Enrico Mangieri

Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA

OBJECTIVES Isoprostanes, stable end-products of oxygen free radical mediated-lipid peroxidation, were measured in the coronary vessels during percutaneous transluminal coronary angioplasty (PTCA) to provide direct evidence for enhanced oxidative stress in a local milieu in vivo. BACKGROUND Percutaneous transluminal coronary angioplasty is associated with complications such as myocardial stunning and accelerated restenosis, which at least in part are mediated by oxygen free radicals. Because isoprostanes are markers of oxidant stress and potent vasoactive compounds, the formation of which is not inhibited by aspirin treatment in vivo, it is possible that these mediators are increased locally during PTCA. METHODS In 12 coronary artery disease patients who were given aspirin and ticlopidine, blood samples from coronary sinus were taken immediately before and immediately upon balloon deflation during PTCA. Isoprostane F2alpha-III, isoprostane F2alpha-VI, and TxB2 were quantified after extraction and chromatography using a stable dilution isotope gas chromatography/mass spectrometry assay. RESULTS Coronary sinus and left main coronary artery levels of iPF2alpha-III and iPF2alpha-VI at baseline were (mean +/- SEM) 40 +/- 9 pg/ml and 115 +/- 10 pg/ml, respectively. The TxB2 levels were undetectable. Following PTCA, isoprostane levels markedly increased (mean +/- SEM): iPF2alpha-III, 125 +/- 12 pg/ml (p < 0.001); iPF2alpha-VI, 295 +/- 20 pg/ml (p < 0.001), whereas TxB2 levels remained undetectable. CONCLUSIONS These results indicate that PTCA induces coronary sinus increase in F2-isoprostane formation, and they also provide direct evidence for enhanced oxidative stress in a local milieu in vivo. Thus, an increased F2-isoprostane formation could play a role in the pathogenesis of some PTCA-associated untoward events.

Angina in Fabry Disease Reflects Coronary Small Vessel Disease

Background—Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear. Methods and Results—Basal troponin I level, exercise stress test, single-photon emission computed tomography imaging with 99mTc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and left ventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external to lumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluated by using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20 mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercise stress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive for stress-induced perfusion defects in all patients with FD with angina. Epicardial coronaries were structurally normal but showed slow flow in all and were associated with aneurisms of posterior left ventricular wall in 3 cases. Histology showed remarkable lumen narrowing of most intramural arteries (mean E/L ratio=3.5±1.2; P<0.001 versus both control groups), because of hypertrophy and proliferation of smooth muscle and endothelial cells, both engulfed by glycosphingolipids. Replacement fibrosis exceeded that of both controls (P<0.001). Small vessel disease correlated with coronary slow flow and extent of fibrosis, but did not with patients’ age, sex, and degree of left ventricular hypertrophy. Conclusions—patients with FD with angina have perfusion defects, slow coronary flow, and luminal narrowing of intramural arteries. Small vessel disease may contribute to symptomatic limitation and progressive myocardial dysfunction.

Three‐Dimensional Echocardiography and 2D‐3D Speckle‐Tracking Imaging in Chronic Pulmonary Hypertension: Diagnostic Accuracy in Detecting Hemodynamic Signs of Right Ventricular (RV) Failure

Background Our aim was to compare three‐dimensional (3D) and 2D and 3D speckle‐tracking (2D‐STE, 3D‐STE) echocardiographic parameters with conventional right ventricular (RV) indexes in patients with chronic pulmonary hypertension (PH), and investigate whether these techniques could result in better correlation with hemodynamic variables indicative of heart failure. Methods and Results Seventy‐three adult patients (mean age, 53±13 years; 44% male) with chronic PH of different etiologies were studied by echocardiography and cardiac catheterization (25 precapillary PH from pulmonary arterial hypertension, 23 obstructive pulmonary heart disease, and 23 postcapillary PH from mitral regurgitation). Thirty healthy subjects (mean age, 54±15 years; 43% male) served as controls. Standard 2D measurements (RV–fractional area change–tricuspid annular plane systolic excursion) and mitral and tricuspid tissue Doppler annular velocities were obtained. RV 3D volumes and global and regional ejection fraction (3D‐RVEF) were determined. RV strains were calculated by 2D‐STE and 3D‐STE. RV 3D global‐free‐wall longitudinal strain (3DGFW‐RVLS), 2D global‐free‐wall longitudinal strain (GFW‐RVLS), apical‐free‐wall longitudinal strain, basal‐free‐wall longitudinal strain, and 3D‐RVEF were lower in patients with precapillary PH (P<0.0001) and postcapillary PH (P<0.01) compared to controls. 3DGFW‐RVLS (hazard ratio 4.6, 95% CI 2.79 to 8.38, P=0.004) and 3D‐RVEF (hazard ratio 5.3, 95% CI 2.85 to 9.89, P=0.002) were independent predictors of mortality. Receiver operating characteristic curves showed that the thresholds offering an adequate compromise between sensitivity and specificity for detecting hemodynamic signs of RV failure were 39% for 3D‐RVEF (AUC 0.89), −17% for 3DGFW‐RVLS (AUC 0.88), −18% for GFW‐RVLS (AUC 0.88), −16% for apical‐free‐wall longitudinal strain (AUC 0.85), 16 mm for tricuspid annular plane systolic excursion (AUC 0.67), and 38% for RV‐FAC (AUC 0.62). Conclusions In chronic PH, 3D, 2D‐STE and 3D‐STE parameters indicate global and regional RV dysfunction that is associated with RV failure hemodynamics better than conventional echo indices.

