Why do aortas cleave or dilate? Clues from an electronic scanning microscopy study in human ascending aortas.

In ascending aorta aneurysms (AscAA) the whole vessel wall dilates, while in aortic dissections (AD) the wall cleaves into two sheets. Both may present fine elastic fragmentation and a decrease in collagen. We analyzed whether alterations in the three-dimensional structure of these fibers could be involved in the pathogenesis of AscAA/AD. Specimens obtained at surgery for these diseases (n = 4 for each) and on coronary artery bypass surgery (controls, n = 4) were submitted to treatments which either preserve collagen or the elastic structure. These samples were examined by scanning electron microscopy. In all groups most of the collagen fibers were packed, forming laminar structures very similar to the elastic lamellae. In AscAA/AD, the fibers showed signs of degradation and/or fragmentation. Elastic tissue was distributed in large sheets with fenestrations, with smaller branches between them. In 1 of the dissection cases and 2 of the aneurysm cases elastic sheet fragmentation, which under light microscopy seems to be located at random, had a pattern of clefts which were irregular but approximately transversal to the main axis of the wall. The recognition of this pattern and the degradation/fragmentation of collagen and elastic fibrils facilitates understanding of why the wall is weak and affected by aneurysms and dissections.

Are telocytes related to maintenance of vascular homeostasis in normal and pathological aorta?

The telocyte (TC) is a new interstitial cell type described in a wide variety of organs and loose connective tissues around small vessels, but its presence in large arteries remains unexplored. TCs have small cell bodies and remarkably thin, long, moniliform processes called telopods (Tps). Using transmission electron microscopy and immunofluorescence, we identified TCs in normal human thoracic aortas and in those with aneurysm or acute dissection (TAAD). In normal aortas the TCs were distributed throughout the connective tissue of the adventitial layer, in its innermost portion and at the zone of transition with the medial layer, with their long axes oriented parallel to the external elastic lamellae, forming a three-dimensional network, without prevalence in the media layer. In contrast, TAAD TCs were present in the medial layer and in regions of neovascularization. The most important feature of the adventitia of diseased aortas was the presence of numerous contacts between TCs and stem cells, including vascular progenitor cells. Although the biologically functional correlations need to be elucidated, the morphological observations presented here provide strong evidence of the involvement of TCs in maintaining vascular homeostasis in pathological situations of tissue injury.

Case Report: The Challenge for Diagnosis of Myocarditis and Transplant Rejection After COVID Infection in a Heart-Transplanted Adolescent.

Patients who have undergone organ transplantation are immunosuppressed hosts, leaving them at a higher risk of infections. SARS-COV-2 has been shown to affect heart-transplanted patients. In this case report, we present the case of a 14-year-old heart transplant recipient who developed signs and symptoms of heart failure, along with fatigue, after a COVID-19 infection. An endomyocardial biopsy was performed to diagnose rejection and to evaluate whether this was myocarditis due to SARS-COV-2. The biopsy showed intense acute cellular rejection (3R) and antibody rejection PAMR1 H+ but was negative for the SARS-CoV-2 virus. The patient received organ rejection therapy with high-dose methylprednisolone and human immunoglobulin. After treatment, her heart function recovered, with biopsy investigations showing a lower level of cellular rejection (1R).

Short-term effects of hydroxyethylstarch resuscitation on systemic and regional hemodynamics and metabolism in a brain-dead canine model.

BACKGROUND: Hydroxyethylstarch (HES) is a synthetic polymer of glucose that has been suggested for therapeutic use in long-term plasma expansion. The aim of this study was to test the hypothesis that the infusion of a small volume of HES may provide benefits in systemic and regional hemodynamics and metabolism in a brain-dead canine model compared with large volume crystalloid resuscitation. METHODS: Fourteen mongrel dogs were subjected to a brain-death protocol by consecutive insufflations of a balloon catheter in the epidural space. One hour after induction of brain-death, the animals were randomly assigned to two groups: NS (0.9% NaCl, 33 mL/kg), and HES (6%HES 450/0.7, 17 mL/Kg). Systemic and regional hemodynamics were evaluated using Swan-Ganz, ultrasonic flowprobes, and arterial catheters. Serial blood samples were collected for blood gas, electrolyte, and serum chemistry analysis. Systemic, hepatic, and splanchnic O(2)-derived variables were also calculated. RESULTS: Epidural balloon insufflations induced a significant increase in mean arterial pressure, cardiac output (MAP and CO, respectively), regional blood flow, and systemic vascular resistance. Following the hyperdynamic phase, severe hypotension with normalization of systemic and regional blood flow was observed. Fluid resuscitation induced a prompt increase in MAP, CO, and portal vein blood flow, and a significant reduction in systemic and pulmonary vascular resistance. There were no differences between groups in metabolic indices, liver function tests (LFTs), or renal function tests. HES was more effective than NS in restoring cardiac performance in the first 2h after fluid resuscitation (P < 0.05). Both tested solutions partially and temporarily restored systemic and regional oxygen delivery. CONCLUSION: Small volumes of 6% HES 450/0.7 improved cardiovascular performance and provided the same regional hemodynamic and metabolic benefits of large volumes of isotonic crystalloid solutions.

