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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2311-2314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018470

RESUMO

Models of muscle contraction are typically based on a measured force-velocity relation embodied as Hill's contractile element [1]. Adopting a particular force-velocity relation dictates the muscle's mechanical properties. Dynamic crossbridge based models, such as Huxley's [2], typically focus on ultrastructural mechanics. This study adapts a dynamic lumped model of cardiac muscle contraction [3] for description of mouse soleus skeletal muscle. This compact, dynamic model exhibits the main features of skeletal muscle contraction with few assumptions. The main differences between cardiac and skeletal muscle dynamics are described. This approach gives one equation and set of parameters capable of modeling isometric and isotonic contractions, skeletal muscle's force-length relation, variations in contractility, and the force-velocity relation. This new constitutive equation may be useful for modeling striated muscle as part of larger biomechanical models.


Assuntos
Músculo Esquelético , Contração Miocárdica , Animais , Coração , Contração Isotônica , Camundongos
2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2598-2601, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018538

RESUMO

INTRODUCTION: Arterial-ventricular coupling (AVC) has been recognized as a key determinant of global cardiovascular performance. Diastolic dysfunction (DD) occurs when inadequate filling of the ventricles is related to an abnormal elevation of intracardiac filling pressures. In some cases, DD is evidenced during cardiac stress, provoked by exercise. OBJECTIVE: To evaluate AVC in individuals with stress evidenced DD, in relation to controls. MATERIALS AND METHODS: Stress echocardiography was applied to assess cardiac function during exercise. Arterial-ventricular coupling was evaluated, based on the assessment of left ventricular and arterial elastances. RESULTS: AVC showed a significant difference at peak exercise compared to controls, basically due to a loss of cardiac contractility. CONCLUSION: The manifestation of AVC coupling imbalance could act as a complementary parameter to support the diagnosis of DD.


Assuntos
Artérias , Ventrículos do Coração , Exercício Físico , Humanos , Contração Miocárdica , Projetos Piloto
3.
Nat Commun ; 11(1): 4283, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883967

RESUMO

Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing.


Assuntos
Matriz Extracelular/metabolismo , Fator 4 de Crescimento de Fibroblastos/metabolismo , Coração , Células-Tronco Embrionárias Murinas/metabolismo , Organoides , Potenciais de Ação , Diamino Aminoácidos/metabolismo , Animais , Biomimética/métodos , Diferenciação Celular , Linhagem Celular , Células Endoteliais , Coração/crescimento & desenvolvimento , Coração/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Contração Miocárdica , Miocárdio , Organoides/citologia , Organoides/crescimento & desenvolvimento , Organoides/ultraestrutura
5.
PLoS One ; 15(8): e0237305, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822421

RESUMO

Diabetes can elicit direct deleterious effects on the myocardium, independent of coronary artery disease or hypertension. These cardiac disturbances are termed diabetic cardiomyopathy showing increased risk of heart failure with or without reduced ejection fraction. Presently, there is no specific treatment for this type of cardiomyopathy and in the case of type I diabetes, it may start in early childhood independent of glycemic control. We hypothesized that alterations in isolated myocyte contractility and cardiac function are present in the early stages of experimental diabetes in rats before overt changes in myocardium structure occur. Diabetes was induced by single-dose injection of streptozotocin (STZ) in rats with data collected from control and diabetic animals 3 weeks after injection. Left ventricle myocyte contractility was measured by single-cell length variation under electrical stimulation. Cardiac function and morphology were studied by high-resolution echocardiography with pulsed-wave tissue Doppler imaging (TDI) measurements and three-lead surface electrocardiogram. Triglycerides, cholesterol and liver enzyme levels were measured from plasma samples obtained from both groups. Myocardial collagen content and perivascular fibrosis of atria and ventricle were studied by histological analysis after picrosirius red staining. Diabetes resulted in altered contractility of isolated cardiac myocytes with increased contraction and relaxation time intervals. Echocardiography showed left atrium dilation, increased end-diastolic LV and posterior wall thickness, with reduced longitudinal systolic peak velocity (S') of the septum mitral annulus at the apical four-chamber view obtained by TDI. Triglycerides, aspartate aminotransferase and alkaline phosphatase were elevated in diabetic animals. Intertitial collagen content was higher in atria of both groups and did not differ among control and diabetic animals. Perivascular intramyocardial arterioles collagen did not differ between groups. These results suggest that alterations in cardiac function are present in the early phase in this model of diabetes type 1 and occur before overt changes in myocardium structure appear as evaluated by intersticial collagen deposition and perivascular fibrosis of intramyocardial arterioles.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Cardiomiopatias Diabéticas/fisiopatologia , Contração Miocárdica , Miócitos Cardíacos/patologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/patologia , Ratos , Estreptozocina
6.
PLoS One ; 15(8): e0236457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790682

