Benjamin S. Wessler

Acute exposure to air pollution triggers atrial fibrillation.

OBJECTIVES This study sought to evaluate the association of air pollution with the onset of atrial fibrillation (AF). BACKGROUND Air pollution in general and more specifically particulate matter has been associated with cardiovascular events. Although ventricular arrhythmias are traditionally thought to convey the increased cardiovascular risk, AF may also contribute. METHODS Patients with dual chamber implantable cardioverter-defibrillators (ICDs) were enrolled and followed prospectively. The association of AF onset with air quality including ambient particulate matter <2.5 μm aerodynamic diameter (PM2.5), black carbon, sulfate, particle number, NO2, SO2, and O3 in the 24 h prior to the arrhythmia was examined utilizing a case-crossover analysis. In sensitivity analyses, associations with air pollution between 2 and 48 h prior to the AF were examined. RESULTS Of 176 patients followed for an average of 1.9 years, 49 patients had 328 episodes of AF lasting ≥ 30 s. Positive but nonsignificant associations were found for PM2.5 in the prior 24 h, but stronger associations were found with shorter exposure windows. The odds of AF increased by 26% (95% confidence interval: 8% to 47%) for each 6.0 μg/m(3) increase in PM2.5 in the 2 h prior to the event (p = 0.004). The odds of AF were highest at the upper quartile of mean PM2.5. CONCLUSIONS PM was associated with increased odds of AF onset within hours following exposure in patients with known cardiac disease. Air pollution is an acute trigger of AF, likely contributing to the pollution-associated adverse cardiac outcomes observed in epidemiological studies.

Drug and Device Effects on Peak Oxygen Consumption, 6-Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction

Background— Although peak oxygen consumption (peak VO2), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction. Methods and Results— We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in VO2, 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak VO2 trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak VO2 and the odds ratio for mortality (r=0.158, P=0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality (r=0.373, P=0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r=−0.065, P=0.82, NT-proBNP: r=−0.667, P=0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality. Conclusions— This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak VO2, 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction.

Transesophageal Echocardiography in Cryptogenic Stroke and Patent Foramen Ovale: Analysis of Putative High-Risk Features From the Risk of Paradoxical Embolism Database

Background—Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), although the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography features such as PFO size, associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these transesophageal echocardiography features with other markers of pathogenicity has not been examined. Methods and Results—We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high-risk transesophageal echocardiography features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n=637) compared with those less likely to have a PFO-attributable stroke (n=657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (odds ratio [OR], 0.92; P=0.53). The presence of neither a hypermobile septum nor a right-to-left shunt at rest was detected more often in those with a probable PFO-attributable stroke (OR, 0.80; P=0.45; OR, 1.15; P=0.11, respectively). Conclusions—We found no evidence that the proposed transesophageal echocardiography risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.

Clinical Prediction Models for Cardiovascular Disease Tufts Predictive Analytics and Comparative Effectiveness Clinical Prediction Model Database

Background—Clinical prediction models (CPMs) estimate the probability of clinical outcomes and hold the potential to improve decision making and individualize care. For patients with cardiovascular disease, there are numerous CPMs available although the extent of this literature is not well described. Methods and Results—We conducted a systematic review for articles containing CPMs for cardiovascular disease published between January 1990 and May 2012. Cardiovascular disease includes coronary heart disease, heart failure, arrhythmias, stroke, venous thromboembolism, and peripheral vascular disease. We created a novel database and characterized CPMs based on the stage of development, population under study, performance, covariates, and predicted outcomes. There are 796 models included in this database. The number of CPMs published each year is increasing steadily over time. Seven hundred seventeen (90%) are de novo CPMs, 21 (3%) are CPM recalibrations, and 58 (7%) are CPM adaptations. This database contains CPMs for 31 index conditions, including 215 CPMs for patients with coronary artery disease, 168 CPMs for population samples, and 79 models for patients with heart failure. There are 77 distinct index/outcome pairings. Of the de novo models in this database, 450 (63%) report a c-statistic and 259 (36%) report some information on calibration. Conclusions—There is an abundance of CPMs available for a wide assortment of cardiovascular disease conditions, with substantial redundancy in the literature. The comparative performance of these models, the consistency of effects and risk estimates across models and the actual and potential clinical impact of this body of literature is poorly understood.