Cardiac Autonomic Nervous System Remodeling May Play a Role in Atrial Fibrillation: A Study of the Autonomic Nervous System and Myocardial Receptors. / A Remodelação do Sistema Nervoso Autônomo Cardíaco pode Desempenhar um Papel na Fibrilação Atrial: Um Estudo do Sistema Nervoso Autônomo e Receptores Miocárdicos.

BACKGROUND: The primary factors that originate and perpetuate atrial fibrillation (AF) are electrical and anatomical substrate alterations. However, the central mechanisms governing AF perpetuation have not been elucidated yet, which is reflected on the modest results of the treatment in patients with long persistent AF. OBJECTIVE: To evaluate if human intrinsic cardiac autonomic nervous system (ICANS) remodeling, including nervous system fibers and muscarinic and ß-adrenergic receptors, play a role in permanent AF. METHODS: Heart necropsy samples from thirteen patients with heart disease and permanent AF and thirteen controls without AF were used. By using immunoperoxidase and histomorphometry quantification, we identified the following: the density of all fibers of the ICANS, sympathetic and parasympathetic fibers; and the percentage of myocardium positive for ß-adrenergic receptors 1, 2 and 3; G protein-coupled receptor kinase-5 (GRK-5); and muscarinic receptors M1 to M5. The results were compared using ANOVA and nested ANOVA and were adjusted according to the left atrium volume for all variables, and ß-blocker use to evaluate the expression of ß-receptors and GRK-5. RESULTS: There was an overall increase in the density of fibers of the ICANS (p=0.006), especially in atrial sympathetic nerve fibers (p=0.017). Only M1 muscarinic receptors were increased (5.87 vs 2.35, p=0.032). For adrenergic receptors, the results were positive for increased expression of ß-3 (37.41 vs 34.18, p=0.039) and GRK-5 (51.16 vs 47.66; p<0.001). ß-blocker use had no impact on ß-receptor expression. CONCLUSION: Increased ICANS innervation and remodeling receptor expression in regions prone to triggering AF may play a role in permanent AF.

FUNDAMENTO: Alterações do substrato elétrico e anatômico do coração são fatores que originam e perpetuam a fibrilação atrial (FA), porém, os mecanismos envolvidos não foram totalmente elucidados ainda. Objetivo: Avaliar o papel do remodelamento do sistema nervoso cardíaco intrínseco (SNCI), incluindo fibras nervosas e receptores muscarínicos e ß-adrenérgicos, na FA permanente humana. MÉTODOS: Foram avaliadas 4 amostras em átrios de 13 corações obtidos em necrópsias de pacientes com doença cardíaca e FA permanente, e em 13 controles com as mesmas doenças, porém, sem FA. Utilizando imunoperoxidase e histomorfometria, quantificamos a densidade das fibras do SNCI, bem como a porcentagem positiva de miocárdio para receptores ß-adrenérgicos 1, 2 e 3, receptor quinase 5 acoplado à proteína G (GRK-5), e receptores muscarínicos 1 a 5. Os resultados foram comparados usando ANOVA e ANOVA hierarquizada e ajustados pelo volume do átrio esquerdo e, para avaliação da expressão de receptores ß e GRK-5, pelo uso de ß-bloqueadores. Adotamos como significativo α = 0,05. RESULTADOS: Houve aumento na densidade das fibras ( p <0,01), especialmente nas fibras simpáticas ( p =0,02). Quanto aos receptores muscarínicos, só houve diferença nos M1, que estavam aumentados (5,87±4,52 vs 2,85±2,40; p =0,03). Quanto aos componentes do sistema adrenérgicos analisados, houve expressão aumentada de ß-3 (37,41 vs 34,18, p =0,04) e GRK-5 (51,16 vs 47,66; p<0,01). O uso de ß-bloqueadores não teve impacto na expressão de receptores beta. CONCLUSÃO: O aumento na inervação do SNCI e a alteração na expressão de receptores em regiões suscetíveis de desencadear FA podem ter um papel na fibrilação atrial permanente.

