presentation for nature

Immerse yourself in our collection of 24 nature-themed PowerPoint and Google Slides templates , showcasing serene landscapes, lush greenery, and environmental motifs.

These designs are ideal for presentations related to ecology, sustainability, conservation, and travel. By using our nature templates, you can create an atmosphere of tranquility and connection with the environment, enhancing your message and engaging your audience.

Whether you’re promoting eco-friendly initiatives, sharing research findings, or educating others on environmental issues, our templates provide a visually stunning backdrop for your content.

Clover Woodland Template

Google Slides , POTX

Green Cycle Template

Tea Leaves Template for PowerPoint and Google Slides

Tropical Leaves Template for PowerPoint and Google Slides

Floral Pastel Template for PowerPoint and Google Slides

Ecology Template for PowerPoint and Google Slides

Retro Pop Mountains Template for PowerPoint and Google Slides

Chart Palette Template for PowerPoint and Google Slides

Green Leaves Flat Lay Template for PowerPoint and Google Slides

Birds Template for PowerPoint and Google Slides

Green Rounded Abstract Template for PowerPoint and Google Slides

Pastel Leaves Template for PowerPoint and Google Slides

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Nature PowerPoint templates and Google Slides themes

Free slides and backgrounds for presentations about nature, clean energy, the environment, renewable energies, recycling, ecology or sustainable economy.

Download these presentation templates ang go green!

Unleash the wild fun in your classroom with this FREE PowerPoint Template and Google Slides Theme. Liven up your classroom with a touch of the jungle!  This free downloadable theme features adorable monkeys swinging through lush green backgrounds and bright banana trees.   It’s more than just cute though – this theme is […]

Cute Monkeys, mini theme and subtraction drag and drop activity.

Flowers and Ladybugs free Spring Season template for google slides and PowerPoint. This free template for Google Slides and PowerPoint is the perfect way to add a touch of springtime cheer to your lessons. It features adorable graphics of flowers, bees, and ladybugs – a charming combination that’s sure to […]

Spring has sprung and it’s time to bring some floral fun to your classroom!

Elevate Your Presentations with Earthy Elegance and Sophistication with this free PowerPoint Template and Google Slides Theme. Beth is a stunning free template for Google Slides and PowerPoint, featuring a soothing palette of earthy tones, organic shapes, and leaves. The template is designed to exude a sense of natural elegance […]

Beth, elegant and versatile free template.

Elegant and classy with flowers and leaves backgrounds free PowerPoint Template and Google Slides Theme Amelia is a free PowerPoint and Google Slides template with elegant and classy floral backgrounds. It is perfect for a wedding slideshow or a poetry presentation. The template features a variety of flowers and leaves […]

Amelia free PowerPoint and Google Slides template with floral backgrounds.

Africa landscapes and animals free PowerPoint Template and Google Slides Theme Africa Viva is perfect to talk about Africa, the savannah or the animal kingdom. It has beautiful sunset colors and papercut style landscapes made with different layers. I’ve included two different title slides, one with the African continent and […]

Africa Viva, free presentation template.

Autumn Stickers free Fall PowerPoint Template and Google Slides Theme This new autumn theme features fall leaves, acorns and mushrooms presented as digital stickers. Perfect for back to school or to present different outdoor activities to experience during fall. I’ve included a morning meeting / daily agenda slide and a […]

Autumn stickers, a fall theme for Google slides and ppt.

Free autumn theme with pumpkins and fall leaves for PowerPoint and Google Slides. Countryside fall template is a cute autumn theme with warm colors that features a little pickup truck with pumpkins, and a tree with falling red, yellow and brown leaves. This template is perfect to celebrate fall or […]

Countryside Fall free slides template.

Neutral watercolors organic shapes free PowerPoint Template and Google Slides Theme This template features neutral watercolor organic shapes and it can be used for presentations about topics such as: Nature: For example, you could use the template to discuss the different types of trees, flowers, or animals in a particular […]

Watercolor Organic Shapes Presentation Template.

Crumpled Paper Texture Background with Cute Succulents, Cacti and Flowers Stickers free PowerPoint Template and Google Slides Theme This free PowerPoint template and Google Slides theme features a crumpled paper texture background with cute succulents, cacti and flowers stickers. It’s the perfect way to add a touch of cuteness and […]

Cute Succulents, Cacti and Flowers Stickers free template.

Apple Picking Season FREE PowerPoint Template and Google Slides Theme Celebrate apple picking season with this free PowerPoint template and Google Slides theme! This template features a beautiful and warm color scheme and illustrations of apples, making it the perfect way to create presentations about the delicious fruit. The template […]

Apple Season free slides theme.

