Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model
- Trends in Cause of Death After Percutaneous Coronary Intervention
- Increased Risk of Acute Myocardial Infarction and Stroke During Hemorrhagic Fever With Renal Syndrome: A Self-Controlled Case Series Study
- Patterns of Statin Initiation, Intensification, and Maximization Among Patients Hospitalized With an Acute Myocardial Infarction
- Predictors of Long-Term Outcomes in Patients With Significant Myxomatous Mitral Regurgitation Undergoing Exercise Echocardiography
- Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy
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Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model
Atrial fibrillation (AF) is commonly characterized by a progressive pattern, moving from spontaneous atrial ectopy to paroxysmal AF and finally to long-standing persistent AF that is often resistant to therapy. The most important obstacle to effective long-term management of AF is the progression of the substrate, as manifested by substantial late AF recurrence rates after initially effective AF ablations. Ultimately, the only way to prevent long-term AF recurrence is to develop effective methods to forestall the molecular mechanisms that lead to substrate progression. The CREM transgenic mouse model of spontaneous AF mimics clinical progression, showing initially isolated atrial ectopy, then repeated bouts of AF, followed by frequent long-lasting AF episodes. We exploited the CREM transgenic mouse to study the molecular basis of AF progression, obtaining evidence that excess calcium leak from the sarcoplasmic reticulum via ryanodine receptor type 2 activates the calcineurin–nuclear factor of activated T cell–Rcan pathway, resulting in atrial dilatation, decreased connexin40 expression, and decreased conduction velocity. Normalization of the ryanodine receptor type 2–mediated calcium leak by crossing CREM transgenic mice with mice having a modified ryanodine receptor type 2 calcium release channel that eliminates calcium leak prevented atrial dilatation, conduction velocity reduction, and AF progression. Thus, our study suggests that ryanodine receptor type 2–mediated sarcoplasmic reticulum calcium leak drives AF progression via the calcineurin–nuclear factor of activated T cell–Rcan system and possibly other remodeling pathways. Our findings present the first clear insights into the molecular mechanisms underlying AF progression and suggest that modulation of ryanodine receptor type 2 may be a novel therapeutic strategy for halting AF development and progression. See p 1276.
Trends in Cause of Death After Percutaneous Coronary Intervention
The cause of long-term death in populations with established coronary disease remains incompletely understood. We evaluated secular trends in cause-specific long-term mortality after index percutaneous coronary intervention (PCI) performed at a single center between 1991 and 2008. Over 2 decades, we found a marked temporal switch from predominantly cardiac to predominantly noncardiac causes of long-term death after PCI, with cardiac causes accounting for only a minority of 5-year deaths in the contemporary era. These trends occurred in all age groups, in patients with single and multivessel disease and whether PCI was performed for stable angina or acute coronary syndromes. This suggests changes in the prognosis of broad populations of patients with coronary disease. After adjusting for multiple cardiac and noncardiac variables, the decline in cardiac mortality was found to be independent of changes in baseline clinical profile, whereas the rise in noncardiac mortality was directly related to an increased prevalence of noncardiac comorbidities at baseline. Moreover, the reduction in cardiac mortality was driven by fewer deaths from myocardial infarction and sudden death but not heart failure. The rise in noncardiac mortality was driven by deaths from cancer and chronic diseases. We believe the findings of this study have important implications for strategic priorities in resource allocation for cardiovascular health, as well as for design of clinical trials. The findings also underscore the importance of a holistic approach in the care of patients with coronary artery disease and provide cause-specific mortality benchmarks to assess the future influence of survival-directed therapies. See p 1286.
Increased Risk of Acute Myocardial Infarction and Stroke During Hemorrhagic Fever With Renal Syndrome: A Self-Controlled Case Series Study
During the first year after hantavirus infection, a higher proportion of the causes of death are cardiovascular. Hantavirus infections activate endothelial cells, causing increased platelet binding and activation. Furthermore, approximately one-fourth of patients diagnosed with hemorrhagic fever with renal syndrome (HFRS), a hantaviral disease, fulfill the criteria for disseminated intravascular coagulopathy. These are imminent portents indicating that cardiovascular sequelae may occur during hantaviral disease. From a cohort of 6643 HFRS patients, we identified individuals with either acute myocardial infarction (AMI) or stroke within the year before and after HFRS disease onset. By using the individuals as their own controls in the self-controlled case series method and by applying 2 different types of analysis, we calculated the incidence rate ratio for AMI and stroke in the first 3 weeks after HFRS. Both analyses showed an increased risk of AMI (≈4- and 6-fold for first and all AMI events, respectively) and stroke (≈16- and 14-fold for first and all stroke events, respectively) in the first 3 weeks after HFRS. The finding that HFRS is a risk factor for AMI and stroke suggests that HFRS patients should be carefully monitored during the course of infection to ensure early recognition of symptoms of impending stroke or AMI and to initiate adequate measures if required. Further studies are needed to investigate the potential benefits of anticoagulants or other treatments to prevent cardiovascular complications during HFRS. See p 1295.