3D Echocardiography for Rheumatic Heart Disease Analysis: Ready for Prime Time.

Rheumatic heart disease (RHD) remains to be a very important health issue worldwide, mainly in underdeveloped countries. It continues to be a leading cause of morbidity and mortality throughout developing countries. RHD is a delayed non-suppurative immunologically mediated inflammatory response to the throat infection caused by a hemolytic streptococcus from the A group (Streptococcus pyogenes). RHD keeps position 1 as the most common cardiovascular disease in young people aged <25 years considering all the continents. The disease can lead to valvular cardiac lesions as well as to carditis. Rheumatic fever valvular injuries lead most commonly to the fusion and thickening of the edges of the cusps and to the fusion, thickening, and shortening of the chordae and ultimately to calcification of the valves. Valvular commissures can also be deeply compromised, leading to severe stenosis. Atrial and ventricular remodeling is also common following rheumatic infection. Mixed valvular lesions are more common than isolated valvular disorders. Echocardiography is the most relevant imaging technique not only to provide diagnostic information but also to enable prognostic data. Further, it presents a very important role for the correction of complications after surgical repair of rheumatic heart valvulopathies. Three-dimensional (3D) echocardiography provides additional anatomical and morphofunctional information of utmost importance for patients presenting rheumatic valvopathies. Accordingly, three-dimensional echocardiography is ready for routine use in patients with RHD presenting with valvular abnormalities.

Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway.

Common features such as elastic fibre destruction, mucoid accumulation, and smooth muscle cell apoptosis are co-localized in aneurysms of the ascending aorta of various aetiologies. Recent experimental studies reported an activation of TGF-beta in aneurysms related to Marfan (and Loeys-Dietz) syndrome. Here we investigate TGF-beta signalling in normal and pathological human ascending aortic wall in syndromic and non-syndromic aneurysmal disease. Aneurysmal ascending aortic specimens, classified according to aetiology: syndromic MFS (n = 15, including two mutations in TGFBR2), associated with BAV (n = 15) or degenerative forms (n = 19), were examined. We show that the amounts of TGF-beta1 protein retained within and released by aneurysmal tissue were greater than for control aortic tissue, whatever the aetiology, contrasting with an unchanged TGF-beta1 mRNA level. The increase in stored TGF-beta1 was associated with enhanced LTBP-1 protein and mRNA levels. These dysregulations of the extracellular ligand are associated with higher phosphorylated Smad2 and Smad2 mRNA levels in the ascending aortic wall from all types of aneurysm. This activation correlated with the degree of elastic fibre fragmentation. Surprisingly, there was no consistent association between the nuclear location of pSmad2 and extracellular TGF-beta1 and LTBP-1 staining and between their respective mRNA expressions. In parallel, decorin was focally increased in aneurysmal media, whereas biglycan was globally decreased in aneurysmal aortas. In conclusion, this study highlights independent dysregulations of TGF-beta retention and Smad2 signalling in syndromic and non-syndromic aneurysms of the ascending aorta.

Mitochondria in aneurysms and dissections of the human ascending aorta.

Factors causing the weakness that underlies thoracic aorta aneurysms and dissections are not well known. Based on the findings of apoptosis and ischemic-like necrosis, we hypothesized a possible role for mitochondrial disturbances in the pathogenesis of these diseases. To evaluate if mitochondria at the aortic medial layer are damaged, samples of ascending aortas with aneurysms (n = 6), acute dissections (n = 5), and hypertensive (n = 9) and normotensive controls (n = 7) were analyzed by transmission electron microscopy. Number of mitochondria, areas of cytoplasm, and areas of mitochondria were measured, and area percentage of the cytoplasm corresponding to mitochondria, their number by unit of area, and their mean area were calculated in randomly taken photographs. Data were compared using one-way analysis of variance or Kruskal-Wallis tests. Significant differences (P ≤ 0.05) were found in the number of mitochondria and their mean area, showing opposite results: the number increased and the mean area decreased from normotensive controls to hypertensive controls to acute dissections to aneurysms, although post hoc tests showed that only the differences between the aneurysms and either both controls (number of mitochondria/mm2: 10.37 in normotensive controls, 15.61 in hypertensive controls, and 43.67 in aneurysms) or normotensive controls only (mean area: 2800.15 in normotensive controls vs 894.91 µm2 in aneurysms) were significant. In conclusion, there are more, smaller mitochondria in ascending aorta aneurysms. This pattern possibly corresponds to dysfunctional mitochondria, indicating that alterations in the dynamics of these organelles may play a role in the pathogenesis of thoracic aorta aneurysms and dissections.

