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We describe a patient who presents with chest discomfort 30 h after having an accident with an all-terrain vehicle. His follow-up coronary computed tomography angiogram revealed early recanalization of his coronary artery with conservative medical therapy. (Level of Difficulty: Intermediate.), Graphical abstract

Lower pH after out-of-hospital cardiac arrest (OHCA) has been associated with worsening neurologic outcome, with7.2 identified as an "unfavorable resuscitation feature" in consensus treatment algorithms despite conflicting data. This study aimed to describe the relationship between decremental post-resuscitation pH and neurologic outcomes after OHCA.Consecutive OHCA patients treated with targeted temperature management (TTM) at multiple US centers from 2008 to 2017 were evaluated. Poor neurologic outcome at hospital discharge was defined as cerebral performance category ≥3. The exposure was initial arterial pH after return of spontaneous circulation (ROSC) analyzed in decremental 0.05 thresholds. Potential confounders (demographics, history, resuscitation characteristics, initial studies) were defined a priori and controlled for via ATT-weighting on the inverse propensity score plus direct adjustment for the linear propensity score.Of 723 patients, 589 (80%) experienced poor neurologic outcome at hospital discharge. After propensity-adjustment with excellent covariate balance, the adjusted odds ratios for poor neurologic outcome by pH threshold were: ≤7.3: 2.0 (1.0-4.0); ≤7.25: 1.9 (1.2-3.1); ≤7.2: 2.1 (1.3-3.3); ≤7.15: 1.9 (1.2-3.1); ≤7.1: 2.4 (1.4-4.1); ≤7.05: 3.1 (1.5-6.3); ≤7.0: 4.5 (1.8-12).No increased hazard of progressively poor neurologic outcomes was observed in resuscitated OHCA patients treated with TTM until the initial post-ROSC arterial pH was at least ≤7.1. This threshold is more acidic than in current guidelines, suggesting the possibility that post-arrest pH may be utilized presently as an inappropriately-pessimistic prognosticator.

Objective: There is an unmet need for noninvasive continuous blood pressure (BP) monitoring technologies in various clinical settings. We examined the accuracy of noninvasive Caretaker device against invasively measured central aortic BP. Methods: Beat-to-beat BP by Caretaker was recorded simultaneously with central aortic BP measured in patients undergoing cardiac catheterization. We derived correlations and Bland-Altman comparisons, after calibrating the Caretaker with 20 seconds of the initial catheter readings, as well as trend analyses for both systolic (SBP) and diastolic BP (DBP). We also measured left ventricular ejection time (LVET) from both aortic pressure tracing and Caretaker and compared the two. Results: A total of 47 patients were included in the study. A total of 31,369 beats obtained during the diagnostic portion of coronary angiogram were used for analysis. The correlations for SBP and DBP were 0.89 and 0.78, respectively (p < 0.001 for both). The Bland-Altman comparison yielded overall mean differences of 2.11 mmHg (SD 7.40) for SBP and 1.46 mmHg (SD 6.12) for DBP respectively (p Conclusion: Beat-to-beat BP by Caretaker showed excellent agreement and high concordance in the direction and the degree of BP change with central aortic BP. This study supports the satisfactory performance of the Caretaker device in continuous tracking of beat-to-beat BP and LVET measurements.

AB Background: Both intense endurance training and valvular regurgitation place a volume load on the right and left ventricles, potentially leading to dilation, but their effects in combination are not well-known. Purpose: The purpose of this case series is to describe the combined volume load of intense endurance athletic training and regurgitant valvular disease as well as the challenging assessment of each component's cardiovascular effect. Methods: In this article, the clinical course of three elite endurance athletes with congenital valvular disease were reviewed. Results: A swimmer with aortic regurgitation, a cyclist with aortic regurgitation, and a cyclist with pulmonary regurgitation were found to have severe dilation of the associated ventricles despite continuing to train at an elite level without symptoms. Conclusions: Because of the cumulative effects of endurance training and valvular regurgitation, each athlete manifested ventricular dilation out of proportion to their valvular disease and symptoms. Although the effects of congenital valvular disease and athletic remodeling on ventricular dilation have been thoroughly studied individually, their cumulative effect is not well understood. This complicates the assessment of athletes with valvular regurgitation and underscores the need for athlete-specific recommendations for valve replacement.

Background Out‐of‐hospital cardiac arrest ( OHCA ) results in significant morbidity and mortality, primarily from neurologic injury. Predicting neurologic outcome early post‐ OHCA remains difficult in patients receiving targeted temperature management. Methods and Results Retrospective analysis was performed on consecutive OHCA patients receiving targeted temperature management (32–34°C) for 24 hours at a tertiary‐care center from 2008 to 2012 (development cohort, n=122). The primary outcome was favorable neurologic outcome at hospital discharge, defined as cerebral performance category 1 to 2 (poor 3–5). Patient demographics, pre‐ OHCA diagnoses, and initial laboratory studies post‐resuscitation were compared between favorable and poor neurologic outcomes with multivariable logistic regression used to develop a simple scoring system ( C‐ GRA pH ). The C‐ GRA pH score ranges 0 to 5 using equally weighted variables: ( C ): coronary artery disease, known pre‐ OHCA ; ( G ): glucose ≥200 mg/dL; ( R ): rhythm of arrest not ventricular tachycardia/fibrillation; ( A ): age >45; ( pH ): arterial pH ≤7.0. A validation cohort (n=344) included subsequent patients from the initial site (n=72) and an external quaternary‐care health system (n=272) from 2012 to 2014. The c‐statistic for predicting neurologic outcome was 0.82 (0.74–0.90, P P C‐ GRA pH score, similar rates of favorable neurologic outcome were seen in both cohorts, 70% each for low (0–1, n=60), 22% versus 19% for medium (2–3, n=307), and 0% versus 2% for high (4–5, n=99) C‐ GRA pH scores in the development and validation cohorts, respectively. Conclusions C‐ GRA pH stratifies neurologic outcomes following OHCA in patients receiving targeted temperature management (32–34°C) using objective data available at hospital presentation, identifying patient subsets with disproportionally favorable ( C‐ GRA pH ≤1) and poor ( C‐ GRA pH ≥4) prognoses.

Low initial pH after out-of-hospital cardiac arrest (OHCA) has been associated with poor neurologic outcome (NO), with

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with ≥50% stenosis, Group 2 (n = 56) had one vessel with ≥50% stenosis and Group 3 (n = 70) had two or more vessels with ≥50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.

