Cardiomyocyte dysfunction during the chronic phase of Chagas disease (original) (raw)
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Altered Cardiomyocyte Function and Trypanosoma cruzi Persistence in Chagas Disease
The American journal of tropical medicine and hygiene, 2016
Chagas disease, caused by the triatominae Trypanosoma cruzi, is one of the leading causes of heart malfunctioning in Latin America. The cardiac phenotype is observed in 20-30% of infected people 10-40 years after their primary infection. The cardiac complications during Chagas disease range from cardiac arrhythmias to heart failure, with important involvement of the right ventricle. Interestingly, no studies have evaluated the electrical properties of right ventricle myocytes during Chagas disease and correlated them to parasite persistence. Taking advantage of a murine model of Chagas disease, we studied the histological and electrical properties of right ventricle in acute (30 days postinfection [dpi]) and chronic phases (90 dpi) of infected mice with the Colombian strain of T. cruzi and their correlation to parasite persistence. We observed an increase in collagen deposition and inflammatory infiltrate at both 30 and 90 dpi. Furthermore, using reverse transcriptase polymerase cha...
Cardiovascular Research, 2000
Objective: Myocardial cellular electrophysiology and intracellular Ca regulation are altered in heart failure. The extent of these 21 changes may vary within the layers of the ventricular wall. To examine this, cell size, action potential and intracellular Ca transient characteristics (Fura-2) were measured in single cardiac myocytes from sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricle of rabbits with heart failure. Methods: Myocytes were isolated from animals with heart failure induced by chronic coronary artery ligation and from sham operated controls. Trans-membrane potential was measured using high resistance microelectrodes electrodes (30 MV; 2 M KCl). Fura-2 was loaded into cells by incubation with the AM form. Subsequent fluorescence measurements 21 were used to measure intracellular Ca concentration at a range of stimulus frequencies. Results: Resting cell length was significantly greater in the heart failure group; |115% of control values in sub-epicardial and mid-myocardial cells, and |108% in sub-endocardial cells. Using criteria described by previous studies on other mammalian hearts, functional M cells were identified by a higher maximum rate of depolarisation and longer action potential duration at 90% repolarisation (APD) compared to the two other myocyte sub-types. In 90 21 the heart failure group, APD and Ca transient duration (CaD) were prolonged in sub-epicardial and M cells but shortened in 90 50 sub-endocardial myocytes. These changes were significant at lower stimulus frequencies, but the relative effect diminished at higher 21 frequencies (3 Hz). Peak systolic [Ca ] was reduced in sub-epicardial and M cells but increased in sub-endocardial cells in the heart 21 failure group compared to controls. At higher stimulus frequencies, end diastolic Ca levels were lower in sub-epicardial cells but higher in sub-endocardial myocytes of the heart failure group compared with controls. In general, changes were greater in heart failure animals with more severe in vivo ventricular dysfunction (ejection fraction #44%). Conclusions: Heart failure was associated with an increased 21 cell size throughout the left ventricle, but the form of the changes in electrophysiology and Ca transient were dependent on the myocyte sub-type. In particular sub-endocardial cells displayed markedly different changes compared to the other myocyte sub-types.
A novel substrate for arrhythmias in Chagas disease
PLOS Neglected Tropical Diseases, 2021
Background Chagas disease (CD) is a neglected disease that induces heart failure and arrhythmias in approximately 30% of patients during the chronic phase of the disease. Despite major efforts to understand the cellular pathophysiology of CD there are still relevant open questions to be addressed. In the present investigation we aimed to evaluate the contribution of the Na+/Ca2+ exchanger (NCX) in the electrical remodeling of isolated cardiomyocytes from an experimental murine model of chronic CD. Methodology/Principal findings Male C57BL/6 mice were infected with Colombian strain of Trypanosoma cruzi. Experiments were conducted in isolated left ventricular cardiomyocytes from mice 180–200 days post-infection and with age-matched controls. Whole-cell patch-clamp technique was used to measure cellular excitability and Real-time PCR for parasite detection. In current-clamp experiments, we found that action potential (AP) repolarization was prolonged in cardiomyocytes from chagasic mic...