World Oceans Day Free PowerPoint Template and Google Slides Theme Celebrate World Oceans Day with this free PowerPoint template and Google Slides theme! This template features a beautiful blue color scheme and ocean-themed images, making it the perfect way to create presentations about the importance of our oceans. The template […]

World Oceans Day free PowerPoint template.

Free Earth Day animated template for Google Slides and PowerPoint. You can use this PowerPoint template and Google Slides theme to raise awareness of environmental issues. It features beautiful visuals and resources of planet Earth, which you can customize freely to make the presentation your own. Earth Day is an […]

Earth Day free ppt and Google Slides template.

Free interactive choice board and mini theme + morning meeting / daily agenda slide for Google Slides and PowerPoint. This free interactive choice board and mini theme with morning meeting / daily agenda slide is perfect for the little ones. Let’s learn about the importance of bees with this black […]

Bees are awesome. Interactive choice board and mini theme.

Free spring template with flowers and ladybugs for Google Slides and PowerPoint. Flowery slides to celebrate spring or if you just are in the mood for flowers and ladybugs. Colorful template that uses theme colors for almost all objects (all the colors are customizable thru the edit theme option, except […]

Flowers and Ladybugs free slides template.

Cute sunflowers Template for PowerPoint and Google Slides Cute illustrated PowerPoint template and Google Slides theme with sunflowers. You can use it to talk about wellness, for example. It includes a morning meeting layout in case you want to use it in your classroom! DOWNLOAD POWERPOINT OPEN IN GOOGLE SLIDES

Cute sunflowers, Google Slides and ppt template.

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Top 35 Nature PowerPoint Templates to Enjoy the Splendid Beauty of Nature!

Deepali Khatri

If you are in your office on a beautiful day and you see the wonderful weather outside, it will be hard for you to focus on what’s going inside. Well, if you can’t take your viewers outside, you can surely bring the outdoors inside by making the use of these predesigned PowerPoint slide designs.

Enjoy the beauty and explore different colors of nature with our creative collection of Top 35 Spring PPT templates. Take the time to unplug and delve into nature’s beauty with the best collection of these predesigned PowerPoint slide design.

Whether you want to advertise organic products or create a presentation on the ways to save mother nature, these PPT slides will serve as the best tool for such purposes. Promote your business and advertise seasonal sports using our beautifully designed Nature PowerPoint templates.

Forest Nature PowerPoint Template-1

Get this readymade Forest Nature PowerPoint Template

Explain the concept of afforestation and deforestation through this visually appealing PowerPoint template. Educate your students about the importance of wildlife for ecological balance and how it helps in maintaining a balance of nature. Familiarize your viewers with the various species existing on this earth and their contribution to each other. Showcase how trees play an important role in saving many lives with the assistance of this forest nature PowerPoint template.

Beach Enjoy Nature PowerPoint Template-2

Click Here to Get this Beautifully Designed Beach Enjoy Nature PowerPoint Template

This slide is perfect to advertise your beach business and for promoting the hotels and restaurants on the beach. Enjoy the season of spring and summer and prepare a list of things you need to carry along with you while planning a trip to a beach. Explore the beauty and different colors of nature. One can also employ this slide to advertise water sports.

Lake Nature PowerPoint Template-3

Download this Lake Nature PowerPoint Slide Design

Create awareness on the benefits of yoga, exercising, walking, and meditation with this professionally designed PowerPoint slide design. Feel the beauty of nature and create outstanding presentations with this lake nature PowerPoint template. Explore the greatest collection of Nature PowerPoint templates at SlideTeam and deliver quality rich presentations in just no time. The slide can also be incorporated by the teachers to educate the students about the importance of the ecosystem.

Eagle Over Davidson Nature PowerPoint Templates And PowerPoint Backgrounds-4

Click Here to Get This Eagle Over Davidson Nature PPT Slide Show

This wonderful slide can be used to showcase the beauty of nature in the winter morning. Display the pleasant beauty of snow and promote your business in hilly areas. Incorporate the slide to advertise your business camping and hiking products. List down the camping and survival equipment using the predesigned PowerPoint layout.

Sunset Nature PowerPoint Template-5

Click Here to Get this Sunset Nature PowerPoint Template

Showcase the beauty of nature using this readily available sunset nature PowerPoint slide design. The above-shown template depicts the beautiful colors from a sunset. The presenter can present the phenomenon called scattering because of which sunset takes place. Depict the fundamental relation between nature and humans using this PPT slide.

Italian Mountain Nature PowerPoint Templates And PowerPoint Backgrounds-6

Click Here to Get this Italian Mountain Nature PowerPoint Template

Explain the worth of nature and its valuable resources using this Italian mountain nature PowerPoint slide show. This slide can also be used for promoting the institutes providing coaching for skiing. Promote the businesses located in the hilly areas. Showcase the benefits one can have from meditation in the hilly areas. Admire the beauty of nature with this mountain nature PowerPoint slide.

