Treating Acute “No-Reflow” with Intracoronary Adenosine in 4 Patients during Percutaneous Coronary Intervention

Angiographic evidence of impaired tissue perfusion, known as the “no-reflow” phenomenon, is a serious complication of percutaneous coronary intervention—one that is associated with increased mortality rates. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms that are responsible for no-reflow. Herein, we report the cases of 4 patients who developed the no-reflow phenomenon after elective percutaneous coronary intervention to their native coronary arteries and saphenous vein grafts. In all 4 patients, and without adverse effects, small bolus doses of adenosine through the guiding catheter improved epicardial perfusion—measured by either Thrombolysis In Myocardial Infarction (TIMI) flow grade or corrected TIMI frame count—and tissue-level perfusion, graded according to myocardial blush. In view of adenosine''s extremely short half-life in blood, the continuous administration of adenosine into the distal vascular bed throughout percutaneous coronary intervention may further improve outcomes by reversing or preventing the no-reflow phenomenon.Key words: Adenosine/administration & dosage/physiology/therapeutic use, angioplasty, transluminal, percutaneous coronary/adverse effects/methods, atherosclerosis/complications/therapy, cardiotonic agents/administration & dosage/therapeutic use, coronary vessels/drug effects, creatine kinase/blood, dose-response relationship, drug, graft occlusion, vascular/therapy, myocardial reperfusion/methods, treatment outcome, vasodilator agents/administration & dosage/therapeutic usePercutaneous coronary intervention (PCI) is frequently used to treat atherosclerosis-induced stenosis in native coronary arteries and in degenerated saphenous vein grafts (SVGs). Although PCI has a high initial success rate, enzymatic evidence of myocardial cell necrosis occurs in 22% to 44% of patients after apparently uneventful PCI procedures.^1,2 Microvascular obstruction (due in part to embolization of platelets and atheromatous débris) and intense vasoconstriction of the distal bed (secondary to the release of potent humoral mediators) are responsible for microinfarction after PCI.^3–6 In some patients, vascular compromise manifests itself during the procedure as an abrupt decrease in epicardial blood flow—Thrombolysis In Myocardial Infarction (TIMI) grade 0 to 1—which is known as the “no-reflow” or “slow-reflow” phenomenon. The compromise occurs in the absence of apparent dissection, coronary spasm, thrombus formation, substantial residual stenosis, or distal-vessel cutoff that is suggestive of macroembolization.Adenosine attenuates mechanisms that are responsible for the no-reflow phenomenon.⁷ We describe here the cases of 4 patients in whom intracoronary adenosine reversed no-reflow during PCI of the native coronary vessels and SVGs, as measured by TIMI flow grade, corrected TIMI frame count (CTFC), and myocardial blush grade (MBG).     

Variables predictive of good functional outcome following thrombolytic therapy in the Thrombolysis in Myocardial Infarction phase II (TIMI II) pilot study

Before commencing the randomized Thrombolysis in Myocardial Infarction phase II (TIMI II) study, 370 patients were administered intravenous recombinant tissue plasminogen activator (rt-PA) within 4 hours of onset of acute myocardial infarction (AMI) and assigned to 2-hour (immediate) percutaneous transluminal angioplasty (n = 33), 18- to 48-hour (delayed) angioplasty (n = 288) or no angioplasty (n = 49) in a nonrandomized, observational pilot study. Left ventricular ejection fraction at rest and during exercise was assessed by gated equilibrium radionuclide ventriculography at hospital discharge and again at 6 weeks. At hospital discharge, ejection fraction averaged 50% at rest and 56% at peak exercise. At 6-week follow-up, ejection fraction averaged 50% at rest and 53% at peak exercise. At 6-week follow-up, resting ejection fraction average 49% in the 2-hour angioplasty group, 49% in the 18- to 48-hour angioplasty group and 55% in the no-angioplasty group. Variables independently predicting "good functional outcome" at 6-week follow-up (survival with resting ejection fraction greater than equal to 50% and no decrease with exercise) in the 18- to 48-hour angioplasty group were fewer leads with ST-segment elevation greater than or equal to 0.1 mV, younger age, rapid normalization during rt-PA infusion of ST segments or dramatic relief of chest pain, absence of arrhythmias within the first 24 hours of treatment initiation, no prior infarction and not a cigarette smoker at entry. Thus, the TIMI II pilot study demonstrates that most patients with AMI of less than or equal to 4-hour duration treated with rt-PA have good ventricular function after AMI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporal Contribution of Myeloid-Lineage TLR4 to the Transition to Chronic Pain: A Focus on Sex Differences

