Topic: Journal Club Selection

Abstract

Non-coding RNAs in cardiac inflammation: key drivers in the pathophysiology of heart failure.

Sansonetti M, De Windt LJ
Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation.

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: 20 Jul 2022; 118:2058-2073
Sansonetti M, De Windt LJ
Cardiovasc Res: 20 Jul 2022; 118:2058-2073 | PMID: 34097013
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Adiponectin and cardiometabolic trait and mortality: where do we go?

Jang AY, Scherer PE, Kim JY, Lim S, Koh KK
Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.

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: 20 Jul 2022; 118:2074-2084
Jang AY, Scherer PE, Kim JY, Lim S, Koh KK
Cardiovasc Res: 20 Jul 2022; 118:2074-2084 | PMID: 34117867
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology.

Petraina A, Nogales C, Krahn T, Mucke H, ... Hobbs AJ, Schmidt HHHW
Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3\'-5\'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.

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

Cardiovasc Res: 20 Jul 2022; 118:2085-2102
Petraina A, Nogales C, Krahn T, Mucke H, ... Hobbs AJ, Schmidt HHHW
Cardiovasc Res: 20 Jul 2022; 118:2085-2102 | PMID: 34270705
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Testosterone therapy and cardiovascular diseases.

Cittadini A, Isidori AM, Salzano A
Since it was first synthesized in 1935, testosterone (T) has been viewed as the mythical Fountain of Youth, promising rejuvenation, restoring sexual appetites, growing stronger muscles, and quicker thinking. T is endowed with direct effects on myocardial and vascular structure and function, as well as on risk factors for cardiovascular (CV) disease. Indeed, low serum T levels are a risk factor for diabetes, metabolic syndrome, inflammation, and dyslipidaemia. Moreover, many studies have shown that T deficiency per se is an independent risk factor of CV and all-cause mortality. On this background and due to direct-to-patient marketing by drug companies, we have witnessed to the widespread use of T replacement therapy without clear indications particularly in late-life onset hypogonadism. The current review will dwell upon current evidence and controversies surrounding the role of T in the pathophysiology of CV diseases, the link between circulating T levels and CV risk, and the use of replacing T as a possible adjuvant treatment in specific CV disorders. Specifically, recent findings suggest that heart failure and type 2 diabetes mellitus represent two potential targets of T therapy once that a state of hypogonadism is diagnosed. However, only if ongoing studies solve the CV safety issue the T orchid may eventually \'bloom\'.

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: 20 Jul 2022; 118:2039-2057
Cittadini A, Isidori AM, Salzano A
Cardiovasc Res: 20 Jul 2022; 118:2039-2057 | PMID: 34293112
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Interleukin-5-induced eosinophil population improves cardiac function after myocardial infarction.

Xu JY, Xiong YY, Tang RJ, Jiang WY, ... Li XD, Yang YJ
Aims
Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.
Methods and results
MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.
Conclusion
IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.

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: 20 Jul 2022; 118:2165-2178
Xu JY, Xiong YY, Tang RJ, Jiang WY, ... Li XD, Yang YJ
Cardiovasc Res: 20 Jul 2022; 118:2165-2178 | PMID: 34259869
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells.

Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, ... Furmanik M, Schurgers L
Aims
Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms.
Methods and results
We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro, nicotine-induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels.
Conclusion
In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.

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

Cardiovasc Res: 20 Jul 2022; 118:2196-2210
Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, ... Furmanik M, Schurgers L
Cardiovasc Res: 20 Jul 2022; 118:2196-2210 | PMID: 34273166
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.

Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Aims
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.
Methods and results
Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.
Conclusion
Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

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: 22 Jun 2022; 118:1728-1741
Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Cardiovasc Res: 22 Jun 2022; 118:1728-1741 | PMID: 34028533
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group.

Wyckoff MH, Singletary EM, Soar J, Olasveengen TM, ... Berg KM, Collaborators
The International Liaison Committee on Resuscitation initiated a continuous review of new, peer-reviewed published cardiopulmonary resuscitation science. This is the fifth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; a more comprehensive review was done in 2020. This latest summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation task force science experts. Topics covered by systematic reviews in this summary include resuscitation topics of video-based dispatch systems; head-up cardiopulmonary resuscitation; early coronary angiography after return of spontaneous circulation; cardiopulmonary resuscitation in the prone patient; cord management at birth for preterm and term infants; devices for administering positive-pressure ventilation at birth; family presence during neonatal resuscitation; self-directed, digitally based basic life support education and training in adults and children; coronavirus disease 2019 infection risk to rescuers from patients in cardiac arrest; and first aid topics, including cooling with water for thermal burns, oral rehydration for exertional dehydration, pediatric tourniquet use, and methods of tick removal. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, according to the Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations or good practice statements. Insights into the deliberations of the task forces are provided in Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces listed priority knowledge gaps for further research.



Circulation: 30 Dec 2021; 145:e645-e721
Wyckoff MH, Singletary EM, Soar J, Olasveengen TM, ... Berg KM, Collaborators
Circulation: 30 Dec 2021; 145:e645-e721 | PMID: 34813356
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Left ventricular longitudinal strain alterations in asymptomatic or mildly symptomatic paediatric patients with SARS-CoV-2 infection.