Flower Nature PowerPoint Template-7

Click Here to Get this Flower Nature PowerPoint Template

Incorporate this flower nature PowerPoint template and get a better exposure to nature that will make you feel better emotionally. The PPT slide can also be used to explain the contribution nature makes to your physical wellbeing. Inspired by nature, we at SlideTeam have created such templates that will help you enjoy and feel the beauty of nature. Deliver quality rich presentations on nature-related topics using the predesigned flower PowerPoint slide.

Child Observing Nature PowerPoint Template-8

Click Here to Get this Visually Appealing Child Observing Nature PPT Template

Explore different colors of nature and teach children about the existing species. This slide can also be incorporated to guide viewers about the ways of gardening. You can even advertise and promote your organic products. Educate kids on how they can save the environment and create awareness about global warming. Enjoy the beauty of tulips and flora and fauna taking advantage of this wonderful nature PowerPoint slide.

Sunflower Nature PowerPoint Template-9

Click Here to Get This Amazing Sunflower Nature PPT Slide Design

Flowers are a symbol of love, passion, desire, joy, and happiness. Spread love using these professionally curated PPT slide show. Enjoy the season of spring and summer. Sunflowers are known for being happy. The template can also be used for wishing someone. Prepare a beautiful video for your loved ones and write a suitable quote on this wonderful slide.

Sunlight Nature PowerPoint Template-10

Download this Sunlight nature PPT Layout

Showcase the beauty of nature with this sunlight Nature PowerPoint template and mention the ways you can protect nature. The slide can also be employed to educate the students on how to save trees and other natural resources. One can also take advantage of this Nature’s PPT slide to promote their organic products.

Tree Nature PowerPoint Template-11

Grab this Tree Nature PowerPoint slide show

Familiarize people with the concept of afforestation and deforestation. Jot down the ways they can save valuable resources. Elucidate how trees are important for us and how they contribute oxygen to the environment. Display the uses of trees and the importance of planting trees in the schools using this professionally designed tree PowerPoint slide.

Sunlight Nature PowerPoint Template-12

Click Here to Grab this Readymade Sunlight Nature PowerPoint Slide

Make powerful PPTs and describe nature and its beauty through this sunlight nature PowerPoint slide. School teachers can incorporate the slide to and guide the students how by preserving nature, the planets and all its inhabitants are guaranteed a supply of clean water and fresh air. Showcase the health benefits one can have from jogging, walking and running in the morning and its impact on one’s physical and mental health.

Beautiful Ocean Nature PowerPoint Template-13

Download this Predesigned Beautiful Ocean Nature PPT Layout

Create awareness on the benefits of yoga, running, meditation with this amazing beautiful ocean nature PPT slide show. Mention the ways one can save water and other valuable natural resources. Oceans are the lifeblood of Earth providing us with oxygen and absorbing carbon. Make an impactful PPT presentation with this predeveloped beautiful ocean nature PowerPoint layout.

Purple Hosta Nature PowerPoint Template-14

Download this Predesigned Purple Hosta Nature PowerPoint Slide Show

Protect your mother nature and showcase the ways one can save natural resources. Grab the attention of the viewers with this refreshing and surprising beauty of this wonderful purple Hosta nature PowerPoint slide design. A presenter can use this template to explain the features of Hosta flowers and the care tips one must keep in mind while dealing with these flowers.

Gerbera Flower Nature PowerPoint Template-15

Download this Gerbera Flower Nature PPT Template

These flowers are the symbol of innocence and purity. You can incorporate the slide to make beautiful cards for your friends, family and loved ones. Wish them the best using this template and prepare cards for their birthdays and anniversary. Make a wonderful video for your partner by adding pleasant music at the background and incorporating these beautifully designed flower nature PowerPoint graphics.

Leaves Reflection Nature PowerPoint Template-16

Click Here to Grab this Leaves Reflection Nature PPT Slide Design

Save the environment and educate people about the ways they can save the valuable resources of the environment. The slide can be used by those people who want to promote and advertise products related to nature. One can also jot down the ways to enjoy the beauty of nature. Mention the services nature and humans provide to each other.

Fall Forest Nature PowerPoint Template-17

Click Here to Get this Fall Forest Nature PowerPoint Slide Design

Showcase the importance and beauty of the forest with the help of this readily available forest nature PowerPoint template. This professionally designed forest nature PowerPoint slide can be used to advertise the water sports and adventures. Spread awareness to conserve water and plant more trees by taking advantage of this forest nature PowerPoint template.

Happy Flowers Nature PowerPoint Template-18

Click Here to Get this Happy Flowers Nature PowerPoint Slide Design

Flowers never go out of fashion, so give your presentation a flowery touch. Enlist the upcoming events and educate toddlers about the different fruits and flowers that we get from nature. Enjoy the season of spring and summer and spread the love with the assistance of this predeveloped happy flowers nature PowerPoint template.

