Topic: Journal Club Selection

Abstract

The utility of strain imaging in the cardiac surveillance of bone marrow transplant patients.

Deshmukh T, Emerson P, Geenty P, Mahendran S, ... Gottlieb D, Thomas L
Objective
To evaluate the utility of two-dimensional multiplanar speckle tracking strain to assess for cardiotoxicity post allogenic bone marrow transplantation (BMT) for haematological conditions.
Methods
Cross-sectional study of 120 consecutive patients post-BMT (80 pretreated with anthracyclines (BMT+AC), 40 BMT alone) recruited from a late effects haematology clinic, compared with 80 healthy controls, as part of a long-term cardiotoxicity surveillance study (mean duration from BMT to transthoracic echocardiogram 6±6 years). Left ventricular global longitudinal strain (LV GLS), global circumferential strain (LV GCS) and right ventricular free wall strain (RV FWS) were compared with traditionl parameters of function including LV ejection fraction (LVEF) and RV fractional area change.
Results
LV GLS (-17.7±3.0% vs -20.2±1.9%), LV GCS (-14.7±3.5% vs -20.4±2.1%) and RV FWS (-22.6±4.7% vs -28.0±3.8%) were all significantly (p=0.001) reduced in BMT+AC versus controls, while only LV GCS (-15.9±3.5% vs -20.4±2.1%) and RV FWS (-23.9±3.5% vs -28.0±3.8%) were significantly (p=0.001) reduced in BMT group versus controls. Even in patients with LVEF >53%, ~75% of patients in both BMT groups demonstrated a reduction in GCS.
Conclusion
Multiplanar strain identifies a greater number of BMT patients with subclinical LV dysfunction rather than by GLS alone, and should be evaluated as part of post-BMT patient surveillence. Reduction in GCS is possibly due to effects of preconditioning, and is not fully explained by AC exposure.

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

Heart: 30 Mar 2022; 108:550-557
Deshmukh T, Emerson P, Geenty P, Mahendran S, ... Gottlieb D, Thomas L
Heart: 30 Mar 2022; 108:550-557 | PMID: 34301770
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Impact:
Abstract

Left Ventricular Thrombus Following Acute Myocardial Infarction: JACC State-of-the-Art Review.

Camaj A, Fuster V, Giustino G, Bienstock SW, ... Dweck MR, Goldman ME
The incidence of left ventricular (LV) thrombus following acute myocardial infarction has markedly declined in recent decades caused by advancements in reperfusion and antithrombotic therapies. Despite this, embolic events remain the most feared complication of LV thrombus necessitating systemic anticoagulation. Mechanistically, LV thrombus development depends on Virchow\'s triad (ie, endothelial injury from myocardial infarction, blood stasis from LV dysfunction, and hypercoagulability triggered by inflammation, with each of these elements representing potential therapeutic targets). Diagnostic modalities include transthoracic echocardiography with or without ultrasound-enhancing agents and cardiac magnetic resonance. Most LV thrombi develop within the first 2 weeks post-acute myocardial infarction, and the role of surveillance imaging appears limited. Vitamin K antagonists remain the mainstay of therapy because the efficacy of direct oral anticoagulants is less well established. Only meager data support the routine use of prophylactic anticoagulation, even in high-risk patients.

Copyright © 2022. Published by Elsevier Inc.

J Am Coll Cardiol: 14 Mar 2022; 79:1010-1022
Camaj A, Fuster V, Giustino G, Bienstock SW, ... Dweck MR, Goldman ME
J Am Coll Cardiol: 14 Mar 2022; 79:1010-1022 | PMID: 35272796
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Abstract

Restoring Sinus Rhythm Reverses Cardiac Remodeling and Reduces Valvular Regurgitation in Patients With Atrial Fibrillation.

Soulat-Dufour L, Lang S, Addetia K, Ederhy S, ... Lang RM, Cohen A
Background
Cardiac chamber remodeling in atrial fibrillation (AF) reflects the progression of cardiac rhythm and may affect functional regurgitation.
Objectives
The purpose of this study was to explore the 3-dimensional echocardiographic variables of cardiac cavity remodeling and the impact on functional regurgitation in patients with AF with/without sinus rhythm restoration at 12 months.
Methods
A total of 117 consecutive patients hospitalized for AF were examined using serial 3-dimensional transthoracic echocardiography at admission, at 6 months, and at 12 months (337 examinations).
Results
During follow-up, 47 patients with active restoration of sinus rhythm (SR) (through cardioversion and/or ablation) had a decrease in all atrial indexed volumes (Vi), end-systolic (ES) right ventricular (RV) Vi, an increase in end-diastolic (ED) left ventricular Vi, and an improvement in 4-chambers function (P < 0.05). Patients with absence/failure of restoration of SR (n = 39) had an increase in ED left atrial Vi and ED/ES RV Vi without modification of 4-chambers function, except for a decrease in left atrial emptying fraction (P < 0.05). Patients with spontaneous restoration of SR (n = 31) had no changes in Vi or function. The authors found an improvement vs baseline in severity of functional regurgitation in patients with active restoration of SR (tricuspid and mitral regurgitation) and in spontaneous restoration of SR (tricuspid regurgitation) (P < 0.05). In multivariable analysis, right atrial and/or left atrial reverse remodeling exclusively correlated with intervention (cardioversion and/or ablation) during 12-month follow-up.
Conclusions
Management of AF should focus on restoration of SR to induce anatomical (all atrial Vi, ES RV Vi) and/or functional (4 chambers) cardiac cavity reverse remodeling and reduce severity of functional regurgitation. (Thromboembolic and Bleeding Risk Stratification in Patients With Non-valvular Atrial Fibrillation [FASTRHAC]; NCT02741349).

