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1.
Nat Commun ; 12(1): 5272, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489440

RESUMO

The normal function of heart muscle depends on its ability to contract more strongly at longer length. Increased venous filling stretches relaxed heart muscle cells, triggering a stronger contraction in the next beat- the Frank-Starling relation. Conversely, heart muscle cells are inactivated when they shorten during ejection, accelerating relaxation to facilitate refilling before the next beat. Although both effects are essential for the efficient function of the heart, the underlying mechanisms were unknown. Using bifunctional fluorescent probes on the regulatory light chain of the myosin motor we show that its N-terminal domain may be captured in the folded OFF state of the myosin dimer at the end of the working-stroke of the actin-attached motor, whilst its C-terminal domain joins the OFF state only after motor detachment from actin. We propose that sequential folding of myosin motors onto the filament backbone may be responsible for shortening-induced de-activation in the heart.


Assuntos
Miocárdio/metabolismo , Miosinas/metabolismo , Animais , Cálcio/metabolismo , Masculino , Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Cadeias Leves de Miosina/química , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Ratos Wistar , Sarcômeros/metabolismo
2.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299010

RESUMO

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.


Assuntos
ATPase de Ca(2+) e Mg(2+)/metabolismo , Cálcio/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/fisiologia , Retículo Sarcoplasmático/metabolismo , Adenosina Trifosfatases/metabolismo , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Animais , Antioxidantes/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotônicos/farmacologia , Dobutamina/farmacologia , Dobutamina/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Humanos
3.
Adv Healthc Mater ; 10(16): e2001716, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34197053

RESUMO

Quantifying cardiac contractile force is of paramount important in studying mechanical heart failure and screening therapeutic drugs. However, most existing methods can only measure the in-plane component of twitch force of cardiomyocytes, such that mismatching the centripetal compressive stress of heart beating in physiology. Here, a non-destructive method is developed for quantifying the compressive stress and mapping the distribution of the local stress within the 3D cardiac tissues. In detail, elastic gelatin microspheres labeled with fluorescence beads are fabricated by microfluidic chips with high throughput, and they serve as built-in pressure sensors which are wrapped by cardiomyocytes in 3D tissues. The deformation of microspheres and the displacements of fluorescent beads induced by the contraction of cardiomyocytes are demonstrated to characterize the amount and distribution of the centripetal compressive stress. Further, the method shows a potent capability to locally quantify contractile force variation of 3D cardiac tissues, which is induced by agonist (norepinephrine) and inhibitor (blebbistatin). On the whole, the method significantly improves the 3D measurement of mechanical force in vitro and provides a solution for locally quantifying the compressive stress within engineered cardiac tissues.


Assuntos
Gelatina , Miócitos Cardíacos , Humanos , Microesferas , Contração Miocárdica , Pressão
4.
Fish Physiol Biochem ; 47(4): 1329-1339, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241764

RESUMO

The spatial-temporal organization of the activation, repolarization and hemodynamics of the heart ventricle in rainbow trout, Oncorhynchus mykiss, adapted to a temperature of 5-7 °C, were studied from the normal sinus rhythm (21.6 ± 4.9 bpm) to the highest possible heart rhythm (HR) (60 bpm), during which deterioration of the contractile activity of the myocardium occurred. Regardless of the HR, the main pattern of excitation of the heart ventricle was the movement of the depolarization wave from the dorsal areas of the base in the base-apical and ventral directions with the capture of the entire thickness of the walls, with a slight difference in the time of activation of the subendocardium compared to the subepicardium. The increase in HR above the sinus rhythm caused significant shortening of local repolarization durations in all areas and layers (endocardial, intramural and subepicardial) of the heart ventricle. Changes in local durations of repolarization led to an increase in the heterogeneity of repolarization of the ventricular myocardium; as a result, a deterioration of its contractility was observed. In relation to the sinus rhythm, the maximal systolic pressure in the heart ventricle decreased, the diastolic and end-diastolic pressure increased, and the maximum rates of pressure rise and fall decreased. In rainbow trout adapted to a temperature of 5-7 °C at sinus rhythm, the pumping function of the heart was probably within the upper limit of the physiological norm, and a further increase in the heart rate led to a decline in myocardial contractility.


