Byron K. Lee

Asymptomatic cardiac disease following mediastinal irradiation

OBJECTIVES This study was designed to evaluate the potential benefit of screening previously irradiated patients with echocardiography. BACKGROUND Mediastinal irradiation is known to cause cardiac disease. However, the prevalence of asymptomatic cardiac disease and the potential for intervention before symptom development are unknown. METHODS We recruited 294 asymptomatic patients (mean age 42 +/- 9 years, 49% men, mean mantle irradiation dose 43 +/- 0.3 Gy) treated with at least 35 Gy to the mediastinum for Hodgkins disease. After providing written consent, each patient underwent electrocardiography and transthoracic echocardiography. Valvular disease was common and increased with time following irradiation. Patients who had received irradiation more than 20 years before evaluation had significantly more mild or greater aortic regurgitation (60% vs. 4%, p < 0.0001), moderate or greater tricuspid regurgitation (4% vs. 0%, p = 0.06), and aortic stenosis (16% vs. 0%, p = 0.0008) than those who had received irradiation within 10 years. The number needed to screen to detect one candidate for endocarditis prophylaxis was 13 (95% confidence interval [CI] 7 to 44) for patients treated within 10 years and 1.6 (95% CI 1.3 to 1.9) for those treated at least 20 years ago. Compared with the Framingham Heart Study population, mildly reduced left ventricular fractional shortening (<30%) was more common (36% vs. 3%), and age- and gender-adjusted left ventricular mass was lower (90 +/- 27 g/m vs. 117 g/m) in irradiated patients. CONCLUSIONS There is a high prevalence of asymptomatic heart disease in general, and aortic valvular disease in particular, following mediastinal irradiation. Screening echocardiography should be considered for patients with a history of mediastinal irradiation.

Structural imprints in vivo decode RNA regulatory mechanisms

Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2′-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA–protein interactions and N6-methyladenosine (m6A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.

Screening for Coronary Artery Disease After Mediastinal Irradiation for Hodgkin's Disease

PURPOSE Incidental cardiac irradiation during treatment of thoracic neoplasms has increased risks for subsequent acute myocardial infarction or sudden cardiac death. Identifying patients who have a high risk for a coronary event may decrease morbidity and mortality. The objective of this study was to evaluate whether stress imaging can identify severe, unsuspected coronary stenoses in patients who had prior mediastinal irradiation for Hodgkins disease. PATIENTS AND METHODS We enrolled 294 outpatients observed at a tertiary care cancer treatment center after mediastinal irradiation doses 35 Gy for Hodgkins disease who had no known ischemic cardiac disease. Patients underwent stress echocardiography and radionuclide perfusion imaging at one stress session. Coronary angiography was performed at the discretion of the physician. RESULTS Among the 294 participants, 63 (21.4%) had abnormal ventricular images at rest, suggesting prior myocardial injury. During stress testing, 42 patients (14%) developed perfusion defects (n = 26), impaired wall motion (n = 8), or both abnormalities (n = 8). Coronary angiography showed stenosis 50% in 22 patients (55%), less than 50% in nine patients (22.5%), and no stenosis in nine patients (22.5%). Screening led to bypass graft surgery in seven patients. Twenty-three patients developed coronary events during a median of 6.5 years of follow-up, with 10 acute myocardial infarctions (two fatal). CONCLUSION Stress-induced signs of ischemia and significant coronary artery disease are highly prevalent after mediastinal irradiation in young patients. Stress testing identifies asymptomatic individuals at high risk for acute myocardial infarction or sudden cardiac death.

Risk Stratification for Arrhythmic Sudden Cardiac Death Identifying the Roadblocks

Athough it is difficult to determine the precise number, the range for the number of sudden cardiac deaths (SCDs) per year in the United States alone has been reported from 184 000 to 462 000,1 with estimates that 50% to 70% are due to tachyarrhythmic mechanisms. Regardless of where within this range the true number lies, this represents a large epidemiological problem that warrants serious attention and attempts to identify solutions. There are many obstacles to achieving this laudable goal. First and foremost, although the vast majority of SCD victims have underlying structural heart disease (in particular, coronary artery disease), a significant percentage of SCD victims have previously unrecognized cardiac disease2; on autopsy, advanced coronary artery disease with or without evidence of unstable plaques and acute or healed myocardial infarctions (often clinically silent) are commonly detected.2,3 The American Heart Association estimates that 195 000 first silent myocardial infarctions occur per year.4 Strategies to reduce SCD among individuals without known cardiac disease must therefore focus on better screening and identification of risk factors for coronary disease, with either known risk factors or heretofore unknown or unidentified risk factors. In patients with known cardiac disease, there may be diverse pathogeneses for sudden death, including primary ventricular tachyarrhythmias and acute myocardial ischemia/infarction, among others. Although therapies exist for treatment of life-threatening ventricular tachyarrhythmias and prevention of myocardial infarction/coronary artery plaque rupture, significant challenges exist in identifying the individual patient within population subgroups who is at substantial personal risk of these events, and in whom the most intensive therapies could and should be applied. Although the incidence of out-of-hospital cardiac arrest due to ventricular tachycardia/fibrillation appears to be declining over time,4 this pathogenesis for SCD still occurs commonly. This article will therefore focus on the challenges and roadblocks …

