Jesse W. Currier

Coronary Angioplasty in Diabetic Patients The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry

BACKGROUND Patients with diabetes mellitus are at increased risk of cardiovascular disease. To date, the baseline status and subsequent outcomes of diabetic coronary angioplasty (percutaneous transluminal coronary angioplasty, or PTCA) patients with advanced atherosclerotic disease and with procedures performed across North America have not been well characterized. METHODS AND RESULTS Data on baseline clinical and angiographic characteristics and short- and long-term outcomes of 281 diabetic and 1833 nondiabetic PTCA patients in the multicenter National Heart, Lung, and Blood Institute 1985-1986 PTCA Registry were analyzed. Diabetic patients were older, were more likely to be female, and had more comorbid baseline conditions, triplevessel disease, and atherosclerotic lesions. Angiographic success and completeness of revascularization did not differ significantly, yet diabetic patients experienced more in-hospital death (women) and nonfatal myocardial infarction. Nine-year mortality was twice as high in diabetic patients (35.9% versus 17.9%). Similarly, 9-year rates of nonfatal myocardial infarction (29.0% versus 18.5%), bypass surgery (36.7% versus 27.4%), and repeat PTCA (43.7% versus 36.5%) were higher in diabetics than in nondiabetics. In multivariate analysis, diabetes remained a significant predictor of decreased 9-year survival and other untoward events. CONCLUSIONS Compared with nondiabetic PTCA patients, diabetic patients have more extensive and diffuse atherosclerotic disease. Despite similar probability of angiographic success, diabetic patients are more likely to suffer in-hospital death(women) and nonfatal myocardial infarction. Long-term survival and freedom from myocardial infarction and coronary revascularization is also reduced in diabetic PTCA patients. Whether PTCA or coronary bypass surgery is more suitable for these patients is currently under investigation.

Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model.

BACKGROUND In de novo human atherosclerosis, compensatory vessel enlargement limits the effect of intimal plaque formation on lumen narrowing. We hypothesized that arterial remodeling may also play an important role in determining the chronic lumen size after angioplasty and tested this hypothesis using the hypercholesterolemic rabbit iliac artery angioplasty model. METHODS AND RESULTS Morphometric analysis of histological cross-sectional areas of vessels from animals killed immediately after angioplasty (acute group, n = 11) were compared with the same areas from animals killed 4 weeks after the procedure (chronic group, n = 37), when restenosis occurs in this model. The area circumscribed by the internal elastic lamina (IEL) increased by 20% from acute to 4 week follow-up after angioplasty (acute group, 2.36 +/- 0.45 mm2, chronic group, 2.84 +/- 0.89 mm2). Over the same time period, intimal area increased by 0.82 mm2. Despite this increase in intimal area, lumen area decreased by only 0.34 mm2 because of the compensatory enlargement of the IEL area. In the chronic group, polynomial regression analysis revealed a quadratic relation between intimal area and lumen area (R2 = .35, P < .001). A lumen area of 0.45 mm2 (the nadir of the quadratic relation) was used to divide the chronic group into two subgroups: restenotic (n = 21; lumen area, < 0.45 mm2) and nonrestenotic (n = 16; lumen area, > 0.45 mm2). By definition, there was a significant difference in lumen area between the two subgroups (0.15 +/- 0.15 mm2 for restenotic; 0.73 +/- 0.18 mm2 for nonrestenotic). Surprisingly, the intimal areas in the two subgroups were virtually identical (2.41 +/- 0.92 mm2 for restenotic, 2.49 +/- 0.69 mm2 for nonrestenotic, P = NS). The difference in the lumen area between restenotic and nonrestenotic vessels was a result of the significantly greater IEL area in the nonrestenotic subgroup (3.22 +/- 0.83 mm2 for nonrestenotic, 2.56 +/- 0.84 mm2 for restenotic, P < .05). In both restenotic and nonrestenotic vessels, the IEL area increased with increases in intimal area. In the restenotic arteries, the slope of this correlation was < 1, showing inadequate compensatory enlargement for the intimal plaque. In the nonrestenotic vessels, the slope was > 1, limiting the effect of intimal plaque on luminal narrowing. CONCLUSIONS These data indicate that the iliac artery in an atherosclerotic rabbit model compensates for intimal formation after angioplasty by vessel enlargement. Furthermore, the degree of vessel enlargement is more important than intimal area in determining the chronic lumen size.