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

J Am Coll Cardiol: 14 Mar 2022; 79:951-961
Soulat-Dufour L, Lang S, Addetia K, Ederhy S, ... Lang RM, Cohen A
J Am Coll Cardiol: 14 Mar 2022; 79:951-961 | PMID: 35272799
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Abstract

Trends in the pharmacological management of atrial fibrillation in UK general practice 2008-2018.

Phillips K, Subramanian A, Thomas GN, Khan N, ... Fabritz L, Adderley NJ
Objective
The pharmacological management of atrial fibrillation (AF) comprises anticoagulation, for stroke prophylaxis, and rate or rhythm control drugs to alleviate symptoms and prevent heart failure. The aim of this study was to investigate trends in the proportion of patients with AF prescribed pharmacological therapies in the UK between 2008 and 2018.
Methods
Eleven sequential cross-sectional analyses were performed yearly from 2008 to 2018. Data were derived from an anonymised UK primary care database. Outcomes were the proportion of patients with AF prescribed anticoagulants, rhythm and rate control drugs in the whole cohort, those at high risk of stroke and those with coexisting heart failure.
Results
Between 2008 and 2018, the proportion of patients prescribed anticoagulants increased from 45.3% (95% CI 45.0% to 45.7%) to 71.1% (95% CI 70.7% to 71.5%) driven by increased prescription of non-vitamin K antagonist anticoagulants. The proportion of patients prescribed rate control drugs remained constant between 2008 and 2018 (69.3% (95% CI 68.9% to 69.6%) to 71.6% (95% CI 71.2% to 71.9%)). The proportion of patients prescribed rhythm control therapy by general practitioners (GPs) decreased from 9.5% (95% CI 9.3% to 9.7%) to 5.4% (95% CI 5.2% to 5.6%).
Conclusions
There has been an increase in the proportion of patients with AF appropriately prescribed anticoagulants following National Institute for Health and Care Excellence and European Society of Cardiology guidelines, which correlates with improvements in mortality and stroke outcomes. Beta-blockers appear increasingly favoured over digoxin for rate control. There has been a steady decline in GP prescribing rates for rhythm control drugs, possibly related to concerns over efficacy and safety and increased availability of AF ablation.

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

Heart: 30 Mar 2022; 108:517-522
Phillips K, Subramanian A, Thomas GN, Khan N, ... Fabritz L, Adderley NJ
Heart: 30 Mar 2022; 108:517-522 | PMID: 34226195
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Abstract

Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020.

Wall SM
Intercalated cells make up about a third of all cells within the connecting tubule and the collecting duct and are subclassified as type A, type B and non-A, non-B based on the subcellular distribution of the H+-ATPase, which dictates whether it secretes H+ or HCO3-. Type B intercalated cells mediate Cl- absorption and HCO3- secretion, which occurs largely through the anion exchanger pendrin. Pendrin is stimulated by angiotensin II via the angiotensin type 1a receptor and by aldosterone through MR (mineralocorticoid receptor). Aldosterone stimulates pendrin expression and function, in part, through the alkalosis it generates. Pendrin-mediated HCO3- secretion increases in models of metabolic alkalosis, which attenuates the alkalosis. However, pendrin-positive intercalated cells also regulate blood pressure, at least partly, through pendrin-mediated Cl- absorption and through their indirect effect on the epithelial Na+ channel, ENaC. This aldosterone-induced increase in pendrin secondarily stimulates ENaC, thereby contributing to the aldosterone pressor response. This review describes the contribution of pendrin-positive intercalated cells to Na+, K+, Cl- and acid-base balance.



Hypertension: 30 Mar 2022; 79:706-716
Wall SM
Hypertension: 30 Mar 2022; 79:706-716 | PMID: 35109661
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Abstract

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.

Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J
Aims
Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.
Methods and results
Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.
Conclusion
We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.
Key question
Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Whether circadian nuclear receptor Rev-erba is present in platelets and regulates platelet function remains unknown.
Key finding
We provide the first evidence that Rev-erba is functionally expressed in platelets and acts as a positive regulator of platelet activation/thrombus formation through the oligophrenin-1-mediated RhoA/ERM signalling pathway.
Take home message
Our observations highlight the importance of circadian clock machinery in platelet physiology and support the notion that Rev-erba may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 09 Mar 2022; epub ahead of print
Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J
Eur Heart J: 09 Mar 2022; epub ahead of print | PMID: 35267019
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Abstract

Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study.

Komen JJ, Pottegård A, Mantel-Teeuwisse AK, Forslund T, ... Kjerpeseth LJ, Klungel OH
Aims
There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant.
Methods and results
We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94).
Conclusion
These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial.
Key question
What is the association between anticoagulant treatment and stroke and bleeding rate, in patients with one non-sex-related risk factor for stroke?
Key findings

Take-home message
These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a hypothesis that can be tested through a randomized controlled trial.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 09 Mar 2022; epub ahead of print
Komen JJ, Pottegård A, Mantel-Teeuwisse AK, Forslund T, ... Kjerpeseth LJ, Klungel OH
Eur Heart J: 09 Mar 2022; epub ahead of print | PMID: 35265981
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Abstract

CT or Invasive Coronary Angiography in Stable Chest Pain.

Maurovich-Horvat P, Bosserdt M, Kofoed KF, Rieckmann N, ... Martus P, Dewey M
Background
In the diagnosis of obstructive coronary artery disease (CAD), computed tomography (CT) is an accurate, noninvasive alternative to invasive coronary angiography (ICA). However, the comparative effectiveness of CT and ICA in the management of CAD to reduce the frequency of major adverse cardiovascular events is uncertain.
Methods
We conducted a pragmatic, randomized trial comparing CT with ICA as initial diagnostic imaging strategies for guiding the treatment of patients with stable chest pain who had an intermediate pretest probability of obstructive CAD and were referred for ICA at one of 26 European centers. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. Key secondary outcomes were procedure-related complications and angina pectoris.
Results
Among 3561 patients (56.2% of whom were women), follow-up was complete for 3523 (98.9%). Major adverse cardiovascular events occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 (3.0%) in the ICA group (hazard ratio, 0.70; 95% confidence interval [CI], 0.46 to 1.07; P = 0.10). Major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13 to 0.55). Angina during the final 4 weeks of follow-up was reported in 8.8% of the patients in the CT group and in 7.5% of those in the ICA group (odds ratio, 1.17; 95% CI, 0.92 to 1.48).
Conclusions
Among patients referred for ICA because of stable chest pain and intermediate pretest probability of CAD, the risk of major adverse cardiovascular events was similar in the CT group and the ICA group. The frequency of major procedure-related complications was lower with an initial CT strategy. (Funded by the European Union Seventh Framework Program and others; DISCHARGE ClinicalTrials.gov number, NCT02400229.).

