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1.
J Physiol ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900932

RESUMO

KEY POINTS: Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri-infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri-infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat-to-beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO). Myocytes isolated from the peri-infarct region have more DADs and spontaneous action potentials, with spontaneous Ca2+ release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post-MI remodelling are present in both peri-infarct and remote myocytes. These data highlight the importance of altered myocyte adrenergic responses in the peri-infarct region as source and substrate of post-MI arrhythmias. ABSTRACT: Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri-infarct zone forms a substrate for re-entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post-MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri-infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR) was higher in the peri-infarct than in the remote region. Myocytes isolated from the peri-infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri-infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P < 0.001), correlating with DAD activity. In contrast to these regional distinctions under ISO, alterations in Ca2+ handling at baseline and myocyte hypertrophy were present throughout the left ventricle (LV). Expression of some of the related genes was, however, different between the regions. In conclusion, altered myocyte adrenergic responses in the peri-infarct but not the remote region provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re-entry. These findings stimulate further exploration of region-specific therapies targeting myocytes and autonomic modulation.

2.
Eur Heart J ; 40(46): 3745-3747, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31811721
4.
Sci Rep ; 9(1): 8879, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222006

RESUMO

After myocardial infarction, resident fibroblasts (Fb) differentiate towards myofibroblasts (MyoFb), generating the scar tissue and the interstitial fibrosis seen in the adjacent myocardium. Fb and MyoFb have the potential to interact with cardiac myocytes (CMs) but insight into the phenotype-specific role and mode of interaction is still incomplete. Our objectives are to further define the modulation of CMs by MyoFbs compared to Fbs, as well as the role of direct contact through gap junctions vs. soluble mediators, using Fbs and CMs from pig left ventricle. Fbs were treated to maintain an undifferentiated state (SD-208) or to attain full differentiation to MyoFb (TGF-ß1). Fbs and MyoFbs were co-cultured with CMs, with the possibility of direct contact or separated by a Thincert membrane. Only in direct co-culture, both Fbs and MyoFbs were able to decrease CM viability after 2 days. Only MyoFbs induced significant distal spreading of CMs in both direct and indirect co-culture. MyoFbs, but not Fbs, readily made connections with CMs in direct co-culture and connexin 43 expression in MyoFb was higher than in Fb. When coupled to CMs, MyoFbs reduced the CM action potential duration and hyperpolarized the CM resting membrane potential. Uncoupling reversed these effects. In conclusion, MyoFbs, but not Fbs, alter the CM structural phenotype. MyoFbs, but not Fbs, are likely to electrically connect to CMs and thereby modulate the CM membrane potential. These data provide further support for an active role of MyoFbs in the arrhythmogenic substrate after cardiac remodelling.

5.
Eur Heart J ; 40(28): 2363-2374, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31162536

RESUMO

AIMS: Comprehensive data on research undertaken in cardiovascular medicine can inform the scientific community and can support policy building. We used the publication output from 2004 to 2013 and the 2014 references to these documents, to identify research topics and trends in the field of cardiovascular disease. METHODS AND RESULTS: Text fragments were extracted from the titles and abstracts of 478 000 publications using natural language processing. Through machine-learning algorithms, these text fragments combined to identify specific topics across all publications. A second method, which included cross-references, assigned each publication document to a specific cluster. Experts named the topics and document clusters based on various outputs from these semi-automatic methods. We identified and labelled 175 cardiovascular topics and 20 large document clusters, with concordance between the approaches. Overarching, strongly growing topics in clinical and population sciences are evidence-based guidance for treatment, research on outcomes, prognosis, and risk factors. 'Hot' topics include novel treatments in valve disease and in coronary artery disease, and imaging. Basic research decreases its share over time but sees substantial growth of research on stem cells and tissue engineering, as well as in translational research. Inflammation, biomarkers, metabolic syndrome, obesity, and lipids are hot topics across population, clinical and basic research, supporting integration across the cardiovascular field. CONCLUSION: Growth in clinical and population research emphasizes improving patient outcomes through novel treatments, risk stratification, and prevention. Translation and innovation redefine basic research in cardiovascular disease. Medical need, funding and publishing policies, and scientific opportunities are potential drivers for these evolutions.

