Publications by authors named "Stephane Heymans"

200 Publications

Intravitreal injection of anti-miRs against miR-142-3p reduces angiogenesis and microglia activation in a mouse model of laser-induced choroidal neovascularization.

Aging (Albany NY) 2021 May 5;13. Epub 2021 May 5.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.

Age-related macular degeneration (AMD) is a worldwide leading cause of blindness affecting individuals over 50 years old. The most aggressive form, wet AMD, is characterized by choroidal neovascularization (CNV) and inflammation involving microglia recruitment. By using a laser-induced CNV mouse model, we provide evidence for a key role played by miR-142-3p during CNV formation. MiR-142-3p was overexpressed in murine CNV lesions and its pharmacological inhibition decreased vascular and microglia densities by 46% and 30%, respectively. Consistently, miR-142-3p overexpression with mimics resulted in an increase of 136% and 126% of blood vessels and microglia recruitment. Interestingly, miR-142-3p expression was linked to the activation state of mouse microglia cells as determined by morphological analysis (cell solidity) through a computational method. , miR-142-3p overexpression in human microglia cells (HMC3) modulated microglia activation, as shown by CD68 levels. Interestingly, miR142-3p modulation also regulated the production of VEGF-A, the main pro-angiogenic factor. Together, these data strongly support the unprecedented importance of miR-142-3p-dependent vascular-inflammation axis during CNV progression, through microglia activation.
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http://dx.doi.org/10.18632/aging.203035DOI Listing
May 2021

Sex differences in the longitudinal relationship of low-grade inflammation and echocardiographic measures in the Hoorn and FLEMENGHO Study.

PLoS One 2021 4;16(5):e0251148. Epub 2021 May 4.

Department of Epidemiology & Data Science, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: This study aimed to determine the within-person and between-persons associations of low-grade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex.

Methods: Biomarkers and echocardiographic measures were measured at both baseline and follow-up in the Hoorn Study (n = 383) and FLEMENGHO (n = 491). Individual biomarker levels were combined into either a Z-score of LGI (CRP, SAA, IL-6, IL-8, TNF-α and sICAM-1) or ED (sICAM-1, sVCAM-1, sE-selectin and sTM). Mixed models were used to determine within-person and between-persons associations of biomarker Z-scores with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). These associations were adjusted for a-priori selected confounders.

Results: Overall Z-scores for LGI or ED were not associated with echocardiographic measures. Effect modification by sex was apparent for ED with LVEF in both cohorts (P-for interaction = 0.08 and 0.06), but stratified results were not consistent. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF (P-for interaction≤0.05). In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF of 2.2 (-4.5;0.01) %. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF of 1.6 (-2.7;-0.5) %.

Conclusion: Our study did not show consistent associations of LGI and ED with echocardiographic measures. Some evidence of effect modification by sex was present for ED and specific biomarkers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251148PLOS
May 2021

Parvovirus B19 DNA detectable in hearts of patients with dilated cardiomyopathy, but absent or inactive in blood.

ESC Heart Fail 2021 May 1. Epub 2021 May 1.

Department of Blood-borne Infections, Donor Medicine Research, Sanquin Blood Supply Foundation, Amsterdam, The Netherlands.

Aims: Parvovirus B19 (B19V) is often assumed to be a cause of dilated cardiomyopathy (DCM), based on the quantification of B19V DNA in endomyocardial biopsies (EMB). Whether the presence of B19V DNA correlates with active infection is still debated. Application of the enzyme endonuclease to blood samples results in degradation of B19V DNA remnants but leaves viral particles intact, which enables differentiation between active and past infection. In this study, the susceptibility to degradation by endonuclease of B19V DNA in blood was compared between DCM patients and a control group of recent B19V infections.

Methods And Results: Twenty blood samples from 20 adult patients with DCM, who previously tested positive for B19V DNA in EMB and/or blood, were tested with B19V PCR before and after application of endonuclease to the samples. Six blood samples tested positive for B19V DNA with a mean viral load of 2.3 × 10  IU/mL. In five samples, B19V DNA became undetectable after endonuclease (100% load reduction); in one sample DNA load showed a 23% log load reduction (viral load before endonuclease: 9.1 × 10  IU/mL; after: 6.5 × 10  IU/mL). Presence of cardiac inflammation did not differ between patients with B19V DNAemia (1/4) and patients without B19V DNAemia (6/14) (P value = 1.0). In all 18 control samples of proven recent B19V infections, DNA remained detectable after application of endonuclease, showing only a mean log load reduction of 2.3% (mean viral load before endonuclease: 8.1 × 10  IU/mL; after: 8.0 × 10  IU/mL). Load reduction differed significantly between the DCM group and the control group; indicating the presence of intact viral particles in the control group with proven active infection and the presence of DNA remnants in the DCM group (P value = 0.000).

