Management of severe aortic stenosis in the presence of an 8 mm right coronary stent protrusion.

Management of a protruding coronary stent into the aortic root in patients undergoing evaluation for transcatheter aortic valve replacement can be challenging. We describe a patient treated with stent trimming and surgical aortic valve replacement, highlighting the importance of a multidisciplinary evaluation and selection process in this complex scenario.

Human Growth Factor/Immunoglobulin Complexes for Treatment of Myocardial Ischemia-Reperfusion Injury.

Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48-72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.

Pharmacodynamic Effects When Clopidogrel is Given Before Cangrelor Discontinuation.

OBJECTIVE: To determine whether initiation of clopidogrel before discontinuation of cangrelor would impact on the recovery of platelet reactivity. BACKGROUND: The active metabolite of clopidogrel cannot bind to P2Y12 when cangrelor occupies the receptor. Pharmacodynamic studies have shown that this interaction is avoided when clopidogrel is given at the end of the cangrelor infusion. We found that antiplatelet effects of another thienopyridine, prasugrel, were apparent when prasugrel was administered 0.5 hour before cangrelor was stopped. METHODS: Platelet function studies (light transmission aggregometry, VerifyNow, and flow cytometry) were performed on blood from patients with stable coronary artery disease who were taking aspirin when a loading dose of clopidogrel (600 mg) was given during a cangrelor infusion (0.5 and 1 hour before cangrelor was stopped). Results were compared with those obtained when clopidogrel was given immediately after cangrelor was stopped. RESULTS: Administration of clopidogrel 0.5 and 1 hour before discontinuation of the cangrelor infusion did not prevent recovery of platelet reactivity more effectively than administration at the end of the infusion. CONCLUSION: Our results support the previously established strategy of administering clopidogrel immediately after discontinuation of cangrelor. Earlier administration increases the recovery of platelet function.

Pharmacodynamic effects during the transition between cangrelor and prasugrel.

OBJECTIVE: The aim of this study was to determine the impact of cangrelor and prasugrel on the pharmacodynamic effects of each agent. BACKGROUND: The development of an intravenous P2Y12 antagonist necessitates transition between intravenous and oral therapy. METHODS: Patients (n=15) with stable coronary artery disease who were taking 81 mg aspirin daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 60 mg dose of prasugrel at 1 h (n=3), 1.5 h (n=6), 2 h (n=3), or 2.5 h (n=3). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 µmol/l ADP, VerifyNow, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 10 mg of prasugrel daily for either 5 days (n=6) or 6 days (n=6). On study day 8, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. RESULTS: During cangrelor infusion (days 1 and 8), extensive inhibition of platelet function, reflected by limited residual platelet reactivity, was apparent. On day 1, transient (limited to the first hour after cangrelor was stopped) but substantial (>50%) recovery of platelet reactivity was observed. This recovery was attenuated when prasugrel was given at 1.5 h (30 min before cangrelor was stopped). CONCLUSION: Prasugrel did not alter the antiplatelet effects of cangrelor, but transient recovery of platelet reactivity was apparent during the transition from cangrelor to prasugrel. Recovery of platelet reactivity was limited when prasugrel was administered 30 min before the end of the cangrelor infusion.

Pharmacodynamic effects during the transition between cangrelor and ticagrelor.

OBJECTIVES: This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor. BACKGROUND: Cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents. METHODS: Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 µmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. RESULTS: During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity. CONCLUSIONS: Ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor. Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.

Erythropoietin induces positive inotropic and lusitropic effects in murine and human myocardium.

Initial clinical studies indicate a potential beneficial effect of erythropoietin (EPO) in patients with anemia and heart failure. Here, we investigate the direct contractile effects of erythropoietin on myocardial tissue. Treatment with EPO (50U/mL) using excitable murine and human left ventricular muscle preparations resulted in a 37% and 62% increase in twitch tension, respectively (P<0.05). Isolated murine cardiomyocytes exposed to EPO demonstrated a 41% increase in peak sarcomere shortening (P=0.012). Using compounds that specifically stimulate a non-erythropoietic EPO receptor yielded similar increases in contractile dynamics. Cardiomyocyte Ca(2+)dynamics showed an 18% increase in peak calcium in EPO treated cardiomyocytes over controls (P=0.03). Studies in muscle strips skinned after EPO treatment demonstrated a phosphorylation dependant increase in the viscous modulus as well as an increase in oscillatory work. The EPO mediated increase in peak sarcomere shortening was abrogated by PI3-K blockade via wortmannin and by non-isozyme specific PKC blockade by chelerythrine. Finally, EPO treatment resulted in an increase in PKCε in the particulate cellular fraction, indicating activation of this isoform. EPO exhibits direct positive inotropic and lusitropic effects in cardiomyocytes and ventricular muscle preparation. These effects are mediated through PI3-K and PKCε isoform signaling to directly affect both calcium release dynamics and myofilament function.

