M. Horrigan

Clinical and angiographic results with the next-generation resolute stent system A prospective, multicenter, first-in-human trial

OBJECTIVES The RESOLUTE trial examined the safety and efficacy of a next-generation zotarolimus-eluting coronary stent, Resolute (Medtronic CardioVascular Inc., Santa Rosa, California). BACKGROUND Revascularization benefits associated with current drug-eluting stents are often diminished in the presence of complex coronary lesions and in certain patient cohorts. Resolute uses a new proprietary polymer coating that extends the duration of drug delivery to match the longer healing duration often experienced in more complex cases. METHODS The RESOLUTE trial was a prospective, nonrandomized, multicenter study of the Resolute stent in 139 patients with de novo coronary lesions with reference vessel diameters > or =2.5 and < or =3.5 mm and lesion length > or =14 and < or =27 mm. The primary end point was 9-month in-stent late lumen loss by quantitative coronary angiography. Secondary end points included major adverse cardiac events (MACE) at 30 days, 6, 9, and 12 months; acute device, lesion, and procedure success; and 9-month target vessel failure (TVF), target lesion revascularization (TLR), stent thrombosis, neointimal hyperplastic (NIH) volume, and percent NIH volume obstruction. RESULTS The 9-month in-stent late lumen loss was 0.22 +/- 0.27 mm. Cumulative MACE were 4.3%, 4.3%, 7.2%, and 8.7% at 30 days, 6, 9, and 12 months, respectively. Acute lesion, procedure, and device success rates were 100.0%, 95.7%, and 99.3%, respectively. At 9 months, TLR was 0.0%, TVF was 6.5%, stent thrombosis was 0.0%, NIH volume was 6.55 +/- 7.83 mm(3), and percent NIH volume obstruction was 3.73 +/- 4.05%. CONCLUSIONS In this feasibility study, the Resolute stent demonstrated low in-stent late lumen loss, minimal neointimal hyperplastic ingrowth, low TLR, no stent thrombosis, and acceptable TVF and MACE. (The RESOLUTE Clinical Trial; NCT00248079).

Low-Normal or Excessive Body Mass Index: Newly Identified and Powerful Risk Factors for Death and Other Complications With Percutaneous Coronary Intervention

Recognized risk factors account for only a small portion of the variance in the 4% to 10% incidence of major ischemic events associated with percutaneous coronary intervention. Body mass index (BMI) (body weight in kg/[height in m]2) is a clinically useful estimate of body fat and has been shown to correlate with mortality from several causes. We sought to evaluate the effect of BMI as a potential risk factor for the complications of percutaneous coronary intervention in 3,571 consecutive percutaneous coronary intervention patients treated at a single referral center. Patients were prospectively divided into the nonobese (BMI < or = 25), mildly obese (BMI 26-35), and very obese (BMI > 35), based on accepted definitions. Multiple logistic regression analyses were used to determine the correlates of major complications from 25 candidate variables, including BMI < or = 25 (n = 614 patients) and BMI > 35 (n = 275 patients), recorded prospectively in a relational database. Death occurred in 2.8% of the BMI < or = 25 group, in 3.7% of the BMI > 35 group, and in 0.9% of the BMI 26-34 group (p < 0.001), but there was no difference in the incidence of other ischemic events. Blood product transfusion was required in 12% of the BMI < or = 25 group, in 7% of the BMI 25-34 group, and in 8% of the BMI > 35% group (p = 0.003). Multivariate analysis, after adjustment for other significant correlates, demonstrated that both BMI < or = 25 (odds ratio [OR] = 2.7, p = 0.005) and BMI > 35 (OR = 7.4, p < 0.001) were independent correlates of death. Low-normal or high BMI is a newly described and powerful risk factor for in-hospital death after percutaneous coronary intervention.

Reduction in Myocardial Infarct Size by Basic Fibroblast Growth Factor After Temporary Coronary Occlusion in a Canine Model

BACKGROUND Basic fibroblast growth factor (bFGF) has been shown to reduce infarct size in canine acute myocardial infarction; however, the mechanism of tissue salvage remains uncertain. We evaluated the effect of bFGF on infarct size in a model of acute infarction in which coronary occlusion was followed by prolonged reperfusion and sought to determine whether reperfusion attenuates the stimulus for myocardial neovascularization. METHODS AND RESULTS Anesthetized dogs undergoing 4-hour balloon occlusion of the left anterior descending coronary artery were treated with intracoronary bFGF (n = 8) or vehicle (n = 6). Ten-microgram doses of bFGF were administered 10 minutes after occlusion and again immediately before reperfusion. Left ventriculograms were obtained before occlusion, after reperfusion, and preceding euthanasia on day 7. Infarct size, expressed as a percentage of the area at risk, was reduced in bFGF-treated dogs (13.7 +/- 2.1% versus 28 +/- 3.4%; P = .002). Changes in left ventricular ejection fraction, capillary density, and cellular proliferation-assessed immunohistochemically with factor VIII and proliferating cell nuclear antigen antibodies-were similar in both groups. To assess coronary vasomotor responses to bFGF, a separate hemodynamic study was performed in five anesthetized nonischemic dogs in which incremental bFGF doses up to 100 micrograms induced no vasodilator response. CONCLUSIONS Treatment with bFGF was associated with a reduction in infarct size without hemodynamic effects or evidence of neovascularization. These data suggest that bFGF mediates myocardial salvage independently of angiogenesis and that reperfusion after infarction may attenuate the stimulus for neovascularization.

