Tim A. Fischell

Analysis of 1-Year Clinical Outcomes in the SIRIUS Trial A Randomized Trial of a Sirolimus-Eluting Stent Versus a Standard Stent in Patients at High Risk for Coronary Restenosis

Background—This study evaluated a large group of patients enrolled in a double-blind randomized trial of the sirolimus-eluting stent to document whether the initial clinical improvement seen in previous smaller series is maintained out to 12 months and to study the potential treatment effect in patient subsets known to be at increased risk of restenosis. Methods and Results—A total of 1058 patients with de novo native coronary stenosis undergoing clinically indicated percutaneous coronary intervention were randomly assigned to sirolimus-eluting stent (533) or control bare stent (525). Procedural success and in-hospital outcomes were excellent and did not differ between the 2 groups. At 9 months, clinical restenosis, defined as target-lesion revascularization, was 4.1% in the sirolimus limb versus 16.6% in the control limb (P <0.001). At 12 months, the absolute difference in target-lesion revascularization continued to increase and was 4.9% versus 20% (P <0.001). There were no differences in death or myocardial infarction rates. In high-risk patient subsets, defined by vessel size, lesion length, and presence of diabetes mellitus, there was a 70% to 80% reduction in clinical restenosis at 1 year. Conclusions—Placement of the sirolimus-eluting stent results in continued clinical improvement at 1 year after initial implantation, with significant reduction in clinical restenosis as defined by target-lesion revascularization. Between 9 and 12 months, the absolute reduction of clinical restenosis continues to increase. Even in high-risk subsets of patients, there is a 70% to 80% relative reduction in clinical restenosis at 12 months with this drug-eluting stent.

Transesophageal two-dimensional echocardiography and color Doppler flow velocity mapping in the evaluation of cardiac valve prostheses.

To determine the value of transesophageal ultrasound in the assessment of cardiac valve prostheses, 14 patients with clinically suspected mitral prosthesis malfunction were studied by transthoracic and transesophageal two-dimensional imaging as well as by color Doppler flow velocity mapping (color Doppler). Patients underwent left ventricular angiography (n = 13), surgery (n = 11), or both angiography and surgery (n = 10). Nine patients had only mitral valve replacement, four patients had both mitral and aortic valve replacement, and one patient had mitral, aortic, and tricuspid valve replacement. There were 16 biological and four mechanical prostheses. The degree of mitral regurgitation was graded by both transthoracic and transesophageal color Doppler according to the area of the regurgitant jet visualized and was compared with a three-point classification of mitral regurgitation by left ventricular angiography judged by observers blinded to the echocardiographic results. All transesophageal studies were performed without complication and were well tolerated. The pathological morphology of the mitral prosthesis was additionally or more clearly visualized by transesophageal two-dimensional imaging and subsequently proven at surgery in three patients with flail leaflets and one patient with a vegetation compared with images obtained by the transthoracic approach. Valvular regurgitation was graded by the transthoracic approach as absent in four patients, mild in two patients, moderate in five patients, and severe in only three patients. The transesophageal assessment showed absence of mitral regurgitation in two patients, moderate regurgitation in two patients, and severe regurgitation in 10 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.

BACKGROUND Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis. METHODS AND RESULTS Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002). CONCLUSIONS The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.

Fish oil improves endothelium-dependent coronary vasodilation in heart transplant recipients

OBJECTIVES The purpose of this study was to determine whether dietary fish oil supplementation enhances endothelium-mediated vasodilator responses in human heart transplant recipients, a group known to have coronary artery disease and endothelial dysfunction. BACKGROUND Omega-3 fatty acid supplementation has been shown to enhance endothelium-dependent coronary vasodilation in animal models of atherosclerosis. METHODS Endothelium-dependent vasodilator responses to intracoronary acetylcholine infusion and endothelium-independent responses to nitroglycerin were evaluated in heart transplant recipients who received a high dose of dietary supplementation with omega-3 fatty acids for 3 weeks (5 g of eicosapentaenoic acid plus docosahexaenoic acid/day, n = 7) and compared with responses in a group of matched heart transplant recipients who did not receive fish oil (control patients, n = 7). Acetylcholine was selectively infused into the midportion of the left anterior descending or left circumflex coronary artery, with the noninfused left coronary artery serving as a control vessel. Serial coronary angiograms were performed after infusion with increasing doses of acetylcholine (infused concentrations 10(-6) to 10(-3) mol/liter) and after intracoronary nitroglycerin administration. RESULTS The patients treated with fish oil showed a normal vasodilator response to acetylcholine with 14 +/- 2.5% and 15 +/- 7% vasodilation (vs. baseline diameter) at infused acetylcholine concentrations of 10(-5) and 10(-4) mol/liter, respectively. In contrast, the control patients demonstrated vasoconstrictor responses (-1 +/- 1% and -9 +/- 4%) to acetylcholine at these same doses (p < 0.05 and < 0.005, respectively, for treated vs. control patients). There were no differences in the response to nitroglycerin between the control and treated patients. CONCLUSIONS Dietary supplementation with fish oil significantly alters endothelium-dependent coronary vasodilation in heart transplant recipients without alteration of the responses to endothelium-independent vasodilation. Whether this enhancement of endothelial function can beneficially alter the natural history of heart transplant atherosclerosis warrants further study.