Two hour bivalirudin infusion after PCI for ST elevation myocardial infarction.

The standard of care for STEMI PCI for the past decade has been aspirin, clopidogrel, heparin, and a glycoprotein IIbIIIa receptor inhibitor (GPI). A bivalirudin strategy was shown to be superior to a GPI strategy in the HORIZONS AMI trial for net adverse clinical events (combined MACE and bleeding). An increased risk of acute stent thrombosis in the bivalirudin arm may have prevented broader adoption of bivalirudin for this indication. We hypothesized that acute stent thrombosis risk could be ameliorated by a 2 h infusion of bivalirudin following STEMI PCI. We implemented a multicenter, prospective registry for all STEMI patients in Vermont treated at a single PCI center. Each patient was routinely pre-loaded with dual antiplatelet therapy and 75% received an unfractionated heparin bolus prior to PCI. The utilization of bivalirudin bolus and continued 2 h infusion after PCI was routine with GPI bailout optional. 128 consecutive STEMI patients underwent primary PCI from October 1, 2008 to September 30, 2009. 92% of primary PCI patients received bivalrudin during and after the procedure with a 9% rate of bail out GPI. There was one case of probable or definite acute stent thrombosis (0.7%), and this single case occurred despite use of bailout GPI. Despite the prolonged infusion of bivalirudin, major bleeding occurred in only 1.7% of STEMI patients. In conclusion, prolonging bivalirudin for 2 h after STEMI PCI may be a promising method to alleviate acute stent thrombosis risk without losing the bleeding complication benefit of the bivalirudin strategy.

Consistent door-to-balloon times of less than 90 minutes for STEMI patients transferred for primary PCI.

BACKGROUND: Recent data from large national registries show that < 15% of patients with ST-elevation myocardial infarction (STEMI) transferred for primary percutaneous intervention (PCI) actually meet the door-to-balloon (D2B) goal of < or = 90 minutes, and only onethird achieve D2B times of < or = 120 minutes. We established a streamlined STEMI protocol to allow rapid transfer of STEMI patients for primary PCI to meet the ACC D2B goal of < or = 90 minutes in at least 75% of the patients. METHODS: From February 2007 to August 2008, 37 consecutive patients presenting with STEMI to a community hospital in Vermont were transferred 26 miles to the University of Vermont (UVM) for primary PCI. Three time intervals were evaluated: presentation to departure time at the referring hospital, transfer time and UVM PCI time (time from arrival to the cath lab to balloon time). Total D2B time was defined as presentation to the first hospital to first balloon inflation. RESULTS: The majority of transfers (69%) occurred off-hours. All patients received aspirin and clopidogrel and heparin pre-PCI. Median presentation to departure time at the STEMI referral hospital, total transfer and UVM PCI times were 26 (20, 33), 36 (34, 40) and 20 (16, 22) minutes, respectively. The median D2B time was 82 (77, 91) minutes, with 73% of patients achieving the goal D2B of < or = 90 minutes, and 94% achieving a D2B time of < or = 120 minutes. CONCLUSION: For patients in a rural setting who present with STEMI, transfer of approximately 30 miles for timely primary PCI can be achieved in nearly 75% of patients using a simplified streamlined protocol.

Atypical presentation of anomalous origin of the left main coronary artery from the pulmonary artery.

Anomalous origin of the left main coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly that usually presents in childhood. Ninety percent of the patients with ALCAPA die within the first year of life without surgical intervention. In adults, ALCAPA is associated with left ventricular dysfunction, mitral regurgitation, and sudden death. The present report describes the case of an adult patient who presented with an abnormal stress test and ALCAPA was diagnosed during cardiac catheterization.

Extravascular closure for patients with high-risk femoral anatomy.