Effectiveness of Two-Year Clopidogrel Aspirin in Abolishing the Risk of Very Late Thrombosis After Drug-Eluting Stent Implantation (from the TYCOON (Two-Year ClOpidOgrel Need) Study)

It remains unclear whether dual antiplatelet therapy >12 months might carry a better prognosis after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). To address the hypothesis that in the real world the risk of very late thrombosis after PCI with DESs can be decreased by an extended use of clopidogrel, we set up the Two-Year ClOpidOgrel Need (TYCOON) registry and prospectively investigated the impact on very late thrombosis of 12- versus 24-month dual antiplatelet regimens in an unselected population. The registry enrolled 897 consecutive patients who underwent PCI with stenting from January 1, 2003, to December 31, 2004, and had dual antiplatelet therapy. All patients had a 4-year clinical follow-up. In the 447 patients with DES implantation, the dual antiplatelet regimen after PCI was given for 12 months in the 173 patients treated in 2003 (12-month group) and for 24 months in the 274 patients treated in 2004 (24-month group). Comparison between groups did not reveal any significant difference in baseline clinical characteristics, angiographic and procedural features, and major adverse cardiac events. During follow-up, there were 5 cases of stent thrombosis after PCI in the 12-month DES group and 1 case in the 24-month DES group (p = 0.02). Specifically, there were 2 cases of subacute thrombosis (1 in each group), no case of late thrombosis, and 4 cases of very late thrombosis occurring at 13, 15, 17, and 23 months after DES implantation in the 12-month group only. In conclusion, a 2-year dual antiplatelet regimen with aspirin and clopidogrel can prevent the occurrence of very late stent thrombosis after PCI with DESs.

Intravenous Ascorbic Acid Infusion Improves Myocardial Perfusion Grade During Elective Percutaneous Coronary Intervention. Relationship With Oxidative Stress Markers

OBJECTIVES Our goal was to explore whether antioxidant vitamin C infusion is able to affect the microcirculation perfusion in patients undergoing elective percutaneous coronary intervention for stable angina. BACKGROUND Periprocedural myocardial injury in the setting of elective percutaneous coronary intervention is associated with increased risk of death, recurrent infarction, and revascularization at follow-up. Despite excellent epicardial blood flow, impaired microcirculatory reperfusion may persist and increases the risk of vascular recurrences. Post-percutaneous coronary intervention induced-oxidative stress is one of the potential mechanisms accounting for impaired perfusion. METHODS Fifty-six patients were enrolled in a prospective, single-center, randomized study comparing 1 g vitamin C infusion (16.6 mg/min, over 1 h before percutaneous coronary intervention) versus placebo. RESULTS At the baseline, Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade <2 was observed in 89% and in 86% of patients randomized to the placebo or vitamin C infusion group, respectively (p > 0.05). After percutaneous coronary intervention, these percentages decreased in the placebo group (32%) and in greater measure in the vitamin C group (4%, p < 0.01). Complete microcirculatory reperfusion (TIMI myocardial perfusion grade = 3) was achieved in 79% of the vitamin C-treated group compared with 39% of the placebo group (p < 0.01); 8-hydroxy-2-deoxyguanosine (p < 0.002) and 8-iso-prostaglandin F(2alpha) (p < 0.02) plasma levels significantly increased in the placebo group while they were significantly reduced in the vitamin C-treated group (p < 0.0001). TIMI myocardial perfusion grade changes from the baseline showed significant correlation with 8-hydroxy-2-deoxyguanosine (p < 0.006) or 8-iso-prostaglandin F(2alpha) (p < 0.01) plasma levels changes. CONCLUSIONS In patients undergoing elective percutaneous coronary intervention, impaired microcirculatory reperfusion is improved by vitamin C infusion suggesting that oxidative stress is implicated in such a phenomenon.

