Gary S. Roubin

Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia.

Restenosis after successful PTCA remains a major problem limiting the efficacy of the procedure. The pathophysiologic mechanism of restenosis has been enigmatic so far, but accumulated evidence strongly suggests that intimal hyperplasia is the major mechanism. Based on current understanding of the process of intimal hyperplasia, one unifying concept may be that there are at least two major local biologic determinants influencing this process, lesion characteristics and regional flow dynamics. Lesion characteristics include the plaque structure and the quantity of smooth muscle. These may provide the anatomic substrate that determines the extent of injury and the degree of smooth muscle cell proliferation. The amount of smooth muscle cells in the stenotic lesion activated by injury to undergo proliferation may determine the eventual bulk of the restenotic lesion. In addition, low wall shear stress could promote intimal hyperplasia and cause structural change of vessels to decrease the lumen, whereas high wall shear stress exerts the opposite effects. Intimal hyperplasia after balloon injury is a complex process involving platelets, growth factors, endothelial cells, smooth muscle cells, mechanical injury, wall shear stress, and probably other unknown factors. Platelets not only contribute growth factors such as PDGF but also cause organized thrombus. Different growth factors may be involved in initiating smooth muscle cell proliferation and may come from many different sources, including smooth muscle cells, endothelial cells, and macrophages. Intact confluent endothelial cells may produce heparin sulfates and inhibit intimal proliferation; however, regenerating endothelial cells may have the opposite effect. Thus, the proliferative potential of smooth muscle cells, endothelial recovery, extent of injury, wall shear stress, and other unknown factors may all influence this process. Based on these concepts concerning the biology of restenosis, some research directions concerning potential forms of therapy are proposed.

Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty

To determine predictors of acute coronary closure after PTCA performed with steerable catheter systems, we compared 140 procedures complicated by acute closure and 311 representative successful attempts from 4,772 procedures performed between April 1982 and March 1986. Sixteen clinical, 35 angiographic, and seven procedural variables were analyzed. Multivariate analysis found seven independent preprocedural factors related to closure: stenosis length of 2 or more luminal diameters, female gender, stenosis at a bend point of 45 degrees or more, stenosis at a branch point, stenosis-associated thrombus (filling defect or staining), other stenoses in the same vessel, and multivessel disease. In addition, four procedural factors were found to be associated with closure by univariate analysis: post-PTCA percent stenosis (p less than .001), intimal tear or dissection (p less than .001), use of prolonged heparin infusion (p less than .001), and post-PTCA gradient of 20 mm Hg or more (p = .004). Multivariate analysis of both preprocedural and procedural variables found six factors independently related to closure: post-PTCA percent stenosis, dissection, prolonged post-PTCA use of heparin, branch point location, fixed bend point location, and other stenoses in the vessel dilated. The risk of coronary closure after PTCA has many determinants. While an estimation of risk can be made before performing PTCA, the most powerful predictors of closure can only be assessed during the procedure itself.

Multicenter investigation of coronary stenting to treat acute or threatened closure after percutaneous transluminal coronary angioplasty : clinical and angiographic outcomes

OBJECTIVES This study reports on the initial experience with the Gianturco-Roubin flexible coronary stent. The immediate and 6-month efficacy of the device and the incidence of the complications of death, myocardial infarction, emergency coronary artery bypass surgery and recurrent ischemic events are presented. BACKGROUND Abrupt or threatened vessel closure after coronary angioplasty is associated with increased risk of myocardial infarction, emergency coronary artery bypass graft surgery and in-hospital death. When dissection or prolapse of dilated plaque into the lumen is unresponsive to additional or prolonged balloon catheter inflation, coronary stenting offers a nonsurgical mechanical means to rapidly restore stable vessel geometry and adequate coronary blood flow. METHODS From September 1988 through June 1991, 518 patients underwent attempted coronary stenting with the 20-mm long Gianturco-Roubin coronary stent for acute or threatened vessel closure after angioplasty. In 494 patients, one or more stents were deployed. Thirty-two percent of patients received stents for acute closure and 69% for threatened closure. RESULTS Successful deployment was achieved in 95.4% of patients. Overall, stenting resulted in an immediate angiographic improvement in the diameter stenosis from 63 +/- 25% before stenting to 15 +/- 14% after stenting. Emergency coronary artery bypass graft surgery was required in 4.3% (21 of 493 patients). The incidence of in-hospital myocardial infarction (Q wave and non-Q wave) was 5.5% (27 of 493 patients). At 6 months, myocardial infarction was infrequent, occurring in 1.6% (8 of 493 patients). The incidence of in-hospital death was 2.2% (11 of 493 patients). Late death occurred in 7 patients (1.4%) and 34 patients (6.9%) required later bypass graft surgery. Complications included blood loss, primarily from the arterial access site, and subacute thrombosis of the stented vessel in 43 patients (8.7%). CONCLUSIONS The early multicenter experience suggests that this stent is a useful adjunct to coronary angioplasty to prevent or minimize complications associated with flow-limiting coronary artery dissections previously correctable only by surgery. Although this study was not randomized, it demonstrated a high technical success rate and encouraging results with respect to the low incidence of emergency coronary artery bypass graft surgery and myocardial infarction.

