Topic: Journal Club Selection

Abstract

Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease.

Goyal S, Tisdale J, Schmidt M, Kanter J, ... Colvin RA, Bonner M
Gene therapy with LentiGlobin for sickle cell disease (bb1111, lovotibeglogene autotemcel) consists of autologous transplantation of a patient\'s hematopoietic stem cells transduced with the BB305 lentiviral vector that encodes the βA-T87Q-globin gene. Acute myeloid leukemia developed in a woman approximately 5.5 years after she had received LentiGlobin for sickle cell disease as part of the initial cohort (Group A) of the HGB-206 study. An analysis of peripheral-blood samples revealed that blast cells contained a BB305 lentiviral vector insertion site. The results of an investigation of causality indicated that the leukemia was unlikely to be related to vector insertion, given the location of the insertion site, the very low transgene expression in blast cells, and the lack of an effect on expression of surrounding genes. Several somatic mutations predisposing to acute myeloid leukemia were present after diagnosis, which suggests that patients with sickle cell disease are at increased risk for hematologic malignant conditions after transplantation, most likely because of a combination of risks associated with underlying sickle cell disease, transplantation procedure, and inadequate disease control after treatment. (Funded by Bluebird Bio.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 12 Jan 2022; 386:138-147
Goyal S, Tisdale J, Schmidt M, Kanter J, ... Colvin RA, Bonner M
N Engl J Med: 12 Jan 2022; 386:138-147 | PMID: 34898140
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Abstract

24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk.

Ma Y, He FJ, Sun Q, Yuan C, ... Cook NR, Hu FB
Background
The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method.
Methods
We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis.
Results
Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94).
Conclusions
Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 19 Jan 2022; 386:252-263
Ma Y, He FJ, Sun Q, Yuan C, ... Cook NR, Hu FB
N Engl J Med: 19 Jan 2022; 386:252-263 | PMID: 34767706
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Abstract

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

Beaton A, Okello E, Rwebembera J, Grobler A, ... Sable CA, Steer AC
Background
Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown.
Methods
We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years.
Results
Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis).
Conclusions
Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 19 Jan 2022; 386:230-240
Beaton A, Okello E, Rwebembera J, Grobler A, ... Sable CA, Steer AC
N Engl J Med: 19 Jan 2022; 386:230-240 | PMID: 34767321
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Abstract

Determinants of outcomes following surgery for type A acute aortic dissection: the UK National Adult Cardiac Surgical Audit.

Benedetto U, Dimagli A, Kaura A, Sinha S, ... Tsang G, Akowuah E
Aims 
Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK.
Methods and results
We identified 4203 patients undergoing TAAAD surgery in the UK (2009-18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02-1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51-2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14-1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90-4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71-3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00-3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14-9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86-2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes.
Conclusions 
Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Dec 2021; 43:44-52
Benedetto U, Dimagli A, Kaura A, Sinha S, ... Tsang G, Akowuah E
Eur Heart J: 27 Dec 2021; 43:44-52 | PMID: 34468733
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Abstract

Coronary Atherosclerotic Plaque Regression: JACC State-of-the-Art Review.

Dawson LP, Lum M, Nerleker N, Nicholls SJ, Layland J
Over the last 3 decades there have been substantial improvements in treatments aimed at reducing cardiovascular (CV) events. As these treatments have been developed, there have been parallel improvements in coronary imaging modalities that can assess plaque volumes and composition, using both invasive and noninvasive techniques. Plaque progression can be seen to precede CV events, and therefore, many studies have longitudinally assessed changes in plaque characteristics in response to various treatments, aiming to demonstrate plaque regression and improvements in high-risk features, with the rationale being that this will reduce CV events. In the past, decisions surrounding treatments for atherosclerosis have been informed by population-based risk scores for initiation in primary prevention and low-density lipoprotein cholesterol levels for titration in secondary prevention. If outcome data linking plaque regression to reduced CV events emerge, it may become possible to directly image plaque treatment response to guide management decisions.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Jan 2022; 79:66-82
Dawson LP, Lum M, Nerleker N, Nicholls SJ, Layland J
J Am Coll Cardiol: 03 Jan 2022; 79:66-82 | PMID: 34991791
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Abstract

Management of Atrial Fibrillation in Patients 75 Years and Older: JACC State-of-the-Art Review.