Drier air, lower temperatures, and triggering of paroxysmal atrial fibrillation.

Background: The few previous studies on the onset of paroxysmal atrial fibrillation and meteorologic conditions have focused on outdoor temperature and hospital admissions, but hospital admissions are a crude indicator of atrial fibrillation incidence, and studies have found other weather measures in addition to temperature to be associated with cardiovascular outcomes. Methods: Two hundred patients with dual chamber implantable cardioverter-defibrillators were enrolled and followed prospectively from 2006 to 2010 for new onset episodes of atrial fibrillation. The date and time of arrhythmia episodes documented by the implanted cardioverter-defibrillators were linked to meteorologic data and examined using a case-crossover analysis. We evaluated associations with outdoor temperature, apparent temperature, air pressure, and three measures of humidity (relative humidity, dew point, and absolute humidity). Results: Of the 200 enrolled patients, 49 patients experienced 328 atrial fibrillation episodes lasting ≥30 seconds. Lower temperatures in the prior 48 hours were positively associated with atrial fibrillation. Lower absolute humidity (ie, drier air) had the strongest and most consistent association: each 0.5 g/m3 decrease in the prior 24 hours increased the odds of atrial fibrillation by 4% (95% confidence interval [CI]: 0%, 7%) and by 5% (95% CI: 2%, 8%) for exposure in the prior 2 hours. Results were similar for dew point but slightly weaker. Conclusions: Recent exposure to drier air and lower temperatures were associated with the onset of atrial fibrillation among patients with known cardiac disease, supporting the hypothesis that meteorologic conditions trigger acute cardiovascular episodes.

The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study

Background: For patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), it is unknown whether the magnitude of right-to-left shunt (RLSh) measured by contrast transcranial Doppler (c-TCD) is correlated with the likelihood an identified PFO is related to CS as determined by the Risk of Paradoxical Embolism (RoPE) score. Additionally, for patients with CS, it is unknown whether PFO assessment by c-TCD is more sensitive for identifying RLSh compared with transesophageal echocardiography (TEE). Our aim was to determine the significance of RLSh grade by c-TCD in patients with PFO and CS. Methods: We evaluated patients with CS who had RLSh quantified by c-TCD in the Multicenter Study into RLSh in Cryptogenic Stroke (CODICIA) to determine whether there is an association between c-TCD shunt grade and the RoPE Score. For patients who underwent c-TCD and TEE, we determined whether there is agreement in identifying and grading RLSh between these two modalities. Results: The RoPE score predicted the presence versus the absence of RLSh documented by c-TCD (c-statistic = 0.66). For patients with documented RLSh by c-TCD, shunt severity was correlated with increasing RoPE score (rank correlation (r) = 0.15, p = 0.01). Among 293 patients who had both c-TCD and TEE performed, c-TCD was more sensitive (98.7%) for detecting RLSh. Of the 97 patients with no PFO identified on TEE, 28 (29%) had a large amount of RLSh seen on c-TCD. Conclusions: For patients with CS, severity of RLSh by c-TCD is positively correlated with the RoPE score, indicating that this technique for shunt grading identifies patients more likely to have pathogenic rather than incidental PFOs. c-TCD is also more sensitive in detecting RLSh than TEE. These findings suggest an important role for c-TCD in the evaluation of PFO in the setting of CS.

