All Phenotypes Asph<tm1Egk> MGI Mouse

premature death ( J:130155 )

• 25% of mice die by 3 months and over 50% by 12 months of age

cardiovascular system phenotype ( J:130155 )

N	• despite premature death and abnormal myocardial fiber physiology, mice do not exhibit any cardiac morphological alterations or structural abnormalities

increased cardiac muscle contractility ( J:130155 )

• fractional shortening is increased 19% compared to in wild-type mice and the rate corrected velocity of circumferential fiber shortening is increased 30% compared to in wild-type mice

• mice exhibit decreased ejection time compared to in wild-type mice

irregular heartbeat ( J:130155 )

• short-term isoproterenol stimulation elicits arrhythmias, including premature ventricular contractions, atrioventricular heart block, and ventricular tachycardia

ventricular tachycardia ( J:130155 )

• short-term isoproterenol stimulation elicits arrhythmias, including ventricular tachycardia

ventricular premature beat ( J:130155 )

• short-term isoproterenol stimulation frequently elicits premature ventricular contractions

• long-term isoproterenol infusion also induces premature ventricular contractions; these occur in isolation and as couplets over 2 weeks

atrioventricular block ( J:130155 )

• short-term isoproterenol stimulation elicits arrhythmias, including atrioventricular heart block

• long-term isoproterenol stimulation also induces atrioventricular heart block

abnormal sinoatrial node conduction ( J:130155 )

• long-term isoproterenol stimulation induces sinus asystole

abnormal myocardial fiber physiology ( J:130155 )

• sodium calcium ion exchanged current is increased by 67% compared to in wild-type cardiomyocytes

• peak calcium is increased 54% and constant calcium decay is shorter compared to in wild-type cardiomyocytes

• the amplitude of caffeine-induced calcium release is increased 30% and subsequent constant calcium decay is decreased compared to in wild-type cardiomyocytes

• cardiomyocytes exhibit a blunted response to beta-adrenergic stimulus compared to wild-type cardiomyocytes

• however, maximal beta-adrenergic stimulated parameter are similar to in wild-type cardiomyocytes

• myocytes exhibit increased calcium spark frequency and amplitude compared to in wild type cardiomyocytes

abnormal response of heart to induced stress ( J:130155 )

• following 2 to 3 trains of 5 Hz field stimulation, 16% of cardiomyocytes exhibit aftercontractions unlike wild-type cells and treatment with isoproterenol increased aftercontraction frequency to 54% compared to 8% in similarly treated wild-type cells

• following 2 to 3 trains of 5 Hz field stimulation and isoproterenol treatment, 60% of cardiomyocytes exhibit abnormal calcium transients compared to 9% of similarly treated wild type cells

• under increased frequency of stimulation (5 Hz), 32% of cardiomyocytes exhibit delayed afterdepolarizations (DADs) compared to 6% of similarly treated wild-type cells

• under increased frequency of stimulation (5 Hz) and following treatment with isoproterenol, 90% of cardiomyocytes exhibit DADs with 72% suprathreshold compared to 21% of wild-type cells with 43% suprathreshold