Quantitative rotational thallium-201 tomography for identifying and localizing coronary artery disease.

The purpose of this study was to develop and validate a method for quantifying the uptake, redistribution, and washout of thallium-201 (201Tl) obtained with rotational tomography. This method generates maximum count circumferential profiles of the short-axis slices of the left ventricle, translates them into polar coordinate profiles, and displays them as a bullseye plot, which consists of a series of concentric circles with the apex at the center and the base at the periphery. Normal limits were established for the distribution of 201Tl in 36 patients with a low (less than 5%) probability of coronary artery disease (CAD). Forty-five patients who had undergone coronary angiography were used as a pilot group to define criteria for the identification and localization of perfusion defects. The best agreement with the results of angiography was found when abnormal regions of the bullseye were defined as contiguous defects over 2.5 SDs below normal. These criteria were applied prospectively to 210 points (179 points with greater than 50% diameter stenosis and 31 with less than 50%). Visual, quantitative, and combined visual and quantitative analysis were compared for overall detection of disease and for detection of individual vessel involvement. The overall sensitivity for detection of disease by these methods was 97%, 95%, and 95%, respectively. The specificities were 68%, 74%, and 71% respectively. The sensitivity for detection of individual vessel involvement with the bullseye alone was 78% for the left anterior descending artery (LAD), 89% for the right coronary artery (RCA), and 65% for the left circumflex (LCx). For visual analysis, the results were 70%, 88%, and 50%, respectively, while the use of visual and quantitative analysis combined identified 75% of LAD, 87% of RCA, and 55% of LCx lesions. We conclude that quantitative analysis of rotational 201Tl tomographic images is a highly accurate technique for determining the presence and location of CAD.

Influence of balloon size on initial success, acute complications, and restenosis after percutaneous transluminal coronary angioplasty. A prospective randomized study.

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) is strongly associated with incomplete initial dilatation. To determine if oversized PTCA balloons would reduce the restenosis rate without increasing the risk of arterial dissection and acute complications, we prospectively randomized 336 patients to receive either smaller or larger balloons. Thirty-four percent of patients had multivessel disease and 18% had multisite dilatation. One hundred sixty-nine patients were randomized to PTCA with a larger balloon and 167 to PTCA with a smaller balloon. Balloon:artery diameter ratios were 1.13 +/- 0.14 in the larger group and 0.93 +/- 0.12 in the smaller group (p less than 0.001). The trial was halted as clinically important differences in acute complications emerged. Emergency bypass graft surgery, usually for the treatment of arterial dissection, was required in 7.1% of patients in the larger balloon group and 3.6% of patients in the smaller balloon group (p = 0.15). Myocardial infarction (Q wave and non-Q wave) complicated 7.7% of procedures in which large balloons were assigned and 3.0% of procedures in which small balloons were assigned (p = 0.056). There were no deaths in either group. The incidence of bypass surgery was 1.7% when the balloon:artery ratio was less than 0.9, 3.1% when the ratio was 0.9-1.1, and 7.8% when it was greater than 1.1. Stepwise logistic regression analysis demonstrated that larger balloon assignment, multiple lesion dilatation, and multivessel coronary artery disease were independent predictors of emergency surgery. Angiographic restudy rates were 50% in the larger group and 60% in the smaller group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Postcatheterization vascular complications associated with percutaneous transluminal coronary angioplasty.

The threat of a vascular complication exists in association with any percutaneous arterial catheterization, but is greater in the more complex interventional techniques. During a 3 1/2-year period from January 1985 through June 1988, 4988 percutaneous transluminal coronary angioplasty procedures were performed at Emory University Hospital. All patients were given heparin during the cardiac intervention, and all had a catheter introducer left in place for several hours after completion of the procedure. Fifty-five iatrogenic vascular complications developed in 52 patients (1%), resulting in 54 corrective operations. Pseudoaneurysm, the most frequent complication, was seen in 35 patients (64%). This was followed by arteriovenous fistula in eight (15%), uncontrolled hemorrhage in six (11%), arterial thrombosis in three (6%), peripheral embolization in two (4%), and bowel ischemia in one patient. The outcome of surgical therapy in the entire group was quite acceptable with no operative mortality, no extremity amputation, and a 7.4% complication rate. Variables that correlated with an increased risk of peripheral vascular problems after percutaneous transluminal coronary angioplasty included advanced age, female gender, thrombolytic therapy, and postprocedural anticoagulation. Variables that did not appear to correlate were hypertension, diabetes, prior percutaneous transluminal coronary angioplasty, antiplatelet therapy, or the size of the guiding catheter used.

