Invasive hemodynamic characteristics of low gradient severe aortic stenosis despite preserved ejection fraction.

OBJECTIVES: The study sought to compare echocardiographic with invasive hemodynamic data in patients with "paradoxic" aortic stenosis and in patients with conventionally defined severe aortic stenosis. BACKGROUND: Controversy exists whether low gradient severe aortic stenosis despite preserved ejection fraction ("paradoxic" aortic stenosis; aortic valve area <1 cm(2), mean gradient <40 mm Hg, ejection fraction >50%), which has been mainly diagnosed by echocardiography (echo), may be largely due to mistakes in echocardiographic measurements. METHODS: We compared echocardiographic and invasive hemodynamic data from 58 patients (43% male, mean age 77 ± 5 years) with "paradoxic" aortic stenosis. Data of 22 patients (45% male, mean age 73 ± 7 years) with conventionally defined severe aortic stenosis area (aortic valve area ≤1 cm(2), mean gradient >40 mm Hg, ejection fraction ≥50%) were also analyzed. RESULTS: In patients with "paradoxic" aortic stenosis, orifice area by echo (0.80 ± 0.15 cm(2)) and catheterization showed modest agreement, whether stroke volume was measured by oxymetry (0.69 ± 0.16 cm(2), bias 0.14 ± 0.17 cm(2)), or by thermodilution (0.85 ± 0.19 cm(2), bias -0.03 ± 0.19 cm(2)). Mean systolic gradients were very similar (32 ± 7 mm Hg vs. 31 ± 6 mm Hg; bias -0.08 ± 7.8 mm Hg). In comparison, in patients with conventionally defined severe aortic stenosis, orifice area by echo was 0.72 ± 0.17 cm(2) and by catheterization 0.51 ± 0.15 cm(2) (oxymetry) and 0.68 ± 0.21 cm(2) (thermodilution), respectively, and mean systolic gradient 51 ± 10 mm Hg and 55 ± 8 mm Hg, respectively. Ejection fractions did not differ significantly in both groups. Ascending aortic diameter was significantly smaller in the "paradoxic" aortic stenosis group than in patients with conventionally defined severe aortic stenosis (28 ± 5 mm vs. 31 ± 5 mm), and energy loss index was significantly larger (0.51 ± 0.12 cm(2)/m(2) vs. 0.42 ± 0.09 cm(2)/m(2), respectively). Heart rate and mean blood pressure during echo and catheterization were not significantly different. CONCLUSIONS: Occurrence of low gradient severe aortic stenosis despite preserved ejection fraction was confirmed by invasive hemodynamics and was not the result of a systematic bias in the echo calculation of aortic orifice area.

A myocardial ischemia- and reperfusion-induced injury is mediated by reactive oxygen species released from blood platelets.

In recent experimental studies, blood platelets have been found to exhibit some cardiodepressive effects in ischemic and reperfused guinea pig hearts independent of thrombus formation. These effects seemed to be mediated by reactive oxygen species (ROS). However, the source of these ROS - platelets or heart - remained still unknown. Isolated, buffer-perfused and pressure-volume work performing guinea pig hearts were exposed to a low-flow ischemia (1 ml/min) of 30 min duration and reperfused at a constant flow of 5 ml/min. Human thrombocytes were administered as 1 min bolus (20 000 thrombocytes/µl perfusion buffer) in the 15th min of ischemia or in the 1st or 5th min of reperfusion in the presence of thrombin (0.3 U/ml perfusion buffer). Recovery of external heart work (REHW) was expressed as ratio between postischemic and preischemic EHW in percent. Intracoronary platelet retention (RET) was quantified as percent of platelets applied. In a second set of experiments, thrombocytes were incubated with 10 µM of the irreversible NADPH oxidase blocker diphenyliodonium chloride and washed twice, thereafter, and administered according to the same protocol as described above. Hearts exposed to ischemia and reperfusion in the presence of thrombin but without application of platelets served as controls. Controls without application of platelets did not reveal a severe compromisation of myocardial function (REHW 85.5 ± 1%). However, addition of platelets during ischemia or in the 1st or 5th min of reperfusion led to a significant reduction of REHW as compared with controls (REHW 62.4 ± 6, 53.9 ± 3, 40.5 ± 3, respectively). Application of platelets pretreated with diphenyliodonium chloride did not reveal any cardiodepressive effects being significantly different from controls without platelet application. Moreover, treatment of platelets with diphenyliodonium chloride did not significantly decrease intracoronary platelet retention. In conclusion, these results demonstrate that cardiodepressive effects of human thrombocytes in ischemic and reperfused guinea pig hearts are mediated by ROS released from thrombocytes and not the heart.

