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2.
Biophys J ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31447110

RESUMO

Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. To link doxorubicin-induced changes in cardiac cellular and tissue mechanical properties to overall cardiac function, we apply a multiscale biophysical biomechanics model of the heart to measure the plausibility of changes in model parameters representing the passive, active, or anatomical properties of the left ventricle for reproducing measured patient phenotypes. We create representative models of healthy controls (N = 10) and patients with HF induced by (N = 22) or unrelated to (N = 25) doxorubicin therapy. The model predicts that HF in the absence of doxorubicin is characterized by a 2- to 3-fold stiffness increase, decreased tension (0-20%), and ventricular dilation (of order 10-30%). HF due to doxorubicin was similar but showed stronger bias toward reduced active contraction (10-30%) and less dilation (0-20%). We find that changes in active, passive, and anatomical properties all play a role in doxorubicin-induced cardiotoxicity phenotypes. Differences in parameter changes between patient groups are consistent with doxorubicin cardiotoxicity having a greater dependence on reduced cellular contraction and less anatomical remodeling than HF not caused by doxorubicin.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31202754

RESUMO

OBJECTIVES: This study sought to investigate the prevalence of systolic dysfunction using global longitudinal strain (GLS) and its prognostic value in relatives of dilated cardiomyopathy (DCM) patients that had normal left ventricular ejection fraction (LVEF). BACKGROUND: DCM relatives are advised to undergo cardiac assessment including echocardiography, irrespective of the genetic status of the index patient. Even though LVEF is normal, the question remains whether this indicates absence of disease or simply normal cardiac volumes. GLS may provide additional information regarding (sub)clinical cardiac abnormalities and thus allow earlier disease detection. METHODS: A total of 251 DCM relatives and 251 control subjects with a normal LVEF (≥55%) were screened. Automated software measured the GLS on echocardiographic 2-, 3-, and 4-chamber views. The cutoff value for abnormal strain was >-21.5. Median follow-up was 40 months (interquartile range: 5 to 80 months). Primary outcome was the combination of death and cardiac hospitalization. RESULTS: A total of 120 relatives and 83 control subjects showed abnormal GLS (48% vs. 33%, respectively; p < 0.001). Abnormal GLS was independently associated with DCM relatives and cardiovascular risk factors, rather than genetic mutations. Subjects with abnormal GLS had more frequent cardiac hospitalizations and a higher mortality as compared with subjects with normal GLS (hazard ratio: 3.29; 95% confidence interval: 1.58 to 6.87; p = 0.001). Additionally, follow-up LVEF was measured in a subset of relatives, and it decreased significantly in those with abnormal as compared with normal GLS (p = 0.006). CONCLUSIONS: Relatives of DCM patients had a significantly higher prevalence of systolic dysfunction detected by GLS despite normal LVEF compared with control subjects, independent of age, sex, comorbidities, and genotype. Abnormal GLS was associated with LVEF deterioration, cardiac hospitalization, and death.

6.
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.

7.
Clin Res Cardiol ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31062082

RESUMO

BACKGROUND: Hypertension, obesity and diabetes are major and potentially modifiable "risk factors" for cardiovascular diseases. Identification of biomarkers specific to these risk factors may help understanding the underlying pathophysiological pathways, and developing individual treatment. METHODS: The FIBRO-TARGETS (targeting cardiac fibrosis for heart failure treatment) consortium has merged data from 12 patient cohorts in 1 common database of > 12,000 patients. Three mutually exclusive main phenotypic groups were identified ("cases"): (1) "hypertensive"; (2) "obese"; and (3) "diabetic"; age-sex matched in a 1:2 proportion with "healthy controls" without any of these phenotypes. Proteomic associations were studied using a biostatistical method based on LASSO and confronted with machine-learning and complex network approaches. RESULTS: The case:control distribution by each cardiovascular phenotype was hypertension (50:100), obesity (50:98), and diabetes (36:72). Of the 86 studied proteins, 4 were found to be independently associated with hypertension: GDF-15, LEP, SORT-1 and FABP-2; 3 with obesity: CEACAM-8, LEP and PRELP; and 4 with diabetes: GDF-15, REN, CXCL-1 and SCF. GDF-15 (hypertension + diabetes) and LEP (hypertension + obesity) are shared by 2 different phenotypes. A machine-learning approach confirmed GDF-15, LEP and SORT-1 as discriminant biomarkers for the hypertension group, and LEP plus PRELP for the obesity group. Complex network analyses provided insight on the mechanisms underlying these disease phenotypes where fibrosis may play a central role. CONCLUSION: Patients with "mutually exclusive" phenotypes display distinct bioprofiles that might underpin different biological pathways, potentially leading to fibrosis. Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case-control analyses. Patients with "mutually exclusive" phenotypes (blue: obesity, hypertension and diabetes) display distinct protein bioprofiles (green: decreased expression; red: increased expression) that might underpin different biological pathways (orange arrow), potentially leading to fibrosis.