Reversal of “no reflow” during vein graft stenting using high velocity boluses of intracoronary adenosine

Slow or no reflow is a serious problem complicating catheter-based revascularization of degenerated saphenous vein bypass grafts. We examined the efficacy of rapidly delivered, high-velocity injections of intracoronary adenosine to reverse 11 slow-flow events complicating stenting of diseased bypass grafts. Ten of 11 events were rapidly improved to TIMI 3 flow by this technique within 3.8+/-1.6 min of the initial adenosine injection. In an ex vivo model, 3-ml syringes created higher peak pressures and velocities than 10- and 20-ml syringes. We conclude that rapid and repeated high-velocity intragraft administration of adenosine is a promising new approach to promptly reverse no-reflow events complicating PTCA and stenting of diseased saphenous vein grafts. Ex vivo studies demonstrate a potentially important mechanical advantage with the use of small syringes for injection. Further randomized studies will be required to better define the mechanism(s) and efficacy of this approach for treating no reflow, including its use in native vessels.

Clinical demonstration that catheter-delivered ultrasound energy reverses arterial vasoconstriction

OBJECTIVES This study was designed to describe the clinical effects of ultrasound energy on guide-wire-induced arterial vasoconstriction. BACKGROUND We have previously shown that ultrasound energy (20 kHz) delivered by a wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptor-mediated and voltage-dependent vasoconstriction in vitro. METHODS A high intensity, low frequency ultrasound catheter system was used to recanalize total occlusions in the superficial femoral arteries of two patients. After recanalization, the proximal residual stenoses were each less than 15%. However, distal arterial vasospasm was found angiographically in a popliteal artery of one patient and in an anterior tibial artery of another. Subsequently, the ultrasound catheter probe was advanced to the sites of arterial vasospasm (diffuse in one, focal in one). RESULTS After 30 and 90 s, respectively, of exposure to ultrasound energy with a frequency of 19.5 kHz, peak tip amplitude of 111 microns and power output at the transducer of 25 W, the vasospasm resolved in each arterial segment. CONCLUSIONS Our findings are the first reported clinical cases documenting that catheter-delivered low frequency, high intensity ultrasound induces arterial vasodilation at the site of vasoconstriction. These biologic effects appear to be relatively unique for an angioplasty device and may have potential clinical importance.

Ultrasonic energy. Effects on vascular function and integrity.

BackgroundUltrasonic energy transmitted via flexible wire probes provides a new means of ablating atherosclerotic plaque. We studied the effects of ultrasonic energy (20 kHz) delivered via a ball-tipped wire probe on arterial vasomotor behavior in rabbit thoracic aortas in a perfused whole-vessel model. Methods and ResultsAfter precontraction with phenylephrine (10-` M) or KCI (60 mM), the effects of ultrasonic energy (0.7–5.5 Wx60 seconds, 42–330 J) on arterial vasomotor behavior were measured using long-axis ultrasonic vessel imaging of the proximal (ultrasonic probetreated) and distal (untreated) control segments. The efficacy of plaque ablation at these same probe-tip power outputs was evaluated in atherosclerotic, human cadaver iliofemoral arteries. Ultrasonic energy caused dose (energy)-dependent relaxation in rabbit aortas after precontraction with phenylephrine in arteries with endothelium (n = 8) and without endothelium (n = 8) (p < 0.001 versus ultrasound treated at power outputs of 2.9 and 5.5 W). There was no difference in the relaxation dose responses between endothelialized and endothelially denuded segments (p = NS). Ultrasonic energy also caused significant relaxation (67 + 8%) after voltage-dependent precontraction with 60 mM KCI. Temperature measurements revealed less than 1 ° C warming of the vessel wall during as long as 2 minutes of treatment at a power output of 5.5 W. Pathological examination showed no smooth muscle injury at (moderate) power outputs that caused arterial relaxation. At probe-tip power outputs of 2.9–5.5 W, ultrasonic energy recanalized two of two totally occluded cadaveric iliofemoral vessel segments. The ultrasonic ablation catheter was also demonstrated to cause arterial relaxation in a recanalized canine femoral artery in vivo. ConclusionsUltrasonic energy delivered via a flexible-wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptormediated and voltage-dependent vasoconstriction in vitro. At moderate power outputs, this relaxation response does not appear to be due to thermal effects or irreversible smooth muscle cell injury. This vasorelaxant effect of ultrasonic energy is also apparent in vivo, at doses that effectively ablate atherosclerotic plaque, and may improve the safety of arterial recanalization using ultrasonic energy.