Assuntos
Função Atrial , Oncorhynchus mykiss/fisiologia , Função Ventricular , Animais , Estimulação Elétrica , Feminino , Átrios do Coração , Frequência Cardíaca , Ventrículos do Coração , Hemodinâmica , Masculino , Contração Miocárdica
5.
Methods Mol Biol ; 2319: 31-44, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331240

RESUMO

Isolated cardiac tissue allows investigators to study mechanisms underlying normal and pathological conditions, which would otherwise be difficult or impossible to perform in vivo. In contrast to ventricular muscle strip preparations, papillary muscles can be prepared without severely damaging the muscle tissue. In this preparation, the isolated papillary muscle is fixed in an environmentally controlled organ bath chamber and electrically stimulated. The evoked twitch force is recorded using a pressure transducer, and parameters such as twitch force amplitude and twitch kinetics are analyzed. A variety of experimental protocols can be performed to investigate the calcium- and frequency-dependent contractility as well as dose-response curves of contractile agents, as well as simulation of pathologic conditions such as acute cardiac ischemia. Mouse papillary muscle preparations have long been the mainstay for studying interactions between intracellular calcium regulation and contractile responses under a number of simulated pathophysiological conditions. These studies are often used to complement in vitro studies performed using isolated neonatal rat cardiac myocytes. In this procedure, we describe how neonatal rat papillary muscles can also be prepared for use in contractile studies.


Assuntos
Contração Miocárdica/fisiologia , Miócitos Cardíacos/fisiologia , Músculos Papilares/fisiologia , Animais , Animais Recém-Nascidos , Estimulação Elétrica , Ratos , Equipamentos Cirúrgicos
6.
Nat Commun ; 12(1): 4583, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321484

RESUMO

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.


Assuntos
Cálcio/metabolismo , Cardiomiopatia Dilatada/metabolismo , Homeostase , Canal de Ânion 2 Dependente de Voltagem/genética , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Animais , Apoptose , Sinalização do Cálcio , Cardiomiopatia Dilatada/mortalidade , Insuficiência Cardíaca/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Transcriptoma
7.
Sci Transl Med ; 13(603)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290054

RESUMO

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.


Assuntos
Desmossomos , Células-Tronco Pluripotentes Induzidas , Humanos , Contração Miocárdica , Miócitos Cardíacos , Fenótipo , Engenharia Tecidual
8.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207886

RESUMO

Interleukin-1ß (IL-1ß), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.


Assuntos
Infarto Miocárdico de Parede Anterior/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/farmacologia , Animais , Infarto Miocárdico de Parede Anterior/metabolismo , Infarto Miocárdico de Parede Anterior/patologia , Anti-Inflamatórios/farmacologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diástole , Modelos Animais de Doenças , Inflamassomos/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia
9.
Medicine (Baltimore) ; 100(27): e25915, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232164

RESUMO

ABSTRACT: Early right ventricular dysfunction in patients with non-advanced idiopathic pulmonary fibrosis (IPF) has not been fully elucidated. Thus, we aimed to assess right ventricular functions in IPF patients and controls by speckle-tracking strain echocardiography at rest and peak exercise.We screened 116 IPF patients from February to August 2019 to include 20 patients with no history of oxygen therapy, peripheral saturation levels ≥92% at rest, Gender-Age-Physiology Index score ≤5, and modified Medical Research Council score ≤3. Additionally, we enrolled 10 matched controls. Transthoracic echocardiography images were acquired at rest and during a cardiopulmonary exercise test. We analyzed 2-dimensional echocardiographic parameters and right ventricular function using the global longitudinal strain assessed by the 2-dimensional speckle-tracking technique.In the control group, we found normal values of right ventricle longitudinal strain (RVLS) at rest and at peak exercise, the latter being much more negative (-23.6 ±â€Š2.2% and -26.8 ±â€Š3.1%, respectively; P < .001). By contrast, RVLS values in the IPF group increased from -21.1 ±â€Š3.8% at rest to -17.0 ±â€Š4.5% at peak exercise (P < .001). The exercise revealed a difference between the 2 groups as the mean RVLS values moved during peak exercise in opposite directions. Patients with IPF got worse, whereas control patients presented improved right ventricular contractility.Right ventricular dysfunction was unveiled by speckle-tracking echocardiography during exercise in non-advanced IPF patients. We suggest that this reflects an inadequate right ventricular-arterial coupling decreasing the right ventricular longitudinal contraction during exercise in these patients. This parameter may be useful as an early index of suspected pulmonary hypertension.


