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2.
EMBO Mol Med ; : e10018, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31468715

RESUMO

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end-stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti-hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co-factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31384933

RESUMO

Acetyl-salicylic acid (ASA) is the basic anti-thrombotic therapy used for single anti-platelet therapy (SAPT) in primary as well as secondary prevention of atherosclerotic disease. Dual anti-platelet therapy (DAPT) is the cornerstone of maintenance medication following elective percutaneous coronary intervention or acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina). DAPT duration has been frequently discussed. Currently, guideline recommendations strengthen the importance of individualised treatment to reduce bleeding risk based on clinical predictors, of which older age is an important one. Patients aged ≥75 years are often underrepresented in randomised clinical trials, but present a patient cohort deemed both at heightened ischaemic as well as bleeding risk. We aimed to summarise the evidence or the lack of evidence for anti-platelet treatment strategies in patients aged ≥75 years including combinations with anticoagulants in secondary prevention or coronary interventions in elderly patients with atrial fibrillation. This review article represents the authors interpretation of available data and is not discussed by a formal task force; it is intended to point out missing evidence and to provide age-specific data for individualised decision making, which is currently encouraged by the guidelines.

4.
Circ Res ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31434553

RESUMO

RATIONALE: Mechanistic insight into the inflammatory response after acute myocardial infarction (MI) may inform new molecularly-targeted treatment strategies to prevent chronic heart failure. OBJECTIVE: We identified the sulfatase SULF2 in an in silico secretome analysis in bone marrow cells from patients with acute MI and detected increased sulfatase activity in myocardial autopsy samples. SULF2 (Sulf2 in mice) and its isoform SULF1 (Sulf1) act as endo-sulfatases removing 6 O sulfate groups from heparan sulfate (HS) in the extracellular space, thus eliminating docking sites for HS binding proteins. We hypothesized that the Sulfs have a role in tissue repair after MI. METHODS AND RESULTS: Both Sulfs were dynamically upregulated after coronary artery ligation in mice, attaining peak expression and activity levels during the first week after injury. Sulf2 was expressed by monocytes and macrophages, Sulf1 by endothelial cells and fibroblasts. Infarct border-zone capillarization was impaired, scar size increased, and cardiac dysfunction more pronounced in mice with a genetic deletion of either Sulf1 or Sulf2. Studies in bone marrow-chimeric Sulf-deficient mice and Sulf-deficient cardiac endothelial cells established that inflammatory cell-derived Sulf2 and endothelial cell-autonomous Sulf1 promote angiogenesis. Mechanistically, both Sulfs reduced HS sulfation in the infarcted myocardium, thereby diminishing vascular endothelial growth factor A (Vegfa) interaction with HS. Along this line, both Sulfs rendered infarcted mouse heart explants responsive to the angiogenic effects of HS-binding Vegfa164 but did not modulate the angiogenic effects of non-HS-binding Vegfa120. Treating wild-type mice systemically with the small molecule HS antagonist surfen (bis 2 methyl-4-amino-quinolyl-6-carbamide, 1 mg/kg/day) for 7 days after MI released Vegfa from HS, enhanced infarct border-zone capillarization, and exerted sustained beneficial effects on cardiac function and survival. CONCLUSIONS: These findings establish HS-editing Sulfs as critical inducers of postinfarction angiogenesis and identify HS sulfation as a therapeutic target for ischemic tissue repair.