Reduction in myocardial infarct size by basic fibroblast growth factor following coronary occlusion in a canine model

In a canine model of permanent coronary occlusion it has been shown that basic fibroblast growth factor (bFGF) reduced infarct size and this was associated with an increase in myocardial capillary density a week after infarction. In a preliminary work from our own laboratory using a model of occlusion followed by prolonged reperfusion we observed a similar reduction in infarct size without evidence of myocardial neovascularization. The aim of the present investigation was to evaluate the effects of bFGF on infarct size and blood flow to the infarct zone in an acute experiment in which myocardial neovascularization would be excluded as a mechanism by the short duration of the study. Seventeen mongrel dogs were anesthetized and the heart was exposed through a left thoracotomy. The left anterior descending (LAD) coronary artery was isolated and occluded for 3 h. Fifteen min after LAD occlusion dogs received bFGF 20 microg of bFGF (n=6) or placebo (n=11) by intracoronary injection infused over 5 min. We measured heart rate, aortic pressure, regional coronary blood flow (CBF), regional shortening fraction (SF) at 1, 30 and 180 min of occlusion, then the LAD was reperfused for 5 min then the dogs were euthanized and infarct size was measured. Regional CBF was similar between the two groups of dogs throughout all the study. The SF was similar between the two groups prior the onset of ischemia and at the beginning of the ischemic period. After 180 min of ischemia SF was 2.7+/-4.1% for bFGF and -3.1+/-4.7 for placebo (P=0.049), and during reperfusion SF was 3.4+/-4.6% for bFGF and 0.4+/-1.0% for placebo treated dogs (P=0.023). The infarct size, normalized for the area at risk was 14.2+/-5.2% in bFGF group vs 25.8+/-8.2% in placebo group (P=0.015). In summary we have demonstrated that bFGF significantly limits myocardial necrosis after acute coronary occlusion, and that this occurred without an increase in regional myocardial perfusion and within a period of time too brief for angiogenesis to have occurred. By exclusion, it appears that the salutary effect of bFGF is likely to be mediated by a cellular mechanism. The mechanism or mechanisms responsible for myocardial salvage by bFGF may have significant potential to be exploited in the clinical arena as the basis for therapies to protect the acutely ischemic myocardium.

Long-term clinical outcomes with the next-generation Resolute Stent System: a report of the two-year follow-up from the RESOLUTE clinical trial.

AIMS The 12-month results of RESOLUTE were favourable for the new Resolute stent. Two-year safety and efficacy results from RESOLUTE have been evaluated and are now reported. METHODS AND RESULTS RESOLUTE was a prospective, multicentre, non-randomised, single-arm, controlled trial of the Resolute stent in 139 participants with symptomatic ischaemic heart disease due to single de novo lesions in a native coronary artery. The 2-year rates of MACE (all-cause death, myocardial infarction, emergent cardiac bypass surgery, and target lesion revascularisation [TLR]), death, late stent thrombosis, target vessel revascularisation (TVR), and target vessel failure (TVF) were assessed. Clinical events included two MACE (one TLR; one non-cardiac death) occurring between year one and two resulting in cumulative 2-year TLR, TVR, and TVF rates of 1.4%, 1.4%, and 7.9%, respectively. One possible stent thrombosis event occurred in the first year after stent implantation however no late or very late ARC-defined definite and probable stent thromboses occurred through two years. CONCLUSIONS The 2-year data from RESOLUTE demonstrated no safety concerns including no late stent thrombosis or loss of effectiveness with the Resolute stent. The finding that few events occurred in year two is encouraging, yet requires verification in a larger population.

Outcomes after percutaneous coronary intervention of ostial lesions in the era of drug-eluting stents.

Ostial lesions are a difficult subset associated with suboptimal outcomes after percutaneous coronary intervention (PCI). The aim of this study was to analyze outcomes of ostial lesions in contemporary Australian interventional practice.

Advances in percutaneous treatment for adult valvular heart disease

Valvular heart disease occurs in 2–3% of the general population with an increase in prevalence with advancing age. The aetiology of valvular heart disease has evolved in recent decades with degenerative aortic and mitral valve disease supplanting rheumatic heart disease as a primary cause. The common valve lesions to be discussed in this article are aortic stenosis and mitral regurgitation. The traditional approach to calcific aortic stenosis when either symptoms or left ventricular impairment develops is surgical aortic valve replacement and it remains a treatment with excellent outcomes. In recent years there has been interest in less invasive approaches, including percutaneous and transapical aortic valve implantation. With refinements in technology these approaches are becoming a potential treatment option, primarily for high‐risk patients who may otherwise be unsuitable for traditional open surgical treatment. Catheter‐based approaches for mitral valve disease are also evolving. Mitral regurgitation may often be the result of mitral annular dilatation seen in patients with an enlarged left ventricle or left atrium. Percutaneous implantation of a constricting device in the coronary sinus, which lies in close proximity to the mitral annulus, results in a change to the geometry of the mitral valve and reduced regurgitation. Another technique in patients with degenerative mitral regurgitation is the endovascular edge‐to‐edge repair in which coaptation of the mitral valve leaflets can be improved with a percutaneously deployed clip. Small patient series indicate that these new techniques are promising. As such, advances in percutaneous interventional and surgical approaches have the potential to further improve outcomes for selected patients with valvular heart disease.

