Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Vascular Endothelial Growth Factor–Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis
- Chest Compression Alone Cardiopulmonary Resuscitation Is Associated With Better Long-Term Survival Compared with Standard Cardiopulmonary Resuscitation
- Duration of Cardiopulmonary Resuscitation and Illness Category Impact Survival and Neurologic Outcomes for In-hospital Pediatric Cardiac Arrests
- Morbidity and Mortality in Heart Transplant Candidates Supported With Mechanical Circulatory Support: Is Reappraisal of the Current United Network for Organ Sharing Thoracic Organ Allocation Policy Justified?
- Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7
- Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Collagen-Induced Platelet Aggregation Independently of Its Transcription Factor Activity
- A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis
- Supplemental Materials
- Info & Metrics
Vascular Endothelial Growth Factor–Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis
Insufficient vascular supply predisposes to tissue ischemia and infarction. Currently used treatments are based on surgical intervention and drugs that do not provide full recovery and may have side effects. New-generation therapies based on growth factor–stimulated angiogenesis provide exciting possibilities for improving the treatment of patients with tissue ischemia. However, the development of such therapies using, for example, the most potent angiogenic inducer, vascular endothelial growth factor (VEGF), is hindered by side effects such as angioma formation, vascular leakage, and inflammation, especially when used at high effective doses. On the other hand, low doses of VEGF stimulate the growth of unstable vessels, which are prone to regression after the therapy. Thus, the narrow range of effective concentrations of VEGF represents the main challenge for therapeutics development. Combined administration of growth factors such as VEGF and angiopoietin-1 to stimulate growth of more mature vessels has the disadvantages of unequal tissue distribution, different pharmacokinetic profiles, and higher cost compared with a single protein treatment. In the present study, we have developed a unique protein, called VA1, which combines the potent vessel growth stimulatory activity of VEGF and the permeability-inhibiting properties of angiopoietin-1. VA1 has a longer tissue half-life than VEGF; it strongly stimulates the antiapoptotic Akt pathway in endothelial cells; and it promotes vessel stability without angioma development. These properties make VA1 an attractive candidate for proangiogenic gene therapy. See p 424.
Chest Compression Alone Cardiopulmonary Resuscitation Is Associated With Better Long-Term Survival Compared with Standard Cardiopulmonary Resuscitation
Early bystander cardiopulmonary resuscitation (CPR) is the foundation for successful cardiac arrest resuscitation. Unfortunately, the majority of persons who have had cardiac arrests do not receive bystander CPR before arrival of professional rescuers. In comparison with traditional chest compression plus recue breathing, chest compression alone is a CPR strategy that simplifies the psychomotor requirement and may enable easier training and more widespread implementation. However, the long-term survival effects of chest compression alone versus compression plus rescue breathing among bystanders in a generalizable community setting is uncertain. The current study leveraged 2 randomized clinical trials of 2500 cardiac arrest events involving dispatcher-assisted CPR instruction to evaluate whether long-term prognosis differed among those who received chest compression alone in comparison with those who received compression plus recue breathing. Those who received chest compression alone experienced a 10% relative benefit in survival in comparison with compression plus rescue breathing. These findings provide strong support for long-term mortality benefit of a dispatcher CPR instruction strategy consisting of chest compression alone rather than compression plus rescue breathing among adult patients with cardiac arrest. Emergency dispatchers have a vital role in resuscitation, and community stakeholders should leverage this important role to increase early arrest recognition and effective layperson CPR and, in turn, improve survival following cardiac arrest. Bystanders can proceed with the chest compression alone approach with the appreciation that this strategy on average provides optimal long-term survival benefit. See p 435.
Duration of Cardiopulmonary Resuscitation and Illness Category Impact Survival and Neurologic Outcomes for In-hospital Pediatric Cardiac Arrests
This study analyzes data from a large, national registry of cardiopulmonary resuscitation (CPR) process of care and outcomes to show that outcomes are best with shorter durations of CPR and that many children survive after prolonged CPR (>35 minutes of CPR). Practicing clinicians who have the potential to care for children (even unexpectedly) should appreciate the potential for good outcomes after prolonged CPR in children, especially among certain patient groups. In addition, these data strongly support the importance of initial effective CPR to increase the likelihood of return of spontaneous circulation promptly, which in turn is associated with a greater likelihood of survival to discharge. The majority of pulseless cardiac arrest survivors in this study had good neurological outcomes even after prolonged CPR, which contradicts previous notions that CPR is futile after 20 minutes. See p 442.
Morbidity and Mortality in Heart Transplant Candidates Supported With Mechanical Circulatory Support: Is Reappraisal of the Current United Network for Organ Sharing Thoracic Organ Allocation Policy Justified?
Heart transplant candidates supported with left ventricular assist devices (LVADs) are granted 30 days in high-urgency status 1A and indefinite time in intermediate-urgency status 1B. Improvement in outcomes observed with the new continuous-flow LVADs has brought into question whether current allocation policy, implemented in the pulsatile-flow LVAD era, is still justified. The United Network for Organ Sharing (UNOS) registry was used to analyze the risk of death or delisting while on the heart transplant waiting list in 33 073 candidates listed from 1999 to 2011. Study groups were selected on the basis of the need for an LVAD and UNOS listing status. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States. Waiting list mortality decreased in the current compared with the first era. In the current era, patients with continuous-flow LVADs had a mortality risk that was similar to that of status 2 patients (lowest priority) and lower than for status 1B and 1A listed candidates. This was a significant change compared with the first era, in which the mortality of pulsatile-flow LVAD–supported patients was higher than that of status 2 patients and similar to that of status 1B patients. However, status upgrade for LVAD-related complications occurred frequently in both eras and significantly increased the risk of adverse outcomes. The risk of mortality and morbidity was highest in patients with biventricular assist devices and temporary VADs. These results may help to guide optimal allocation of donor hearts. See p 452.
Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7
Heart transplantation is a lifesaving procedure for patients with end-stage heart failure and provides a better survival and quality of life in comparison with medical treatment or device-based therapies. Recently, advances in immunosuppression and improved clinical care have enhanced the early survival of patients with cardiac transplants. However, >20% of patients do not survive beyond 3 years, and those who survive are afflicted with the long-term complications associated with chronic immunosuppression (eg, posttransplant diabetes mellitus, coronary vasculopathy, nephropathy, infections, and malignancies). To improve transplantation outcomes and lessen the need for life-long immunosuppression, it is crucial to continue the development of novel immunomodulatory strategies. Short-term targeting of the purinergic receptor P2X7 (P2X7R) may provide a novel therapeutic opportunity. Soon after transplantation, purine ATP is released by necrotic cells and causes the activation of graft-infiltrating T cells, which sense ATP by the highly expressed receptor P2X7R. Our data show that short-term P2X7R targeting with periodate-oxidized ATP robustly promotes, in a fully-mismatched model of acute rejection, long-term cardiac transplant survival in 80% of recipients, with preservation of immunocompetence. Moreover, periodate-oxidized ATP inhibits the development of coronary vasculopathy in a model of chronic rejection. Nearly 80 clinical trials are registered on the National Institutes of Health web site to promote long-term graft function, and none of these is designed to target P2X7R-mediated alloimmunity. Because novel P2X7R inhibitors are available for clinical use (eg, periodate-oxidized ATP, CE-224,535, AZD9056, and GSK1482160), short-term P2X7R targeting may have considerable translational potential by promoting cardiac transplant acceptance, thereby lessening the need for chronic immunosuppression and preventing the development of coronary vasculopathy. See p 463.
Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Collagen-Induced Platelet Aggregation Independently of Its Transcription Factor Activity
In conditions of inflammation, platelets often deviate from their normal path of activation to become hyperactive in response to various agonists that are in solution or affixed to subendothelial matrix. This platelet hyperactivity is a known risk factor for atherosclerosis and thrombosis, but its underlying mechanisms remain poorly understood. Using specific inhibitors and transgenic mice, we have shown that the signal transducer and activator of transcription 3 (STAT3) is activated in collagen-stimulated human and mouse platelets. Activated STAT3 serves as a protein scaffold to facilitate the catalytic interaction between the kinase Syk (spleen tyrosine kinase) and the substrate PLCγ2, leading to enhanced collagen-induced calcium mobilization and platelet activation/aggregation. These data demonstrate a nontranscriptional activity of STAT3 that facilitates a crosstalk between the proinflammatory cytokine interleukin-6 and hemostasis/thrombosis signals in platelets. This crosstalk could provide a mechanism for platelets to become hyperactive in diverse clinical conditions that share a common pathology of inflammation. Blocking STAT3 and its intracellular signal pathway could potentially reduce and prevent arterial thrombosis. Hyperactive platelets are also known to be insensitive to aspirin. Targeting STAT3 could therefore improve aspirin efficacy by reducing inflammation-induced platelet hyperactivity with a minimal impact on the physiologically critical process of hemostasis. See p 476.
A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis
Epidemiological studies over the past decade have shown that diabetes mellitus significantly affects the process of atherosclerosis formation and the following cardiovascular events. Endothelial cell (EC) dysfunction and inflammation are blamed for the pathogenesis of atherosclerosis and cardiovascular complications in diabetic patients, and anti-inflammatory therapy has gained increasing attention in the drug development for cardiovascular diseases. Voluminous evidence showing that the diabetic condition activates proinflammatory signaling pathways, but little is known about diabetes mellitus–mediated inhibition of anti-inflammatory responses that are activated by factors such as steady laminar flow. Our study strongly suggests that diabetes mellitus activates p90 ribosomal S6 kinase (p90RSK), which directly inhibits steady laminar flow–induced transcriptional activation of extracellular-signal regulated kinase 5 (ERK5), an atheroprotective nonclassical mitogen-activated protein kinase. This inhibition induces inflammatory responses in ECs and promotes EC dysfunction. Fluoromethyl ketone-methoxyethylamine, a specific inhibitor of p90RSK, counteracted diabetes mellitus–mediated EC inflammation and dysfunction, suggesting p90RSK activation as a key harmful event in diabetes mellitus. Interestingly, fluoromethyl ketone-methoxyethylamine could not improve these conditions in endothelial-specific ERK5 knockout mice, indicating a critical role of ERK5 in fluoromethyl ketone-methoxyethylamine–mediated improvement of EC function. Fluoromethyl ketone-methoxyethylamine significantly inhibited, and the depletion of endothelial ERK5 accelerated, atherosclerosis formation in ApoE−/− and LDL−/− mice, confirming the importance of the p90RSK-ERK5 module in clinically relevant end points of atherosclerosis. The p90RSK-ERK5 module should be an attractive drug target because it has unique features that distinguish it from other classical mitogen-activated protein kinase signaling. We believe that regulating ERK5 transcriptional activity is critical for controlling EC inflammation and dysfunction, which should provide a new therapeutic strategy for reducing atherosclerosis. See p 486.
- © 2013 by Lippincott Williams & Wilkins
- Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7
- Supplemental Materials
- Info & Metrics