Roles of thrombin and platelet membrane glycoprotein IIb/IIIa in platelet-subendothelial deposition after angioplasty in an ex vivo whole artery model.

BackgroundPlatelet deposition at the site of injury caused by balloon angioplasty is associated with acute closure and restenosis. Methods and ResultsIn a new ex vivo whole artery angioplasty model, we examined the roles of thrombin inhibition with D-Phe-Pro-ArgCH2C1 (PPACK) and inhibition of the platelet membrane fibrinogen receptor glycoprotein lIb/Illa (GPIIb/IIIa) with monoclonal antibody 7E3 on platelet deposition at the site of balloon injury. Fresh rabbit aortas were mounted in a perfusion chamber. One half of the mounted arterial segment was dilated with a standard angioplasty balloon catheter and the uninjured half served as the control segment. The vessels were perfused with human blood at physiological pressure and shear rates of 180–250 second` for 30 minutes. Platelet deposition was measured using 1`In-labeled platelets and scanning electron microscopy. With heparin (2 units/ml) antigcoagulation, 8.2 ± 2.2x106 platelets/cm2 were deposited at the site of balloon injury compared with 0.7 ± 0.2x106 platelets/cm2 on uninjured segments (p < 0.02, n = 7). PPACK was tested at a concentration (10 μM) that totally inhibited platelet aggregation in response to thrombin. 7E3 was tested at a concentration (10 μg/ml) that totally inhibited platelet aggregation. Platelet deposition at the site of balloon injury was reduced 47% by PPACK and 70% by 7E3 compared with heparin. ConclusionsAt shear rates seen in nonstenotic coronary arteries, PPACK and 7E3 are more effective than heparin in reducing platelet deposition at the site of balloon injury. The significant inhibition of platelet deposition by PPACK demonstrates the importance of heparin-resistant thrombin in platelet thrombus formation. The 7E3 results suggest that approximately 70% of platelet deposition at the site of balloon injury is GPIIb/IIIa dependent and that the remaining 30% results from non-GPIIb/IIIa-mediated platelet-subendothelial adhesion. Finally, the ex vivo whole artery system is a useful model for studying platelet-vessel wall interactions under physiologically defined parameters.

Immediate and one-year safety of intracoronary ultrasonic imaging. Evaluation with serial quantitative angiography.

BACKGROUND Intracoronary ultrasound (ICUS) has the ability to quantitatively evaluate vessel wall morphology and is well suited for serial studies of coronary artery disease regression and progression. However, the potential risk for catheter-induced endothelial damage and accelerated atherosclerosis in instrumented vessels is a concern. The acute effects as well as the 1-year safety of ICUS regarding its impact on the atherosclerotic process were assessed. METHODS AND RESULTS The acute studies include 240 intracoronary studies performed in 170 cardiac transplant recipients. Patients were systematically heparinized. Only vessels > or = 2 mm in diameter were visualized. Coronary arteries of 38 patients were measured by quantitative coronary angiography in matched angiograms at an interval of 1 year after the initial ICUS examination was performed to assess long-term effects. The angiographic measurements in the previously instrumented and noninstrumented vessels were compared. Forty-nine vessels that had been imaged (IM) in these 38 patients with a 5F ICUS catheter were compared with 61 vessels not previously imaged (NIM) in the same patients. Absolute and percentage change in angiographically measured mean vessel diameters in the ICUS imaged and nonimaged segments were compared. Despite pretreatment with nitroglycerin, 20 patients (8.3%) had angiographically evident coronary spasm. In all cases, this was reversed by giving nitroglycerin. One year after the original imaging study, no difference was noted between imaged and nonimaged vessels in change in absolute vessel diameter (IM, -0.11 +/- 0.28 mm vs NIM, -0.07 +/- 0.22 mm; P = .49) or in percentage change in diameter (IM, -5 +/- 11% vs NIM, -3 +/- 7%; P = .32). CONCLUSIONS Intracoronary ultrasound in cardiac transplant recipients was associated with no clinical morbidity and a low incidence of vessel spasm in large and medium-size coronary arteries. It does not accelerate progression of angiographically quantifiable coronary artery disease. This study suggests that ICUS can be safely used even in coronary arteries not undergoing interventions.

Coronary Embolization Following Balloon Dilation of Lipid-Core Plaques

balloon dilation of a coronary stenosis containing a lipid core plaque (LCP) may be complicated by distal embolization of plaque contents, leading to slow or no-reflow and peri-stenting myocardial infarction (MI) ([1][1]). Near-infrared spectroscopy (NIRS) (LipiScan Coronary Imaging System,