- Dynamic Mechanism for Initiation of Ventricular Fibrillation In Vivo
- Longitudinal Strain Delay Index by Speckle Tracking Imaging: A New Marker of Response to Cardiac Resynchronization Therapy
- Delayed Arterial Healing and Increased Late Stent Thrombosis at Culprit Sites After Drug-Eluting Stent Placement for Acute Myocardial Infarction Patients: An Autopsy Study
- Long-Term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Multivessel Coronary Artery Disease: A Meta-Analysis With 5-Year Patient-Level Data From the ARTS, ERACI-II, MASS-II, and SoS Trials
- Drug-Eluting Versus Bare Metal Stents in Patients With ST-Segment–Elevation Myocardial Infarction: Eight-Month Follow-Up in the Drug Elution and Distal Protection in Acute Myocardial Infarction (DEDICATION) Trial
- Impact of In-Hospital Revascularization on Survival in Patients With Non–ST-Elevation Acute Coronary Syndrome and Congestive Heart Failure
- Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque
- Fhl-1, a New Key Protein in Pulmonary Hypertension
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Dynamic Mechanism for Initiation of Ventricular Fibrillation In Vivo
Our study demonstrates a novel mechanism of induction of ventricular fibrillation in vivo in intact normal beagle dogs. This work may contribute to our understanding of the mechanisms leading to the development of ventricular fibrillation in the structurally normal heart. For example, in patients with idiopathic ventricular fibrillation, focal ectopic ventricular activity originating in the Purkinje network is thought to trigger the onset of ventricular fibrillation. Our work also may be clinically relevant to patients with channelopathies, ie, long-QT syndrome, in which typically a short-long-short sequence of premature stimuli induces ventricular tachycardia and fibrillation. We showed in our study that such specific patterns (called CLVF, cycle lengths inducing VF) can indeed lead to ventricular fibrillation by creating conduction block and wave break, depending on the restitution properties of the action potential duration and conduction velocity. In that regard, a potential therapeutic application of our work is to specifically target the restitution parameters with drugs so that CLVF would no longer lead to ventricular fibrillation. We showed that the calcium channel blocker verapamil exerts antifibrillatory effects by altering restitution parameters but not at clinically relevant dosages. However, we postulate that other drugs may prove to have antiarrhythmic effects by altering the restitution parameters of a patient and thus may prevent the induction of ventricular fibrillation rather than by suppressing the premature stimuli. See p 1123.
Longitudinal Strain Delay Index by Speckle Tracking Imaging: A New Marker of Response to Cardiac Resynchronization Therapy
Recent results from the PROSPECT and RETHINQ trials might suggest that a relatively limited and simple quantification of left ventricular dyssynchrony has suboptimal accuracy for the identification of responders to cardiac resynchronization therapy. In the present study, we introduce a new method, the strain delay index, to quantify response to cardiac resynchronization therapy. Rather than simply measuring left ventricular dyssynchrony, we propose to quantify the potential gain of contractility expected after the best possible cardiac resynchronization. The potential gain, in turn, should predict reverse remodeling after resynchronization therapy. The strain delay index combines the importance of left ventricular dyssynchrony and residual contractility and provides a better understanding of the physiological response to cardiac resynchronization therapy. This index should improve the ability to identify potential responders to cardiac resynchronization therapy in the future. The sophistication of the strain delay index relative to Doppler-derived parameters might be of particular importance in the narrow-QRS population, in whom the degree of dyssynchrony may be less and thus more challenging to quantify. Future efforts should focus on validation of the method in current clinical practice along with implementation of software modifications to facilitate ease of use. Additionally, because the strain delay index is computed from regional strain curves, its accuracy is dependent on the precision of the method used to quantify myocardial contractility. Importantly, therefore, the strain delay index can be computed from imaging modalities other than ultrasound (ie, cardiac magnetic resonance and CT) and should be tested in patients with poor acoustic windows. See p 1130.