Assuntos
Terapia por Exercício/métodos , Exercício Físico/fisiologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Fibrose Pulmonar Idiopática/fisiopatologia , Contração Miocárdica/fisiologia , Função Ventricular Direita/fisiologia , Idoso , Estudos Transversais , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Fibrose Pulmonar Idiopática/complicações , Masculino
10.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205607

RESUMO

The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (IK1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis that the co-culturing of hiCMs with a human embryonic kidney (HEK) cell-line expressing the Kir2.1 channel (HEK-IK1) can generate an electrical syncytium with an adult-like cardiac electrophysiology. The mechanical activity of co-cultures using different HEK-IK1:hiCM ratios was compared with co-cultures using wildtype (HEK-WT:hiCM) or hiCM alone on days 3-8 after plating. Only ratios of 1:3 and 1:1 showed a significant reduction in spontaneous rate at days 4 and 6, suggesting that IK1 was influencing the electrophysiology. Detailed analysis at day 4 revealed an increased incidence of quiescent wells or sub-areas. Electrical activity showed a decreased action potential duration (APD) at 20% and 50%, but not at 90%, alongside a reduced amplitude of the aggregate AP signal. A computational model of the 1:1 co-culture replicates the electrophysiological effects of HEK-WT. The addition of the IK1 conductance reduced the spontaneous rate and APD20, 50 and 90, and minor variation in the intercellular conductance caused quiescence. In conclusion, a 1:1 co-culture HEK-IK1:hiCM caused changes in electrophysiology and spontaneous activity consistent with the integration of IK1 into the electrical syncytium. However, the additional electrical effects of the HEK cell at 1:1 increased the possibility of electrical quiescence before sufficient IK1 was integrated into the syncytium.


Assuntos
Técnicas de Cocultura/métodos , Miócitos Cardíacos/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Células Gigantes , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas , Contração Miocárdica
11.
Methods Mol Biol ; 2320: 171-180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302658

RESUMO

Engineered cardiac tissue (ECT) derived from human induced pluripotent stem cells (iPSCs) can replicate human heart in vitro and be applied to drug discovery and heart disease models. The contraction force of ECT is an important indicator of its function and of the disease phenotype. Here we describe a construction method of ECT using the Flexcell® Tissue Train® culture system and a contraction force measurement method based on the Frank-Starling law.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Engenharia Tecidual/métodos , Células Cultivadas , Humanos
12.
Echocardiography ; 38(8): 1235-1244, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34085722

RESUMO

BACKGROUND: Myocardial volume is assumed to be constant over the cardiac cycle in the echocardiographic models used by professional guidelines, despite evidence that suggests otherwise. The aim of this paper is to use literature-derived myocardial strain values from healthy patients to determine if myocardial volume changes during the cardiac cycle. METHODS: A systematic review for studies with longitudinal, radial, and circumferential strain from echocardiography in healthy volunteers ultimately yielded 16 studies, corresponding to 2917 patients. Myocardial volume in systole (MVs) and diastole (MVd) was used to calculate MVs/MVd for each study by applying this published strain data to three models: the standard ellipsoid geometric model, a thin-apex geometric model, and a strain-volume ratio. RESULTS: MVs/MVd<1 in 14 of the 16 studies, when computed using these three models. A sensitivity analysis of the two geometric models was performed by varying the dimensions of the ellipsoid and calculating MVs/MVd. This demonstrated little variability in MVs/MVd, suggesting that strain values were the primary determinant of MVs/MVd rather than the geometric model used. Another sensitivity analysis using the 97.5th percentile of each orthogonal strain demonstrated that even with extreme values, in the largest two studies of healthy populations, the calculated MVs/MVd was <1. CONCLUSIONS: Healthy human myocardium appears to decrease in volume during systole. This is seen in MRI studies and is clinically relevant, but this study demonstrates that this characteristic was also present but unrecognized in the existing echocardiography literature.


