Rosana Hernandez

Contribution of Gene Sequence Variations of the Hepatic Cytochrome P450 3A4 Enzyme to Variability in Individual Responsiveness to Clopidogrel

Objectives—Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results—The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation (P=0.025) and better responsiveness (P=0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P=0.025), increased platelet inhibition (P=0.006), and a more optimal drug response (P=0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Conclusions—The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.

Findings of intravascular ultrasound during acute stent thrombosis

Objective: To evaluate the potential role of intravascular ultrasound (IVUS) in evaluating patients experiencing an episode of acute stent thrombosis. Design and setting: Prospective observational study in a cardiac catheterisation laboratory in a university teaching hospital. Patients and interventions: IVUS was used to examine 12 patients undergoing coronary interventions for stent thrombosis to gain further mechanistic insights and to guide treatment. IVUS studies were obtained before and after intervention with a motorised pullback device. Main outcome measures: Qualitative and volumetric IVUS analyses. Results: Angiographically, 10 patients had occluded vessels and two patients had intraluminal filling defects within the stent. IVUS showed an occlusive thrombus in all patients. Thrombus volume was 90 (77) mm3, which was 51 (21)% of total stent volume. There was evidence of severe stent underexpansion in most patients and no patient fulfilled standard criteria for optimal stent implantation. Stent malapposition was detected in four patients, edge dissections were seen in two patients, and significant inflow-outflow disease was present in 11 patients. During interventions IVUS findings led to the use of higher pressures or larger balloons than those used during initial stenting in 10 patients. In addition, four patients required additional stenting, whereas a thrombectomy device alone was selected for one patient. After the procedure final minimum stent area (7.1 (2.1) v 5.3 (2) mm2, p < 0.005) and stent expansion (83.2 (17) v 62.1 (15)%, p < 0.005) improved compared with pre-interventional values. However, residual lining thrombus was still visualised in eight patients (25 (19) mm3, accounting for a 17% of final stent volume). Conclusions: IVUS provides an attractive technique to characterise fully the pattern of stent thrombosis, to identify readily the underlying mechanical predisposing factors, and to guide repeated coronary interventions.

Determinants of coronary compliance in patients with coronary artery disease: an intravascular ultrasound study.

OBJECTIVES The aim of this study was to elucidate determinants of coronary compliance in patients with coronary artery disease. BACKGROUND Intravascular ultrasound potentially enables in vivo evaluation of coronary artery compliance. METHODS Twenty-seven patients (mean age [+/- SD] 57 +/- 11 years, three women) undergoing coronary angioplasty were studied with intravascular ultrasound imaging. A mechanical intravascular ultrasound system (4.8F, 20 MHz) was used. A total of 58 different coronary segments (proximal to the target angiographic lesion) were studied. Of these, 35 were located in the left anterior descending, 9 in the left main, 8 in the left circumflex and 6 in the right coronary arteries. During intravascular ultrasound imaging, 22 segments (38%) appeared normal, but 36 (62%) had plaque (24 fibrotic, 3 lipidic and 9 calcified). Systolic-diastolic changes in area (delta A) and pressure (delta P) with respect to vessel area (A) were used to study normalized compliance (Normalized compliance = [delta A/A]/delta P [mm Hg-1 x 10(3)]). RESULTS Lumen area and plaque area were 12.6 +/- 5.7 and 3 +/- 3 min2, respectively. Plaque was concentric (more than two quadrants) at 10 sites, but the remaining 26 plaques were eccentric. Compliance was inversely related to age (r = -0.34, p < 0.05) but was not related to other clinical variables. Compliance was greater in the left main coronary artery (3.9 +/- 2.1 vs. 1.8 +/- 1.2 mm Hg-1, p < 0.05) and in coronary segments with normal findings on ultrasound imaging (2.9 +/- 1.9 vs. 1.6 +/- 1.1 mm Hg-1, p < 0.01). Moreover, at diseased coronary segments compliance was lower in calcified plaques than in other types of plaques (1.2 +/- 0.7 vs. 2.3 +/- 1.6 mm Hg-1, p < 0.01) but was similar in concentric and eccentric plaques (1.6 +/- 1.5 vs. 1.6 +/- 0.9 mm Hg-1). Plaque area (r = -0.38, p < 0.01) was inversely correlated with compliance. On multivariate analysis, only age and plaque area were independently related to compliance. CONCLUSIONS Intravascular ultrasound may be used to evaluate compliance in patients with coronary artery disease. Compliance is reduced with increasing age and is mainly determined by the arterial site and by the presence, size and characteristics of plaque on intravascular ultrasound imaging.

