Simone Palatresi

Increased Oxidative Stress and Platelet Activation in Patients With Hypertension and Renovascular Disease

Background—Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. Methods and Results—We measured the urinary excretion of 8-iso-prostaglandin (PG) F2&agr; and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2&agr; was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients , urinary 8-iso-PGF2&agr; correlated with 11-dehydro-TXB2 (rs=0.48;P <0.05) and renal vein renin (rs=0.67;P <0.005) and angiotensin II (rs=0.65;P =0.005) ratios. A reduction in 8-iso-PGF2&agr; after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2&agr; were related to baseline lipid peroxidation (rs=−0.73;P <0.001), renal vein angiotensin II (rs=−0.70;P <0.01) and renin (rs=−0.63;P <0.05) ratios. Conclusions—Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Angioplasty of atherosclerotic and fibromuscular renal artery stenosis: Time course and predicting factors of the effects on renal function

The effects of percutaneous transluminal renal angioplasty (PTRA) on the renal function of stenotic kidneys are usually assessed by evaluating the changes in serum creatinine, which is quite a rough indicator of glomerular filtration rate (GFR). In 27 hypertensive patients with 19 atherosclerotic and 11 fibromuscular significant renal artery stenoses, we investigated with renal scintigraphy the short-term (5 days) and long-term (10 months) effects of a technically successful PTRA (in seven cases combined with a stent implantation) on GFR of the stenotic and contralateral kidneys; these measurements were combined with those of plasma renin activity (PRA) and of angiotensin II (AII). We found that in short-term studies after PTRA GFR rose from 29.7 +/- 3.5 to 34.6 +/- 3.1 mL/min and from 36.9 +/- 4.0 to 45.1 +/- 4.3 mL/min, respectively, in atherosclerotic and fibromuscular poststenotic kidneys. In long-term studies GFR further and significantly increased, to 37.8 +/- 3.2 mL/min in the former group, whereas it stabilized in the latter group (46.0 +/- 3.6 mL/min). In patients with fibromuscular stenosis these changes in GFR were associated with clear-cut reductions in blood pressure (BP), PRA, and AII; these decrements also occurred in patients with atherosclerotic stenosis but to a much lesser extent. We also found that in short- and long-term studies the percent of PTRA-induced increments of GFR in the poststenotic kidneys were inversely correlated with the baseline values of GFR. In addition, the absolute and percent increments of GFR were positively correlated with the basal levels of AII. Thus the time course of the improvement in GFR after angioplasty may differ in kidneys, depending on the etiology of the stenosis, in that in those with fibromuscular stenosis it was entirely apparent within a few days whereas in those with atherosclerotic stenosis it required several months to be fully expressed. Also, it appears that the more compromised kidneys are those that benefit most from the dilatation and that AII levels are useful indicators of the possibility that the stenotic kidney will have a favorable functional outcome in terms of restoration of renal blood flow.

Myocardial blood flow and infarct size after CD133+ cell injection in large myocardial infarction with good recanalization and poor reperfusion: Results from a randomized controlled trial

Objective Large acute ST-elevation myocardial infarction (STEMI) sometimes leaves extensive ischemic damage despite timely and successful primary angioplasty. This clinical picture of good recanalization with incomplete reperfusion represents a good model to assess the reparative potential of locally administered cell therapy. Thus, we conducted a randomized controlled trial aimed at evaluating the effect of intracoronary administration of CD133+ stem cells on myocardial blood flow and function in this setting. Methods Fifteen patients with large anterior STEMI, myocardial blush grade 0–1 and more than 50% ST-elevation recovery after optimal coronary recanalization (TIMI 3 flow) with stenting were randomly assigned to receive CD133+ cells from either bone marrow (group A) or peripheral blood (group B), or to stay on drug therapy alone (group C). The cells were intracoronary injected within 10–14 days of STEMI. Infarct-related myocardial blood flow (MBF) was evaluated by NH3 positron emission tomography 2–5 days before cell administration and after 1 year. Results MBF increased in the infarct area from 0.419 (0.390–0.623) to 0.544 (0.371–0.729) ml/min per g in group A, decreased from 0.547 (0.505–0.683) to 0.295 (0.237–0.472) ml/min per g in group B and only slightly changed from 0.554 (0.413–0.662) to 0.491 (0.453–0.717) ml/min per g in group C (A vs. C: P = 0.023; B vs. C: P = 0.066). Left ventricular volume tended to increase more in groups B and C than in group A, ejection fraction and wall motion score index remained stable in the three groups. Conclusion These findings support the hypothesis that intracoronary administration of bone marrow-derived, but not peripheral blood-derived CD133+ cells 10–14 days after STEMI may improve long-term perfusion.