Conclusion: During recent B19V infection, viral DNA levels in blood were unaffected by endonuclease. In contrast, B19V DNA in blood in patients with DCM became undetectable or strongly reduced after application of endonuclease. Circulating viral DNA in this subset of patients with presumed parvovirus-associated DCM does not consist of intact viral particles. Viral replicative activity cannot be assumed from demonstrating B19V DNA in cardiac tissue or in blood in DCM patients.
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http://dx.doi.org/10.1002/ehf2.13341DOI Listing
May 2021

The combination of PICP blood levels and LGE at CMR provides additional prognostic information in idiopathic Dilated Cardiomyopathy.

Eur J Heart Fail 2021 Apr 30. Epub 2021 Apr 30.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: To determine the prognostic value of multilevel assessment of fibrosis in DCM patients.

Methods And Results: We quantified fibrosis in 209 DCM patients at three levels: i. non-invasive late-gadolinium enhancement (LGE) at cardiovascular magnetic resonance (CMR); ii. blood biomarkers (amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)), iii. Invasive endomyocardial biopsy (EMB, collagen volume fraction (CVF)). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization or life-threatening arrhythmias, after adjusting for known clinical predictors (adjusted hazard ratios (HR): LGE 3.54, 95%CI 1.90-6.60; P < 0.001 and PICP 1.02; 95%CI 1.01-1.03; P = 0.001). The combination of LGE and PICP provides the highest prognostic benefit in prediction (Likelihood Ratio test p = 0.007) and reclassification (NRI: 0.28,p = 0.02; and IDI: 0.139,p = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (Log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated to distinct cardiac transcriptomic profiles.

Conclusion: The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM-patients with LGE and elevated PICP.
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http://dx.doi.org/10.1002/ejhf.2201DOI Listing
April 2021

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Eur J Heart Fail 2021 Apr 7. Epub 2021 Apr 7.

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1002/ejhf.2140DOI Listing
April 2021

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Eur Heart J 2021 Apr;42(16):1554-1568

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060056PMC
April 2021

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

Eur Heart J Cardiovasc Pharmacother 2021 Apr 2. Epub 2021 Apr 2.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, 1433, U1116, France.

Background: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined.

Aims: To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone`s effect.

Methods: HOMAGE (Heart OMics in Aging) was a prospective multicenter randomized open-label blinded Endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, month 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations were used.

Results: The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5)mmHg and DBP by -3.2 (-4.8 to -1.7)mmHg (p < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP < 130/80 mmHg (36 vs. 26%; p = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionp=0.041).

Conclusion: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.
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http://dx.doi.org/10.1093/ehjcvp/pvab031DOI Listing
April 2021

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Eur J Heart Fail 2021 Feb 20. Epub 2021 Feb 20.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
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http://dx.doi.org/10.1002/ejhf.2133DOI Listing
February 2021

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

Basic Res Cardiol 2021 Feb 9;116(1):10. Epub 2021 Feb 9.

Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium.

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.
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http://dx.doi.org/10.1007/s00395-021-00846-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873123PMC
February 2021

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

JACC Heart Fail 2021 Apr 3;9(4):268-277. Epub 2021 Feb 3.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.

Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.

Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.

Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).

Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
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http://dx.doi.org/10.1016/j.jchf.2020.11.010DOI Listing
April 2021

Reciprocal organ interactions during heart failure-a position paper from the ESC working group on myocardial function.

Cardiovasc Res 2021 Jan 22. Epub 2021 Jan 22.

Department of Medicine, Surgery and Dentistry, University of Salerno, Italy.

Heart failure-either with reduced or preserved ejection fraction (HFrEF/HFpEF)-is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs.
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http://dx.doi.org/10.1093/cvr/cvab009DOI Listing
January 2021

Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double-blind, randomized, placebo-controlled clinical trial.

Eur J Heart Fail 2021 Feb 7;23(2):302-309. Epub 2021 Jan 7.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.

Aims: Previous uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled, single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence.

Methods And Results: Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6-min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end-diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573], MLHFQ [IVIg 0 (-7;5) vs. placebo -2 (-6;6), P = 0.904] and LVEDV (IVIg -16 ± 49 mL/m vs. placebo -29 ± 40 mL/m ; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.

Conclusion: Intravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.

Clinical Trial Registration: ClinicalTrials.gov ID NCT00892112.
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http://dx.doi.org/10.1002/ejhf.2082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048650PMC
February 2021

Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation.

