Circulation: Arrhythmia and Electrophysiology
Atrioventricular nodal reentrant tachycardia (AVNRT) has not previously been described as a heritable condition. This study analyzed patients who underwent radiofrequency ablation, identifying the occurrence of familial AVNRT defined as presence in at least 2 first-degree relatives. The results of this study are the first to report the prevalence of familial AVNRT, suggesting some degree of heritability.
Familial Occurrence of Atrioventricular Nodal Reentrant Tachycardia
Yoav Michowitz, MD Adi Anis-Heusler, MD Eyal Reinstein, MD Oholi Tovia-Brodie, MD Aharon Glick, MD Bernard Belhassen, MD
Correspondence to: Bernard Belhassen, MD, Department of Cardiology, Tel-Aviv Sourasky Medical Center, Weizman St 6, Tel-Aviv 64239, Israel. E-mail
BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) is considered a sporadic disease occurring in ≈22.5 cases per 10 000 in the general population. We define the prevalence and characteristics of familial AVNRT among patients who underwent radiofrequency ablation.
METHODS AND RESULTS: Ablation reports of all patients with familial AVNRT (at least 2 first-degree family members) who underwent radiofrequency ablation in our institution and in another hospital were reviewed. There were 1587 patients from our institution, of whom 20 had ≥1 first-degree relatives with AVNRT. This indicates a familial AVNRT prevalence of 127 cases per 10 000 (95% confidence interval, 82–196/10 000). First-degree relatives of patients with AVNRT presented a hazard ratio of at least 3.6 for exhibiting AVNRT compared with the general population. After inclusion of 4 families with familial AVNRT who underwent ablation at another hospital our population study comprised a total of 24 families (50 patients) with AVNRT. Patients at ablation were younger in the familial AVNRT group when compared with the sporadic AVNRT group (44.2±19 versus 54.8±18 years old, P=0.0001). The male/female ratio was similar, with female predominance. The supraventricular tachycardia mechanism was typical slow/fast reentry in most cases in both groups. The most common familial relationship in our 24 families included a parent and a child in 67% of cases and less often 2 siblings (29%).
CONCLUSIONS: Familial AVNRT prevalence is higher than previously believed suggesting that this arrhythmia may have a genetic component. Autosomal dominance with incomplete penetrance is the most likely mode of inheritance.
Circ Arrhythm Electrophysiol. 2017;10:e004680. DOI: 10.1161/CIRCEP.116.004680.
Circulation: Cardiovascular Genetics
This study analyzed epigenetic changes related to serum lipids to identify novel potential pathways involved in lipid regulation. The results highlight associations of DNA methylation with lipid levels and identify an association of epigenetic regulation of reverse cholesterol transport with cardiovascular events.
Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
Åsa K. Hedman, PhD Michael M. Mendelson, MD Riccardo E. Marioni, PhD Stefan Gustafsson, PhD Roby Joehanes, PhD Marguerite R. Irvin, PhD Degui Zhi, PhD Johanna K. Sandling, PhD Chen Yao, PhD Chunyu Liu, PhD Liming Liang, PhD Tianxiao Huan, PhD Allan F. McRae, PhD Serkalem Demissie, PhD Sonia Shah, PhD John M. Starr, MD, PhD L. Adrienne Cupples, PhD Panos Deloukas, PhD Timothy D. Spector, MD Johan Sundström, MD, PhD Ronald M. Krauss, MD Donna K. Arnett, PhD Ian J. Deary, PhD Lars Lind, MD, PhD Daniel Levy, MD Erik Ingelsson, MD, PhD
Correspondence to: Erik Ingelsson, MD, PhD, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Mail code 5773, Stanford, CA 94305, USA. E-mail
BACKGROUND: Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications.
METHODS AND RESULTS: To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P<1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P=8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15–1.66; P=0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (PTC=0.004, PHDL-C=0.008, and Ptriglycerides=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus.
CONCLUSIONS: We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
Circ Cardiovascular Genetics. 2017;10:e001487. DOI: 10.1161/CIRCGENETICS.116.001487.
Circulation: Cardiovascular Imaging
Factors that affect left atrial structural changes are largely unknown. This analysis of the Dallas Heart Study leveraged cardiac MRI at 2 visits a mean of 8 years apart to determine left atrial volume and analyze associations of changes in volume. Factors influencing left atrial enlargement over time were black and Hispanic race/ethnicity, increases in left ventricular mass, changes in N-terminal probrain natriuretic peptide, changes in body mass index driven by visceral fat mass change, and increases in systolic blood pressure. The findings suggest blood pressure control and weight loss are potentially modifiable mediators of left atrial dilation.
