All Phenotypes Hrc<tm1.1Desa> MGI Mouse

premature death ( J:243733 )

• about 25% of mice die by 6 months of age and about 50% die by 10 months

dilated heart left ventricle ( J:243733 )

• left ventricular dimensions are moderately increased

decreased cardiac muscle contractility ( J:243733 )

• 3-4 month old mice show decreased fractional shortening and hearts ex vivo show reduced contraction

• rate of contraction (+dP/dt) is reduced by 25% in hearts

• cardiomyocytes exhibit decreased fractional shortening by 19% and rates of contraction are decreased by 16%

decreased cardiac muscle relaxation ( J:243733 )

• rates of relaxation are decreased by 25% in cardiomyocytes

• rate of relaxation (-dP/dt) is reduced by 22% in hearts

abnormal heart echocardiography feature ( J:243733 )

• echocardiography shows decreased fractional shorting by 14%, left ventricular pressure reduced by 18%, moderately increased left ventricular dimensions, and slightly decreased intraventricular septum and posterior wall thickness in 3-4 month old mice

• 12 month old mice show a trend towards decreased fractional shortening and increased cardiac dimensions (left ventricular end systolic diameter and left ventricular end diastolic diameter)

• however, acute heart failure is not seen

abnormal heart left ventricle pressure ( J:243733 )

• left ventricular pressure is reduced by 18%

ventricular tachycardia ( J:243733 )

• stress conditions induce episodes of ventricular tachycardia, including monomorphic and bidirectional ventricular tachycardia

irregular heartbeat ( J:243733 )

• mice exhibit increased incidence of ventricular arrhythmias under stress conditions, with acute caffeine-epinephrine administration inducing complex forms of ventricular arrhythmias such as premature ventricular contractions clustered as couplets or bigeminy, and episodes of ventricular tachycardia, including monomorphic and bidirectional ventricular tachycardia

• treatment with KN-93, an inhibitor of CaMKII, reduces the occurrence of arrhythmic events, particularly life-threatening ones

ventricular premature beat ( J:243733 )

• stress conditions induce premature ventricular contractions clustered as couplets or bigeminy

abnormal myocardial fiber physiology ( J:243733 )

• cardiomyocytes exhibit increased occurrence of aftercontractions, calcium aftertransients, and triggered activity of spontaneous delayed afterdepolarizations

• under baseline conditions, cardiomyocytes show reduced contraction, calcium transients and sarcoplasmic reticulum calcium load

• cardiomyocytes exhibit increased total sarcoplasmic reticulum calcium leak by 58% and increased ratio of sarcoplasmic reticulum leak to sarcoplasmic reticulum calcium load by 68%, without an increase in calcium spark and wave frequency

• isoproterenol treatment increases contractility parameters, enhances the amplitude of calcium transients, shortens the rate of decay and increases the sarcoplasmic reticulum calcium load

• treatment of cardiomyocytes with KN-93 partly reduces the occurrence of spontaneous aftercontractions

abnormal myocardial fiber currents ( J:243733 )

• calcium wave propagation is slower, the duration of the associated sodium/calcium exchange current is increased and action potential duration is increased in cardiomyocytes indicating slower conduction and electrical remodeling of cardiomyocytes

increased response of heart to induced stress ( J:243733 )

• 71% of mice under acute catecholaminergic stress, induced by epinephrine and caffeine, develop complex premature ventricular contractions (bigeminy) and 57% develop ventricular tachycardia episodes indicating increased incidence of ventricular arrhythmias under stress