Assuntos
Ecocardiografia , Miocárdio , Diástole , Humanos , Imageamento por Ressonância Magnética , Contração Miocárdica , Sístole
13.
Methods Mol Biol ; 2277: 405-421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080165

RESUMO

The more recent studies of human pathologies have essentially revealed the complexity of the interactions involved at the different levels of integration in organ physiology. Integrated organ thus reveals functional properties not predictable by underlying molecular events. It is therefore obvious that current fine molecular analyses of pathologies should be fruitfully combined with integrative approaches of whole organ function. It follows that an important issue in the comprehension of the link between molecular events in pathologies and whole organ function/dysfunction is the development of new experimental strategies aimed at the study of the integrated organ physiology. Cardiovascular diseases are a good example as heart submitted to ischemic conditions has to cope both with a decreased supply of nutrients and oxygen, and the necessary increased activity required to sustain whole body-including the heart itself-oxygenation.By combining the principles of control analysis with noninvasive 31P NMR measurement of the energetic intermediates and simultaneous measurement of heart contractile activity, we developed MoCA (for Modular Control and regulation Analysis), an integrative approach designed to study in situ control and regulation of cardiac energetics during contraction in intact beating perfused isolated heart (Diolez et al., Am J Physiol Regul Integr Comp Physiol 293(1):R13-R19, 2007). Because it gives real access to integrated organ function, MoCA brings out a new type of information-the "elasticities," referring to integrated internal responses to metabolic changes-that may be a key to the understanding of the processes involved in pathologies. MoCA can potentially be used not only to detect the origin of the defects associated with the pathology, but also to provide the quantitative description of the routes by which these defects-or also drugs-modulate global heart function, therefore opening therapeutic perspectives. This review presents selected examples of the applications to isolated intact beating heart that evidence different modes of energetic regulation of cardiac contraction. We also discuss the clinical application by using noninvasive 31P cardiac energetics examination under clinical conditions for detection of heart pathologies.


Assuntos
Metabolismo Energético , Espectroscopia de Ressonância Magnética/métodos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Animais , Cálcio/metabolismo , Cardiotônicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Epinefrina/metabolismo , Cobaias , Coração/efeitos dos fármacos , Homeostase , Humanos , Masculino , Mitocôndrias Cardíacas/metabolismo , Miofibrilas/metabolismo , Técnicas de Cultura de Órgãos/métodos , Ratos , Simendana/farmacologia
14.
Comput Biol Med ; 135: 104565, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34157469

RESUMO

Zebrafish is a powerful and widely-used model system for a host of biological investigations, including cardiovascular studies and genetic screening. Zebrafish are readily assessable during developmental stages; however, the current methods for quantifying and monitoring cardiac functions mainly involve tedious manual work and inconsistent estimations. In this paper, we developed and validated a Zebrafish Automatic Cardiovascular Assessment Framework (ZACAF) based on a U-net deep learning model for automated assessment of cardiovascular indices, such as ejection fraction (EF) and fractional shortening (FS) from microscopic videos of wildtype and cardiomyopathy mutant zebrafish embryos. Our approach yielded favorable performance with accuracy above 90% compared with manual processing. We used only black and white regular microscopic recordings with frame rates of 5-20 frames per second (fps); thus, the framework could be widely applicable with any laboratory resources and infrastructure. Most importantly, the automatic feature holds promise to enable efficient, consistent, and reliable processing and analysis capacity for large amounts of videos, which can be generated by diverse collaborating teams.


Assuntos
Cardiomiopatias , Sistema Cardiovascular , Aprendizado Profundo , Animais , Contração Miocárdica , Peixe-Zebra
15.
Circ Cardiovasc Imaging ; 14(6): e012459, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34126756

RESUMO

BACKGROUND: Our goal was to evaluate the ability of cardiovascular magnetic resonance for detecting and predicting cardiac dysfunction in patients receiving cancer therapy. Left ventricular ejection fraction, global and regional strain utilizing fast-strain-encoded, T1 and T2 mapping, and cardiac biomarkers (troponin and BNP [brain natriuretic peptide]) were analyzed. METHODS: Sixty-one patients (47 with breast cancer, 11 with non-Hodgkin lymphoma, and 3 with Hodgkin lymphoma) underwent cardiovascular magnetic resonance scans at baseline and at regular intervals during 2 years of follow-up. The percentage of all left ventricular myocardial segments with strain ≤-17% (normal myocardium [%]) was analyzed. Clinical cardiotoxicity (CTX) and sub-CTX were defined according to standard measures. RESULTS: Nine (15%) patients developed CTX, 26 (43%) had sub-CTX. Of the 35 patients with CTX or sub-CTX, 24 (69%) were treated with cardioprotective medications and showed recovery of cardiac function. The amount of normal myocardium (%) exhibited markedly higher accuracy for the detection of CTX and sub-CTX compared with left ventricular ejection fraction, T1, and T2 mapping as well as troponin I (Δareas under the curve=0.20, 0.24, and 0.46 for normal myocardium (%) versus left ventricular ejection fraction, troponin I, and T1 mapping, P<0.001 for all). In addition, normal myocardium (%) at baseline accurately identified patients with subsequent CTX (P<0.001), which was not achieved by any other markers. CONCLUSIONS: Normal myocardium (%) derived by fast-strain-encoded cardiovascular magnetic resonance, is an accurate and sensitive tool that can establish cardiac safety in patients with cancer undergoing cardiotoxic chemotherapy not only for the early detection but also for the prediction of those at risk of developing CTX. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03543228.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Diagnóstico Precoce , Cardiopatias/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Peptídeo Natriurético Encefálico/sangue , Troponina I/sangue , Idoso , Biomarcadores/sangue , Neoplasias da Mama/sangue , Cardiotoxicidade , Feminino , Seguimentos , Cardiopatias/sangue , Cardiopatias/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
16.
J Biol Chem ; 297(1): 100893, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34153319