Objectives: The goal of this study was to determine the proportion of patients with left main coronary disease (LMCD) with unfavorable characteristics for percutaneous coronary intervention (PCI). Background: Published series suggest that LMCD can be treated percutaneously, however, the proportion of patients in whom PCI is an option based on angiographic criteria is unknown. Methods: In 13,228 consecutive coronary angiograms, 476 (3.6%) patients had ≤60% stenosis of the left main. In 232 patients with unprotected LMCD, the clinical characteristics and angiograms were reviewed with six features chosen as “unfavorable” for PCI: (1) Bifurcation LMCD, (2) occlusion of a major coronary, (3) ejection fraction

Fractional flow reserve (FFR) has been shown to be a useful physiologic index of coronary lesion severity in myocardial beds of patients without prior infarction and in those with remote infarction. Acute myocardial infarction (AMI) causes myocardial necrosis and microvascular stunning, embolization, and damage. Whether FFR remains a useful index of epicardial flow in the setting of recent myocardial infarction is not established. Cardiac risk factors, serum troponin I, angiographic minimal lumen diameter (MLD), percent diameter stenosis (DS), lesion length, vessel reference diameter, hyperemic central aortic pressure, hyperemic pressure distal to stenosis, and FFR were compared in 43 vessels subtending recent AMI beds to 25 control vessels, matched by lesion length and MLD, in patients without AMI. There were no differences in DS, MLD, lesion length, or reference diameter between AMI and non-AMI groups. Patients with AMI had mean troponin I levels of 91.8 +/- 162 ng/ml. Left ventricular ejection fraction was significantly lower in patients with than without AMI (55 +/- 9% vs 62 +/- 8%, p0.05). There were no significant differences in hyperemic central aortic pressure (92 +/- 13 vs 99 +/- 15 mm Hg, p = NS), hyperemic pressure distal to the stenosis (62 +/- 17 vs 66 +/- 19 mm Hg, p = NS), or FFR (0.67 +/- 17 vs 0.68 +/- 17, p = NS) between recent AMI and non-AMI control patients. There was a significant correlation between DS and FFR for both patients with (p0.001) and without (p = 0.003) infarctions. Thus, FFR and the relation between FFR and DS of lesions subtending AMI was not significantly different from FFR of angiographically matched lesions in patients without AMI.

Few randomized studies compare outcomes for focal vs. diffuse in-stent restenosis (ISR) using conventional treatments. The purpose of this study was to compare the rates of major adverse cardiac events (MACEs) for focal vs. diffuse ISR using conventional techniques. One hundred thirteen patients with ISR were prospectively classified as focal (10 mm) or diffuse (10 mm). Focal ISR was randomized to balloon angioplasty (n = 29) or restenting (n = 29) and diffuse ISR randomized to rotational atherectomy (n = 30) or restenting (n = 25). At 9 months, patients with focal ISR had higher survival free of MACEs than patients with diffuse ISR (86% vs. 63%; P0.005), with no difference between techniques. Only the presence of diffuse ISR was an independent predictor of MACE at 9 months. Thus, focal ISR has a low rate of MACE compared to diffuse ISR, which carries a high event rate regardless of treatment employed.

We tested the hypothesis that experienced interventional cardiologists can identify patients with fractional flow reserve (FFR)0.75 either by visual assessment of the angiogram or by quantitative coronary angiography (QCA). Estimation of the significance of moderate lesions is difficult. FFR can determine the physiologic significance of a stenosis. Data comparing visual assessment and QCA of moderate lesions with FFR are limited. FFR was measured in 83 moderate lesions defined as having a 40% to 70% stenosis by visual inspection. An FFR0.75 was considered "significant." Lesions were visually assessed by 3 experienced interventional cardiologists and their significance estimated. QCA was performed. Both analyses were compared with FFR. FFR averaged 0.82 +/- 0.11 and was0.75 in 15 of 83 lesions (18%). The reviewers' classification was concordant with the FFR in about half the lesions. Concordance between reviewers was poor (Spearman's rho = 0.36). Visual assessment resulted in good sensitivity (80%) and negative predictive value (91%), but poor specificity (47%) and positive predictive value (25%) compared with FFR. By QCA, no patient with stenosis60% or minimal luminal diameter1.4 mm had FFR0.75. QCA did not discriminate the significance of lesions outside of these parameters. Thus, neither visual assessment of an angiogram by experienced interventional cardiologists nor QCA can accurately predict the significance of most moderate narrowings.

Background The presence of viability in an infarct zone implies an intact microvasculature. We hypothesized that coronary flow reserve (CFR), which assesses the microcirculation, would correlate with the extent of viability in infarction zones. Methods CFR was measured after stenting in 17 patients with single vessel disease >48 hours from infarction. Viability was determined with use of single-photon emission computed tomography sestamibi imaging. Results Sestamibi uptake in the infarct zone correlated with CFR in the infarct artery ( r = 0.62, P =.008) and sestamibi uptake in the infarct zone was greater in patients with normal CFR than in patients with abnormal CFR (61.9 ± 9.1% vs 46.3 ± 9.6%, P =.004). In addition, CFR was greater in patients with viability compared with patients without viability (2.4 ± 1.3 vs 1.4 ± 0.4, P =.015). Conclusions CFR correlates with the extent of viability after infarction. Preserved CFR in an infarct-related artery implies preserved viability. (Am Heart J 2001;141:456-62.)

Background There is no method of quantifying the severity of mitral regurgitation (MR) from injection of tracer directly into the left ventricular (LV) cavity, a method commonly used in the cardiac catheterization laboratory. Methods and Results We used a previously validated mathematical model that derives regurgitant fraction (RF) from the relative tracer washout from the left atrial (LA) and LV cavities. Thirty-nine patients referred for diagnostic cardiac catheterization with clinical evidence of possible MR were included in the study. Five milliliters of a microbubble mixture was power-injected into the LV during simultaneously performed contrast echocardiography. Relative changes in background-subtracted video intensity were measured from the LV and LA, and the resultant model-derived RF was correlated with the severity of MR on cineangiography. The severity of MR ranged from 0 to 4+ on cineangiography with corresponding model-derived RF of 0 to 0.69 on contrast echocardiography. A close linear relation was noted between angiographic severity of MR and model-derived RF on contrast echocardiography ( y = 0.1 x + 0.03, r = 0.89, P Conclusions We describe a new method of measuring the severity of MR in the cardiac catheterization laboratory. Apart from being quantitative, this method can be safely used during cardiac catheterization in patients in whom iodinated contrast agents may be potentially harmful. (Am Heart J 2000;139:1109-13.)