Restenosis after percutaneous transluminal coronary angioplasty: Have we been aiming at the wrong target?

Restenosis after percutaneous coronary balloon angioplasty remains a significant problem. Despite success with a variety of agents in animal models, no agent has proved clearly successful in reducing restenosis in humans. There are many potential reasons for this, but one possibility is that because of our incomplete understanding of the restenotic process, therapy has been directed at the wrong target. Arterial remodeling (changes in total vessel area or changes in area circumscribed by the internal elastic lamina) is well described in de novo atherosclerosis, and there is increasing evidence that this process occurs after angioplasty. Thus, restenosis can be thought of not merely as neointimal formation in response to balloon injury, but as arterial remodeling in response to balloon injury and neointimal formation. Arterial remodeling may consist of actual constriction of the artery, as has been described in some animal models and in preliminary fashion in humans, or of compensatory enlargement as has been described in de novo atherosclerosis and in the hypercholesterolemic rabbit iliac artery model. Arterial constriction can result in restenosis with minimal neointimal formation. Compensatory enlargement accommodates significant amounts of neointimal formation, with preservation of lumen area despite an increase in neointimal area adequate to cause restenosis in a noncompensated artery. This expanded paradigm of arterial remodeling and intimal formation may in part account for the lack of success in clinical trials to date, and therapy directed at arterial remodeling as well as intimal formation may be required to reduce restenosis after coronary interventions.

Remodeling of the coronary artery after vascular injury

Vascular injury, such as angioplasty, induces a complex healing process that is analogous to generalized wound healing. Following initial injury, platelet thrombi and an acute inflammatory response occur, followed by cellular inhibition by monocytes/macrophages, proliferation of vascular smooth muscle cells, and extracellular matrix deposition. The injury repair concludes with organization of the matrix and reendothelialization. Recent studies suggest that restenosis or renarrowing after vascular injury is due to two components: a cellular proliferative process leading to intimal hyperplasia and remodeling of the vessel with a change in vessel geometry. Animal and clinical studies have shown that at least 60% of restenosis can be explained by unfavorable remodeling with vessel constriction rather than intimal hyperplasia. Although a number of factors appear to be associated with remodeling, alterations in extracellular matrix metabolism may be most important.

Low molecular weight heparin (enoxaparin) reduces restenosis after iliac angioplasty in the hypercholesterolemic rabbit

Smooth muscle cell proliferation is central to the process of restenosis. Attempts to inhibit the events leading to this proliferation have met with little success. In addition to its known antithrombotic effects, heparin also has inhibitory effects on smooth muscle cell proliferation. These effects appear to be unrelated to its anticoagulant properties and are retained in low molecular weight heparin derivatives. Although the use of heparin for as long as 18 to 24 h after coronary angioplasty in humans has not prevented restenosis, longer treatment periods have not been assessed. This study examines the effect of treatment with a low molecular weight heparin (enoxaparin) in a hypercholesterolemic rabbit iliac artery model. Control rabbits had a mean iliac artery diameter of 0.70 +/- 0.06 mm, which increased to 1.73 +/- 0.09 mm after balloon angioplasty. At follow-up angiography 4 weeks later, the mean vessel diameter was 0.56 +/- 0.12 mm. Animals treated with low dose enoxaparin (1 mg/kg per day) for 4 weeks and high dose enoxaparin (10 mg/kg per day) for either 2 or 4 weeks had similar mean luminal diameters before and immediately after angioplasty. At follow-up angiography, the mean luminal diameter was 0.82 +/- 0.17 mm for low dose enoxaparin, 1.04 +/- 0.20 mm for 2 week high dose enoxaparin (p = 0.03 versus control) and 1.19 +/- 0.09 mm for 4 week high dose enoxaparin (p = 0.001 versus control). When defined as loss of 50% of the initial gain achieved with angioplasty, restenosis was found in all control vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Collagen Content Is Significantly Lower in Restenotic Versus Nonrestenotic Vessels After Balloon Angioplasty in the Atherosclerotic Rabbit Model