Anoxia-reoxygenation enhances platelet thromboxane A2 production via reactive oxygen species-generated NOX2: effect in patients undergoing elective percutaneous coronary intervention.

Objective—Platelets undergoing anoxia-reoxygenation (AR) simultaneously increase reactive oxygen species (ROS) and thromboxane (Tx) B2. Our aim was to assess whether there is an interplay between activation of NOX2, the catalytic subunit of NADPH oxidase, and platelet TxB2 in vitro and in vivo. Methods and Results—Platelets that underwent AR had enhanced ROS. This was associated with NOX2 activation and was inhibited by incubation with NOX2-blocking peptide. AR was associated with TxB2 and isoprostane production, which were inhibited by NOX2-blocking peptide, vitamin C, and the inhibitor of phospholipase A2. Platelet incubation with 100 &mgr;mol/L aspirin fully prevented AR-induced TxA2 but did not affect isoprostane production. We included 56 aspirin-treated patients undergoing elective percutaneous coronary intervention (PCI) who were randomly allocated to receive either placebo or intravenous infusion of 1 g of vitamin C. Blood TxB2, isoprostanes, and soluble NOX2-derived peptide, a marker of systemic NADPH oxidase activation, significantly increased at 60 and 120 minutes after PCI in placebo-treated but not in vitamin C-treated patients. Conclusion—AR is associated with overproduction of platelet TxB2 and isoprostanes, which is dependent on NOX2-dependent ROS generation. Low doses of aspirin are unable to prevent TxB2 formation in patients who undergo PCI.

Early detection of coronary artery disease by 64-slice multidetector computed tomography in asymptomatic hypertensive high-risk patients

BACKGROUND The 64-slice multidetector-row computed tomography (MDCT) is an accurate noninvasive technique for assessing the degree of luminal narrowing in coronary arteries of patients with chronic ischemic disease. Aim of this study was to determine the value of MDCT in comparison to invasive coronary angiography (ICA) for detecting the presence and extent of coronary atherosclerotic plaques in a population of asymptomatic, hypertensive patients considered to be at high risk for cardiovascular events. METHODS We studied 67 asymptomatic, hypertensive patients at high-risk (Euro Score >5%). All patients had negative or nondiagnostic findings at exercise stress testing and therefore underwent both MDCT and ICA. RESULTS In the per-patient analysis, MDCT correctly identified 16/17 (94%) patients with significant coronary artery disease involving at least 1 vessel and 48/50 (96%) normal subjects. In the per-segment analysis, MDCT correctly detected 21/22 (95%) coronary segments with a stenosis >or=50% and 856/868 (98%) normal segments, with a high negative predictivity of normal scans (100%). There was a good concordance between MDCT and ICA, with a high Pearson correlation coefficient between the coronary narrowings with the two techniques (r=0.84, p<0.01). Mean coronary calcium score was higher for the 17 patients with significant coronary artery disease on ICA than in the 50 patients without (422+/-223 HU vs 72+/-21 HU p<0.001). The ROC curves identified 160 as the best calcium volumetric score cut-off value able to identify >or=1 significant coronary stenosis with sensitivity 88% and specificity 85%. CONCLUSIONS MDCT is an excellent noninvasive technique for early identification of significant coronary stenoses in high risk asymptomatic hypertensive patients and might provide unique information for the screening of this broad population.

Recovery of contractility of viable myocardium during inotropic stimulation is not dependent on an increase of myocardial blood flow in the absence of collateral filling

OBJECTIVES The purpose of this study was to determine whether contractile recovery induced by dobutamine in dysfunctioning viable myocardium supplied by nearly occluded vessels is related to an increase in blood flow in the absence of collaterals. BACKGROUND Dobutamine is used to improve contractility in ventricular dysfunction during acute myocardial infarction. However, it is unclear whether a significant increase in regional blood flow may be involved in dobutamine effect. METHODS Twenty patients with 5- to 10-day old anterior infarction and > or =90% left anterior descending coronary artery stenosis underwent 99mTc-Sestamibi tomography (to assess myocardial perfusion) at rest and during low dose (5 to 10 microg/kg/min) dobutamine echocardiography. Rest echocardiography and scintigraphy were repeated >1 month after revascularization. Nine patients had collaterals to the infarcted territory (group A), and 11 did not (group B). RESULTS Baseline wall motion score was similar in both groups (score 15.9+/-1.3 vs. 17.4+/-2.0, p = NS), whereas significant changes at dobutamine and postrevascularization studies were detected (F[2,30] = 409.79, p < 0.0001). Wall motion score improved significantly (p < 0.001) in group A both at dobutamine (-5.3+/-2.2) and at postrevascularization study (-5.5+/-1.9), as well as in group B (-3.9+/-2.8 and -4.5+/-2.4, respectively). Baseline 99mTc-Sestamibi uptake was similar in both groups (62.9+/-9.7% vs. 60.3+/-10.4%, p = NS), whereas at dobutamine and postrevascularization studies a significant change (F[2,30] = 65.17, p < 0.0001) and interaction between the two groups (F[2,30] = 33.14, p < 0.0001) were present. Tracer uptake increased significantly in group A both at dobutamine (+ 10.9+/-7.9%, p < 0.001) and at postrevascularization study (12.1+/-8.7%, p < 0.001). Conversely, group B patients showed no change in tracer uptake after dobutamine test (-0.4+/-5.8, p = NS), but only after revascularization (+8.8+/-7.2%, p < 0.001). CONCLUSIONS The increase in contractility induced by low dose dobutamine infusion in dysfunctional viable myocardium supplied by nearly occluded vessels occurs even in the absence of a significant increase in blood flow.

