Kazuaki Shirota

Glucose-insulin-potassium solution improves left ventricular mechanics in diabetes

BACKGROUND The mechanism by which glucose-insulin-potassium solutions enhance recovery of left ventricular function after myocardial ischemia in diabetic patients is not well understood. We evaluated the effect of glucose-insulin-potassium on ventriculoarterial coupling and left ventricular mechanics in a chronic ovine model of diabetes. METHODS Diabetes was induced in 6 sheep with streptozotocin. After 6 months of diabetes, the response of the left ventricular pressure-volume relationship to 60 minutes of intravenous glucose-insulin-potassium solution (1,000 mL of 5% dextrose in water, 100 IU of regular insulin, 90 mmol of KCl at 1.5 mL x kg(-1) x h(-1)) was determined. RESULTS Glucose-insulin-potassium solution increased end-systolic elastance 68% (p = 0.01) and improved ventriculoarterial coupling (1.7+/-0.3 to 1.0+/-0.1; p < 0.01). Potential energy decreased 35% (p = 0.01), and pressure-volume area decreased 20% (p = 0.01). However, stroke work did not change; therefore stroke work efficiency increased from 50.1%+/-3.5% to 60.2%+/-5.1% (p = 0.01). CONCLUSIONS Glucose-insulin-potassium solution improves left ventricular contractility and ventriculoarterial coupling in diabetes. Left ventricular mechanics is improved by decreasing total mechanical work without significantly affecting stroke work, resulting in improved stroke work efficiency. Improved efficiency facilitates understanding of the enhanced tolerance to myocardial ischemia afforded by glucose-insulin-potassium solution.

Ventricular remodeling after cardiomyoplasty in heart failure sheep: passive and dynamic effects

BACKGROUND Recent reports claim that cardiomyoplasty (CMP) has a girdling effect on the left ventricle, to prevent dilatation and functional deterioration, but the mechanism of its long-term effects on the native heart is not known. We compared the relative role of CMPs active squeezing and passive girdling in chronically failing hearts. METHODS After induction of stable heart failure (left ventricular ejection fraction = 27% +/- 7%) by staged coronary microembolization, CMP was performed in 11 of 18 sheep. After 8 weeks pacing training of the latissimus dorsi muscle (LDM), cardiac assist was begun with 1:2 synchronous bursts in 6 sheep (d-CMP, n = 6), and the LDM in the passive group (p-CMP, n = 5) remained unstimulated. Four (base line) and 30 weeks after induction of heart failure, the pressure-volume relationship was derived. RESULTS After 30 weeks in d-CMP the slope (Emax) of the end-systolic pressure-volume relationship increased by 66% +/- 55% (p < 0.05) and external work efficiency by 48% +/- 41% (p < 0.01). In the passive CMP and control groups, slope and external work efficiency were unchanged. Conversely, left ventricular end-diastolic volume decreased (-14% +/- 12%, p < 0.05) in the dynamic CMP group compared with a static course in the passive CMP group (3% +/- 10%, p > 0.05) and an increase (18% +/- 15%, p < 0.05) in controls. CONCLUSIONS Dynamic CMP improved native hearts contractility and external work efficiency. In addition, whereas passive CMP has simply a girdling effect, dynamic CMP also induces reverse left ventricular chamber remodeling.

Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep

OBJECTIVE Energy metabolism is altered in the diabetic heart. However, direct in vivo evidence that diabetes impairs energetics at the chamber level is lacking. Therefore, we investigated the effect of diabetes on left ventricular (LV) energetics in a chronic ovine model. METHODS Diabetes was induced in Merino-cross sheep with streptozotocin. Experiments were performed in five animals following 12 months untreated diabetes and six animals served as controls. Open-chest anesthetized sheep were instrumented to determine the LV pressure-volume relationship, oxygen consumption and free fatty acid uptake. RESULTS Diabetes impaired LV contractility (1.5+/-0.5 vs. 2.3+/-0.5 mmHg/ml, P<0.01). Stroke work was preserved but stroke work efficiency (stroke work/pressure-volume area) deteriorated (52+/-4 vs. 58+/-3%, P<0.01). Plasma free fatty acid levels increased (1885+/-1078 vs. 354+/-203 mmol/l, P<0.01) as did LV free fatty acid uptake (312+/-278 vs. 90+/-47 micromol/beat per 100 g LV, P=0.04). Contractile efficiency decreased (31.9+/-1.4 vs. 50.0+/-8.7%, P<0.01) while unloaded oxygen consumption did not change significantly. Therefore, LV oxygen utilization efficiency (stroke work/LV oxygen consumption) was compromised in the diabetic heart (14.9+/-2.8 vs. 24.3+/-4.0%, P<0.001). CONCLUSION This is the first study to demonstrate that diabetes alters ventricular energetics in vivo. LV oxygen utilization efficiency is impaired as a consequence of decreased contractile efficiency and stroke work efficiency. Impaired efficiency of oxygen utilization may explain in part the increased sensitivity of the diabetic heart to ischemia and the accelerated deterioration of ventricular function in diabetic patients.