BACKGROUND It is recognized that restenosis is primarily due to alterations in geometric remodeling of the extracellular matrix rather than intimal hyperplasia. Prior studies have shown that angioplasty stimulates an increase in both synthesis and degradation of collagen in the atherosclerotic vessel. However, differences in collagen content and metabolism between restenotic and nonrestenotic vessels have not been examined. METHODS AND RESULTS Four weeks after angioplasty in an atherosclerotic rabbit model, collagen content in restenotic and nonrestenotic vessels was measured both biochemically by hydroxyproline quantitation and histologically by a digital subtraction method with the use of circularly polarized images of picrosirius red-stained sections. Collagenase and gelatinase activity also were measured in the same restenotic and nonrestenotic vessels by use of a radiosubstrate assay. Collagen content was found to be significantly lower in restenotic vessels than in nonrestenotic vessels both biochemically (127.0 +/- 32.6 versus 212.6 +/- 84.3 micrograms/mg tissue; n = 11 vessels; P < .05) and histologically (67.3 +/- 7.9% versus 76.3 +/- 11.8% area fraction; n = 20 sections from 6 vessels; P = .05). There was a significant inverse correlation between biochemically determined collagen content and gelatinase activity (P = .02) and a significant correlation between histologically determined lumen are and percent collagen content (P = .0071). CONCLUSIONS Collagen content is significantly decreased in restenotic versus nonrestenotic vessels after angioplasty in the atherosclerotic rabbit model. The increased collagen content in nonrestenotic vessels was associated with preserved lumen area and may play a role in geometric remodeling after angioplasty.

Prevention of Post‐PTCA Restenosis

Significant improvements in the success of angioplasty combined with a major reduction in complications have led to widespread use of the technique in the treatment of symptomatic patients with coronary disease. Restenosis, however, remains the most significant limitation of angioplasty, occurring in 20-50% of patients following a successful procedure. Over the past 10 years, more than 40 large randomized pharmacological trials have attempted to address this problem. Currently no single agent has clearly been shown to reduce restenosis. As a consequence of intensive research, improved understanding of the pathophysiology of restenosis as well as the design of clinical studies necessary to study the process has resulted. Recent experimental studies suggest that vascular remodeling may be as important as intimal hyperplasia, and future trials will need to address this aspect of the restenosis process. Current approaches to preventing restenosis include the use of combined drug therapy to attack several pathophysiological processes, local delivery of drug at the site of the injury to maximize drug effect, and the use of highly specific drugs including local gene therapy.

Arterial Remodeling at the Reference Site After Angioplasty in the Atherosclerotic Rabbit Model

Recent studies suggest that arterial remodeling plays an important role in restenosis and that remodeling at the reference site may also occur. To assess the chronic effect of the reference site remodeling on angioplasty results, we evaluated reference site remodeling in an experimental atherosclerotic restenosis model. Histological sections of iliac stenoses and their associated proximal reference segments from 50 atherosclerotic rabbits killed 4 weeks after angioplasty were analyzed. Lumen area (LA), external elastic lamina area (EEL), and intimal plus medial areas (I+M) were measured at the lesion (L) and reference (R) sites. Angiography was performed preangioplasty, immediately postangioplasty, and 4 weeks postangioplasty. Restenosis was defined as an angiographic loss/gain ratio of greater than 50% at follow-up angiography. Twenty-three lesions were restenotic (R+) and 32 were not (R-). There was no difference in reference site diameters (RD) between these two groups at the time of angioplasty. However, RDs were significantly smaller in the R+ group than in the R- group (1.24+/-0.18 versus 1.52+/-0.28 mm, n=55, P<.01) at 4-week follow-up. Morphometric analysis also showed a smaller LA(R) in the R+ group (0.85+/-0.27 versus 1.06+/-0.37 mm2, n=55, P<.02), whereas there was no difference in I+M(R) between the two groups. EEL(R) significantly correlated with EEL(L), LA(R), and I+M(R) in both groups combined (r=.53, n=55, P<.0001; r=.62, n = 55, P < .0001; and r = .86, n = 55, P < .0001, respectively). Remodeling can favorably and unfavorably affect both the lesion and the reference sites and appears to occur in parallel and proportionately at both sites. These data suggest that angiographic measurement of late percent stenosis using reference site diameters may lead to an underestimation of the percent luminal narrowing in restenotic lesions because unfavorable remodeling occurs in both the lesion and reference sites in restenotic vessels.