Sirico D, Di Chiara C, Costenaro P, Bonfante F, ... Giaquinto C, Di Salvo G
Aims
Compared with adult patients, clinical manifestations of children\'s coronavirus disease-2019 (COVID-19) are generally perceived as less severe. The objective of this study was to evaluate cardiac involvement in previously healthy children with asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.
Methods and results
We analysed a cohort of 53 paediatric patients (29 males, 55%), mean age 7.5 ± 4.7 years, who had a confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or only mildly symptomatic for COVID-19. Patients underwent standard transthoracic echocardiogram and speckle tracking echocardiographic study at least 3 months after diagnosis. Thirty-two age, sex, and body surface area comparable healthy subjects were used as control group. Left ventricular ejection fraction was within normal limits but significantly lower in the cases group compared to controls (62.4 ± 4.1% vs. 65.2 ± 5.5%; P = 0.012). Tricuspid annular plane systolic excursion (20.1 ± 3 mm vs. 19.8 ± 3.4 mm; P = 0.822) and left ventricular (LV) global longitudinal strain (-21.9 ± 2.4% vs. -22.6 ± 2.5%; P = 0.208) were comparable between the two groups. Regional LV strain analysis showed a significant reduction of the LV mid-wall segments strain among cases compared to controls. Furthermore, in the cases group, there were 14 subjects (26%) with a regional peak systolic strain below -16% (-2.5 Z score in our healthy cohort) in at least two segments. These subjects did not show any difference regarding symptoms or serological findings.
Conclusion
SARS-CoV-2 infection may affect left ventricular deformation in 26% of children despite an asymptomatic or only mildly symptomatic acute illness. A follow-up is needed to verify the reversibility of these alterations and their impact on long-term outcomes.

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

Eur Heart J Cardiovasc Imaging: 21 Jul 2022; 23:1083-1089
Sirico D, Di Chiara C, Costenaro P, Bonfante F, ... Giaquinto C, Di Salvo G
Eur Heart J Cardiovasc Imaging: 21 Jul 2022; 23:1083-1089 | PMID: 34219155
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure.

Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Aims
Hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by post-translational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling. Here, the aim of this study was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF.
Methods and results
We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy.
Conclusion
We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.

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: 22 Jun 2022; 118:1771-1784
Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Cardiovasc Res: 22 Jun 2022; 118:1771-1784 | PMID: 34132787
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between computed tomography-derived tricuspid annular dimensions and prognosis: insights from whole-beat computed tomography assessment.

Hirasawa K, Fortuni F, van Rosendael PJ, Ajmone Marsan N, Bax JJ, Delgado V
Aims
Tricuspid regurgitation (TR) has been associated with outcome in patients treated with transcatheter aortic valve implantation (TAVI). Tricuspid annulus (TA) dimensions are associated with TR. However, the TA is highly dynamic during the cardiac cycle, and the interaction between the TA dimensions, TR, and patient prognosis has never been evaluated. This study aimed to characterize the dynamics of the TA along with the cardiac cycle and its association with prognosis in patients undergoing TAVI.
Methods and results
Patients with severe aortic stenosis who underwent whole-beat computed tomography (n = 393, mean age 80 ± 7 years, 53% male) were included. The ratio between anterior-posterior (AP) and septal-lateral (SL) diameter of the TA was calculated at end-systole (ES), mid-diastole (MD), and end-diastole (ED) to characterize the TA shape throughout the cardiac cycle. The primary endpoint was all-cause mortality. During a median follow-up of 3.6 (1.7-5.5) years, 146 patients died. While all the TA parameters at ES and MD were not associated with all-cause mortality, a low AP/SL ratio at ED (more circular geometry) was independently related with all-cause mortality (hazard ratio: 4.717, 95% confidence interval: 1.481-15.152; P = 0.009). In addition, a more circular TA shape at ED (AP/SL ratio < 1.20) was also associated with more right atrial and ventricular dilation, more frequently significant TR, and a higher prevalence of atrial fibrillation.
Conclusion
Circular remodelling of the TA shape at ED is associated with more right atrial and ventricular dilation, and a higher long-term mortality after TAVI. The evaluation of the TA shape at ED may be a useful parameter in the risk stratification of patients undergoing TAVI.

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

Eur Heart J Cardiovasc Imaging: 21 Jul 2022; 23:1090-1097
Hirasawa K, Fortuni F, van Rosendael PJ, Ajmone Marsan N, Bax JJ, Delgado V
Eur Heart J Cardiovasc Imaging: 21 Jul 2022; 23:1090-1097 | PMID: 34279577
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Human coronary microvascular contractile dysfunction associates with viable synthetic smooth muscle cells.

Dora KA, Borysova L, Ye X, Powell C, ... Smart N, Ascione R
Aims
Coronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study.
Methods and results
Intramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments.
Conclusion
These data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction.

