abstract

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11:00 m 4063 RoutetoChaosinVentricularFibrillationRevaaled byTiasueSizeReduction Y.-H. Kim, T. Ikeda, T.-J. Wu, C.A. Athill, A. Garfinkel, J.N. Weiss, H.S. Karagueuzian, P.-S. Chen. Wehavepresented evidence that ventricular fibrillation is deterministic chaos arising from quasiperiodicify (QP). The purpose of this studywes to determine whether the transition from chaos (VF) to QP, to periodicity (ventricular tschycardia, VT) could be produced by progressivelydecreasing tieme size. In RV free wall, mbrane potentials (TMPs) were recorded on the endocardium, and simultaneous computerized mapping (480 bipolar electrodes, 1.6 mm resolution) was dona on the epicardium during VF. The tissue size was progressively reduced by cutting. All tissues fibrillated spontaneously. The critical mass to sustain VF wee 24.0 g (16.IY. of heart weight). Between baseline and third cut, there was a reduction of the maximum number of wavefronts (WF) (4.5 + 0.6 vs. 1.7 + 0.4, p < 0.01), an increaae of life-span of reentrant WF (2.0 + 1.0 vs. 6.6 + 4.1, p < an increase of cycle length (102.6+ 10.9 ms vs. 144.1 + 27.8 ms, p < 0.01), and an increase of mean diastolic interval (11.8 + 4.5 ms vs. 36.3 + 18.2 ms, p < 0.01). At baseline, Polncar6 plot of TMP showed ring like structure, and Fourierspaotrum showed Iowfrequency modulation, indicating chaos arising via QP. After 40% size reduction, low frequency oscillations in intervals and frequency spectrum, and a ring like structure in Poincar6 plot were present, compatible with QP. After 50% reduction, regular pertodicity appeared. A decrease of the number of oscillators (VVF)in VF by tissue size reduction wasassaiated with a parallel conversion of chaotic dynamics, through quasiperiodicify, to periodicity. 11:15 Hy~rchol.atero,e~ia,~Pairs~~~r~i~~~aPa~iW, Roleof NitricOxide A.J. Maxwell, J. Niebauer, P.S. Lin, P.S.Tsao, D. Bernstein, J.P. Cooke. We obsewed in a pilot study that apolipoprotein E knockout (apoE) mice exhibit asignifieantlyrSduCSdmaximal oxygen uptake (V02mex) in responseto treadmill tesfingcampared towildtypa controls. Thisstudy was performed to confirm and expand this obsewation toothermeasures of aero- biccepacity; to determine if this effect is secmdaty to hypercholesterolemia; and to explore possible mechanisms. Methods and Results: Eight week old wild type (n = 30) and apoE C57BU6J mice (n = 16) were divided into groups receiving either a regular chcwor high cholesterol diet. At the beginning of the study,and again aftera4 week period, the mice were treadmill-tested to exerciee capacity (V02, respiratory quotient (RQ), anaerobic threshold (AT), diefenee run to exhaustion (DISTe), and aerobic work capacity (AWC)). At sacrifice, aortae were hawested fordetenmination of endotheliumdepandent and independent vascular relaxation and stimulated aortic NO production. At eight weeks of age, exercise capacity was similar in both wild type and apoE mice. However, by 12 weeka of age, exercise capacity had deteriorated in the apoE and the cholesterol fed mice. The V02mex, AT, the change in DISTe from fr to 12 weeks (ADISTe) and AWC were inversely related (p = 0.03, 0.004, 0.0001 and 0.05, respectively) and the RQ at exhaustion was directly related (p= 0.01) to serum cholesterol level. Hyparchoiesterolemia inhibited endotheliumdepandent vascular relaxation in the apoE groups compared with wild type mice (p < 0.02). There was an inverse trend between aortic nitric oxide production and total cholesterol (r= –36, p = 0.06). This is the first study to indicate that hyparcholesterolemia impairs exercise capacity. The degree of impairment is correlated with the level of senrm cholesterol. This effeef occurs in both diet-induced and genet- iesfly determined hypercholesterolemic mice. The dysfunction is correlated with a reduction in endotheliumdependent relaxation and endothelial nitric oxide production. 