increased or lower risk of exercise triggered events.
  • Figure 1 .1 is a diagram depicting a .method of determining, female LQT.I patients at increased risk of sudden cardiac death.
  • the present invention will be described in connection with a preferred embodiment, however, it will be understood that there is no intent to limit the invention to the embodiment described. On the contrary, the intent is to cover all alternatives, modifications, and ' equivalents as may be included within the spirit and scope of the invention as defined by this specification, claims and the attached drawings.
  • Congenital long QT syndrome is characterized by way of an electrocardiograph (ECG) where there is a prolonged QT interval manifested by ventricular arrhythmias that may result in life -threatening cardiac events and sudden cardiac death.
  • ECG electrocardiograph
  • Current treatment for congenital long QT syndrome includes beta-blockers, implantable cardioverter-defibrillators fTCDs), and surgical left cervicothoracie sympathetic denervation (LCSD). While beta-blocker therapy is considered a first line of therapy, and some practitioners admimster beta-blockers to all long QT syndrome patients, there i s a subset of individuals with long QT syndrome genotypes where beta-blocker therapy is not effective and they remain symptomatic. There remains a need for additional long QT syndrome therapies that may require a more targeted approach to treatment.
  • LQTl Long QT syndrome type-l
  • KCNOJ KCNOJ gene encoding the a suimo.it of the slowly activating potassium channel ⁇ ».
  • Exercise is the main trigger for cardiac arrhy thmic events in patients with LQTl (Schwartz Pi, Priori SG, Spazzolini C.
  • ⁇ -adrenergic receptors Activation of ⁇ -adrenergic receptors ( ⁇ -AR) is the major signaling pathway contributing to increase in heart rate and cardiac output during exercise.
  • ⁇ -AR activation leads to activation of protein kinase A (P A). which directly phosphorylates the KCNQi suhunit, increasing 1K s function (Walsh KB, Kass RS. Regulation of a heart potassium channel b protein kinase A. and C Science. 1988;242:67-69.
  • Marx SO KLurokawa J, Reifcen S, Motoike H, D'Armiento J, Marks AR, Kass RS. Requirement of a macromoiecular signaling complex for beta adrenergic receptor modulation of the KCNQI -KCNE l potassium channel. Science. 2002;295:496-499)
  • the primary translated protein (isoform 1) of KCNQI consists of 676 amino acid residue with an intracellular N-terminus region, 6 membrane-spanning segments with two connecting cytoplasmic loops (C-loops) and an intracellular C-terniinus region (Jespersen T, Grunnet M, Olesen SP, The KCNQi potassium channel: From gene to physiological function. Physiology (B ihesdah 2005;20:408-416). Prior genotype-phenotype studies have provided important information regarding the effect of location and coding type of the channel mutations on the phenotypic manifestations and clinical course of LQTl patients.
  • the study comprised 860 patients with genetically confirmed KCNQ1 mutations derived from 170 proband -identified families.
  • the proband in each family had QTc prolongation not due to a known secondary cause.
  • the subjects were drawn from the Rochester (a ⁇ 637), the Netherlands (n ::: 94), the Japanese (n :::: 82), the Danish (n ::: 43), and the Swedish (n ::: 4) portions of the Multieenter Mutation Registry. All .subjects or their guardians provided informed consent for the genetic and clinical studies,. Patients with congenital deafness or patients with multiple LQTS associated mutations were excluded from the study. Phenotype characterization
  • Routine clinical and electrocardiographic parameters were acquired at the time of enrollment in each of the registries.
  • follow-up was censored at age 41 years to minimize the influence of coronary disease on cardiac events.
  • Measured parameters on the first recorded ECG included
  • the KCNQl mutations were identified with the use of standard genetic tests performed in academic molecular-genetic laboratories. Genetic alterations of the amino acid sequence were characterized by location and by the specific type of mutation (m!ssense, splice site, in-frame insertions/deletions, nonsense, stop eodon, and fratneshiit).