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigorously characterize a novel spatiotemporal transgenic mouse line, Cx3CR1-Cre^ERT2-eYFP;TLR4^fl/fl (TLR4 cKO) to specifically knock out TLR4 only in microglia and no other myeloid-lineage cells. Using this transgenic mouse, we find that early TLR4 cKO results in profound improvement in chronic, but not acute, allodynia in males, with a significant but less robust effect in females. In contrast, late TLR4 cKO results in partial improvement in allodynia in both sexes, suggesting that downstream cellular or molecular TLR4-independent events may have already been triggered. Overall, we find that the contribution of TLR4 is time- and microglia-dependent in both sexes; however, females also rely on peripheral myeloid-lineage (or other TLR4 expressing) cells to trigger chronic pain.SIGNIFICANCE STATEMENT The contribution of myeloid cell TLR4 to sex-specific pain progression remains controversial. We used complementary pharmacologic and transgenic approaches to specifically manipulate TLR4 based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We discovered that microglial TLR4 contributes to early pain progression in males, and to a lesser extent in females. We further found that maintenance of chronic pain likely occurs through myeloid TLR4-independent mechanisms in both sexes. Together, we define a more nuanced contribution of this receptor to the acute-to-chronic pain transition in a mouse model of complex regional pain syndrome.     

Integrating Patient Reported Outcomes With Clinical Cancer Registry Data: A Feasibility Study of the Electronic Patient-Reported Outcomes From Cancer Survivors (ePOCS) System

Background

Routine measurement of Patient Reported Outcomes (PROs) linked with clinical data across the patient pathway is increasingly important for informing future care planning. The innovative electronic Patient-reported Outcomes from Cancer Survivors (ePOCS) system was developed to integrate PROs, collected online at specified post-diagnostic time-points, with clinical and treatment data in cancer registries.

Objective

This study tested the technical and clinical feasibility of ePOCS by running the system with a sample of potentially curable breast, colorectal, and prostate cancer patients in their first 15 months post diagnosis.

Methods

Patients completed questionnaires comprising multiple Patient Reported Outcome Measures (PROMs) via ePOCS within 6 months (T1), and at 9 (T2) and 15 (T3) months, post diagnosis. Feasibility outcomes included system informatics performance, patient recruitment, retention, representativeness and questionnaire completion (response rate), patient feedback, and administration burden involved in running the system.

Results

ePOCS ran efficiently with few technical problems. Patient participation was 55.21% (636/1152) overall, although varied by approach mode, and was considerably higher among patients approached face-to-face (61.4%, 490/798) than by telephone (48.8%, 21/43) or letter (41.0%, 125/305). Older and less affluent patients were less likely to join (both P<.001). Most non-consenters (71.1%, 234/329) cited information technology reasons (ie, difficulty using a computer). Questionnaires were fully or partially completed by 85.1% (541/636) of invited participants at T1 (80 questions total), 70.0% (442/631) at T2 (102-108 questions), and 66.3% (414/624) at T3 (148-154 questions), and fully completed at all three time-points by 57.6% (344/597) of participants. Reminders (mainly via email) effectively prompted responses. The PROs were successfully linked with cancer registry data for 100% of patients (N=636). Participant feedback was encouraging and positive, with most patients reporting that they found ePOCS easy to use and that, if asked, they would continue using the system long-term (86.2%, 361/419). ePOCS was not administratively burdensome to run day-to-day, and patient-initiated inquiries averaged just 11 inquiries per month.

Conclusions

The informatics underlying the ePOCS system demonstrated successful proof-of-concept – the system successfully linked PROs with registry data for 100% of the patients. The majority of patients were keen to engage. Participation rates are likely to improve as the Internet becomes more universally adopted. ePOCS can help overcome the challenges of routinely collecting PROs and linking with clinical data, which is integral for treatment and supportive care planning and for targeting service provision.     

Angiographic changes in saphenous vein grafts are predictors of clinical outcomes

Background Previous studies have suggested that angiographic evidence of disease progression in coronary arteries increases the risk of subsequent coronary clinical events. This study ascertained whether patients enrolled in the Post Coronary Artery Bypass Graft Clinical Trial (POST CABG) who had substantial progression of atherosclerosis in ≥1 saphenous vein grafts (on the basis of assessment of baseline and follow-up angiograms obtained 4-5 years after study entry), but who had not reported clinical symptoms before follow-up angiography, were at a higher risk of subsequent events than patients who did not have substantial progression of atherosclerosis (decrease ≥0.6 mm in lumen diameter at site of greatest change from baseline). Methods All 1351 patients enrolled in the trial underwent baseline angiography; only the 961 patients who had follow-up angiography and no coronary events before the follow-up study were included in this analysis. The clinical center staff contacted patients to ascertain the events that had occurred after follow-up angiography (approximately 3.4 years later). Results Sixty-nine patients had died; 870 patients or relatives were interviewed, and 22 patients could not be contacted. Univariable estimates of relative risk associated with substantial progression ranged from 2.2 (P < .001) for cardiovascular death or nonfatal myocardial infarction to 3.3 (P < .001) for revascularization. Multivariable and univariable estimates of risk were similar. Conclusions The findings provide evidence that patients who had substantial progression of atherosclerosis in vein grafts are at an increased risk for subsequent coronary events and suggest that angiographic changes in vein grafts are appropriate surrogate measures for clinical outcomes. (Am Heart J 2003;145:262-9.)     

Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.     

Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study

We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% +/- 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.