Copyright © 2022 Massachusetts Medical Society.

N Engl J Med: 03 Mar 2022; epub ahead of print
Maurovich-Horvat P, Bosserdt M, Kofoed KF, Rieckmann N, ... Martus P, Dewey M
N Engl J Med: 03 Mar 2022; epub ahead of print | PMID: 35240010
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Abstract

Early invasive versus non-invasive assessment in patients with suspected non-ST-elevation acute coronary syndrome.

Kite TA, Ladwiniec A, Arnold JR, McCann GP, Moss AJ
Non-ST-elevation acute coronary syndrome (NSTE-ACS) comprises a broad spectrum of disease ranging from unstable angina to myocardial infarction. International guidelines recommend a routine invasive strategy for managing patients with NSTE-ACS at high to very high-risk, supported by evidence of improved composite ischaemic outcomes as compared with a selective invasive strategy. However, accurate diagnosis of NSTE-ACS in the acute setting is challenging due to the spectrum of non-coronary disease that can manifest with similar symptoms. Heterogeneous clinical presentations and limited uptake of risk prediction tools can confound physician decision-making regarding the use and timing of invasive coronary angiography (ICA). Large proportions of patients with suspected NSTE-ACS do not require revascularisation but may unnecessarily undergo ICA with its attendant risks and associated costs. Advances in coronary CT angiography and cardiac MRI have prompted evaluation of whether non-invasive strategies may improve patient selection, or whether tailored approaches are better suited to specific subgroups. Future directions include (1) better understanding of risk stratification as a guide to investigation and therapy in suspected NSTE-ACS, (2) randomised clinical trials of non-invasive imaging versus standard of care approaches prior to ICA and (3) defining the optimal timing of very early ICA in high-risk NSTE-ACS.

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

Heart: 30 Mar 2022; 108:500-506
Kite TA, Ladwiniec A, Arnold JR, McCann GP, Moss AJ
Heart: 30 Mar 2022; 108:500-506 | PMID: 34234006
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Abstract

Coronary revascularisation outcomes in patients with cancer.

Leedy D, Tiwana JK, Mamas M, Hira R, Cheng R
Cancer and coronary artery disease (CAD) overlap in traditional risk factors as well as molecular mechanisms underpinning the development of these two disease states. Patients with cancer are at increased risk of developing CAD, representing a high-risk population that are increasingly undergoing coronary revascularisation. Over 1 in 10 patients with CAD that require revascularisation with either percutaneous coronary intervention or coronary artery bypass grafting have either a history of cancer or active cancer. These patients are typically older, have more comorbidities and have more extensive CAD compared with patients without cancer. Haematological abnormalities with competing risks of thrombosis and bleeding pose further unique challenges during and after revascularisation. Management of patients with concurrent cancer and CAD requiring revascularisation is challenging as these patients carry a higher risk of morbidity and mortality compared with those without cancer, often driven by the underlying cancer and associated comorbidities. However, due to variability by different types and stages of cancer, revascularisation outcomes are specific to cancer characteristics such as the timing of onset, cancer subtype and site, stage, presence of metastases, and cancer-related therapies received. Recent studies have provided insights into defining revascularisation outcomes, procedural considerations and best practices in managing patients with cancer. Nevertheless, many gaps remain that require further studies to inform clinical best practices in this population.

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

Heart: 30 Mar 2022; 108:507-516
Leedy D, Tiwana JK, Mamas M, Hira R, Cheng R
Heart: 30 Mar 2022; 108:507-516 | PMID: 34415850
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Abstract

Variability in Coronary Artery Disease Testing for Patients With New-Onset Heart Failure.

Zheng J, Heidenreich PA, Kohsaka S, Fearon WF, Sandhu AT
Background
Coronary artery disease (CAD) is the most common cause of new-onset heart failure (HF). Although guidelines recommend ischemic evaluation in this population, testing has historically been underutilized.
Objectives
This study aimed to identify contemporary trends in CAD testing for patients with new-onset HF, particularly after publication of the STICHES (Surgical Treatment for Ischemic Heart Failure Extension Study), and to characterize geographic and clinician-level variability in testing patterns.
Methods
We determined the proportion of patients with incident HF who received CAD testing from 2004 to 2019 using an administrative claims database covering commercial insurance and Medicare. We identified demographic and clinical predictors of CAD testing during the 90 days before and after initial diagnosis. Patients were grouped by their county of residence to assess national variation. Patients were then linked to their primary care physician and/or cardiologist to evaluate variation across clinicians.
Results
Among 558,322 patients with new-onset HF, 34.8% underwent CAD testing and 9.3% underwent revascularization. After multivariable adjustment, patients who underwent CAD testing were more likely to be younger, male, diagnosed in an acute care setting, and have systolic dysfunction or recent cardiogenic shock. Incidence of CAD testing remained flat without significant change post-STICHES. Covariate-adjusted testing rates varied from 20% to 45% across counties. The likelihood of testing was higher among patients co-managed by a cardiologist (adjusted OR: 5.12; 95% CI: 4.98-5.27) but varied substantially across cardiologists (IQR: 50.9%-62.4%).
Conclusions
Most patients with new-onset HF across inpatient and outpatient settings did not receive timely testing for CAD. Substantial variability in testing persists across regions and clinicians.

