Circulation: Arrhythmia and Electrophysiology
Although cardiac resynchronization therapy (CRT) may reduce functional mitral regurgitation (MR) in some patients with heart failure and reduced ejection fraction, the role of optimization of lead position on MR reduction is unclear. In this substudy, the authors found that longer LV electric delay at the LV stimulation site was associated with greater MR reduction and reverse remodeling after CRT. These findings suggest that optimization of LV lead placement may contribute to reduction in MR after CRT.
Longer Left Ventricular Electric Delay Reduces Mitral Regurgitation After Cardiac Resynchronization Therapy: Mechanistic Insights from the SMART-AV Study (SmartDelay Determined AV Optimization)
A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy
Neal A. Chatterjee, MD Michael R. Gold, MD, PhD Alan D. Waggoner, MHS Michael H. Picard, MD Kenneth M. Stein, MD Yinghong Yu, MS Timothy E. Meyer, PhD Nicholas Wold, MS Kenneth A. Ellenbogen, MD Jagmeet P. Singh, MD, PhD
Correspondence to: Jagmeet P. Singh, MD, PhD, Cardiac Arrhythmia Service, Massachusetts General Hospital Heart Center, GRB 109, 55 Fruit St, Boston, MA 02411. E-mail
BACKGROUND: Mitral regurgitation (MR) is associated with worse survival in those undergoing cardiac resynchronization therapy (CRT). Left ventricular (LV) lead position in CRT may ameliorate mechanisms of MR. We examine the association between a longer LV electric delay (QLV) at the LV stimulation site and MR reduction after CRT.
METHODS AND RESULTS: QLV was assessed retrospectively in 426 patients enrolled in the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in CRT). QLV was defined as the time from QRS onset to the first large peak of the LV electrogram. Linear regression and logistic regression were used to assess the association between baseline QLV and MR reduction at 6 months (absolute change in vena contracta width and odds of ≥1 grade reduction in MR). At baseline, there was no difference in MR grade, LV dyssynchrony, or LV volumes in those with QLV above versus below the median (95 ms). After multivariable adjustment, increasing QLV was an independent predictor of MR reduction at 6 months as reflected by an increased odds of MR response (odds ratio: 1.13 [1.03–1.25]/10 ms increase QLV; P=0.02) and a decrease in vena contracta width (P<0.001). At 3 months, longer QLV (≥median) was associated with significant decrease in LV end-systolic volume (ΔLV end-systolic volume −28.2±38.9 versus −4.9±33.8 mL, P<0.001). Adjustment for 3-month ΔLV end-systolic volume attenuated the association between QLV and 6-month MR reduction.
CONCLUSIONS: In patients undergoing CRT, longer QLV was an independent predictor of MR reduction at 6 months and associated with interval 3-month LV reverse remodeling. These findings provide a mechanistic basis for using an electric-targeting LV lead strategy at the time of CRT implant.
Circ Arrhythm Electrophysiol. 2016;9:e004346. DOI: 10.1161/CIRCEP.116.004346.
Circulation: Cardiovascular Genetics
There is limited understanding of the transcriptome changes in neonatal heart chambers during maturation of the heart, particularly the coordinated regulation of long noncoding RNAs (lncRNAs) and messenger RNA (mRNA). This study provides a high-resolution landscape on neonatal mouse cardiac lncRNAs and identifies a potential interaction with mRNA transcriptome during cardiac maturation. Moreover, a specific interaction between Ppp1r1b-lncRNA and its corresponding gene partner Tcap provided a molecular signature that differentiated congenital heart defect phenotypes. These results highlight the potential power of transcriptomics to identify molecular mechanisms involved in perinatal circulatory transition in heart and the discovery of potential diagnostic and therapeutic targets for congenital heart defects.
Decoding the Long Noncoding RNA During Cardiac Maturation
A Roadmap for Functional Discovery
Marlin Touma, MD, PhD Xuedong Kang, PhD Yan Zhao, PhD Ashley A. Cass, BS Fuying Gao, PhD Reshma Biniwale, MD Giovanni Coppola, MD Xinshu Xiao, PhD Brian Reemtsen, MD Yibin Wang, PhD
Correspondence to: Marlin Touma, MD, PhD, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, B2-375, MDCC, Los Angeles, CA 90095. E-mailor Yibin Wang, PhD, David Geffen School of Medicine, University of California, Los Angeles, 650 Charles E. Young Dr, BH 569, CHS, Los Angeles, CA 90095. E-mail
BACKGROUND: Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated.
METHODS AND RESULTS: From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene coexpression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes.
CONCLUSIONS: The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.
Circ Cardiovascular Genetics. 2016;9:395–407. DOI: 10.1161/CIRCGENETICS.115.001363.
Circulation: Cardiovascular Imaging
Previous studies suggest long-term physical training is associated with the development of myocardial fibrosis in middle-aged athletes. This current study evaluated 92 seniors, categorized by their histories of committed exercise, who underwent cardiac MRI and late gadolinium enhancement assessment of fibrosis. The results suggest that consistent and increasing physical activity was not associated the prevalence of myocardial fibrosis, supporting the need for the evaluation of individualized exercise dosages and level evaluation.