  • the membrane spanning region of the KCNQl -encoded channel was defined as the coding sequence involving amino add residues between 120-170 (SI-S2), 196-241 (S3-S4), and 263- 355 (S5-S6), with the C-loops region between residues 1 71-195 (S2-S3) and 242-262 (S4-S5), as depicted in Figure I .
  • the N-terminus region was defined before residue 120 and the C- terminus region after residue 355.
  • Figure 1 is a diagram depicting -frequency and locaiion of mutations in the KCNQl Potassium Channel from a study of 860 subjects.
  • the a subunit involves the ' -terminus (N), 6 membrane-spanning segments, 2 intraeytoplasmie loops (S2-S3 and S4-S5) and the C-temiinus portion (C).
  • N ' -terminus
  • S2-S3 and S4-S5 2 intraeytoplasmie loops
  • C-temiinus portion C.
  • the size of the circles in Figure 1 reflect the number of subjects with mutations at the respective locations.
  • Mutant KCNQl cDNA was iransfeeted in combination with WT-KCNQ 1 to mimic the heterozygous nature of the disease (WT-KCNQl :mutant KCNQl :KCN B 1-0.5:0.5:1).
  • WT-KCNQl :mutant KCNQl :KCN B 1-0.5:0.5:1 We measured ion channel currents, in the presence and absence of f orskoim, a protein kinase A activator. Details of the molecular biology and electrophysiological methods are described further later in this specification. End point
  • the primary end point of the study was ⁇ he occurrence of a first life-threatening cardiac event, comprising aborted cardiac arrest (ACA) requiring external defibrillation as part of the 5 resuscitation) or LQTS-related sudden cardiac death (SCD) abrupt in onset without evident cause, if witnessed, or death that, was not explained by any other cause if it occurred in a non- witnessed setting).
  • ACA aborted cardiac arrest
  • SCD LQTS-related sudden cardiac death
  • the probability of a first life-threatening cardiac event by the mutation-location and type subgroups was graphically displayed according to the method of Kaplan and Meier, with comparison of cumulative probability of events by the log-rank test.
  • the Cox proportional- hazards sun'ivorship model was used to evaiisate the independent contribution of clinical, and genetic factors to the first occurrence of a Hfe-ihreatening cardiac event, from birth through age 0 40 years.
  • C-loop-missense mutations was determined by adding "time-dependent ⁇ -bloeker ⁇ -by- ⁇ mutation category" interaction term to the multivariate Cox model Since almost all subjects were first- and second-degree relatives of probands, we adjusted for the effect of potential lack of independence between subjects using the robust sandwich estimator for family membership.
  • missense mutations were further categorized according to their location: there were 29 different, mutations in C-temiinus or N- terrninas regions (27 in C ⁇ terminus), 34 mutations in membrane spanning regions, and 16 mutaiions in the C-l op regions (8 in S4-S5 loop and 8 in S2-S3 loop).
  • KCNQ1 :KCNE1 DNA was expressed either at a ratio of 1 :1 or 0.5:1 in order to mimic the hapioinsuffieient phenolype in HEK293T cells.
  • Each mutant KCNQ.I was expressed in combination with WT-KCNQJ t mimic heterozygous mutation (WT-KCNQl :mutant KCNQl;K£NEI : ⁇ Q.5:Q.5: l ⁇ .
  • Each mutant current was compared to the current observed from hapioinsuffieient control channel. (0.5 ng ⁇ -KCNQI: I ng KCNE1) from the same passage cells.
  • Cells were also co-iransiected with 0.2 ng pEGFP-Nl (Clontech, La Jolia, CA) for positive identification of transfected cells by fluorescence. All the transfecfion was done by using Fugene HD trasnfection kit (Roche, Mannheim, Germany). Cells were re-plated on small glass cover slide (VW1L West Chester, PA) coated with 0.02 % gelatin 24 hours after transfectkm by using Accutase (Innovative Ceil technologies, inc., San Diego, CA) and use For experiment 48 hours after transfection.