Volgman AS, Nair G, Lyubarova R, Merchant FM, ... Kirkpatrick JN, Benjamin EJ
The prevalence of atrial fibrillation (AF) is increasing as the population ages. AF treatment-related complications also increase markedly in older adults (defined as ≥75 years of age for this review). The older AF population has a high risk of stroke, bleeding, and death. Syncope and fall-related injuries are the most common reasons for nonprescription of oral anticoagulation (OAC), and are more common in older adults when OACs are used with antiarrhythmic drugs. Digoxin may be useful for rate control, but associations with increased mortality limit its use. Beyond rate and rhythm control considerations, stroke prophylaxis is critical to AF management, and the benefits of direct OACs, compared with warfarin, extend to older adults. Invasive procedures such as AF catheter ablation, pacemaker implantation/atrioventricular junction ablation, and left atrial appendage occlusion may be useful in appropriately selected cases. However, older adults have generally been under-represented in clinical trials.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Jan 2022; 79:166-179
Volgman AS, Nair G, Lyubarova R, Merchant FM, ... Kirkpatrick JN, Benjamin EJ
J Am Coll Cardiol: 17 Jan 2022; 79:166-179 | PMID: 35027110
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Abstract

The year in cardiovascular medicine 2021: heart failure and cardiomyopathies.

Bauersachs J, de Boer RA, Lindenfeld J, Bozkurt B
In the year 2021, the universal definition and classification of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with preserved ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

Eur Heart J: 02 Jan 2022; epub ahead of print
Bauersachs J, de Boer RA, Lindenfeld J, Bozkurt B
Eur Heart J: 02 Jan 2022; epub ahead of print | PMID: 34974611
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Abstract

Risk-Adjusted, 30-Day Home Time After Transcatheter Aortic Valve Replacement as a Hospital-Level Performance Metric.

Mentias A, Keshvani N, Desai MY, Kumbhani DJ, ... Girotra S, Pandey A
Background
Patient-centric measures of hospital performance for transcatheter aortic valve replacement (TAVR) are needed.
Objectives
This study evaluated 30-day, risk-adjusted home time as a hospital performance metric for patients who underwent TAVR.
Methods
This study identified 160,792 Medicare beneficiaries who underwent elective TAVR from 2015 to 2019. Home time was calculated for each patient as the number of days alive and spent outside the hospital, skilled nursing facility (SNF), and long-term acute care facility for 30 days after the TAVR procedure date. Correlations between risk-adjusted, 30-day home time and other metrics (30-day, risk-adjusted readmission rate [RSRR], 30-day, risk-adjusted mortality rate [RSMR], and annual TAVR volume) were estimated using Pearson\'s correlation. Meaningful upward or downward reclassification (≥2 quartile ranks) in hospital performance based on quartiles of risk-adjusted, 30-day home time compared with quartiles of other measures were assessed.
Results
Median risk-adjusted, 30-day home time was 27.4 days (interquartile range [IQR]: 26.3-28.5 days). The largest proportion of days lost from 30-day home time was hospital stay after TAVR and SNF stay. An inverse correlation was observed between hospital-level, risk-adjusted, 30-day home time and 30-day RSRR (r = -0.465; P < 0.001) and 30-day RSMR (r = -0.3996; P < 0.001). The use of the 30-day, risk-adjusted home time was associated with reclassification in hospital performance rank hospitals compared with other metrics (9.1% up-classified, 11.2% down-classified vs RSRR; 9.1% up-classified, 10.3% down-classified vs RSMR; and 20.1% up-classified, 19.3% down-classified vs annual TAVR volume).
Conclusions
Risk-adjusted, 30-day home time represents a novel patient-centered performance metric for TAVR hospitals that may provide a complimentary assessment to currently used metrics.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Jan 2022; 79:132-144
Mentias A, Keshvani N, Desai MY, Kumbhani DJ, ... Girotra S, Pandey A
J Am Coll Cardiol: 17 Jan 2022; 79:132-144 | PMID: 35027108
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Abstract