Influence of Left Ventricular Lead Location on Outcomes in the COMPANION Study

Introduction: There are no randomized controlled trial data that evaluate mortality and hospitalization rates in cardiac resynchronization therapy (CRT) recipients based on left ventricular (LV) lead location. We analyzed the event‐driven outcomes of mortality and hospitalization as well as functional outcomes including Functional Class, Quality‐of‐Life, and 6‐minute walk distance in 1,520 patients enrolled in the COMPANION study of CRT versus optimal medical therapy.

RNA Duplex Map in Living Cells Reveals Higher-Order Transcriptome Structure

RNA has the intrinsic property to base pair, forming complex structures fundamental to its diverse functions. Here, we develop PARIS, a method based on reversible psoralen crosslinking for global mapping of RNA duplexes with near base-pair resolution in living cells. PARIS analysis in three human and mouse cell types reveals frequent long-range structures, higher-order architectures, and RNA-RNA interactions in trans across the transcriptome. PARIS determines base-pairing interactions on an individual-molecule level, revealing pervasive alternative conformations. We used PARIS-determined helices to guide phylogenetic analysis of RNA structures and discovered conserved long-range and alternative structures. XIST, a long noncoding RNA (lncRNA) essential for X chromosome inactivation, folds into evolutionarily conserved RNA structural domains that span many kilobases. XIST A-repeat forms complex inter-repeat duplexes that nucleate higher-order assembly of the key epigenetic silencing protein SPEN. PARIS is a generally applicable and versatile method that provides novel insights into the RNA structurome and interactome. VIDEO ABSTRACT.

Intracardiac and extracardiac markers of inflammation during atrial fibrillation

BACKGROUND A decrease in inflammation after cure of atrial arrhythmias suggests that such arrhythmias are proinflammatory, and lower inflammatory marker levels in the coronary sinus suggest that atrial arrhythmias result in intracardiac appropriation of inflammatory cytokines. OBJECTIVE The purpose of this study was to investigate the effect of atrial fibrillation on inflammatory markers drawn from intracardiac and extracardiac chambers. METHODS We performed a case-control study of 167 AF patients and 207 controls. Blood from intracardiac and extracardiac sites was obtained from a subset of patients undergoing curative AF ablation (n = 46). RESULTS No significant differences in C-reactive protein (CRP) or interleukin-6 (IL-6) levels were seen between patients with and those without a history of AF. Both levels were significantly higher when blood was drawn during AF than during sinus rhythm: median CRP 3.1 mg/dL (interquartile range [IQR] 1.0-6.0) versus 1.7 mg/dL (IQR 0.7-3.9, P = .0005); median IL-6 2.3 ng/mL (IQR 1.5-3.9) versus 1.5 ng/mL (IQR 0.7-2.5, P = .007). This finding persisted after adjusting for potential confounders. AF ablation patients in AF exhibited a positive median left atrial minus coronary sinus gradient CRP (0.3 mg/dL, IQR -0.03-1.1), whereas those in sinus rhythm had a negative median left atrial minus coronary sinus gradient CRP (-0.2, IQR -0.8-[-0.02], P = .01). Femoral artery minus femoral vein gradients in AF versus sinus rhythm did not show any differences. CONCLUSION AF at the time of the blood draw, rather than a history of AF, was independently associated with inflammation. Differences in transcardiac gradients suggest that AF results in sequestration of inflammatory cytokines in the heart.