Abstract —All- trans -retinoic acid (atRA) has potent in vitro effects on a number of processes involved in vascular injury and repair, such as modulating smooth muscle cell (SMC) proliferation and inducing SMC differentiation, and may play an important role in the in vivo response to vascular injury. We hypothesized that atRA would limit restenosis after balloon angioplasty through SMC-modulated changes in plaque size and vessel geometry. Balloon angioplasty was performed on rabbits with focal femoral atherosclerosis randomized to treatment with atRA or saline. At 28 days after balloon angioplasty, minimal luminal diameter was significantly larger in the atRA group (1.24±0.17 versus 1.12±0.22 mm, P =0.02). Histomorphometry confirmed a larger lumen area (0.51±0.20 versus 0.34±0.13 mm 2 , P =0.004) in the atRA group, with no difference in absolute plaque area. Internal elastic lamina and external elastic lamina areas were significantly larger in the atRA group (0.89±0.27 versus 0.66±0.24 mm 2 , P =0.001, and 1.29±0.38 versus 0.98±0.32 mm 2 , P =0.001, respectively). Vessel sections exhibited significantly more α-actin and desmin immunostaining ( P =0.01) in the atRA-treated group. No differences in early cellular proliferation and collagen content were detected with the use of bromodeoxyuridine. In this atherosclerotic model of vascular injury, atRA limits restenosis after balloon angioplasty by effects secondary to overall vessel segment enlargement at the angioplasty site rather than by effects on plaque size or cellular proliferation. Increased α-actin and desmin immunostaining suggest a possible role for phenotypic modulation of SMCs in this favorable remodeling effect.

In 108 consecutive patients without abrupt vessel closure referred for repeat coronary angiography within 30 days of successful coronary intervention, 28 (26%) were found with restenosis at the treated site. None of the 27 patients who underwent stenting were found to have early restenosis; balloon angioplasty without stenting was the only independent predictor of early restenosis in patients with recurrent symptoms within 30 days of intervention.

Recent studies demonstrate increased cellular adhesion molecule expression by neointimal endothelium overlying primary and restenotic atherosclerotic plaque. In this study, we developed an atherosclerotic mouse model of arterial injury and characterized adhesion molecule expression after injury. Sixteen apolipoprotein-E-(ApoE)-deficient mice fed a Western-type diet for 4 weeks underwent carotid artery wire denudation at week 2. For each segment, the extent of neointima formation and medial thickening, or adhesion molecule expression, were scored separately on a scale from 0 (no plaque/thickening or expression) to 3 (extensive plaque/thickening or expression) using Movat staining (n = 3) or immunohistochemical analysis (n = 13). Histology revealed significant medial thickening (1.8 ± 0.9 vs. 0.3 ± 0.5, p < 0.001) versus controls and pronounced staining for monocytes/macrophages in the wall of injured vessels. Immunohistochemical analysis showed more robust expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the luminal surface of injured arteries versus controls (2.2 ± 0.6 vs. 1.4 ± 0.7, p < 0.01, and 2.5 ± 0.5 vs. 1.2 ± 0.6, p < 0.001, respectively). Injury increased adventitial ICAM-1 expression (2.6 ± 0.5 vs. 1.6 ± 0.5, p < 0.002) and medial VCAM-1 expression (2.2 ± 0.6 vs. 1.2 ± 0.7, p < 0.004). Thus, carotid injury results in significant medial thickening and increases adhesion molecule expression beyond that induced in ApoE-deficient mice fed a Western diet alone. The observation of macrophage infiltration into the media at sites of increased ICAM-1 and VCAM-1 expression suggests that these molecules may mediate monocyte/macrophage trafficking into the wall of injured arteries.

The aim of this study was to compare perfusion patterns on myocardial contrast echocardiography with those on myocardial perfusion scintigraphy for the assessment of myocardial viability in patients with previous myocardial infarclion. Accordingly, perfusion scores with the two techniquew were compared in 91 ventricular regions in 21 patients with previous (>6 weeks old) myocardial infarction. Complete concordance between the two techniques was found in 63 (69%) regions; 25 (27%) regions were discordant by only 1 grade, and complete discordance (2 grades) was found in only 3 (3%) regions. A kappa statistic of 0.65 indicated good concordance between the two techniques. Although the scores on both techniques demonstrated a relation with the wall motion score, the correlation between the myocardial contrast echocardiography and wall motion scores was closer ( r =-0.63 vs r =-0.50, p =0.05). It is concluded that myocardial contrast echocardiography provides similar information regarding myocardial viability as myocardial perfusion scintigraphy in patients with coronary artery disease and previous myocardial infarction.

Background Although residual myocardial viability in patients with coronary artery disease and extensive regional asynergy is associated with improved ventricular function after coronary bypass surgery, the relationship between viability and clinical outcome after surgery is unclear. We hypothesized that patients with poor ventricular function and predominantly viable myocardium have a better outcome after bypass surgery compared with those with less viability. Methods and Results Seventy patients with multivessel coronary artery disease and left ventricular ejection fractions 201 Tl scintigraphy before coronary bypass surgery were analyzed retrospectively. 201 Tl scintigrams were reviewed blindly, and each segment was assigned a score based on defect magnitude. Segmental viability scores were summed and divided by the number of segments visualized to determine a viability index. The viability index was significantly related to 3-year survival free of cardiac event (cardiac death or heart transplant) after bypass surgery ( P =.011) and was independent of age, ejection fraction, and number of diseased coronary vessels. Patients with greater viability (group 1; viability index >0.67; n=33) were similar to patients with less viability (group 2; viability index ≤0.67; n=37) with respect to age, comorbidities, and extent of coronary artery disease. There were 6 cardiac deaths and no heart transplants in group 1 patients and 15 cardiac deaths and two transplants in group 2 patients. Survival free of cardiac death or transplantation was significantly better in group 1 patients on Kaplan-Meier analysis ( P =.018). Conclusions We conclude that resting 201 Tl scintigraphy may be useful in preoperative risk stratification for identification of patients more likely to benefit from surgical revascularization.