RESUMO

Fibrosis is a pronounced feature of heart disease and the result of dysregulated activation of resident cardiac fibroblasts (CFs). Recent work identified stress-induced degradation of the cytoskeletal protein ßIV-spectrin as an important step in CF activation and cardiac fibrosis. Furthermore, loss of ßIV-spectrin was found to depend on Ca2+/calmodulin-dependent kinase II (CaMKII). Therefore, we sought to determine the mechanism for CaMKII-dependent regulation of ßIV-spectrin and CF activity. Computational screening and MS revealed a critical serine residue (S2250 in mouse and S2254 in human) in ßIV-spectrin phosphorylated by CaMKII. Disruption of ßIV-spectrin/CaMKII interaction or alanine substitution of ßIV-spectrin Ser2250 (ßIV-S2254A) prevented CaMKII-induced degradation, whereas a phosphomimetic construct (ßIV-spectrin with glutamic acid substitution at serine 2254 [ßIV-S2254E]) showed accelerated degradation in the absence of CaMKII. To assess the physiological significance of this phosphorylation event, we expressed exogenous ßIV-S2254A and ßIV-S2254E constructs in ßIV-spectrin-deficient CFs, which have increased proliferation and fibrotic gene expression compared with WT CFs. ßIV-S2254A but not ßIV-S2254E normalized CF proliferation, gene expression, and contractility. Pathophysiological targeting of ßIV-spectrin phosphorylation and subsequent degradation was identified in CFs activated with the profibrotic ligand angiotensin II, resulting in increased proliferation and signal transducer and activation of transcription 3 nuclear accumulation. While therapeutic delivery of exogenous WT ßIV-spectrin partially reversed these trends, ßIV-S2254A completely negated increased CF proliferation and signal transducer and activation of transcription 3 translocation. Moreover, we observed ßIV-spectrin phosphorylation and associated loss in total protein within human heart tissue following heart failure. Together, these data illustrate a considerable role for the ßIV-spectrin/CaMKII interaction in activating profibrotic signaling.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fibrose Endomiocárdica/metabolismo , Miofibroblastos/metabolismo , Espectrina/metabolismo , Substituição de Aminoácidos , Animais , Células COS , Proliferação de Células , Células Cultivadas , Chlorocebus aethiops , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miofibroblastos/fisiologia , Fosforilação , Espectrina/genética
17.
Genes Cells ; 26(8): 583-595, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34060165

RESUMO

Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin-assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca2+ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca2+ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca2+ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca2+ transients. Thus, SMIFH2 has opposing effects on the Ca2+ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca2+ -release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca2+ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca2+ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca2+ handling.


Assuntos
Sinalização do Cálcio , Coração/efeitos dos fármacos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Coração/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Rana catesbeiana , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Especificidade da Espécie , Tionas/farmacologia , Uracila/análogos & derivados , Uracila/farmacologia
18.
Am J Physiol Heart Circ Physiol ; 321(1): H162-H174, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085842

