- Open Heart Surgery in Patients With Sickle Cell Hemoglobinopathy
- Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy for Pulmonary Arterial Hypertension
- Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy
- Laboratory Measures of Exercise Capacity and Ventricular Characteristics and Function Are Weakly Associated With Functional Health Status After Fontan Procedure
- Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications: Assessment From the Acute Catheterization and Urgent Intervention Triage Strategy Trial
- Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
- Relationship Between Cardiac Rehabilitation and Long-Term Risks of Death and Myocardial Infarction Among Elderly Medicare Beneficiaries
- Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention: Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction TRITON-TIMI 38
- Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti–Toll-Like Receptor-2 Antibody
- Dispatcher-Assisted Cardiopulmonary Resuscitation: Risks for Patients Not in Cardiac Arrest
- Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation
- Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy
- Endothelial-Specific Deletion of Connexin40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion
- Histone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed Flow
- Rosuvastatin in the Prevention of Stroke Among Men and Women With Elevated Levels of C-Reactive Protein: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)
- Natural History of Very Severe Aortic Stenosis
- Info & Metrics
Open Heart Surgery in Patients With Sickle Cell Hemoglobinopathy
Sickle cell disorders are associated with increased risk of sickling, resulting in vasoocclusive complications. The information available for patients with sickle cell hemoglobinopathies undergoing any cardiac operations using cardiopulmonary bypass is sparse. In this study, a retrospective review of 47 patients with sickle cell disease or sickle cell trait undergoing open heart surgery at a single institution over an 11-year time period demonstrated that these patients should not be denied the needed cardiac surgical treatment. Intraoperative monitoring of venous and arterial oxygen content, pH, and body temperature is critical for a successful operation. These data support the view that heart valve surgery and surgery for congenital heart diseases can be performed safely and with acceptable outcomes in patients with sickle cell disease or sickle cell trait. See p 14.
Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy for Pulmonary Arterial Hypertension
Advanced therapies for pulmonary arterial hypertension are currently considered for patients with Eisenmenger syndrome because they have been shown to improve exercise capacity and pulmonary hemodynamics. The rate of death in this population, although lower compared with other causes of pulmonary arterial hypertension, remains alarmingly high. No data exist to date on a potential survival benefit of advanced therapy in Eisenmenger syndrome, which was the subject of this study. Our data from a single center on a large contemporary cohort of adults with Eisenmenger complex showed advanced therapy to be associated with significantly improved survival rate. Survival benefits should be considered together with improved hemodynamics and functional class when decisions are made about advanced therapies in this population. See p 20.
Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy
Neurological impairment in children with complex congenital heart disease may originate in the fetal period, before postnatal medical or surgical intervention. This hypothesis is supported by the present study, in which we compared third-trimester fetuses with complex congenital heart defects with normal control fetuses by using quantitative magnetic resonance imaging. Fetuses with heart disease had smaller brain volume and spectroscopic evidence of abnormal cerebral metabolism, with the most pronounced abnormalities in fetuses with lesions that predispose to reduced cerebral substrate supply. See p 26.
Laboratory Measures of Exercise Capacity and Ventricular Characteristics and Function Are Weakly Associated With Functional Health Status After Fontan Procedure
As mortality rate has declined dramatically for repair of even the most complex congenital heart disease patients, clinical care will focus increasingly on preventing and treating morbidities and improving functional health status. Patients with a functional single ventricle who have had the Fontan procedure are at high risk for suboptimal functional health status. Determination of associations of functional health status with laboratory measures, which may suggest pathophysiological mechanisms, are important for planning interventions and outcome measures for clinical trials. We performed a cross-sectional assessment of patients 6 to 18 years of age who had undergone the Fontan procedure. Our results showed that laboratory measures of exercise capacity and ventricular characteristics and function, as assessed objectively by brain natriuretic peptide levels, exercise testing, echocardiography, and magnetic resonance imaging, were only weakly associated with results from a validated questionnaire measure of physical and psychosocial functional health status. This suggests that strategies aimed at preserving indices of ventricular form and function as assessed by laboratory testing may have little effect on current functional health status. The impact of treatment strategies targeted toward those with important laboratory abnormalities in the pathological range may influence functional health status to an unknown degree but should be an important component of future studies. Strategies targeting functional health status and its noncardiac determinants directly, such as through rehabilitation programs and by addressing psychosocial morbidities, may have a greater impact on health-related quality of life. Such programs should be developed and evaluated for these high-risk and complex patients. See p 34.
Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications: Assessment From the Acute Catheterization and Urgent Intervention Triage Strategy Trial
On the basis of analysis of 13 819 patients with an acute coronary syndrome treated with contemporary antithrombotic strategies in the randomized Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, we developed prognostic models for the risk of myocardial infarction (MI) and risk of non–coronary artery bypass grafting major bleeding and examined the manner in which bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor affected these risks in individual patients. The risk factors for MI and major bleeding differed substantially, with only baseline ST-segment deviation and older age predicting both. In a covariate-adjusted analysis, treatment with bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor was associated with a nonsignificant 8% increase in MI but a significant 50% reduction in major bleeding. Both MI and major bleeding affected subsequent mortality rate, with hazard ratios of 2.7 and 2.9, respectively (both P<0.001). Given the individual patient risk profiles and the fact that bivalirudin prevented ≈6 major bleeds for each MI that might occur, bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor had an estimated reduction in bleeding risk that was greater than the estimated increase in MI risk for nearly all patients. When one considers each patient’s risk profile for MI and non–coronary artery bypass grafting major bleeding and the relative risk of these events with alternative antithrombotic strategies, a selection of the optimal pharmacological regimen for the individual patient can be made that would minimize the occurrence of these adverse events and their impact on subsequent mortality rate. See p 43.
Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
The inverse relationship between high-density lipoprotein cholesterol and risk of coronary heart disease suggests that therapeutic elevation of high-density lipoprotein cholesterol may provide an effective means of prevention of coronary heart disease. Pharmacological inhibition of cholesteryl ester transfer protein (CETP) leads to elevation in high-density lipoprotein cholesterol, but torcetrapib (the first-in-class CETP inhibitor) increased the risk of cardiovascular events in the ILLUMINATE trial (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events), which may have resulted from an unexpected blood pressure–elevating effect of this agent. We used common genetic polymorphisms in the CETP gene to distinguish whether the hypertensive action of torcetrapib was mechanism based or off target, because a genetic study of these variants can be considered to be a type of natural randomized trial of a “clean” low-dose CETP inhibitor with no off-target actions. Common CETP gene polymorphisms and torcetrapib treatment had concordant effects on 8 lipid and lipoprotein markers, including high-density lipoprotein cholesterol, but CETP gene variants had no effect on blood pressure. The blood pressure–elevating effect of torcetrapib appears to be an off-target action that is unlikely to be shared by chemically dissimilar CETP inhibitors. Genetic studies could be used in drug-development programs as a new source of randomized evidence for drug-target validation in humans. See p 52.
Relationship Between Cardiac Rehabilitation and Long-Term Risks of Death and Myocardial Infarction Among Elderly Medicare Beneficiaries
Exercise-based cardiac rehabilitation is recognized as an important part of the long-term management of coronary artery disease. It is associated with improved survival rate and beneficial changes in risk factors associated with coronary artery disease. However, the relationship between the dose of early outpatient cardiac rehabilitation and long-term outcomes is unknown. Using a large national sample of Medicare beneficiaries who attended any cardiac rehabilitation, we found that there was a strong dose–response relationship between the number of sessions attended and long-term risks of death and myocardial infarction. Attending all 36 sessions reimbursed by Medicare was associated with substantially lower risks of death and myocardial infarction at 4 years compared with attending any number of fewer sessions. However, only 18% of patients who attended any cardiac rehabilitation sessions attended all 36 sessions. Combined with the fact that a minority of eligible patients attends any cardiac rehabilitation in the first place, the proportion of patients who attend all of the sessions to which they are entitled is small. Our findings suggest that physicians should promote greater use of cardiac rehabilitation services and should strive to understand the barriers that prevent patients from completing a full course of early outpatient cardiac rehabilitation. See p 63.
Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention: Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction TRITON-TIMI 38
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed that for patients with acute coronary syndromes and planned percutaneous coronary intervention, prasugrel was associated with a significantly reduced rate of the composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke at the expense of an increased risk of TIMI major bleeding not related to coronary artery bypass graft surgery. The extent to which prasugrel should be considered the thienopyridine of choice for acute coronary syndrome patients undergoing percutaneous coronary intervention, however, depends not only on the balance between thrombotic and bleeding events but also on the economic implications, especially in light of the potentially large population of patients who may be candidates for this therapy. This study uses data from TRITON to evaluate the cost-effectiveness of prasugrel versus clopidogrel from the perspective of the US healthcare system. Using current drug prices of $4.62/d for clopidogrel and $5.45/d for prasugrel, we found that treatment with prasugrel versus clopidogrel for a median of 14.7 months was associated with lower costs and life expectancy gains both during the initial 30 days and from 31 days throughout the rest of the trial follow-up period, both overall and for most subgroups studied, including high-risk subgroups of patients with diabetes or ST-segment–elevation myocardial infarction. Results from the comparison of prasugrel with generic clopidogrel, likely to become available in the United States in 2011, at a hypothetical price for clopidogrel of $1/d yielded an overall increase in costs during the trial period of $996 per patient and an associated incremental cost-effectiveness ratio of $9727 per life-year gained, still favorable compared with many other accepted interventions. See p 71.
Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti–Toll-Like Receptor-2 Antibody
Over the past few decades, many molecular targets have been studied to limit the excessive tissue loss that occurs during the reperfusion phase after ischemia. This so-called myocardial ischemia/reperfusion injury limits the full potential of reperfusion therapy. Unfortunately, successful clinical translation of preclinical promises remains to be established. Our understanding of the pathogenesis of myocardial ischemia/reperfusion injury became much clearer with the discovery of Toll-like receptors (TLRs). The role of innate immunity in cardiac ischemia appeared to be more pivotal than we thought. More important, TLRs hold great promise as a therapeutic target within the innate immune system, also beyond cardiac ischemia, without affecting host defense or proper scar formation after infarction. In the present study, we show the first therapeutic application of an anti-TLR2 antibody after myocardial ischemia and reperfusion. We found that circulating TLR2 mediates myocardial ischemia/reperfusion injury. Administration of a TLR2 antagonist just 5 minutes before reperfusion reduces infarct size and improves cardiac performance and geometry. Furthermore, antagonizing TLR2 reduces inflammation and cell death after infarction. Our results reappraised the critical role of TLRs in cardiac ischemia and elucidated the mechanisms by which TLR2 mediates myocardial ischemia/reperfusion injury. Our results establish TLR2 as a novel therapeutic target for the treatment of acute myocardial infarction, even when it is initiated in the late ischemic period. For this reason, we provide a rationale for anti-TLR2 treatment initiated either in the ambulance or in the catheterization laboratory before reperfusion. See p 80.
Dispatcher-Assisted Cardiopulmonary Resuscitation: Risks for Patients Not in Cardiac Arrest
Cardiopulmonary resuscitation (CPR) instructions provided over the telephone by the 9-1-1 emergency dispatcher can substantially increase bystander-initiated CPR and thereby increase the chance for survival from out-of-hospital cardiac arrest. Nevertheless, identification of cardiac arrest by dispatchers and bystanders can sometimes be challenging. A number of conditions can resemble cardiac arrest; consequently, patients who are not in cardiac arrest can receive CPR. The risk of bystander CPR for patients not in arrest is uncertain and has implications for how assertive dispatch is in instructing CPR. This article reports on a 2½-year prospective study of dispatcher-assisted CPR in King County, Washington. Of the 1700 patients for whom dispatcher CPR instructions were initiated during the study period, 55% (938 of 1700) were in arrest, 45% (762 of 1700) were not in arrest, and 18% (313 of 1700) were not in arrest and progressed to receive bystander chest compressions. Of the patients not in arrest who received chest compressions, 12% experienced discomfort, and 2% sustained injuries likely or possibly caused by bystander CPR. The injuries were characterized most often by rib fracture, and no patients suffered visceral organ injury. The results of the present investigation indicate that the frequency of serious injury related to dispatcher-assisted bystander CPR among nonarrest patients is low. When coupled with the established benefits of bystander CPR among those with arrest, the results support an assertive program of dispatcher-assisted CPR. See p 91.
Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation
Pulmonary arterial hypertension is a disease of the small pulmonary arteries that is characterized by progressive pulmonary vascular remodeling, vasoconstriction, and thrombosis. These changes lead to increased pulmonary vascular pressures and cause right heart failure, which leads to death. In general, therapies have not been effective in reversing the pathophysiological changes associated with pulmonary arterial hypertension. Our investigations define inhaled nebulized sodium nitrite as a potential therapy for pulmonary arterial hypertension. These data demonstrate that sodium nitrite can prevent or reverse pulmonary arterial hypertension in multiple experimental animal models of this disease process. Furthermore, these data show that nitrite is enzymatically converted to vasoactive nitric oxide in lung tissue and pulmonary artery smooth muscle cells via xanthine oxidoreductase. These findings help to define a therapy that may be useful in the treatment of patients with this insidious disease that to this point has lacked effective pharmacological therapies. See p 98.
Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy
High-density lipoprotein (HDL) has long been considered an antiatherosclerotic lipoprotein. This has been suggested on the basis of the inverse association of plasma HDL levels with coronary disease and the risk of cardiovascular events. Furthermore, HDL has been observed to promote reverse cholesterol transport and to exert endothelial-protective effects; however, these effects were demonstrated in HDL from healthy subjects or in reconstituted HDL. The present study suggests that, in contrast to HDL from healthy subjects, HDL from patients with diabetes mellitus and metabolic syndrome loses important endothelial-protective effects, such as the capacity to stimulate endothelial nitric oxide production or to promote endothelial progenitor cell–mediated endothelial repair. These observations are likely important for the understanding of the vascular effects of HDL-raising therapies, which may be particularly vasoprotective if the “on-treatment” HDL exerts beneficial vascular effects. Notably, extended-release niacin therapy, at present the most effective agent in clinical use for increasing HDL, improved the capacity of HDL from diabetic patients to stimulate endothelial-protective effects. See p 110.
Endothelial-Specific Deletion of Connexin40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion
Endothelial dysfunction, the initiating event of atherosclerosis, is characterized by increased expression of adhesion molecules and cytokines, which promotes the transmigration of leukocytes into the atherosclerotic lesion. This study provides evidence that connexin40 (Cx40), a gap junction protein expressed in endothelial cells, regulates the activity of the membrane-bound 5′-ecto-nucleotidase (CD73). The activity of endothelial CD73 generates adenosine from the hydrolysis of adenine nucleotides. Adenosine, in turn, activates surface membrane receptors to trigger antiadhesion signals for leukocytes to the endothelium. We have generated an atherosclerosis-susceptible mouse line in which Cx40 is specifically deleted from the endothelium. Endothelial deletion of Cx40 accelerated atherosclerotic lesion formation and coincided with increased expression of vascular cell adhesion molecule-1 as well as decreased expression of CD73. The antiadhesive role of Cx40 was confirmed in an endothelial cell line by specific targeting of Cx40 with antisense and small interfering RNA. We also found that functional Cx40 intercellular channels convey antiadhesion signals for leukocytes. Thus, Cx40-dependent regulation of CD73 may contribute to the spatial propagation of antiinflammatory and antiadhesive responses within the endothelium. These findings provide a molecular basis for therapeutic modulation of Cx40-mediated intercellular communication, which may be beneficial not only in atherosclerosis but for other inflammatory diseases as well. Of note, Cx40 gene polymorphisms affecting protein expression levels have been associated recently with hypertension in humans. Future investigations should determine whether these polymorphisms might be of use in atherosclerosis risk assessment. See p 123.