Lifelong Physical Activity Regardless of Dose Is Not Associated with Myocardial Fibrosis
Shuaib M. Abdullah, MD, MSCs Kyler W. Barkley, MD Paul S. Bhella, MD Jeffrey L. Hastings, MD, MS Susan Matulevicius, MD, MSCs Naoki Fujimoto, MD, PhD Shigeki Shibata, MD, PhD Graeme Carrick-Ranson, PhD M. Dean Palmer, MS Nainesh Gandhi, MD Laura F. DeFina, MD Benjamin D. Levine, MD
Correspondence to: Benjamin D. Levine, MD, Institute for Exercise and Environmental Medicine, 7232 Greenville Ave, Suite 435, Dallas, TX 75231. E-mail
BACKGROUND: Recent reports have suggested that long-term, intensive physical training may be associated with adverse cardiovascular effects, including the development of myocardial fibrosis. However, the dose–response association of different levels of lifelong physical activity on myocardial fibrosis has not been evaluated.
METHODS AND RESULTS: Seniors free of major chronic illnesses were recruited from predefined populations based on the consistent documentation of stable physical activity over >25 years and were classified into 4 groups by the number of sessions/week of aerobic activities ≥30 minutes: sedentary (group 1), <2 sessions; casual (group 2), 2 to 3 sessions; committed (group 3), 4 to 5 sessions; and Masters athletes (group 4), 6 to 7 sessions plus regular competitions. All subjects underwent cardiopulmonary exercise testing and cardiac MRI, including late gadolinium enhancement assessment of fibrosis. Ninety-two subjects (mean age 69 years, 27% women) were enrolled. No significant differences in age or sex were seen between groups. Median peak oxygen uptake was 25, 26, 32, and 40 mL/kg/min for groups 1, 2, 3, and 4, respectively. Cardiac MRI demonstrated increasing left ventricular end-diastolic volumes, end-systolic volumes, stroke volumes, and masses with increasing doses of lifelong physical activity. One subject in group 2 had late gadolinium enhancement in a noncoronary distribution, and no subjects in groups 3 and 4 had evidence of late gadolinium enhancement.
CONCLUSIONS: A lifelong history of consistent physical activity, regardless of dose ranging from sedentary to competitive marathon running, was not associated with the development of focal myocardial fibrosis.
Circ Cardiovasc Imaging. 2016;9:e005511. DOI: 10.1161/CIRCIMAGING.116.005511.
Circulation: Cardiovascular Interventions
Bifurcation lesions remain challenging for unprotected percutaneous coronary intervention (PCI) in the left main coronary artery, even in the drug-eluting stent (DES) era. This observational study compares clinical outcomes of a 1-stent strategy and a 2-stent strategy for these complex lesions. The 2-stent strategy was associated with a higher risk of side-branch restenosis, but no difference in major adverse events. These results support a selective 2-stent strategy when necessary in patients with unprotected distal left main disease.
Comparison Between 1- and 2-Stent Strategies in Unprotected Distal Left Main Disease
The Milan and New-Tokyo Registry
Kensuke Takagi, MD Toru Naganuma, MD Alaide Chieffo, MD Yusuke Fujino, MD Azeem Latib, MD Satoko Tahara, MD Hisaaki Ishiguro, MD Matteo Montorfano, MD Mauro Carlino, MD Hiroyoshi Kawamoto, MD Naoyuki Kurita, MD Koji Hozawa, MD Shotaro Nakamura, MD Sunao Nakamura, MD Antonio Colombo, MD
Correspondence to: Antonio Colombo, MD, EMO-GVM Centro Cuore Columbus, 48 Via M. Buonarroti, 20145 Milan, Italy. E-mail
BACKGROUND: There are only little data available on the comparison of clinical outcomes between a 1-stent strategy (1-SS) and a 2-stent strategy (2-SS) for percutaneous coronary intervention in unprotected distal left main disease.
METHODS AND RESULTS: Between April 2005 and August 2011, we recruited 937 consecutive unprotected distal left main patients treated with drug-eluting stents (1-SS, 608 patients; 2-SS, 329 patients). Major adverse cardiovascular events were defined as all-cause death, myocardial infarction, or target lesion revascularization (TLR) during the median follow-up period of 1592 days. Furthermore, the individual components of major adverse cardiovascular events, cardiac death, and stent thrombosis were evaluated. More complex lesions were seen with 2-SS than with 1-SS. Cardiac death occurred more frequently with 1-SS than with 2-SS (propensity score–adjusted hazard ratio, 0.52; 95% confidence interval, 0.29–0.64; P=0.03), whereas TLR occurred more frequently with 2-SS than with 1-SS (propensity score–adjusted hazard ratio, 1.59; 95% confidence interval, 1.15–2.20; P=0.005). TLR was mainly driven by revascularizations after restenosis at the ostial left circumflex artery (propensity score–adjusted hazard ratio, 1.94; 95% confidence interval, 1.33–2.82; P=0.001). However, there were no differences in major adverse cardiovascular events, all-cause death, stent thrombosis, and myocardial infarction. Of the 139 pairs that were propensity score matched, only TLRs were significantly higher in the 2-SS group (hazard ratio, 1.59; 95% confidence interval, 1.00–2.53; P=0.05).