RESUMO

Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (CardiacCRT+) were analyzed. CardiacCRT+ cardiomyocytes showed increased contractility and Ca2+ transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of CardiacCRT+ mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from CardiacCRT+ mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, CardiacCRT+ hearts showed less efficient cardiac function than sham control hearts due to an increased ATP production from glycolysis relative to glucose oxidation. During reperfusion, this inefficiency was reversed, with CardiacCRT+ hearts exhibiting better functional recovery and increased cardiac efficiency compared to sham control hearts. On the other hand, mechanical stretching of isolated cardiac fibroblasts activated the IRE1α branch of the unfolded protein response pathway as well as induction of Col1A2 and TGFß gene expression ex vivo, which were all suppressed by tauroursodeoxycholic acid.


Assuntos
Calreticulina/metabolismo , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Calreticulina/genética , Células Cultivadas , Metabolismo Energético , Frequência Cardíaca , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Isquemia Miocárdica/genética , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/patologia , Regulação para Cima
7.
Transplantation ; 104(9): 1890-1898, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32826843

RESUMO

BACKGROUND: Ex situ heart perfusion (ESHP) limits ischemic periods and enables continuous monitoring of donated hearts; however, a validated assessment method to predict cardiac performance has yet to be established. We compare biventricular contractile and metabolic parameters measured during ESHP to determine the best evaluation strategy to estimate cardiac function following transplantation. METHODS: Donor pigs were assigned to undergo beating-heart donation (n = 9) or donation after circulatory death (n = 8) induced by hypoxia. Hearts were preserved for 4 hours with ESHP while invasive and noninvasive (NI) biventricular contractile, and metabolic assessments were performed. Following transplantation, hearts were evaluated at 3 hours of reperfusion. Spearman correlation was used to determine the relationship between ESHP parameters and posttransplant function. RESULTS: We performed 17 transplants; 14 successfully weaned from bypass (beating-heart donation versus donation after circulatory death; P = 0.580). Left ventricular invasive preload recruitable stroke work (PRSW) (r = 0.770; P = 0.009), NI PRSW (r = 0.730; P = 0.001), and NI maximum elastance (r = 0.706; P = 0.002) strongly correlated with cardiac index (CI) following transplantation. Right ventricular NI PRSW moderately correlated to CI following transplantation (r = 0.688; P = 0.003). Lactate levels were weakly correlated with CI following transplantation (r = -0.495; P = 0.043). None of the echocardiography measurements correlated with cardiac function following transplantation. CONCLUSIONS: Left ventricular functional parameters, especially ventricular work and reserve, provided the best estimation of myocardial performance following transplantation. Furthermore, simple NI estimates of ventricular function proved useful in this setting. Right ventricular and metabolic measurements were limited in their ability to correlate with myocardial recovery. This emphasizes the need for an ESHP platform capable of assessing myocardial contractility and suggests that metabolic parameters alone do not provide a reliable evaluation.