4-Year Outcomes After Left Atrial Appendage Closure Versus Nonwarfarin Oral Anticoagulation for Atrial Fibrillation.

Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY, PRAGUE-17 Trial Investigators
Background
The PRAGUE-17 (Left Atrial Appendage Closure vs Novel Anticoagulation Agents in Atrial Fibrillation) trial demonstrated that left atrial appendage closure (LAAC) was noninferior to nonwarfarin direct oral anticoagulants (DOACs) for preventing major neurological, cardiovascular, or bleeding events in patients with atrial fibrillation (AF) who were at high risk.
Objectives
This study sought to assess the prespecified long-term (4-year) outcomes in PRAGUE-17.
Methods
PRAGUE-17 was a randomized noninferiority trial comparing percutaneous LAAC (Watchman or Amulet) with DOACs (95% apixaban) in patients with nonvalvular AF and with a history of cardioembolism, clinically-relevant bleeding, or both CHA2DS2-VASc ≥3 and HASBLED ≥2. The primary endpoint was a composite of cardioembolic events (stroke, transient ischemic attack, or systemic embolism), cardiovascular death, clinically relevant bleeding, or procedure-/device-related complications (LAAC group only). The primary analysis was modified intention-to-treat.
Results
This study randomized 402 patients with AF (201 per group, age 73.3 ± 7.0 years, 65.7% male, CHA2DS2-VASc 4.7 ±1.5, HASBLED 3.1 ± 0.9). After 3.5 years median follow-up (1,354 patient-years), LAAC was noninferior to DOACs for the primary endpoint by modified intention-to-treat (subdistribution HR [sHR]: 0.81; 95% CI: 0.56-1.18; P = 0.27; P for noninferiority = 0.006). For the components of the composite endpoint, the corresponding sHRs were 0.68 (95% CI: 0.39-1.20; P = 0.19) for cardiovascular death, 1.14 (95% CI: 0.56-2.30; P = 0.72) for all-stroke/transient ischemic attack, 0.75 (95% CI: 0.44-1.27; P = 0.28) for clinically relevant bleeding, and 0.55 (95% CI: 0.31-0.97; P = 0.039) for nonprocedural clinically relevant bleeding. The primary endpoint outcomes were similar in the per-protocol (sHR: 0.80; 95% CI: 0.54-1.18; P = 0.25) and on-treatment (sHR: 0.82; 95% CI: 0.56-1.20; P = 0.30) analyses.
Conclusions
In long-term follow-up of PRAGUE-17, LAAC remains noninferior to DOACs for preventing major cardiovascular, neurological, or bleeding events. Furthermore, nonprocedural bleeding was significantly reduced with LAAC. (PRAGUE-17 [Left Atrial Appendage Closure vs Novel Anticoagulation Agents in Atrial Fibrillation]; NCT02426944).

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Jan 2022; 79:1-14
Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY, PRAGUE-17 Trial Investigators
J Am Coll Cardiol: 03 Jan 2022; 79:1-14 | PMID: 34748929
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Abstract

Genes that Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts.

Aguado BA, Walker CJ, Grim JC, Schroeder ME, ... Leinwand LA, Anseth KS
Background: Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored.
Methods:
Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-sequencing was used to define pathways involved in driving sex-dependent activation. Interventions using small molecule inhibitors and small interfering RNA (siRNA) transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors.
Results:
In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, alpha-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Conclusions: Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.