Copyright © 2022 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 07 Mar 2022; 79:849-860
Zheng J, Heidenreich PA, Kohsaka S, Fearon WF, Sandhu AT
J Am Coll Cardiol: 07 Mar 2022; 79:849-860 | PMID: 35241218
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Abstract

Reference values of left and right atrial volumes and phasic function based on a large sample of healthy Chinese adults: A cardiovascular magnetic resonance study.

Gao Y, Zhang Z, Zhou S, Li G, ... Li K, Pohost GM
Background
The left and right atrial (LA and RA) size and function are tightly linked to the morbidity and mortality of multiple cardiovascular diseases. We aimed to establish cardiovascular magnetic resonance (CMR) reference values for LA and RA volumes and phasic function based on a large sample of healthy Chinese adults.
Methods
408 validated healthy Chinese adults (54% men; aged 21-70 years) were included. LA and RA maximum, minimum, and pre-atrial contraction volumes (Vmax, Vmin, and Vpac); total, passive, and booster emptying fractions (EF total, EF passive, and EF booster); and total, passive, and active emptying volumes (TEV, PEV, and AEV) were measured on cine CMR. Normal reference values were calculated and were stratified by sex and age decades.
Results
Men demonstrated greater LAVmax, LAVmin, LAVpac, LAPEV, RAVmax, RAVmin, RAVpac, RATEV, and RAAEV, while women had higher LAEF total, LAEF booster, RAEF total, RAEF passive, and RAEF booster (all p < 0.05). Age was positively correlated with LAVpac and RAVpac in both sexes but was positively correlated with LAVmax, LAVmin, RAVmax, and RAVmin only in women (all p < 0.05). For both sexes, aging was associated with decreased LAEF total, LAEF passive, RAEF total, and RAEF passive, but increased LAEF booster (all p < 0.05).
Conclusion
We systematically provide age- and sex-specific CMR reference values for LA and RA volumes and phasic function based on a large sample of healthy Chinese adults with a wide age range. Both age and sex are closely associated with biatrial volumes and function.

Copyright © 2022 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Mar 2022; 352:180-187
Gao Y, Zhang Z, Zhou S, Li G, ... Li K, Pohost GM
Int J Cardiol: 31 Mar 2022; 352:180-187 | PMID: 35124105
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Abstract

Clinical Outcomes in Patients With Delayed Hospitalization for Non-ST-Segment Elevation Myocardial Infarction.

Cha JJ, Bae S, Park DW, Park JH, ... Jeong MH, Ahn TH
Background
Recently, the number of patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) has reduced, whereas increased mortality was reported. A plausible explanation for increased mortality was prehospital delay because of patients\' reticence of their symptoms.
Objectives
The purpose of this study was to investigate the association between prehospital delay and clinical outcomes in patients with NSTEMI
Methods:
Among 13,104 patients from the Korea-Acute-Myocardial-Infarction-Registry-National Institutes of Health, the authors evaluated 6,544 patients with NSTEMI. Study patients were categorized into 2 groups according to symptom-to-door (StD) time (<24 or ≥24 hours). The primary outcome was 3-year all-cause mortality, and the secondary outcome was 3-year composite of all-cause mortality, recurrent MI, and hospitalization for heart failure.
Results
Overall, 1,827 (27.9%) patients were classified into the StD time ≥24 hours group. The StD time ≥24 hours group had higher all-cause mortality (17.0% vs 10.5%; P < 0.001) and incidence of secondary outcomes (23.3% vs 15.7%; P < 0.001) than the StD time <24 hours group. The higher all-cause mortality in the StD time ≥24 hours group was observed consistently in the subgroup analysis regarding age, sex, atypical chest pain, dyspnea, Q-wave in electrocardiogram, use of emergency medical services, hypertension, diabetes mellitus, chronic kidney disease, left ventricle dysfunction, TIMI (Thrombolysis In Myocardial Infarction) flow, and the GRACE risk score. In the multivariable analysis, independent predictors of prehospital delay were the elderly, women, nonspecific symptoms such as atypical chest pain or dyspnea, diabetes, and no use of emergency medical services.
Conclusions
Prehospital delay is associated with an increased risk of 3-year all-cause mortality in patients with NSTEMI. (iCReaT Study No. C110016).

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

J Am Coll Cardiol: 28 Feb 2022; 79:311-323
Cha JJ, Bae S, Park DW, Park JH, ... Jeong MH, Ahn TH
J Am Coll Cardiol: 28 Feb 2022; 79:311-323 | PMID: 35086652
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Abstract

Race- and Gender-Based Differences in Cardiac Structure and Function and Risk of Heart Failure.

Chandra A, Skali H, Claggett B, Solomon SD, ... Chang PP, Shah AM
Background
Although heart failure (HF) risk and cardiac structure/function reportedly differ according to race and gender, limited data exist in late life when risk of HF is highest.
Objectives
The goal of this study was to evaluate race/gender-based differences in HF risk factors, cardiac structure/function, and incident HF in late life.
Methods
This analysis included 5,149 HF-free participants from ARIC (Atherosclerosis Risk In Communities), a prospective epidemiologic cohort study, who attended visit 5 (2011-2013) and underwent echocardiography. Participants were subsequently followed up for a median 5.5 years for incident HF/death.
Results
Patients\' mean age was 75 ± 5 years, 59% were women, and 20% were Black. Male gender and Black race were associated with lower mean left ventricular ejection fraction. Black race was also associated with greater left ventricular wall thickness and concentricity, differences that persisted after adjusting for cardiovascular comorbidities. After adjusting for cardiovascular comorbidities, men were at higher risk for HF and heart failure with reduced ejection fraction (HFrEF) in Black participants compared with White participants (HF: HR of 2.36 [95% CI: 1.37-4.08] vs 1.16 [95% CI: 0.89-1.51], interaction P = 0.016; HFrEF: HR of 3.70 [95% CI: 1.72-7.95] vs 1.55 [95% CI: 1.01-2.37] respectively, interaction P = 0.039). Black race was associated with a higher incidence of HF overall and HFrEF in men only (HF: 1.65 [95% CI: 1.07-2.53] vs 0.76 [95% CI: 0.49-1.17]; HFrEF: HR of 2.55 [95% CI: 1.46-4.44] vs 0.91 [95% CI: 0.46-1.83]). No race/gender-based differences were observed in risk of incident heart failure with preserved ejection fraction.
Conclusions
Among older persons free of HF, men and Black participants exhibit worse systolic performance and are at heightened risk for HFrEF, whereas the risk of heart failure with preserved ejection fraction is similar across gender and race groups.