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

Cardiovasc Res: 29 Jun 2022; 118:1978-1992
Dora KA, Borysova L, Ye X, Powell C, ... Smart N, Ascione R
Cardiovasc Res: 29 Jun 2022; 118:1978-1992 | PMID: 34173824
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Vascular histopathology and connective tissue ultrastructure in spontaneous coronary artery dissection: pathophysiological and clinical implications.

Margaritis M, Saini F, Baranowska-Clarke AA, Parsons S, ... Sheppard MN, Adlam D
Aims 
Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and in rare cases sudden cardiac death (SCD). Connective tissue abnormalities, coronary inflammation, increased coronary vasa vasorum (VV) density, and coronary fibromuscular dysplasia have all been implicated in the pathophysiology of SCAD but have not previously been systematically assessed. We designed a study to investigate the coronary histological and dermal collagen ultrastructural findings in SCAD.
Methods and results
Thirty-six autopsy SCAD cases were compared with 359 SCAD survivors. Coronary and myocardial histology and immunohistochemistry were undertaken. Transmission electron microscopy (TEM) of dermal extracellular matrix (ECM) components of n = 31 SCAD survivors and n = 16 healthy volunteers were compared. Autopsy cases were more likely male (19% vs. 5%; P = 0.0004) with greater proximal left coronary involvement (56% vs. 18%; P < 0.0001) compared to SCAD survivors. N = 24 (66%) of cases showed no myocardial infarction on macro- or microscopic examination consistent with arrhythmogenic death. There was significantly (P < 0.001) higher inflammation in cases with delayed-onset death vs. sudden death and significantly more inflammation surrounding the dissected vs. non-dissected vessel segments. N = 17 (47%) cases showed limited intimal fibro-elastic thickening but no features of fibromuscular dysplasia and no endothelial or internal elastic lamina abnormalities. There were no differences in VV density between SCAD and control cases. TEM revealed no general ultrastructural differences in ECM components or markers of fibroblast metabolic activity.
Conclusions 
Assessment of SCD requires careful exclusion of SCAD, particularly in cases without myocardial necrosis. Peri-coronary inflammation in SCAD is distinct from vasculitides and likely a reaction to, rather than a cause for SCAD. Coronary fibromuscular dysplasia or increased VV density does not appear pathophysiologically important. Dermal connective tissue changes are not common in SCAD survivors.

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

Cardiovasc Res: 22 Jun 2022; 118:1835-1848
Margaritis M, Saini F, Baranowska-Clarke AA, Parsons S, ... Sheppard MN, Adlam D
Cardiovasc Res: 22 Jun 2022; 118:1835-1848 | PMID: 34048532
Go to: DOI | PubMed | PDF | Google Scholar |
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Anticoagulation in atrial fibrillation and liver disease: a pooled-analysis of >20 000 patients.

Chen S, Pürerfellner H, Meyer C, Sommer P, ... Chun JKR, Schmidt B
Aims
Anticoagulation for atrial fibrillation patients with liver disease represents a clinical dilemma. We sought to evaluate the efficacy/safety of different anticoagulation, i.e. vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in such patient group.
Methods and results
This was a pooled-analysis enrolling up-to-date clinical data. Two subsets: subset A (VKA vs. Non-Anticoagulation) and subset B (NOACs vs. VKA) were pre-specified. The study outcomes were ischaemic stroke (IS)/thromboembolism (TE), major bleeding (MB), intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and all-cause mortality. A total of 20 042 patients\' data were analysed (subset A: N = 10 275, subset B: N = 9767). Overall mean age: 71 ± 11 years, mean CHA2DS2-VASc score: 4.0 ± 1.8, mean HAS-BLED score: 3.6 ± 1.2. The majority of the patients had Child-Pugh category (A-B). As compared with Non-Anticoagulation, VKA seemed to reduce the risk of IS/TE [odds ratio (OR): 0.60, P = 0.05], but heighten the risk of all-bleeding events including MB (OR: 2.81, P = 0.01), ICB (OR: 1.60, P = 0.01), and GIB (OR: 3.32, P = 0.01). When compared with VKA, NOACs had similar efficacy in reducing the risk of IS/TE (OR: 0.82, P = 0.64), significantly lower risk of MB (OR: 0.54, P = 0.0003) and ICB (OR: 0.35, P < 0.0001), and trend towards reduced risk of GIB (OR: 0.72, P = 0.12) and all-cause mortality (OR: 0.79, P = 0.35). The favourable effects were maintained in subgroups of individual NOAC.
Conclusions
VKA appears to reduce the risk of IS/TE but increase all-bleeding events. NOACs have similar effect in reducing the risk of IS/TE and have significantly lower risk of MB and ICB as compared with VKA. NOACs seem to be associated with better clinical outcome than VKA in patients with mild-moderate liver disease.

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

Eur Heart J Cardiovasc Pharmacother: 08 Jun 2022; 8:336-345
Chen S, Pürerfellner H, Meyer C, Sommer P, ... Chun JKR, Schmidt B
Eur Heart J Cardiovasc Pharmacother: 08 Jun 2022; 8:336-345 | PMID: 33871577
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
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
Go to: DOI | PubMed | PDF | Google Scholar |
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.