J Cell Mol Med 2021 Jan 9;25(2):729-741. Epub 2020 Dec 9.

Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.

The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we investigated whether the clinically approved DPP-4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease. Sixteen-week-old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin-supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F ). The reduced F was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP-4 directly cleaved titin in vitro, resulting in an increased F , which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4-mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS-induced early diastolic dysfunction in human.
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http://dx.doi.org/10.1111/jcmm.16122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812306PMC
January 2021

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.

Eur Heart J 2021 Feb;42(6):684-696

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, U1116, France.

Aims : To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.

Methods And Results : Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.

Conclusions : Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.
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http://dx.doi.org/10.1093/eurheartj/ehaa758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878013PMC
February 2021

Vascular ring anomaly in a patient with phosphomannomutase 2 deficiency: A case report and review of the literature.

JIMD Rep 2020 Nov 19;56(1):27-33. Epub 2020 Aug 19.

Department of Clinical Genomics Mayo Clinic Rochester Minnesota USA.

Background: Congenital disorders of glycosylation (CDG) are a group of metabolic disorders well known to be associated with developmental delay and central nervous system anomalies. The most common CDG is caused by pathogenic variants in the phosphomannomutase 2 gene (), which impairs one of the first steps of N-glycosylation and affects multiple organ systems. Cardiac involvement can include pericardial effusion, cardiomyopathy, and arrhythmia, while an association with cardiovascular congenital anomalies is not well studied.

Case Summary: We report a 6-year-old individual who initially presented with inverted nipples, developmental delay, and failure to thrive at 3 months of age. At 4 months, due to feeding problems, swallowing exam and echocardiography were performed which revealed a vascular ring anomaly based on a right aortic arch and aberrant left subclavian artery. Subsequent whole exome gene sequencing revealed two pathogenic PMM2-CDG variants (E139K/R141H) and no known pathogenic mutations related to congenital heart defect (CHD).

Discussion: This is the first report of vascular ring anomaly in a patient with PMM2-CDG. We conducted a literature review of PMM2-CDG patients with reported CHD. Of the 14 patients with PMM2-CDG and cardiac malformation, the most common CHD's were tetralogy of Fallot, patent ductus arteriosus, and truncus arteriosus. The potential important link between CDG and CHD is stressed and discussed. Furthermore, the importance of multidisciplinary care for CDG patients including early referral to pediatric cardiologists is highlighted.
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http://dx.doi.org/10.1002/jmd2.12160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653259PMC
November 2020

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

Eur Heart J 2021 01;42(2):162-174

Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Aims: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.

Methods And Results: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.

Conclusion: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.
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http://dx.doi.org/10.1093/eurheartj/ehaa841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813623PMC
January 2021

Natriuretic peptides for the detection of diastolic dysfunction and heart failure with preserved ejection fraction-a systematic review and meta-analysis.

BMC Med 2020 10 30;18(1):290. Epub 2020 Oct 30.

Department of Epidemiology & Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, VU University Medical Centre, De Boelelaan 1089a, 1081HV, Amsterdam, The Netherlands.

Background: An overview of the diagnostic performance of natriuretic peptides (NPs) for the detection of diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF), in a non-acute setting, is currently lacking.

Methods: We performed a systematic literature search in PubMed and Embase.com (May 13, 2019). Studies were included when they (1) reported diagnostic performance measures, (2) are for the detection of DD or HFpEF in a non-acute setting, (3) are compared with a control group without DD or HFpEF or with patients with heart failure with reduced ejection fraction, (4) are in a cross-sectional design. Two investigators independently assessed risk of bias of the included studies according to the QUADAS-2 checklist. Results were meta-analysed when three or more studies reported a similar diagnostic measure.

Results: From 11,728 titles/abstracts, we included 51 studies. The meta-analysis indicated a reasonable diagnostic performance for both NPs for the detection of DD and HFpEF based on AUC values of approximately 0.80 (0.73-0.87; I = 86%). For both NPs, sensitivity was lower than specificity for the detection of DD and HFpEF: approximately 65% (51-85%; I = 95%) versus 80% (70-90%; I = 97%), respectively. Both NPs have adequate ability to rule out DD: negative predictive value of approximately 85% (78-93%; I = 95%). The ability of both NPs to prove DD is lower: positive predictive value of approximately 60% (30-90%; I = 99%).

Conclusion: The diagnostic performance of NPs for the detection of DD and HFpEF is reasonable. However, they may be used to rule out DD or HFpEF, and not for the diagnosis of DD or HFpEF.
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http://dx.doi.org/10.1186/s12916-020-01764-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599104PMC
October 2020

Prednisone and azathioprine in patients with inflammatory cardiomyopathy: systematic review and meta-analysis.