Cardiomyoplasty reduces myocardial oxygen consumption: implications for direct mechanical compression

BACKGROUND This study investigates the possibility of reducing myocardial oxygen consumption by dynamic cardiomyoplasty in chronic heart failure. The sheep model used is relevant for cardiac assist using direct mechanical cardiac compression. METHODS In 7 sheep, heart failure was induced by staged intracoronary microembolization followed by dynamic cardiomyoplasty. Six months later, the effect of latissimus dorsi muscle stimulation in the 2:1 mode (on, cardiomyoplasty; off, control) was studied. Left ventricular pressure-volume loops were obtained by conductance, micromanometer, and inferior vena cava occlusion catheter. Myocardial oxygen consumption was derived from left main coronary artery blood flow and oxygen content of arterial and coronary sinus blood. RESULTS Cardiomyoplasty had no significant effect on left ventricular hemodynamic variables such as end-systolic pressure. However, cardiomyoplasty increased stroke volume and ejection fraction significantly by 11% +/- 12% and 11% +/- 10%, respectively. Although pressure-volume area and external work did not increase with cardiomyoplasty, myocardial oxygen consumption decreased by 21% +/- 11%. Therefore, cardiomyoplasty increased myocardial efficiency (external work/myocardial oxygen consumption) by 16% +/- 13%. CONCLUSIONS Despite limited hemodynamic improvement from dynamic cardiac compression by cardiomyoplasty in sheep with chronic heart failure, myocardial oxygen consumption was significantly reduced. These findings provide a rationale for reverse remodeling of the failing heart using direct mechanical compression.

Direct compression of the failing heart reestablishes maximal mechanical efficiency.

BACKGROUND In failing hearts, homeostatic mechanisms contrive to maximize stroke work and maintain normal arterial blood pressure at the expense of energetic efficiency. In contrast dobutamine reestablishes maximal mechanical efficiency by promoting energetically optimal loading conditions. However, dobutamine also wastefully increases nonmechanical oxygen consumption. We investigated whether direct mechanical cardiac compression would reestablish maximal mechanical efficiency without the oxygen-wasting effect. METHODS The pressure-volume relationship and myocardial oxygen consumption were derived in sheep using left ventricular pressure and volume from manometer-tipped and conductance catheters, and coronary flow from Transonics flow probe. RESULTS Propranolol hydrochloride and atropine sulfate were administered to reduce ejection fraction to 21% when ventricular elastance fell to 1.35 mm Hg/mL and mechanical efficiency to 79% of maximal. Low-pressure direct mechanical compression of the failing heart restored mechanical efficiency to 94% of maximal and realigned optimal left ventricular end-systolic pressure with operating left ventricular end-systolic pressure without altering nonmechanical oxygen consumption. CONCLUSIONS We conclude that direct cardiac compression restores mechanical efficiency to normal maximum without wasting energy on additional nonmechanical activity.

Influence of varying conduit resistance on native heart function with nonpulsatile left heart bypass

Nonpulsatile left heart bypass (NPLHB) represents a new era in cardiac support. We examined the impact of circuit resistance on ventricular loading with NPLHB. Pressure head-flow (H-Q) curves of NPLHB were measured with four grades of circuit resistance in a mock circulation. Lower resistance result, in a shallower H-Q relationship. Based on this results, NPLHB (ventricular apex to descending aorta) with ratios of 75% and 100% was evaluated for its hemodynamic effect in seven anesthetized sheep. Two grades of circuit resistance were generated with each bypass flow. A shallower H-Q relationship was noted at the lower circuit resistance when increased bypass flow fluctuations occurred during a single cardiac cycle (75%:0.9 ±0.4 to 12.2±2.8,P<0.0001; and 100%: 0.6±0.1 to 2.3 ±1.2l/min,P=0.011, with higher and lower resistance, respectively). Improved left ventricular peak pressure also resulted (75%:112±9 to 104±8,P=0.0002; and 100%: 59±26 to 13±5 mmHg,P=0.0045). In conclusion, NPLHB with lower circuit resistance improves the bypass flow response to change in pressure head during the cardiac cycle. This results in increased systolic bypass flow and improved systolic pressure unloading. Therefore, circuit resistance needs to be taken into account when designing NPLHB systems and when assessing their pump effect.