11:30 n 4065 UeeofMicrobubbleDestructionasaNovel Approach for’QuantificationofMyocardial Perfuaion WithContrastEchocsrdiogrsrphy DuringVenous InfusionofContrast K. Wei, S. Fircozan, A.R. Jayaweere, D.M. Skyba, N.C. Goodman, S, Kaul. Charfotteaville, Quantification of myocardial perfusion is difficult from a venous injection of microbubbles using echocsrdiography. We hypothesized that ultrasound in- duced bubble destruction can be used for quantifying myocardial perfusion during venous administration of microbubbles. If bubbles are administered as a continuous infusion, then destroying them in the myocardium and mea- suring their myocardial rate of reappearance will provide a measure of mean myocardial microbubble velocity. In-vitro experiments were performed where either flow was held constant and pulsing intewal was altered or vice versa, In-vivo experiments involved ‘6 dogs whose IAD was cannulated and ike flow set at 5-6 rates using a roller-pump. Microbubbles (MRX-115) were delivered as a constant infusion and imaging was performed at end-systole with another ultrasound pulse applied at varying intewals prior to that. Video intensity in the systolic image was then plotted against the pulsing intewal and the relation was fit to an expcmentialfunction y = A (l-e-Et), where y is video intensity at a pulsing interval t, A is the peak video intensity, and B is the rate constant that determines the initial rate of rise of video intensity. Both in the in vitro and in vivo experiments, an excellent correlation was found between flow and the rate constant B (ranging from r = 0.66 to r = 0.98). It is concluded that myocardial perfusion can be quantified during venous infusion of contrast with a novel approach that utilizes the destruction of microbubbles during ultrasound exposure. ~ yo.ngln.eStig.tO~SAW.rdSCOmWtitiO.: Molecular and Cellular Cardiology Monday,March17, 1997, 2:00 p.m.-3:3O p.m. AnaheimConventionCenter,RoomAl 9 2:00 I l~en~fiCationof theFiratf-ocusforFamilialAtrial FlbnllattonUtilizinga RapidNovelPooledDNA Strategy R. Brugada, T. Tapscott, G. Czernuszewicz, A.J. Marian, A. Iglesias, J. Girona, A. Domingo, L. Mont, J. Brugada, L.L. Bachinski, R. Roberts. o Atnal fibrillation is the most common suatained dysrhythm encountered in clinical practice and is said to account for over one third of all strokes overthe age of 65 years. It affects over 2 million Americans. Since preaent therapy ia ineffective in preventing or eliminating AF, the therapeutic aim is to control the rate of the ventricular response while utilizing antiplatelet and anticoagulant therapy to decreaae the incidence of systemic emboli, particularly to the brain. The total emotional, medical and financial burden imposed by chronic medical therapy and the subsequent high incidence of stroke is immense. The total cost is estimated at rnorethan $9 billion a year. Amolecularbasisfor AF has yet to be determined. One approach, which has been successful for metabolic dieorders, is to identify the defective gene responsible forafamilial form of the disease. Accordingly, we identified a family of 26 members in which atrial fibrillation was segregating as a highly penetrant autosomal dominant disease. DNA from ail family members was mllacted and genotype analysis wee conducted using short-tandem-repeat-polymorphic markers. A novel approach utilizing pooled DNA samples allowed for rapid screening of the genome which identified four regions of potential loci for the gene within a few weeks. Linkage analysis was conducted on markers in these four regions and LOD scores of 3.60 were obtained with the markers DIOS669 and DIOS607. Haplo~pe analysis using markers across a 70 CM region revealed that the region co-segregating with the disease is located between D1OS561and D1OSI866, an intewal of about 26cM located on chromosome 10q2.Thus, we have identified thefirst bcueforfamilial atrialfibrillation. Using a novel genome screening strategy in an autosomal dominant diseaae, we reduced the time to identify the locus by more than 75Y0.Application of thia novel strategy in the future will reduce time and cost to identify new disease related genes. Identification of the gene in this family should elucidate the mechanism responsible for the familial form and also for the more common acquired form of the disease and provide new and more effective therapy.