In-hospital cardiac mortality after acute closure after coronary angioplasty: Analysis of risk factors from 8,207 procedures

Cardiac death consequent to acute vessel closure after coronary angioplasty occurred in 13 of 294 closures from 8,207 consecutive procedures performed at two centers since 1981 (0.16% cardiac mortality rate). To determine the predictors of cardiac death after acute coronary closure, 50 clinical, angiographic and procedural variables were analyzed by an observer unaware of the clinical outcome for each of the 13 patients who died and also 100 patients randomly chosen, in whom vessel closure after angioplasty did not result in death during hospitalization. Univariate analysis found female gender (p less than 0.0001), collateral channels from the vessel dilated (p less than 0.0001), use of balloon counterpulsation (p less than 0.0002), pre- and postprocedural hypotension (p = 0.0003 and p = 0.003, respectively), jeopardy score greater than or equal to 2.5 (p = 0.003), left ventricular hypertrophy (p = 0.013), hypertension (p = 0.02), diabetes (p = 0.02) and multivessel disease (p = 0.03) to be predictive of death. Multivariate analysis found collateral vessels, female gender and multivessel disease to be independent predictors of death. Thus, cardiac death after elective coronary angioplasty is very rare in experienced centers and occurs most often in women with a large amount of potentially ischemic myocardium. Hypotension often precedes the fatal closure event. Close attention to the amount of potentially ischemic myocardium and to the fluid volume status of these patients would seem to be especially warranted.

Importance of stenosis morphology in the estimation of restenosis risk after elective percutaneous transluminal coronary angioplasty.

To determine the importance of predilatation stenosis morphology on the risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA), 500 procedures were randomly chosen for analysis from 3,839 consecutive successful PTCA procedures. Angiographic follow-up was available for 308 patients (62%) at a mean of 7.3 +/- 3.4 months after PTCA. One dilated site was randomly chosen per procedure. One hundred and one sites had documented restenosis (greater than or equal to 50% mean diameter stenosis from multiple projections) by quantitative angiography (33% of all sites restudied and 20% of all sites dilated). Twenty-eight morphologic variables and 20 other angiographic, clinical and procedural variables were analyzed by an observer blinded to clinical outcome. Univariate analysis found post-PTCA percent stenosis greater than 30% (p = 0.005), bend point location (p = 0.01), post-PTCA gradient greater than 15 mm Hg (p = 0.02), angina class III to IV (p = 0.03), age (p = 0.04) and the absence of dissection (p = 0.04) to predict restenosis. Multivariate analysis found only 2 significant (p less than 0.05) independent predictors of restenosis: post-PTCA percent stenosis greater than 30% and bend point location. Restenosis occurred in 41% of lesions located at an end-diastolic vessel angle greater than or equal to 45 degrees compared with 28% in lesions on lesser bends. Thus, only 1 predilatation morphologic characteristic, stenosis location at a bend point, was an important independent predictor of restenosis, and should be considered when assessing patients for PTCA.

Histopathologic phenomena at the site of percutaneous transluminal coronary angioplasty: The problem of restenosis

Seventeen postangioplasty cases were morphologically studied at postmortem. Four of the eleven, early and intermediate cases (few hours to 1 month from angioplasty to death), revealed intraluminal thrombi, although in only two cases were those thrombi occlusive. Almost all of the nine early cases (eight of nine) exhibited intimal disruptions. Except for two of these cases in which circumferential and/or longitudinal dissections were present, the remainder of the intimal cracks were superficial and of limited extent. Limited dissection between intima and media is not considered a serious or detrimental local event. The early cases showed an aneurysmal dilatation of the plaque-free segment of the arterial wall in eccentric plaques. This finding was interpreted as the result of uneven distribution of the dilating force (circumferential stress) on the aterial wall. Late cases (survival over 1 month) revealed characteristic medial and intimal lesions indicative of the initial dilatation injury. It is hypothesized that intrinsic arterial wall changes (medial disruption) at the plaque-free segment and the resulting altered arterial geometry at the site of dilatation have a significant hemodynamic effect on the vascular conduit and may enhance and sustain the myoproliferative intimal response.

Effect of pretreatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty

It is unknown whether the addition of dipyridamole to aspirin as pretreatment for patients undergoing percutaneous transluminal coronary angioplasty (PTCA) decreases acute complications. In this study 232 patients were prospectively randomized to receive either aspirin 325 mg orally 3 times daily (group 1, n = 115) or aspirin 325 mg orally 3 times daily plus dipyridamole 75 mg orally 3 times daily (group 2, n = 117) before elective PTCA. All clinical, angiographic and PTCA-related variables were similar between groups. Angiographic success rate was 93% in both groups. Clinical success was achieved in 107 patients (92%) in group 1 and in 101 patients (88%) in group 2 (difference not significant). Q-wave myocardial infarction occurred in 2 patients (1.7%) in group 1 and 5 patients (4.3%) in group 2 (difference not significant). Emergency coronary artery bypass grafting was required in 3 patients (2.6%) in group 1 and 7 patients (6.1%) in group 2 (difference not significant). There was 1 in-hospital death (in group 2). In this study, the addition of dipyridamole to aspirin as pretreatment of patients undergoing PTCA did not significantly reduce acute complications compared to aspirin alone.