Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Brugada-Like Syndrome in Infancy Presenting With Rapid Ventricular Tachycardia and Intraventricular Conduction Delay
- Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST): A 2-Center Randomized Clinical Trial
- Treatment of Unexplained Syncope: A Multicenter, Randomized Trial of Cardiac Pacing Guided by Adenosine 5′-Triphosphate Testing
- Impact of Blood Pressure and Blood Pressure Change During Middle Age on the Remaining Lifetime Risk for Cardiovascular Disease: The Cardiovascular Lifetime Risk Pooling Project
- Status of Cardiovascular Health in US Adults: Prevalence Estimates From the National Health and Nutrition Examination Surveys (NHANES) 2003–2008
- Physician Procedure Volume and Complications of Cardioverter-Defibrillator Implantation
- Glycogen Synthase Kinase-3α Limits Ischemic Injury, Cardiac Rupture, Post–Myocardial Infarction Remodeling and Death
- Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis
- Multipotent Vasculogenic Pericytes From Human Pluripotent Stem Cells Promote Recovery of Murine Ischemic Limb
- Safety and Efficacy of Allogeneic Cell Therapy in Infarcted Rats Transplanted With Mismatched Cardiosphere-Derived Cells
- Survival in Childhood Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long- Term PAH Disease Management
- Comparison of the Durations of Mild Therapeutic Hypothermia on Outcome After Cardiopulmonary Resuscitation in the Rat
- Supervised Exercise Versus Primary Stenting for Claudication Resulting From Aortoiliac Peripheral Artery Disease: Six-Month Outcomes From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study
- Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4
- Niacin Inhibits Vascular Inflammation via the Induction of Heme Oxygenase-1
- Info & Metrics
Brugada-Like Syndrome in Infancy Presenting With Rapid Ventricular Tachycardia and Intraventricular Conduction Delay
In clinical practice, the occurrence of rapid ventricular tachycardia in an infant is sufficiently uncommon that a comprehensive diagnostic evaluation usually ensues. This includes cardiac structural and functional assessment and metabolic, infectious disease, and toxicological analysis. In the absence of a clear etiology among these categorical entities (and perhaps even in the presence of drug-induced ventricular tachycardia), and, especially if the infant's ECG shows ventricular conduction delay while in sinus rhythm, a cardiac depolarizing channel defect should be considered. This diagnosis is supported by characteristic prolongation of the QRS duration during intravenous infusion of procainamide or by demonstration of a disease-causing gene mutation coding for a subunit of the cardiac L-type calcium channel (CACNB2) or the cardiac sodium channel (SCN5A). Making the diagnosis of what may be considered Brugada-like syndrome is of clinical importance for 2 reasons: reliable pharmacotherapy to prevent potentially fatal ventricular tachycardia recurrences has not yet been established; and infants may be especially vulnerable to such recurrences during febrile illnesses and following immunizations, both common events during infancy. Although medical therapy may be individualized based on response to drugs attempted during the initial event, antiarrhythmic drug use should be considered adjunctive therapy. Effective management strategies should include aggressive antipyretic therapy during febrile illnesses, prophylactic antipyretic drugs with immunizations, and perhaps inpatient telemetry associated with these events. Implantable cardioverter-defibrillator implantation may be life-saving once the infant is of sufficient size, acknowledging the high complication rate of device use in infancy. See p 14.
Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST): A 2-Center Randomized Clinical Trial
Catheter ablation (CA) and minimally invasive surgical ablation (SA) have become accepted therapy for antiarrhythmia drug–refractory atrial fibrillation (AF). This study describes the first randomized clinical trial comparing the efficacy and safety of CA and SA during 12 months of follow-up. One hundred twenty-four patients with antiarrhythmia drug–refractory atrial fibrillation with left atrial dilatation and hypertension (42 patients, 33%) or failed prior CA (82 patients, 67%) were randomized to CA (63 patients) or SA (61 patients). CA consisted of linear antral pulmonary vein isolation and optional additional lines. SA consisted of bipolar radiofrequency isolation of the bilateral pulmonary vein, ganglionated plexi ablation, and left atrial appendage excision with optional additional lines. Follow-up at 6 and 12 months was performed by ECG and 7-day Holter recording. The primary end point, freedom from left atrial arrhythmia >30 seconds without antiarrhythmia drugs after 12 months, was 36.5% for CA and 65.6% for SA (P=0.0022). There was no difference in effect for subgroups, which was also consistent at both sites. The primary safety end point of significant adverse events during the 12-month follow-up was significantly higher for SA than for CA (n=21 [34.4%] versus n=101 [5.9%]; P=0.027), driven mainly by procedural complications such as pneumothorax and bleeding. In the CA group, 1 patient died at 1 month of subarachnoid hemorrhage while on vitamin K antagonists. The results indicate that in atrial fibrillation patients with dilated left atrial and hypertension or failed prior CA, SA is superior in achieving freedom from left atrial arrhythmias after 12 months of follow-up at the cost of a higher procedural serious adverse event rate. These findings may guide physicians and patients in choosing between these invasive treatments for atrial fibrillation. See p 23.