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

J Am Coll Cardiol: 28 Feb 2022; 79:355-368
Chandra A, Skali H, Claggett B, Solomon SD, ... Chang PP, Shah AM
J Am Coll Cardiol: 28 Feb 2022; 79:355-368 | PMID: 35086658
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Impact:
Abstract

Criteria for Iron Deficiency in Patients With Heart Failure.

Masini G, Graham FJ, Pellicori P, Cleland JGF, ... Inciardi RM, Clark AL
Background
Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder interpretation of serum ferritin.
Objectives
This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF.
Methods
Prevalence, relationship with patients\' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019.
Results
Of 4,422 patients with HF (median age 75 years [range: 68-82 years], 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 μmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 μmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09).
Conclusions
Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 28 Feb 2022; 79:341-351
Masini G, Graham FJ, Pellicori P, Cleland JGF, ... Inciardi RM, Clark AL
J Am Coll Cardiol: 28 Feb 2022; 79:341-351 | PMID: 35086656
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Abstract

Relation of Cardiorenal Syndrome to Mitral and Tricuspid Regurgitation in Acute Decompensated Heart Failure.

Seghatol FF, Martin KD, Haj-Asaad A, Xie M, Prabhu SD
This study aimed to investigate the role of secondary mitral regurgitation (MR) and tricuspid regurgitation (TR) in the pathogenesis of cardiorenal syndrome (CRS). Worsening renal function in patients with acute decompensated heart failure receiving diuretic therapy is defined as CRS and is related to central venous congestion. The role of secondary MR and TR is not well studied. We retrospectively reviewed the electronic medical records of 80 consecutive patients hospitalized with acute decompensated heart failure. Patients were divided into 2 groups: group 1 (CRS) if creatinine increased >0.3 mg/dl from baseline and group 2 (no CRS) if creatinine remained stable or improved with diuretic therapy. Admission creatinine was higher in group 1 compared with group 2 (1.5 vs 1.2 mg/dl, p = 0.033). The magnitude of MR and TR were higher by both visual assessment (moderate to severe [3+] or severe [4+] MR in 68% of patients in group 1 vs 3% in group 2, p <0.0001; 3+ or 4+ TR in 48% of patients in group 1 vs 10% in group 2, p = 0.0004) and by vena contracta (MR 0.6 ± 0.2 cm in group 1 vs 0.4 ± 0.1 cm in group 2, p <0.0001; TR 0.5 ± 0.2 cm in group 1 vs 0.4 ± 0.2 cm in group 2, p = 0.0013). By using receiver operating characteristic curves, MR and TR were the most sensitive parameters in predicting CRS. In conclusion, renal function on admission and moderate to severe or severe MR and TR are highly predictive of the risk of developing CRS.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Mar 2022; 168:99-104
Seghatol FF, Martin KD, Haj-Asaad A, Xie M, Prabhu SD
Am J Cardiol: 31 Mar 2022; 168:99-104 | PMID: 35045927
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Abstract

CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells.

Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Background
Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2+ monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation.
Methods
We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects.
Results
We demonstrated that CCL17 is expressed in CCR2+ macrophages and cluster of differentiation 11b+ conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17+ macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling.
Conclusions
These findings identify CCL17 as a proinflammatory mediator of CCR2+ macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.



Circulation: 07 Mar 2022; 145:765-782
Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Circulation: 07 Mar 2022; 145:765-782 | PMID: 35113652
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Abstract

Improved Outcomes Following the Ross Procedure Compared With Bioprosthetic Aortic Valve Replacement.

Mazine A, David TE, Stoklosa K, Chung J, Lafreniere-Roula M, Ouzounian M
Background
The ideal aortic valve substitute for young and middle-aged adults remains elusive.
Objectives
This study sought to compare the long-term outcomes of patients undergoing the Ross procedure and those receiving bioprosthetic aortic valve replacements (AVRs).
Methods
Consecutive patients aged 16-60 years who underwent a Ross procedure or surgical bioprosthetic AVR at the Toronto General Hospital between 1990 and 2014 were identified. Propensity score matching was used to account for differences in baseline characteristics. The primary outcome was all-cause mortality. Secondary outcomes included valve reintervention, valve deterioration, endocarditis, thromboembolic events, and permanent pacemaker implantation.
Results
Propensity score matching yielded 108 pairs of patients. The median age was 41 years (IQR: 34-47 years). Baseline characteristics were similar between the matched groups. There was no operative mortality in either group. Mean follow-up was 14.5 ± 7.2 years. All-cause mortality was lower following the Ross procedure (HR: 0.35; 95% CI: 0.14-0.90; P = 0.028). Using death as a competing risk, the Ross procedure was associated with lower rates of reintervention (HR: 0.21; 95% CI: 0.10-0.41; P < 0.001), valve deterioration (HR: 0.25; 95% CI: 0.14-0.45; P < 0.001), thromboembolic events (HR: 0.15; 95% CI: 0.05-0.50; P = 0.002), and permanent pacemaker implantation (HR: 0.22; 95% CI: 0.07-0.64; P = 0.006).
Conclusions
In this propensity-matched study, the Ross procedure was associated with better long-term survival and freedom from adverse valve-related events compared with bioprosthetic AVR. In specialized centers with sufficient expertise, the Ross procedure should be considered the primary option for young and middle-aged adults undergoing AVR.

