Alan N. Tenaglia

Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial

BACKGROUND Recombinant fibroblast growth factor-2 (rFGF-2) improves perfusion in models of myocardial and hindlimb ischaemia. We investigated whether one or two doses of intra-arterial rFGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. METHODS 190 patients with intermittent claudication caused by infra-inguinal atherosclerosis were randomly assigned (1:1:1) bilateral intra-arterial infusions of placebo on days 1 and 30 (n=63); rFGF-2 (30 microg/kg) on day 1 and placebo on day 30 (single-dose, n=66); or rFGF-2 (30 microg/kg) on days 1 and 30 (double-dose, n=61). Primary outcome was 90-day change in peak walking time. Secondary outcomes included ankle-brachial pressure index and safety. The main analysis was per protocol. FINDINGS Before 90 days, six patients had undergone peripheral revascularisation and were excluded, and ten withdrew or had missing data. 174 were therefore assessed for primary outcome. Peak walking time at 90 days was increased by 0.60 min with placebo, by 1.77 min with single-dose, and by 1.54 min with double-dose. By ANOVA, the difference between groups was p=0.075. In a secondary intention-to-treat analysis, in which all 190 patients were included, the difference was p=0.034. Pairwise comparison showed a significant difference between placebo and single-dose (p=0.026) but placebo and double-dose did not differ by much (p=0.45). Serious adverse events were similar in all groups. INTERPRETATION Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion. The findings of TRAFFIC provide evidence of clinical therapeutic angiogenesis by intra-arterial infusion of an angiogenic protein.

In vivo validation of compensatory enlargement of atherosclerotic coronary arteries

Necropsy examinations and epicardial ultrasound studies have suggested that atherosclerotic coronary arteries undergo compensatory enlargement. This increase in vessel size may be an important mechanism for maintaining myocardial blood flow. It also is of fundamental importance in the angiographic study of coronary disease progression and regression. The purpose of this study was to determine, using intracoronary ultrasound, whether coronary arteries undergo adaptive expansion in vivo. Forty-four consecutive patients were studied (30 men, 14 women; mean age 56 +/- 10 years). Eighty intravascular ultrasound images were analyzed (32 left main, 23 left anterior descending and 25 right coronary arteries). Internal elastic lamina area, a measure of overall vessel size increased as plaque area expanded (r = 0.57, p = 0.0001, SEE = 5.5 mm2). When the left main, left anterior descending and right coronary arteries were examined individually, there continued to be as great or greater positive correlation between internal elastic lamina and plaque area (left anterior descending: r = 0.75, p = 0.0001; right coronary arteries: r = 0.63, p = 0.0007; left main: r = 0.56, p = 0.0009), implying that each of the vessels and all in aggregate underwent adaptive enlargement. When only those vessels with < 30% area stenosis were examined, internal elastic lamina correlated well with plaque area (r = 0.79, and p = 0.0001), and for each 1 mm2 increase in plaque area, internal elastic lamina increased 2.7 mm2. This suggests that arterial enlargement may overcompensate for early atherosclerotic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Unrecognized left main coronary artery disease in patients undergoing interventional procedures

Selective, coronary arteriographic, catheter-based, intravascular ultrasound images were obtained to determine the presence and extent of angiographically undetected or underestimated left main (LM) coronary arterial narrowing in patients receiving coronary interventional therapy. Coronary arteriograms were determined to be either normal or abnormal by visual inspection. Abnormal arteriograms were digitized and quantitated using a semiautomated edge-detection algorithm. Thirty-eight patients receiving percutaneous treatment of stenoses in the left coronary artery system were studied. Optimal LM coronary angiograms were obtained in 2 views, and intravascular ultrasound images were obtained after the coronary interventional procedure. Intravascular ultrasound detected plaque in 24 of 27 angiographically normal LM arteries (89%), whereas narrowing was observed in 11 of 11 angiographically abnormal LM arteries (100%). Eight of 38 patients (21%) had > 40% area stenosis by intravascular ultrasound. In patients with angiographic disease, there was no correlation between quantitative angiographic and ultrasound percent area stenosis (r = 0.12; p = 0.72; SEE 19%). The median plaque area was not different between angiographically normal (0.05 cm2; 0.03, 0.08 [25th, 75th percentile]) and abnormal (0.06 cm2; 0.03, 0.1) patients. The median percent area stenosis in arteriographically normal subjects (26%; 14, 32%) was less than that in abnormal ones (37%; 20, 46%) (p = 0.03). Unrecognized LM disease is widespread and often underestimated in patients with normal LM angiograms undergoing interventional procedures. Plaque area is similar for angiographically normal and insignificantly abnormal vessels. This study suggests that intravascular ultrasound overcomes the limitations of silhouette imaging and can be a clinically useful, adjunctive method to evaluate LM coronary artery disease.