Dysfunction of Diastolic [Ca2+] in Cardiomyocytes Isolated From Chagasic Patients
Revista Española de Cardiología (English Edition), 2011
Introduction and objectives: Chagas is an endemic disease in Latin America, caused by the parasite Trypanosoma cruzi, which usually affects the functioning of the heart. We have studied the regulation of intracellular calcium in cardiomyocytes isolated from chagasic patients with different degrees of heart dysfunction. Methods: Calcium selective microelectrodes were used to simultaneously measure diastolic calcium concentration ([Ca 2+ ] d ) and resting membrane potential in endomyocardial biopsies obtained from chagasic patients and controls. Results: The [Ca 2+ ] d increased by 123%, 295%, and 738% in chagasic patients in functional class I, II, and III, respectively, in relation to controls. Membrane potential showed a partial depolarization of 6% in functional class I, 10% in functional class II, and 22% in functional class III, compared to control values. Alteration in the [Ca 2+ ] d was partially reverted by 1-[6-[[(17ß)-3-metoxyestra-1,3,5(10)-trien-17yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), a b-phospholipase C antagonist, and by 2aminoethoxydiphenyl-borate (2-APB), an inositol 1,4,5-trisphosphate receptor blocker. Phenylephrine, an agent that induces a rapid transient increase in 1,4,5-trisphosphate intracellular content, produced a rise in [Ca 2+ ] d , higher in chagasic cardiomyocytes than in controls, and its effect was fully inhibited by 2-APB. Conclusions: In cardiomyocytes from chagasic patients there is a dysfunction of the regulation of the [Ca 2+ ] d , which correlates with the cardiac abnormalities observed in the different stages of the disease. This disturbance in the regulation of intracellular calcium appears to be associated with alterations in the regulation of intracellular messenger inositol 1,4,5-trisphosphate. ß 2011 Sociedad Españ ola de Cardiología. Published by Elsevier Españ a, S.L. All rights reserved. Disfunció n de la [Ca 2+ ] diastó lica en cardiomiocitos aislados de pacientes chagá sicos Palabras clave: Enfermedad de Chagas Calcio Inositol trifosfato Microelectrodos de calcio U-73122 2-aminoetoxidifenil borato Fenilefrina R E S U M E N Introduccio´n y objetivos: La enfermedad de Chagas es un mal endé mico en Latinoamé rica, causado por el pará sito Trypanosoma cruzi, que generalmente afecta al funcionamiento del corazó n. Estudiamos la regulació n del calcio intracelular en cardiomiocitos de pacientes chagá sicos con diversos grados de deterioro funcional. Me´todos: Se utilizaron microelectrodos selectivos para el calcio para determinar simultá neamente la concentració n diastó lica de calcio ([Ca 2+ ] d ) y el potencial de membrana en biopsias endomiocá rdicas de pacientes chagá sicos y controles. Resultados: La [Ca 2+ ] d aumentó el 123, el 295 y el 738% en los pacientes chagá sicos de los grupos funcionales I, II y III, respectivamente, respecto a los controles. El potencial de membrana mostró una parcial despolarizació n de un 6% en el grupo funcional I, el 10% en el II y el 22% en el III respecto a los controles. La [Ca 2+ ] d se revirtió parcialmente con 1-[6-[[(17ß)-3-metoxiestra-1,3,5(10)-trieno-17il]amino]hexil]-1H-pirrole-2,5-diona (U-73122), antagonista de la betafosfolipasa C, y 2-aminoetoxidifenil borato (2-APB), inhibidor de los receptores de inositol 1,4,5-trifosfato. La fenilefrina, fá rmaco que induce una rá pida elevació n del contenido intracelular del inositol 1,4,5-trifosfato, incrementó la [Ca 2+ ] d en cardiomiocitos controles y chagá sicos, que fue mayor en los cardiomicitos chagá sicos y se inhibió por 2-APB.