The potent growth factors and chemoattractants alpha-thrombin and transforming growth factor-beta1 (TGF-beta1) have both been identified at sites of arterial injury, however the interaction between these two factors has not been defined. By Northern hybridization analyses, accumulation of both a 1.9- and a 2.4-kb transcript of TGF-beta1 were detected and occurred in a time- and dose-dependent fashion following alpha-thrombin stimulation of cultured vascular smooth muscle cells (VSMC). This induction of TGF-beta1 mRNA required the proteolytic activity of thrombin and was mimicked by a thrombin-receptor-(TR)-activating peptide or TRAP (SFFLRNP). Increases in alpha-thrombin-induced TGF-beta1 message expression were insensitive to cycloheximide, but sensitive to actinomycin D. Furthermore, the induction of TGF-beta1 mRNA expression correlated with the production of latent TGF-beta1 protein in alpha-thrombin-conditioned media. In summary, alpha-thrombin stimulation of VSMC induces transcriptional activation of the TGF-beta1 gene through proteolytic activation of the cloned seven-transmembrane TR resulting in the formation of latent TGF-beta1 protein. These results demonstrate a potential mechanism whereby alpha-thrombin may modulate the vascular response to injury through TGF-beta1-dependent mechanisms.

Background We have previously shown that the intravascular rheology of sonicated air-filled albumin microbubbles is similar to that of red blood cells (RBCs) and that their myocardial transit rate is also similar to that of RBCs in the beating canine heart. In the present study, we tested the hypothesis that the myocardial transit rates of these microbubbles reflect those of RBCs in humans at different coronary flow rates. Methods and Results RBC and microbubble transit rates were measured in 17 patients undergoing coronary angiography: in 8, measurements were made only at rest, whereas in 9, they were performed both at rest and during a pacing-induced increase in coronary blood flow. A γ-variate function was used to derive mean RBC and microbubble transit rates from the time-activity and time-intensity plots after the left main injection of RBCs and microbubbles, respectively. There was linear correlation between the myocardial transit rates with both tracers with the slope of the correlation determined by the specific echocardiographic system that was used. Microbubble transit rate consistently overestimated RBC transit rate due to artificial narrowing of the time-intensity curves caused by chest wall attenuation of the echocardiographic signal, which was confirmed through in vitro experiments. Conclusions There is close correlation between air-filled albumin microbubbles and RBC rheology in the human myocardium. The use of these microbubbles in the cardiac catheterization laboratory could, therefore, provide further insights into myocardial blood flow/myocardial blood volume relations in humans.

Background A 2-hour infusion of the direct thrombin inhibitor hirudin at the time of balloon angioplasty limits restenosis in the focally atherosclerotic rabbit. Although short-term administration of hirudin may have a prolonged biological effect, the effect of hirudin on vessel thrombin activity has not been previously studied in an animal model of angioplasty. We hypothesized that a short intravenous infusion of hirudin would result in prolonged inhibition of arterial wall–associated thrombin activity (ATA) after angioplasty. Methods and Results Sixty-one rabbits received recombinant hirudin (r-hirudin) (1 mg/kg bolus plus 1 mg · kg − 1 · h − 1 ×2 hours) or bolus heparin (controls, 150 U/kg) intravenously at the time of femoral balloon angioplasty. ATA was measured through exposure of arterial segments ex vivo to fibrinogen and conducting an assay for fibrinopeptide A (FPA). ATA was low in nonballooned, atherosclerotic vessels (FPA=0.5±0.3 ng · mL − 1 · mg − 1 ) but increased significantly at 24 hours after angioplasty in the heparin group (3.7±0.9 ng · mL − 1 · mg − 1 , P P =NS versus baseline, P Conclusions A 2-hour intravenous infusion of r-hirudin suppressed ATA measured 24 hours after angioplasty in the focally atherosclerotic rabbit. This prolonged biological effect may account, in part, for the reduction in restenosis seen in this model.

Background Thrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation. Methods and Results Femoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with 3 H-thymidine and killed 1 hour later, and labeling indexes were determined. A significant increase in the index of 3 H-thymidine–labeled nuclei was observed in the intima of “ballooned” arteries compared with “nonballooned” atherosclerotic arteries at both 30 hours (0.06±0.05 versus 0.01±0.01, P P P =.12). Hirudin had no effect on the 3 H-thymidine labeling indexes at any of the time points studied despite the fact that hirudin treatment in group 3 rabbits resulted in less cross-sectional area narrowing by plaque at both 7 and 28 days after angioplasty (41±16 versus 24±12 at 7 days and 60±21 versus 44±17 at 28 days, heparin versus hirudin; P Conclusions Balloon angioplasty resulted in a marked increase in cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin failed to reduce early 3 H-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 days after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days after balloon angioplasty in this animal model.

Thrombin has been implicated in vascular smooth muscle cell (VSMC) proliferation after vessel injury. Its proliferative effects, which are mediated via proteolytic activation of a receptor similar or identical to the cloned thrombin receptor (TR), have markedly delayed kinetics. The present study demonstrates that, despite rapid thrombin receptor activation and similar time to S phase entry compared with classic polypeptide growth factors, prolonged thrombin exposure is required to promote maximal VSMC mitogenesis. Flow cytometric analysis of thrombin-stimulated cells revealed that thrombin induced a progressive increase in the growth fraction over 3 days in culture, an effect that was blocked by hirudin even late after thrombin addition. Northern blot hybridization after thrombin stimulation demonstrated that thrombin upregulates TR mRNA expression within 6 h. These findings indicate that VSMC proliferate in response to prolonged thrombin exposure and suggest that the mitogenic delay may involve not only the thrombin-dependent synthesis and activation of newly made TR but also the progressive thrombin-dependent recruitment of cells into the growth fraction.

Thrombin receptor stimulation in vitro signals many cellular events that are associated with the response to vascular injury in vivo. Indeed, we have previously shown that human α-thrombin and the 14-amino acid human thrombin receptor-activating peptide (huTRAP-14) stimulate proliferation of cultured rat aortic smooth muscle cells (SMC). In the present studies, the mitogenic response of rabbit vascular SMC to thrombin and huTRAP-14 was assessed using [3H]thymidine incorporation and cell number. Results demonstrated that thrombin stimulated mitogenesis of rabbit vascular SMC in culture and that the thrombin response was dependent on proteolytic activity. However, huTRAP-14 was not mitogenic for rabbit vascular SMC. Thus, there are species differences in huTRAP-14 responsiveness. As rat and rabbit models continue to be used extensively to evaluate mechanisms and potential therapies for human restenosis, it is important to identify any species differences in the mechanism whereby thrombin exerts its biological effects. © 1995 Wiley-Liss, Inc.

