Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Long-Term Safety and Effectiveness of Mechanical Versus Biologic Aortic Valve Prostheses in Older Patients: Results From the Society of Thoracic Surgeons Adult Cardiac Surgery National Database
- Repeat Coronary Revascularization After Coronary Artery Bypass Surgery in Older Adults: The Society of Thoracic Surgeons’ National Experience, 1991–2007
- Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension
- Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity
- Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway
- Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children
- Vascular Endothelial Cell Growth–Activated XBP1 Splicing in Endothelial Cells Is Crucial for Angiogenesis
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Long-Term Safety and Effectiveness of Mechanical Versus Biologic Aortic Valve Prostheses in Older Patients: Results From the Society of Thoracic Surgeons Adult Cardiac Surgery National Database
Estimates indicate that nearly 80 000 aortic valve replacements are performed annually in the United States on an increasingly older and sicker population, yet data are scarce regarding the relative safety and effectiveness of aortic valve prosthesis in elderly patients. Using data from the Society of Thoracic Surgeons Adult Cardiac Surgery Database, we followed patients aged 65 to 80 years undergoing aortic valve replacement (with a biological or mechanical prosthesis) from 1991 to 1999 at 605 centers. We sought to evaluate the long-term mortality and valve-related complications in bioprosthetic versus mechanical aortic valves, as well as the consistency of our findings among commonly encountered patient subgroups. We found that among the elderly, the incidence of both mortality and valve-associated morbidities was high in the first 12 years after aortic valve replacement. Mechanical valves were associated with improved late survival and long-term prosthesis durability, yet they were also associated with an increased incidence of bleeding and stroke. In summary, the comparative safety and effectiveness of prosthetic heart valves was highly dependent on patient age and underlying comorbidities. Our findings emphasize the complexity of choosing an appropriate prosthesis based on the individual needs and risks specific to each patient. These findings highlight the necessity for careful discussion and thorough communication between patients and their healthcare providers, in hopes of making an appropriate decision that is tailored to each individual patient’s unique profile. See p 1647.
Repeat Coronary Revascularization After Coronary Artery Bypass Surgery in Older Adults: The Society of Thoracic Surgeons’ National Experience, 1991–2007
There is currently a paucity of information on contemporary rates of repeat revascularization after coronary artery bypass graft surgery, and there is a pressing need to establish national benchmarks for reference. We used data from the Society of Thoracic Surgeons National Adult Cardiac Surgery Database and the Centers for Medicare & Medicaid Services to determine long-term rates of repeat revascularization after initial coronary artery bypass graft surgery, describe temporal trends in repeat revascularization, identify patient-level factors associated with early and late repeat revascularization, and determine whether rates vary among hospital providers. After examining Society of Thoracic Surgeons and Centers for Medicare & Medicaid Services data on 723 134 patients aged ≥65 years, we found that the rate of repeat revascularization after coronary artery bypass graft in older individuals was low during nearly 2 decades of follow-up, and the vast majority of procedures during this time were percutaneous coronary interventions. Repeat revascularization rates have increased slightly over time, but remain low; approximately 2% to 3% of patients will undergo revascularization annually. Important factors associated with higher rates of repeat revascularization at 1 and 5 years after surgery included younger age and female sex, traditional cardiovascular risk factors for atherosclerosis, and incomplete revascularization. We observed modest variation in rates of repeat revascularization among centers in the Society of Thoracic Surgeons database. Our study has clinical significance because the information provided in this report provides national benchmarks that should be useful in future studies dealing with revascularization. See p 1656.
Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension
Hyperplasia of pulmonary-artery smooth muscle cells (PA-SMCs) is the primary determinant of the pulmonary vessel remodeling process that underlies pulmonary hypertension (PH). Because similarities exist between cancer and PH, drugs designed to treat malignant proliferative disorders might prove useful for treating PH. Nutlins are anticancer agents that disrupt the interaction between p53 and its negative regulator murine double minute 2, a specific p53 ubiquitin ligase and transcriptional inhibitor. Here, we showed that Nutlin-3a attenuated or reversed PH in 3 distinct experimental mouse models, decreased the number of proliferating PA-SMCs, induced PA-SMC senescence in vitro, and increased the number of p21-stained senescent cells. Interestingly, Nutlin-3a markedly increased lung p53 protein and downstream p53 gene expression in mice with PH, whereas only minor effects were noted in control mice without PH. The absence of nutlin toxicity for normal tissue may be ascribable to differential activities of murine double minute 2 in proliferative versus nonproliferative cells. Thus, Nutlin-3a holds promise as a prosenescence treatment targeting PA-SMCs during PH progression. See p 1664.
Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity
Cardiac toxicity is a side effect of many pharmaceutical compounds and is a leading cause for drug withdrawal from market because of safety concerns. Current preclinical methods to measure cardiotoxicity are inefficient and rely on genetically altered cell lines, such as human embryonic kidney cells, and Chinese hamster ovary cells, which do not accurately simulate human heart cells (cardiomyocytes). Recent technological advancement has enabled the generation of human induced pluripotent stem cells (hiPSCs) from the skin, which can be used to generate patient-specific cardiomyocytes (hiPSC-CMs) in vitro. The hiPSC-CMs generated in this fashion carry all the genetic information from the individuals from whom they are derived. In this report, we validate the capacity of a hiPSC-CM library to be used as a clinical trial in a dish model for accurate detection of patient-specific drug responses. Our results demonstrate that hiPSC-CMs can detect drug-induced cardiac toxicity more accurately than the preclinical tests currently in use by pharmaceutical companies and mandated by the US Food and Drug Administration (human ether-a-go-go–related gene assay). We further demonstrate that hiPSC-CMs can be used in personalized medical assays to assess the genetic susceptibilities of distinct individuals to drug-induced cardiac toxicities. This is important given that the majority of cardiotoxic drugs have a low incidence of harmful effects for the general population, and are largely only toxic to specific patient populations with determined genetic traits. We believe these findings strongly support the addition of hiPSC-CM–based assays to preclinical drug toxicity screening protocols and drug development for the acceleration of safe pharmaceutical compounds to the market. See p 1677.
Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway
The clinical significance of this investigation goes beyond simply understanding mechanisms mediating catecholamine cardiomyopathy and the role of adenylyl cyclase, oxidative stress, and the type 5 adenylyl cyclase (AC5)/Sirt1/FoxO3a pathway. These results will have direct application to clinical conditions of elevated circulating catecholamines (eg, pheochromocytoma), but more importantly potentially for all clinical conditions of elevated sympathetic activity (eg, heart failure). Currently, β-adrenergic receptor blockers play an important role in protecting against sympathetic stress in heart failure, but their efficacy is far from perfect. AC5 is in the β-adrenergic signaling pathway but is not a β-blocker. Therefore, discovering drugs to inhibit AC5 could be a major benefit for heart failure therapy, either alone or in combination with beta blockers. See p 1692.
Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children
The Berlin Heart EXCOR Pediatric ventricular assist device was recently approved by the Food and Drug Administration for bridge to heart transplantation in children. Although data from the Food and Drug Administration trial suggest that 90% of children can be bridged to transplantation with the EXCOR, with a stroke risk of 29%, the primary Food and Drug Administration cohort captured only one fourth of all US children implanted with the EXCOR during the 3-year study period. In this study, we examined EXCOR outcomes in all 204 children implanted during the study period. Overall survival in this unselected cohort was lower at 75%, and the risk of neurological dysfunction was similar at 29%. Children were more likely to die on EXCOR support if they had significant renal or hepatic impairment at implantation or right ventricular failure requiring biventricular assist device support. In addition, children weighing <5 kg fared significantly worse, a finding that merits further study. These findings demonstrate that EXCOR survival varies considerably and depends heavily on patient characteristics at implantation, underscoring the need to pay careful attention to patient selection practices. Specifically, waiting too long to implant a device so that renal, hepatic, or right ventricular function has significantly deteriorated sharply increases the risk of death on EXCOR support, and implanting too early may also escalate mortality by exposing children unnecessarily to the risks of ventricular assist device support such as stroke, which was the leading cause of death. It is encouraging to note that even within the short 3-year time frame of this study, pediatric centers that have refined their patient characteristics over time are observing significantly lower patient mortality. See p 1702.
Vascular Endothelial Cell Growth–Activated XBP1 Splicing in Endothelial Cells Is Crucial for Angiogenesis
Angiogenesis contributes to the restoration of blood flow in ischemic tissues, in which vascular endothelial growth factor–mediated endothelial cell migration and proliferation plays an important role. In the present study, we found that vascular endothelial growth factor can directly activate mRNA splicing of an endoplasmic reticulum stress-related protein X-box binding protein 1 (XBP1). We uncover a novel direct interaction between spliced XBP1 and PI3K leading to Akt phosphorylation. The overall effect was to increase β-catenin nuclear translocation and E2F2 expression leading to cell growth and proliferation. Global disruption of murine XBP1 gene reduced embryonic blood vessel formation partially attributable to a diminished number of CD31+ and Flk1+ endothelial cells. Although endothelial specific knockout XBP1 mice could survive, retinal vasculogenesis was retarded at the first week postnatal. In a hindlimb ischemia model, XBP1 deficiency in endothelial cells impaired angiogenesis and blood reperfusion, which may be attributable to decreased Akt/GSK3β phosphorylation. These results suggest that XBP1 can function in growth factor signal pathways, regulating endothelial proliferation and angiogenesis. Therefore, XBP1 may serve as a putative target for novel therapeutic approaches in cardiovascular diseases. Detailed elucidation of the mechanism involved would enable us to design new drugs that could interfere with XBP1 function in endothelial cells and successfully restoration of blood flow in ischemic tissues. See p 1712.
- © 2013 American Heart Association, Inc.
- Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension
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