Treatment of Unexplained Syncope: A Multicenter, Randomized Trial of Cardiac Pacing Guided by Adenosine 5′-Triphosphate Testing
Syncope commonly occurs in the general population, especially in the elderly; its origin remains unexplained in up to 40% of patients. Permanent cardiac pacing represents an effective therapy in patients with syncope of unknown origin that results from neurally mediated cardio-inhibition. The ATP test was introduced in 1986 as a convenient and safe tool to identify patients with syncope of unknown origin with neurally mediated cardiac inhibition. This patient-blinded, multicenter, randomized trial demonstrated that, in patients with syncope of unknown origin and a positive ATP test with no other precluding possible indications, cardiac pacing is an effective therapy, leading to a significant reduction of syncope recurrences. Although only some patients with syncope of unknown origin have a positive ATP test, this quick and safe procedure should be considered part of the armamentarium of syncope diagnosis. See p 31.
Impact of Blood Pressure and Blood Pressure Change During Middle Age on the Remaining Lifetime Risk for Cardiovascular Disease: The Cardiovascular Lifetime Risk Pooling Project
Prior estimates of lifetime risk for cardiovascular disease (CVD) examined the impact of blood pressure (BP) at the index age and did not account for changes in BP over time. Using pooled data from 7 diverse US cohort studies, we examined how changes in BP during middle age affect the lifetime risk for CVD, coronary heart disease, and stroke. Remaining lifetime risk from 55 years of age for CVD, coronary heart disease, and stroke was estimated for 61 585 white and black men and women by BP strata and by changes in BP over an average of 14 years. Lifetime risk for CVD was 52.5% (95% confidence interval, 51.3–53.7) for men and 39.9% (95% confidence interval, 38.7–41.0) for women. Lifetime risk for CVD was higher for blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining lifetime risk for CVD, 21% to 41%, compared with individuals who had or developed hypertension by 55 years of age, 49.4% to 69.0%. Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining lifetime risk for CVD, and there may be a dose-response effect for the length of time at high BP levels. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension to reduce the lifetime risk for CVD. See p 37.
Status of Cardiovascular Health in US Adults: Prevalence Estimates From the National Health and Nutrition Examination Surveys (NHANES) 2003–2008
The American Heart Association has committed to the goal of improving the cardiovascular health of all Americans by 20% by the year 2020. In this article, we estimate the current status of cardiovascular health in the United States according to age, sex, and race/ethnicity groups. These data highlight the very high prevalence of unfavorable lifestyle (eg, adverse diet and physical activity trends contributing to epidemic obesity, ongoing smoking) and environmental factors (eg, excess sodium in the food supply) in the United States and the resulting adverse distributions of key health factors such as blood glucose, total cholesterol, and blood pressure. Clearly, both public health policy initiatives and renewed emphasis on individual patient behavior change are needed to improve the adverse levels of cardiovascular health. These estimates may assist clinicians and policymakers in identifying components of cardiovascular health that currently need improvement in specific patient populations. Data suggest that improvements in even a single component (such as through weight loss or modest increases in physical activity) can result in enhancements in multiple other aspects of cardiovascular health. Thus, clinical emphasis on taking components of cardiovascular health 1 step forward from poor to intermediate health through lifestyle and/or medication use or from intermediate to ideal health through lifestyle can result in important benefits for the individual and substantial shifts in the population burden of disease resulting in greater achievement of healthy longevity. Clinicians and patients can assess their personal cardiovascular health and receive advice on improving it from the American Heart Association at www.mylifecheck.org. See p 45.
