Effects of right, left, and biventricular pacing on myocardial perfusion in ischemic conditions.

OBJECTIVES: In normal hearts, the distribution of regional myocardial perfusion is altered by ventricular pacing. Little is known about the impact of ventricular pacing on regional myocardial perfusion in ischemic conditions. In this acute echocardiographic study, we compared the respective effects of right ventricular pacing (RVP), left ventricular pacing (LVP), and biventricular pacing (BVP) on regional perfusion in a swine model of graded ischemia. METHODS AND RESULTS: Ventricular pacing leads were placed at the apex of the right ventricle and on the lateral wall of the left ventricle in nine open-chest pigs. Myocardial contrast echocardiography was successively performed during spontaneous rhythm (SR), RVP, LVP, and BVP in random order at baseline and during three stages of incremental ischemia (left anterior descending + circumflex). At baseline, RVP decreased myocardial perfusion of the septal and inferior walls compared to SR (P < 0.05), whereas LVP decreased perfusion of the lateral wall (P < 0.05). No significant differences were observed in regional perfusion during BVP compared to SR. In ischemic conditions, RVP worsened myocardial perfusion in the ischemic anterior wall as well as in the septal and inferior walls (P < 0.05), whereas both LVP and BVP did not alter perfusion in the ischemic area compared to SR. CONCLUSION: Compared to baseline, in ischemic conditions, RVP has a more pronounced detrimental impact on perfusion abnormalities. In contrast, BVP induced a significant improvement in local myocardial perfusion. Therefore, BVP could be preferred to RVP in patients with ischemic cardiomyopathy.

Quantitative analysis of function and perfusion during dobutamine stress in the detection of coronary stenoses: two-dimensional strain and contrast echocardiography investigations.

BACKGROUND: The recent development of accurate methods to measure two-dimensional strain during dobutamine stress echocardiography has reactivated the debate as to the respective value of myocardial perfusion versus myocardial function assessment in detecting coronary stenoses. The aim of our study was to compare the effects of progressive coronary constrictions on two-dimensional strain and myocardial contrast echocardiography parameters during stress conditions. METHODS: Nine open-chest pigs were studied in the setting of various degrees of coronary constrictions. Two-dimensional strain and myocardial contrast echocardiography with Flash refilling sequence acquisitions were obtained at rest and during dobutamine infusion. Values of longitudinal strain (LS), circumferential strain (CS), radial strain (RS), and wall thickening, as well as myocardial perfusion parameter (A.b), were then calculated. RESULTS: At rest, accuracy for detecting coronary stenosis was higher for CS, LS, and A.b (74%, 67%, and 69%, respectively) than for RS or wall thickening (62% and 64%, respectively). Dobutamine stress echocardiography increased the accuracy of A.b and LS to 77% and to 73%, respectively. Sensitivity during stress was higher for CS (93%) and A.b (77%), whereas specificity was higher for LS (89%) than for other parameters. Combined evaluations (CS+A.b, CS+LS, and LS+A.b) during dobutamine stress echocardiography improved both sensitivity and accuracy for detecting coronary stenosis. CONCLUSION: Quantitative evaluation of contraction by LS and CS analysis and perfusion (A.b) during stress echocardiography resulted in similar accuracy levels, whereas the radial component was less accurate. Maximal sensitivities and accuracies were obtained by combined evaluations during stress.

Effect of diazoxide on flavoprotein oxidation and reactive oxygen species generation during ischemia-reperfusion: a study on Langendorff-perfused rat hearts using optic fibers.

This study analyzed the oxidant generation during ischemia-reperfusion protocols of Langendorff-perfused rat hearts, preconditioned with a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) opener (i.e., diazoxide). The autofluorescence of mitochondrial flavoproteins, and that of the total NAD(P)H pool on the one hand and the fluorescence of dyes sensitive to H(2)O(2) or O(2)(*-) [i.e., the dihydrodichlorofluoroscein (H(2)DCF) and dihydroethidine (DHE), respectively] on the other, were noninvasively measured at the surface of the left ventricular wall by means of optic fibers. Isolated perfused rat hearts were subjected to an ischemia-reperfusion protocol. Opening mitoK(ATP) with diazoxide (100 microM) 1) improved the recovery of the rate-pressure product after reperfusion (72 +/- 2 vs. 16.8 +/- 2.5% of baseline value in control group, P < 0.01), and 2) attenuated the oxidant generation during both ischemic (-46 +/- 5% H(2)DCF oxidation and -40 +/- 3% DHE oxidation vs. control group, P < 0.01) and reperfusion (-26 +/- 2% H(2)DCF oxidation and -23 +/- 2% DHE oxidation vs. control group, P < 0.01) periods. All of these effects were abolished by coperfusion of 5-hydroxydecanoic acid (500 microM), a mitoK(ATP) blocker. During the preconditioning phase, diazoxide induced a transient, reversible, and 5-hydroxydecanoic acid-sensitive flavoprotein and H(2)DCF (but not DHE) oxidation. In conclusion, the diazoxide-mediated cardioprotection is supported by a moderate H(2)O(2) production during the preconditioning phase and a strong decrease in oxidant generation during the subsequent ischemic and reperfusion phases.

Experimental validation of circumferential, longitudinal, and radial 2-dimensional strain during dobutamine stress echocardiography in ischemic conditions.