Delayed Arterial Healing and Increased Late Stent Thrombosis at Culprit Sites After Drug-Eluting Stent Placement for Acute Myocardial Infarction Patients: An Autopsy Study
The approval of the current generation of polymeric Cypher and Taxus drug-eluting stents (DES) by the US Food and Drug Administration was based on randomized clinical trial data demonstrating impressive reductions in restenosis compared with bare metal stents in patients without evidence of acute myocardial infarction (AMI). The long-term clinical safety of DES implantation for AMI indication remains uncertain. Using autopsy data, we evaluated the pathological responses of the stented segment in patients treated with DES for AMI versus stable angina. Coronary plaque morphology in patients with AMI was significantly different from that in patients with stable angina and was characterized by greater necrotic core area, thinner overlying fibrous cap, and a greater number of struts penetrating the necrotic core. A significantly higher incidence of late stent thrombosis was observed in patients with AMI compared with those with stable angina. Culprit sites (ie, sites of plaque rupture) in patients with AMI were associated with a substantial delay in healing compared with culprit sites (fibroatheroma) in patients with stable angina and nonculprit sites within the same lesion. Furthermore, there was a significant negative correlation between fibrous cap thickness and the presence of uncovered struts (ie, the thinner the fibrous cap, the greater the presence of uncovered struts). Collectively, these results emphasize the importance of underlying plaque morphology in the healing response of coronary vessels after DES placement. Our findings suggest that an increased risk of late thrombotic complications might be expected in patients treated with DES for AMI. See p 1130.
Long-Term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Multivessel Coronary Artery Disease: A Meta-Analysis With 5-Year Patient-Level Data From the ARTS, ERACI-II, MASS-II, and SoS Trials
Randomized trials that studied clinical outcome after percutaneous coronary intervention (PCI) with bare metal stenting versus coronary artery bypass grafting (CABG) are underpowered to properly assess safety end points like death, stroke, and myocardial infarction. Pooling data from randomized controlled trials increases the statistical power and allows better assessment of the treatment effect in high-risk subgroups. The present pooled analysis of 3051 patients in 4 randomized trials evaluating the relative safety and efficacy of PCI with stenting and CABG for the treatment of multivessel coronary artery disease demonstrates that both treatment modalities provided similar long-term safety profiles. At 5 years, the cumulative incidence of death, myocardial infarction, and stroke was similar in patients randomized to PCI with stenting versus CABG (16.7% versus 16.9%, respectively; hazard ratio, 1.04; 95% confidence interval, 0.86 to 1.27; P=0.69). Repeat revascularization, however, occurred significantly more frequently after PCI than CABG (29.0% versus 7.9%, respectively; hazard ratio, 0.23; 95% confidence interval, 0.18 to 0.29; P<0.001). Several large-scale randomized trials like the Future Revascularization Evaluation in Patients With Diabetes: Optimal Management of Multivessel Disease, and Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery are currently comparing the safety and effectiveness of CABG and PCI with drug-eluting stents. Whether drug-eluting stents will tip the balance between safety and efficacy of PCI and CABG is to be examined. See p 1146.
Drug-Eluting Versus Bare Metal Stents in Patients With ST-Segment–Elevation Myocardial Infarction: Eight-Month Follow-Up in the Drug Elution and Distal Protection in Acute Myocardial Infarction (DEDICATION) Trial
Primary percutaneous coronary intervention is the treatment of choice in patients with ST-segment–elevation myocardial infarction and <12 hours duration of pain, but whereas implantation of drug-eluting stents is known to reduce the development of restenosis in most patients, treatment of ST-segment–elevation myocardial infarction is considered an off-label indication of their use. We randomized patients with ST-segment–elevation myocardial infarction to have a drug-eluting or a bare metal stent implanted in their target vessel in connection with primary percutaneous coronary intervention and evaluated their angiographic and clinical outcome. We observed a reduction in the need for repeat revascularization in the drug-eluting stent group, reflecting a significant reduction in neointimal hyperplasia as determined by angiography. We also observed a tendency to an increased rate of cardiac death in the drug-eluting stent group that was not explained by a higher rate of stent thrombosis, a finding that warrants continued clinical follow-up of the patients. See p 1155.