Assuntos
Transplante de Coração/métodos , Preservação de Órgãos/métodos , Perfusão , Doadores de Tecidos , Função Ventricular Esquerda/fisiologia , Animais , Ecocardiografia , Masculino , Contração Miocárdica , Miocárdio/metabolismo , Suínos
8.
J Vis Exp ; (160)2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32628167

RESUMO

In this article, we describe the steps required to isolate a single permeabilized ("skinned") cardiomyocyte and attach it to a force-measuring apparatus and a motor to perform functional studies. These studies will allow measurement of cardiomyocyte stiffness (passive force) and its activation with different calcium (Ca2+)-containing solutions to determine, amongst others: maximum force development, myofilament Ca2+-sensitivity (pCa50), cooperativity (nHill) and the rate of force redevelopment (ktr). This method also enables determination of the effects of drugs acting directly on myofilaments and of the expression of exogenous recombinant proteins on both active and passive properties of cardiomyocytes. Clinically, skinned cardiomyocyte studies highlight the pathophysiology of many myocardial diseases and allow in vitro assessment of the impact of therapeutic interventions targeting the myofilaments. Altogether, this technique enables the clarification of cardiac pathophysiology by investigating correlations between in vitro and in vivo parameters in animal models and human tissue obtained during open heart or transplant surgery.


Assuntos
Citoesqueleto de Actina/metabolismo , Cálcio/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Contração Miocárdica , Miócitos Cardíacos/fisiologia , Animais , Camundongos , Miócitos Cardíacos/citologia , Miofibrilas
9.
Am J Cardiol ; 128: 45-53, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650923

RESUMO

Early-onset cardiomyopathy is a major concern for people with type 1 diabetes mellitus (DM). Studies examining myocardial deformation indices early in the disease process in people with have provided conflicting results. Accordingly, the objective was to examine left ventricular (LV) function in adolescents with type 1 DM using novel measures of cardiomyopathy, termed ventricular discoordination indices, including systolic stretch fraction (SSF), and our newly developed diastolic relaxation fraction (DRF). Adolescents with DM (n = 16) and healthy controls (n = 20) underwent cardiac MRI (CMR) tissue tracking analysis for standard volumetric and functional analysis. Segment-specific circumferential strain and strain rate indices were evaluated to calculate standard mechanical dyssynchrony and discoordination. SSF and DRF were calculated from strain rate data. There were no global or regional group differences between participants with DM and controls in standard LV strain mechanics. However, youth with DM had lower diastolic strain rate around the inferior septal and free wall region (all p <0.05) as well as higher SSF (p = 0.03) and DRF (p <0.001) compared with controls. None of the CMR indices correlated with HbA1c or diabetes duration. In conclusion, our results suggest that adolescents with DM have LV systolic and diastolic discoordination, providing early evidence of cardiomyopathy despite their young age. The presence of discoordination in the setting of normal LV size and function suggests that the proposed novel discoordination indices could serve as a more sensitive marker of cardiomyopathy than previously employed mechanical deformation indices.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Contração Miocárdica/fisiologia , Disfunção Ventricular Esquerda/epidemiologia , Função Ventricular Esquerda , Adolescente , Estudos de Casos e Controles , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/fisiopatologia , Diástole , Feminino , Humanos , Imagem por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Masculino , Sístole , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
10.
PLoS Comput Biol ; 16(7): e1008048, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658888

RESUMO

Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+→AP coupling and AP→Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue's susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.


Assuntos
Remodelamento Atrial , Insuficiência Cardíaca/fisiopatologia , Potenciais de Ação , Algoritmos , Animais , Fibrilação Atrial/fisiopatologia , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Simulação por Computador , Cães , Condutividade Elétrica , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Camundongos , Modelos Cardiovasculares , Contração Miocárdica , Miócitos Cardíacos/patologia , Fosforilação , Retículo Sarcoplasmático/metabolismo
11.
Nat Commun ; 11(1): 3405, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636378

RESUMO

Omecamtiv mecarbil (OM) is a putative positive inotropic tool for treatment of systolic heart dysfunction, based on the finding that in vivo it increases the ejection fraction and in vitro it prolongs the actin-bond life time of the cardiac and slow-skeletal muscle isoforms of myosin. OM action in situ, however, is still poorly understood as the enhanced Ca2+-sensitivity of the myofilaments is at odds with the reduction of force and rate of force development observed at saturating Ca2+. Here we show, by combining fast sarcomere-level mechanics and ATPase measurements in single slow demembranated fibres from rabbit soleus, that the depressant effect of OM on the force per attached motor is reversed, without effect on the ATPase rate, by physiological concentrations of inorganic phosphate (Pi) (1-10 mM). This mechanism could underpin an energetically efficient reduction of systolic tension cost in OM-treated patients, whenever [Pi] increases with heart-beat frequency.


