Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
- Growth Properties of Cardiac Stem Cells Are a Novel Biomarker of Patients’ Outcome After Coronary Bypass Surgery
- Outcome Impact of Coronary Revascularization Strategy Reclassification With Fractional Flow Reserve at Time of Diagnostic Angiography: Insights From a Large French Multicenter Fractional Flow Reserve Registry
- Mental Disorders Across the Adult Life Course and Future Coronary Heart Disease: Evidence for General Susceptibility
- Reporting Trends and Outcomes in ST-Segment–Elevation Myocardial Infarction National Hospital Quality Assessment Programs
- Inaccuracy of Estimated Resting Oxygen Uptake in the Clinical Setting
- Pathology of Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus- and Paclitaxel-Eluting Stents in Humans
- Neurological Injury After Neonatal Cardiac Surgery: A Randomized, Controlled Trial of 2 Perfusion Techniques
- Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial
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Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. There is substantial information available about cellular electrophysiological abnormalities in patients with long-standing persistent AF, but the atrial-cellular pathophysiology in patients with paroxysmal AF (pAF) is largely unknown. Here, we used simultaneous measurements of intracellular [Ca2+] and membrane current/potential in atrial cardiomyocytes from sinus rhythm and pAF patients (last AF episode a median of 10–20 days preoperatively), together with biochemistry and computational modeling, to define the cellular and molecular mechanisms promoting atrial arrhythmogenesis in pAF. L-type Ca2+ currents and action potential durations were unaltered in pAF patients, indicating the absence of typical AF-associated remodeling. However, cardiomyocytes from pAF patients had enhanced diastolic sarcoplasmic reticulum (SR) Ca2+ leak and increased susceptibility to spontaneous diastolic SR Ca2+-release events, causing delayed after-depolarizations/triggered activities that promote atrial ectopic (focal) activity. Pharmacological and biochemical studies indicated that the susceptibility to spontaneous cellular activity in pAF was attributable to enhanced SR Ca2+ uptake, resulting from phospholamban hyperphosphorylation (removing phospholamban-induced inhibition of SR uptake), and ryanodine receptor (SR Ca2+ release) channel dysregulation, including enhanced ryanodine receptor expression and increased single-channel open probability. Simulation studies indicated that both increased SR Ca2+ leak and enhanced SR Ca2+ uptake likely contribute to aberrant diastolic SR Ca2+–release events. Our findings constitute the first direct evidence for an important role of Ca2+-dependent ectopic activity in atrial arrhythmogenesis of pAF patients and provide insights into underlying mechanisms. The cellular and molecular mechanisms underlying abnormal Ca2+ handling in pAF are distinct from those of long-standing persistent AF patients, suggesting possible opportunities to develop tailored therapeutic approaches for pAF. See p 145.
Growth Properties of Cardiac Stem Cells Are a Novel Biomarker of Patients’ Outcome After Coronary Bypass Surgery
The efficacy of bypass surgery in improving ventricular function in patients with severe coronary atherosclerosis and ischemic cardiomyopathy cannot be easily predicted. The preoperative conditions may be similar, but the mid- and long-term evolution of cardiac pathology may differ significantly, emphasizing the need to identify determinants that may help anticipating clinical outcome. Successful revascularization and positive left ventricular remodeling may depend on factors intrinsic to the heart or extrinsic to the myocardium. Our findings suggest that variables intrinsic to the myocardium, ie, cardiac stem cell growth reserve, and extrinsic to the heart, ie, the systemic level of insulin-like growth factor-1, positively correlate with increases in ejection fraction, wall thickness in systole and diastole, and decreases in systolic and diastolic diameters and chamber volume following revascularization. Importantly, the growth kinetics of cardiac stem cells included shorter population-doubling time, longer telomeres, higher telomerase activity, and enhanced insulin-like growth factor-1 receptor expression. Conversely, attenuated cardiac stem cell growth and a decline in insulin-like growth factor-1 level in the circulation were characterized by an opposite response with a decrease in ejection fraction and an expansion in chamber volume, both accurate predictors of increased mortality in this patient population. Three criteria define a biomarker: its accuracy, its ability to give information that cannot be obtained from clinical assessment, and its relevance on medical decision. The cardiac stem cell phenotypes defined in the current report fulfill these 3 criteria; they are highly reproducible, provide an understanding at the fundamental cellular level of the pathological heart, and suggest new therapeutic strategies. See p 157.