Circulation: 09 Jan 2022; epub ahead of print
Aguado BA, Walker CJ, Grim JC, Schroeder ME, ... Leinwand LA, Anseth KS
Circulation: 09 Jan 2022; epub ahead of print | PMID: 35000411
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Abstract

ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.

Cheng P, Wirka RC, Clarke LS, Zhao Q, ... Kundaje A, Quertermous T
Background: Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci.
Methods:
We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function.
Results:
CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Conclusions: These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.




Circulation: 05 Jan 2022; epub ahead of print
Cheng P, Wirka RC, Clarke LS, Zhao Q, ... Kundaje A, Quertermous T
Circulation: 05 Jan 2022; epub ahead of print | PMID: 34990206
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Abstract

Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

Song S, Tien CL, Cui H, Basil P, ... Zhang L, Sun Z
Background: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear.
Methods:
We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-seq, ChIP-seq, proteomics, and metabolomics) analyses, and performed dietary and pharmacologic rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts.
Results:
KO mice display progressive dilated cardiomyopathy (DCM) and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. Increasing dietary lipids or sugars supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acids availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorates cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with DCM. Conclusions: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipids supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human DCM. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and DCM.




Circulation: 16 Jan 2022; epub ahead of print
Song S, Tien CL, Cui H, Basil P, ... Zhang L, Sun Z
Circulation: 16 Jan 2022; epub ahead of print | PMID: 35034472
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Abstract

Implantable cardiac defibrillator events in patients with arrhythmogenic right ventricular cardiomyopathy.

Woźniak O, Borowiec K, Konka M, Cicha-Mikołajczyk A, ... Poślednik K, Biernacka EK
Objective
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of sudden cardiac death. Optimal risk stratification is still under debate. The main purpose of this long-term, single-centre observation was to analyse predictors of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) interventions in the population of patients with ARVC with a high risk of life-threatening arrhythmias.
Methods
The study comprised 65 adult patients (median age 40 years, 48 men) with a definite diagnosis of ARVC who received ICD over a time span of 20 years in primary (40%) or secondary (60%) prevention of sudden cardiac death. The study endpoints were first appropriate and inappropriate ICD interventions (shock or antitachycardia pacing) after device implantation.
Results
During a median follow-up of 7.75 years after ICD implantation, nine patients died and six individuals underwent heart transplantation. Appropriate ICD interventions occurred in 43 patients (66.2%) and inappropriate ICD interventions in 18 patients (27.7%). Multivariable analysis using cause-specific hazard model identified three predictors of appropriate ICD interventions: right ventricle dysfunction (cause-specific HR 2.85, 95% CI 1.56 to 5.21, p<0.001), age <40 years at ICD implantation (cause-specific HR 2.37, 95% CI 1.13 to 4.94, p=0.022) and a history of sustained ventricular tachycardia (cause-specific HR 2.55, 95% CI 1.16 to 5.63, p=0.020). Predictors of inappropriate ICD therapy were not found. Complications related to ICD implantation occurred in 12 patients.
Conclusions
Right ventricle dysfunction, age <40 years and a history of sustained ventricular tachycardia were predictors of appropriate ICD interventions in patients with ARVC. The results may be used to improve risk stratification before ICD implantation.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Dec 2021; 108:22-28
Woźniak O, Borowiec K, Konka M, Cicha-Mikołajczyk A, ... Poślednik K, Biernacka EK
Heart: 30 Dec 2021; 108:22-28 | PMID: 33674353
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Abstract

Risk of left atrial appendage thrombus and stroke in patients with atrial fibrillation and mitral regurgitation.

Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Objective
To investigate the association of mitral regurgitation (MR) on thromboembolic risk of patients with non-valvular atrial fibrillation (NVAF) undergoing transoesophageal echocardiography (TEE)-guided cardioversion.
Methods
Data for consecutive patients who underwent TEE-guided cardioversion for NVAF between 2000 and 2012 were analysed. MR severity was assessed by Doppler echocardiography and classified as ≤mild, moderate or severe. Left atrial appendage emptying velocities were averaged for five consecutive cycles. Multivariable regression models were used to identify independent predictors of left atrial appendage thrombus (LAAT) and stroke.
Results
2950 patients (age, 69.3±12.2 years, 67% men) were analysed. 2173 (73.7%) had ≤mild MR; 631 (21.4%), moderate MR; and 146 (4.9%), severe MR. Patients with moderate (age, 72.4±10.7 years) and severe (age, 72.8±12.1 years) MR were older than those with ≤mild MR (age, 68.2±12.5 years). The prevalence of LAAT was 1.5% (n=43). CHA2DS2-VASc scores (≤mild MR, 3.0±1.6; moderate MR, 3.5±1.5; severe MR, 3.9±1.5; p<0.001) and heart failure frequency (≤mild MR, 38.4%; moderate MR, 48.0%; severe MR, 69.2%; p<0.001) were increasingly higher with greater MR severity. Multivariable logistic regression analysis showed no association of moderate MR (OR 0.77, 95% CI 0.38 to 1.56) or severe MR (OR 0.55, 95% CI 0.21 to 1.49) with LAAT. During a mean follow-up of 7.3±5.1 years (median 7.5, IQR, 2.7-10.9), 216 patients had an ischaemic stroke. Adjusted Cox regression analysis showed no significant association of moderate MR (HR 1.22, 95% CI 0.88 to 1.68) or severe MR (HR 0.73, 95% CI 0.31 to 1.46) with stroke.
Conclusions
Among patients with NVAF, the presence or severity of MR was not associated with a decreased risk of LAAT or stroke.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Dec 2021; 108:29-36
Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Heart: 30 Dec 2021; 108:29-36 | PMID: 33766985
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Impact:
Abstract

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Akdis D, Chen L, Saguner AM, Zhang N, ... Song J, Duru F
Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC.
Methods and results
ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels.
Conclusion
Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Am Heart J: 30 Jan 2022; 244:66-76
Akdis D, Chen L, Saguner AM, Zhang N, ... Song J, Duru F
Am Heart J: 30 Jan 2022; 244:66-76 | PMID: 34756894
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Abstract

Deep learning-based computer-aided heart sound analysis in children with left-to-right shunt congenital heart disease.

Liu J, Wang H, Yang Z, Quan J, Liu L, Tian J
Objective
The purpose of this study was to explore a new algorithm model capable of leverage deep learning to screen and diagnose specific types of left-to-right shunt congenital heart disease (CHD) in children.
Methods
Using deep learning, screening models were constructed to identify 884 heart sound recordings from children with left-to-right shunt CHD. The most suitable model for each type was summarized and compared with expert auscultation. An exploratory analysis was conducted to assess whether there were correlations between heart sounds and left ventricular ejection fraction (LVEF), pulmonary artery pressure, and malformation size.
Results
The residual convolution recurrent neural network (RCRnet) classification model had higher accuracy than other models with respect to atrial septal defect (ASD), ventricular septum defect (VSD), patent ductus arteriosus (PDA) and combined CHD, and the best auscultation sites were determined to be the 4th, 5th, 2nd and 3rd auscultation areas, respectively. The diagnostic results of this model were better than those derived from expert auscultation, with sensitivity values of 0.932-1.000, specificity values of 0.944-0.997, precision values of 0.888-0.997 and accuracy values of 0.940-0.994. Absolute Pearson correlation coefficient values between heart sounds of the four types of CHD and LVEF, right ventricular systolic pressure (RVSP) and malformation size were all less than 0.3.
Conclusions
The RCRnet model can preliminarily determine types of left-to-right shunt CHD and improve diagnostic efficiency, which may provide a new choice algorithmic CHD screening in children.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Jan 2022; 348:58-64
Liu J, Wang H, Yang Z, Quan J, Liu L, Tian J
Int J Cardiol: 31 Jan 2022; 348:58-64 | PMID: 34902505
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Abstract

Pulmonary percutaneous valve implantation in large native right ventricular outflow tract with 32 mm Myval transcatheter heart valve.

