Robert J. Chisholm

Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience.

OBJECTIVES The aim of this study was: 1) to evaluate the acute and late outcomes of a transcatheter aortic valve implantation (TAVI) program including both the transfemoral (TF) and transapical (TA) approaches; and 2) to determine the results of TAVI in patients deemed inoperable because of either porcelain aorta or frailty. BACKGROUND Very few data exist on the results of a comprehensive TAVI program including both TA and TF approaches for the treatment of severe aortic stenosis in patients at very high or prohibitive surgical risk. METHODS Consecutive patients who underwent TAVI with the Edwards valve (Edwards Lifesciences, Inc., Irvine, California) between January 2005 and June 2009 in 6 Canadian centers were included. RESULTS A total of 345 procedures (TF: 168, TA: 177) were performed in 339 patients. The predicted surgical mortality (Society of Thoracic Surgeons risk score) was 9.8 +/- 6.4%. The procedural success rate was 93.3%, and 30-day mortality was 10.4% (TF: 9.5%, TA: 11.3%). After a median follow-up of 8 months (25th to 75th interquartile range: 3 to 14 months) the mortality rate was 22.1%. The predictors of cumulative late mortality were peri-procedural sepsis (hazard ratio [HR]: 3.49, 95% confidence interval [CI]: 1.48 to 8.28) or need for hemodynamic support (HR: 2.58, 95% CI: 1.11 to 6), pulmonary hypertension (PH) (HR: 1.88, 95% CI: 1.17 to 3), chronic kidney disease (CKD) (HR: 2.30, 95% CI: 1.38 to 3.84), and chronic obstructive pulmonary disease (COPD) (HR: 1.75, 95% CI: 1.09 to 2.83). Patients with either porcelain aorta (18%) or frailty (25%) exhibited acute outcomes similar to the rest of the study population, and porcelain aorta patients tended to have a better survival rate at 1-year follow-up. CONCLUSIONS A TAVI program including both TF and TA approaches was associated with comparable mortality as predicted by surgical risk calculators for the treatment of patients at very high or prohibitive surgical risk, including porcelain aorta and frail patients. Baseline (PH, COPD, CKD) and peri-procedural (hemodynamic support, sepsis) factors but not the approach determined worse outcomes.

Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis.

Remodeling of the vessel wall after balloon angioplasty injury is incompletely understood, and in particular, the role of extracellular matrix synthesis in restenosis has received little attention. The objective of the present study was to determine the sequence of changes in collagen, elastin, and proteoglycan synthesis and content after balloon injury and to relate these changes to growth of the intimal lesions and extent of cell proliferation. In a double-injury non-cholesterol-fed model, right iliac arterial lesions in 43 rabbits were treated with balloon angioplasty, and the rabbits were killed at five time points ranging from immediate to 12 weeks. Vessel wall collagen and elastin content and synthesis were measured after incubation with 14C-proline and separation with a cyanogen bromide extraction procedure. Sulfated glycosaminoglycan synthesis was measured after incubation with [35S]sulfate, papain digestion, and ethanol precipitation. Continuous in vivo infusion of bromodeoxyuridine (96 hours) was used to assess cell proliferation. The intimal area significantly increased from 0.27 +/- 0.08 to 0.73 +/- 0.11 mm2 between 0 and 12 weeks. Intimal and medial cell proliferation were modest and peaked at 1 week (labeling indexes of 4.8% and 3.0%, respectively) and then markedly declined by 2 weeks. Significant increases in collagen, elastin, and proteoglycan synthesis, up to 4 to 10 times above control nondamaged contralateral iliac arteries, were noted at 1, 2, and 4 weeks. These increases in synthesis were accompanied by significant increases in collagen and elastin content (by approximately 35%) that coincided with the temporal increase in cross-sectional area.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Outcomes After Transcatheter Aortic Valve Implantation Insights on Prognostic Factors and Valve Durability From the Canadian Multicenter Experience

OBJECTIVES This study sought to evaluate the long-term outcomes after transcatheter aortic valve implantation (TAVI) in the Multicenter Canadian Experience study, with special focus on the causes and predictors of late mortality and valve durability. BACKGROUND Very few data exist on the long-term outcomes associated with TAVI. METHODS This was a multicenter study including 339 patients considered to be nonoperable or at very high surgical risk (mean age: 81 ± 8 years; Society of Thoracic Surgeons score: 9.8 ± 6.4%) who underwent TAVI with a balloon-expandable Edwards valve (transfemoral: 48%, transapical: 52%). Follow-up was available in 99% of the patients, and serial echocardiographic exams were evaluated in a central echocardiography core laboratory. RESULTS At a mean follow-up of 42 ± 15 months 188 patients (55.5%) had died. The causes of late death (152 patients) were noncardiac (59.2%), cardiac (23.0%), and unknown (17.8%). The predictors of late mortality were chronic obstructive pulmonary disease (hazard ratio [HR]: 2.18, 95% confidence interval [CI]: 1.53 to 3.11), chronic kidney disease (HR: 1.08 for each decrease of 10 ml/min in estimated glomerular filtration rate, 95% CI: 1.01 to 1.19), chronic atrial fibrillation (HR: 1.44, 95% CI: 1.02 to 2.03), and frailty (HR: 1.52, 95% CI: 1.07 to 2.17). A mild nonclinically significant decrease in valve area occurred at 2-year follow-up (p < 0.01), but no further reduction in valve area was observed up to 4-year follow-up. No changes in residual aortic regurgitation and no cases of structural valve failure were observed during the follow-up period. CONCLUSIONS Approximately one-half of the patients who underwent TAVI because of a high or prohibitive surgical risk profile had died at a mean follow-up of 3.5 years. Late mortality was due to noncardiac comorbidities in more than one-half of patients. No clinically significant deterioration in valve function was observed throughout the follow-up period.