Outcome Impact of Coronary Revascularization Strategy Reclassification With Fractional Flow Reserve at Time of Diagnostic Angiography: Insights From a Large French Multicenter Fractional Flow Reserve Registry
Although recent data suggest that fractional flow reserve (FFR) can be useful in guiding coronary revascularization in patients referred for a percutaneous coronary intervention procedure (DEFER, Fractional Flow Reserve versus Angiography for Multivessel Evaluation [FAME], Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 [FAME2]), its benefit in patients referred for diagnostic angiography remains unclear. The present report investigated the role of FFR in the choice of treatment modalities in 1075 patients referred for diagnostic angiography in 20 French centers. It first demonstrates that the use of FFR marginally changes the proportion of patients referred to each treatment modality. The strategy a priori based on angiography was medical therapy in 55% and revascularization in 45% (percutaneous coronary intervention, 38%; coronary artery bypass surgery, 7%). The applied strategy after FFR was medical therapy in 58% and revascularization in 42% (percutaneous coronary intervention, 32%; coronary artery bypass surgery, 10%). It further demonstrates that the use of FFR is associated with reclassification of the initial treatment modality in 43% of cases: in 33% of a priori medical patients, in 56% of patients undergoing a priori percutaneous coronary intervention, and in 62% of patients undergoing a priori coronary artery bypass surgery. Finally it shows that reclassification by FFR (n=464) is associated with a major cardiac event rate (11.2%) and a proportion of patients free of angina (94%) at 1-year similar to patients in whom FFR results concurred with the angiography-based decision. To conclude, this study shows that performing FFR during diagnostic angiography is associated with reclassification of the treatment modality in about half of the patients. It demonstrates that it is safe to pursue a revascularization strategy divergent from that suggested by angiography alone when guided by FFR. It further supports the concept of physiology-guided coronary revascularization and provides an important basis for future studies. See p 173.
Mental Disorders Across the Adult Life Course and Future Coronary Heart Disease: Evidence for General Susceptibility
There is evidence from longitudinal studies that people with schizophrenia and other psychotic disorders have an increased risk of developing coronary heart disease (CHD). Depression and anxiety have also been linked with an increased risk of CHD. Whether mental disorder in general—even in milder forms—makes people more susceptible to CHD and what factors explain this increased risk has been unclear. In this longitudinal study of >1 million men, we found that a wide range of mental disorders—schizophrenia, other nonaffective psychotic disorders, bipolar disorders, depressive disorders, personality disorders, alcohol-related and other substance use disorders, and the most common forms of mental illness, neurotic and adjustment disorders—were associated with an increased risk of CHD. This increased risk was evident both in young men diagnosed with mental disorders at ≈18 years of age during a psychiatric examination on conscription and in older men diagnosed on later psychiatric hospital admission. Smoking and risky alcohol intake at 18 years of age explained to a large degree the link between mental disorder at that time and subsequent CHD, but virtually all associations persisted after the adjustment for early-life socioeconomic status, body mass index, diabetes mellitus, blood pressure and intelligence measured at conscription, and education and later-life socioeconomic position. Our findings suggest that mental disorders pose a huge public health burden in terms of premature illness and death attributable to CHD. The physical health care of people with mental disorders needs to be a priority for clinicians if this burden is to be reduced. See p 186.
Reporting Trends and Outcomes in ST-Segment–Elevation Myocardial Infarction National Hospital Quality Assessment Programs
This analysis by McCabe et al investigates the frequency with which patients who undergo primary PCI for an ST-segment elevation myocardial infarction are not reported to the Centers for Medicaid and Medicare Services (CMS) for the purposes of tracking door-to-balloon time performance and whether those patients that are reported are an adequate representation of the total population. They found that over a quarter of all STEMI patients at 3 Massachusetts institutions were not reported to CMS and that frequency increased considerably between 2005 and 2011, consistent with the expansion of CMS-reporting exclusion criteria. Patients not reported to CMS were generally more ill at presentation and had markedly worse outcomes at 1 year. Performance on door-to-balloon time metrics demonstrated significant improvement throughout the study period but gains were more modest when patients excluded from CMS reporting were also considered. These findings may help add context to quality and performance data in primary percutaneous coronary intervention, particularly in light of recently enacted Value-Based Purchasing schemes, which rely on such data to calculate hospital reimbursement rates from CMS. See p 194.
Inaccuracy of Estimated Resting Oxygen Uptake in the Clinical Setting
The Fick method is the gold-standard for determining cardiac output in numerous clinical scenarios. A primary determinant of Fick-derived cardiac output is resting oxygen uptake (O2), which if inaccurately estimated will proportionally manifest as commensurate error in estimation of cardiac output, a hemodynamic parameter directly influencing critical clinical decision-making. Our study demonstrates the inaccuracies of estimating O2 with commonly used formulae compared with its direct measurement. It is important to consider these limitations when calculating cardiac output based on estimated O2, especially in obese and severely obese individuals as commonly encountered in contemporary practice. When accurate hemodynamic assessment is important for clinical decision-making, O2 should be directly measured. See p 203.