  • Figure 2 is a graph of Kaplan-Meier estimates of cumulative probability of a life threatening cardiac event b mutation, location and type in 4 subgroups. There was a significantly higher event rate in the C- loop- mi ssense subgroup as compared with the other 3 subgroups (p log rank ⁇ 0.001). Thus, at age 40 years the rate of life threatening cardiac events was 33 percent in patients with C-loop-missense mutations as compared with ⁇ 16 percent in patients with other mutations, as illustrated in Figure 2, In Figure 2, AC ⁇ aborted cardiac arrest. LQTS ⁇ long QT syndrome. The numbers in parentheses in Figure 2 reflect the cumulative event rate at that point in time.
  • Multivariate analysis showed a significant differential effect of ⁇ -blocker therap on the outcome of patients with C-loop-missense mutation as compared with those who had other mutations, as summarized in Table 3 below.
  • S-bloeker therapy was associated with a significant 88% reduction (P :;:: 0.02) in the risk of life threatening events among patients with C-loop- missense mutations, whereas the benefit of ⁇ -blocker therapy was significantly attenuated among patients with other .mutations in the KCNQ1 channel (adjusted hazard ratio of 0.82 [P :::; 0.68j; P-value for treatinent-by-mutatioii-IocationAype interactionTM 0.04).
  • Figure 3 is a bar graph depicting risk of hie threatening cardiac events by mutation location and beta blocker treatment. Consistent with those findings, the rate of A borted Cardiac Arrest or Sudden Cardiac Death, as depicted in Figure 3, was lowest among patients with C-Ioop-missense mutations who were treated with Beta-blockers and highest among patients with C-l.oop-missen.se mutations who were not treated with beta-blockers (0,17 vs. 1.1 1 per 100 patient -years, respectively), whereas patients with other mutations in the CNQ1 channel exhibited intermediate and similar rates of 3 ⁇ 4 -threatening events with- and without beta-blocker therapy (0.36 and 0.38 per 100 patient -years, respectively.
  • Event rates per 100 person-years were calculated by dividing the number of events during the period of ⁇ -hiockcr therapy or the absence of ⁇ - b!ocker therapy by person-years, and multiplying the results by 100.
  • ACATM aborted cardiac death.
  • Table 3. M ultivariate .analysis: response to ⁇ -bloeker therapy
  • G l 68R and S225L are missense mutations located in the membrane spanning region: R243C and V254M are missense mutations located in the cytoplasmic loops region.
  • beta- blockers were associated with a significant greater reduction in the risk of life-threatening cardiac events among patients with mutations located in the C- loops as compared with all other mutations. It is conceivable that during ⁇ -adrenergic stimulation patients with mutations located in the C- loops have an unopposed increase in inward C ⁇ currents and prolongation of repolarization due to blunted P A- ediated activation of JK S . ⁇
  • 3- blockers may decrease these unopposed inward Ca ⁇ ! currents, shorten repolarization and reduce the risk for ventricular arrhythmias (Huffaker R, Lam ST, Weiss JN, ogan B. Intracellular calcium, cycling, early afierdepolarixations, and reentry in simulated long QT syndrome. Heart Rhythm. 2004; 1 :44 ⁇ - 448), whereas patients with other mutations do not exhibit such an effect.
  • the international LQTS Registry records therapies that are prescribed at the discretion of the treating physicians to enrolled subjects, and therefore ⁇ -blocker administration, was not randomized. We have therefore carried out multivariate analyses that used beta -blocker therapy as a time-dependent covariate, and have further evaluated the benefit of medical therapy with
  • beta-blockers within higher- and lower- risk subsets of LQTl patients.
  • Mutaiioii-specific information should be assessed and incorporated into the risk assessment and the management of LQT1 patients.