Pond Beauty Nature PowerPoint Template-19

Download this Pond Beauty Nature PPT Template

Create inspiring presentations about nature and raise awareness. Showcase the contribution nature makes to your physical wellbeing. Display that exposure to nature not only makes you feel better emotionally but it also helps in reducing a lot of health problems. The above-shown slide can also be incorporated to mention the ways one can save nature.

Pink Rose Nature PowerPoint Templates PPT Themes And Graphics-20

Click Here to Get this Pink Rose Nature PowerPoint Template

The above-shown template depicts the beauty of nature. The slide can be used to wish a birthday or anniversary to your loved ones. Prepare a beautiful video by incorporating this professionally designed pink rose nature PowerPoint layout. Add soothing music in the background and post this video on your partner’s timeline.

Save Earth And Water Protection Flat PowerPoint Design-21

Get this Save Earth and Water Protection PowerPoint Slide Show

Prepare impactful PPT presentations on save water and write the quotes and slogans on this predeveloped save earth PowerPoint slide. The PPT slide can be incorporated by the schoolteachers in their sessions to prepare a presentation for the students. List down the ways they can save water for the future generation by downloading this readymade PPT layout.

Garden Nature PowerPoint Templates Pathway Growth PPT Slide-22

Click Here to Grab This Garden Nature PowerPoint Template

Enjoy the beauty of nature and showcase the benefits of jogging, meditation and walking in the early morning. Give a fresh start to your presentation with this green tree garden nature PowerPoint slide show. Grab the attention of your viewers by bringing the outdoors inside while delivering your presentation using this PowerPoint template.

Butterfly Background Nature PowerPoint Templates and PowerPoint Backgrounds-23

Download this Creative Butterfly Background Nature PowerPoint Slide Show

Enlighten your audience with the importance of flora and fauna. Showcase the scenic beauty of various places. List down the places you want to visit. Take your audience for a nature tour taking advantage of this readily available PowerPoint template. You can not take your audience out while delivering any presentation but you can bring nature inside by making impactful presentations using this slide.

Pink Tulip Nature PowerPoint Templates And PowerPoint Backgrounds-24

Download this Amazingly Curated Pink Tulip Nature PPT Slide Show

This slide can be used for natural, decorative, artistic and love presentation. Enjoy the beauty of tulips and make powerful PowerPoint presentations. The template can also be employed for showcasing the ways one can protect the mother nature. Enjoy and feel the beauty of nature with this professionally curated PowerPoint layout.

Bumble Bee Nature PowerPoint Templates And PowerPoint Backgrounds-25

Click Here to Grab this Beautifully Designed Bumble Bee Nature PowerPoint Layout

Give your presentation a flowery touch with this bumblebee nature PowerPoint layout. Present your business in new ways. Create an interesting PPT template presentation by downloading this slide. Add as many slides to this PowerPoint theme as you want. Prepare a beautiful video for your loved ones using this PPT template.

Butterfly Nature PowerPoint Templates And PowerPoint Backgrounds-26

Click Here to Grab This Butterfly Nature PowerPoint Slide Design

This PPT slide can be used to create decorations and crafts for children. Educate people on how they can save the environment and the natural resources like butterflies, plants, and trees. Showcase the importance of nature for the survival of human beings and the things provided by nature.

Autumn Park Nature PowerPoint Templates And PowerPoint Backgrounds-27

Download this Readily Available Autumn Park Nature PPT Guide

Teach toddlers about the various season of nature. Feel the pleasure of the beautiful red, yellow and orange color in the season of autumn. Get a perfect sense of relaxation and warmth using this template. One can use this PPT slide for all the nature-related presentations.

Morning on The Farm Nature PowerPoint Template-28

Download this Morning on the Farm Nature PowerPoint Template

The presenter can use the PPT slide to make the audience familiar with farming and agriculture. Advertise organic farming and the different techniques of farming. Explore the different colors of nature with this creatively designed morning on the farm PowerPoint slide show.

Dew Drops Nature PowerPoint Template-29

Click Here to Grab This Readymade Dew Drops Nature PowerPoint Slide Show

If you can’t take your audience outside while giving a PPT presentation, you can use this template to bring the outdoors inside. Use this slide in your next presentation and talk about the beauty of nature. The above shown template depicts beautiful dewdrops in the winter morning. Spread awareness for preserving nature and natural resources using the slide show.

Vineyard Nature PowerPoint Background and Template-30

Download this Predesigned Vineyard Nature PowerPoint Graphic

Feel the warmth of the sun and enjoy the pleasant beauty using this beautifully designed PowerPoint template. Create awareness on the benefits of yoga, meditation, exercising. This slide is a PowerPoint theme for giving a consistent, professional look to all the slides and can be downloaded in JPG and PDF file formats. Describe the beauty of a sunset and explain the scientific phenomenon behind the sunrise and sunset.