Factors Associated With Left Atrial Remodeling in the General Population
Walter Oliver Gwendolyn Matthews, BS Colby R. Ayers, MS Sonia Garg, MD Sachin Gupta, MD Ian J. Neeland, MD Mark H. Drazner, MD, MSc Jarett D. Berry, MD, MS Susan Matulevicius, MD, MSc James A. de Lemos, MD
Correspondence to: James A. de Lemos, MD, University of Texas Southwestern Medical Center, 5909 Harry Hines Boulevard, E 5.7528, Dallas, TX 75390, USA. E-mail
BACKGROUND: Although contributors to remodeling of the left ventricle (LV) have been well studied in general population cohorts, few data are available describing factors influencing changes in left atrial (LA) structure.
METHODS AND RESULTS: Maximum LA volume was determined by cardiac MRI among 748 participants in the Dallas Heart Study at 2 visits a mean of 8 years apart. Associations of changes in LA volume (ΔLAV) with traditional risk factors, biomarkers, LV geometry, and remodeling by cardiac MRI and detailed measurements of global and regional adiposity (by MRI and dual-energy x ray absorptiometry) were assessed using multivariable linear regression. Greater ΔLAV was independently associated with black and Hispanic race/ethnicity, change in systolic blood pressure, LV mass and ΔLV mass, N-terminal probrain natriuretic peptide and change in N-terminal probrain natriuretic peptide, and body mass index (P<0.05 for each). In subanalyses, the associations of ΔLAV with LV mass parameters were driven by associations with baseline and ΔLV end-diastolic volume (P<0.0001 for each) and not wall thickness (P=0.21). Associations of ΔLAV with body mass index were explained exclusively by associations with visceral fat mass (P=0.002), with no association seen between ΔLAV and subcutaneous abdominal fat (P=0.47) or lower body fat (P=0.30).
CONCLUSIONS: Left atrial dilatation in the population is more common in black and Hispanic than in white individuals and is associated with parallel changes in the LV. LA dilatation may be mediated by blood pressure control and the development of visceral adiposity.
Circ Cardiovasc Imaging. 2017;10:e005047. DOI: 10.1161/CIRCIMAGING.116.005047.
Circulation: Cardiovascular Interventions
The long-term results after the double kissing crush technique for coronary artery bifurcation lesions are unknown. This study reports long-term, 5-year follow-up of the DKCRUSH-II study comparing the provisional stenting and the double kissing crush techniques. The original study reported no difference in major adverse cardiovascular events at 12 months with less target lesion revascularization by double kissing crush technique. The results of 5-year follow-up report a trend toward benefit in major adverse cardiac event by double kissing crush technique versus provisional stenting (P=0.051) and sustained benefits in less target vessel revascularization.
Clinical Outcome of Double Kissing Crush Versus Provisional Stenting of Coronary Artery Bifurcation Lesions
The 5-Year Follow-Up Results From a Randomized and Multicenter DKCRUSH-II Study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions)
Shao-Liang Chen, MD Teguh Santoso, MD Jun-Jie Zhang, PhD Fei Ye, MD Ya-Wei Xu, MD Qiang Fu, MD Jing Kan, MBBS Feng-Fu Zhang, MD Yong Zhou, MD Du-Jiang Xie, MD Tak W. Kwan, MD
Correspondence to: Shao-Liang Chen, MD, Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Rd, Nanjing 210006, China. E-mail
BACKGROUND: Provisional stenting is effective for anatomic simple bifurcation lesions. Double kissing crush stenting reduces the 1-year rate of target lesion revascularization. This study aimed to investigate the 5-year clinical results of the DKCRUSH-II study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions).
METHODS AND RESULTS: A total of 370 patients with coronary bifurcation lesions who were randomly assigned to either the double kissing crush or provisional stenting group in the DKCRUSH-II study were followed for 5 years. The primary end point was the occurrence of a major adverse cardiac event at 5 years. Patients were classified by simple and complex bifurcation lesions according to the DEFINITION criteria (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents). At 5 years, the major adverse cardiac event rate (23.8%) in the provisional stenting group was insignificantly different to that of the double kissing group (15.7%; P=0.051). However, the difference in the target lesion revascularization rate between 2 groups was sustained through the 5-year follow-up (16.2% versus 8.6%; P=0.027). The definite and probable stent thrombosis rate was 2.7% in each group (P=1.0). Complex bifurcation was associated with a higher rate of target lesion revascularization (21.6%) at 5 years compared with 11.1% in patients with a simple bifurcation (P=0.037), with an extremely high rate in the provisional stenting group (36.8% versus 12.5%, P=0.005) mainly because of final kissing balloon inflation (19.4% versus 5.2%; P=0.036).
CONCLUSIONS: The double kissing crush stenting technique for coronary bifurcation lesions is associated with a lower rate of target lesion revascularization. The optimal stenting approach based on the lesions’ complexity may improve the revascularization for patients with complex bifurcations.
CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org. Unique identifier: ChiCTR-TRC-0000015.
Circ Cardiovasc Interv. 2017;10:e004497. DOI: 10.1161/CIRCINTERVENTIONS.116.004497.
