Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Safety and Efficacy of a Totally Subcutaneous Implantable-Cardioverter Defibrillator
- Intervention for Recoarctation in the Single Ventricle Reconstruction Trial: Incidence, Risk, and Outcomes
- AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy: An Analysis From the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 Trial
- Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Kinase A Differentially Regulate Sarcoplasmic Reticulum Ca2+ Leak in Human Cardiac Pathology
- Endothelial-Like Progenitor Cells Engineered to Produce Prostacyclin Rescue Monocrotaline-Induced Pulmonary Arterial Hypertension and Provide Right Ventricle Benefits
- Waveform Analysis–Guided Treatment Versus a Standard Shock-First Protocol for the Treatment of Out-of-Hospital Cardiac Arrest Presenting in Ventricular Fibrillation: Results of an International Randomized, Controlled Trial
- Stratified Meta-Analysis of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Hospitalized Patients
- Info & Metrics
Safety and Efficacy of a Totally Subcutaneous Implantable-Cardioverter Defibrillator
The implantable cardioverter-defibrillator decreases mortality in selected populations at increased risk of sudden cardiac death. This benefit is mitigated in part by both short- and long-term complications of the defibrillator implant or system, most commonly associated with transvenous leads. In an effort to minimize lead complications, a totally subcutaneous implantable cardioverter-defibrillator system was developed to avoid the need for transvenous lead placement. The present study is the first large prospective trial of this system, and it was designed to evaluate the effectiveness and safety of the subcutaneous implantable cardioverter-defibrillator. The primary effectiveness and safety end points were met, demonstrating a very high termination rate of induced ventricular tachyarrhythmias and an acceptably low complication rate. Moreover, the defibrillation efficacy is stable over time for both spontaneous and induced arrhythmias. The device effectively withholds shocks for most supraventricular arrhythmias, particularly if the conditional zone is activated for discrimination. To achieve reliable defibrillation and arrhythmia discrimination, the device delivers only high-energy shocks (80 J), and the time to therapy is typically ≈20 seconds. This is consistent with the longer time to therapy now recommended to improve patient outcomes on the basis of the Multicenter Automatic Defibrillator Implantation Trial—Reduce Inappropriate Therapy study. The results of the present study indicate that the subcutaneous implantable cardioverter-defibrillator is a viable alternative to transvenous systems among patients who do not require pacing therapy for heart failure, bradycardia, or ventricular tachycardia. See p 944.
Intervention for Recoarctation in the Single Ventricle Reconstruction Trial: Incidence, Risk, and Outcomes
Children born with the hypoplastic left heart syndrome and related single right ventricle anomalies suffer from significant morbidities and high mortality rates. Residual or recurrent recoarctation of the aorta is an important contributor to morbidity and may increase mortality. We performed a retrospective cohort study using data collected from the Single Ventricle Reconstruction trial to describe the incidence and timing of intervention for recoarctation, factors that predict intervention, and the impact of recoarctation with intervention on morbidity and mortality. We found that recoarctation intervention is common, with an incidence at 1, 3, 6, and 12 months of 0%, 3%, 16%, and 23%, respectively. This varies widely by center (from 0–50 interventions per 100 patient-years) and often occurs relatively late in the interstage course. By multivariable analysis, factors associated with recoarctation intervention included the peak echocardiographic arch gradient at Norwood discharge and receipt of a right ventricle–to–pulmonary artery shunt. However, when modeling was repeated using the assigned shunt type (intention to treat), there was no longer a significant association, perhaps implicating factors associated with shunt crossover or a potential survivor bias. Recoarctation with intervention was associated with comorbidities assessed before stage II surgery, including higher pulmonary vascular resistance and increased echocardiographic right ventricular chamber dimensions. Recoarctation with intervention was not associated with decreased 12-month transplantation-free survival. Thus, intervention for recoarctation is relatively common but may be difficult to predict early in the clinical course. Although recoarctation contributes to morbidities, with intervention, 12-month outcomes were not affected. See p 954.
AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy: An Analysis From the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 Trial
Lipoprotein(a) [Lp(a)] is a circulating lipoprotein composed of an apolipoprotein B100 molecule covalently bound to a liver-derived glycoprotein, apolipoprotein(a). In epidemiological and genetic analyses, Lp(a) has emerged as an important risk factor for the development of cardiovascular disease. The 2011 European Society of Cardiology/European Atheroscloerosis Society guidelines recommend screening for elevated Lp(a) in people at high risk for cardiovascular disease or with a strong family history of premature atherothrombotic disease. There are limited therapeutic options for lowering Lp(a) levels. We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a) levels in the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 trial, a randomized, phase 2 trial of AMG145 versus placebo. We found that compared with placebo, AMG145 significantly lowers Lp(a) in subjects with hypercholesterolemia receiving background therapy with statin with or without ezetimibe. Specifically, we observed dose-response relationships at both dosing frequencies, with progressively more robust reductions in Lp(a), up to 32%, from baseline to week 12. We found that the reduction in Lp(a) with AMG145 was consistent across several important subgroups including age, sex, race, history of diabetes mellitus, and background statin regimen. Although the clinical benefit of Lp(a) reduction remains undefined, these data lend further support to studying the impact of PCSK9 inhibition with AMG145 in a phase 3 clinical outcomes trial. See p 962.
Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Kinase A Differentially Regulate Sarcoplasmic Reticulum Ca2+ Leak in Human Cardiac Pathology
Contractile dysfunction and sudden cardiac death caused by arrhythmias are the clinically most important phenotypes in subjects with structural heart disease. A better insight into the underlying molecular mechanisms and signaling pathways may provide new toeholds for the development of future clinical therapies. Recent studies have identified the emergence of spontaneous diastolic sarcoplasmic (SR) Ca2+ release events from the SR ryanodine receptor (RyR2) as a crucial factor for cardiac contractile dysfunction and arrhythmogenic triggers. In the present study, we clarify that this deleterious SR Ca2+ leak increases from cardiac hypertrophy to heart failure in human myocardium. This is accompanied by profound disturbances of Ca2+ homeostasis. We provide the first evidence that protein kinase A, which is generally activated via the β-adrenergic pathway, functionally regulates RyR2 gating in human cardiac hypertrophy but appears to have lost the ability to modulate RyR2 gating in human heart failure. In contrast, we identified the Ca2+/calmodulin-dependent protein kinase II (CaMKII) as being primarily responsible for an elevated SR Ca2+ leak occurring in the human failing heart. Thus, the present findings identify CaMKII instead of protein kinase A as a potent inducer of the SR Ca2+ leak, which suggests that inhibition of CaMKII may be a promising treatment option for contractile dysfunction and arrhythmias. As inhibition or ablation of CaMKII has been shown to attenuate or prevent the development of heart failure in animal models via additional pathways, future drug or gene therapy approaches should address key clinical aspects of CaMKII inhibition in patients with heart failure or arrhythmias. See p 970.
Endothelial-Like Progenitor Cells Engineered to Produce Prostacyclin Rescue Monocrotaline-Induced Pulmonary Arterial Hypertension and Provide Right Ventricle Benefits
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally high blood pressure in the pulmonary arteries. The median survival of PAH patients is <3 years without treatment. Intravenous prostacyclin is the only therapy that has been shown to increase survival rate. However, intravenous prostacyclin has a short half-life and must be delivered systemically via an indwelling intravenous catheter. In the present study, we showed that endothelial-like progenitor cells (ELPCs) engineered to produce prostacyclin rescued monocrotaline-induced PAH in rats and offered right ventricle benefits. The 1-time delivery of 1.5×106 engineered ELPCs provided therapeutic benefits for at least 4 weeks and may offer a promising option for PAH patients. The combined therapy of engineered ELPCs plus treprostinil (a prostacyclin analog) showed increased efficacy over that of the engineered ELPCs or treprostinil alone in preventing right ventricular systolic pressure increase and right ventricular hypertrophy. Jugular vein delivery localized the transplanted cells primarily in the lungs, and hepatocellular and renal function were not affected after cell transplantation. Right ventricle genomic gene expression analysis revealed that the restoration of several monocrotaline -altered genes and neurotransmitter pathways may be the potential mechanism by which engineered ELPCs provide right ventricle benefits. These findings may provide novel therapeutic targets for early intervention in the treatment of a compromised right ventricle in PAH patients. Engineered ELPCs may be useful as a monotherapy to treat PAH or may be used in combination therapy to help reduce the dose of prostacyclin. See p 982.
