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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.08.002 Byline: Marco V. Perez (a), Frederick E. Dewey (a), Rachel Marcus (a), Euan A. Ashley (a), Amin A. Al-Ahmad (a), Paul J. Wang (a), Victor F. Froelicher (a)(b) Abstract: Atrial fibrillation (AF) is the most prevalent arrhythmia in the United States and accounts for more than 750,000 strokes per year. Noninvasive predictors of AF may help identify patients at risk of developing AF. Our objective was to identify the electrocardiographic characteristics associated with onset of AF. Author Affiliation: (a) Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA (b) Cardiovascular Medicine, Palo Alto Veterans Affairs Health Care System, Stanford, CA Article History: Received 26 May 2009; Accepted 6 August 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2008.01.025 Byline: Amir H. Sadrzadeh Rafie (a), Frederick E. Dewey (b), Jonathan Myers (c), Victor F. Froelicher (c) Abstract: The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification of patients referred for exercise testing, but it does not consider age. We aimed to determine if age could improve the prognostic power of the DTS and if so, to modify the DTS nomogram to include age. Author Affiliation: (a) Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford , CA (b) Stanford University School of Medicine, Stanford, CA (c) VA Palo Alto Health Care System, Palo Alto, CA Article History: Received 10 November 2007; Accepted 22 January 2008

Background The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can affect clinical management, including risk stratification and selection of pharmacotherapy on the basis of the type of ion channel affected, but results from the current gene panel testing requires 4–16 weeks before return to clinicians. Objective A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker and cardioverter-defibrillator implantation and sympathectomy on day of life 2. We sought to provide a rapid molecular diagnosis for the optimization of treatment strategies. Methods We performed Clinical Laboratory Improvement Amendments–certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life. Results We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by follow-up genotyping. The unbiased assessment of the entire catalog of human genes provided by WGS revealed a maternally inherited variant of unknown significance in a novel gene. Conclusion Rapid clinical WGS provides faster and more comprehensive diagnostic information at 10 days of life than does standard gene panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS can provide more timely and clinically actionable information than can a standard commercial test. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to evaluate the predictive accuracy of a cardiopulmonary exercise test (CPX) score. Background: Cardiopulmonary exercise test responses, including peak VO2, markers of ventilatory inefficiency (eg, the VE/VCO2 slope and oxygen uptake efficiency slope [OUES]), and hemodynamic responses, such as heart rate recovery (HRR) and chronotropic incompetence (CRI) are strong predictors of outcomes in patients with heart failure (HF). However, there is a need for simplified approaches that integrate the additive prognostic information from CPX. Methods: At 4 institutions, 710 patients with HF (568 male/142 female, mean age 56 ± 13 years, resting left ventricular ejection fraction 33 ± 14%) underwent CPX and were followed for cardiac-related mortality and separately for major cardiac events (death, hospitalization for HF, transplantation, left ventricular assist device implantation) for a mean of 29 ± 25 months. The age-adjusted prognostic power of peak VO2, VE/VCO2 slope, OUES (VO2 = a log10VE + b), resting end-tidal carbon dioxide pressure (PetCO2), HRR, and CRI were determined using Cox proportional hazards analysis, optimal cutpoints were determined, the variables were weighted, and a multivariate score was derived. Results: There were 175 composite outcomes. The VE/VCO2 slope (≥34) was the strongest predictor of risk and was attributed a relative weight of 7, with weighted scores for abnormal HRR (≤6 beats at 1 minute), OUES (>1.4), PetCO2 (<33 mm Hg), and peak VO2 (≤14 mL kg−1 min−1) having scores of 5, 3, 3, and 2, respectively. Chronotropic incompetence was not a significant predictor and was excluded from the score. A summed score >15 was associated with an annual mortality rate of 27% and a relative risk of 7.6, whereas a score <5 was associated with a mortality rate of 0.4%. The composite score was the most accurate predictor of cardiovascular events among all CPX responses considered (concordance indexes 0.77 for mortality and 0.75 for composite outcome composed of mortality, transplantation, left ventricular assist device implantation, and HF-related hospitalization). The summed score remained significantly associated with increased risk after adjusting for age, gender, body mass index, ejection fraction, and cardiomyopathy type. Conclusion: A multivariable score based on readily available CPX responses provides a simple and integrated method that powerfully predicts outcomes in patients with HF. [Copyright &y& Elsevier]

The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification. Our aim was to determine if other variables could improve the prognostic power of the DTS and if so, to modify the DTS nomogram. From a total of 1,959 patients referred for exercise testing at the Palo Alto VA Medical Center from 1997 to 2006 (a mean follow-up of 5.4 years), we studied 1,759 male veterans (age 57 ± 12 years) free of heart failure. Double product (DP) was calculated by multiplying systolic blood pressure and heart rate; variables and their products were subtracted to obtain the differences between at rest and maximal exercise (reserve) and recovery. Of all the hemodynamic measurements, DP reserve was the strongest predictor of cardiovascular death (CVD) (Wald Z-score −3.84, p <0.001) after adjustment for potential confounders. When the components of DTS were entered in the Cox hazard model with DP reserve and age, only DP reserve and age were chosen (p <0.00001). Using the Cox coefficients, a score calculated by [age − DTS – 3 × (DP reserve/1,000)] yielded an area under the curve of 0.84 compared with 0.76 for the DTS. Using this equation, a nomogram was constructed by adding age and DP reserve to the original DTS nomogram improving estimation of annual CVD. In conclusion, we propose an age and DP reserve-adjusted DTS nomogram that improves the prognostic estimates of average annual CVD over the DTS alone. [Copyright &y& Elsevier]

Background: The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification of patients referred for exercise testing, but it does not consider age. We aimed to determine if age could improve the prognostic power of the DTS and if so, to modify the DTS nomogram to include age.Methods: Of 1,959 patients referred for exercise testing from 1997 to 2006, 1,759 male veterans (age range 23-86 years) remained after exclusion of female and patients with heart failure. Cardiovascular mortality was the main outcome considered.Results: Cox survival analysis was performed entering age and the DTS; both were significant (P Conclusions: We propose an age-adjusted DTS nomogram that improves the prognostic estimates of average annual CV mortality over the DTS alone. This nomogram requires external validation and extension to women. [ABSTRACT FROM AUTHOR]

There is considerable recent evidence that parameters thought to reflect the complex interaction between the autonomic nervous system and the cardiovascular system during exercise testing can provide significant prognostic information. Specific variables of great importance include heart rate (HR) response to exercise (reserve), HR recovery after exercise, and multiple components of HR variability both at rest and with exercise. Poor HR response to exercise has been strongly associated with sudden cardiac death and HR recovery from a standard exercise test has been shown to be predictive of mortality. In addition, there are limited studies evaluating the components of HR variability at rest and during exercise and their prognostic significance. Research continues seeking to refine these exercise measurements and further define their prognostic value. Future findings should augment the power of the exercise test in risk-stratifying cardiovascular patients. [Copyright &y& Elsevier]

Background: The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function.Objectives: This study sought to identify genetic variations associated with response to HF therapy.Methods: This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography.Results: Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model.Conclusions: A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model. [ABSTRACT FROM AUTHOR]