Assuntos
Miosinas Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miosinas/metabolismo , Fosfatos/farmacologia , Ureia/análogos & derivados , Adenosina Trifosfatases/metabolismo , Animais , Cálcio/metabolismo , Sinergismo Farmacológico , Masculino , Músculo Esquelético/metabolismo , Coelhos , Sarcômeros/metabolismo , Estresse Mecânico , Ureia/farmacologia
12.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
13.
Am J Physiol Heart Circ Physiol ; 319(2): H306-H319, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618513

RESUMO

Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin-filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. Contraction and Ca2+ reuptake times were slowed, which contrast with some findings in murine models of myofilament Ca2+ desensitization. We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in sodium-calcium exchanger activity. We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes expressing DCM mutations. These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM. Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes. However, we find several common pathways such as increased relaxation times and NFAT activation that are also hallmarks of HCM. This suggests more complex intracellular signaling underpinning DCM, driven by the primary mutation.NEW & NOTEWORTHY Dilated cardiomyopathy (DCM) is a frequently occurring cardiac disorder with a degree of genetic inheritance. We have found that DCM mutations in proteins that regulate the contractile machinery cause alterations to contraction, calcium-handling, and some new signaling pathways that provide stimuli for disease development. We have used guinea pig cells that recapitulate human calcium-handling and introduced the mutations using adenovirus gene transduction to look at the initial triggers of disease before remodeling.


Assuntos
Sinalização do Cálcio , Cardiomiopatia Dilatada/genética , Proteínas dos Microfilamentos/genética , Mutação , Contração Miocárdica , Miócitos Cardíacos/enzimologia , Fatores de Transcrição NFATC/metabolismo , Proteína Oncogênica v-akt/metabolismo , Função Ventricular Esquerda , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/fisiopatologia , Células Cultivadas , Predisposição Genética para Doença , Cobaias , Masculino , Proteínas dos Microfilamentos/metabolismo , Fenótipo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo
15.
Int J Cardiovasc Imaging ; 36(10): 2027-2038, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32533279

RESUMO

In patients with heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM) and obesity are important comorbidities as well as major risk factors. Their conjoint impact on the myocardium provides insight into the HFpEF aetiology. We sought to investigate the association between obesity, DM, and their combined effect on alterations in the myocardial tissue in HFpEF patients. One hundred and sixty-two HFpEF patients (55 ± 12 years, 95 men) and 45 healthy subjects (53 ± 12 years, 27 men) were included. Patients were classified according to comorbidity prevalence (36 obese patients without DM, 53 diabetic patients without obesity, and 73 patients with both). Myocardial remodeling, fibrosis, and longitudinal contractility were quantified with cardiovascular magnetic resonance imaging using cine and myocardial native T1 images. Patients with DM and obesity had impaired global longitudinal strain (GLS) and increased myocardial native T1 compared to patients with only one comorbidity (DM + Obesity vs. DM and Obesity; GLS, - 15 ± 2.1 vs - 16.5 ± 2.4 and - 16.7 ± 2.2%; native T1, 1162 ± 37 vs 1129 ± 25 and 1069 ± 29 ms; P < 0.0001 for all). A negative synergistic effect of combined obesity and DM prevalence was observed for native T1 (np2 = 0.273, p = 0.002) and GLS (np2 = 0.288, p < 0.0001). Additionally, severity of insulin resistance was associated with GLS (R = 0.590, P < 0.0001), and native T1 (R = 0.349, P < 0.0001). The conjoint effect of obesity and DM in HFpEF patients is associated with diffuse myocardial fibrosis and deterioration in GLS. The negative synergistic effects observed on the myocardium may be related to severity of insulin resistance.