8.
Circ Heart Fail ; 12(5): e005897, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31104495

RESUMO

Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

9.
PLoS One ; 14(4): e0209534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933983

RESUMO

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and at lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.

10.
Sci Rep ; 9(1): 6055, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988323

RESUMO

Heart failure (HF) is the leading cause of death in the Western world. Pathophysiological processes underlying HF development, including cardiac hypertrophy, fibrosis and inflammation, are controlled by specific microRNAs (miRNAs). Whereas most studies investigate miRNA function in one particular cardiac cell type, their multicellular function is poorly investigated. The present study probed 194 miRNAs -differentially expressed in cardiac inflammatory disease - for regulating cardiomyocyte size, cardiac fibroblasts collagen content, and macrophage polarization. Of the tested miRNAs, 13%, 26%, and 41% modulated cardiomyocyte size, fibroblast collagen production, and macrophage polarization, respectively. Seventeen miRNAs affected all three cellular processes, including miRNAs with established (miR-210) and unknown roles in cardiac pathophysiology (miR-145-3p). These miRNAs with a multi-cellular function commonly target various genes. In-depth analysis in vitro of previously unstudied miRNAs revealed that the observed phenotypical alterations concurred with changes in transcript and protein levels of hypertrophy-, fibrosis- and inflammation-related genes. MiR-145-3p and miR-891a-3p were identified to regulate the fibrotic response, whereas miR-223-3p, miR-486-3p, and miR-488-5p modulated macrophage activation and polarisation. In conclusion, miRNAs are multi-cellular regulators of different cellular processes underlying cardiac disease. We identified previously undescribed roles of miRNAs in hypertrophy, fibrosis, and inflammation, and attribute new cellular effects to various well-known miRNAs.

11.
Eur Heart J ; 40(26): 2155-2163, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30957868

RESUMO

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

12.
Eur J Heart Fail ; 21(3): 272-285, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714667

RESUMO

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.

13.
Circ Heart Fail ; 11(11): e005220, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571196

RESUMO

BACKGROUND: Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters. METHODS AND RESULTS: Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with ß-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN, genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09-0.42]; P<0.0001). TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09-6.20]; P=0.038 and 0.11 [0.01-0.99]; P=0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24-0.91]; P=0.009 and 0.18 [0.04-0.82]; P=0.007, respectively), and LVRR is an independent predictor for event-free survival. CONCLUSIONS: The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.


Assuntos
Cardiomiopatia Dilatada , Função Ventricular Esquerda , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Feminino , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Volume Sistólico/genética , Volume Sistólico/fisiologia , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia
16.
Eur Heart J ; 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30295807

RESUMO

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

18.
Sci Rep ; 8(1): 11922, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093686

RESUMO

Diabetic retinopathy (DR) is one of the major complications of diabetes, which eventually leads to blindness. Up to date, no animal model has yet shown all the co-morbidities often observed in DR patients. Here, we investigated whether obese 42 weeks old ZSF1 rat, which spontaneously develops diabetes, hypertension and obesity, would be a suitable model to study DR. Although arteriolar tortuosity increased in retinas from obese as compared to lean (hypertensive only) ZSF1 rats, vascular density pericyte coverage, microglia number, vascular morphology and retinal thickness were not affected by diabetes. These results show that, despite high glucose levels, obese ZSF1 rats did not develop DR. Such observations prompted us to investigate whether the expression of genes, possibly able to contain DR development, was affected. Accordingly, mRNA sequencing analysis showed that genes (i.e. Npy and crystallins), known to have a protective role, were upregulated in retinas from obese ZSF1 rats. Lack of retina damage, despite obesity, hypertension and diabetes, makes the 42 weeks of age ZSF1 rats a suitable animal model to identify genes with a protective function in DR. Further characterisation of the identified genes and downstream pathways could provide more therapeutic targets for the treat DR.

20.
Crit Care Med ; 46(9): e945-e954, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29979224

RESUMO

OBJECTIVES: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock. DESIGN: Prospective, randomized controlled experimental murine study and clinical cohort analysis. SETTING: University research laboratory and ICU at a tertiary-care center. PATIENTS: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting. SUBJECTS: C57Bl/6J and genetic background-matched microRNA-155 knockout mice. INTERVENTIONS: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings. MEASUREMENTS AND MAIN RESULTS: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings. CONCLUSIONS: Our study demonstrates multiple new microRNA-155-mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.

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