Rodríguez Ogando A, Ballesteros F, Martínez JLZ
Pulmonary percutaneous valve implantation (PPVI) is feasible with satisfactory mid-term results in patients with native right ventricular outflow tract (RVOT) and has been increasingly used instead of surgically implantable pulmonary valves. Creating a stable landing zone with a diameter less than the largest commercially available valve (previously available 29 mm and currently available 32 mm) is crucial for technical success of the procedure, limiting the number of suitable candidates for PPVI. We report the case of PPVI with a 32 mm Myval transcatheter heart valve in a patient with a large native RVOT (pre-stented with AndraStent XXL mounted on a 35 × 60 mm valve balloon catheter) lesion who had Tetralogy of Fallot surgically corrected. The post-procedural outcomes of this case were satisfactory with no complications reported during the hospital stay.

© 2021 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 31 Dec 2021; 99:E38-E42
Rodríguez Ogando A, Ballesteros F, Martínez JLZ
Catheter Cardiovasc Interv: 31 Dec 2021; 99:E38-E42 | PMID: 34674370
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Abstract

Safety of transoesophageal echocardiography during structural heart disease interventions under procedural sedation: a single-centre study.

Afzal S, Zeus T, Hofsähs T, Kuballa M, ... Kelm M, Hellhammer K
Aims
The aim of this study was to determine the incidence of transoesophageal echocardiography (TOE)-related adverse events (AEs) during structural heart disease (SHD) interventions and to identify potential risk factors.
Methods and results
We retrospectively analysed 898 consecutive patients undergoing TOE-guided SHD interventions under procedural sedation. TOE-related AEs were classified as bleeding complications, mechanical lesions, conversion to general anaesthesia with intubation, and the occurrence of pneumonia. A follow-up was conducted up to 3 months after the intervention. TOE-related AEs were observed in 5.3% of the patients (n = 48). The highest rate of AEs was observed in the percutaneous mitral valve repair (PMVR) group with 8.2% (n = 32), whereas 4.8% (n = 11) of the patients in the left atrial appendage group and 1.8% (n = 5) in the patent foramen ovale/atrial septal defect group developed a TOE-related AE (P = 0.001). The most frequent AE was pneumonia with an incidence of 2.6% (n = 26) in the total cohort. Bleeding events occurred in 1.8% (n = 16) of the patients, mostly in the PMVR group with 2.1% (n = 8). In the multivariate regression analysis, we found a lower haemoglobin {odds ratio (OR) [95% confidence interval (CI)]: 8.82 (0.68-0.98) P = 0.025} and an obstructive sleep apnoea syndrome (OSAS) [OR (95% CI): 2.51 (1.08-5.84) P = 0.033] to be associated with AE. Furthermore, AEs were related to procedural time [OR (95% CI): 1.01 (1.0-1.01) P = 0.056] and oral anticoagulation [OR (95% CI): 1.97 (0.9-4.3) P = 0.076] with borderline significance in the multivariate regression analysis. No persistent damages were observed.
Conclusion
TOE-related AEs during SHD interventions are clinically relevant. It was highest in patients undergoing PMVR. A lower baseline haemoglobin level and an OSAS were found to be associated with the occurrence of a TOE-related AE.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Imaging: 02 Jan 2022; epub ahead of print
Afzal S, Zeus T, Hofsähs T, Kuballa M, ... Kelm M, Hellhammer K
Eur Heart J Cardiovasc Imaging: 02 Jan 2022; epub ahead of print | PMID: 34977935
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This program is still in alpha version.