Intravascular ultrasound imaging of angiographically normal coronary segments in patients with coronary artery disease

Intravascular ultrasound imaging (IVUS) constitutes a new diagnostic technique that provides unique information concerning arterial wall structure and luminal dimensions. To assess the anatomic features of angiographically normal coronary arteries in patients with coronary artery disease, 25 patients (aged 61 +/- 9 years) underwent an IVUS examination before coronary angioplasty. A mechanical (20 MHz) IVUS system was used. Atherosclerotic plaques were identified by IVUS as well-defined structures of variable echodensity protruding into the coronary lumen or disrupting normal coronary wall architecture. Five (20%) patients had minor angiographic irregularities proximal to the target lesion, and all 5 had plaque on IVUS. In the remaining 20 patients the coronary segments proximal to the target lesion were angiographically normal. Of these, IVUS demonstrated the presence of plaque in 16 (80%) patients at 19 different angiographic sites (3 lipidic, 13 fibrotic, 3 calcified). Fifteen plaques had a semilunar appearance and did not disrupt luminal contour, but four clearly protruded into the coronary lumen. Six plaques were located in the left main artery, 4 in the left anterior descending artery, 4 in the left circumflex artery, 4 in the right coronary artery, and 1 in a vein graft. On quantitative angiography, luminal diameter, at sites angiographically normal but with plaque on IVUS, was 3.6 +/- 1 mm. At these sites, both minimal luminal diameter (3.5 +/- 1 mm) and maximal luminal diameter (4.3 +/- 1 mm) on IVUS correlated (r = 0.59 and r = 0.61, respectively) with angiographic measurements (p < 0.05). No complications resulted from the IVUS study.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and angiographic implications of coronary stenting in thrombus-containing lesions.

OBJECTIVES This study sought to determine the results of coronary stenting in thrombus-laden lesions. BACKGROUND The angiographic evidence of intracoronary thrombus has classically been considered a formal contraindication to stent implantation. However, with increasing use of stenting, the indications for this technique have widened to include treatment of patients who have an acute coronary syndrome or lesions with adverse anatomic features. METHODS We studied 86 consecutive patients (mean age +/- SD 61 +/- 11 years, 14 women) undergoing coronary stenting of a thrombus-containing lesion; the procedure was performed electively in 39% and after angioplasty failure in 61%. Sixty-four patients (75%) were treated for unstable angina, and 19 (22%) underwent the procedure during an acute myocardial infarction. A specific protocol that included clinical and late angiographic follow-up was used. RESULTS Angiographic success was obtained in 83 patients (96%). Five patients (6%) died during the hospital stay despite angiographic success; four of these had cardiogenic shock, and one (1%) had subacute stent thrombosis. Non-Q wave myocardial infarction developed in five additional patients (6%), and four of these five had data consistent with distal embolization. Of the 78 patients discharged with angiographic success, 67 (86%) were event-free and clinically improved at last follow-up visit (12 +/- 11 months). During the follow-up period, eight patients required repeat angioplasty, one patient required heart transplantation, and two patients died. Quantitative angiography demonstrated excellent angiographic results after stenting (minimal lumen diameter 0.31 +/- 0.4 vs. 2.77 +/- 0.6 mm). Late angiographic follow-up (5.5 +/- 1 months) was obtained in 50 patients with 54 lesions (93% of eligible), revealing a minimal lumen diameter of 2.0 +/- 1 mm and restenosis (lumen narrowing > 50%) in 18 lesions (33%). CONCLUSIONS Coronary stenting constitutes an effective therapeutic strategy for patients with thrombus-containing lesions, either after failure of initial angioplasty or electively as the primary procedure. Coronary stenting in this adverse anatomic setting results in a high degree of angiographic success, a low incidence of subacute thrombosis and an acceptable restenosis rate.

