Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+-Ca2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation
- Long-Term Outcomes of Mechanical Valve Replacement in Patients With Atrial Fibrillation: Impact of the Maze Procedure
- Early Developmental Outcome in Children With Hypoplastic Left Heart Syndrome and Related Anomalies: The Single Ventricle Reconstruction Trial
- Triggers of Hospitalization for Venous Thromboembolism
- Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring Study
- Cardiac G-Protein–Coupled Receptor Kinase 2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction
- Late Results of Percutaneous Mitral Commissurotomy up to 20 Years: Development and Validation of a Risk Score Predicting Late Functional Results From a Series of 912 Patients
- Pulmonary Arterial Hypertension in Patients Treated by Dasatinib
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Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+-Ca2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation
Atrial remodeling during atrial fibrillation (AF) increases the likelihood of ectopic (triggered) activity and reentry, which promote AF initiation and maintenance. Emerging evidence suggests critical involvement of abnormal subcellular Ca2+ signaling in AF. Although it is widely believed that altered Ca2+ signaling predisposes to delayed afterdepolarizations and triggered activity in AF patients, this has not yet been demonstrated. Here, we conducted for the first time simultaneous recordings of intracellular Ca2+ and membrane current/potentials in human atrial cardiomyocytes from sinus rhythm and AF patients. We found that AF is associated with enhanced diastolic Ca2+ leak from the principal cellular Ca2+ store, the sarcoplasmic reticulum, via malfunctioning sarcoplasmic reticulum ryanodine receptor (RyR2) channels. The leaked Ca2+ was exchanged for Na+ by an upregulated Na+-Ca2+ exchanger, causing substantial depolarizing transient inward currents and increasing the susceptibility to cellular delayed afterdepolarizations/triggered activity. Pharmacological and biochemical studies showed that the primary mechanism for RyR2 dysfunction was hyperphosphorylation by upregulated Ca2+/calmodulin-dependent protein kinase-II. Protein kinase A, which can also cause RyR2 hyperphosphorylation, was found to play at most a secondary role. These findings add to our appreciation of the phenomenon of AF begets AF, indicating that, in addition to the well-established tendency of AF to promote its own persistence by remodeling the reentrant substrate, it can enhance spontaneous ectopic (triggered) activity, which induces reentry. Although the contribution of these cellular Ca2+-mediated proarrhythmic events to ectopic foci in AF patients in vivo remains to be confirmed, the concept of specifically targeting diastolic sarcoplasmic reticulum Ca2+ leak mechanisms might open novel therapeutic avenues to prevent atrial arrhythmogenesis by normalizing cellular Ca2+ handling. See p 2059.
Long-Term Outcomes of Mechanical Valve Replacement in Patients With Atrial Fibrillation: Impact of the Maze Procedure
It has remained controversial whether the concomitant maze procedure may improve long-term clinical outcomes in chronic atrial fibrillation patients who undergo mechanical heart valve replacement. In the present study, a retrospective analysis was carried out on 569 consecutive patients with atrial fibrillation–associated valvular heart disease who underwent mechanical valve replacement. Of them, 317 patients concomitantly underwent the maze procedure and 252 underwent mechanical valve replacement alone. After adjustment for differences in baseline risk profiles between the 2 groups of patients, patients who had undergone the maze procedure were at similar risks of death (hazard ratio, 1.15; 95% confidence interval, 0.65–2.03; P=0.63) but were at a significantly lower risk of thromboembolic events (hazard ratio, 0.29; 95% confidence interval, 0.12–0.73; P=0.008) compared with those who underwent valve replacement alone at a median follow-up of 63.6 months (range, 0.2–149.9 months). The effect of superior event-free survival by the concomitant maze procedure was notable in a low-risk EuroSCORE (0–3) subgroup (P=0.049), but it was insignificant in a high-risk EuroSCORE (≥4) subgroup (P=0.65). Furthermore, the combination of the maze procedure resulted in superior left ventricular (P<0.001) and tricuspid valvular functions (P<0.001) compared with valve replacement alone on echocardiographic assessments performed at a median of 52.7 months (range, 6.0–146.8 months) after surgery. These findings suggest that the combination of the maze procedure is a reasonable option for this population, especially for those with low risks of surgery. Further prospective, randomized studies are needed to confirm the findings of this study. See p 2071.