Pathology of Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus- and Paclitaxel-Eluting Stents in Humans
Clinical trials have demonstrated that the second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent and is noninferior or superior to the sirolimus-eluting stent in terms of safety and efficacy. However, histological vascular responses to the CoCr-EES versus the sirolimus-eluting stent and paclitaxel-eluting stent have not been reported in humans. The present autopsy study demonstrated for the first time that CoCr-EES exhibit significantly greater strut coverage with less inflammation (with no case of hypersensitivity) and fibrin deposition and a decrease in late stent thrombosis compared with first-generation drug-eluting stents in humans. In addition, greater strut coverage in CoCr-EES versus sirolimus-eluting stents and paclitaxel-eluting stents was observed consistently irrespective of lesion characteristics and indications for stenting. These findings support greater clinical safety of CoCr-EES versus first-generation drug-eluting stents, even for “off-label” indications. On the other hand, the present study also revealed that CoCr-EES showed progressive neointimal growth up to 3 years, which was similar to first-generation drug-eluting stents. Moreover, the prevalence of neoatherosclerosis and fracture-related adverse events (restenosis or thrombosis) in CoCr-EES was comparable to that in sirolimus-eluting and paclitaxel-eluting stents. It is believed that neoatherosclerosis develops and progresses over time, and, similarly, the frequency of stent fracture increases with advancing duration of implantation because of continuous stress on the stents and metal fatigue. The present pathological findings indicate that careful long-term follow-up is still required even after CoCr-EES placement. See p 211.
Neurological Injury After Neonatal Cardiac Surgery: A Randomized, Controlled Trial of 2 Perfusion Techniques
As yet, it is unknown whether deep hypothermic circulatory arrest or antegrade cerebral perfusion (ACP) is the preferred perfusion technique during aortic arch reconstructions in neonates. We assessed this in a randomized, controlled trial and performed magnetic resonance imaging of the brain before and shortly after surgery in 37 neonates. We found evidence of cerebral injury in 19 of 37 neonates (51%) before surgery. After surgery, new injury was seen in 27 of 36 neonates (75%), with no difference between deep hypothermic circulatory arrest and ACP (14/18 [78%] versus 13/18 [72%]; P=0.66). Most injury both before and after surgery was white matter injury, but specifically after ACP we observed infarctions in the thalamic and basal ganglia regions in 6 of 18 neonates (33%). We hypothesize that this is attributable to the advancement of microparticles or air emboli during selective perfusion of the right brachiocephalic artery, as is performed during ACP. Furthermore, the high incidence of postoperative white matter injury (seen in 22/36 [61%] of the cohort) was further investigated, and lower Pco2 was identified as a risk factor for white matter injury. In conclusion, in this study, we were unable to demonstrate a difference in incidence of perioperative cerebral injury after ACP compared with deep hypothermic circulatory arrest. Furthermore, because more focal infarctions were noted in the infants with ACP, this technique may be more harmful. See p 224.
Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease, impairs low-density lipoprotein cholesterol (LDL-C) clearance from plasma through its pivotal role of signaling the degradation of LDL-C receptors. Evolocumab is a fully human monoclonal antibody targeted against PCSK9. In 4 separate phase 2 dose ranging studies of 12 weeks’ duration in patients on statins, with familial hypercholesterolemia, with low risk hypercholesterolemia not on statins, and with statin intolerance, evolocumab reduced LDL-C by up to 65%. The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER), a global clinical trial, included 1104 patients who completed the 4 phase 2 studies and were randomized 2:1, regardless of their phase 2 study assignment, to either open-label subcutaneous evolocumab 420 mg every 4 weeks plus standard of care or standard of care alone. Patients who first received evolocumab in OSLER experienced a 52.3% LDL-C reduction after week 52 (P<0.0001) compared with the phase 2 parent study pretreatment baseline. Patients randomized to continue evolocumab after completing phase 2 studies experienced persistent stable reductions in LDL-C. Patients who discontinued evolocumab on entry into OSLER had their LDL-C levels return to near baseline without a rebound effect. Adverse events were largely balanced between groups except for minor injection-site reactions. No neutralizing antidrug antibodies were detected during 52 weeks of follow-up. OSLER, the first large, longer-term evaluation of anti-PCSK9 therapy, shows that evolocumab is well tolerated and demonstrates continued efficacy over 1 year of treatment in a diverse group of patients with hypercholesterolemia. See p 234.
- © 2013 American Heart Association, Inc.
- Inaccuracy of Estimated Resting Oxygen Uptake in the Clinical Setting
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