Assuntos
Diabetes Mellitus/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Obesidade/fisiopatologia , Volume Sistólico , Função Ventricular Esquerda , Adulto , Idoso , Boston/epidemiologia , Comorbidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Feminino , Fibrose , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Obesidade/diagnóstico , Obesidade/epidemiologia , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , Fatores de Risco , Remodelação Ventricular
16.
PLoS Comput Biol ; 16(6): e1007572, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502205

RESUMO

Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.


Assuntos
Cálcio/metabolismo , Ventrículos do Coração/metabolismo , Íons , Células Musculares/metabolismo , Animais , Simulação por Computador , Citosol/metabolismo , Homeostase , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Coelhos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sístole
17.
Medicine (Baltimore) ; 99(21): e20349, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481325

RESUMO

AIMS: The purpose of the present trial is to determine whether opening co-existing chronic total occlusions (CTOs) using percutaneous coronary interventions (PCIs) improves cardiac function in patients with multi-vessel disease (MVD). Patients with MVD are defined as having at least one additional major vessel exhibiting no less than 75% stenosis combined with the presence of a CTO artery. METHODS AND RESULTS: Patients will be prospectively recruited who meet the following criteria:Patients presenting with no necrosis of myocardial tissue in the territory of the CTO will be excluded. Recruited patients will be randomized into 2 groups: those undergoing PCI of only the non-CTO artery (non-CTO PCI group), and those undergoing PCI of the non-CTO artery concurrently with the CTO artery (CTO-PCI group). The primary outcome will be the change in cardiac function evaluated via CMR at a 12-month of follow-up appointment, which will be compared to a baseline measurement. Secondary outcomes include occurrence of major cardiac events, CMR-assessed myocardial viability in the CTO-supplied territory, and quality of life assessed by Seattle angina questionnaire, Patient Health Questionnaire 9 and Generalized Anxiety Disorder Scale-7 after 12-month follow-up. CONCLUSION: The SOS-moral trial will provide data necessary to determine whether to open concurrent CTOs among MVD patients with CMR-detected necrotic myocardial tissue.


Assuntos
Oclusão Coronária/cirurgia , Vasos Coronários/diagnóstico por imagem , Contração Miocárdica/fisiologia , Intervenção Coronária Percutânea/métodos , Função Ventricular Esquerda/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Angiografia Coronária , Oclusão Coronária/diagnóstico , Vasos Coronários/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
18.
PLoS One ; 15(5): e0233719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469960

RESUMO

The formation of a tube-like structure is a basic step in the making of functional hearts in vertebrates and invertebrates and therefore, its understanding provides important information on heart development and function. In Drosophila, the cardiac tube originates from two bilateral rows of dorsally migrating cells. On meeting at the dorsal midline, coordinated changes in cell shape and adhesive properties transform the two sheets of cells into a linear tube. ECM and transmembrane proteins linked to the cytoskeleton play an important role during these dynamic processes. Here we characterize the requirement of Cbl-Associated Protein (CAP) in Drosophila heart formation. In embryos, CAP is expressed in late migrating cardioblasts and is located preferentially at their luminal and abluminal periphery. CAP mutations result in irregular cardioblast alignment and imprecisely controlled cardioblast numbers. Furthermore, CAP mutant embryos show a strongly reduced heart lumen and an aberrant shape of lumen forming cardioblasts. Analysis of double heterozygous animals reveals a genetic interaction of CAP with Integrin- and Talin-encoding genes. In post-embryonic stages, CAP closely colocalizes with Integrin near Z-bands and at cell-cell contact sites. CAP mutants exhibit a reduced contractility in larval hearts and show a locally disrupted morphology, which correlates with a reduced pumping efficiency. Our observations imply a function of CAP in linking Integrin signaling with the actin cytoskeleton. As a modulator of the cytoskeleton, CAP is involved in the establishment of proper cell shapes during cardioblast alignment and cardiac lumen formation in the Drosophila embryo. Furthermore, CAP is required for correct heart function throughout development.