We hypothesized that viable myocardium can be identified in patients with poor left ventricular (LV) systolic function caused by recent or prior infarction using myocardial contrast echocardiography. Accordingly, 39 patients with reduced LV ejection fraction (range 0.10 to 0.40) and recent (n = 30) or remote (n = 9) myocardial infarction were studied. Echocardiography was performed at baseline and at 1 month to assess regional function (1 = normal, 5 = dyskinesia) in 12 segments/patient; the segments were also scored for contrast effect (1 = homogenous, 0.5 = partial, 0 = none) during contrast echocardiography performed in the cardiac catheterization laboratory. Four patients had unsuccessful angioplasty of occluded arteries and were treated medically, 9 were treated medically because of noncritical coronary stenoses (80%), and 26 underwent revascularization (16 angioplasty and 10 bypass operation). Twelve segments could not be visualized (2 each in 6 patients), and 30 segments continued to be subserved by totally occluded arteries because of unsuccessful angioplasty in 4 patients. Of the remaining 426 segments, 186 (44%) demonstrated baseline wall motion scores ofor = 3. The best correlate of 1-month wall motion score in these segments was the contrast score (p = -0.62), with better 1-month function noted in segments with more contrast. The overall perfusion status of LV myocardium also correlated (p = -0.59) with global LV systolic function at 1 month. We conclude that myocardial contrast echocardiography can be used during cardiac catheterization to define myocardial segments that are viable in patients with poor LV systolic function caused by recent or remote myocardial infarction.

BACKGROUND There is increasing recognition of myocardial angiotensin-converting enzyme, which is induced with the development of left ventricular hypertrophy (LVH). The potential physiological significance of subsequent increased angiotensin I to II conversion in the presence of LVH is unclear but has been postulated to cause abnormal Ca2+ handling and secondary diastolic dysfunction. Accordingly, we hypothesized that acute angiotensin-converting enzyme inhibition would result in decreased production of angiotensin II and improved active (Ca(2+)-dependent) relaxation in patients with hypertensive LVH. METHODS AND RESULTS Intracoronary (IC) enalaprilat was administered to 25 patients with and without LVH secondary to essential hypertension. Indexes of diastolic and systolic LV function were determined from pressure (micromanometer)-volume (conductance) analysis at steady state and with occlusion of the inferior vena cava. Patients were divided into those receiving high- (5.0 mg, n = 15) and low-dose (1.5 mg, n = 10) IC enalaprilat during a 30-minute infusion at 1 mL/min. The high-dose patients were further divided along the median normalized LV wall thickness of 0.671 cm/m2. The time constant of isovolumic relaxation (TauL) was prolonged at baseline in patients receiving high-dose enalaprilat with wall thickness > 0.671 cm/m2 (TauL, 56 +/- 2 versus 44 +/- 2 and 45 +/- 2 milliseconds, respectively, P < .01 by ANOVA) and shortened only in this patient group (TauL, 49 +/- 3 versus 46 +/- 2 and 43 +/- 2 milliseconds, respectively, P < .01 versus baseline and other groups by ANOVA). The improvement in TauL was directly proportional to the degree of LVH (r = .92, P < .001). Although there was a decrease in LV end-diastolic pressure (23 +/- 2 to 15 +/- 1 mm Hg, P < .01) and volume (86 +/- 8 to 67 +/- 9 mL/m2, P < .05) in those patients with a reduction in TauL, this is due to movement down a similar diastolic pressure-volume relation with no change in chamber elastic stiffness (0.023 +/- 0.002 to 0.025 +/- 0.004 mL-1, P = NS). CONCLUSIONS Intracoronary enalaprilat resulted in an improvement in active (Ca(2+)-dependent) relaxation in those patients with more severe hypertensive LVH. The improvement in active relaxation was directly proportional to the severity of LVH. These results support the hypothesis that the cardiac renin-angiotensin system is an important determinant of active diastolic function in hypertensive LVH.

Myocardial systolic contractile dysfunction can occur despitepreservation of myocardial viability, conditions referred to as myocardial 'stunning' or 'hibernation.' Because simple assessment of wall motion does not adequately distinguish nonviable from viable but noncontracting myocardial regions, clinicians require alternate methods to assess whether strategies might be useful. Nuclear imaging techniques can provide relatively precise, clinically relevant information regarding the status of myocardial viability, despite the presence of regional or global systolic dysfunction.

BACKGROUND Balloon angioplasty of atherosclerotic arteries results in activation of the coagulation cascade. Several coagulation factors, including factor Xa and thrombin, are mitogenic for vascular smooth muscle cells in vitro and thus may play a role in restenosis after balloon angioplasty. Specific inhibition of factor Xa can be achieved with recombinant antistasin (rATS) or tick anticoagulant peptide (rTAP). We hypothesized that inhibition of Xa would limit restenosis after balloon angioplasty in an atherosclerotic rabbit model. METHODS AND RESULTS Focal femoral atherosclerosis was induced by air desiccation injury and a high-cholesterol diet in 38 New Zealand White rabbits. Recombinant antistasin (n = 20 arteries) or rTAP (n = 14 arteries) was administered by intravenous bolus at the time of balloon angioplasty and followed by a 2-hour infusion; controls (n = 21 arteries) received bolus heparin alone (150 U/kg). Therapeutic prolongation of the activated partial thromboplastin time occurred, and antithrombotic drug levels were achieved in all animals. Luminal diameter in millimeters by quantitative angiography did not differ between treatment groups before (1.1 +/- 0.2 for controls, 1.1 +/- 0.2 for rATS, and 1.1 +/- 0.3 for rTAP) or after balloon angioplasty (1.5 +/- 0.3 for controls, 1.4 +/- 0.2 for rATS, and 1.4 +/- 0.2 for rTAP). At 28 days, treatment with factor Xa inhibitors tended to result in arteries with larger luminal diameter than controls (1.2 +/- 0.3 for rATS, 1.2 +/- 0.3 for rTAP versus 1.0 +/- 0.3 for control, P = .09 by one-way ANOVA). Restenosis, defined as reduction in angiographic luminal diameter (in mm) from 2 hours after angioplasty to 28 days after angioplasty was less in the rATS group than in controls (-0.2 +/- 0.1 versus -0.5 +/- 0.4, P < .001) and tended to be less in the rTAP group (-0.3 +/- 0.2 versus -0.5 +/- 0.4, P = .07). Quantitative histopathological analysis showed less percent cross-sectional area narrowing by plaque in both rATS- and rTAP-treated arteries compared with controls (42 +/- 21%, 47 +/- 18%, and 63 +/- 14%, respectively; P < .01 by one-way ANOVA). CONCLUSIONS We conclude that a 2-hour infusion of rATS or rTAP reduced angiographic restenosis and resulted in less luminal cross-sectional narrowing by plaque compared with controls.