ESC Heart Fail 2020 10 27;7(5):2278-2296. Epub 2020 Jul 27.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

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http://dx.doi.org/10.1002/ehf2.12762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524236PMC
October 2020

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Eur J Heart Fail 2020 12 12;22(12):2272-2289. Epub 2020 Nov 12.

Medical University of Graz, University Heart Center - Division of Cardiology, Graz, Austria.

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.
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http://dx.doi.org/10.1002/ejhf.2029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894564PMC
December 2020

Heart Failure Association of the European Society of Cardiology update on sodium-glucose co-transporter 2 inhibitors in heart failure.

Eur J Heart Fail 2020 11 27;22(11):1984-1986. Epub 2020 Oct 27.

Centre for Heart Diseases, Faculty of Health Sciences, Wrocław Medical University, Wrocław, Poland.

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: • Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. • Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline-directed medical therapy regardless of the presence of type 2 diabetes mellitus.
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http://dx.doi.org/10.1002/ejhf.2026DOI Listing
November 2020

Network integration and modelling of dynamic drug responses at multi-omics levels.

Commun Biol 2020 Oct 15;3(1):573. Epub 2020 Oct 15.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.

Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.
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http://dx.doi.org/10.1038/s42003-020-01302-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567116PMC
October 2020

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Nat Rev Cardiol 2021 03 12;18(3):169-193. Epub 2020 Oct 12.

Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.
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http://dx.doi.org/10.1038/s41569-020-00435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548534PMC
March 2021

The HFA-PEFF and H FPEF scores largely disagree in classifying patients with suspected heart failure with preserved ejection fraction.

Eur J Heart Fail 2020 Oct 4. Epub 2020 Oct 4.

Department of Cardiology, Maastricht University Medical Centre (MUMC+), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.

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http://dx.doi.org/10.1002/ejhf.2019DOI Listing
October 2020

Cardiac Inflammation Impedes Response to Cardiac Resynchronization Therapy in Patients With Idiopathic Dilated Cardiomyopathy.

Circ Arrhythm Electrophysiol 2020 11 30;13(11):e008727. Epub 2020 Sep 30.

Cardiovascular Research Institute (CARIM), Departments of Cardiology (J.A.J.V., J.J.M., A.M.W.v.S., M.T.H.M.H., V.P.M.v.E., C.K., J.G.L.M.L., H.J.G.M.C., H.-P.B.-L.R., K.V., S.R.B.H., M.R.H.), Maastricht University Medical Center, the Netherlands.

Background: Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of nonresponse to CRT in patients with DCM using endomyocardial biopsies.

Methods: Within the Maastricht and Innsbruck registries of patients with DCM, 99 patients underwent endomyocardial biopsies before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm. Echocardiographic left ventricular end-systolic volume reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and nonresponders.

Results: Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation before implantation was negatively associated with response to CRT (25% of responders, 47% of nonresponders; odds ratio 0.3 [0.12-0.76]; =0.01). Endomyocardial biopsies fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test <0.001). Cardiac transcriptomic profiling of endomyocardial biopsies reveals a strong proinflammatory and profibrotic signature in the hearts of nonresponders compared with responders. In particular, , and were significantly higher expressed in the hearts of nonresponders.

Conclusions: Cardiac inflammation along with a transcriptomic profile of high expression of combined proinflammatory and profibrotic genes are associated with a poor response to CRT in patients with DCM.
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http://dx.doi.org/10.1161/CIRCEP.120.008727DOI Listing
November 2020

The effect of different anaesthetics on echocardiographic evaluation of diastolic dysfunction in a heart failure with preserved ejection fraction model.

Sci Rep 2020 09 24;10(1):15701. Epub 2020 Sep 24.

Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Bus 911, 3000, Leuven, Belgium.