Comparison of MB fraction of creatine kinase mass and troponin I serum levels with necropsy findings in acute myocardial infarction.

Serum levels of troponin and heart-related fraction of creatine kinase (CK-MB) mass are used as diagnostic and prognostic criteria in myocardial infarction, but the relation between those levels and the necropsy-determined size of necrosis has not been tested in human beings. In this retrospective study, 1-cm-thick transverse sections of the ventricles were cut from the base to the apex in the necropsy hearts of 27 patients aged 47 to 86 years (mean 66, median 69; 19 men). Total and necrotic areas were measured using a computer-linked image analysis system. The weights of the necrotic areas were also calculated. The correlations of the areas and weights of necrotic myocardium with the highest serum values of CK-MB mass and troponin I, which had been quantified during life by chemiluminescence immunoassays, were verified by Pearson's test; results were considered significant at p

Collagen is reduced and disrupted in human aneurysms and dissections of ascending aorta.

In ascending aorta aneurysms, there is an enlargement of the whole vessel, whereas aortic dissections (ADs) are characterized by the cleavage of the wall into 2 sheets at the external half. We searched if alterations in collagen could be related to these diseases. Sections of aortas from 14 case patients with acute dissections, 10 case patients with aneurysms, and 9 control subjects were stained with picrosirius. Slides were analyzed under polarized microscopy to evaluate the structure of collagen fibers. The proportion of collagen was calculated in each half of the medial layer by color detection in a computerized image analysis system. Collagen appearance under polarized light was consistent with collagenolysis. The mean collagen proportions at the inner and outer halves, respectively, were 0.50 +/- 0.13 and 0.40 +/- 0.08 in the control group, 0.20 +/- 0.10 and 0.18 +/- 0.12 in the AD group, and 0.33 +/- 0.12 and 0.19 +/- 0.12 in the aneurysm group. The AD (P < .01) and control (P = .04) groups had less collagen at the external half; no difference was found in the aneurysm group (P = .71). In both halves, there was less collagen in the case patients than in the control subjects (all P < .01), but at the internal half, the decrease was significantly greater in the case patients with aneurysms than in those with dissections (P = .03; at the external half, P = .99). Aortic dissections and aneurysms show a decrease in collagen content that could be related to a weakness of the wall underlying the diseases, but the locations of the decrease differ: in dissections, it is situated mostly at the external portion of the media (site of cleavage), whereas in aneurysms, it is more diffuse, consistent with the global enlargement.

Picrosirius-polarization staining method as an efficient histopathological tool for collagenolysis detection in vesical prolapse lesions.

The Picrosirius-polarization method has been indicated as a selective histochemical stain for collagen detection in tissue sections. This method can also be of value for studying collagen degradation given that, under polarized light, collagen displays birefringence due to its molecular order. The aim of this study is to highlight this staining method as an additional instrument for a rapid and excellent confirmatory diagnosis of the presence of collagenolysis in connective tissue in the vaginal wall with vesical prolapse lesion, in tissue sections. Dramatic changes in collagen morphology were found in vaginal mucosa in vesical prolapse disorder: they were weakly stained by Sirius red and under polarized light appeared as thin, pale (weakly birefringent), greenish, and with fibers more scattered, while the histoarchitecture of the organ showed a disrupted appearance. Thus, in the present study, we showed in vaginal mucosa in the vesicle prolapse that corroded collagenous framework appears as fragmentary and irregularly separated collagenous structures, that are weakly birefringent, corresponding to a molecular disorganization of these fibers caused by collagenolysis.

A New Experimental Device for Transapical Access of the Aortic and Mitral Valves as well as the Aorta in its Various Segments.