Assuntos
Movimento Celular , Proteínas de Drosophila/metabolismo , Embrião não Mamífero/embriologia , Coração/embriologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Contração Miocárdica , Organogênese , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Proteínas de Transporte de Monossacarídeos/genética , Mutação
19.
Am J Cardiol ; 127: 163-168, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32444028

RESUMO

Anthracycline-induced cardiotoxicity can lead to clinical and subclinical heart failure. Decrease of global longitudinal strain is a predictor for heart failure. Early detection of subclinical cardiotoxicity is crucial for timely intervention and prevention of further progression. Cardiac function of 41 survivors of childhood acute lymphoblastic leukemia (ALL) was assessed. Values of cardiac troponin T, N-terminal-pro-brain natriuretic peptide, conventional and myocardial 2D strain echocardiography were measured before (T = 0), during (T = 1, cumulative dose of 120 mg/m2), shortly after (T = 2) and long after anthracycline treatment (T = 3, ≥5 years after anthracycline exposure). Cardiac function of survivors at the latest follow up was compared with 70 healthy age-matched controls. None of the survivors showed clinical signs of cardiac failure at T = 3. Strain values decreased during anthracycline treatment and an ongoing reduction was seen at the latest follow-up (T = 3) with preserved cardiac function (normal ejection fraction and shortening fraction). At T = 1, a relative reduction in longitudinal strain (≥10% compared with baseline) was observed in 38% of the survivors, which increased to 54% at T=3. ALL survivors showed significantly lower conventional and myocardial 2D strain values, especially strain rate, compared with healthy age-matched controls. At T = 3, we did not find any abnormal cardiac troponin T levels. Six percent of the survivors showed abnormal N-terminal-pro-brain natriuretic peptide levels. This prospective study showed an ongoing reduction of 2D myocardial strain and strain rate, with preserved left ventricular ejection fraction (≤10% decrease compared with baseline) in asymptomatic ALL survivors at late follow-up.


Assuntos
Antraciclinas/uso terapêutico , Ecocardiografia/métodos , Eletrocardiografia , Cardiopatias/fisiopatologia , Contração Miocárdica/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Humanos , Masculino , Países Baixos/epidemiologia , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo
20.
Anesth Analg ; 131(2): 527-536, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371741

RESUMO

BACKGROUND: Catecholamine inotropes are frequently used after cardiopulmonary bypass (CPB) but may have undesirable effects. The aim was to identify whether the routine use of inhaled pulmonary vasodilators might reduce the requirement for inotrope drugs after cardiac surgery. METHODS: Retrospective cohort study of sequential patients undergoing cardiac surgery at the Royal Melbourne Hospital performed by a single surgeon and anesthesia care team, within 14 months before and after routine implementation of inhaled pulmonary vasodilators, August 2017. Milrinone 4 mg and iloprost 20 µg were inhaled using a vibrating mesh nebulizer (Aerogen) before initiation of CPB and at chest closure. Other aspects of clinical management were unaltered over the time period. Two investigators blinded to each other extracted data from electronic and written medical records. The primary outcome was any use of inotropes in the perioperative period; a Fisher exact test was used to analyze any differences between the 2 groups. Demographic data, hemodynamic data, and use of inotropes and vasopressors were collected from induction of anesthesia to 36 hours postoperative in the intensive care unit (ICU). Hospital and ICU length of stay, cost, and complications were collected. RESULTS: Any use of inotropes was significantly lower with inhaled pulmonary dilators (62.5% vs 86.8%, odds ratio [95% confidence interval {CI}], 0.253 (0.083-0.764); P = .011), including intraoperative inotrope use (37.5% vs 86.8%, odds ratio [95% CI], 0.091 (0.03-0.275); P < .001). ICU length of stay was significantly lower with inhaled pulmonary dilators (45 hours, interquartile range [IQR], 27-65 vs 50 hours, IQR, 45-74; P = .026). There were no significant differences among major postoperative complications or costs between groups. CONCLUSIONS: Routine use of inhaled milrinone 4 mg and iloprost 20 µg before and after CPB is associated with reduced postoperative inotrope use.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Iloprosta/administração & dosagem , Complicações Intraoperatórias/prevenção & controle , Milrinona/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Administração por Inalação , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiotônicos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Cuidados Intraoperatórios/métodos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/etiologia , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Projetos Piloto , Estudos Retrospectivos
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