RESUMO

Long-chain acylcarnitines (LCACs) are known to directly alter cardiac contractility and electrophysiology. However, the acute effect of LCACs on human cardiac function is unknown. We aimed to determine the effect of LCAC 18:1, which has been associated with cardiovascular disease, on the contractility and arrhythmia susceptibility of human atrial myocardium. Additionally, we aimed to assess how LCAC 18:1 alters Ca2+ influx and spontaneous Ca2+ release in vitro. Human right atrial trabeculae (n = 32) stimulated at 1 Hz were treated with LCAC 18:1 at a range of concentrations (1-25 µM) for a 45-min period. Exposure to the LCAC induced a dose-dependent positive inotropic effect on myocardial contractility (maximal 1.5-fold increase vs. control). At the 25 µM dose (n = 8), this was paralleled by an enhanced propensity for spontaneous contractions (50% increase). Furthermore, all LCAC 18:1 effects on myocardial function were reversed following LCAC 18:1 washout. In fluo-4-AM-loaded HEK293 cells, LCAC 18:1 dose dependently increased cytosolic Ca2+ influx relative to vehicle controls and the short-chain acylcarnitine C3. In HEK293 cells expressing ryanodine receptor (RyR2), this increased Ca2+ influx was linked to an increased propensity for RyR2-mediated spontaneous Ca2+ release events. Our study is the first to show that LCAC 18:1 directly and acutely alters human myocardial function and in vitro Ca2+ handling. The metabolite promotes proarrhythmic muscle contractions and increases contractility. The exploratory findings in vitro suggest that LCAC 18:1 increases proarrhythmic RyR2-mediated spontaneous Ca2+ release propensity. The direct effects of metabolites on human myocardial function are essential to understand cardiometabolic dysfunction.NEW & NOTEWORTHY For the first time, the fatty acid metabolite, long-chain acylcarnitine 18:1, is shown to acutely increase the arrhythmia susceptibility and contractility of human atrial myocardium. In vitro, this was linked to an influx of Ca2+ and an enhanced propensity for spontaneous RyR2-mediated Ca2+ release.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Carnitina/análogos & derivados , Átrios do Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Carnitina/farmacologia , Feminino , Átrios do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo
19.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072954

RESUMO

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca2+ (CaV1.2) channels in individual myocytes to open briefly. The level of this Ca2+ influx tunes the amplitude of Ca2+-induced Ca2+ release from ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum and thus the magnitude of the elevation in intracellular Ca2+ concentration and ultimately the downstream contraction. The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. Trafficking of these channels and their auxiliary subunits to the cell surface is thus tightly controlled and regulated to ensure adequate sarcolemmal expression to sustain this critical process. To that end, recent discoveries have revealed the existence of internal reservoirs of preformed CaV1.2 channels that can be rapidly mobilized to enhance sarcolemmal expression in times of acute stress when hemodynamic and metabolic demand increases. In this review, we provide an overview of the current thinking on CaV1.2 channel trafficking dynamics in the heart. We highlight the numerous points of control including the biosynthetic pathway, the endosomal recycling pathway, ubiquitination, and lysosomal and proteasomal degradation pathways, and discuss the effects of ß-adrenergic and angiotensin receptor signaling cascades on this process.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Sinalização do Cálcio , Cálcio/metabolismo , Ventrículos do Coração/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Ventrículos do Coração/citologia , Humanos , Miócitos Cardíacos/citologia
20.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064778

RESUMO

Kynurenic acid (KYNA) is derived from tryptophan, formed by the kynurenic pathway. KYNA is being widely studied as a biomarker for neurological and cardiovascular diseases, as it is found in ischemic conditions as a protective agent; however, little is known about its effect after ischemia-reperfusion in the vascular system. We induced ischemia for 30 min followed by 5 min reperfusion (I/R) in the rat aorta for KYNA evaluation using functional assays combined with proteomics. KYNA recovered the exacerbated contraction induced by phenylephrine and relaxation induced by acetylcholine or sodium nitroprussiate in the I/R aorta, with vessel responses returning to values observed without I/R. The functional recovery can be related to the antioxidant activity of KYNA, which may be acting on the endothelium-injury prevention, especially during reperfusion, and to proteins that regulate neurotransmission and cell repair/growth, expressed after the KYNA treatment. These proteins interacted in a network, confirming a protein profile expression for endothelium and neuron repair after I/R. Thus, the KYNA treatment had the ability to recover the functionality of injured ischemic-reperfusion aorta, by tissue repairing and control of neurotransmitter release, which reinforces its role in the post-ischemic condition, and can be useful in the treatment of such disease.


Assuntos
Aorta/patologia , Ácido Cinurênico/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteômica , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Modelos Animais de Doenças , Ácido Cinurênico/farmacologia , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
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