The Role of PET with 13N-Ammonia and 18F-FDG in the Assessment of Myocardial Perfusion and Metabolism in Patients with Recent AMI and Intracoronary Stem Cell Injection

Over the last decade, the effects of stem cell therapy on cardiac repair after acute myocardial infarction (AMI) have been investigated with different imaging techniques. We evaluated a new imaging approach using 13N-ammonia and 18F-FDG PET for a combined analysis of cardiac perfusion, metabolism, and function in patients treated with intracoronary injection of endothelial progenitors or with conventional therapy for AMI. Methods: A total of 15 patients were randomly assigned to 3 groups based on different treatments (group A: bone marrow–derived stem cells; group B: peripheral blood–derived stem cells; group C: standard therapy alone). The number of scarred and viable segments, along with the infarct size and the extent of the viable area, were determined on a 9-segment 13N-ammonia/18F-FDG PET polar map. Myocardial blood flow (MBF) was calculated for each segment on the ammonia polar map, whereas a global evaluation of left ventricular function was obtained by estimating left ventricular ejection fraction (LVEF) and end-diastolic volume, both derived from electrocardiography-gated 18F-FDG images. Both intragroup and intergroup comparative analyses of the mean values of each parameter were performed at baseline and 3, 6, and 12 mo after AMI. During follow-up, major cardiac events were also registered. Results: A significant decrease (P < 0.05) in the number of scarred segments and infarct size was observed in group A, along with an increase in MBF (P < 0.05) and a mild improvement in cardiac function. Lack of infarct size shrinkage in group B was associated with a marked impairment of MBF (P = 0.01) and cardiac dysfunction. Ambiguous changes in infarct size, MBF, and LVEF were found in group C. No differences in number of viable segments or in extent of viable area were found among the groups. At clinical follow-up, no major cardiac events occurred in group A patients, whereas 2 patients of group B experienced in-stent occlusion and one patient of group C received a transplant for heart failure. Conclusion: Our data suggest that a single nuclear imaging technique accurately analyzes changes in myocardial perfusion and metabolism occurring after stem cell transplantation.

Plasma endothelin levels : a meaningless number?

Endothelin (ET)-1 is a potent vasoactive peptide which is mostly secreted toward the vessel wall and the circulatory levels of which are quite low; for these reasons changes in plasma ET-1 may be difficult to detect even after the application of strong stimuli, which, in theory, should profoundly alter its production. We have examined the effects of a number of such stimuli and found that in humans the only one which consistently increased plasma ET-1 was the exposure to hypobaric hypoxia; moreover under these circumstances the increments in plasma ET-1 were correlated with the changes in pulmonary systolic pressure, suggesting a role of circulating ET-1 in the adaptation of pulmonary vessels to high altitude. In contrast no consistent changes of ET-1 were observed in response to sympathetic activation induced either by exposure to cold, standing, reduction in blood pressure and blood withdrawal. In response to angioplasty of renal artery stenosis a concomitant reduction in plasma ET-1 and angiotensin II (AngII) was observed in patients who, prior to angioplasty, had a high degree of activation of the renin system, supporting the possibility that in these specific conditions AngII may actually stimulate ET-1 production in vivo.

Usefulness and limits of distal echo-Doppler velocimetric indices for assessing renal hemodynamics in stenotic and non-stenotic kidneys.

Background Distal echo-Doppler velocimetric indices are widely used for revealing the presence of a renal artery stenosis but there is scarce information as to whether they reflect the renal hemodynamics in stenotic and non-stenotic kidneys. Objectives and methods We evaluated the pulsatility and resistive indices (PI and RI), acceleration (A) and acceleration time (A t) and correlated their values with those of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), renal vascular resistance (RVR) and filtration fraction (FF) estimated by single kidney scintigraphy in 24 kidneys with 70–95% renal artery stenosis (atherosclerotic n = 17, fibromuscular n = 7) and in 27 non-stenotic kidneys (11 contralateral to renal artery stenosis and 16 of patients with essential hypertension). In patients with stenotic kidneys, these measurements were repeated within 7 days after a successful percutaneous transluminal renal angioplasty (PTRA) (in 11 arteries performed in combination with stent implantation). Results Prior to dilation we found that the stenotic kidneys had significantly lower values of ERPF, GFR and higher RVR than the non-stenotic kidneys and that these hemodynamic alterations were associated with those, also statistically significant, of the four velocimetric indices. In non-stenotic kidneys, there were highly significant relationships between PI and ERPF, and RVR (r = − 0.68 and 0.81 respectively P < 0.01); similar relationships were found for RI (r = − 0.67 and 0.78 P < 0.01) whereas no such correlations were found between these two velocimetric indices and GFR and FF; also no correlations were found between A and A t and ERPF, GFR, RVR and FF. In stenotic kidneys no significant correlations were found between any of the velocimetric and the hemodynamic indices. Renal artery dilation induced clear cut increments in ERPF, GFR and reduction in RVR in post-stenotic kidneys, which were associated with normalization of all four velocimetric indices. No relationships were observed between the renal hemodynamic and the velocimetric changes induced by dilation; however in post-stenotic kidneys the relationships between PI and RI, ERPF and RVR were restored as in non-stenotic kidneys. Conclusions These data indicate that PI and RI can be used to assess ERPF and RVR both in non-stenotic and post-stenotic kidneys; however, none of the velocimetric indices examined in this study can provide valid informations on the renal hemodynamics of stenotic kidneys and on their changes induced by PTRA.

P-171: Relationship between echo-Doppler velocimetric indices and renal hemodinamics in stenotic and non stenotic kidneys

creased significantly during the first 6 months (from 302.4 6 6.6 to 151.8 6 13.3 g; mean6 SEM) after renal transplantation, but increased during the following 6 months (2936 10.5 g; mean6 SEM). Pulse pressure remained unchanged throug-hout the study period (before renal transplantation: 60.76 2.7 mmHg, 12 months after allo-grafting: 61.8 6 3.2 mmHg; mean6 SEM). There was no correlation (Pearsson) between LVH and pulse pressure. Pulse pressure was strongly correlated with age (P,0.01), whereas LVM correlated positively with BMI (P ,0.04). In renal transplant recipients, there is no association between LVH and pulse pressure.