Early Developmental Outcome in Children With Hypoplastic Left Heart Syndrome and Related Anomalies: The Single Ventricle Reconstruction Trial
Survival to adulthood is becoming a reality for patients with hypoplastic left heart syndrome and related single right ventricle anomalies treated with staged palliation from the Norwood operation to the Fontan procedure. We assessed neurodevelopment at age 14 months in the 15-center, randomized Single Ventricle Reconstruction trial by using the Psychomotor Development Index and Mental Development Index of the Bayley Scales of Infant Development-Second Edition. We found a high prevalence of neurodevelopmental impairment in patients with hypoplastic left heart syndrome and related single right ventricle anomalies. Lower Bayley Scales of Infant Development-Second Edition scores at age 14 months were predicted by both innate patient factors and measures of greater severity of illness. Patient factors that portended greater risk included the presence of genetic syndromes or other anomalies, lower maternal education, and lower birth weight. Patients with a more complicated postoperative course following the Norwood procedure also had worse outcomes, as indicated by independent risk factors of longer postoperative mechanical ventilation or hospital stay. Between Norwood discharge and age 12 months, a greater number of complications were also associated with worse development, a novel finding that highlights ongoing brain vulnerability and opportunities for intervention. Neither the type of systemic-to-pulmonary-artery shunt nor bypass-related variables were predictors of Bayley Scales of Infant Development-Second Edition scores in multivariable analyses. Thus, patient characteristics and indices of greater severity of illness were the factors most highly associated with later neurodevelopmental outcome. Substantial improvement in neurodevelopmental outcome in this vulnerable population is thus likely to require inclusion of interventions that occur outside the operating room. See p 2081.
Triggers of Hospitalization for Venous Thromboembolism
There are >330 000 hospital admissions for venous thromboembolism annually in the United States. The objective of this study was to evaluate triggers, or acute transitory exposures, of such hospitalizations that potentially are amenable to change. We designed a case-crossover study using the databases of the Health and Retirement Study, a longitudinal study of a nationally representative sample of older Americans, linked to Medicare files. This design incorporates a within-person comparison (90 days before the hospitalization versus other time periods) and is particularly useful in controlling for factors such as hereditary conditions, sex, race, and past comorbidities. We found that over half (52%) of all hospitalizations for venous thromboembolism were preceded by an infection and that the risk of such hospitalizations was 2.9-fold greater within 90 days of an infection than at other times. Both respiratory and non–respiratory tract infections were associated with greater risk. Individuals were at 9.3-fold greater risk of hospitalization for venous thromboembolism within 90 days of receiving erythropoiesis-stimulating agents than at other times. In addition, the results suggest that blood transfusion is a significant trigger of hospitalization for venous thromboembolism, independent of major surgeries, infection, injuries, and immobility. We recommend that clinical prediction rules and patient informational sources be updated to include infection, erythropoiesis-stimulating agents, and blood transfusion as risk factors for venous thromboembolism. See p 2092.
Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring Study
Numerous biomarkers representing various biological pathways have been independently implicated in cerebrovascular disease, but their relative contribution to the prediction of clinical cerebrovascular disease is uncertain. In a middle-aged community sample, we used a multimarker approach to identify plausible biomarkers associated with clinical and subclinical vascular brain injury. This approach also permitted us to assess the contribution of each biomarker to clinical risk reclassification after accounting for standard vascular risk factors that comprise the Framingham Stroke Risk Profile. In analyses adjusted for traditional risk factors, we observed an association between an aggregate panel of biomarkers, including markers of inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (plasma homocysteine and urinary albumin/creatinine ratio), and the risk of stroke/transient ischemic attack and with magnetic resonance imaging brain volumes. In further analyses, we identified that higher B-type natriuretic peptide levels and albuminuria were associated with the risk of stroke/transient ischemic attack and that the addition of these biomarker data provided incremental information over clinical risk factors predicting stroke. We further indentified that albuminuria (but not B-type natriuretic peptide) was also associated with smaller brain volume, as were higher C-reactive protein, D-dimer, and plasma homocysteine levels. Our findings are consistent with prior observations that alterations in several different biological pathways may underlie the pathophysiology of clinical and subclinical brain disease. However, whether the knowledge of B-type natriuretic peptide and albuminuria may be used to target individuals at risk of stroke for more intense primary prevention or monitoring requires further investigation. See p 2100.