Thrombolytic therapy in patients requiring cardiopulmonary resuscitation.

Cardiopulmonary resuscitation (CPR) is often considered a contraindication to thrombolytic therapy for acute myocardial infarction. Of 708 patients involved in the first 3 Thrombolysis and Angioplasty in Myocardial Infarction trials of lytic therapy for acute infarction, 59 patients required less than 10 minutes of CPR before receiving lytic therapy (CPR greater than 10 minutes was an exclusion of the trials) or required CPR within 6 hours of treatment. The patients receiving CPR were similar to the remainder of the group with respect to baseline demographics. The indication for CPR was usually ventricular fibrillation (73%) or ventricular tachycardia (24%). The median duration of CPR was 1 minute, with twenty-fifth and seventy-fifth percentiles of 1 and 5 minutes, respectively. The median number of cardioversions/defibrillations performed was 2 (twenty-fifth and seventy-fifth percentiles of 1 and 3 minutes, respectively). Patients receiving CPR were more likely to have anterior infarctions (66 vs 39%), the left anterior descending artery as the infarct-related artery (63 vs 38%) and lower ejection fractions on the initial ventriculogram (46 +/- 11 vs 52 +/- 12%) than those not receiving CPR. In-hospital mortality was 12 vs 6% with most deaths due to pump failure (57%) or arrhythmia (29%) in the CPR group and pump failure (38%) or reinfarction (25%) in the non-CPR group. At 7 day follow-up the CPR group had a significant increase in ejection fraction (+5 +/- 9%) compared with no change in non-CPR group. There were no bleeding complications directly attributed to CPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary ultrasound predictors of adverse outcomes after coronary artery interventions

OBJECTIVES The purpose of this study was to determine the association between qualitative and quantitative lesion characteristics as assessed by intracoronary ultrasound imaging and adverse outcomes after coronary artery interventions. BACKGROUND Restenosis and other adverse outcomes after coronary artery interventions may be difficult to predict from clinical or angiographic data. Intracoronary ultrasound imaging provides additional data that could prove useful. METHODS Immediately after successful coronary artery interventions (angiographic residual stenosis < or = 50%), 69 patients underwent intracoronary ultrasound imaging. Images were assessed qualitatively for plaque composition and topography and for dissection. Quantitative data included measurement of minimal lumen diameter, lumen area, plaque area and percent area stenosis at the treatment and adjacent reference sites. Adverse outcome was defined as death, coronary bypass surgery, myocardial infarction or angiographic restenosis. RESULTS Of the 69 patients, 1 died, 3 had bypass surgery and 1 had a myocardial infarction before planned 6-month repeat catheterization. Two patients were lost to follow-up study. Of the remaining 62 patients, 56 (90%) agreed to follow-up catheterization and 25 (45%) of the 56 had restenosis. Thus, 30 patients had an adverse outcome and 37 had no adverse event. The incidence of dissection detected by ultrasound imaging after an intervention was significantly greater in patients with than in those without a subsequent adverse event (63% vs. 35%, p < 0.05). The severity of dissection also appeared to be related to outcome (p < 0.05). Other qualitative and quantitative variables were not significantly different between the two patient groups. CONCLUSIONS Dissection, as assessed by intracoronary ultrasound imaging after a coronary artery intervention, can identify patients at increased risk of subsequent adverse events. Additional studies are warranted to explore whether such imaging may allow modification of interventional procedures to improve outcome.

Intimal Hyperplasia After Balloon Injury Is Attenuated by Blocking Selectins

BACKGROUND Cell adhesion molecules facilitate the adherence of platelets and leukocytes to the vascular endothelium in response to injury. Restenosis after balloon angioplasty is thought to represent the response to vascular injury. The role of cell adhesion in this process is unclear. METHODS AND RESULTS This study was performed in New Zealand White rabbits that underwent balloon angioplasty of the iliac artery. Expression of the cell adhesion molecule E-selectin on endothelium was determined by immunohistochemistry and increased at 6 hours with a peak expression 24 to 48 hours after balloon injury, returning to baseline by 1 week. The expression of L-selectin on circulating leukocytes, measured by flow cytometry, was significantly increased at 48 hours, with return to baseline by 1 week. In seven animals, the selectins were blocked with an analogue of sialyl-Lewis(x) given as an I.V. bolus of 10 mg/kg followed by 2 mg x kg(-1) x h(-1) I.P. infusion for 7 days. After 4 weeks, compared with control animals, the study group had a larger lumen area (57.7 versus 44.7 mm2, P<.05), smaller intima area (9.0 versus 19.2 mm2, P<.01), smaller intima/media ratio (0.4 versus 1.0, P<.01), and a smaller percent area stenosis (15.6% versus 34.3%, P<.01). CONCLUSIONS The cell adhesion molecules E-selectin and L-selectin are expressed after balloon injury. Blockade of the selectins has a favorable effect on the response to vascular injury.