OBJECTIVES: The aim of this study was to assess and validate 2-dimensional (2D) strain for the detection of ischemia during dobutamine stress echocardiography (DSE). BACKGROUND: Evaluation of abnormalities of left ventricular (LV) function from wall thickening during DSE is unsatisfactory and requires a high level of expertise. METHODS: In 10 open-chest anesthetized pigs, myocardial deformation was studied before and during dobutamine infusion, under control and ischemic conditions produced by various degrees of coronary artery constriction: 2 of nonflow-limiting stenoses (NFLS) of increasing severity reducing left anterior descending artery hyperemic flow by 40% and 70% and 2 flow-limiting stenoses (FLS) reducing resting coronary flow by 25% and 50%. Agreement between 2D strain echocardiography and sonomicrometry (reference method) was evaluated by linear regression and Bland-Altman analysis. RESULTS: Good correlation and agreement were observed between 2-dimensional strain and sonomicrometry at rest and during dobutamine infusion; longitudinal strain: r = 0.77, p < 0.001 and r = 0.80, p < 0.001; radial strain: r = 0.57, p < 0.05 and r = 0.63, p < 0.05; and circumferential strain: r = 0.74, p < 0.001 and r = 0.58, p < 0.001. Circumferential and longitudinal strains in the risk area were significantly decreased at rest in the presence of FLS and during dobutamine infusion in the presence of NFLS. By contrast, radial strain was significantly decreased in the presence of severe FLS only during dobutamine infusion. CONCLUSIONS: The 2D strain provides accurate assessment of LV regional function. Evaluation of circumferential and longitudinal strains during DSE has real potential for quantitative evaluation of LV deformation in the routine assessment of ischemia.

Sarcoplasmic ATP-sensitive potassium channel blocker HMR1098 protects the ischemic heart: implication of calcium, complex I, reactive oxygen species and mitochondrial ATP-sensitive potassium channel.

The aim of this study was to investigate the effects of HMR1098, a selective blocker of sarcolemmal ATP-sensitive potassium channel (sarcK(ATP)), in Langendorff-perfused rat hearts submitted to ischemia and reperfusion. The recovery of heart hemodynamic and mitochondrial function, studied on skinned fibers, was analyzed after 30-min global ischemia followed by 20-min reperfusion. Infarct size was quantified on a regional ischemia model after 2-h reperfusion. We report that the perfusion of 10 microM HMR1098 before ischemia, delays the onset of ischemic contracture, improves recovery of cardiac function upon reperfusion, preserves the mitochondrial architecture, and finally decreases infarct size. This HMR1098-induced cardioprotection is prevented by 1 mM 2-mercaptopropionylglycine, an antioxidant, and by 100 nM nifedipine, an L-type calcium channel blocker. Concomitantly, it is shown that HMR1098 perfusion induces (i) a transient and specific inhibition of the respiratory chain complex I and, (ii) an increase in the averaged intracellular calcium concentration probed by the in situ measurement of indo-1 fluorescence. Finally, all the beneficial effects of HMR1098 were strongly inhibited by 5-hydroxydecanoate and abolished by glibenclamide, two mitoK(ATP) blockers. This study demonstrates that the HMR1098-induced cardioprotection occurs indirectly through extracellular calcium influx, respiratory chain complex inhibition, reactive oxygen species production and mitoK(ATP) opening. Taken together, these data suggest that a functional interaction between sarcK(ATP) and mitoK(ATP) exists in isolated rat heart ischemia model, which is mediated by extracellular calcium influx.

MitoK(ATP)-dependent changes in mitochondrial volume and in complex II activity during ischemic and pharmacological preconditioning of Langendorff-perfused rat heart.

It has been proposed that activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) is part of signaling pathways triggering the cardioprotection afforded by ischemic preconditioning of the heart. This work was to analyze the mitochondrial function profile of Langendorff-perfused rat hearts during the different phases of various ischemia-reperfusion protocols. Specifically, skinned fibers of ischemic preconditioned hearts exhibit a decline in the succinate-supported respiration and complex II activity during ischemia, followed by a recovery during reperfusion. Meanwhile, the apparent affinity of respiration for ADP (which reflects the matrix volume expansion) is increased during preconditioning stimulus and, to a larger extent, during prolonged ischemia. This evolution pattern is mimicked by diazoxide and abolished by 5-hydroxydecanoate. It is concluded that opening the mitoK(ATP) channel mediates the preservation of mitochondrial structure-function via a mitochondrial matrix shrinkage and a reversible inactivation of complex II during prolonged ischemic insult.

Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart.

The aim of this study was to investigate mitochondrial alterations in an animal model of chronic myocardial ischemia in rats obtained by surgical constriction of the left coronary artery. Resting coronary blood flow was measured using the fluorescent microsphere technique. Contractile function, defined by rate-pressure product, and myocardial oxygen consumption were measured in a Langendorff preparation. The mitochondrial function was evaluated on permeabilized skinned fibers. Three weeks after surgery, ischemic hearts showed a significant decrease in coronary blood flow compared with sham. Hemodynamic measurements showed a significant systolic and diastolic dysfunction. Alterations in mitochondrial function in ischemic hearts were mainly characterized by a significant decrease in the maximal velocity and apparent half-saturation constant for ADP, loss of the stimulatory effect of creatine, and a stimulatory effect of exogenous cytochrome c. These functional alterations were supported by structural alterations characterized by mitochondrial clustering and swelling associated with membrane rupture. We conclude that the alterations in systolic function after chronic ischemia are supported by severe modifications of mitochondrial structure and function.