5.
J Affect Disord ; 257: 678-683, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377604

RESUMO

OBJECTIVE: Congenital heart disease is the most common congenital malformation. In adult congenital heart disease (ACHD), the prevalence of major depressive disorder (MDD) is increased. Beyond its immanent health risks, increased epi­ and paracardial adipose tissue has been described in MDD. Epicardial adipose tissue (EAT) is a fat depot surrounding the heart, and it is hypothesized to be associated with coronary artery disease, left-ventricular dysfunction and atrial fibrillation, being frequent problems in ACHD long-term management. We here examined whether EAT is increased in depressed patients with ACHD. METHODS: Two-hundred and ten ACHD outpatients (mean age 35.5y, 43% female) were included. MDD was diagnosed according to DSM-IV criteria using expert interviews. EAT was measured using echocardiography. Further assessments comprised NT-proBNP, left and right ventricular end-diastolic diameter, left-ventricular ejection fraction, smoking behavior and physical activity. RESULTS: Of 210 patients, 53 (25.2%) were diagnosed with MDD. EAT was increased in depressed ACHD (F = 5.04; df = 1; p = 0.026). Depressed male patients were less physically active (p < 0.05) and smoked more cigarettes (p < 0.05). EAT was positively predicted by depression severity (p = 0.039), body mass index (p < 0.001), and negatively predicted by physical activity (p = 0.019). CONCLUSIONS: The presence of MDD is associated with an increased amount of EAT in ACHD, and is dependent on depression severity. Further, the amount of EAT is at least in part mediated by a more sedentary lifestyle. Given the long-term health risks associated with increased EAT, interventions aiming at increased physical activity, smoking cessation and early identification of comorbid MDD may be recommended in ACHD.

6.
Clin Res Cardiol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401672

RESUMO

AIMS: In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. METHODS AND RESULTS: In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect-infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect-upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect-upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67-0.92). CONCLUSION: Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

7.
Sci Rep ; 9(1): 10139, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300720

RESUMO

Sex hormones influence the prevalence and the outcome of heart diseases. The conversion of testosterone to its more active metabolite dihydrotestosterone drives cardiac growth and dysfunction, while inhibition of this step by the anti-androgenic drug finasteride counteracts these pathological processes in preclinical models. In this retrospective, observational study, we aim to investigate whether finasteride, which is in clinical use mainly for prostate disease, might ameliorate cardiac hypertrophy and heart failure in patients. Retrospective chart review of 1041 medical cases with heart failure between 1995 and 2015 was conducted. Stratification was performed by concomitant prostate treatment status (tamsulosin versus finasteride). A propensity score analysis yielded a total of 328 matched medical cases without residual differences in the baseline patient characteristics. In this propensity score matched samples, anti-androgenic therapy with finasteride was associated with significantly reduced left ventricular hypertrophy (interventricular septal thickness 13.3 ± 2.4 mm control vs. 12.6 ± 2.1 mm finasteride group (p = 0.029); estimated average treatment effects on the treated: -0.7 mm, 95% CI mean difference -1.3 to -0.1). In this retrospective analysis anti-androgenic therapy with finasteride for prostate disease was associated with attenuated cardiac hypertrophy in patients with heart failure. Therefore, our data encourage further analysis of this approach in larger heart failure patient cohorts.

8.
JCI Insight ; 52019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31335322

RESUMO

Cardiac pressure overload (for example due to aortic stenosis) induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis in patients. In contrast to adult, neonatal mice can efficiently regenerate the heart after injury in the first week after birth. To decipher whether insufficient cardiac regeneration contributes to the progression of pressure overload dependent disease, we established a transverse aortic constriction protocol in neonatal mice (nTAC). nTAC in the non-regenerative stage (at postnatal day P7) induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, nTAC in the regenerative stage (at P1) largely prevented these maladaptive responses and was in particular associated with enhanced myocardial angiogenesis and increased cardiomyocyte proliferation, which both supported adaptation during nTAC. A comparative transcriptomic analysis between hearts after regenerative versus non-regenerative nTAC suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover novel potential therapeutic strategies.