Risk Stratification for Sudden Cardiac Death A Plan for the Future

Sudden cardiac death (SCD) remains a high priority public health problem necessitating a multi-pronged approach for treatment and prevention. Tachyarrhythmic sudden cardiac death (SCD-VT/VF; ie, death attributable to potentially reversible ventricular tachyarrhythmias [ventricular tachycardia (VT) or fibrillation (VF)]), is a major cause of SCD. Accurate assessment of risk for SCD-VT/VF is of critical importance to assist clinical decision-making regarding prescription of preventive therapies that reduce mortality. These therapeutic decisions include adherence to standard medical therapies, often in conjunction with tailored medications, implantable devices, catheter ablation, or heretofore untested treatments, such as spinal cord stimulation.1 In cases in which the therapy is invasive or carries its own risk, such as these latter interventions, each should be based on reliable demonstration of added benefit to the patient. Pre-emptive risk stratification for SCD-VT/VF has substantial implications to public health for the following reasons: (1) Heart disease remains the number 1 cause of death in the United States, with >600 000 deaths attributable to heart disease annually reported by the National Center for Health Statistics (http://www.cdc.gov/nchs/fastats/deaths.htm); (2) Approximately half of these deaths are estimated to be sudden; (3) Approximately 50% of all SCDs are the first recognized cardiac event; and (4) Only a minority of those who suffer out-of-hospital cardiac arrest will ultimately survive. Although the incidence of VF as a cause of out-of-hospital cardiac arrest is declining, it remains a leading cause.2 The introduction of the implantable cardioverter-defibrillator (ICD)—an effective, but costly therapy—has had meaningful, but limited, population impact on SCD2; thus, there are opportunities for new approaches (Figure) to address SCD. In particular, improved risk stratification techniques that identify individuals at high risk for SCD-VT/VF could have substantial impact,3 saving lives while stewarding medical resources for cases in which they are most effective. Since 2005, annual meetings …

Markers of inflammation before and after curative ablation of atrial flutter

BACKGROUND Atrial arrhythmias are associated with inflammation. The cause and effect of the association are unknown. OBJECTIVE The purpose of this study was to test the hypothesis that atrial tachyarrhythmias contribute to inflammation. METHODS We performed a prospective observational study wherein C-reactive protein (CRP) and interleukin-6 (IL-6) levels from the femoral vein and coronary sinus (CS) were compared before curative ablation for atrial flutter (AFL; n = 59) and paroxysmal supraventricular tachycardia (SVT; n = 110). Follow-up levels were obtained at 1 and 6 months. RESULTS Peripheral levels of both biomarkers were significantly higher in the AFL group. After multivariate adjustment, only those in the AFL group who presented in AFL or atrial fibrillation (AF) had significantly elevated CRP levels (odds ratio 1.26; P = .033). Levels of each marker were similar in the CS and peripheral blood in the SVT group; in the AFL group, both CRP and IL-6 were significantly lower in the CS than in the periphery (P = .0076 and P = .0021, respectively). CRP was significantly lower a median of 47 days after AFL ablation (from a median of 6.28 mg/L to a median of 2.92 mg/L; P = .028) and remained reduced at second follow-up. IL-6 decreased across three time points after AFL ablation (P = .002). No reduction in inflammatory biomarkers was observed after SVT ablation. CONCLUSIONS CRP and IL-6 levels are elevated in patients presenting in AFL. Given the lower CS values in these patients, their origin appears to be systemic rather than cardiac. Because these levels significantly fall after ablation of AFL, the atrial tachyarrhythmia appears to be the cause (not the effect) of the inflammation.

Long-term electrical survival analysis of Riata and Riata ST silicone leads: National Veterans Affairs experience

BACKGROUND A medical device advisory issued by St Jude Medical in November 2011 estimated 0.63% all-cause abrasion rate on their Riata and Riata ST silicone high-voltage lead families (Riata/ST), leading to Food and Drug Administration class I recall. We performed an independent comparative, long-term electrical survival analysis of Riata/ST and 3 other high-voltage lead families in a large national cohort of patients. OBJECTIVE To evaluate long-term electrical survival of Riata/ST leads relative to other commonly evaluated high-voltage leads. METHODS Failure rates of Riata/ST, Sprint Quattro Secure (Quattro), Sprint Fidelis (Fidelis), and Endotak Reliance G/SG (Endotak) leads from the Veterans Administrations National Cardiac Device Surveillance Center database, consisting of 24,145 patients with remote transmissions since 2003, were analyzed. Survival Probabilities were determined with Kaplan-Meier survival analysis and compared using the log-rank test. RESULTS Of 1,403 Riata/ST, 6,091 Quattro, 5,073 Fidelis, and 2,401 Endotak leads identified, 5-year survival probability of Riata/ST leads (97.5%) was significantly lower than that of Quattro (99.3%) and Endotak (99.4%) leads (P <.0001) but higher than that of Fidelis leads (89.6%) (P <.0001). Riata ST leads showed a 5-year survival of 95.5% (95% confidence interval 92.4-97.4) compared to 98.4% (95% confidence interval 97.1-99.1) in Riata leads (P = .003). CONCLUSIONS There is decreased survival probability of Riata/ST leads compared to other contemporary high-voltage leads, with decreased survival of Riata ST silicone compared to Riata lead series. Careful long-term follow-up should be maintained in patients with Riata/ST leads in order to prevent inappropriate shocks or failed device interventions. Our results were determined in advance of Food and Drug Administration class I recall, which suggested that large-scale remote monitoring may be an effective tool for continued implantable cardioverter-defibrillator system surveillance.