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

J Am Coll Cardiol: 14 Mar 2022; 79:993-1005
Mazine A, David TE, Stoklosa K, Chung J, Lafreniere-Roula M, Ouzounian M
J Am Coll Cardiol: 14 Mar 2022; 79:993-1005 | PMID: 35272805
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Impact:
Abstract

Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics.

Swerdlow DI, Rider DA, Yavari A, Wikström Lindholm M, Campion GV, Nissen SE
Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining \'high risk\' is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.

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

Cardiovasc Res: 25 Mar 2022; 118:1218-1231
Swerdlow DI, Rider DA, Yavari A, Wikström Lindholm M, Campion GV, Nissen SE
Cardiovasc Res: 25 Mar 2022; 118:1218-1231 | PMID: 33769464
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Abstract

Myocardial Fibrosis Predicts Ventricular Arrhythmias and Sudden Death After Cardiac Electronic Device Implantation.

Leyva F, Zegard A, Okafor O, Foley P, ... Prasad SK, Qiu T
Background
Increasing evidence supports a link between myocardial fibrosis (MF) and ventricular arrhythmias.
Objectives
The purpose of this study was to determine whether presence of myocardial fibrosis on visual assessment (MFVA) and gray zone fibrosis (GZF) mass predicts sudden cardiac death (SCD) and ventricular fibrillation/sustained ventricular tachycardia after cardiac implantable electronic device (CIED) implantation.
Methods
In this prospective study, total fibrosis and GZF mass, quantified using cardiovascular magnetic resonance, was assessed in relation to the primary endpoint of SCD and the secondary, arrhythmic endpoint of SCD or ventricular arrhythmias after CIED implantation.
Results
Among 700 patients (age 68.0 ± 12.0 years), 27 (3.85%) experienced a SCD and 121 (17.3%) met the arrhythmic endpoint over median 6.93 years (IQR: 5.82-9.32 years). MFVA predicted SCD (HR: 26.3; 95% CI: 3.7-3,337; negative predictive value: 100%). In competing risk analyses, MFVA also predicted the arrhythmic endpoint (subdistribution HR: 19.9; 95% CI: 6.4-61.9; negative predictive value: 98.6%). Compared with no MFVA, a GZF mass measured with the 5SD method (GZF5SD) >17 g was associated with highest risk of SCD (HR: 44.6; 95% CI: 6.12-5,685) and the arrhythmic endpoint (subdistribution HR: 30.3; 95% CI: 9.6-95.8). Adding GZF5SD mass to MFVA led to reclassification of 39% for SCD and 50.2% for the arrhythmic endpoint. In contrast, LVEF did not predict either endpoint.
Conclusions
In CIED recipients, MFVA excluded patients at risk of SCD and virtually excluded ventricular arrhythmias. Quantified GZF5SD mass added predictive value in relation to SCD and the arrhythmic endpoint.

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

J Am Coll Cardiol: 21 Feb 2022; 79:665-678
Leyva F, Zegard A, Okafor O, Foley P, ... Prasad SK, Qiu T
J Am Coll Cardiol: 21 Feb 2022; 79:665-678 | PMID: 35177196
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Abstract

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications.

Greenberg HZE, Zhao G, Shah AM, Zhang M
Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

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

Cardiovasc Res: 06 May 2022; 118:1433-1451
Greenberg HZE, Zhao G, Shah AM, Zhang M
Cardiovasc Res: 06 May 2022; 118:1433-1451 | PMID: 33881501
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Abstract

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

Zhuang L, Jia K, Chen C, Li Z, ... Chen K, Yan X
Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Since kinases have been reported to modulate mitochondrial function, we investigated the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure.
Methods:
We engineered DYRK1B transgenic and knock out mice and used transverse aortic constriction (TAC) to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis and mitochondrial functional analysis.
Results:
We found that DYRK1B expression was clearly upregulated in failing human myocardium as well as in hypertrophic murine hearts. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated TAC-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α. Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.




Circulation: 01 Mar 2022; epub ahead of print
Zhuang L, Jia K, Chen C, Li Z, ... Chen K, Yan X
Circulation: 01 Mar 2022; epub ahead of print | PMID: 35235343
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Abstract

Autonomic Neuromodulation for Atrial Fibrillation Following Cardiac Surgery: JACC Review Topic of the Week.

Zafeiropoulos S, Doundoulakis I, Farmakis IT, Miyara S, ... Stavrakis S, Zanos S
Autonomic neuromodulation therapies (ANMTs) (ie, ganglionated plexus ablation, epicardial injections for temporary neurotoxicity, low-level vagus nerve stimulation [LL-VNS], stellate ganglion block, baroreceptor stimulation, spinal cord stimulation, and renal nerve denervation) constitute an emerging therapeutic approach for arrhythmias. Very little is known about ANMTs\' preventive potential for postoperative atrial fibrillation (POAF) after cardiac surgery. The purpose of this review is to summarize and critically appraise the currently available evidence. Herein, the authors conducted a systematic review of 922 articles that yielded 7 randomized controlled trials. In the meta-analysis, ANMTs reduced POAF incidence (OR: 0.37; 95% CI: 0.25 to 0.55) and burden (mean difference [MD]: -3.51 hours; 95% CI: -6.64 to -0.38 hours), length of stay (MD: -0.82 days; 95% CI: -1.59 to -0.04 days), and interleukin-6 (MD: -79.92 pg/mL; 95% CI: -151.12 to -8.33 pg/mL), mainly attributed to LL-VNS and epicardial injections. Moving forward, these findings establish a base for future larger and comparative trials with ANMTs, to optimize and expand their use.