OBJECTIVE:: To present the results of a new experimental device developed to facilitate the transapical access in endovascular treatment of structural heart diseases. It aims to reduce the risk of bleeding and complications in this type of access and demonstrate the device as a safe, fast and effective alternative. METHODS:: CorPoint is composed of three parts: introducer, base with coiled spring, and closing capsule. By rotating movements, the spring is introduced into the myocardium and progressively approaches the base to the surface of the heart. Guidewires and catheters are inserted through the hollow central part and, at the end of the procedure, the capsule is screwed over the base, therefore stopping any bleeding. RESULTS:: The device was implanted in 15 pigs, weighing 60 kg each, through an anterolateral thoracotomy, while catheters were introduced and guided by fluoroscopy. All animals had minimal bleeding; introducers with diameter up to 22 Fr were used and various catheters and guidewires were easily handled. After finishing the procedure, the closing capsule was attached and no bleeding was observed at the site. CONCLUSION:: This new device has proved effective, fast and secure for the transapical access. This shows great potential for use, especially by ensuring an easier and direct access to the mitral and aortic valves; the shortest distance to be traveled by catheters; access to the ascending and descending aorta; decreased bleeding complications; decreased surgical time; and the possibility of allowing the technique to evolve and become totally percutaneous.

Absence of mycobacterial DNA in peripheral blood and artery specimens in patients with Takayasu arteritis.

The objective of this study was to demonstrate the presence of mycobacterial nucleic acid sequences in peripheral blood and arteries from patients with Takayasu arteritis (TA). Polymerase chain reaction was performed to detect mycobacterial DNA from three different nucleic acid sequences including the insertion sequence (IS) 6110, the 65-kDa heat shock protein gene (HSP65), and the 16S ribosomal RNA (rRNA) gene in peripheral blood from 32 TA patients and in arterial specimens from 10 TA patients. Twenty-eight HIV-negative patients with pulmonary tuberculosis prior to therapy were tested for IS6110 in peripheral blood as positive controls, and 24 blood donors were evaluated as healthy controls (HC). All TA patients were negative for the insertion sequence IS6110 and for HSP65 and 16S rRNA genes in blood samples and in arterial specimens. IS6110 sequence was found in peripheral blood from 22 (78.5 %) patients with pulmonary tuberculosis but not in HC. In conclusion, the strategy of mycobacterial-specific nucleic acid amplification in the peripheral blood and arterial specimens of TA patients was unable to lend support to the association between TA and tuberculosis long suggested in the literature.

Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy: A Randomized Clinical Trial.

Importance: In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), interventions reducing the progression of myocardial disease could affect survival. Objective: To assess the effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis (MF) identified on cardiovascular magnetic resonance (CMR). Design, Setting, and Participants: A randomized clinical trial conducted in 2 centers included 76 male patients with DMD or BMD undergoing 2 CMR studies with a 2-year interval for ventricular function and MF assessment. In a non-intent-to-treat trial, 42 patients with MF and normal left ventricular ejection fraction (LVEF) were randomized (1:1) to receive or not receive ACE inhibitor therapy. The study was conducted from June 26, 2009, to June 30, 2012. Data analysis was performed from June 30, 2013, to October 3, 2016. Interventions: Randomization (1:1) to receive or not receive ACE inhibitor therapy. Main Outcomes and Measures: Primary outcome was MF progression from baseline to the 2-year CMR study. Results: Of the 76 male patients included in the study, 70 had DMD (92%) and 6 had BMD (8%); mean (SD) age at baseline was 13.1 (4.4) years. Myocardial fibrosis was present in 55 patients (72%) and LV systolic dysfunction was identified in 13 patients (24%). Myocardial fibrosis at baseline was an independent indicator of lower LVEF at follow-up (coefficient [SE], -0.16 [0.07]; P = .03). Among patients with MF and preserved LVEF (42 [55%]), those randomized (21 patients in each arm) to receive ACE inhibitors demonstrated slower MF progression compared with the untreated group (mean [SD] increase of 3.1% [7.4%] vs 10.0% [6.2%] as a percentage of LV mass; P = .001). In multivariate analysis, ACE inhibitor therapy was an independent indicator of decreased MF progression (coefficient [SE], -4.51 [2.11]; P = .04). Patients with MF noted on CMR had a higher probability of cardiovascular events (event rate, 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P = .04). Conclusions and Relevance: In this 2-year, follow-up, randomized clinical trial of patients with Duchenne or Becker muscular dystrophy whose LVEF was preserved and MF was present as determined on CMR, ACE inhibitor therapy was associated with significantly slower progression of MF. The presence of MF was associated with worse patient prognosis. Trial Registration: clinicaltrials.org Identifier: NCT02432885.