Intracoronary thrombus and complex morphology in unstable angina. Relation to timing of angiography and in-hospital cardiac events.

In 78 consecutive patients with unstable angina, we performed coronary angiography randomized to either the first day of presentation or later during the hospital admission to assess the frequency of intracoronary thrombus and complex coronary morphology relative to the time of symptomatic presentation and the impact of these angiographic features on outcome. Early angiography (17 +/- 6 hours) was performed in 42 patients and late angiography in 36 patients (5.7 +/- 2.1 days). Twelve patients randomized to late angiography required urgent cardiac catheterization 3.9 +/- 2.2 days after admission. Coronary thrombi were present in 43% (18 of 42) of early angiography patients and in 38% (14 of 36) of late angiography patients (p = NS). Only 21% (five of 24) late elective angiography patients had coronary thrombi, but 75% (nine of 12) of late urgent angiography patients had thrombi (p less than 0.05 vs. both early and late elective angiography patients). There was no difference in the frequency of complex coronary morphology among patients randomized to early angiography (42%, or 15 of 36), late urgent angiography (42%, or five of 12), and late elective angiography (38%, or nine of 24). Cardiac events (death, myocardial infarction, and urgent revascularization) were more frequent in the patients with coronary thrombus (73%, or 23 of 32), complex coronary morphology (55%, or 16 of 29), and multiple-vessel disease (58%, or 29 of 50) than in the patients without these angiographic features (17%, or eight of 46; 31%, or 15 of 49; and 7%, or two of 28, respectively; all p less than 0.05). Multiple regression analysis demonstrated that coronary thrombus was the best angiographic predictor of cardiac events. Thus, angiographic detection of intracoronary thrombi varies according to the temporal relation between angiography and chest pain at rest.

In Vivo Collagen Turnover Following Experimental Balloon Angioplasty Injury and the Role of Matrix Metalloproteinases

Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [14C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750 +/- 143 to 500 +/- 78 micrograms hydroxyproline per segment, P < .004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.

Characterization of Operator Learning Curve for Transradial Coronary Interventions

Background—Transradial percutaneous coronary intervention (TR-PCI) improves clinical outcomes compared to the transfemoral (TF) approach. However, inadequate training and experience has limited widespread adoption by interventional cardiologists. Methods and Results—Clinical and procedural characteristics for TR-PCI were prospectively collected from 1999 to 2008. To identify minimum case volume for optimum clinical benefit, single-vessel TR-PCI cases were chronologically ranked and stratified into 1 to 50, 51 to 100, 101 to 150 and 151 to 300 case volume groups for operators starting the TR approach at the study institution. Cases by operators with a >300 TR-PCI case volume comprised the control group. TR-PCI failure rates, contrast use, guide usage, and fluoroscopy time were compared among groups. A total of 1672 patients underwent TR-PCI by 28 operators. TR-PCI failure occurred in 4% and was higher in the 1 to 50 case volume group compared to the 51 to 100 (P=0.007) and control (P=0.01) groups. Contrast use was greater in the 1 to 50 group (180±79 mL) compared to the 151 to 300 (157±75 mL, P=0.02) and control (168±79 mL, P=0.05) groups. Fluoroscopy time was higher in the 1 to 50 group (15±10 minutes) compared to the 101 to 150 (13±10 minutes, P=0.04) and control (12±9 minutes, P=0.02) groups. Reasons for TR-PCI failure included spasm (38%), subclavian tortuousity (16%), poor guide support (16%), failed access (10%), and radial loop (7%). Case volume was significantly correlated with TR-PCI failure (&bgr;=−0.0076, P=0.0028), and odds of failure was reduced by 32% for each 50 increments in case volume. Conclusions—TR-PCI success depends on operator experience, and a case volume of ≥50 cases is required to achieve outcomes comparable to experienced operators. These findings have implications both for PCI operators looking to expand their skills and for defining standards for training.