Heart failure with preserved ejection fraction (HFpEF) is currently untreated. Therapeutics development demands effective diagnosis of diastolic dysfunction in animal models mimicking human pathology, which requires appropriate anaesthetics. Here, we investigated which anaesthetic, ketamine/xylazine or isoflurane, could be used to reveal diastolic dysfunction in HFpEF-diseased obese ZSF1 rats by echocardiography. First, diastolic dysfunction was confirmed by pressure-volume loops in obese compared to lean control ZSF1 rats. In echocardiography, ketamine/xylazine, unlike isoflurane, was able to demonstrate impaired relaxation in obese ZSF1 rats, as reflected by impaired early (E) and late (A) filling peak velocities, decreased E/A ratio, and a prolonged deceleration and isovolumic relaxation time. Interestingly, ketamine/xylazine induced a wider separation of both tissue and pulsed wave Doppler-derived echocardiographic waves required for diastolic dysfunction diagnosis, potentially by reducing the heart rate (HR), while isoflurane resulted in merged waves. To assess whether HR-lowering alone explained the differences between the anaesthetics, echocardiography measurements under isoflurane with and without the HR-lowering drug ivabradine were compared. However, diastolic dysfunction could not be diagnosed in ivabradine-treated obese ZSF1 rats. In summary, ketamine/xylazine compared to isoflurane is the anaesthetic of choice to detect diastolic dysfunction by echocardiography in rodent HFpEF, which was only partly mediated by HR-lowering.
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http://dx.doi.org/10.1038/s41598-020-72924-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518268PMC
September 2020

Anthracycline-Related Heart Failure: Certain Knowledge and Open Questions : Where Do we Stand with Chemotherapyinduced Cardiotoxicity?

Curr Heart Fail Rep 2020 12 23;17(6):357-364. Epub 2020 Sep 23.

Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6229, Maastricht, The Netherlands.

In the last decade, cardio-oncology has become a discipline on its own, with tremendous research going on to unravel the mechanisms underpinning different manifestations of cardiotoxicity caused by anticancer drugs. Although this domain is much broader than the effect of chemotherapy alone, a lot of questions about anthracycline-induced cardiotoxicity remain unknown. In this invited review, we provide insights in molecular mechanisms behind anthracycline-induced cardiotoxicity and put it in a clinical framework emphasizing the need for patients to understand, detect, and treat this detrimental condition.
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http://dx.doi.org/10.1007/s11897-020-00489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683464PMC
December 2020

Distinct Cardiac Transcriptomic Clustering in Titin and Lamin A/C-Associated Dilated Cardiomyopathy Patients.

Circulation 2020 Sep 21;142(12):1230-1232. Epub 2020 Sep 21.

Department of Cardiology, Cardiovascular Research Institute (CARIM) (J.A.J.V., M.R.H., E.L.R., S.R.B.H.), Maastricht University Medical Center, The Netherlands.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045118DOI Listing
September 2020

Implications of Genetic Testing in Dilated Cardiomyopathy.

Circ Genom Precis Med 2020 10 3;13(5):476-487. Epub 2020 Sep 3.

Department of Clinical Genetics (J.A.J.V., I.P.C.K., P.W., G.R.F.C., E.K.V., A.v.d.W., H.G.B.).

Background: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome.

Methods: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias.

Results: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM (=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM (<0.001).

Conclusions: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.
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http://dx.doi.org/10.1161/CIRCGEN.120.003031DOI Listing
October 2020

Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart.

Basic Res Cardiol 2020 08 3;115(5):53. Epub 2020 Aug 3.

Clinic III for Internal Medicine, University Clinic Homburg, 66421, Homburg, Germany.

In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to HO by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for HO elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in skeletal muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control HO emission in cardiac mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, HO emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases HO emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting HO-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, HO emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of HO-eliminating capacity increases HO emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing HO emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for HO elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.
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http://dx.doi.org/10.1007/s00395-020-0815-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399685PMC
August 2020

Cardiac dysfunction in cancer patients: beyond direct cardiomyocyte damage of anticancer drugs: novel cardio-oncology insights from the joint 2019 meeting of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Cardiovasc Res 2020 09;116(11):1820-1834

Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

In western countries, cardiovascular (CV) disease and cancer are the leading causes of death in the ageing population. Recent epidemiological data suggest that cancer is more frequent in patients with prevalent or incident CV disease, in particular, heart failure (HF). Indeed, there is a tight link in terms of shared risk factors and mechanisms between HF and cancer. HF induced by anticancer therapies has been extensively studied, primarily focusing on the toxic effects that anti-tumour treatments exert on cardiomyocytes. In this Cardio-Oncology update, members of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart discuss novel evidence interconnecting cardiac dysfunction and cancer via pathways in which cardiomyocytes may be involved but are not central. In particular, the multiple roles of cardiac stromal cells (endothelial cells and fibroblasts) and inflammatory cells are highlighted. Also, the gut microbiota is depicted as a new player at the crossroads between HF and cancer. Finally, the role of non-coding RNAs in Cardio-Oncology is also addressed. All these insights are expected to fuel additional research efforts in the field of Cardio-Oncology.
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http://dx.doi.org/10.1093/cvr/cvaa222DOI Listing
September 2020