River Nature PowerPoint Backgrounds and Templates-31

Grab this Professionally Designed River Nature PowerPoint Template

Showcase the importance and the role played by rivers in the ecology of the rainforest. Also, rivers provide a habitat for wildlife which can be easily displayed using this beautifully designed river PowerPoint slide show. Showcase the various rivers of the world and let the students be aware of the various features of each river.

Green Earth Nature PowerPoint Background And Template-32

Get this Customizable Green Earth Nature PowerPoint Slide Design

Spread awareness and mention the ways one can save the planet Earth. Explain the concept of global warming and the ways one can deal with it. The slide can also be incorporated to familiarize the audience with the 3R’s i.e. recycle, reuse and reduce. Talk about the measures to control environmental pollution with the help of this predesigned PowerPoint template.

Water Fall Nature PowerPoint Templates And PowerPoint Backgrounds-33

Click Here to Download this Amazing WaterFall Nature PPT Slide Show

Make a powerful PowerPoint presentation on the wonders of nature. Talk about the famous Niagara Falls and its beauty. The safety measure one should take at the place can also be displayed taking the assistance of this readymade PPT template. Showcase the scenic beauty of your country taking the assistance of this readily available PowerPoint template.

Tropical Sunset Nature PowerPoint Templates And PowerPoint Backgrounds-34

Click Here to Download this Tropical Sunset Nature PowerPoint Design

The slide is the best tool to advertise adventure and water spots. Reflect the beauty of nature at the sunset using this PPT template. Create inspiring PowerPoint Presentation and showcase the beautiful colors caused by sunset in the atmosphere. Prepare a list of places you want to travel with this readily available PowerPoint slide design.

Bamboo Nature PowerPoint Templates and PowerPoint Backgrounds-35

Get this Readily Available Bamboo Nature PowerPoint Slide Show

Explain the benefits of bamboo and educate children about the bamboo species. Incorporate the template to depict the uses of bamboo and how these help in making roads and medicines, food, fuel, paper, and other similar things.  Share the facts related to a bamboo tree with this predesigned PowerPoint slide show.

Choose the best among the available templates and create an impactful presentation in no time.

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Nature Powerpoint templates and Google Slides themes

Discover the best Nature PowerPoint templates and Google Slides themes that you can use in your presentations.

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Free Nature PowerPoint Templates

Nature epitomizes beauty and wonder. Drawing inspiration from its myriad elements, we have meticulously crafted an exceptional collection of Nature-themed PowerPoint templates and PPT slide templates. Elevate your next presentation with these 100% free slide designs that seamlessly integrate the sky, wind, earth, fire, flora, mountains, and more. Our complimentary Nature PPT templates for PowerPoint & Google Slides are curated with precision, ensuring you captivate your audience with the essence and splendor of the natural world.

Free Climate Change PowerPoint Template

Free Green Leaf PPT Template

Free Green Field PowerPoint Template

Free Eyes PowerPoint Template

Free Hurricane Storm PowerPoint Template

Free Bonsai PowerPoint Template

Free Island Presentation Template

Free Green Leaf PowerPoint Template

Free Mountaineering PowerPoint Template

It’s a good idea to use the nature PowerPoint templates and elements in your presentation because sometimes presentations are delivered in the office or in a classroom and people who is attending the conference may forget for some minutes that we live around Nature. For example, check out this Water PowerPoint template.

What is a Nature Background for PowerPoint?

Nature backgrounds and nature PowerPoint templates are designs created for presentations featuring background stock images in HD, nature illustrations and vectors.

How Nature Backgrounds can be used in PowerPoint presentations?

The nature backgrounds can be used in many different ways. A presenter or presentation designer might choose to include nature backgrounds as part of their presentation design when he/she wants to depict a sense of natural style.

What are different types of Nature backgrounds for presentations?

The nature backgrounds category includes different types of natural backgrounds. There are several types of natural backgrounds that can be used in presentations, for example you may download free water & sea backgrounds, realistic photo backgrounds, green backgrounds, backgrounds with forests and trees, backgrounds with flowers.

In this section, you can find creative natural backgrounds and presentation templates.

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Nature PowerPoint Presentation And Google Slides Templates

Nature Presentation Slides

Nature encompasses the vast and diverse world of the natural environment, including all living and non-living things found on Earth. It comprises ecosystems, landscapes, flora, and fauna, showcasing the beauty and harmony of the natural world. From majestic mountains and serene forests to vibrant coral reefs and teeming rainforests, nature offers endless wonders to explore and appreciate. It provides essential resources, such as clean air, water, and fertile soil, while also offering opportunities for recreation, inspiration, and solace. With this customizable template, you can capture the essence of nature's splendor and raise awareness about the importance of preserving and protecting our precious natural heritage.