Circulation: Cardiovascular Quality and Outcomes
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have demonstrated profound reductions in low-density-lipoprotein cholesterol. However, there have been concerns over potential neurocognitive effects with the class. This meta-analysis evaluates the safety of PCSK9 inhibitors across 11 studies. The overall results suggest PCSK9 is not associated with severe adverse effects, musculoskeletal effects, or stroke; however, there is a signal for increased neurocognitive adverse effects in a subgroup analysis from the larger outcomes studies. Nevertheless, overall rates of neurocognitive adverse events were low. The findings support the ongoing need to evaluate neurocognitive outcomes with the class.
Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors
Abdur Rahman Khan, MD Chirag Bavishi, MD Haris Riaz, MD Talha A. Farid, MD Sobia Khan, MBBS Michel Atlas, MLS Glenn Hirsch, MD Sohail Ikram, MD Roberto Bolli, MD
Correspondence to: Roberto Bolli, MD, Institute of Molecular Cardiology, University of Louisville, ACB, Third Floor, 550 S. Jackson Street, Louisville, KY 40292, USA. E-mail
BACKGROUND: There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors.
METHODS AND RESULTS: Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel-Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88−1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87−1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64−2.59), or stroke (OR, 1.44; 95% CI, 0.57−3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34−6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups.
CONCLUSIONS: Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and postmarketing surveillance.
Circ Cardiovasc Qual Outcomes. 2017;10:e003153. DOI: 10.1161/CIRCOUTCOMES.116.003153.
Circulation: Heart Failure
This meta-analysis investigated the relationship between renin–angiotensin aldosterone system (RAAS) inhibitors in heart failure (HF) patients with reduced ejection fraction (HFREF) and HF patients with preserved ejection fraction (HFPEF) with worsening renal function, clinical outcomes, and mortality. The results show RAAS inhibitors induce renal dysfunction in both HF phenotypes; there is an increase in mortality risk with worsening renal function in patients with HFPEF. The study advises caution to clinicians when evaluating HFPEF patients during RAAS treatment. However, whether worsening renal function served as a marker of worsening clinical status or was specifically the cause of poorer outcomes is unclear.
Renin–Angiotensin System Inhibition, Worsening Renal Function, and Outcome in Heart Failure Patients With Reduced and Preserved Ejection Fraction
A Meta-Analysis of Published Study Data
Iris E. Beldhuis, BSc Koen W. Streng, MD Jozine M. Ter Maaten, MD, PhD Adriaan A. Voors, MD, PhD Peter van der Meer, MD, PhD Patrick Rossignol, MD, PhD John J.V. McMurray, MD Kevin Damman, MD, PhD
Correspondence to: Kevin Damman, MD, PhD, Department of Cardiology, University Medical Center Groningen, Hanzeplein 1, 9700RB Groningen, The Netherlands. E-mail
BACKGROUND: Renin–angiotensin aldosterone system (RAAS) inhibitors significantly improve outcome in heart failure (HF) patients with reduced ejection fraction (HFREF), irrespective of the occurrence of worsening renal function (WRF). However, in HF patients with preserved ejection fraction (HFPEF), RAAS inhibitors have not been shown to improve outcome but are still frequently prescribed.
METHODS AND RESULTS: Random effect meta-analysis was performed to investigate the relationship between RAAS inhibitor therapy, WRF in both HF phenotypes, and mortality. Studies were selected based on literature search in MEDLINE and included randomized, placebo controlled trials of RAAS inhibitors in chronic HF. The primary outcome consisted of the interaction analysis for the association between RAAS inhibition–induced WRF, HF phenotype, and outcome. A total of 8 studies (6 HFREF and 2 HFPEF, including 28 961 patients) were included in our analysis. WRF was more frequent in the RAAS inhibitor group, compared with the placebo group, in both HFREF and HFPEF. In HFREF, WRF induced by RAAS inhibitor therapy was associated with a less increased relative risk of mortality (relative risk, 1.19 (1.08–1.31); P<0.001), compared with WRF induced by placebo (relative risk, 1.48 (1.35–1.62); P<0.001; P for interaction 0.005). In contrast, WRF induced by RAAS inhibitor therapy was strongly associated with worse outcomes in HFPEF (relative risk, 1.78 (1.43–2.21); P<0.001), whereas placebo-induced WRF was not (relative risk, 1.25 (0.88–1.77); P=0.21; P for interaction 0.002).
CONCLUSIONS: RAAS inhibitors induce renal dysfunction in both HFREF and HFPEF. However, in contrast to patients with HFREF where mortality increase with WRF is small, HFPEF patients with RAAS inhibitor–induced WRF have an increased mortality risk, without experiencing improved outcome with RAAS inhibition.
Circ Heart Failure. 2017;10:e003588. DOI: 10.1161/CIRCHEARTFAILURE.116.003588.
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- © 2017 American Heart Association, Inc.