Experience with low-dose intracoronary recombinant tissue-type plasminogen activator for nonacute total occlusions before percutaneous transluminal coronary angioplasty

The primary success rate for angioplasty of total occlusions is significantly worse than for subtotal lesions. Pharmacologic recanalization of total occlusions before angioplasty has the potential to improve the primary success rate. To determine the ability of recombinant tissue-type plasminogen activator (rt-PA) to recanalize occlusive thrombi before elective percutaneous transluminal coronary angioplasty, 12 patients with total occlusions, 100% obstruction and Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow, and 5 with functional total occlusions, severe stenoses and TIMI grade 1 flow received an intracoronary infusion of rt-PA. The first 10 patients received 0.2 mg/min for 90 minutes, and the next 7 patients received 0.4 mg/min for 60 minutes. Flow improved by greater than or equal to 1 TIMI grade in 11 patients. Mean TIMI flow improved from 0.3 +/- 0.5 to 1.5 +/- 1.2 (p less than 0.0001). There was a significant improvement in severity of stenosis after rt-PA infusion by both digital caliper (99 +/- 2 vs 84 +/- 16%; p less than 0.0001) and quantitative videodensitometric area assessment (99 +/- 3 vs 94 +/- 6%; p less than 0.004). Angioplasty was successful in 16 of 17 patients (94%). There were 2 out-of-laboratory abrupt closures at 4 days; both were medically treated and 1 had a small myocardial infarction. Only 1 patient had a bleeding complication significant enough to need a transfusion. It is concluded that low-dose intracoronary rt-PA is effective at lysing thrombi less than 3 weeks old. This approach warrants further investigation since it may significantly improve the primary success rate of percutaneous transluminal coronary angioplasty in patients with occlusive thrombus.

Percutaneous intervention of left main coronary artery compression by pulmonary artery aneurysm

Background: Extrinsic compression of the left main coronary artery (LMCA) by a pulmonary artery aneurysm (PAA) has become increasingly recognized as an etiology of angina in patients with pulmonary arterial hypertension (PAH). The purpose of this study was to assess the feasibility and efficacy of LMCA stenting in the treatment LMCA stenosis because of PAA. Methods: Retrospective analysis of data on patients with PAH who presented with angina and underwent percutaneous intervention of their LMCA compression because of PAA was performed. Results: Five patients (age 51 ± 16 years, all female) with PAH presented with angina and underwent LMCA stenting between 2007 and 2009. Four had positive cardiac enzymes. LMCA compression because of a PAA was diagnosed in all patients with cardiac CT angiography after echocardiography demonstrated an enlarged pulmonary artery. LMCA stenting was successfully performed in all patients with resolution of angina and electrocardiographic abnormalities. After a mean follow‐up of 16.6 ± 15.7 months (range of 5–39 months), patients remained angina free, no complications of the procedure were noted, and long term stent patency was confirmed in three of the five patients who underwent repeat cardiac CT angiography. Conclusions: LMCA stenting appears to be a feasible and durable option in patients who present with angina because of compression by PAA. This procedure was well tolerated and is of particular value given the increased surgical risk in patients with PAH.