Features of the templates:

• 100 % customizable slides and easy to download.
• Slides available in different nodes & colors.
• Slide contained in 16:9 and 4:3 format.
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• Well-crafted template with instant download facility.
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• Nature pledge

International Day for Biological Diversity - 22 May 2024

The Theme of Biodiversity Day 2024: "Be part of the Plan"

May 13, 2024

Biodiversity Day 2024

When: 22 May 2024

Theme: Be part of the Plan

Official website: https://www.cbd.int/biodiversity-day

Lead: The Convention on Biological Diversity

“Be part of the Plan”, the theme of International Day for Biological Diversity (IDB) 2024, is a call to action for all stakeholders to halt and reverse the loss of biodiversity by supporting the implementation of the Kunming-Montreal Global Biodiversity Framework, also referred to as the Biodiversity Plan . 

The Biodiversity Plan offers opportunities for cooperation and partnerships among diverse actors. 

Governments, indigenous peoples and local communities, non-governmental organizations, lawmakers, businesses, and individuals are encouraged to highlight the ways in which they are supporting the implementation of the Biodiversity Plan. 

We are all #PartofThePlan.

IDB 2024 is expected to increase the visibility momentum in the lead-up to the sixteenth meeting of the Conference of the Parties to the Convention on Biological Diversity (COP 16) , to be held in Colombia from 21 October to 1 November 2024. 

What is Biodiversity?

Biodiversity describes the wide range of life forms on Earth, spanning from genes to entire ecosystems. It encompasses the processes that maintain life, including evolution, ecology, and cultural practices. Biodiversity encompasses not only rare, threatened, or endangered species but all living beings, from well-known organisms like humans to lesser-known ones such as microbes, fungi, and invertebrates. 

Why is Biodiversity Important?  

Biodiversity plays a vital role in multiple aspects of our lives. Its importance lies in the numerous benefits humans derive from it, including essential needs like food, fuel, shelter, and medicine. Additionally, ecosystems offer critical services like pollination, seed dispersal, climate regulation, water purification, nutrient cycling, and pest control. Moreover, biodiversity holds value beyond known benefits, potentially offering new medicines and other services yet to be discovered. 

Nature in Action

Heart of fire

SGP Cabo Verde, and their partners on the ground are #PartofThePlan. This highlight seeks to raise awareness and understanding of work to strengthen the protectio...

Along ancient routes

In the vast expanse of the Rift Valley/Red Sea flyway, where azure waters meet golden sands, over 1.5 million birds – representing 37 species, five of whom are gl...

In the line of fire

Over the last two decades, fires have caused more than a quarter of all tree cover loss. If there is hope for the world's forested areas, it can be found in Costa...

From Scourge to Sustainability

From discarded bags at the bottom of the Mariana Trench, to microscopic particles in human placentas, to debris in space, plastics are ubiquitous. This extremely ...

Belarus is Developing an Online Map of Protected Nature Areas

Belarus has recently launched its first online map showcasing specially protected natural areas, marking a significant milestone in country's conservation efforts...

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• Published: 21 May 2024

Treg-derived TGF-β1 dampens cGAS-STING signaling to downregulate the expression of class I MHC complex in multiple myeloma

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• Xianshi Li 1 ,
• Yanqi Lu 1 &
• Xun Lai 1  

Scientific Reports volume  14 , Article number:  11593 ( 2024 ) Cite this article

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• Cancer microenvironment

Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of major histocompatibility complexes (MHC) class I molecule and elevated programmed death ligand 1 (PDL1) in MM cells, along with an enriched population of regulatory T cells (Tregs). To investigate Treg's influence on MM cells, we established a co-culture system using Tregs from MM patients and the MM cell lines (MM.1S and SK-MM-1) in vitro and assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo. In vitro, Tregs induced transforming growth factor beta-1 (TGF-β1) production, downregulated MHC I members, and increased PDL1 expression in MM cells. Treg-derived TGF-β1 suppressed the cGAS-STING pathway, contributing to the loss of MHC I molecule expression and PDL1 upregulation. Correspondingly, neutralizing TGF-β1 or activating the cGAS-STING pathway restored MHC I and PDL1 expression, effectively countering the pro-tumorigenic effect of Tregs on MM cells in vivo. These data elucidated how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells, potentially providing therapeutic strategies, such as neutralizing TGF-β1 or activating the cGAS-STING pathway, to address the immune escape and immunosuppressive dynamics in MM.