Cardiac G-Protein–Coupled Receptor Kinase 2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction
G-protein–coupled receptor kinase 2 (GRK2) is a molecular culprit in the development and progression of heart failure (HF). We now provide the molecular basis for potential benefits of therapeutic strategies aiming at GRK2 inhibition. With our current study we demonstrate that loss of GRK2 in cardiac myocytes enhances excitation-contraction coupling in unstressed hearts and in failing myocytes. We show that this enhancement of excitation-contraction coupling occurs through differential regulation of sarcolemmal versus sarcoplasmic reticulum Ca2+ handling, with the net result being improved Ca2+ transients without sarcoplasmic reticulum Ca2+ overload leading to reversal of the HF phenotype. Further, we demonstrate that the beneficial effects seen with GRK2 inhibition in HF were associated with marked amelioration of cardiac myocyte contractility and significant improvements in intracellular Ca2+ cycling effected by modulation of the cardiac L-type Ca2+ channels. A clearly novel finding is the compartmentalization of intracellular signaling by GRK2 and thereby differential regulation of Ca2+ signaling. Overall, our current results explain the beneficial effects of GRK2 knockout in cardiac myocytes with intracellular changes in Ca2+ cycling being orchestrated to improve overall cardiac-myocyte contractility. Furthermore, our study demonstrates that this interplay between GRK2 and the L-type Ca2+ channels might represent an attractive target to correct deranged Ca2+ cycling in the failing heart. Future gene therapies or pharmacological strategies will thus potentially directly target this interplay and might thus contribute to further improvements in clinical HF treatment. See p 2108.
Late Results of Percutaneous Mitral Commissurotomy up to 20 Years: Development and Validation of a Risk Score Predicting Late Functional Results From a Series of 912 Patients
Percutaneous mitral commissurotomy is the reference treatment for mitral stenosis in young patients with favorable valvular anatomy. Less favorable presentations are frequently encountered in Western countries. The evaluation of long-term functional results is clinically relevant given the relatively young age of treated patients and their good life expectancy. Predictive factors of late results have been identified, but there is currently no method for easily assessing the prognosis of individual patients. This is of particular importance given the diversity of patient subsets in mitral stenosis. The present study reports the longest follow-up, up to 20 years, in a population of 1024 patients with diverse characteristics who underwent percutaneous mitral commissurotomy. We found that 30% of patients had good functional results at 20 years, ie, survival without cardiovascular death or mitral intervention and in New York Heart Association class I or II. In the 912 patients who had good immediate results from percutaneous mitral commissurotomy, we analyzed the predictive factors of late functional results. This study highlights that, besides final mitral valve area, final gradient is a strong predictor of late functional results and thus should also be systematically considered in the evaluation of the immediate results of percutaneous mitral commissurotomy. From the predictive factors identified, we derived a user-friendly score combining 7 variables enabling the probability of good functional results to be assessed in any given patient with good discrimination and concordance between predicted and observed rates. The wide application of this original and simple score should be encouraged in current practice to improve individualized patient information and follow-up. See p 2119.
Pulmonary Arterial Hypertension in Patients Treated by Dasatinib
The prognosis of chronic myelogenous leukemia has been transformed by tyrosine kinase inhibitors that inhibit BCR/ABL kinase, such as imatinib, dasatinib, and nilotinib. The present report summarizes the clinical characteristics and outcomes of 9 incident cases of severe precapillary pulmonary hypertension (PH) fulfilling the criteria of pulmonary arterial hypertension induced by dasatinib use identified from the French PH registry. PH occurred after 8 to 48 months of dasatinib exposure. Most patients had severe symptoms and marked hemodynamic compromise at time of PH diagnosis. Based on our registry and data from the national pharmacovigilance agency, the lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Of note, clinical, functional, and hemodynamic improvements were generally observed after dasatinib withdrawal. Nevertheless, all subjects remained at least mildly symptomatic and had persistent abnormal hemodynamics. Even if PH is a rare complication in patients treated with dasatinib, the increased use of this agent in the treatment of chronic myelogenous leukemia may result in higher numbers of patients at risk of developing drug-induced pulmonary arterial hypertension. Physicians need to be aware of this complication to appropriately monitor and manage these patients. We therefore recommend screening routinely for PH by echocardiography before commencing dasatinib and performing additional diagnostic testing in patients developing dyspnea or other symptoms suggestive of PH. Where these investigations indicate possible PH, a right heart catheterization is mandatory to confirm the diagnosis and mechanisms of PH. See p 2128.
- © 2012 American Heart Association, Inc.
- Triggers of Hospitalization for Venous Thromboembolism
- Pulmonary Arterial Hypertension in Patients Treated by Dasatinib
- Info & Metrics