Lecture Notes in Computer Science, 2008
Chagas' Disease is an endemic infection in many areas of South and Central America that may cause a fatal type of myocarditis. In the acute phase of the disease, ventricular extrasystoles and tachycardia have been reported. Experiments with cardiac myocytes in the acute stage of Chagas' Disease have suggested a depression of Ito, the Ca 2+-independent K + Transient Outward current. In this work we use computational models of left ventricular myocytes of adult rats to qualify the effects of Ito reduction that appear during the acute phase of Chagas' Disease. The simulations are carried out by Web applications based on the CellML language, a recently emerged international standard for the description of biological models. The computational framework supports the development of mathematical models, simulations and visualization of the results. Our preliminary simulation results suggest that the reduction of Ito density elicits modifications of electrophysiological mechanisms that are strongly related to the phenomena of arrhythmia.
The extensive advance in the transgenic mice development technology in the cardiac pathology field requires an accurate knowledge of pathological electrocardiographic traces in murine models that must be clearly different from traces obtained in healthy mice and also reproduce electrocardiographic patterns observed in human cardiac pathologies. Chagas' disease could be an excellent model to distinguish between normal and abnormal murine electrocardiographic patterns, since chagasic myocarditis has a well-defined and widely characterized electrocardiographic signs. In order to identify abnormal electrocardiographic signs in NMRI mice, contrast electrocardiographic analysis between healthy and chagasic was accomplished. Electrocardiographic records were done under general anesthesia on 74 healthy and 174 chagasic mice. Results showed that the electrocardiographic profiles associated to mice with chagasic myocarditis were: atrial disturbances represented as negative, bimodal or double dissimilar P wave; myocarditis revealed a decrease in the amplitude of the QRS complex (mainly R wave) and lengthening of PR, QRS and QT intervals; ventricular repolarization disorders visualized as a decrease in the S wave rise, flattening of J wave which also it can delineate a plateau instead of a peak, prolonged J wave decay, TP segment above the isoelectric line, J wave inversion and U waves emerging from J wave decay that could represent early after depolarizations. In conclusion, the electrocardiographic data associated with mice with acute chagasic myocarditis reflect pathological electrocardiographic characteristics that could be used in the electrocardiographic analysis in cardiac disease mice models.
Calcium sensitivity of force in human ventricular cardiomyocytes from donor and failing hearts
Basic Research in Cardiology, 2002
In failing human myocardium changes occur, in particular, in isoform composition and phosphorylation level of the troponin T (TnT) and troponin I (TnI) subunits of the actin filament and the myosin light chains (MLC-1 and -2), but it is unclear to what extent they influence cardiac performance. This overview concentrates on the relation between contractile function, contractile protein composition and phosphorylation levels in small biopsies from control (donor) hearts, from biopsies obtained during open heart surgery (NYHA Class I – IV) and from end-stage failing (explanted, NYHA class IV) hearts. Furthermore, attention is paid to the effect of the catalytic subunit of protein kinase A on isometric force development in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at different resting sarcomere lengths. A reduction in sarcomere length from 2.2 to 1.8 μm caused reductions in maximum isometric force by approximately 35 % both in donor and in failing cardiomyocytes. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean ΔpCa50 = 0.22). Our findings indicate that 1) TnI phosphorylation contributes to the differences in calcium sensitivity between donor and end-stage failing hearts, 2) human ventricular myocardium is heterogeneous with respect of the phosphorylation of TnT, MLC-2 and the isoform distribution of MLC-1 and MLC-2, and 3) the Frank-Starling mechanism is preserved in end-stage failing myocardium.
The protein composition of the normal and diseased cardiac myocyte
Heart failure …, 1998
We present a classi~cation of the proteins of the cardiomyocyte based on structural and functional properties of the various components of this cell. The following protein families are categorized: 1) the contractile proteins, responsible for the contractile properties; 2) the sarcomeric skeleton, including titin, a-actinin, myomesin, Mprotein, and C-protein, that keeps the contractile~laments in register and ensures sarcomeric stability; 3) the cytoskeletal proteins, i.e., desmin and the microtubules, that maintain the structural order within the cell and connect the cytoplasm and all cellular organelles with the sarcolemma; 4) membrane-associated proteins, such as vinculin, talin, dystrophin, and spectrin, that link the structural components of the intracellular milieu with those of the extracellular matrix via the integrins; and 5) proteins of the intercalated disc, including the cadherins, catenins, desmoplakin, connexin 43, and several others, that ensure stability of the longitudinal cardiomyocyte connections and facilitate impulse conduction.