Influence of chronic liver disease on coronary atherosclerosis vulnerability features.

INTRODUCTION: A lower incidence of acute myocardial infarction was reported in patients with chronic liver disease. OBJECTIVE: To analyze the impact of chronic liver disease on characteristics associated with vulnerability of human coronary artery atherosclerotic plaques. METHODS: One hundred fourteen hearts were collected from 3 groups of individuals: A--38 chronic liver disease patients who died while on the waiting list for liver transplantation; B--38 individuals who died of natural causes; and C--38 individuals who died of accidental causes. The most obstructed portion of the initial 2-cm segment of coronary arteries was histologically evaluated regarding to plaque area, luminal area, inflammation, percentage of fat, and total vessel area. RESULTS: The mean age (years) and male frequency in groups A, B and C were, respectively, 52+/-9 and 79%; 52+/-11 and 71%; and 54+/-18 and 89%. The mean area of the plaque and the incidence of severe plaque inflammation in group A were significantly lower (4.2+/-3.2; 13.2%) than those in the other two groups (6.6+/-4.3; 84.2%, and 6.3+/-4.4; 52.6%) p<0.01. The cross-sectional vessel measures were not statistically different regarding to vessel area (10.5+/-4.6; 12.1+/-4.6; 13.0+/-4.4) p=0.08, luminal obstruction (45%+/-15%; 60%+/-20%; 53%+/-20%) p=0.07, and fat area in the plaque (16%+/-17%; 30%+/-24%; 18%+/-18) p=0.37. In conclusion, compared with the general population, chronic liver disease patients have coronary arteries with smaller intimal plaque and less vessel inflammation. These findings favor the concept that hepatic disease patients are less prone to develop complicated coronary atherosclerosis.

Transforming growth factor-ß1 SMAD effectors and medial cell number in ascending aorta diseases.

In ascending aorta aneurysms and dissections, the extracellular matrix is degraded. Transforming growth factor (TGF)-ß1 modulates its synthesis. The production and presence of SMADs, intracellular effectors of TGF-ß1 signaling, were analyzed in patients with these diseases. To verify whether medial cells are lost, their total numbers were computed. Ascending aorta samples from 19 patients and 18 controls underwent immunoperoxidase reactions to SMADs 2, 3, 4, and 7. Positive and negative cells were counted, and total numbers of cells and positive/total ratios were calculated. Samples from other 14 patients and 7 normal controls were used for the quantification of SMAD3, SMAD4, and SMAD7 mRNA. For SMAD4, both mRNA (2.36 vs. 0.37, P=.03) and ratio of positive cells (0.94 vs. 0.73, P=.02) are increased in patients with ascending aortic diseases. SMAD3 mRNA was also increased (1.19 vs. 0.20, P=.05). The cell ratios of this and the other SMADs, SMAD7 mRNA, and the total cell count did not differ between groups. In conclusion, in ascending aortic aneurysms and dissections, there is an increase in SMAD4, implicated in extracellular matrix production, possibly as an attempt to compensate for extracellular matrix deficiency. Lost medial cells are replaced, since their number is not diminished.

A Remodelação do Sistema Nervoso Autônomo Cardíaco pode Desempenhar um Papel na Fibrilação Atrial: Um Estudo do Sistema Nervoso Autônomo e Receptores Miocárdicos / Cardiac Autonomic Nervous System Remodeling May Play a Role in Atrial Fibrillation: A Study of the Autonomic Nervous System and Myocardial Receptors