Patterns of Statin Initiation, Intensification, and Maximization Among Patients Hospitalized With an Acute Myocardial Infarction
Because trials have shown that intensive statin therapy after an acute myocardial infarction is superior to moderate statins in reducing morbidity and mortality, we sought to examine variations in hospitals’ rates of initiating, intensifying, and maximizing statin therapy after acute myocardial infarction. Among 4340 acute myocardial infarction patients from 24 US hospitals, we found that statin therapy was initiated in nearly 90% of patients during hospitalization, with no variability across sites; however, only 26% of patients taking submaximal statins had their statin therapy intensified, with modest site variability. Furthermore, only 23% of patients were discharged on maximal statin therapy, with substantial hospital variability. We also found that higher levels of low-density lipoprotein cholesterol and ST-segment elevations on admission were each associated with a substantially higher likelihood of intensification and maximization. This likely reflects a belief that these patients are most likely to benefit from more intense statin therapy. However, there is no compelling evidence that there is a differential effect of statin therapy according to either the type of acute myocardial infarction or baseline levels of low-density lipoprotein, which suggests that educating clinicians about the benefits of intensive statin therapy may improve patient care and outcomes. In addition, the creation of system-level interventions, such as modification of existing performance measures, could be used to support more consistent evidence-based practice strategies across hospitals to improve care. See p 1303.
Predictors of Long-Term Outcomes in Patients With Significant Myxomatous Mitral Regurgitation Undergoing Exercise Echocardiography
In 884 consecutive patients (age, 58±14 years; 67% men) with grade III+ or greater myxomatous mitral regurgitation who underwent exercise echocardiography, there were 87 events over 6.4±4 years of follow-up. On survival analysis, percent of age/sex-predicted metabolic equivalents (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P=0.005), heart rate recovery at 1 minute after stress (hazard ratio, 0.29; 95% confidence interval, 0.17–0.50; P<0.001), resting right ventricular systolic pressure (hazard ratio, 1.03; 95% confidence interval, 1.004–1.05; P=0.02), atrial fibrillation (hazard ratio, 1.91; 95% confidence interval, 1.07–3.41; P=0.03), and left ventricular ejection fraction (hazard ratio, 0.96; 95% confidence interval, 0.92–0.99; P=0.04) predicted outcomes. See p 1310.
Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy
Patients with thrombotic thrombocytopenic purpura (TTP) experience life-threatening episodes of microangiopathy that damage kidneys, heart, and brain. Although triggers for these attacks remain elusive, deficiency in ADAMTS13 is an important risk factor. This metalloprotease cleaves von Willebrand factor (VWF) multimers to prevent formation of obstructive platelet–VWF complexes. However, complete ADAMTS13 deficiency does not cause continuous disease, which suggests that additional pathophysiological processes modulate the clinical phenotype of TTP attacks. Plasmin, the key enzyme of the fibrinolytic system, can be activated on vascular endothelium during cellular stress. We set out to investigate whether plasmin can serve as a backup enzyme for ADAMTS13 in the degradation of obstructive pathological platelet–VWF complexes. We identified that plasmin efficiently degrades platelet–VWF complexes. This can take place on the endothelium and may occur at sites of vascular obstructions to mediate clearance. We found confirmatory evidence for such a mechanism in TTP patients, in whom plasmin formation occurs during attacks in a manner that correlates with the extent of microangiopathy. Therapeutic stimulation of plasminogen activation with the thrombolytic agent streptokinase has therapeutic value in a mouse model of TTP by degrading circulating platelet–VWF complexes while restoring primary hemostasis through attenuation of thrombocytopenia. Our findings indicate that plasminogen activation during TTP is a previously unidentified modulator in the clinical presentation of microangiopathy. These findings may aid in our understanding of physiological plasminogen activation and the effectiveness of thrombolytic therapy. Furthermore, our in vivo studies offer primary evidence for the clinical efficacy of thrombolytic agents in the management of TTP. See p 1320.
- © 2014 American Heart Association, Inc.
- Trends in Cause of Death After Percutaneous Coronary Intervention
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