  • Our results highlight the importance of understanding the molecular determinants and mechanisms 5 underlying arrhythmogenesi to identify cardiac risk factors for LQ ' T! patients, and have implications for risk stratification and treatment in LOT patients.
  • Genetic testing includes all forms of testing used to test for and detect genetic disorders. Many forms of genetic testing involve examination of the DMA molecule itself, or may involve biochemical tests for enzym.es, chromosom.es, proteins, or other ] o substances. Genetic testing includes techniques to examine genes or markers near the genes.
  • Genetic testing is often times performed on a sample collected from a patient, such as a sample of blood, hair, skin, or other tissue.
  • a sample collected from a patient such as a sample of blood, hair, skin, or other tissue.
  • collection is that of a buccal smear, where a sample of ceils is collected from, the inside surface of a patient's cheek by way of a swab or brush,
  • Figure 5 is a diagram depicting risk stratification for Aborted Cardiac
  • FIG. 5 is a diagram depicting risk stratification for Aborted Cardiac Arrest or Sudden. Cardiac Death in LOT! patients according to the present invention. Mutation specific risk factors are considered in the risk stratification diagram of Figure 6.
  • steps to be taken may include, for example, performing genetic testing on patients suspected of having long QT syndrome to identify genetic mutations indicati ve of long QT syndrome and processing the results of the genetic testing on a computer, identifying by way of genetic testing mutations in K.CNQJ channel ( " -loops and processing the results of 0 the genetic testing on a computer, evaluating electrocardiogram patient, information on a computer, evaluating patient clinical history on a computer; and defining a therapeutic action to be taken.
  • Therapeutic- actions may include, but are not limited to, use of a beta blocker, use of an implantable cardioverter-defibrillator, alteration of the operation of an implantable cardioverter-defibrillator (such as, for example, by programming), use of surgical left 5 cervieothoracic sympathetic denervation, or use of pharmacological agents, for example, IKs openers, PKC inhibitors, peptides based on the sequence of the c-loop region, c-loop interacting partners that may restore normal channel regulation, drugs thai mimic c-loop peptide action, drugs that bind to c-loop peptides, and drugs that bind to c-loop peptide binding partners.
  • pharmacological agents for example, IKs openers, PKC inhibitors, peptides based on the sequence of the c-loop region, c-loop interacting partners that may restore normal channel regulation, drugs thai mimic c-loop peptid
  • a system for identify ing and reducing the risk of life-threatening 0 ventricular tachyarrhythmias and sudden cardiac death in patients with congenital iype-1 long QT Syndrome comprisin an instrument for genetic testing of LQT ' l syndrome and for identifying K.C QJ channel mutations; an instrument for identifying C-loop missense mutations in the K.CNQ1 channel mutations; and a computer lor associating a therapeutic action with identified C-Ioop missense mutations in the KCNQ! channel
  • the -computer may contain listings of therapeutic actions to be taken, as will be further disclosed herein.
  • Therapeutic actions may include, but are not limited to, formulating a pharmacological agent containing a beta blocker, formulating or directing mixing or adding a type of beta blocker to a pharmacological agent, formulation of a pharmacological agent that includes, for example, IKs openers, PKC inhibitors, peptides ba.sed on the sequence of the e ⁇ !oop region, c-loop interacting partners that may restore normal channel regulation, drags that mimic c-loop peptide action, drugs that bind to c-loop peptides, or drugs that bind to c-loop peptide binding partners, use of an impS.anta.ble cardioverter-dellbrillator, programming or .modification of an implantable cardioverter-defibrillator, the use of surgical left eervicothoracie sympathetic denervation, or the like.
  • a pharmacological agent that includes, for example, IKs openers, PKC inhibitors, peptides ba.sed
  • Such a system that correlates the heretofore described genetic testing with, a therapeutic action may operate on a computer such as a laptop computer, a tablet computer, a smart phone, an instrument containing a processor, a wearable device such as a vvrisiwaieh, heart rate monitor, blood pressure monitor, or the like.