Histone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed Flow
Atherosclerotic lesions form at distinct sites in the arterial tree, suggesting that hemodynamic forces influence the initiation of atherogenesis. In the present study, we show that disturbed flow stabilizes histone deacetylase 3 (HDAC3) protein in endothelial cells and demonstrate that HDAC3 levels correlate with Akt activity. We uncover a novel direct interaction between HDAC3 and Akt and elaborate on the molecular mechanisms involved. Our experiments indicate that the HDAC3–Akt complex formation is critical for the survival of endothelial cells. Clinically, endothelial dysfunction is identified as a major trigger of atherogenesis. Conventional treatments for vascular diseases involve lowering blood cholesterol levels, which may have a role in endothelial protection of the vessel wall. Our experiments identify HDAC3 as a crucial molecule for endothelial viability. Moreover, in vivo experiments in which the mouse aortic isograft model was used confirmed the prominent role of HDAC3 in maintaining the integrity of the vessel and provided further evidence that HDAC3 functions as a prosurvival factor in the vasculature. Therefore, HDAC3 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 HDAC3 function in endothelial cells and successfully retard disease progression. See p 132.
Rosuvastatin in the Prevention of Stroke Among Men and Women With Elevated Levels of C-Reactive Protein: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)
Prior primary prevention trials of statin therapy that used cholesterol criteria for enrollment have not reported significant decreases in stroke risk with active statin therapy. Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) randomized 17 802 men and women without cardiovascular disease with low-density lipoprotein cholesterol levels <130 mg/dL and high-sensitivity C-reactive protein levels ≥2.0 mg/L to rosuvastatin 20 mg daily or placebo. Active therapy with rosuvastatin reduced overall stroke rates nearly by half (48%), largely because of a 51% reduction in ischemic stroke without an increase in the risk of hemorrhagic stroke. Aside from a small increase in the risk of physician-diagnosed diabetes in the rosuvastatin arm, adverse events were similar in the 2 treatment arms. An updated meta-analysis of data from JUPITER and data from prior primary prevention statin trials (West of Scotland Coronary Prevention Study, Air Force/Texas Coronary Atherosclerosis Prevention Study, and Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) revealed a statistically significant 25% reduction in the risk of stroke with active statin therapy in the primary prevention setting. Our data suggest that statin therapy prevents stroke in a primary prevention population with normal levels of low-density lipoprotein cholesterol but elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein. See p 143.
Natural History of Very Severe Aortic Stenosis
This is the first study to assess the outcome of a large series of asymptomatic patients with very severe aortic stenosis managed according to current guidelines. One hundred sixteen consecutive asymptomatic patients with isolated very severe aortic stenosis defined by a peak aortic jet velocity ≥5.0 m/s were prospectively followed up for a median of 61 months. Event-free survival rate (indication for surgery, 90; cardiac death, 6) was poor for patients with a peak aortic jet velocity between 5.0 and 5.5 m/s (n=72), with 76±5% at 1 year, 43±6% at 2 years, 33±6% at 3 years, and 17±5% at 4 years; it was even worse for patients with a peak aortic jet velocity ≥5.5 m/s (n=44), with 44±8% at 1 year, 25±7% at 2 years, 11±5% at 3 years, and 4±4% at 4 years (P<0.0001). In comparison, event-free survival rate for a series of 82 patients with severe aortic stenosis defined by a peak aortic jet velocity between 4.0 and 5.0 m/s was 82±4% at 1 year, 70±5% at 2 years, 49±6% at 3 years, and 39±16% at 4 years. Furthermore, 6 cardiac deaths occurred in previously asymptomatic patients with very severe aortic stenosis, and symptom onset was more severe for patients with higher peak aortic jet velocities. Peak aortic jet velocity thus yields important prognostic information in the group of patients with severe aortic stenosis. Because of the high event rate and the possibility of rapid deterioration, considering early elective surgery might be worthwhile in patients with very severe aortic stenosis even when they are still asymptomatic. See p 151.
- Open Heart Surgery in Patients With Sickle Cell Hemoglobinopathy
- Dispatcher-Assisted Cardiopulmonary Resuscitation: Risks for Patients Not in Cardiac Arrest
- Natural History of Very Severe Aortic Stenosis
- Info & Metrics