CONCLUSIONS: The difference between 1-SS and 2-SS in percutaneous coronary intervention for unprotected distal left main disease may be summarized by the high incidence of TLR, mainly because of restenosis at the ostial left circumflex artery in the 2-SS group.
Circ Cardiovasc Interv. 2016;9:e003359. DOI: 10.1161/CIRCINTERVENTIONS.116.003359.
Circulation: Cardiovascular Quality and Outcomes
This study compares newer machine learning methods with more traditional statistical techniques to develop prediction models for readmissions in heart failure–a topic that is important for policymakers and providers. Though machine learning methods require further optimization and development, the results of this study highlight limitations of standard statistical methods and show improvements in discrimination and a range of prediction metrics with machine learning techniques.
Analysis of Machine Learning Techniques for Heart Failure Readmissions
Bobak J. Mortazavi, PhD Nicholas S. Downing, MD Emily M. Bucholz, MD, PhD Kumar Dharmarajan, MD, MBA Ajay Manhapra, MD Shu-Xia Li, PhD Sahand N. Negahban, PhD Harlan M. Krumholz, MD, SM
Correspondence to: Harlan M. Krumholz, MD, SM, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, 1 Church St, Suite 200, New Haven, CT 06510. E-mail
BACKGROUND: The current ability to predict readmissions in patients with heart failure is modest at best. It is unclear whether machine learning techniques that address higher dimensional, nonlinear relationships among variables would enhance prediction. We sought to compare the effectiveness of several machine learning algorithms for predicting readmissions.
METHODS AND RESULTS: Using data from the Telemonitoring to Improve Heart Failure Outcomes trial, we compared the effectiveness of random forests, boosting, random forests combined hierarchically with support vector machines or logistic regression (LR), and Poisson regression against traditional LR to predict 30- and 180-day all-cause readmissions and readmissions because of heart failure. We randomly selected 50% of patients for a derivation set, and a validation set comprised the remaining patients, validated using 100 bootstrapped iterations. We compared C statistics for discrimination and distributions of observed outcomes in risk deciles for predictive range. In 30-day all-cause readmission prediction, the best performing machine learning model, random forests, provided a 17.8% improvement over LR (mean C statistics, 0.628 and 0.533, respectively). For readmissions because of heart failure, boosting improved the C statistic by 24.9% over LR (mean C statistic 0.678 and 0.543, respectively). For 30-day all-cause readmission, the observed readmission rates in the lowest and highest deciles of predicted risk with random forests (7.8% and 26.2%, respectively) showed a much wider separation than LR (14.2% and 16.4%, respectively).
CONCLUSIONS: Machine learning methods improved the prediction of readmission after hospitalization for heart failure compared with LR and provided the greatest predictive range in observed readmission rates.
Circ Cardiovasc Qual Outcomes. 2016;9:629–640. DOI: 10.1161/CIRCOUTCOMES.116.003039.
Circulation: Heart Failure
This study tested muscle vasoconstriction and muscle sympathetic nerve activity in response to hypoxia and hypercapnia in patients with heart failure (HF) and sleep-disordered breathing (SDB) and in patients with HF and without SDB. The authors report that more severe muscle vasoconstriction and sympathetic nerve activation was reported in HF patients with SDB during peripheral and central chemoreceptor stimulation. These results suggest mechanisms by which SDB may contribute to increased morbidity and mortality in patients with HF as opposed to HF patients without SDB.
Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure
Denise M. L. Lobo, BS Patricia F. Trevizan, BS Edgar Toschi-Dias, PhD Patricia A. Oliveira, MD Rafael B. Piveta, MD Dirceu R. Almeida, MD, PhD Charles Mady, MD, PhD Edimar A. Bocchi, MD, PhD Geraldo Lorenzi-Filho, MD, PhD Holly R. Middlekauff, MD Carlos E. Negrão, PhD
Correspondence to: Carlos E. Negrão, PhD, Instituto do Coração HC/FMUSP, Av Dr Enéas de Carvalho Aguiar, 44-Cerqueira Cesar, São Paulo SP 05403-000, Brazil. E-mail
BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD).
METHODS AND RESULTS: Ninety consecutive patients with HF, New York Heart Association functional class II–III, and left ventricular ejection fraction ≤40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39–53] years) and SDB (n=28, 57 [54–61] years). SDB was characterized by apnea–hypopnea index ≥15 events per hour (polysomnography). Peripheral (10% O2 and 90% N2, with CO2 titrated) and central (7% CO2 and 93% O2) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.01 to all comparisons). Similarly, during hypercapnia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.001 to all comparisons). MSNA were higher in response to hypoxia (P=0.024) and tended to be higher to hypercapnia (P=0.066) in the SDB group.
CONCLUSIONS: Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response.
Circ Heart Fail. 2016;9:e003065. DOI: 10.1161/CIRCHEARTFAILURE.116.003065.
Circulation is available at http://circ.ahajournals.org.
- © 2016 American Heart Association, Inc.