Background. It has been suggested that left ventricular unloading at the time of reperfusion provides superior infarct salvage over reperfusion alone. The purpose of this study was to show that the Hemopump transvalvular axial-flow left ventricular assist device provides superior left ventricular unloading, ischemic zone collateral blood flow, and infarct size reduction compared with intra-aortic balloon counterpulsation and reperfusion alone.Methods and Results. Eighteen dogs were instrumented with regional myocardial function sonomicrometers in the ischemic and control zones. The left anterior descending coronary artery just distal to the first diagonal branch was instrumented with a silk snare and Doppler flow probe. Additionally, pressure catheters were placed in the left atrial appendage, left ventricular apex, and ascending aorta for hemodynamic measurements. Regional myocardial blood flow was determined by using 15 -gm radioactive microspheres. Measurements were made in the control state, immediately after coronary occlusion, at 1 and 2 hours after coronary occlusion, with reperfusion, and 1 hour after reperfusion. In treated animals, left ventricular assistance was maintained during the entire period of occlusion and reperfusion. The Hemopump was associated with a significant decrease in left ventricular systolic and diastolic pressure, whereas mean arterial pressure was maintained. Intra-aortic balloon counterpulsation resulted in no significant changes in left ventricular systolic pressure and a modest decrease in left ventricular diastolic pressure. Regional unloading as assessed by sonomicrometers was significant in the Hemopump animals and absent in the balloon pump animals. Absolute regional myocardial blood flow in the ischemic zone increased slightly (p=0.002) in the Hemopump animals and did not change in the balloon pump animals. Infarct size expressed as percentage of the zone at risk was 62.6% in the control animals, 27.22% in the balloon pump animals, and 21.7% in the Hemopump animals.Conclusions. Mechanical unloading of the ventricle during ischemia and reperfusion appears to result in significant infarct salvage compared with reperfusion alone. The Hemopump appears to provide superior left ventricular systolic and diastolic unloading compared with intra-aortic counterpulsation in

Interpretation of the dynamic cardiovascular parameters on safety pharmacology studies is a challenging process; sometimes, it is difficult to separate normal physiological variations from the effects of the test drug. Data from healthy control Beagle dogs (41 males and 25 females) implanted with telemetry transmitters (DSI, St. Paul, MN) from 34 studies performed from 2003 to 2005 were analyzed. Telemetry data were collected for a 30-s period every 10 min for 24 h after sham dosing. One-hour averages were analyzed. Prior to dosing, heart rate (HR) was 95.6 +/- 26.6 bpm; mean, systolic, and diastolic blood pressure (BP) were 105.3 +/- 12.7, 142.5 +/- 5.3, and 84.7 +/- 11.1 mmHg, respectively. PR, QRS, QT, and corrected (Van de Water) QT intervals were 121 +/- 13, 33 +/- 3, 217 +/- 23, and 245 +/- 18 ms, respectively. Seasonal and slight diurnal patterns were noticed only in HR; BP and body temperature were more stable. PR and QT intervals were inversely related to HR; in addition, the duration of PR was influenced by the light cycle. A comparison of three QT correction formulas demonstrated that Van de Water's formula provided the optimal results in Beagle dogs over a wide range of HR.

The ICH S7B guideline specifically requests the evaluation of the QT interval in in vivo models as an accepted risk factor for fatal tachyarrythmias. While it recommends correcting the QT interval for heart rate (HR), it also concedes that such corrections can yield misleading results. Data acquired from 40 cynomolgus monkeys (CM) and 66 Beagle dogs (BD) on 64 and 166 episodes, respectively, of 25-h ECG data collection in healthy control group animals were analyzed for this publication. The total number of ECGs evaluated was 10,761 (CM) and 24,882 (BD). The two species appear to have some difference in cardiac repolarization regulatory mechanisms. CM are more subject to diurnal fluctuations of autonomic nervous tone, which leads to dramatic variation of QT interval duration (up to 12.7%) at the same HR (60 to 70 bpm) in different light cycles. BD do not have such a variation. Different species require different QT correction formulas. Van de Water's correction provides optimal results in BD; Bazett's correction presents optimal results in CM. Fundamental behavioral differences (domesticated vs wild animals) may require individual approaches in the interpretation of the safety pharmacology studies in various species.

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