BACKGROUND: Vascular closure devices (VCDs) improve patient comfort and decrease time to ambulation. However, VCD studies have excluded patients with high-risk femoral artery anatomy; we examined the safety and efficacy of clip-based extravascular closure in this high-risk group. METHODS: We performed a prospective registry enrolling 98 consecutive patients undergoing diagnostic coronary angiography. Inclusion criteria were femoral artery calcification, moderate femoral artery stenosis, or non-femoral arterial sheath insertion. All patients underwent immediate vessel closure with the Starclose device (Abbott Vascular). Patients with severe femoral arterial disease or femoral arterial diameter < or = 4.0 mm were excluded. Hospital outcomes were assessed prospectively and femoral arterial stenosis was determined by quantitative angiography. RESULTS: Inclusion was mainly related to at least one of 3 main high-risk characteristics: moderate femoral arterial stenosis (30%), femoral arterial calcification (24%) or nonfemoral sheath insertion (46%). The average femoral stenosis was 35.3 +/- 5.1% among patients included for a significant femoral disease. There was a 100% procedural and 94% device success: 1 patient required manual compression for greater than or equal to 30 minutes. The average time from sheath removal to hemostasis was 0.76 +/- 1.3 minutes. Despite the higher-risk anatomy, there were no major vascular complications and only one minor vascular complication. The average time to ambulation was 78.1 +/- 47.3 minutes. CONCLUSIONS: In this prospective registry, the Starclose VCD was safe and effective for early ambulation of patients despite the presence of high-risk femoral arterial anatomy.

Changes in patterns of coronary revascularization strategies for patients with acute coronary syndromes (from the CRUSADE Quality Improvement Initiative).

Since the introduction of drug-eluting stents (DESs), patterns of revascularization strategies for patients with non-ST-segment elevation acute coronary syndromes have not been assessed. We studied 82,924 patients from the CRUSADE Initiative who presented with non-ST-segment elevation acute coronary syndromes and underwent coronary angiography at 365 United States hospitals that had capabilities for surgical (coronary artery bypass grafting [CABG]) and percutaneous (percutaneous coronary intervention [PCI]) revascularization from January 2002 to June 2005. Temporal trends in the use of PCI, CABG, and medical management without revascularization were analyzed with respect to the introduction of DESs. In total, 73,577 patients (89%) had >50% stenosis in > or =1 coronary artery, and there was a significant increase in the use of PCI (vs CABG or medical management without revascularization) during the study period (38.3% vs 52.5%). By quarter 2 of 2005, 80% of patients who underwent PCI received a DES. In total, 18,462 of 25,068 patients (73.6%) with 3-vessel disease (3VD) underwent revascularization and use of CABG decreased for these patients (48.9% to 39.9%, p <0.001), whereas use of PCI increased (51.1% to 60.1%, p <0.001). Factors significantly associated with use of PCI for patients with 3VD who underwent any revascularization included previous PCI, previous CABG, cardiology inpatient care, care at an academic hospital, renal insufficiency, and previous congestive heart failure. In conclusion, coinciding with the introduction of DESs, there has been a significant increase in the use of PCI and, in those patients with 3VD, a decrease in the use of CABG with a shift toward increasing use of PCI. Long-term implications of this shift remain uncertain, especially in patients with 3VD.

Osteoprotegerin is not associated with angiographic coronary calcification.

UNLABELLED: Coronary artery calcification may play a significant role in the pathophysiology of plaque progression and healing. We hypothesized that osteoprotegerin, an inhibitor of osteoclastogenesis, may participate in the calcification of coronary plaques or the response to injury after coronary stenting. A prospective registry was performed in 2004. Blood samples from 100 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI and 24 h after PCI. The concentrations of osteoprotegerin (OPG), C-reactive protein, interleukin-6, and soluble CD40 ligand (sCD40L) were determined by ELISA. Quantitative coronary angiography was performed to define the presence of culprit lesion calcification (CLC). Comparisons among markers of inflammation and tertiles of OPG were stratified with respect to CLC. Patients with CLC (n = 28) compared with no CLC (n = 71) were older (P < 0.01), had lower creatinine clearance (P < 0.01), lower hemoglobin (P = 0.02), and were less likely to smoke (P = 0.04). Patients without CLC were over twice as likely to present with a marker-positive acute coronary syndrome. CLC was associated with less pre-PCI platelet-mediated inflammation as measured by sCD40L (4.65 vs. 7.15 pg/ml, P = 0.05), but not with lower levels of OPG. Inflammatory cytokines increased significantly after PCI for patients with and without CLC. For patients in the highest tertile of OPG at baseline, there was a reduction in OPG after PCI. Systemic osteoprotegerin levels are not associated with angiographic calcification of culprit plaques. For patients with elevated levels of OPG prior to PCI, there is a significant reduction after PCI consistent with a counterregulatory role for OPG. CONDENSED ABSTRACT: Both calcified and non-calcified culprit plaques exhibited a similar inflammatory response to stent-mediated injury. After PCI, osteoprotegerin decreased while proinflammatory cytokines increased, which may be consistent with a counterregulatory role for osteoprotegerin.