Coronary stenting for acute coronary dissection after coronary angioplasty: Implications of residual dissection

OBJECTIVES The aim of this study was to assess the implications of residual coronary dissections after stenting. BACKGROUND Coronary stenting is currently used in selected patients with coronary dissection after angioplasty. However, in some patients the total length of the dissection may not be completely covered with the device. METHODS Forty-two consecutive patients (mean [+/- SD] age 58 +/- 11 years; 39 men, 3 women) undergoing stenting for a major coronary dissection after angioplasty were studied. RESULTS Thirty (67%) coronary dissections were small (< or = 15 mm), and 29 (64%) were occlusive (Thrombolysis in Myocardial Infarction [TIMI] flow grade < or = 2). In 3 patients, coronary stenting was unable to open large occlusive dissections, but a good angiographic result was obtained in 39 patients (93%). After stenting, 22 of these patients (56%) had no visible residual dissections, and 13 (33%) had small and 4 (10%) had large residual dissections. These residual dissections were stable and did not compromise coronary flow. In a repeat angiogram (24 h later) the stent was patent in all 39 patients. However, two patients experienced a subacute stent occlusion. Of the remaining 37 patients, 36 (97%) had a late angiogram after stenting. Quantitative angiography revealed a reduction in minimal lumen diameter at the stent site (2.6 +/- 0.4 vs. 2 +/- 0.7 mm, p < 0.05) and a trend toward improvement in vessel diameter at the site of the previous residual dissection (1.7 +/- 0.6 vs. 1.9 +/- 0.5 mm, p < 0.1). The angiographic image of residual dissection disappeared in all patients. These factors provided a rather smooth angiographic appearance at follow-up. The four patients with large residual dissections after stenting did not have restenosis and were asymptomatic at last visit. CONCLUSIONS Coronary stenting is effective in the management of acute coronary dissections after angioplasty. In this setting, small residual dissections are frequently seen but have a good outcome and disappear at follow-up. Large residual dissections may have a good outcome if coronary flow is not impaired and no residual stenosis is visualized.

Disturbed Coronary Hemodynamics in Vessels with Intermediate Stenoses Evaluated with Fractional Flow Reserve: A Combined Analysis of Epicardial and Microcirculatory Involvement in Ischemic Heart Disease

Background— In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown. Methods and Results— Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR>0.80 and CFR<2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75th percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR>0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR>0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4–31.8)] than those with FFR⩽0.80 [17.3 (95% confidence interval, 13.0–21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR (r=−0.207, P=0.055), and in vessels with FFR>0.80 and CFR<2 (n=28, 39%), IMR had a wide dispersion (7–72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR⩽0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation. Conclusions— A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.

Early angiographic changes of side branches arising from a Palmaz-Sehatz stented coronary segment: Results and clinical implications☆

OBJECTIVES The purpose of this study was to assess the effects and clinical implications of Palmaz-Schatz stent implantation on coronary blood flow in side branches arising from a stented coronary artery segment. BACKGROUND The occlusion of a side branch is a well defined risk after balloon angioplasty. However, the impact of stenting on the coronary flow in side branches arising within the stented segment is unknown. METHODS Forty-six stented coronary artery segments with 79 side branches emerging from the stented segment were analyzed. Angiographic studies were performed before angioplasty, after balloon dilation, immediately after stenting and 24 h later. Side branches were classified as follows: type A (> or = 1 mm in diameter, with ostial narrowing), type B (> or = 1 mm in diameter, without ostial narrowing), type C (< 1 mm in diameter, with ostial narrowing) and type D (< 1 mm in diameter, without ostial narrowing). Quantitative angiography was used to assess the diameter of the side branches. RESULTS Stents were implanted electively in lesions with restenosis (41 stents, 89%) or with a suboptimal result after angioplasty (5 stents, 11%). Nine side branches (11%) were type A, 25 (32%) type B, 7 (9%) type C and 38 (48%) type D. At baseline, 68 side branches had Thrombolysis in Myocardial Infarction (TIMI) trial flow grade 3; 10 had grade 2; and 1 had grade 1. Flow worsened (TIMI grade > or = 1) in six side branches (8%) after balloon dilation and in four side branches (5%) after stenting. One additional side branch (1%) was occluded at 24 h. Of the 34 side branches > or = 1 mm in diameter (mean diameter 1.5 +/- 0.3 mm), 2 (6%) had flow impairment after stenting. Three patients experienced transient angina, but no acute myocardial infarction occurred as a result of a side branch occlusion. CONCLUSIONS Coronary artery stenting does not modify anterograde flow in 90% of side branches. Coronary flow is reduced after stenting in a few branches, but this does not appear to have major clinical relevance.

Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]).

OBJECTIVES This study sought to assess the effectiveness of a strategy of using drug-eluting stents (DES) with a different drug (switch) in patients with DES in-stent restenosis (ISR). BACKGROUND Treatment of patients with DES ISR remains a challenge. METHODS The RIBS-III (Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent) study was a prospective, multicenter study that aimed to assess results of coronary interventions in patients with DES ISR. The use of a different DES was the recommended strategy. The main angiographic endpoint was minimal lumen diameter at 9-month follow-up. The main clinical outcome measure was a composite of cardiac death, myocardial infarction, and target lesion revascularization. RESULTS This study included 363 consecutive patients with DES ISR from 12 Spanish sites. The different-DES strategy was used in 274 patients (75%) and alternative therapeutic modalities (no switch) in 89 patients (25%). Baseline characteristics were similar in the 2 groups, although lesion length was longer in the switch group. At late angiographic follow-up (77% of eligible patients, median: 278 days) minimal lumen diameter was larger (1.86 ± 0.7 mm vs. 1.40 ± 0.8 mm, p = 0.003) and recurrent restenosis rate lower (22% vs. 40%, p = 0.008) in the different-DES group. At the last clinical follow-up (99% of patients, median: 771 days), the combined clinical endpoint occurred less frequently (23% vs. 35%, p = 0.039) in the different-DES group. After adjustment using propensity score analyses, restenosis rate (relative risk: 0.41, 95% confidence interval [CI]: 0.21 to 0.80, p = 0.01), minimal lumen diameter (difference: 0.41 mm, 95% CI: 0.19 to 0.62, p = 0.001), and the event-free survival (hazard ratio: 0.56, 95% CI: 0.33 to 0.96, p = 0.038) remained significantly improved in the switch group. CONCLUSIONS In patients with DES ISR, the implantation of a different DES provides superior late clinical and angiographic results than do alternative interventional modalities.

Combined use of optical coherence tomography and intravascular ultrasound imaging in patients undergoing coronary interventions for stent thrombosis

Objective This prospective study sought to assess the diagnostic value of optical coherence tomography (OCT) compared with intravascular ultrasound (IVUS) in patients presenting with stent thrombosis (ST). Design and setting Although the role of IVUS in this setting has been described, the potential diagnostic value of OCT in patients suffering ST remains poorly defined. Catheterization Laboratory, University Hospital. Patients and interventions Fifteen consecutive patients with ST undergoing rescue coronary interventions under combined IVUS/OCT imaging guidance were analysed. Mean outcome measures Analysis and comparison of OCT and IVUS findings before and after interventions. Results Before intervention, OCT visualised the responsible thrombus in all patients (thrombus area 4.7±2.5 mm2, stent obstruction 82±14%). Minimal stent area was 4.7±2.1 mm2 leading to severe stent underexpansion (expansion 60±21%). Although red or mixed thrombus (14 patients) induced partial strut shadowing (total length 12.3±6 mm), malapposition (six patients), inflow-outflow disease (five patients), uncovered struts (nine patients) and associated in-stent restenosis (five patients, four showing neoatherogenesis) was clearly recognised. IVUS disclosed similar findings but achieved poorer visualisation of thrombus–lumen interface and strut malapposition, and failed to recognise uncovered struts and associated neoatherosclerosis. After interventions, OCT demonstrated a reduced thrombus burden (2.4±1.6 mm2) and stent obstruction (24±14%) with improvements in stent area (6.8±2.9 mm2) and expansion (75±21%) (all p<0.05). IVUS and OCT findings proved to be complementary. Conclusions OCT provides unique insights on the underlying substrate of ST and may be used to optimise results in these challenging interventions. In this setting, OCT and IVUS have complementary diagnostic values.