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

J Am Coll Cardiol: 21 Feb 2022; 79:682-694
Zafeiropoulos S, Doundoulakis I, Farmakis IT, Miyara S, ... Stavrakis S, Zanos S
J Am Coll Cardiol: 21 Feb 2022; 79:682-694 | PMID: 35177198
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Abstract

The role of phosphorylation in atrial fibrillation: a focus on mass spectrometry approaches.

Safabakhsh S, Panwar P, Barichello S, Sangha SS, ... Petegem FV, Laksman Z
Atrial fibrillation (AF) is the most common arrhythmia worldwide. It is associated with significant increases in morbidity in the form of stroke and heart failure, and a doubling in all-cause mortality. The pathophysiology of AF is incompletely understood, and this has contributed to a lack of effective treatments and disease-modifying therapies. An important cellular process that may explain how risk factors give rise to AF includes post-translational modification of proteins. As the most commonly occurring post-translational modification, protein phosphorylation is especially relevant. Although many methods exist for studying protein phosphorylation, a common and highly resolute technique is mass spectrometry (MS). This review will discuss recent evidence surrounding the role of protein phosphorylation in the pathogenesis of AF. MS-based technology to study phosphorylation and uses of MS in other areas of medicine such as oncology will also be presented. Based on these data, future goals and experiments will be outlined that utilize MS technology to better understand the role of phosphorylation in AF and elucidate its role in AF pathophysiology. This may ultimately allow for the development of more effective AF therapies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 25 Mar 2022; 118:1205-1217
Safabakhsh S, Panwar P, Barichello S, Sangha SS, ... Petegem FV, Laksman Z
Cardiovasc Res: 25 Mar 2022; 118:1205-1217 | PMID: 33744917
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Abstract

Prognostic Relevance of Thyroid Disorders in Adults With Congenital Heart Disease.

Fusco F, Scognamiglio G, Guarguagli S, Merola A, ... Romeo E, Sarubbi B
Adults with congenital heart disease (ACHD) are frequently affected by thyroid diseases (TDs). However, the clinical relevance of TD in ACHD remains unknown. We aimed to describe the prevalence of TD in the ACHD population and to ascertain whether TD are associated with worse outcome. Patients with ACHD >18 years attending our tertiary center for a day-case between 2014 and 2019 were included. Clinical data between patients\' first visit and December 2020 were collected. Primary end point was a combination of death, hospitalization for heart failure (HF), and new-onset of arrhythmic events. Secondary end points were each part of the primary outcome as separate end points. A total of 495 patients with ACHD (32.2 [24.5 to 45.6] years; 54% women) were included. Median follow-up was 9.4 (4.5 to 13.1) years. The prevalence of TD was 30%. TD group showed worse clinical status, as demonstrated by N-terminal pro b-type natriuretic peptide values (243.5 [96.5 to 523] vs 94 [45 to 207] pg/ml, p <0.001) and New York Heart Association class (27% vs 13% in class III to IV, p <0.0001) with higher incident rate of adverse events at follow-up (4.45 [3.43 to 5.69] % vs 1.29[0.94 to 1.75] % per person-year, p <0.001). TD were independently associated with higher risk of death (hazard ratio [HR] 4.1, p = 0.009), arrhythmic events (HR 3.8, p <0.0001), and hospitalization for HF (HR 8.02, p <0.0001). There was a fourfold increased risk of primary end point in the TD group even after propensity score matching for clinical variables including age, gender, disease complexity, physiological stage, previous palliative surgery, ventricular function, pulmonary arterial hypertension, cyanosis, and presence of systemic right ventricle (HR 4.47, p <0.0001). In conclusion, TD are predictive of adverse outcome in the ACHD population. Routine screening of thyroid function during follow-up in this population may be helpful to identify those with higher risk of death, arrhythmias, and HF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 28 Feb 2022; 166:107-113
Fusco F, Scognamiglio G, Guarguagli S, Merola A, ... Romeo E, Sarubbi B
Am J Cardiol: 28 Feb 2022; 166:107-113 | PMID: 34930612
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Abstract

Fetal Brain Volume Predicts Neurodevelopment in Congenital Heart Disease.

Sadhwani A, Wypij D, Rofeberg V, Gholipour A, ... Ortinau CM, Rollins CK
Background: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD.
Methods:
Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain MRI and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development (Bayley-III) and the Adaptive Behavior Assessment System (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth parameters, and medical history.
Results:
The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores, and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but not in the control group. Fetal brain volume predicted 10 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18-45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains. Conclusions: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.




Circulation: 09 Feb 2022; epub ahead of print
Sadhwani A, Wypij D, Rofeberg V, Gholipour A, ... Ortinau CM, Rollins CK
Circulation: 09 Feb 2022; epub ahead of print | PMID: 35143287
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Abstract

Abnormal Extracardiac Development in Fetuses With Congenital Heart Disease.

Dovjak GO, Zalewski T, Seidl-Mlczoch E, Ulm PA, ... Kasprian GJ, Ulm B
Background
Knowledge about extracardiac anomalies (ECA) in fetal congenital heart disease (CHD) can improve our understanding of the developmental origins of various outcomes in these infants. The prevalence and spectrum of ECA, including structural brain anomalies (SBA), on magnetic resonance imaging (MRI) in fetuses with different types of CHD and at different gestational ages, is unknown.
Objectives
The purpose of this study was to evaluate ECA rates and types on MRI in fetuses with different types of CHD and across gestation.
Methods
A total of 429 consecutive fetuses with CHD and MRI between 17 and 38 gestational weeks were evaluated. ECA and SBA rates were assessed for each type of CHD and classified by gestational age (<25 or ≥25 weeks) at MRI.
Results
Of all 429 fetuses with CHD, 243 (56.6%) had ECA on MRI, and 109 (25.4%) had SBA. Among the 191 fetuses with normal genetic testing results, the ECA rate was 54.5% and the SBA rate 19.4%. Besides SBA, extrafetal (21.2%) and urogenital anomalies (10.7%) were the most prevalent ECA on MRI in all types of CHD. Predominant SBA were anomalies of hindbrain-midbrain (11.0% of all CHD), dorsal prosencephalon (10.0%) development, and abnormal cerebrospinal fluid spaces (10.5%). There was no difference in the prevalence or pattern of ECA between early (<25 weeks; 45.7%) and late (≥25 weeks; 54.3%) fetal MRI.
Conclusions
ECA and SBA rates on fetal MRI are high across all types of CHD studied, and ECA as well as SBA are already present from midgestation onward.