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Page 1: Abstract

11:00

m4063 Routeto ChaosinVentricularFibrillationRevaaledbyTiasueSizeReduction

Y.-H. Kim, T. Ikeda, T.-J. Wu, C.A. Athill, A. Garfinkel, J.N. Weiss,H.S. Karagueuzian, P.-S.Chen.

Wehavepresented evidence that ventricular fibrillation is deterministic chaosarising from quasiperiodicify (QP).The purposeof this studywes to determinewhether the transition from chaos (VF) to QP, to periodicity (ventriculartschycardia, VT) could be produced by progressivelydecreasing tieme size.In RV free wall, mbrane potentials (TMPs) wererecorded on the endocardium, and simultaneous computerized mapping(480 bipolar electrodes, 1.6 mm resolution) was dona on the epicardiumduring VF. The tissue size was progressively reduced by cutting. All tissuesfibrillated spontaneously. The critical mass to sustain VF wee 24.0 g (16.IY.of heart weight). Between baseline and third cut, there was a reduction ofthe maximum number of wavefronts (WF) (4.5 + 0.6 vs. 1.7 + 0.4, p <0.01), an increaae of life-span of reentrant WF (2.0 + 1.0 vs. 6.6 + 4.1, p <

an increase of cycle length (102.6+ 10.9 ms vs. 144.1 + 27.8 ms, p< 0.01), and an increase of mean diastolic interval (11.8 + 4.5 ms vs. 36.3+ 18.2 ms, p < 0.01). At baseline, Polncar6 plot of TMP showed ring likestructure, and Fourierspaotrum showed Iowfrequency modulation, indicatingchaos arising via QP. After 40% size reduction, low frequency oscillations inintervals and frequency spectrum, and a ring like structure in Poincar6 plotwere present, compatible with QP. After 50% reduction, regular pertodicityappeared. A decrease of the number of oscillators (VVF)in VFby tissue size reduction wasassaiated with a parallel conversion of chaoticdynamics, through quasiperiodicify, to periodicity.

11:15

Hy~rchol.atero,e~ia,~Pairs~~~r~i~~~aPa~iW,Roleof NitricOxide

A.J. Maxwell, J. Niebauer, P.S.Lin, P.S.Tsao, D. Bernstein, J.P. Cooke.

We obsewed in a pilot study that apolipoprotein E knockout(apoE) mice exhibit asignifieantlyrSduCSdmaximaloxygen uptake (V02mex)in responseto treadmill tesfingcampared towildtypa controls. Thisstudy wasperformed to confirm and expand this obsewation toothermeasures of aero-biccepacity; to determine if this effect is secmdaty to hypercholesterolemia;and to explore possible mechanisms.

Methods and Results: Eight week old wild type (n = 30) and apoEC57BU6J mice (n = 16) were divided into groups receiving either a regularchcwor high cholesterol diet. At the beginning of the study,and again aftera4week period, the mice were treadmill-tested toexerciee capacity (V02, respiratory quotient (RQ), anaerobic threshold (AT),diefenee run to exhaustion (DISTe), and aerobic work capacity (AWC)). Atsacrifice, aortae were hawested fordetenmination of endotheliumdepandentand independent vascular relaxation and stimulated aortic NO production. Ateight weeks of age, exercise capacity was similar in both wild type and apoEmice. However, by 12weeka of age, exercise capacity had deteriorated in theapoE and the cholesterol fed mice. The V02mex, AT, the change in DISTefrom fr to 12 weeks (ADISTe) and AWC were inversely related (p = 0.03,0.004, 0.0001 and 0.05, respectively) and the RQ at exhaustion was directlyrelated (p= 0.01) to serum cholesterol level. Hyparchoiesterolemia inhibitedendotheliumdepandent vascular relaxation in the apoE groups comparedwith wild type mice (p < 0.02). There was an inverse trend between aorticnitric oxide production and total cholesterol (r= –36, p = 0.06).

This is the first study to indicate that hyparcholesterolemiaimpairs exercise capacity. The degree of impairment is correlated with thelevel of senrm cholesterol. This effeef occurs in both diet-induced and genet-iesfly determined hypercholesterolemic mice. The dysfunction is correlatedwith a reduction in endotheliumdependent relaxation and endothelial nitricoxide production.