Delayed neurally mediated syncope after inferior wall acute myocardial infarction

L 1 first coined the label vasovagal syncope in 1932 to explain brief loss of consciousness with hypotension and bradycardia. The normal response to a reduction in circulating blood volume or emotion is a stimulation of the sympathetic nervous system. However, neurally mediated syncope (NMS) may occur because of the activation of the Bezold Jarisch reflex, in which stimulation of cardiac stretch leads to a sudden and dramatic interruption of this compensatory sympathetic response, with a similarly dramatic increase in vagal stimulation. This results in a sudden vasodilatation and bradycardia and in turn hypotension and syncope. It has been shown that the Bezold Jarisch reflex can be triggered acutely by inferior wall acute myocardial infarction (AMI). The bradycardic, hypotensive presentation of an inferior wall AMI is familiar to all cardiologists and emergency physicians. Single case reports have also suggested the initiation of NMS with inferior ischemia and subsequent resolution with treatment of the ischemia. An association between inferior wall AMI and the later development of NMS has not been previously described.

Improving Guideline Compliance in Australia With a National Percutaneous Coronary Intervention Outcomes Registry

BACKGROUND Secondary prevention strategies after percutaneous coronary intervention (PCI) include statins and dual anti-platelet therapy, however there are significant gaps between guidelines and practice. Contemporary PCI practice requires comprehensive data collection to allow dynamic auditing and benchmarking of key performance and safety indices. Genesis HeartCare is Australias largest collaborative venture of cardiologists, practising at over 40 public and private hospitals. We hypothesised that measurement and local reporting of data would improve patient outcomes through improving compliance with guideline therapies. METHODS Real-time benchmarking via a national clinical quality and outcomes register, the Genesis Cardiovascular Outcomes Registry (GCOR-PCI). GCOR-PCI prospectively collected clinical, procedural, medication and outcomes data for 6720 consecutive patients undergoing PCI from 10 private hospitals across Australia. Key performance outcomes benchmarked against the aggregated study cohort and international standards were reported to individual sites. The main outcome measure was compliance with guideline medications (statins, anti-platelet agents). RESULTS Early data identified specific practice patterns associated with lower rates of statin therapy post-PCI, which led to changes in practice. Between the first and latest year of data collection there was significant improvement in the rates of statin therapy at discharge (92.1 vs. 94.4% p<0.03) and 12 months post-PCI (87.0 vs. 92.2% p<0.001) and of antiplatelet therapy at 12 months (90.7 vs. 94.3% p<0.001). CONCLUSIONS This large-scale collaboration provides a platform for the development of quality improvement initiatives. Establishment of this clinical quality registry improved patient care by identifying and monitoring gaps in delivery of appropriate therapies, driving key practice change.

The Receptor for Advanced Glycation End Products (RAGE) Is Associated with Persistent Atrial Fibrillation

Objective Upregulation of the receptor for advanced glycation end products (RAGE) has been proposed as a pathophysiological mechanism underlying the development of atrial fibrillation (AF). We sought to investigate if soluble RAGE levels are associated with AF in Caucasian patients. Methods Patients (n = 587) were prospectively recruited and serum levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) measured. The patients included 527 with sinus rhythm, 32 with persistent AF (duration >7 days, n = 32) and 28 with paroxysmal AF (duration <7 days, n = 28). Results Patients with AF were older and had a greater prevalence of heart failure than patients in sinus rhythm. Circulating RAGE levels were higher in patients with persistent AF [median sRAGE 1190 (724–2041) pg/ml and median esRAGE 452 (288–932) pg/ml] compared with paroxysmal AF [sRAGE 799 (583–1033) pg/ml and esRAGE 279 (201–433) pg/ml, p ≤ 0.01] or sinus rhythm [sRAGE 782 (576–1039) pg/ml and esRAGE 289 (192–412) pg/ml, p < 0.001]. In multivariable logistic regression analysis, independent predictors of persistent AF were age, heart failure, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% confidence interval (CI) 1.0–1.1, p = 0.001] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.1–1.4, p < 0.001]. Heart failure and age were the only independent predictors of paroxysmal AF. In AF patients, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% CI 1.1–1.2, p = 0.007] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.0–1.5, p = 0.017] independently predicted persistent compared with paroxysmal AF. Conclusions Soluble RAGE is elevated in Caucasian patients with AF, and both sRAGE and esRAGE predict the presence of persistent AF.