Background: In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD. Methodology/Principal Findings: We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one $90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-c, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p,0.0001), and decreased concentrations of angiostatic ligands CXCL9 (p,0.0001), CXCL10 (p=0.002), and CXCL11 (p=0.0002), and interferon-c (p=0.0004). Conclusions/Significance: Plasma chemokine concentrations are associated with the presence and extent of spontaneously visible coronary artery collaterals and may be mechanistically involved in their recruitment. Citation: Keeley EC, Moorman JR, Liu L, Gimple LW, Lipson LC, et al. (2011) Plasma Chemokine Levels Are Associated with the Presence and Extent of

Objectives. This study describes the technique, clinical characteristics and results of the first 50 patients undergoing percutaneous balloon pericardiotomy as part of a multicenter registry. Background. Percutaneous balloon pericardiotomy involves the use of a percutaneous balloon dilating catheter to create a nonsurgical pericardial window. Methods. Patients eligible for percutaneous balloon pericardiotomy had either cardiac tamponade (n = 36) or a moderate to large pericardial effusion (n = 14). In addition to clinical follow-up, serial echocardiograms and chest X-ray films were obtained. Results. The procedure was considered successful in 46 patients after a mean follow-up period of 3.6 ± 3.3 months. Two patients required an early operation, one for bleeding from a pericardial vessel and one for persistent pericardial catheter drainage. Two patients required a late operation for recurrent tampomde. Minor complications of the procedure included fever in 6 of the first 37 patients (studied before the prophylactic use of antibiotic agents), thoracentesis or chest tube placement in 8 and a small spontaneously resolving pneumothorax in 2. Despite the short-term success of this procedure the long-term progcosis of the 44 patients with malignant pericardial disease remained poor (mean survival time 3.3 ± 3.1 months). Conclusions. Percutaneous balloon pericardiotomy is successful in helping to manage large pericardial effusions, particularly in patients with a malignant condition. It may become the preferred treatment to avoid a more invasive procedure for patients with pericardial effusion and a limited life expectancy.

Objectives: The goal of this study was to compare whether coronary angiography or noninvasive imaging more accurately identifies coronary artery disease (CAD) and predicts mortality in patients with end-stage renal disease (ESRD) under evaluation for transplantation. Background: CAD is a leading cause of mortality in patients with ESRD. The optimal method for identifying CAD in ESRD patients evaluated for transplantation remains controversial with a paucity of prognostic data currently available comparing noninvasive methods to coronary angiography. Methods: The study cohort consisted of 57 patients undergoing both coronary angiography and stress perfusion imaging. Severe CAD was defined by angiography as ≥70% stenosis, and by noninvasive testing as ischemia in ≥1 zone. Follow-up for all cause mortality was 3.3 years. Results: On noninvasive imaging, 63% had ischemia. On angiography, 40% had at least one vessel with severe stenoses. Abnormal perfusion was observed in 56% of patients without severe disease angiographically. Noninvasive imaging had poor specificity (24%) and poor positive predictive value (43%) for identifying severe disease. Angiography but not noninvasive imaging predicted survival; 3 year survival was 50% and 73% for patients with and without severe CAD by angiography (p

We hypothesized that the success of coronary artery bypass graft operations could be assessed by means of on-line quantitative myocardial contrast echocardiography. Accordingly, myocardial contrast echocardiography was performed at baseline and after each placement of venous graft in 21 patients undergoing coronary artery bypass graft operations. Time-intensity plots were generated on-line with the use of a dedicated computer system, and areas under the curve were assessed for each injection. Successful on-line quantitation of myocardial contrast echocardiography data was performed in 17 patients; this allowed comparison before and after coronary artery bypass graft operations for 21 grafts, with agreement between expert visual analysis and quantitative data in 91 % of these cases. Three distinct perfusion patterns were noted on myocardial contrast echocardiography: (1) reduced contrast effect before coronary artery bypass graft operations with improvement after coronary artery bypass graft operations (n = 11); (2) adequate contrast effect before coronary artery bypass graft operations with no change after coronary artery bypass graft operations (n = 9) (for patients in group 2, the mean percentage of coronary stenosis was less than the mean for patients in group 1—67% ± 25 % vs. 88 % ± 20 %, p = 0.05); and (3) no contrast effect either before or after coronary artery bypass graft operations in one patient with previous infarction. One third of the time (34 of 95 injections), on-line quantitation was unsuccessful. Failure was related three times more often to problems associated with myocardial contrast echocardiography, such as attenuation and inadequate quality of bubbles, than to computer failure. Despite its limitations, on-line quantitative myocardial contrast echocardiography is feasible in patients undergoing coronary artery bypass graft operations and provides important objective information regarding the success of revascularization.

Many patients with Ischemic heart disease and depressed left ventricular (LV) function have asynergic zones with sustained microcirculatory perfusion and myocardial metabolic activity that exhibit improved systolic function after coronary revascularization. The 2 predominant noninvasive techniques used to determine myocardial viability in patients with severely depressed LV function are thallium-201 ( 201 TI) scintigraphy and posltron emission tomography (PET). Myocardial extraction of 201 TI is unaltered under experimental conditions of myocardial stunning or short-term hibernation (characterized by decreased flow and ischemic dysfunction). Akinetic or dyskinetic LV wall segments can exhibit normal or near normal 201 TI uptake as long as some residual flow is present. 201 TI scintigraphy can identify viable asynergic segments when performed on patients with severe coronary artery disease who are in the resting state. Many of these patients have initial resting defects that demonstrate delayed redistribution, or mild persistent defects that show improved perfusion and function after revascularization. There is a direct correlation between the extent of 201 TI uptake in zones of severe regional myocardial asynergy and the magnitude of improvement in resting LV ejection fraction after coronary bypass surgery. Rest 201 TI scintigraphy may help in the selection of patients wtth coronary artery disease and severely depressed LV function who would benefit the most from revascularization.