Resumo Fundamento Alterações do substrato elétrico e anatômico do coração são fatores que originam e perpetuam a fibrilação atrial (FA), porém, os mecanismos envolvidos não foram totalmente elucidados ainda. Objetivo: Avaliar o papel do remodelamento do sistema nervoso cardíaco intrínseco (SNCI), incluindo fibras nervosas e receptores muscarínicos e β-adrenérgicos, na FA permanente humana. Métodos Foram avaliadas 4 amostras em átrios de 13 corações obtidos em necrópsias de pacientes com doença cardíaca e FA permanente, e em 13 controles com as mesmas doenças, porém, sem FA. Utilizando imunoperoxidase e histomorfometria, quantificamos a densidade das fibras do SNCI, bem como a porcentagem positiva de miocárdio para receptores β-adrenérgicos 1, 2 e 3, receptor quinase 5 acoplado à proteína G (GRK-5), e receptores muscarínicos 1 a 5. Os resultados foram comparados usando ANOVA e ANOVA hierarquizada e ajustados pelo volume do átrio esquerdo e, para avaliação da expressão de receptores β e GRK-5, pelo uso de β-bloqueadores. Adotamos como significativo α = 0,05. Resultados Houve aumento na densidade das fibras ( p <0,01), especialmente nas fibras simpáticas ( p =0,02). Quanto aos receptores muscarínicos, só houve diferença nos M1, que estavam aumentados (5,87±4,52 vs 2,85±2,40; p =0,03). Quanto aos componentes do sistema adrenérgicos analisados, houve expressão aumentada de β-3 (37,41 vs 34,18, p =0,04) e GRK-5 (51,16 vs 47,66; p<0,01). O uso de β-bloqueadores não teve impacto na expressão de receptores beta. Conclusão O aumento na inervação do SNCI e a alteração na expressão de receptores em regiões suscetíveis de desencadear FA podem ter um papel na fibrilação atrial permanente.

Abstract Background The primary factors that originate and perpetuate atrial fibrillation (AF) are electrical and anatomical substrate alterations. However, the central mechanisms governing AF perpetuation have not been elucidated yet, which is reflected on the modest results of the treatment in patients with long persistent AF. Objective To evaluate if human intrinsic cardiac autonomic nervous system (ICANS) remodeling, including nervous system fibers and muscarinic and β-adrenergic receptors, play a role in permanent AF. Methods Heart necropsy samples from thirteen patients with heart disease and permanent AF and thirteen controls without AF were used. By using immunoperoxidase and histomorphometry quantification, we identified the following: the density of all fibers of the ICANS, sympathetic and parasympathetic fibers; and the percentage of myocardium positive for β-adrenergic receptors 1, 2 and 3; G protein-coupled receptor kinase-5 (GRK-5); and muscarinic receptors M1 to M5. The results were compared using ANOVA and nested ANOVA and were adjusted according to the left atrium volume for all variables, and β-blocker use to evaluate the expression of β-receptors and GRK-5. Results There was an overall increase in the density of fibers of the ICANS (p=0.006), especially in atrial sympathetic nerve fibers (p=0.017). Only M1 muscarinic receptors were increased (5.87 vs 2.35, p=0.032). For adrenergic receptors, the results were positive for increased expression of β-3 (37.41 vs 34.18, p=0.039) and GRK-5 (51.16 vs 47.66; p<0.001). β-blocker use had no impact on β-receptor expression. Conclusion Increased ICANS innervation and remodeling receptor expression in regions prone to triggering AF may play a role in permanent AF.

Different patterns of atherosclerotic remodeling in the thoracic and abdominal aorta.

PURPOSE: To investigate the relationship between the vascular diameter and the extent and histologic characteristics of atherosclerosis in the thoracic and abdominal aortas of patients who died of atherosclerotic disease. METHOD: We measured the vascular diameter and evaluated the percentage atrophy of the medial layer of the thoracic and abdominal aortas of 19 patients who died due to atherosclerotic disease. The extent of plaques, calcification, ulceration, thrombosis, and the amount of fat in the plaques were evaluated semiquantitatively. RESULTS: Atherosclerosis was more severe in the abdominal than the thoracic aorta as indicated by the higher sum of the macroscopic scores (P = .02) and the higher percentage atrophy of the medial layer (P < .001). The diameter of the thoracic, but not of the abdominal aorta, correlated with age (r = 0.56; P = .01), plaque score (r = 0.59; P = .008), calcification score (r = 0.749; P < .001), and fat score (r = 0.48; P = .04). Multiple linear regression showed that age (P = .06) and calcification score (P = .001) were the parameters with the strongest association to thoracic aorta diameter. CONCLUSION: There are some differences regarding atherosclerosis in the thoracic compared to the abdominal aorta. Progressive thoracic aorta atherosclerosis is associated with fat deposition in the plaques, inducing arterial dilation. In the abdominal aorta, atherosclerosis can either have a similar evolution or be associated with less fat deposition in the arterial wall, which would result in more rigidity, hindering compensatory arterial enlargement.