Mechanism and Predictors of Failed Transradial Approach for Percutaneous Coronary Interventions

OBJECTIVES The study aimed to determine the mechanism and predictors of procedural failure in patients undergoing percutaneous coronary intervention (PCI) from the transradial approach (TR). BACKGROUND Transradial approach PCI reduces vascular complications compared with a transfemoral approach (TF). However, the mechanism and predictors of TR-PCI failure have not been well-characterized. METHODS The study population consisted of patients undergoing TR-PCI by low-to-intermediate volume operators with traditional TF guide catheters. Baseline characteristics, procedure details, and clinical outcomes were prospectively collected. Univariate and multivariate analyses were performed to determine independent predictors of TR-PCI failure. RESULTS A total of 2,100 patients underwent TR-PCI and represented 38% of PCI volume. Mean age was 64 +/- 12 years, and 17% were female. Vascular complications occurred in 22 (1%), and TR-PCI failure was observed in 98 (4.7%) patients. The mechanism of TR-PCI failure included inability to advance guide catheter to ascending aorta in 50 (51%), inadequate guide catheter support in 35 (36%), and unsuccessful radial artery puncture in 13 (13%) patients. The PCI was successful in 94 (96%) patients with TR-PCI failure by switching to TF. On multivariate analysis, age >75 years (odds ratio [OR]: 3.86; 95% confidence interval [CI]: 2.33 to 6.40, p = 0.0006), prior coronary artery bypass graft surgery (OR: 7.47; 95% CI: 3.45 to 16.19, p = 0.0002), and height (OR: 0.97; 95% CI: 0.95 to 0.99, p = 0.02) were independent predictors of TR-PCI failure. CONCLUSIONS Transradial approach PCI can be performed by low-to-intermediate volume operators with standard equipment with a low failure rate. Age >75 years, prior coronary artery bypass graft surgery, and short stature are independent predictors of TR-PCI failure. Appropriate patient selection and careful risk assessment are needed to maximize benefits offered by TR-PCI.

Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal

Objectives: Our objective was to analyze the impact of arterial access site, sheath size, timing of sheath removal, and use of access site closure devices on high‐risk patients with acute coronary syndromes (ACS). Background: In the SYNERGY trial, 9,978 patients with ACS were randomly assigned to receive enoxaparin or unfractionated heparin. Methods: This analysis includes 9,404 patients for whom sheath access information was obtained for the first PCI procedure or diagnostic catheterization. Comparisons of baseline, angiographic, and procedural characteristics were carried out according to access site and sheath size. Results: Overall, 9,404 (94%) patients underwent angiography at a median of 21 hr (25th and 75th percentiles: 5, 42) and 4,687 (50%) underwent PCI at a median of 23 hr (6,49) of enrollment. The access site was femoral for 94.9% of cases, radial for 4.4%, and brachial for 0.7%. Radial access was associated with fewer transfusions than femoral access (0.9% vs. 4.8%, P = 0.007). For femoral access, the rates of noncoronary artery bypass grafting (CABG)‐related TIMI major bleeding by sheath size was 1.5% for 4 or 5 French (Fr), 1.6% for 6 Fr, 3.3% for 7 Fr, and 3.8% for ≥ 8 Fr (P < 0.0001). After adjustment for baseline characteristics, femoral access site, larger sheath size, and delayed sheath removal were independent predictors of need for transfusion. Conclusions: Smaller sheaths, radial access, and timely sheath removal may mitigate the bleeding risk associated with potent antithrombotic/platelet therapy and early catheterization.

Plasma Urokinase Antigen and Plasminogen Activator Inhibitor-1 Antigen Levels Predict Angiographic Coronary Restenosis

BACKGROUND The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear. METHODS AND RESULTS We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively; P<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis. CONCLUSIONS Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.

Angiographic morphology in unstable angina pectoris

Complex morphology occurs frequently in unstable angina; however, its relation to symptomatic presentation, timing of angiography and hospital outcome has not been investigated. Accordingly, coronary angiography was performed 5 +/- 2 days after qualifying rest pain in 101 consecutive patients presenting with acute coronary insufficiency (n = 67) or crescendo angina (n = 34). Significant coronary artery disease was defined as any greater than or equal to 50% stenosis, and complex morphology as any stenosis with irregularity, overhang or thrombus. Eight of the 67 patients presenting with acute coronary insufficiency later proved to have a myocardial infarction as the qualifying event (creatine kinase twice normal with elevation of MB fraction). There were no myocardial infarctions in the crescendo angina group. Complex morphology occurred in 61% of patients. Thrombus alone occurred in 27% of patients with unstable angina without myocardial infarction, with similar frequencies between the 2 clinical groups. In contrast, intraluminal thrombi were identified in 78% of patients with acute coronary insufficiency who later proved to have a myocardial infarction as the qualifying event. The need for urgent catheterization (less than 48 hours) prompted by recurrent symptoms was associated with the angiographic findings of intraluminal thrombus (46%) and complex morphology (83%). The presence of complex morphology and intracoronary thrombus was associated with a higher incidence of in-hospital cardiac events, i.e., revascularization, myocardial infarction and death, independent of the incidence of multivessel disease.