9.
Eur J Prev Cardiol ; : 2047487319865055, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349778

RESUMO

OBJECTIVE: The purpose of this study was the diagnostic evaluation of the hospital anxiety and depression scale total score, its depression subscale and the Beck depression inventory II in adults with congenital heart disease. METHODS: This cross-sectional study evaluated 206 patients with congenital heart disease (mean age 35.3 ± 11.7 years; 58.3% men). Major depressive disorder was diagnosed by a structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders IV and disease severity with the Montgomery-Åsberg depression rating scale. Receiver operating characteristics provided assessment of diagnostic accuracy. Youden's J statistic identified optimal cut-off points. RESULTS: Fifty-three participants (25.7%) presented with major depressive disorder. Of these, 28 (52.8%) had mild and 25 (47.2%) had moderate to severe symptoms. In the total cohort, the optimal cut-off of values was >11 in the Beck depression inventory II, >11 in the hospital anxiety and depression scale and >5 in the depression subscale. Optimal cut-off points for moderate to severe major depressive disorder were similar. The cut-offs for mild major depressive disorder were lower (Beck depression inventory II >4; hospital anxiety and depression scale >8; >2 in its depression subscale). In the total cohort the calculated area under the curve varied between 0.906 (hospital anxiety and depression scale) and 0.93 (Beck depression inventory II). Detection of moderate to severe major depressive disorder (area under the curve 0.965-0.98) was excellent; detection of mild major depressive disorder (area under the curve 0.851-0.885) was limited. Patients with major depressive disorder had a significantly lower quality of life, even when they had mild symptoms. CONCLUSION: All scales were excellent for detecting moderate to severe major depressive disorder. Classification of mild major depressive disorder, representing 50% of cases, was limited. Therapy necessitating loss of quality of life is already present in major depressive disorder with mild symptoms. Established cut-off points may still be too high to identify patients with major depressive disorder requiring therapy. External validation is needed to confirm our data.

10.
Sci Rep ; 9(1): 9798, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278348

RESUMO

During angiogenesis, single endothelial cells (EC) specialize into tip cells that guide vessel sprouting towards growth factor gradients and instruct the adjacent vessel stalk. The balance between tip and stalk cells is regulated by endothelial Notch signalling through the expression of Notch ligand Delta-like 4 (Dll4) in tip cells, which suppresses a tip cell fate in adjacent stalk cells. Here we show, using genetic reporter and conditional deletion strategies, that myeloid cells regulate tip cell numbers and Dll4 expression via the Notch ligand Dll1 during vascular development in the retina. Dll1 is selectively expressed by a subpopulation of retinal myeloid cells, which progressively localizes to the sprouting vascular network. Conditional, myeloid-specific deletion of Dll1 impairs endothelial Dll4 tip-stalk gradient resulting in an increase of endothelial tip cells and EC filopodia, accompanied by an increase in vascular density and branching. In vitro, co-culture of human EC with monocyte-derived macrophages induced Dll1 upregulation in macrophages and Dll4 upregulation and an endothelial tip cell signature in EC. Furthermore, culturing human EC on recombinant DLL1 induced endothelial Dll4 expression and a tip cell program, indicating that changes are Dll1-dependent. Thus, myeloid cells regulate tip cell fate and angiogenesis through expression of Notch ligand Dll1.

11.
JCI Insight ; 52019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310588

RESUMO

Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor SOX9 functions as an important regulator during embryogenesis, but recent data point towards an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-sequencing from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and reduced fibroblast proliferation, migration and contraction capacity. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.

14.
Cardiovasc Res ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31243437

RESUMO

Heart disease is a major cause of death worldwide with increasing prevalence, which urges the development of new therapeutic strategies. Over the last few decades, numerous small animal models have been generated to mimic various pathomechanisms contributing to heart failure. Despite some limitations these animal models have greatly advanced our understanding of the pathogenesis of the different etiologies of heart failure and paved the way to understanding the underlying mechanisms and development of successful treatments. These models utilize surgical techniques, genetic modifications, and pharmacological approaches. The present review discusses strengths and limitations of commonly used small animal heart failure models, which continue to provide mechanistic crucial insight and facilitate the development of new treatment strategies for patients with heart failure.

15.
Eur Heart J ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31211324

RESUMO

AIMS: The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons despite extensive statistical adjustments. METHODS AND RESULTS: Forty-four percent of the 6800 patients in the DIG trial had been treated with digoxin before randomization, and half of them were randomly withdrawn from digoxin treatment. We contrast the main randomization-based result of the DIG trial with the observational non-randomized comparison of patients pre-treated or not pre-treated with digoxin. Mortality [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.12-1.34; P < 0.001] and heart failure hospitalizations (HR 1.47, 95% CI 1.33-1.61; P < 0.001) were significantly higher in patients pre-treated with digoxin even after adjustment for baseline population differences. The higher risks for both outcomes in those who had previously received digoxin persisted even if they received placebo during the trial (HR 1.24, 95% CI 1.10-1.40; P < 0.001). This sharply contradicts the neutral effect on mortality and the significant reduction in heart failure hospitalizations observed in the randomized comparison. CONCLUSION: Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.

