Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat

AbstractObjectivesThe purpose of this study was to determine the pathogenic factors and molecular mechanisms involved in fibrosis of the atria.BackgroundFibrosis is an important component of the pathophysiology of atrial fibrillation, especially when the arrhythmia is associated with heart failure (HF) or atrial dilation.MethodsWe used a rat model of myocardial infarction (MI) complicated by various degrees of left ventricular dysfunction and atrial dilation to study fibrosis and matrix metalloproteinase (MMP) activity in the left atrial (LA) myocardium by means of histologic, Western blot, zymographic, and immunohistologic techniques.ResultsThree months after surgical ligature of the left coronary artery, 27 rats had a large MI, 12 were in mild HF, and 15 in severe HF. Both groups had LA enlargement at the echocardiography. Masson’s trichrome and picrosirius staining of tissue sections revealed marked fibrosis at the periphery of trabeculae and also surrounding myolytic myocytes, in both mild and severe HF. In mild HF, the activity and expression of the matrilysin MMP-7 were increased (122%), whereas in severe HF, both MMP-7 (211%) and the gelatinase MMP-2 (187%) were up-regulated. There were no changes in the expression or activity of MMP inhibitors, TIMP-1, -2, and -4. Immunostaining of cryosections showed that MMP-2 was present in the interstitial spaces, whereas MMP-7 accumulated in myolytic myocytes.ConclusionsHemodynamic overload of the atria is an important pathogenic factor of fibrosis; MMP-7 appears to be involved in the early stage of this tissue remodeling process

Adult cardiac myocytes survive and remain excitable during long-term culture on synthetic supports

AbstractObjective: Cardiomyocytes can be transplanted successfully into skeletal and cardiac muscle. Our goal was to determine the feasibility of grafting cardiomyocytes onto various synthetic supports to create an excitable and viable tissue for implantation. Methods: Adult rat cardiomyocytes were cultured over an 8-week period onto different substitutes, including human glutaraldehyde-treated pericardium (n = 3), equine glutaraldehyde-treated pericardium (n = 3), polytetrafluoroethylene (n = 8), Dacron polyester (n = 16), and Vicryl polyglactin (n = 8). Results: Only the cells seeded on the Dacron survived, with the synthetic fibers colonized at 8 weeks. On the other supports, the number of myocytes progressively decreased from the first week, with their density (number of cells per square millimeter) being, after 20 days, 17 ± 2 on the polytetrafluoroethylene and 5 ± 1 on the human or equine pericardium compared with 45 ± 3 on the Dacron. After 8 weeks of culture on Dacron, the sarcomeric protein (sarcomeric α-actinin) was detected in all cells. In addition, the staining was regularly arranged and well aligned in a striated pattern. Spontaneous beating activity was obtained. Moreover, electrical stimulation of the cell preparation resulted in the generation of calcium transients, the frequency of which followed the frequency of the electrical stimulation. Conclusions: These results suggest that adult cardiac myocytes remain viable and excitable during long-term culture on a 3-dimensional Dacron support, which might constitute a new synthetic cardiac tissue. (J Thorac Cardiovasc Surg 2001;121:510-9

An angiopoietin 2, FGF23, and BMP10 biomarker signature differentiates atrial fibrillation from other concomitant cardiovascular conditions

Abstract Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation

Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation: the 8th AFNET/EHRA consensus conference

Aims Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy.Methods and results This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework.Conclusions Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.</p

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Dynamic of ion channel expression at the plasma membrane of cardiomyocytes

Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine-tune ion channel expression and control cardiac excitability

Direct Thrombin Inhibitors Prevent Left Atrial Remodeling Associated With Heart Failure in Rats

International audienceThe present study tested the hypothesis that thrombin participates in formation of left atrial remodeling and that direct oral anticoagulants, such as direct thrombin inhibitors (DTIs), can prevent its progression. In a rat model of heart failure associated with left atrial dilation, we found that chronic treatment with DTIs reduces the atrial remodeling and the duration of atrial fibrillation (AF) episodes induced by burst pacing by inhibiting myocardial hypertrophy and fibrosis. In addition to the prevention of thromboembolism complicating AF, DTIs may be of interest to slow down the progression of the arrhythmogenic substrate