  • Therapeutic actions may also comprise alerts from the computer that are activated upon reaching a specified bodily indicator such as a specified heart rate, a specified heart rhythm, a specified pet-cent oxygen saturation in blood, a specified blood pressure, a specified chemical marker in blood, or the like.
  • the term specified is defined to be any value, numerical or otherwise, that is entered or otherwise programmed into the computer, either by a human or through another source, such, as another computer, a database, a calculation or calculations, and the like.
  • FIG 7 there i shown a diagram depicting methods of targeted risk ⁇ stratification and treatment using the present invention, instruments such as processes, techniques and equipment heretofore described for genetic testing and subsequent iden ification of mutations in C -loops of the KCNQ1 channel as show In 701 of Figure 7.
  • ECO findings are also evaluated in step 703.
  • Clinical history is also used in step 705, with the useful output being the definitio and subsequent taking of therapeutic actions In step 707 through treatment construct.
  • Treatment constructs and related therapeutic actions may include, but are not limited to, the use of beta-blockers, the use of an implantable cardioverter-defibrillator (KID), the use of surgical left cervieothoracic sympathetic denervation (LCSD).
  • KID implantable cardioverter-defibrillator
  • LCSD surgical left cervieothoracic sympathetic denervation
  • Additional possible novel therapeutic modalities (which are currently not given in LQTS patients) that, may be developed and/or evaluated as a result of the present invention include the use of various pharmacological agents such as an IKs opener (for example, 1.-364373 from.
  • an IKs opener for example, 1.-364373 from.
  • a PKC inhibitor for example, Roboxistaurin, a calcium dependent P C inhibitor
  • peptides based on the sequence of the c- ioop region or c-ioop interacting partners such as KCNQ1(S6)/ .CNQ 1 (Cterm /KCNEi(C- terra) that may restore normal channel regulation, drugs tha mimic e-loop peptide action such as drugs that can. either bind to c-loop peptides or to c-ioop peptide binding partners, or the like.
  • Figure 8 is a diagram depicting data sources used for treatment constructs of the present invention.
  • the data sources may, in one embodiment of the present invention, be contained in a data storage device such as a hard disk, solid state memory, an optical device, a magnetic device, a semiconductor device, or the like.
  • the data sources contained on physical media may also be organized or patterned by way of a daiabase, relational database, software program, spreadsheet, file partition, or the like.
  • the data sources may also be connected within or between one another by way of a network., electrical, or optical connection.
  • Clinical dat 803 that may include, tor example, further medical observations of the patient, along with Electrocardiogram data 805, historical data. 807 such as prior syncope data, and genetic testing data 809, are provided .
  • Treatment constructs may be developed or specified by way of a computer or microprocessor based system.
  • FIG. 9 is a diagram depicting a method of determining LQT 1 patient responders and non-responders to beta blocker therapy.
  • a pred.omin.ani medical treatment available for the management of LQTl patients is beta-blocker therapy.
  • Beta blockers are beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenOreceptor antagonists, or beta antagonists that are considered a class of drugs. Examples of beta blockers include, but are not limited to.
  • a method of formulating the composition of a therapeutic agent for treatment of genetic long QT syndrome may include the steps of performing genetic testing on patients suspected of having long QT syndrome to identify genetic mutations indi.cati.ve of long QT syndrome, identifying with genetic testing the specific types of genetic mutations that are indicative of long QT syndrome, separating. KCNQ1. channel.
  • compositions of a therapeutic agent for treatment of genetic long QT syndrome may include the steps of performing genetic testing on patients suspected of having long QT syndrome to identify genetic mutations indicative of long QT syndrome, identifying with genetic testing the specific types of genetic mutations that are indicative of long QT syndrome, separating KCNQ 1 channel C-Ioop missense mutations from other mutations in the K.CNQ!