Impact of In-Hospital Revascularization on Survival in Patients With Non–ST-Elevation Acute Coronary Syndrome and Congestive Heart Failure
This study addresses the role of revascularization in patients with non–ST-elevation acute coronary syndrome who present with congestive heart failure. It is based on an analysis of 29 844 non–ST-elevation acute coronary syndrome patients enrolled in the multinational GRACE registry. Patients with congestive heart failure, who constitute a large subset (17%) of all patients, undergo in-hospital revascularization less frequently than those without heart failure (20% versus 35%, P<0.001). The baseline characteristics of patients with heart failure demonstrated higher risk than those of patients without. After adjustment for differences in baseline characteristics and propensity to undergo revascularization, and after revascularization was taken into account as a time-varying covariate, it appeared that revascularization did not affect in-hospital mortality rates but was associated with a survival benefit at 6-month follow-up. This benefit was consistent in all patient subgroups except women. These data from a large multinational registry reinforce the current guidelines’ recommendation that high-risk non–ST-elevation acute coronary syndrome patients should undergo early coronary angiography with a view to revascularization, and they are consistent with prior trials of revascularization in non–ST-elevation acute coronary syndrome or in patients with cardiogenic shock complicating myocardial infarction. Given that most deaths due to non–ST-elevation acute coronary syndrome occur in this subset, these observations indicate that broader use of revascularization in this group may save lives. Although the finding of a negative interaction between revascularization and female sex must be interpreted with caution in post hoc analyses of relatively small subsets, it emphasizes the need for further study regarding the role of revascularization in women with high-risk acute coronary syndrome. See p 1163.
Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque
Despite intensive management of conventional risk factors, coronary events continue to recur at an unacceptably high rate. Thus, novel therapeutic options for treating coronary heart disease are needed. Inhibition of the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2) with darapladib has emerged as a potential approach to addressing residual risk of cardiovascular events by directly targeting high-risk coronary atheroma. This multicenter study used intravascular ultrasound–derived techniques to characterize coronary atheroma in patients receiving a standard-of-care treatment. The results demonstrate that the necrotic core, a key determinant of plaque vulnerability, continued to increase among patients receiving placebo despite a high level of adherence to recommended therapies. This result is consistent with a proatherogenic role for Lp-PLA2 that is postulated to contribute to plaque vulnerability. In contrast, treatment with the direct Lp-PLA2 inhibitor darapladib added to standard of care prevented necrotic core expansion. Pharmacological intervention with darapladib exerted favorable effects on coronary atheroma consistent with plaque stabilization. These findings suggest that direct Lp-PLA2 inhibition may represent a novel therapeutic approach to reducing residual risk in patients with coronary heart disease. See p 1172.
Fhl-1, a New Key Protein in Pulmonary Hypertension
Pulmonary arterial hypertension is a life-threatening disease that is characterized by aberrant pulmonary vascular remodeling. Pathological alterations of the vasculature include dysregulated smooth muscle cell migration and proliferation in the pulmonary vessel media, which require alterations in cytoskeletal organization. To date, several factors involved in vascular remodeling remain to be identified and characterized. In the present study, a proteome screening approach was used to identify four-and-a-half LIM domain protein (Fhl-1) as a novel molecule involved in pulmonary arterial smooth muscle cell proliferation. This protein belongs to the family of LIM proteins that contain a cysteine-rich, double zinc finger motif that mediates protein-protein interactions of transcription factors, signaling, and cytoskeletal proteins. Proteins containing LIM domains mediate tissue differentiation, oncogenesis, and cytoskeletal organization. In hypoxia-induced pulmonary arterial hypertension, Fhl-1 expression was enhanced at both the onset of the disease and when disease was fully established. In pulmonary arteries from patients with idiopathic pulmonary arterial hypertension, strong upregulation of Fhl-1 was noted compared with healthy donor lungs. The cellular role of Fhl-1 was deciphered by identification of the cytoskeletal protein Talin1 as a novel binding partner of Fhl-1. Both molecules colocalized in pulmonary arterial smooth muscle cells in vitro and in vivo and triggered pulmonary arterial smooth muscle cell migration and proliferation, suggesting that increased levels of Fhl-1 alter cytoskeletal dynamics via interaction with Talin. Furthermore, these observations suggest Fhl-1 as a novel molecular target with therapeutic efficacy in patients with pulmonary arterial hypertension. See p 1183.
- Dynamic Mechanism for Initiation of Ventricular Fibrillation In Vivo
- Fhl-1, a New Key Protein in Pulmonary Hypertension
- Info & Metrics