There have been few studies looking at clinical outcomes in patients on chronic hemodialysis after balloon angioplasty. In the study by Reusser and colleagues, there was an increase in periprocedural complication rates in the hemodialysis group when compared with the control group. 1 Ahmed et al 2 and Kahn et al 3 noted high rates of restenosis, periprocedural complications, and recurrent angina in patients on hemodialysis. Given that only limited published longterm mortality data for hemodialysis patients after balloon angioplasty are available, we performed a cohort study of clinical outcomes after percutaneous coronary intervention in patients on chronic hemodialysis. With use of the hospital billing database and cur

To demonstrate that fractional flow reserve (FFR) of vessels in patients with high left ventricular mass index (LVMI) should be similar to that of matched vessels in patients with normal LVMI.FFR is a physiologic index of coronary lesion severity. It is not known whether FFR remains useful in the setting of increased LVMI, when microvascular abnormalities may be present.LVMI was calculated in 84 patients using contrast left ventriculography after validation with cardiac magnetic resonance imaging. Cardiac risk factors, LV ejection fraction (LVEF), minimal lumen diameter (MLD), percent diameter stenosis (%DS), lesion length and FFR were compared in 22 patients with high LVMI to 62 patients with normal LVMI and angiographically-matched vessels.LVMI was 126 +/- 21 g/m2 in the high LVMI group and 84 +/- 21 g/m2 in the normal LVMI group. There were no differences in age, LVEF, diabetes, hypertension or dyslipidemia between groups. Angiographic lesion characteristics were well matched in patients with high versus normal LVMI (MLD 1.3 +/- 0.6 mm vs. 1.3 +/- 0.6 mm, %DS 61 +/- 13% vs. 62 +/- 13%, and lesion length 14.2 +/- 7.0 mm vs. 14.3 +/- 7.0 mm; p = NS for all). Importantly, no difference in FFR was observed (0.79 +/- 0.12 vs. 0.78 +/- 0.16; p = NS) between the groups, and LVMI did not correlate with FFR in a multivariate analysis.FFR of coronary lesions in patients with high LVMI is no different than FFR of angiographically-matched lesions in patients with normal LVMI, suggesting that high LV mass should not limit the utility of FFR as an index of coronary lesion severity.

Objectives: To determine the outcome of consecutive patients with and without acute coronary syndromes (ACS) in whom revascularization was deferred on the basis of fractional flow reserve (FFR). Background: FFR < 0.75 correlates with ischemia on noninvasive tests and deferral of treatment on the basis of FFR is associated with low event rates in selected populations. Whether these low event rates apply to patients undergoing assessment of moderate stenoses in association with an ACS is not known and is an important clinical question. Methods: Retrospective analysis and 12 month follow-up of consecutive, moderate (50–70%) de novo coronary lesions assessed with FFR. Results: Revascularization was deferred in 120 lesions (111 patients) with FFR ≥ 0.75. ACS was present in 35 patients (40 lesions). The clinical, angiographic and coronary hemodynamic characteristics of patients with and without ACS were similar. Among the 35 patients with ACS, there were 3 deaths, 1 MI, and 6 target vessel revascularizations (TVRs) (15% of lesions). Among the 76 patients without ACS, there were 5 deaths, 1 MI, and 7 TVR's (9% of lesions). Conclusions: Deferral of revascularization based on FFR in patients with ACS and moderate coronary stenoses is associated with acceptable and low event rates at 1 year. © 2006 Wiley-Liss, Inc.

We hypothesized that myocardial perfusion imaging (MPI) would fail to identify all vascular zones with the potential for myocardial ischemia in patients with multivessel coronary disease (MVD). MPI is based on the concept of relative flow reserve. The ability of these techniques to determine the significance of a particular stenosis in the setting of MVD is questionable. Fractional flow reserve (FFR) can determine the significance of individual stenoses. Thirty-six patients with disease involving 88 arteries underwent angiography, FFR, and MPI. FFR was performed using a pressure wire with hyperemia from intracoronary adenosine. Myocardial perfusion images were analyzed quantitatively and segments assigned to a specific coronary artery. The relation between FFR and perfusion was determined for each vascular zone. Of the 88 vessels, the artery was occluded (n=20) or had an abnormal FFRor=0.75 (n=34) in 54 of 88 (61%). MPI showed no defect in 51 zones (58%). Concordance between angiography, FFR, and MPI was seen in 61 of 88 zones (69%). Discordance was seen in the remaining 27 zones (31%) and was predominantly from the finding of a FFR0.75 or total occlusion despite no defect on MPI. In conclusion, many patients with MVD show no perfusion defect in zones supplied by arteries with total occlusion or a FFR0.75. Thus, MPI underestimates ischemic burden and FFR may be better at guiding revascularization decisions than perfusion imaging in patients with MVD.

Diabetic nephropathy is associated with increased cardiovascular events. Coronary atherosclerosis is responsible for many of these events, but other mechanisms such as impaired flow reserve may be involved. The purpose of this study was to define the prevalence and mechanism of abnormal coronary velocity reserve (CVR) in patients with diabetes mellitus who have nephropathy and a normal coronary artery.Patients undergoing catheterization for clinical purposes were enrolled. CVR was measured with a Doppler ultrasound scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11 patients with diabetes mellitus who did not have renal failure, and 21 patients with diabetes mellitus who had nephropathy. A CVR2.0 was considered to be abnormal.Patients with diabetes mellitus who had renal failure had a higher incidence of hypertension and left ventricular hypertrophy. The average peak velocity (APV) at baseline was higher in patients with diabetes mellitus who had renal failure. At peak hyperemia, APV increased in all 3 groups, with no difference between groups. The mean CVR for patients without diabetes was 2.8 +/- 0.8 and was not different from that in patients with diabetes mellitus who did not have renal failure (2.7 +/- 0.7), but was lower than that in patients with diabetes mellitus who had renal failure (1.6 +/- 0.5; P0.001). Abnormal CVR was observed in 9% of patients without diabetes mellitus, 18% of patients with diabetes mellitus who did not have renal failure, and 57% of patients with diabetes mellitus who had renal failure, and abnormal CVR was caused by an elevation of baseline APV in 66% of these cases. The baseline heart rate and the presence of diabetes mellitus with renal failure were independent predictors of abnormal CVR by multivariable analysis.Patients with diabetic nephropathy have abnormalities in CVR in the absence of angiographically evident coronary disease.