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy, which initiates with monoclonal gammopathy of unknown significance and develops into a spectrum of plasma cell dyscrasias including leukemia and extramedullary myeloma 1 , 2 . Individuals with unhealthy lifestyles including chronic drinking and smoking, as well as genetic mutations, are predisposed to MM 3 , 4 . A variety of chemotherapeutic drugs targeting different cellular processes have been approved for MM treatment, including dexamethasone, lenalidomide, doxorubicin, cyclophosphamide, and vincristine. However, the development of drug resistance is a common issue compromising the treatment outcome of all clinical drugs 5 , 6 .

Similar to solid tumors, a prevalent characteristic of MM is the alteration and functional compromise of the patient's immune system 7 . The immunosuppression state is linked to the changes in the abundance and functionality of principal immune cells 8 . Immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor T (CAR-T) cell therapy have been established to boost anticancer immunity in MM patients 9 , 10 . Nevertheless, a portion of MM patients are unresponsive to immunotherapy, which may be due to multiple factors including the highly immunosuppressive bone marrow microenvironment and the downregulation of tumor antigen presentation by MM cells 11 , 12 .

The malignant progression of MM is frequently associated with the dampening of antigen presentation 13 , 14 . For example, there is evidence that major histocompatibility complexes (MHC) class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma, which could undermine the effective recognition of tumor neoantigens 15 . Reduced expression of tumor antigens or MHC together with defective antigen processing and presentation facilitates the immune escape from cytotoxic T lymphocytes (CTLs) 16 . Besides, MM cells could express high levels of immunosuppressive signal molecules such as Programmed Death Ligand 1 (PDL1) to curtail the activation of antitumor immune responses 17 , 18 . Further, MM patients are characterized by the immunosuppressive bone marrow microenvironment enriched with suppressive dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), macrophages, and regulatory T cells (Tregs) 19 . Among the immunosuppressive cells, myeloma-driven Treg expansion largely suppressed the activation of CTLs 20 . However, the interplay between Tregs and MM cells remains to be fully elucidated.

In this study, we attempted to investigate how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells. We established a co-culture system of Tregs isolated from the blood samples of MM patients and MM cell lines, to investigate the mechanism by which Tregs could impact the expression of class I MHC members and PDL1 in MM Cells in vitro. Additionally, we assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo.

Treg expansion is associated with increased IL-10 and TGF-β1 production in MM patients

To compare the cytokine profiles between the healthy controls and MM patients, peripheral blood samples were collected from 20 individuals in each group, and the relative levels of IL-6, TNF-α, IL-4, IL-10, and TGF-β1 were measured. MM patients exhibited a significant decrease in IL-6 and TNF-α levels, while the anti-inflammatory cytokines IL-10 and TGF-β1 showed a marked increase in their blood samples (Fig.  1 A). Additionally, the detection of Tregs using CD4 surface staining and FoxP3 intracellular staining revealed a significant increase in Tregs within the CD4 + cell population (Fig.  1 B). These findings suggest the presence of an immunosuppressive microenvironment in the blood of MM patients.

Treg expansion is associated with the elevated production of Il-10 and TGF-β1 in MM patients. ( A ) ELISA analysis of IL-6, TNF-α, IL-4, IL-10, and TGF-β1 in the blood sample of the healthy controls and MM patients. The mean value of each cytokine in the control groups was set as 1, and the values in the MM group were normalized against the mean value of the control group. ( B ) Detection of Tregs using CD4 surface staining and FoxP3 intracellular staining in the blood sample of the healthy controls and MM patients. (n = 20 samples in each group; n = 3 technical replicates for ELISA measurement for each sample; Student’s t test). * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

Tregs induce downregulation of class I MHC complex and upregulation of PDL1 in MM cells

To investigate the impact of Tregs on the antigen-presenting molecules in MM cells, we conducted co-cultures using human MM cell lines (MM.1S and SK-MM-1) and isolated Tregs from MM patients for 24 h. Compared to the MM cell culture alone, cells co-cultured with Tregs exhibited a significant downregulation of class I MHC complex members (HLA-A, HLA-B, HLA-C, MICA and MICB), while the expression level of immunosuppressive factor PDL1 was upregulated in the MM cells with Treg co-culture (Fig.  2 A,B). As revealed by ELISA analysis, the co-culture with Tregs led to a reduction in the levels of IL-6, TNF-α and CXCL10 in the cell culture supernatant. Conversely, the levels of IL-10 and TGF-β1 were elevated (Fig.  2 C). qRT-PCR analyses in MM cells demonstrated no changes in IL-10 and TGF-β1 mRNA levels upon co-culture with Tregs, while the transcription of IL-6, TNF-α, and CXCL10 mRNAs was suppressed in the presence of Tregs (Fig.  2 D). We further examined the protein levels of SLAMF7 and BCMA (CAR-T therapy targets in MM cells) in two MM cell lines. We did not find significant changes of these two proteins with or without Treg co-culture (Fig.  2 E). Together, these findings suggest that Tregs downregulate class I MHC complex and increases the expression of PDL1 in MM cells.