Physician Procedure Volume and Complications of Cardioverter-Defibrillator Implantation
The outcomes of procedures are often better when they are performed by more experienced physicians and in hospitals with higher procedure volumes. This study examined the relationship between physician procedure volume and in-hospital complications and death after implantation of an implantable cardioverter-defibrillator using data from a national clinical registry of implantable cardioverter-defibrillator procedures. A significant inverse relationship between physician procedure volume and the rate of implantable cardioverter-defibrillator procedural complications was demonstrated, which was not explained by physician specialty, hospital volume, or patient characteristics. These data suggest that concentrating implantable cardioverter-defibrillator implantation in the hands of more experienced physicians may reduce procedural complications. See p 57.
Glycogen Synthase Kinase-3α Limits Ischemic Injury, Cardiac Rupture, Post–Myocardial Infarction Remodeling and Death
Occlusion of a coronary artery typically leads to ST-segment elevation myocardial infarction, for which percutaneous coronary intervention (PCI) or, if PCI is not available, thrombolytics, are the standard of care. The pathways that determine the amount of injury following occlusion of a coronary artery are not clear. If the components of those pathways could be identified, novel therapeutics targeting them could be created. This might be of particular importance when PCI is not readily available or when there will be delays in accessing a catheterization laboratory. Herein, we identify a single factor, a protein kinase known as glycogen synthase kinase-3α (GSK-3α), that modulates injury post–coronary occlusion. In the absence of GSK-3α, infarct size is larger, and mortality, primarily because of cardiac rupture, is increased. Long-term, adverse remodeling including profound fibrosis, and contractile dysfunction leading to heart failure, are more pronounced. It is uncommon to see significant cardioprotection in the setting of a permanent coronary artery occlusion because of the complete absence of flow, but our studies suggest that strategies promoting activation of GSK-3α might prove beneficial, even in the setting of an occluded vessel. See p 65.
Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis
Aortic stenosis is the most common form of valvular heart disease in the Western world and represents a major healthcare burden that is projected to increase with an aging population. However, there are currently no effective medical treatments or biomarkers of disease activity. The pathogenesis of aortic stenosis is incompletely understood, and defining the various stages of this process will be highly important to develop the therapies and biomarkers that are required. Positron emission tomography combined with computed tomography is a noninvasive imaging technique that allows the identification and quantification of specific pathological processes within small anatomic structures, such as the aortic valve. In this study, we sought to test the feasibility, repeatability, and validity of this technique in the evaluation of aortic valve stenosis. Positron emission tomography/computed tomography imaging of the aortic valve was performed to assess inflammation (18F-fluorodeoxyglucose) and active calcification (18F-sodium fluoride) of the valve leaflets. The positron emission tomography/computed tomography findings were compared in 121 patients with a full spectrum of disease severity. Our data have clearly established that this technique is both feasible and repeatable, indicating that these tracers may prove to be useful biomarkers of disease activity. Furthermore, we have demonstrated that 18F-fluorodeoxyglucose and 18F-sodium fluoride activity increase with progressive disease severity. However, uptake of 18F-sodium fluoride appears to predominate in both the early and latter stages of the disease. This may explain the disappointing effects of statin therapy in this condition and indicates that calcification might represent a better target for novel therapeutic interventions. See p 76.
Multipotent Vasculogenic Pericytes From Human Pluripotent Stem Cells Promote Recovery of Murine Ischemic Limb
In this study, we have generated for the first time a novel population of vasculogenic pericytes with multipotent mesodermal features, which is derived from human pluripotent embryonic and induced stem cells. The scalability of human pluripotent stem cells together with the stable phenotype of the highly expandable pericytic derivatives fulfills the demand for sufficient cell quantities for potential autologous clinical transplantation. Our findings support the notion that human pluripotent stem cell pericytes can be generated alongside with vascular endothelial cells from the same source of human pluripotent stem cells in a batch-to-batch consistent manner to treat ischemic diseases and potentially cardiovascular disorders, as well. Additional possible therapeutic applications include syndromes with use of pericytes derived from normal or disease-carrying human pluripotent stem cells to study disease modeling and drug screening, pericyte abnormalities such as hemangiopericytoma, diabetic retinopathy, and Alzheimer disease. See p 87.