Creation of pseudo narrowing during coronary angioplasty.

Abstract Since the initial description of percutaneous transluminal coronary angioplasty (PTCA) by Gruentzig et al,1 the application of PTCA has expanded dramatically, exceeding 300,000 cases annually. Along with this growth, patients with increasingly complex coronary arterial anatomy and lesions are being treated. Technologic advances, coupled with operator experience, have reduced acute procedural risk to an acceptable, although not negligible, level.2 During the performance of PTCA, the interventional cardiologist must quickly recognize and appropriately manage any complication that arises. In addition, the operator must be able to differentiate true complications from pseudocomplications; that is, the operator must recognize the artifactual nature of an apparent complication that is not necessarily what it appears to be. For instance, Espluges et al3 reported the appearance of persistent staining by contrast material of the arterial wall, suggesting significant dissection during PTCA while using a new monorail balloon catheter. The artifact disappeared with balloon deflation3. We report a patient in whom straightening of a tortuous coronary artery by a PTCA guidewire created the false impression of 2 new narrowings during PTCA.

Treatment of long coronary artery narrowings with long angioplasty balloon catheters

Balloon angioplasty of long coronary artery narrowings has been associated with a lower rate of acute success, and a higher rate of acute complications and restenosis than that observed for short narrowings. Angioplasty catheters with longer length balloons (30 and 40 mm) are now available, and the objective of this study was to determine the acute and long-term success for patients with long coronary artery narrowings treated with these longer balloons. All patients with long narrowings (> or = 10 mm) treated with long balloons at 1 institution over a 1-year period were identified (93 narrowings in 89 patients), and acute and long-term outcomes were carefully documented. Procedural success (residual stenosis < or = 50%) was 97%. Abrupt closure occurred in 6% and major dissection in 11% of narrowings. Clinical success (procedural success without in-hospital death, bypass surgery or myocardial infarction) was achieved in 90% of patients. Repeat catheterization was performed in 61 patients (76% of those eligible), and restenosis was found in 50 to 55%, depending on the definition used. The treatment of long coronary artery narrowings using angioplasty catheters with longer balloons leads to high rates of acute success. However, there is a high rate of restenosis. New interventional devices for long lesions should be compared with long balloons in a randomized controlled trial.

Long-Term Outcome Following Successful Reopening of Abrupt Closure After Coronary Angioplasty

Abrupt closure after coronary angioplasty is often successfully treated by repeat dilation. Long-term follow-up, including 6-month repeat catheterization and 12-month clinical evaluation, was obtained in 1,056 patients treated with acute (n = 335) or elective (n = 721) coronary angioplasty to evaluate the long-term impact of successful reopening of abrupt closure. Abrupt closure occurred in 13.5% of patients and was successfully reopened in 58%. Adverse outcomes including restenosis, death, bypass surgery, myocardial infarction and repeat angioplasty were compared between patients with successfully treated abrupt closure and those with successful procedures (residual diameter stenosis < or = 50%) without abrupt closure. For patients with acute angioplasty, the restenosis rates (> 50% diameter stenosis at follow-up) were 64% for those with successfully treated abrupt closure versus 36% for those with successful procedures without abrupt closure (p < 0.01). In addition, subsequent myocardial infarction (12 vs 3%; p = 0.01) and repeat angioplasty (21 vs 10%; p = 0.03) were more frequent in the group with abrupt closure. For patients with elective angioplasty, restenosis was 43% in those with successfully treated abrupt closure versus 45% in those without abrupt closure (p = NS). Subsequent death and myocardial infarction were more frequent in patients with abrupt closure (death: 12 vs 3% [p < 0.01]; myocardial infarction: 13 vs 3% [p < 0.01]). Long-term adverse events are increased in patients with successfully treated abrupt closure compared to those with successful procedures without abrupt closure.

Evidence for a taurine-deficiency cardiomyopathy

R ecently, a study by Pion et al’ demonstrated a feline condition of cardiomyopathy that could be ascribed to dietary deficiency of taurine and could be reversed by dietary supplementation with this amino acid. This finding raises the question of whether there is a taurine-deficient cardiomyopathy in man. Taurine is a p amino acid in which sulfonic acid replaces the carboxyl group of /3 alanine. Because of the sulfonyl group it is not incorporated into proteins but remains as free amino acid in plasma and tissues. It is present in highest concentrations in heart, muscle, central nervous system and platelets. Its exact role is not fully defined but it appears to have an important effect on the function of the heart and central nervous system and also is a major component of bile acids. This review will discuss the regulation of body taurine, how taurine levels in the heart are maintained, the effect of taurine on cardiac function and the possible role of taurine in congestive heart failure.