PMN/platelets coinfused in guinea pig hearts Exposed to low-flow ischemia have no additive cardiodepressive effect.

Recent studies revealed an additive cardiodepressive effect of polymorphonuclear granulocytes (PMN) and thrombocytes in hearts exposed to a no-flow ischemia. To find out whether or not this is also true for isolated guinea pig hearts exposed to a low-flow ischemia, the current study was performed. PMN or thrombocytes, together or separately, were applied as a 1-min bolus (1,000/microl or 20,000/microl, respectively) during ischemia or in reperfusion in the presence of thrombin (0.3 U/ml perfusate). Recovery of external heart work and intracoronary cell retention were quantified in percent. Sole application of PMN or platelets during ischemia and reperfusion significantly compromised myocardial function, whereas coapplication of PMN and platelets did not exhibit any further cardiodepressive effect. Coapplication of cells almost prevented intracoronary platelet retention during ischemia and in reperfusion, as opposed to sole platelet application. Known blockers of endogenously released anti-platelet substances like nitric oxide, PGI(2) or adenosine did not mediate a further aggravation of myocardial dysfunction. The platelet-activating factor (PAF) antagonist WEB 2170 BS, however, significantly improved recovery of external heart work during ischemia and in reperfusion. This indicates that an additive cardiodepressive effect of PMN and platelets in working guinea pig hearts exposed to a low-flow ischemia, cannot be demonstrated, whereas PAF antagonists seem to be cardioprotective, under these conditions. Even addition of fibrinogen to the perfusate, did not show an additive cardiodepressive effect of coapplication of PMN and platelets.

Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban.

In recent studies, we could demonstrate a myocardial dysfunction induced by homologous platelets in ischemic and reperfused guinea pig hearts. Aim of the current study was to find out whether or not this is a phenomenon specific for platelets isolated from guinea pigs and to further examine the mechanisms of a possible cardiodepressive effect of human platelets. Isolated guinea pig hearts were exposed to a 30 min low-flow ischemia (1 ml/min) and reperfused. Human thrombocytes were administered as bolus (20.000 thrombocytes/microl perfusion buffer) in the 15(th) min of ischemia or in the 1(st) or 5(th) min of reperfusion in the presence of thrombin. Recovery of external heart work (REHW) and intracoronary platelet retention (RET) were quantified in percent. In additional experiments, the GPIIb/IIIa-blocker tirofiban (10 microg/ml perfusion buffer) or the radical scavenger superoxide dismutase (SOD-10 U/ml perfusion buffer) were added. Platelet application in the absence of tirofiban, either during ischemia (REHW 75.4 +/- 4%, RET 22.2 +/- 2%) or the 1st min (REHW 71.6 +/- 1%, RET 31.2 +/- 2%) or the 5th min of reperfusion (REHW 63.2 +/- 4%, RET 40.5 +/- 1%) led to a significant reduction of REHW and a significant increase of RET. The coapplication of tirofiban, on the other hand, prevented RET at all three times of platelet application (1.1 +/- 1.7%, 0% or 2.1 +/- 1.2%, respectively). An improvement of REHW, however, could only be noticed during ischemia (89 +/- 2%), whereas coapplication of tirofiban in early (72.9 +/- 3%) or in late reperfusion (74.6 +/- 2%) did not lead to a significant increase of REHW. Coapplication of SOD, on the other hand, significantly improved REHW in early (88.1 +/- 1) or late (95.9 +/- 1) reperfusion but not during ischemia (83.5 +/- 2). Corresponding to REHW, RET was changed significantly by coapplication of SOD during early (1 +/- 2%) or late (0%) reperfusion but not during ischemia (21.1 +/- 4%). We conclude that human thrombocytes are able to induce a myocardial dysfunction in ischemic and reperfused guinea pig hearts mediated by reactive oxygen species and independent of intracoronary platelet adhesion.