Waveform Analysis–Guided Treatment Versus a Standard Shock-First Protocol for the Treatment of Out-of-Hospital Cardiac Arrest Presenting in Ventricular Fibrillation: Results of an International Randomized, Controlled Trial
In the 3 most recent iterations of resuscitation guidelines, recommendations for ventricular fibrillation (VF) have varied, including immediate shock, delayed defibrillation, and most recently the recognition of inconsistent evidence for the most appropriate initial resuscitation strategy for VF. In this study, we sought to implement an automatic external defibrillator–based VF waveform algorithm for the initial treatment of VF among out-of-hospital cardiac arrest patients compared with a standard shock-first protocol. Overall survival between the 2 study arms was equivalent; thus, this study does not provide definitive evidence to clarify the inconsistency concerning the initial treatment of VF. Among patients with low-quality VF who were given 2 minutes of cardiopulmonary resuscitation before initial defibrillation, despite published data suggesting that an improvement in VF score is to be expected, there was wide variation among those patients with regard to the resulting VF score, ranging from significant improvement to marked decline. Although these changes in VF score positively correlated to outcome, the study design did not allow the identification of causative factors or comparison with the shock-first arm. These results suggest a potential for the future use of such technologies to guide prognostic or treatment decisions, emphasize the need to address the quality of CPR during any resuscitation, and yield a number of additional questions for future research. See p 995.
Stratified Meta-Analysis of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Hospitalized Patients
The ideal thromboprophylaxis method in patients at risk of bleeding remains uncertain. Devices that apply intermittent pneumatic compression to the lower limbs can improve venous blood flow in the lower limbs and hence reduce the risk of deep vein thrombosis in patients who are immobile. In this stratified meta-analysis, we assessed the effects of intermittent pneumatic compression of lower limbs compared with no compression, thromboembolic deterrent stockings, or pharmacological thromboprophylaxis on risk of venous thromboembolism. We also assessed whether adding pharmacological thromboprophylaxis to pneumatic compression would improve its effectiveness. A total of 16 164 hospitalized patients from 70 trials met the inclusion criteria and were subjected to meta-analysis. Intermittent pneumatic compression was more effective than no compression in reducing deep vein thrombosis and pulmonary embolism. The number needed to treat to prevent 1 deep vein thrombosis and pulmonary embolism was 11 and 63, respectively. Intermittent pneumatic compression was also more effective than thromboembolic deterrent stockings in reducing deep vein thrombosis and appeared to be as effective as pharmacological thromboprophylaxis but with a reduced risk of bleeding. Adding pharmacological thromboprophylaxis to intermittent pneumatic compression further reduced the risk of deep vein thrombosis compared with using pneumatic compression alone. The current evidence suggests that intermittent pneumatic compression of the lower limbs is effective in reducing venous thromboembolism, and when combined with pharmacological thromboprophylaxis, its effectiveness in reducing venous thromboembolism can be further enhanced. Intermittent pneumatic compression of the lower limbs as part of a multimodality approach to prevent venous thromboembolism in hospitalized patients is strongly recommended. See p 1003.
- © 2013 American Heart Association, Inc.
- Safety and Efficacy of a Totally Subcutaneous Implantable-Cardioverter Defibrillator
- Info & Metrics