Handgrip increases endothelin-1 secretion in normotensive young male offspring of hypertensive parents.

OBJECTIVES We tested the hypothesis that an abnormal response of plasma endothelin-1 (ET-1) is elicited by handgrip exercise (HG) in young normotensive offspring of hypertensive parents. BACKGROUND It has been hypothesized that ET-1 is involved in blood pressure control and plays a pathophysiologic role in the development of clinical hypertension. METHODS Two groups of healthy male subjects, 11 with hypertensive parents (group A) and 10 without a family history of hypertension (group B), underwent 4 min of HG at 50% maximal capacity. Heart rate and blood pressure and plasma levels of ET-1, epinephrine and norepinephrine were measured at baseline, peak HG, and after 2 (R2) and 10 (R10) min of recovery. RESULTS Group A had higher norepinephrine levels than group B throughout the test (baseline 181+/-32 [SEM] vs. 96+/-12 pg/ml, p < 0.05; peak HG 467+/-45 vs. 158+/-12 pg/ml, p < 0.000001; R2 293+/-46 vs. 134+/-8 pg/ml, p < 0.01; RO1 214+/-27 vs. 129+/-10 pg/ml, p < 0.0005); no significant difference in epinephrine levels was detected. Compared with group B subjects, group A had higher baseline ET-1 levels (1.07+/-0.14 vs. 0.59+/-0.11 pg/ml, p < 0.02), which increased to a greater extent at peak HG (1.88+/-0.31 vs. 0.76+/-0.09 pg/ml, p < 0.005) and R2 (2.46+/-0.57 vs. 1.31+/-0.23 pg/ml, p < 0.05) and remained elevated at R10 (3.16+/-0.78 vs. 0.52+/-0.09 pg/ml, p < 0.002). Multivariate analysis demonstrated that only a family history of hypertension (chi-square=7.59, p=0.0059) and ET-1 changes during HG (chi-square=4.23, p=0.0398) were predictive of blood pressure response to HG and that epinephrine and norepinephrine were not. CONCLUSIONS The response to HG in offspring of hypertensive parents produced increased ET-1 plasma levels and resulted in a sustained ET-1 release into the bloodstream during recovery compared with offspring of normotensive parents. This may be an important marker for future clinical hypertension.

Assessment of Right Ventricular Function in Obstructive Sleep Apnea Syndrome and Effects of Continuous Positive Airway Pressure Therapy: A Pilot Study

BACKGROUND It is known that obstructive sleep apnea syndrome (OSAS) can affect right ventricular (RV) performance even in the absence of systemic hypertension and other known cardiac or obstructive pulmonary disease. The purpose of the present study was to assess RV function in OSAS using 3-D echocardiography and speckle tracking echocardiography (STE) and evaluate changes after continuous positive airway pressure (CPAP) treatment. METHODS Thirty-seven patients with OSAS without comorbidities and thirty control subjects were studied using 3-D echocardiography and STE. Fifteen patients underwent CPAP therapy and were studied before and after treatment. RV 3-D ejection fraction was calculated. Peak systolic strain was determined. RV dyssynchrony was defined as SD of the 6 time to peak systolic strain values. RESULTS 3-D RV ejection fraction was lower and RV dyssynchrony was greater in patients with moderate-severe OSAS compared with control subjects in the presence and absence of pulmonary hypertension. 3-D RV ejection fraction and RV dyssynchrony were independently associated with apnea-hypopnea index. Patients treated with CPAP had significant changes in RV parameters. CONCLUSIONS 3-D RV ejection fraction and RV dyssynchrony were abnormal in OSAS patients compared with control subjects and associated with OSAS severity. RV 3-D STE abnormalities improved after chronic application of CPAP.