  • a method of quantifying optimal therapeutic efficacy of a drug .for treatment of congenital long QT syndrome may include
  • a method of measuring a response to beta, blocker therapy in patients with long QT syndrome may include the steps of performing genetic testing on patients suspected of having long QT syndrom to identify genetic mutations indicative of long QT syndrome, identifying by way of genetic testing K.CNQ.1 channel C-Joop missense mutations in genetic testing results, and correlating K.CNQ1 channel C-ioop missense mutations with an improved response to beta blocker therapy over other .mutations responsible for genetic long QT syndrome.
  • Figure 10 is a diagram depicting a method of determining LQ 1 patients at increased or lower risk of exercise triggered events.
  • Our findings show that patients with C-Ioop mutations have increased risk for arrhythmic events during exercise, whereas other LQT.1 mutations are indicative of a significantly lower risk for exercise-triggered events. This data may change current recommendations for sports participation in patients with inherited arrhythmic disorders.
  • Figure 0 further describes our method where an LQT.l patient .1001 undergoes genetic testing to generate genetic testing data 1003 related to lon QT syndrome.
  • the presence of C-ioop mutations 1005 are indicative of increased risk of arrhythmic events during exercise; whereas LQTI patients with no C-Ioop mutations show lower risk of exercise triggered events 1009.
  • Figure 1 1 is a diagram depicting a method of determining female LQTI patients at increased risk of sudden cardiac death.
  • Prior studies suggest that LQ ' T! women have a Sower risk of cardiac events than. men.
  • Our new data sho ws that LQTI women with C ⁇ loops mutations have a very high-risk of sudden cardiac death that is similar to that of men. This new finding has important implications for the management and risk assessment of an important subgroup of LQTS lor whom current information, regarding arrhythmic risk is very limited.
  • Figure 1 1 further describes our method where a female LQTI patient 1 101 undergoes genetic testing to generate genetic testing data 1 103 related to long QT syndrome.
  • C-Ioop mutations 1 105 are indicative of a similar risk of cardiac events as compared to male LQTI patient 1 107; whereas female LQTI patients with no C-Ioop mutations show lower risk of cardiac events than comparable male LQTI patients 1 1.09.

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Abstract

Cette invention concerne des systèmes et des procédés utilisés pour la stratification des risques, les thérapies, le traitement ciblé et la prévention des tachyarrhythmies ventriculaires menaçant le pronostic vital et de la mort subite cardiaque chez les patients atteints du syndrome congénital du QT long de type-1 (lqt1). Des tests génétiques identifiant des mutations génétiques indicatrices du syndrome du QT long sont effectués et séparent les mutations faux-sens des boucles en C des canaux KCNQl des autres mutations. Les mutations faux-sens des boucles en C des canaux KCNQl constituent un indicateur d'une meilleure réponse aux bêtabloquants par rapport aux autres mutations responsables du syndrome génétique du QT long. Le recours à ces données génétiques de test et à la stratification des risques ciblés sert, notamment, à déterminer la composition d'un agent thérapeutique, à prendre des mesures thérapeutiques, à déterminer l'efficacité thérapeutique optimale d'un médicament pour le traitement du syndrome du QT long, à déterminer une réponse aux bêtabloquants chez les patients atteints du syndrome génétique du QT long.
PCT/US2012/036004 2011-05-06 2012-05-01 Stratification, thérapies, traitement ciblé et prévention des tachyarrhythmies ventriculaires WO2012154452A1 (fr)

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CN107011444A (zh) * 2016-01-28 2017-08-04 中国科学院上海生命科学研究院 一种筛选hERG钾离子通道激动剂和毒性检测方法
CN110022908A (zh) * 2016-05-19 2019-07-16 塔布拉拉莎医疗保健公司 具有降低的药物相关毒性的治疗方法和鉴定由处方药物引起的患者伤害的可能性的方法
CN113470822A (zh) * 2021-06-02 2021-10-01 北京清华长庚医院 Lqts患者自我管理方法、装置、计算机设备及存储介质

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