Short-Term Effects of Ketamine and Isoflurane on Left Ventricular Ejection Fraction in an Experimental Swine Model

Background. General anesthesia is an essential element of experimental medical procedures. Ketamine and isoflurane are agents commonly used to induce and maintain anesthesia in animals. The cardiovascular effects of these anesthetic agents are diverse, and the response of global myocardial function is unknown. Methods. In a series of 15 swine, echocardiography measurements of left ventricular ejection fraction (LVEF) were obtained before the animals received anesthesia (baseline), after an intramuscular injection of ketamine (postketamine) and after inhaled isoflurane (postisoflurane). Results. The mean LVEF of an unanesthetized swine was 47 ± 3%. There was a significant decrease in the mean LVEF after administration of ketamine to 41 + 6.5% (P = 0.003). The addition of inhaled isoflurane did not result in further decrease in mean LVEF (mean LVEF 38 ± 7.2%, P = 0.22). Eight of the swine had an increase in their LVEF with sympathetic stimulation. Conclusions. In our experimental model the administration of ketamine was associated with decreased LV function. The decrease may be largely secondary to a blunting of sympathetic tone. The addition of isoflurane to ketamine did not significantly change LV function. A significant number of animals had returned to preanesthesia LV function with sympathetic stimulation.

Field Synopsis of the Role of Sex in Stroke Prediction Models

Background Guidelines for stroke prevention recommend development of sex‐specific stroke risk scores. Incorporating sex in Clinical Prediction Models (CPMs) may support sex‐specific clinical decision making. To better understand their potential to guide sex‐specific care, we conducted a field synopsis of the role of sex in stroke‐related CPMs. Methods and Results We identified stroke‐related CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Database, a systematic summary of cardiovascular CPMs published from January 1990 to May 2012. We report the proportion of models including the effect of sex on stroke incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 92 stroke‐related CPMs, 30 (33%) contained a coefficient for sex or presented sex‐stratified models. Only 12/58 (21%) CPMs predicting outcomes in patients included sex, compared to 18/30 (60%) models predicting first stroke (P<0.0001). Sex was most commonly included in models predicting stroke among a general population (69%). Female sex was consistently associated with reduced mortality after ischemic stroke (n=4) and higher risk of stroke from arrhythmias or coronary revascularization (n=5). Models predicting first stroke versus outcomes among patients with stroke (odds ratio=5.75, 95% CI 2.18–15.14, P<0.001) and those developed from larger versus smaller sample sizes (odds ratio=4.58, 95% CI 1.73–12.13, P=0.002) were significantly more likely to include sex. Conclusions Sex is included in a minority of published CPMs, but more frequently in models predicting incidence of first stroke. The importance of sex‐specific care may be especially well established for primary prevention.

Field Synopsis of Sex in Clinical Prediction Models for Cardiovascular Disease

Background—Several widely used risk scores for cardiovascular disease (CVD) incorporate sex effects, yet there has been no systematic summary of the role of sex in clinical prediction models (CPMs). To better understand the potential of these models to support sex-specific care, we conducted a field synopsis of sex effects in CPMs for CVD. Methods and Results—We identified CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Registry, a comprehensive database of CVD CPMs published from January 1990 to May 2012. We report the proportion of models including sex effects on CVD incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 592 CVD-related CPMs, 193 (33%) included sex as a predictor or presented sex-stratified models. Sex effects were included in 78% (53/68) of models predicting incidence of CVD in a general population, versus only 35% (59/171), 21% (12/58), and 17% (12/72) of models predicting outcomes in patients with coronary artery disease, stroke, and heart failure, respectively. Among sex-including CPMs, women with heart failure were at lower mortality risk in 8 of 8 models; women undergoing revascularization for coronary artery disease were at higher mortality risk in 10 of 12 models. Factors associated with the inclusion of sex effects included the number of outcome events and using cohorts at-risk for CVD (rather than with established CVD). Conclusions—Although CPMs hold promise for supporting sex-specific decision making in CVD clinical care, sex effects are included in only one third of published CPMs.

Neuronal Dysfunction and Medical Therapy in Heart Failure: Can an Imaging Biomarker Help to “Personalize” Therapy?

123I-metaiodobenzylguanidine (123I-MIBG) imaging is a tool for evaluating one of the fundamental pathophysiologic abnormalities seen in heart failure (HF), that of an upregulated sympathetic nervous system and its effect on the myocardium. Although this imaging technique offers information about prognosis for patients treated with contemporary guideline-based HF therapies and improves risk stratification, there are neither rigorous nor sufficient outcome data to suggest that this imaging tool can guide therapeutic decision making or better target subsets of patients with HF for particular therapies.