Abstract —Endothelial activation and leukocyte recruitment are early events in atherosclerosis and the vascular response to injury. Adenosine has anti-inflammatory effects on leukocytes and endothelial cells mediated through its A 2A receptor. We tested the hypothesis that A 2A activation would reduce inflammation and neointimal formation in a murine carotid ligation model. Before injury, mice were randomized to a 7-day subcutaneous infusion of a specific A 2A receptor agonist (ATL-146e, 0.004 μg/kg per minute), vehicle control, ATL-146e plus ZM241385 (a selective A 2A antagonist), or ZM241385 alone. Leukocyte recruitment and adhesion molecule expression were assessed at early time points, and the neointimal area was measured at 14 and 28 days after injury. Compared with control mice, ATL-146e–treated mice had significantly less neutrophil and macrophage recruitment and vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and P-selectin expression in the first 7 days after injury. Neointimal area was markedly and persistently reduced by 80% at 14 and 28 days, despite termination of ATL infusion at 7 days. ATL-146e+ZM241385–treated and ZM241385-treated animals had neointimal areas similar to those of control animals, confirming that the observed effects of ATL-146e were mediated specifically by the A 2A receptor. These data demonstrate that novel stimulation of adenosine A 2A receptors can inhibit early inflammatory processes that are important in neointimal formation after vascular injury.

Intravascular delivery of an E1/E3 deleted adenovirus encoding the hirudin protein reduces neointimal formation in the rat arterial injury model. Given the interspecies variability in response to adenoviral vectors, we tested this same construct in the hirudin-sensitive cholesterol-fed rabbit arterial balloon injury model. We hypothesized that local delivery of an E1/E3-deleted adenovirus encoding hirudin (Ad-Hir) in addition to early hirudin infusion would limit neointimal formation compared to early hirudin alone. Methods and Results: Local delivery of Ad-Hir, 2.5 × 1010 PFU/ml, using a double balloon catheter [n = 6 vessels (v)] produced a 79% reduction in vessel wall thrombin activity at 48 h after balloon angioplasty (BA) compared with vehicle (Veh, n = 6v; p = 0.05). In chronic experiments, hypercholesterolemic rabbits underwent femoral BA, and received either early hirudin alone (n = 9v) or early hirudin plus locally delivered Ad-Hir (early hirudin + Ad-Hir; n = 9v), an E1/E3-deleted adenovirus encoding β-galactosidase (early hirudin + AdGal; n = 7v), or Veh (early hirudin + Veh; n = 10v). Early hirudin + Ad-Hir did not limit the arterial response to injury versus the other groups at 4 weeks after BA. Plaque area, cross-sectional luminal area narrowing by plaque, and T cell infiltration were significantly increased in the adenovirus- versus non-adenovirus-treated arteries. Plaque area correlated with T cell density. Conclusion: Following BA in cholesterol-fed rabbits, local transduction with A-Hir produced a marked reduction in vessel wall-associated thrombin activity. However, this strategy increased rather than decreased the arterial response to BA injury. Our results suggest that the lack of therapeutic effect resulted from adenovirus-stimulated plaque formation, possibly resulting from a T cell-mediated inflammatory response.

In addition to its anticoagulant effects, heparin is known to have antiproliferative effects on vascular smooth muscle cells. Ardeparin is a partially depolymerized (low molecular weight) heparin that has a longer half-life than unfractionated heparin. Following successful coronary balloon angioplasty, 565 patients were randomized to treatment with twice-daily subcutaneous ardeparin 50 anti-Xa U/kg (low dose) or 100 anti Xa U/kg body weight (high dose), or placebo for 3 months. Follow-up angiography was performed in 415 patients at 4 months, or earlier if clinically indicated. Additionally, patients underwent treadmill exercise electrocardiography at 2 weeks and 4 months. This study was designed to test the hypothesis that 3 months of subcutaneous dosing of ardeparin would reduce angiographic restenosis after coronary balloon angioplasty. Ardeparin had no effect on the incidence of angiographic restenosis (prespecified definition: ≥50% luminal diameter narrowing plus a loss of 50% of initial gain or absolute decrease of 20% of luminal diameter). Neither the mean luminal diameters nor mean percent diameter stenoses were different among the treatment groups before, after, or 4 months after balloon angioplasty. On exercise electrocardiography at 2 weeks and 4 months, patients in all treatment groups had similar exercise tolerance, incidence of angina, and frequency of ST depression. Thus, ardeparin treatment given subcutaneously for 3 months after successful balloon angioplasty does not reduce either angiographic or clinical measures of restenosis.

Background Thrombus is important in the pathophysiology of several complications of angioplasty, including abrupt closure and restenosis. Levels of prothrombin fragment F1.2 and fibrinopeptide A reflect thrombin generation and activity. The effect of angioplasty on levels of these markers is unclear. Methods Patients undergoing either balloon angioplasty (n = 30) or directional atherectomy (n = 9) were treated with heparin to maintain an activated clotting time of >300 seconds. Levels of F1.2, fibrinopeptide A, and thrombin-antithrombin complex were measured in the coronary sinus and coronary artery before and after intervention. Angiograms were reviewed for lesion morphologic characteristics and dissection. Results There was no evidence for thrombin generation or increased thrombin activity after angioplasty regardless of lesion morphologic characteristics, dissection, type of intervention, or blood sampling site. In fact, coronary sinus concentrations of F1.2 decreased after intervention (median 0.31 nmol/L; 25th percentile 0.26 nmol/L, 75th percentile 0.37 nmol/L) before intervention to 0.23 nmol/L (25th percentile 0.19 nmol/L, 75th percentile 0.34 nmol/L) after intervention ( P =.002). Conclusions Angioplasty performed in the presence of adequate heparin inhibited thrombin even when there was complex lesion morphology or dissection. These data suggest that heparin provides satisfactory thrombin inhibition during routine angioplasty. (Am Heart J 1999;137:250-7.)

Background —A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone. Methods and Results —Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours’ infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusion±bolus at 24 hours; and early+delayed hirudin: hirudin bolus+2 hours’ infusion, hirudin infusion±bolus at 24 hours. Rabbits were euthanized after 28 days. The early+delayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the early+delayed treatment group compared with controls ( P =0.0001), early hirudin ( P =0.01), or delayed hirudin ( P =0.001). The early+delayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae. Conclusions —Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model.