Safety and Efficacy of Allogeneic Cell Therapy in Infarcted Rats Transplanted With Mismatched Cardiosphere-Derived Cells
Cardiosphere-derived cells (CDCs) are an attractive cell type for cardiomyoplasty after myocardial infarction, and autologous CDCs are already being tested clinically in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial. Autologous therapy avoids immunologic rejection but necessitates patient-specific tissue harvesting, cell processing, and quality control, resulting in 3- to 6-week delays to therapy and possible variations in cell potency related to patient age and comorbidities. The use of universal donor (allogeneic) cells, if safe and effective, would obviate such limitations; however, immune rejection may limit effectiveness regardless of whether it poses safety hazards. Thus, we compared syngeneic and allogeneic CDC transplantation in infarcted rats from immunologically mismatched inbred strains. We demonstrate that allogeneic CDC therapy without immunosuppression is safe and induces only a mild transient local response without signs of systemic immunogenicity. Despite lower long-term engraftment compared with syngeneic cells, allogeneic CDCs produce similar structural and functional beneficial effects (which persist at least 6 months after transplantation). The benefits are due to stimulation of endogenous repair mechanisms and regrowth of recipient heart tissue rather than formation of new donor-derived myocardium. In practice, the present work opens up a new treatment paradigm: CDCs could be grown in large numbers from allogeneic heart tissue in a central facility under strict quality control and banked for future use, enabling safe and effective myocardial repair in a timely, cost-efficient manner. This work motivates the testing of allogeneic human CDCs as a potential clinical product for cellular cardiomyoplasty. See p 100.
Survival in Childhood Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long- Term PAH Disease Management
The importance of this study is the size of the cohort for such a rare disease. The Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pediatric cohort is the most comprehensive prospective database of group 1 childhood pulmonary arterial hypertension reported to date. The size of the study (n=216), number of referral sites (n=26), and geographical distribution make the observations generalizable to clinical US practice. Although descriptive, the information is potentially useful for clinicians because it is a mixed incidence and prevalence cohort collected over 3 years. We describe the characteristics and outcomes of the cohort, and we identify key predictors of survival in childhood pulmonary arterial hypertension. See p 113.
Comparison of the Durations of Mild Therapeutic Hypothermia on Outcome After Cardiopulmonary Resuscitation in the Rat
Recent guidelines from the American Heart Association and the European Resuscitation Council recommend that unconscious adult patients achieving restoration of spontaneous circulation after out-of-hospital cardiac arrest be therapeutically cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm is ventricular fibrillation. Recent studies further demonstrated that both early application of therapeutic hypothermia and rapid achievement of target cooling temperature were key factors for improving neurological outcome and survival. The present study in a rat model of cardiopulmonary resuscitation demonstrated that a shorter duration of mild hypothermia induced rapidly and early after restoration of spontaneous circulation improved postresuscitation microcirculation, myocardial and cerebral functions, and survival as well as, or better than, prolonged duration of hypothermia. Therefore, a shorter duration of hypothermia induced rapidly and early after restoration of spontaneous circulation may be an optimal solution for therapeutic hypothermia that improves the outcome of resuscitation significantly and reduces the complications from and cost of therapeutic hypothermia. See p 123.
Supervised Exercise Versus Primary Stenting for Claudication Resulting From Aortoiliac Peripheral Artery Disease: Six-Month Outcomes From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study
Claudication is the most common ischemic symptom of peripheral artery disease (PAD), affecting approximately 30% of these patients and limiting pain-free walking in over 2 million Americans. There are 3 treatments available to improve these symptoms, including claudication pharmacotherapy (cilostazol), supervised exercise, and endovascular revascularization, but little data comparing their relative efficacy, harm, and cost-effectiveness. There has been a marked rise in use of invasive (percutaneous) angioplasty and stenting, while PAD exercise programs remain mostly unavailable. The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study is an NHLBI-sponsored comparative effectiveness clinical investigation that randomly assigned 111 patients with aortoiliac PAD (the optimal anatomic site for stenting) to receive 1 of 3 treatments: optimal medical care (OMC, using home exercise and cilostazol), OMC plus supervised exercise (SE), or OMC plus stent revascularization (ST). At 6 months of follow-up (the primary end point), the improvement in peak walking time was greatest for SE, intermediate for ST, and least with OMC (mean change versus baseline 5.8±4.6, 3.7±4.9, and 1.2±2.6 minutes, respectively; P=0.02 for ST versus OMC; and P=0.04 for SE versus ST). Disease-specific quality of life improved with both SE and ST compared with OMC, but the improvement was greater with ST than SE. This study demonstrates that supervised exercise treatment results in superior treadmill walking performance than stent placement for patients with aortoiliac PAD. The longer-term impact of SE and ST on functional status and health economic outcomes in individuals with aortoiliac PAD will be assessed at 18 months. See p 130.
Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4
The most effective way to limit myocardial infarct (MI) size is the earliest reperfusion of the ischemic myocardium. Although primary percutaneous coronary intervention achieves epicardial coronary artery reperfusion, paradoxical abnormal myocardial perfusion persists in 5% to 50% of MI patients despite the lack of angiographic evidence of mechanical vessel obstruction, a condition known as no-reflow. Reperfusion of the ischemic myocardium can induce reperfusion injury, ie, microvascular dysfunction and leaky vessels that promote edema and leukocyte infiltration. In these patients, the no-reflow phenomenon is a strong predictor of poor clinical outcome and of 5-year mortality. New strategies aimed at preventing no-reflow therefore represent a major medical need. We previously demonstrated that angiopoietin-like 4 (ANGPTL4) inhibits vascular permeability. Here, we showed induced ANGPTL4 expression in cardiac tissue from MI patients and in a mouse model. By the use of ANGPTL4 knockout mice, we showed that MI size was increased, and, whereas cardiomyocyte survival was not affected per se, major loss of integrity of coronary vessel network was evidenced. The knockout phenotype was rescued by administrating human recombinant ANGPTL4, which counteracted ischemia-induced vascular endothelial growth factor signaling and disruption of endothelial cell junctions, thereby leading to subsequent protection of the coronary capillary network and reduction of infarct size. ANGPTL4 also reduced infarct size in a nonrodent species, ie, in rabbit, by preserving vascular integrity and reducing no-reflow. Therefore, ANGPTL4 represents a promising pharmacological and therapeutic approach, either alone or in combination with other strategies, for cardioprotection during acute MI by targeting the no-reflow phenomenon. See p 140.
Niacin Inhibits Vascular Inflammation via the Induction of Heme Oxygenase-1
Niacin reduces plasma triglyceride, low-density lipoprotein, and lipoprotein(a) levels while raising that of high-density lipoproteins. Niacin also reduces plasma free fatty acid levels, albeit transiently. Niacin has been shown to promote regression of atherosclerosis and reduce cardiovascular events in humans. Until recently, niacin has not been used widely because it causes severe flushing that most people consider unacceptable. Partial alleviation of these side effects by use of extended release formulations, as well as combined therapy with the prostaglandin receptor antagonist laropriprant has increased niacin use, especially in association with statins. Combination therapy with niacin and a statin reduces the residual risk that persists in many people with dyslipidemia who are already being treated with a high dose of statin. In contrast to the large body of knowledge about the mechanisms by which statins protect against cardiovascular disease, the cardioprotective effects of niacin are not understood. The authors have reported previously that niacin inhibits vascular inflammation independent of changes in plasma lipid levels. The work described in this report demonstrates that the lipid-independent inhibition of vascular inflammation by niacin involves the induction of heme oxygenase-1 via activation of nuclear factor-E2-related factor 2 and the p38 mitogen-activated protein kinase signaling pathway. Hene oxygenase-1 is a cytoprotective protein whose expression is associated with therapeutic benefits in several pathological conditions such as atherosclerosis and inflammation. These results indicate that some of the cardioprotective effects of niacin may be due to its ability to induce heme oxygenase-1. See p 150.
- © 2011 American Heart Association, Inc.
- Physician Procedure Volume and Complications of Cardioverter-Defibrillator Implantation
- Niacin Inhibits Vascular Inflammation via the Induction of Heme Oxygenase-1
- Info & Metrics