6.
J Am Coll Cardiol ; 73(18): 2267-2282, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31072570

RESUMO

BACKGROUND: Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible. OBJECTIVES: The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility. METHODS: Fibroblasts were isolated from the left ventricle of the explanted hearts of transplant recipients (ischemic and dilated cardiomyopathy), and from nonused donor hearts. Fibroblasts were maintained in culture without passaging for 4 or 8 days (treatment studies). Phenotyping included functional testing, immunostaining, and expression studies for markers of differentiation. These data were complemented with immunohistology and expression studies in tissue samples. RESULTS: Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-ß1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature α-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-ß1 pathway is activated. Inhibition of TGF-ß1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of α-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels. CONCLUSION: MyoFb in end-stage HF have a variable degree of differentiation and retain the capacity to return to a less activated state, validating the potential for developing antifibrotic therapy targeting MyoFb.

7.
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.


Assuntos
Miocardite/patologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Osteonectina/metabolismo , Animais , Células Cultivadas , Infecções por Coxsackievirus/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/virologia , Masculino , Camundongos , Contração Miocárdica , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/virologia , Osteonectina/análise , Ratos Wistar
9.
Front Physiol ; 9: 1381, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30344493

RESUMO

The onset of cardiac arrhythmias depends on the electrophysiological and structural properties of cardiac tissue. Electrophysiological remodeling of myocytes due to the presence of adipocytes constitutes a possibly important pathway in the pathogenesis of atrial fibrillation. In this paper we perform an in-silico study of the effect of such myocyte remodeling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources-spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69-87 % increase in APD 90 and an increase of the RMP by 2.5-5.5 mV). In a generic 2D setup we show that adipose tissue remodeling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodeled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria.

10.
Cardiovasc Res ; 114(11): 1512-1524, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29668881

RESUMO

Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM). Methods and results: Single LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation-contraction coupling. Conclusions: In HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.


Assuntos
Arritmias Cardíacas/metabolismo , Sinalização do Cálcio , Cardiomiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Idoso , Animais , Arritmias Cardíacas/fisiopatologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Acoplamento Excitação-Contração , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica , Infarto do Miocárdio/fisiopatologia , NADPH Oxidase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Sus scrofa , Fatores de Tempo , Função Ventricular Esquerda , Remodelação Ventricular
11.
J Am Coll Cardiol ; 71(14): 1584-1589, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29622166

RESUMO

The concern about predominance of basic discovery research and lack of translation into clinical medicine, and segregation between these research communities, led the authors to study these research communities through mapping networks of publications and cross-references. Cardiovascular research from 1993 to 2013 was published in 565 journals, including 104 new journals. Only 50% were published in core cardiovascular journals, such as the Journal of the American College of Cardiology, whereas one-half of cardiovascular publications were found in broader biomedical/multidisciplinary journals. The growth of the clinical journal community and merging into one broad journal community suggests a decreasing dichotomy between basic/preclinical and clinical research, potentially contributing to bridging the translational gap.


Assuntos
Pesquisa Biomédica/métodos , Cardiologia , Doenças Cardiovasculares , Publicações/tendências , Traduções , Bibliometria , Humanos
12.
Sci Rep ; 8(1): 2050, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29391548

RESUMO

The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset.