11:30

n4065 Ueeof MicrobubbleDestructionasa NovelApproachfor’Quantificationof MyocardialPerfuaionWithContrastEchocsrdiogrsrphyDuringVenousInfusionof Contrast

K. Wei, S. Fircozan, A.R. Jayaweere, D.M. Skyba, N.C. Goodman, S, Kaul.Charfotteaville,

Quantification of myocardial perfusion is difficult from a venous injection ofmicrobubbles using echocsrdiography. We hypothesized that ultrasound in-duced bubble destruction can be used for quantifying myocardial perfusion

during venous administration of microbubbles. If bubbles are administeredas a continuous infusion, then destroying them in the myocardium and mea-suring their myocardial rate of reappearance will provide a measure of meanmyocardial microbubble velocity. In-vitro experiments were performed whereeither flow was held constant and pulsing intewal was altered or vice versa,In-vivo experiments involved ‘6 dogs whose IAD was cannulated and ikeflow set at 5-6 rates using a roller-pump. Microbubbles (MRX-115) weredelivered as a constant infusion and imaging was performed at end-systolewith another ultrasound pulse applied at varying intewals prior to that. Videointensity in the systolic image was then plotted against the pulsing intewaland the relation was fit to an expcmential function y = A (l-e-Et), where y isvideo intensity at a pulsing interval t, A is the peak video intensity, and B isthe rate constant that determines the initial rate of rise of video intensity. Bothin the in vitro and in vivo experiments, an excellent correlation was foundbetween flow and the rate constant B (ranging from r = 0.66 to r = 0.98).It is concluded that myocardial perfusion can be quantified during venousinfusion of contrast with a novel approach that utilizes the destruction ofmicrobubbles during ultrasound exposure.

~ yo.ngln.eStig.tO~SAW.rdSCOmWtitiO.:Molecular and Cellular Cardiology

Monday,March17, 1997, 2:00 p.m.-3:3O p.m.AnaheimConventionCenter,RoomAl 9

2:00

I l~en~fiCationofthe Firatf-ocusforFamilialAtrialFlbnllattonUtilizinga RapidNovelPooledDNAStrategy

R. Brugada, T. Tapscott, G. Czernuszewicz, A.J. Marian, A. Iglesias,J. Girona, A. Domingo, L. Mont, J. Brugada, L.L. Bachinski, R. Roberts.

o

Atnal fibrillation is the most common suatained dysrhythm encountered inclinical practice and is said to account for over one third of all strokes overtheage of 65 years. It affects over 2 million Americans. Since preaent therapy iaineffective in preventing or eliminating AF, the therapeutic aim is to control therate of the ventricular response while utilizing antiplatelet and anticoagulanttherapy to decreaae the incidence of systemic emboli, particularly to thebrain. The total emotional, medical and financial burden imposed by chronicmedical therapy and the subsequent high incidence of stroke is immense.The total cost is estimated at rnorethan $9 billion a year. AmolecularbasisforAF has yet to be determined. One approach, which has been successful formetabolic dieorders, is to identify the defective gene responsible forafamilialform of the disease. Accordingly, we identified a family of 26 membersin which atrial fibrillation was segregating as a highly penetrant autosomaldominant disease. DNA from ail family members was mllacted and genotypeanalysis wee conducted using short-tandem-repeat-polymorphic markers. Anovel approach utilizing pooled DNA samples allowed for rapid screening ofthe genome which identified four regions of potential loci for the gene withina few weeks. Linkage analysis was conducted on markers in these fourregions and LOD scores of 3.60 were obtained with the markers DIOS669and DIOS607. Haplo~pe analysis using markers across a 70 CM regionrevealed that the region co-segregating with the disease is located betweenD1OS561and D1OSI866, an intewal of about 26cM located on chromosome10q2.Thus, we have identified thefirst bcueforfamilial atrialfibrillation. Usinga novel genome screening strategy in an autosomal dominant diseaae, wereduced the time to identify the locus by more than 75Y0.Application of thianovel strategy in the future will reduce time and cost to identify new diseaserelated genes. Identification of the gene in this family should elucidate themechanism responsible for the familial form and also for the more commonacquired form of the disease and provide new and more effective therapy.