The evaluation and management of cardiogenic shock.

Cardiogenic shock (CS) continues to be the leading cause of death in patients who present to the hospital with acute myocardial infarction (AMI). Mortality in patients with AMI complicated by CS remains extremely high, with 1-month mortality rates ranging from 40% to 60%. Although pump failure is the dominant etiologic feature of CS after AMI, the inflammatory system has been implicated in its pathogenesis. The dominant therapy for treatment of CS is early mechanical revascularization with either percutaneous coronary intervention or coronary artery bypass graft surgery. Supportive measures such as intravenous vasopressors or intra-aortic balloon counterpulsation can complement the benefit of definitive revascularization. Newer therapies are directed at mitigating the inflammatory response or supporting cardiovascular function until either patient recovery or until other destination therapy is available. The strategies in this critical pathway outline the general approach in treating CS after AMI at our institution.

Relation of leukocytosis to C-reactive protein and interleukin-6 among patients undergoing percutaneous coronary intervention.

An elevated white blood cell (WBC) count and elevated C-reactive protein (CRP) have been associated with an increased risk of adverse cardiac events. The relation between these 2 parameters of heightened systemic inflammation was characterized in patients who underwent percutaneous coronary intervention (PCI). Femoral arterial blood samples from a prospective registry of 100 patients who underwent PCI were obtained immediately before the procedure. The concentrations of CRP and interleukin-6 were determined by an enzyme-linked immunosorbent assay. Patients were stratified according to tertiles of ascending WBC counts before PCI. Univariate analysis compared patients in the highest WBC count tertile with the lower tertiles for clinical, angiographic, and procedural characteristics, as well as pre-PCI cytokine concentrations. Multiple logistic regression analysis was performed to examine the association between the elevated WBC count and baseline elevations in either CRP or interleukin-6, accounting for the simultaneous effect of confounding characteristics. Approximately 75% of patients had stable or unstable angina pectoris versus a marker-positive acute coronary syndrome. Patients in the highest WBC count tertile were more likely to be smokers, have received unfractionated heparin, have a marker-positive acute coronary syndrome, and have a CRP >3.0 mg/L. Multivariate analysis showed that only elevated troponin-I before PCI was independently associated with the highest WBC count tertile (odds ratio 10.9, 95% confidence interval 3.7 to 32.4, p < 0.01). In patients with negative troponin I findings, CRP >3.0 mg/L was a powerful independent predictor of an elevated pre-PCI WBC count (odds ratio 3.78, 95% confidence interval 1.07 to 13.3, p = 0.04). In conclusion, in patients with troponin I negative coronary syndromes, a pre-PCI elevation in the WBC count reflected cytokine-mediated inflammation.

Systemic inflammation after drug-eluting stent placement.

BACKGROUND: Systemic inflammation after coronary intervention identifies patients at increased risk of subsequent cardiac events. Cardiac events are less frequent after use of drug eluting stents (DES) compared with bare metal stents (BMS). Thus, we sought to determine whether attenuation of the systemic inflammatory response was contributing to the improved outcomes. METHODS: A prospective registry was initiated in late 2003. Peripheral venous blood samples from 75 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI, and both 1 hour and 24 hours after stenting. The concentrations of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL1-Ra) were determined by ELISA. Eleven patients were excluded from the analysis because they had both DES and BMS. RESULTS: Patients treated with BMS (n=29) compared with DES (n=34) had a higher incidence of marker-positive acute coronary syndromes (40% vs. 17%, p=0.06), vein graft PCI (p=0.02) and a larger final balloon diameter (p=0.04). Consistent with the lower baseline clinical risk, pre-PCI concentrations of cytokines were lower in the DES group (p=0.04 for IL-6 and p=0.08 for CRP). Comparable and significant increases in CRP, IL-6 and IL1-Ra were evident 24 hours after PCI in patients treated with either DES or BMS. After controlling for baseline levels of CRP, there remained a similar and robust (300%) relative increase in CRP for both DES and BMS patients. CONCLUSIONS: The inflammatory response to PCI appears similar in those treated with DES and BMS. Accordingly, the reduction in restenosis after DES is likely not mediated by attenuation of the systemic markers CRP, IL-1Ra, or IL-6.