Assuntos
Adipócitos/patologia , Arritmias Cardíacas/patologia , Modelos Cardiovasculares , Miofibroblastos/patologia , Adipócitos/fisiologia , Arritmias Cardíacas/fisiopatologia , Movimento Celular , Humanos , Miócitos Cardíacos/patologia , Miofibroblastos/fisiologia
16.
Sci Rep ; 7(1): 10801, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28883544

RESUMO

Fibroblast (Fb) differentiation and interstitial fibrosis contribute to cardiac remodeling and loss of function after myocardial infarction (MI). We investigated regional presence and regulation of fibrosis in a pig MI model. In vivo analysis of regional function and perfusion defined three regions: the scar, the myocardium adjacent to the scar (MIadjacent, reduced function, reduced perfusion reserve), and the remote myocardium (MIremote, minimal functional deficit, maintained perfusion). Interstitial and perivascular fibrosis, and increase of collagen type I, was only observed in the MIadjacent. Fb activated protein-alpha (FAP-α) was enriched in MIadjacent compared to MIremote. TGF-ß1, which triggers Fb differentiation, was upregulated in both MIadjacent and MIremote, whereas lysyl oxidase, a regulator of collagen cross-linking, and the proteoglycans decorin and biglycan were only increased in the MIadjacent. Fb isolated and cultured for 4 days had myoFb characteristics with little difference between MIremote and MIadjacent, although RNA sequencing revealed differences in gene expression profiles. Fbs from all regions maintained proliferative capacity, and induced contraction of 3-D collagen matrices but scar myoFb was more effective. These data suggest that after MI, signaling through TGF-ß1, possibly related to increased mechanical load, drives Fb activation throughout the left ventricle while regional signaling determines further maturation and extracellular matrix remodeling after MI.


Assuntos
Diferenciação Celular , Fibroblastos/fisiologia , Fibrose/patologia , Ventrículos do Coração/patologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Animais , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Gelatinases/metabolismo , Proteínas de Membrana/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Proteoglicanas/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais , Estresse Mecânico , Suínos , Fator de Crescimento Transformador beta1/metabolismo
17.
Cardiovasc Res ; 113(11): 1403-1417, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859293

RESUMO

Aims: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. Methods and results: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting. The HRC-Ser81Ala mice presented increased mortality in the absence of structural or histological abnormalities, indicating that early death may be arrhythmia-related. Indeed, under stress-but not baseline-conditions, the HRC-Ser81Ala mice developed ventricular arrhythmias, whilst at the cardiomyocyte level they exhibited increased occurrence of triggered activity. Cardiac contraction was decreased in vivo, ex vivo, and in vitro. Additionally, Ca2+ transients and SR Ca2+ load were both reduced suggesting that cytosolic Ca2+ overload is not the underlying proarrhythmic mechanism. Interestingly, total SR Ca2+ leak was increased in HRC-Ser81Ala cardiomyocytes, without an increase in Ca2+ spark and wave frequency. However, Ca2+ wave propagation was significantly slower and the duration of the associated Na/Ca exchange current was increased. Moreover, action potential duration was also increased. Notably, Ca2+/Calmodulin kinase II (CaMKII) phosphorylation of the ryanodine receptor was increased, whilst KN-93, an inhibitor of CaMKII, reduced the occurrence of arrhythmias. Conclusions: The homologous mutation Ser81Ala in HRC in mice, corresponding to Ser96Ala in humans, is associated with sudden death and depressed cardiac function. Ventricular arrhythmias are related to abnormal Ca2+ cycling across the SR. The data further support a role for CaMKII with the perspective to treat arrhythmias through CaMKII inhibition.


Assuntos
Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Homeostase/fisiologia , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/genética , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Morte Súbita Cardíaca , Modelos Animais de Doenças , Camundongos Transgênicos , Contração Miocárdica/genética , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo
20.
Eur Heart J ; 38(21): 1632-1637, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28329235

RESUMO

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.


Assuntos
Cardiologia/normas , Guias de Prática Clínica como Assunto , Saúde Pública/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Cardiologia/educação , Cardiologia/ética , Difusão de Inovações , Revelação , Humanos , Consentimento Livre e Esclarecido , Segurança do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Medição de Risco
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