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

J Am Coll Cardiol: 06 Dec 2021; 78:2312-2322
Dovjak GO, Zalewski T, Seidl-Mlczoch E, Ulm PA, ... Kasprian GJ, Ulm B
J Am Coll Cardiol: 06 Dec 2021; 78:2312-2322 | PMID: 34857093
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Impact:
Abstract

Is there a benefit of ICD treatment in patients with persistent severely reduced systolic left ventricular function after TAVI?

Nies RJ, Frerker C, Adam M, Kuhn E, ... Baldus S, Schmidt T
Background
In patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) and heart failure with severely reduced ejection fraction, prediction of postprocedural left ventricular ejection fraction (LVEF) improvement is challenging. Decision-making and timing for implantable cardioverter defibrillator (ICD) treatment are difficult and benefit is still unclear in this patient population.
Objective

Aims:
of the study were to analyse long-term overall mortality in TAVI-patients with a preprocedural LVEF ≤ 35% regarding LVEF improvement and effect of ICD therapy.
Methods and results
Retrospective analysis of a high-risk TAVI-population suffering from severe AS and heart failure with a LVEF ≤ 35%. Out of 1485 TAVI-patients treated at this center between January 2013 and April 2018, 120 patients revealed a preprocedural LVEF ≤ 35% and had sufficient follow-up. 36.7% (44/120) of the patients suffered from persistent reduced LVEF without a postprocedural increase above 35% within 1 year after TAVI or before death, respectively. Overall mortality was neither significantly reduced by LVEF recovery above 35% (p = 0.31) nor by additional ICD treatment in patients with persistent LVEF ≤ 35% (p = 0.33).
Conclusion
In high-risk TAVI-patients suffering from heart failure with LVEF ≤ 35%, LVEF improvement to more than 35% did not reduce overall mortality. Patients with postprocedural persistent LVEF reduction did not seem to benefit from ICD treatment. Effects of LVEF improvement and ICD treatment on mortality are masked by the competing risk of death from relevant comorbidities.

© 2021. The Author(s).

Clin Res Cardiol: 01 May 2022; 111:492-501
Nies RJ, Frerker C, Adam M, Kuhn E, ... Baldus S, Schmidt T
Clin Res Cardiol: 01 May 2022; 111:492-501 | PMID: 33758967
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Impact:
Abstract

Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

Glazer AM, Davogustto GE, Shaffer CM, Vanoye CG, ... Roden DM, eMERGE Network
Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability.
Methods:
The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells.
Results:
As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.




Circulation: 20 Dec 2021; epub ahead of print
Glazer AM, Davogustto GE, Shaffer CM, Vanoye CG, ... Roden DM, eMERGE Network
Circulation: 20 Dec 2021; epub ahead of print | PMID: 34930020
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Impact:
Abstract

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Jordan E, Peterson L, Ai T, Asatryan B, ... Ware J, Hershberger RE
Background
Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.
Methods
An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.
Results
Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.
Conclusions
In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.



Circulation: 05 Jul 2021; 144:7-19
Jordan E, Peterson L, Ai T, Asatryan B, ... Ware J, Hershberger RE
Circulation: 05 Jul 2021; 144:7-19 | PMID: 33947203
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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

Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes.

Blue GM, Mekel M, Das D, Troup M, ... Dunwoodie SL, Winlaw DS
Background
The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A \"ciliopathy\" and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects.
Methods
Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.
Results
Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes (P < .001), NDD genes (P < .001) as well as across the three gene panels (P < .001).
Conclusion
We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Am Heart J: 30 Jan 2022; 244:1-13
Blue GM, Mekel M, Das D, Troup M, ... Dunwoodie SL, Winlaw DS
Am Heart J: 30 Jan 2022; 244:1-13 | PMID: 34670123
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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

Defining the importance of stress reduction in managing cardiovascular disease - the role of exercise.

Popovic D, Bjelobrk M, Tesic M, Seman S, ... Arena R, PIVOT Network
Traditional risk factors for cardiovascular disease (CVD) have long been the focus of preventive strategies. The impact of family stress, depression, anxiety, hostility, pessimism, job strain, social isolation, lack of purpose in life and social support, are well recognized risks for CVD development, however they are under-appreciated in clinical practice guidelines. The purpose of this article is to review the impact of acute and chronic stress on CVD risk, elaborate repositioning in guidelines, with emphasis to approaches for stress reduction. Regular exercise, both aerobic and resistance, leads to better adaptiveness to other types of stress, however, it remains unknown whether the total amount of stress one can receive before negative health effects is unlimited. Evidently, marked reductions in stress related disorders are shown following formal cardiac rehabilitation programs. Attendance of cardiac rehabilitation is highly recommended for the stress-related mortality risk reduction. Innovative approaches to offset the broad challenges that CVD pose, augmented by sustained exposure to stress, are desperately needed, but hindered by a lack of successful population-level interventions that promote lasting change.

Copyright © 2021. Published by Elsevier Inc.

Prog Cardiovasc Dis: 03 Feb 2022; epub ahead of print
Popovic D, Bjelobrk M, Tesic M, Seman S, ... Arena R, PIVOT Network
Prog Cardiovasc Dis: 03 Feb 2022; epub ahead of print | PMID: 35131232
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This program is still in alpha version.