16.
Eur J Heart Fail ; 21(7): 827-843, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243866

RESUMO

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre-existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline-directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress-mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease-specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter-defibrillators, cardiac resynchronization therapy and implanted long-term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.

17.
Clin Res Cardiol ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236691

RESUMO

BACKGROUND: Subclinical atrial fibrillation (AF) is the underlying cause in a relevant part of patients with embolic stroke of unknown source (ESUS). This pilot study aims to identify novel echocardiographic parameters predicting AF subsequently detected in patients originally hospitalized with ESUS. METHODS AND RESULTS: Patients with acute ischemic stroke [baseline diagnosis of ESUS (n = 69), stroke of macro- or microvascular cause (n = 16/25), stroke caused by AF (n = 5)] and controls with paroxysmal AF without acute ischemic stroke (n = 22) as well as healthy controls of young and old age (n = 21/17) in sinus rhythm were included (overall n = 175). Echocardiography was performed in all participants. Prolonged Holter-ECG-monitoring was performed in all stroke patients. In the overall cohort, septal total atrial conduction time (sPA-TDI), left atrial (LA) volume index to tissue Doppler velocity (LAVI/a`) and second negative peak strain rate during LA contraction (SRa), representing echocardiographic parameters of LA remodelling and function, were statistically significant different in patients with and without AF and predictive for subclinical AF (multivariate regression analysis: sPA-TDI: HR 1.06 [1.04-1.08], p < 0.001; LAVI/a`: HR 0.85, [0.74-0.97], p = 0.02; SRa: HR 2.35 [0.9-5.5], p = 0.05). Multivariate Cox regression analysis revealed sPA-TDI as an independent predictor of AF in ESUS patients (sPA-TDI: HR 1.10 [1.04-1.17], p = 0.001). A sPA-TDI of 126 ms strictly discriminated between presence and absence of subclinical AF within 48 h after initiation of Holter-ECG-monitoring in ESUS patients. CONCLUSIONS: sPA-TDI seems to be a strong independent predictor of subclinical AF in patients hospitalized for ESUS and might support risk-stratified clinical decision making in these patients. Septal Total Atrial Conduction Time (sPA-TDI) determined by echocardiography for prediction of Atrial Fibrillation in Embolic Stroke of Unknown Source (ESUS).

18.
Cardiol Young ; 29(5): 602-609, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036097

RESUMO

BACKGROUND: Late Fontan survivors are at high risk to experience heart failure and death. Therefore, the current study sought to investigate the role of non-invasive diagnostics as prognostic markers for failure of the systemic ventricle following Fontan procedure. METHODS: This monocentric, longitudinal observational study included 60 patients with a median age of 24.5 (19-29) years, who were subjected to cardiac magnetic resonance imaging, echocardiography, cardiopulmonary exercise testing, and blood analysis. The primary endpoint of this study was decompensated heart failure with symptoms at rest, peripheral and/or pulmonary edema, and/or death. RESULTS: During a follow-up of 24 months, 5 patients died and 5 patients suffered from decompensated heart failure. Clinical (NYHA class, initial surgery), functional (VO2 peak, ejection fraction, cardiac index), circulating biomarkers (N-terminal pro brain natriuretic peptide), and imaging parameters (end diastolic volume index, end systolic volume index, mass-index, contractility, afterload) were significantly related to the primary endpoint. Multi-variate regression analysis identified afterload as assessed by cardiac magnetic resonance imaging as an independent predictor of the primary endpoint (hazard ratio 1.98, 95% confidence interval 1.19-3.29, p = 0.009). CONCLUSION: We identified distinct parameters of cardiopulmonary exercise testing, cardiac magnetic resonance imaging, and blood testing as markers for future decompensated heart failure and death in patients with Fontan circulation. Importantly, our data also identify increased afterload as an independent predictor for increased morbidity and mortality. This parameter is easy to assess by non-invasive cardiac magnetic resonance imaging. Its modulation may represent a potential therapeutic approach target in these high-risk patients.

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