Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Implantable Cardioverter-Defibrillator Therapy Before Death: High Risk for Painful Shocks at End of Life
- Role of Small-Conductance Calcium-Activated Potassium Channels in Atrial Electrophysiology and Fibrillation in the Dog
- Electromagnetic Interference With Implantable Cardioverter-Defibrillators at Power Frequency: An In Vivo Study
- Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase
- Relationship Between Intravascular Ultrasound Guidance and Clinical Outcomes After Drug-Eluting Stents: The Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) Study
- Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance
- Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism
- Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling
- Mild Antithrombin Deficiency and Risk of Recurrent Venous Thromboembolism: A Prospective Cohort Study
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Implantable Cardioverter-Defibrillator Therapy Before Death: High Risk for Painful Shocks at End of Life
The cause and nature of death in the growing population treated with implantable defibrillators have been insufficiently investigated. An increased knowledge of the incidence of ventricular arrhythmia and shock treatment at the end of life for patients with an implantable defibrillator may lead to improved care and a lower incidence of unnecessary and painful shocks for patients close to death. This study shows that such patients often die in the hospital of late-stage heart failure. More than one third of patients have ventricular arrhythmia 1 hour before death, and almost one fourth experience shock treatment during the last 24 hours. The majority of all patients in the present study had a do-not-resuscitate order but still had shock therapy programmed “on,” which exposed these patients to the risk of painful shocks. It is important for healthcare providers to take action in deciding to deactivate the implantable defibrillator in terminally ill patients. See p 422.
Role of Small-Conductance Calcium-Activated Potassium Channels in Atrial Electrophysiology and Fibrillation in the Dog
There is increasing evidence for a role of calcium-dependent potassium (SK) channels in cardiac electrophysiology, including gene-wide association studies showing that variants of a calcium-dependent potassium-channel gene (KCNN3) are an important risk factor for atrial fibrillation (AF) in man. In this study, we examined the role of SK channels in the electrophysiological properties of canine atrial tissue. We used patch-clamp methods to record whole-cell and single-channel SK currents from dog left atrial (LA) and pulmonary vein (PV) cells, in both normal dogs and dogs subjected to 1 week of rapid atrial pacing to mimic AF. In addition, we exploited a selective SK channel channel blocker (NS8593) to study the functional role of the channel. Measurable whole-cell SK current was detected in dog atrial cells, larger in PV than LA. In addition, atrial tachypacing enhanced SK-current amplitude. Consistent with the ion-current data, blocking SK channels prolonged atrial repolarization, with larger changes in PV than LA and larger increases in cells from tachypaced dogs than normal dogs. Single-channel open probability was enhanced by atrial tachypacing but was not significantly different in PV versus LA. Measurements of SK-channel subunit protein expression showed differences consistent with the relative ion-current differences between PV and LA and between tachypacing and control. In vivo SK-channel block with NS8593 prolonged refractoriness and suppressed AF, implying that SK channels are involved in atrial repolarization and contribute to the control of AF sustainability. These findings suggest that SK-channel gene variants may modulate the risk of AF by altering atrial repolarization and that SK-channel blockers might be an interesting target for AF-suppressing therapy. See p 430.
Electromagnetic Interference With Implantable Cardioverter-Defibrillators at Power Frequency: An In Vivo Study
To date, reliable systematic data on electromagnetic interferences on implantable cardioverter-defibrillators are scarce despite a high potential clinical relevance. Current recommendations by the manufacturers are very conservative with respect to exposure of implantable cardioverter-defibrillator patients to electric and magnetic fields (EMFs). This is based on the assumption that EMFs may lead to harmful interferences with the device. Recommendations on the code of behavior on how to handle electric and magnetic field sources in everyday life are inconsistent and are not based on in vivo studies. Decision making for implantable cardioverter-defibrillator implantation for the primary prevention in job-related EMF-exposed patients and subsequent recommendation of early retirement is often complex. National and international guidelines for the protection of humans exposed to EMF exclude patients wearing electric cardiac implants. The present study shows that electromagnetic interferences occur predominantly in relatively strong EMFs, which are normally present only in occupational environments. Moreover, we demonstrate a strong dependency on the programmed sensitivity of the device. Additionally, our data suggest that individual thresholds of electromagnetic interferences can be obtained and compared with the individual exposure of the patient. These results are important for clinicians to optimize the implantation procedure to achieve maximum obtainable intracardiac electrogram potentials, to choose appropriate device programming, and to provide advice for the management of patients with foreseeable high EMF exposure. Nonetheless, further investigations are needed to investigate patient- and device-related predictors of electromagnetic interferences. This may help to develop better sensing algorithms and to design new implantable cardioverter-defibrillator leads for the prevention of harmful electromagnetic interferences of implantable cardioverter-defibrillators. See p 441.
Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase
The work identifies a new signaling pathway for the modulation of cardiac hypertrophic remodeling and opens possibilities for translational applications to the treatment of human cardiac diseases beyond current pharmacological agents. β3 adrenoceptors (AR) are classically known as metabolic receptors, but in the heart they oppose the classic effects of β1-2 AR activation. Because β3-ARs are upregulated in diseased hearts, this study uses mouse genetic models and overexpression in cardiac myocytes to test whether this upregulation is adaptive or deleterious in the setting of neurohormonal stress. The results point to β3-AR–mediated protection from hypertrophic and fibrotic remodeling that involves the recruitment of both neuronal and endothelial nitric oxide synthases, 2 constitutive nitric oxide synthases in cardiac myocytes that cooperatively preserve NO/cyclic GMP signaling in the face of cardiac stress. This offers the possibility to combine new agonists at β3-AR with specific phosphodiesterase inhibitors that potentiate cyclic GMP to oppose maladaptive cardiac remodeling. See p 451.
Relationship Between Intravascular Ultrasound Guidance and Clinical Outcomes After Drug-Eluting Stents: The Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) Study
Prior small to modest-sized studies suggest a benefit of intravascular ultrasound (IVUS) guidance in noncomplex lesions. Whether IVUS guidance is associated with improved clinical outcomes after drug-eluting stent (DES) implantation in an unrestricted patient population is unknown. Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) was a prospective, multicenter, nonrandomized “all-comers” study of 8583 consecutive patients at 11 international centers designed to determine the frequency, timing, and correlates of stent thrombosis and adverse clinical events after DES. Propensity-adjusted multivariable analysis was performed to examine the relationship between IVUS guidance and 1-year outcomes. IVUS was utilized in 3349 patients (39%), and larger-diameter devices, longer stents, and/or higher inflation pressures were used in 74% of IVUS-guided cases. IVUS guidance compared with angiography guidance was associated with reduced 1-year rates of definite/probable stent thrombosis (0.6% versus 1.0%; adjusted hazard ratio, 0.40; 95% confidence interval, 0.21–0.73; P=0.003), myocardial infarction (2.5% versus 3.7%; adjusted hazard ratio, 0.66; 95% confidence interval, 0.49–0.88; P=0.004), and composite adjudicated major adverse cardiac events (cardiac death, myocardial infarction, or stent thrombosis) (3.1% versus 4.7%; adjusted hazard ratio, 0.70; 95% confidence interval, 0.55–0.88; P=0.002). The benefits of IVUS were especially evident in patients with acute coronary syndromes and complex lesions, although significant reductions in major adverse cardiac events were present in all patient subgroups including stable angina and single-vessel disease. In ADAPT-DES, the largest study of IVUS use to date, IVUS guidance was associated with a reduction in stent thrombosis, myocardial infarction, and major adverse cardiac events within 1 year after DES implantation. See p 463.
Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance
Because inflammation and diabetes mellitus are interwoven processes that potentiate each other, there is interest in temporally characterizing insulin resistance and the endothelial inflammatory processes that lead to accelerated atherosclerosis. To closely mimic the human condition, we studied adult nonhuman primates (rhesus macaques) at baseline and at regular intervals for 2 years after they were started on a high-fat diet. There was rapid onset of diet-induced obesity and insulin resistance on intravenous glucose tolerance testing in the first 4 months, which then progressed very gradually over the rest of the study period. Carotid artery endothelial activation assessed by contrast ultrasound molecular imaging of P-selectin and vascular cell adhesion molecule-1 was increased over baseline by 4 to 8 months and, in contrast to insulin resistance, progressively increased over the 2-year period (5- to 7-fold greater than control at 2 years). Endothelial expression of adhesion molecules occurred before any detectable changes in carotid intima-medial thickness and did not directly correlate with systemic markers of inflammation such as C-reactive protein. These data indicate that endothelial expression of adhesion molecules involved in atherogenesis coincides with the development of obesity and insulin resistance and progressively increases according to the time, but not necessarily the severity, of insulin resistance. From a clinical perspective, the progressive nature of the vascular inflammatory response may explain in part the increased risk for atherosclerotic disease in obese patients and patients with insulin resistance who do not necessarily progress to overt diabetes mellitus. See p 471.
Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism
Acute pulmonary embolism remains a potentially life-threatening disease. The most important predictors of early death are systemic arterial hypotension and imaging or biomarker evidence of right ventricular dysfunction at the time of diagnosis. For patients at increased risk of death, prompt revascularization by systemic fibrinolysis improves right ventricular dysfunction and may improve survival and recurrent embolism; however, it is associated with a high rate of major bleeding complications. In routine clinical practice, many patients at increased risk are managed with anticoagulation therapy alone without attempting revascularization. The Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) trial investigated whether a fixed-dose, catheter-directed, ultrasound-assisted thrombolysis regimen (10 mg recombinant tissue plasminogen activator per treated lung over 15 hours; n=30) is superior to management with anticoagulation alone (n=29) in the reversal of right ventricular dilatation in intermediate-risk patients. Patients were eligible if they had embolism of at least 1 main or lower lobe pulmonary artery and echocardiographic right ventricular to left ventricular ratio ≥1.0. There was significant reversal of right ventricular dilatation at 24 hours in the catheter group, whereas no improvement in right ventricular enlargement was found in the heparin alone group. There were no major bleeding complications in either study group. Future studies will determine the clinical efficacy and safety of ultrasound-assisted thrombolysis for treating patients at increased risk of death. See p 479.
Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling
The ductus arteriosus (DA) is a fetal bypass artery between the aorta and the pulmonary artery. Although the DA closes immediately after birth, it remains open in some infants, a condition known as patent DA. Patent DA remains a frequent problem among premature infants with significant morbidity and mortality. Both vascular contraction and remodeling (ie, intimal thickening) are required for complete anatomical closure of the DA. Decreased elastogengesis is known as a hallmark of DA remodeling and is thought to contribute to intimal thickening of the DA. However, the molecular mechanisms of decreased elastogenesis are not fully understood. Herein, we show that prostaglandin E2 (PGE2) receptor EP4 signaling promotes degradation of the mature lysyl oxidase protein, a cross-linking enzyme for elastic fibers, only in the DA, leading to decreased elastogenesis. The newly recognized PGE-EP4-c-Src-PLCγ-signaling pathway most likely contributes to the lysosomal degradation of lysyl oxidase. Based on these data, it appears that PGE-EP4 signaling is required for DA remodeling and that inhibition of this signaling by cyclooxygenase inhibitors may attenuate DA remodeling after birth, especially in premature infants in which the DA is not fully remodeled. Activation of the c-Src-PLCγ signaling pathway may be an additional strategy to promote anatomical closure of the immature DA. See p 487.
Mild Antithrombin Deficiency and Risk of Recurrent Venous Thromboembolism: A Prospective Cohort Study
Antithrombin deficiency is a recognized major thrombophilic condition. Because most available studies reported data on patients with overt antithrombin deficiency (levels 40–70%), in this prospective study we sought to evaluate the risk of symptomatic venous thromboembolism (VTE) recurrence in a population of patients with “mild” antithrombin deficiency (levels 70–80%) compared with patients with normal antithrombin levels (ie, >80%) and those with overt antithrombin deficiency. We found that patients with mild antithrombin deficiency have a risk of recurrent VTE that is significantly higher than patients with normal antithrombin levels (>80%) and similar to that observed in patients with overt antithrombin deficiency. In our study, patients with unprovoked VTE treated for a definite time with oral anticoagulants (ie, 3–12 months) had annual recurrence rates >5% in the presence of both overt and mild antithrombin deficiency and <5% with normal antithrombin levels, with these differences being statistically significant. This finding suggests that in patients screened for thrombophilia after a first VTE event, even a mild decrease in antithrombin levels should be taken into account in the individual assessment of treatment duration. These findings have some important clinical implications for decisions about the optimal duration of secondary prevention of VTE, and, because this association is particularly relevant in patients with unprovoked VTE, mild antithrombin deficiency may be considered an additional variable to determine the optimal individual duration of secondary prevention with anticoagulant drugs. See p 497.
- © 2013 American Heart Association, Inc.
- Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling
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