Tregs induce the downregulation of MHC complexes and promote the expression of PDL1 in MM cells. To investigate the impact of Tregs on the antigen presenting molecules in MM cells, human MM cell lines (MM.1S and SK-MM-1) were co-cultured with isolated Tregs from the MM patients at a ratio of 1:0.5 for 24 h. ( A ) qRT-PCR analsyis of HLA-A, HLA-B, HLA-C, MICA, MICB, and PDL1 in MM cells in the absence or the presence of Tregs. ( B ) Western blot analysis of HLA-A, MICA, MICB, and PDL1 in MM cells in the absence or the presence of Tregs. ( C ) ELISA analysis of IL-6, TNF-α and CXCL10 in the cell culture supernatant. ( D ) qRT-PCR analyses of IL-10, TGF-β1, IL-6, TNF-α and CXCL10 mRNAs in MM cells. ( E ) Western blot analysis of the protein levels of SLAMF7 and BCMA in MM cells in the absence or the presence of Tregs. (n = 3 independent experiments; n = 3 technical replicates for ELISA and qRT-PCR measurement in each experimental sample. Student’s t test). * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

Tregs suppress the cGAS-STING pathway in MM cells

Given that the cGAS-STING signaling pathway drives the expression of IL-6, TNF-α and CXCL10, we next attempted to investigate the impact of Tregs on the cGAS-STING pathway in MM cells. qRT-PCR analysis revealed a decrease in the mRNA levels of cGAS and STING in both MM.1S and SK-MM-1 cells upon co-culture with Tregs, while the mRNA levels of TBK1 and IRF3 remained unchanged (Fig.  3 A). We further examined the activation state of cGAS-STING signaling by detecting the phosphorylation levels of TBK1 and IRF3 in MM cells in the presence or absence of Tregs. With the decreased protein levels of cGAS and STING in the presence of Tregs, the phosphorylation levels of TBK1 and IRF3 were also diminished in MM cells in the presence of Tregs (Fig.  3 B). Thus, this could implicate that Tregs dampen cGAS-STING pathway in MM cells.

Tregs dampen the cGAS-STING pathway in MM cells. To investigate the impact of Tregs on the antigen presenting molecules in MM cells, human MM cell lines (MM.1S and SK-MM-1) were co-cultured with isolated Tregs from the MM patients at a ratio of 1:0.5 for 24 h. ( A ) qRT-PCR analysis of the mRNA levels of cGAS, STING, TBK1 and IRF3 in human MM cell lines (MM.1S and SK-MM-1) with or without Tregs co-culture. ( B ) Western blot analysis of the protein levels of cGAS, STING, TBK1, p-TBK1, IRF3 and p-IRF3 in the MM cells with or without Tregs co-culture. (n = 3 independent experiments; n = 3 technical replicates for qRT-PCR measurement in each experimental sample. Student’s t test). * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

STING agonist counteracts Treg-mediated effects on MM cells

Next, we investigated whether the reactivation of cGAS-STING signaling could counteract the impact of Tregs on MM cells. STING agonist-4, a stimulator of STING receptor that has been demonstrated to induce the phosphorylation of IRF3 and STING 21 , was administered to MM cells in the presence of Tregs. STING agonist-4 did not influence the mRNA levels of cGAS, STING, TBK1 and IRF3 (Fig.  4 A). Nevertheless, its application successfully reactivated cGAS-STING signaling in MM cells co-cultured with Tregs, as evidenced by the restoration of TBK1 and IRF3 phosphorylation (Fig.  4 B). Additionally, STING agonist-4 was capable of reinstating the expression of class I MHC complex members while reducing the expression of PDL1 in MM cells (Fig.  4 C). ELISA analysis further revealed that although the levels of IL-10 and TGF-β1 remained unaffected by STING agonist-4 (as these cytokines are produced by Tregs), STING agonist-4 treatment significantly increased the production of IL-6, TNF-α and CXCL10 in MM cells when co-cultured with Tregs (Fig.  4 D). These data indicate that the Treg-mediated suppression of cGAS-STING signaling contributes to the downregulation of MHC complex members and the upregulation of PDL1 in MM cells.

STING agonist counteracts the effect of Tregs on MM cells. STING agonist-4 was applied at 1 μM in the MM cells in the presence of Tregs co-culture (MM cells were co-cultured with isolated Tregs at a ratio of 1:0.5 for 24 h). ( A ) qRT-PCR analysis of cGAS, STING, TBK1 and IRF3 at the mRNA levels. ( B ). Western blot analysis of the protein levels of cGAS, STING, TBK1, p-TBK1, IRF3 and p-IRF3. ( C ). qRT-PCR analsyis of HLA-A, HLA-B, HLA-C, MICA, MICB, and PDL1. ( D ). ELISA analysis of IL-10, TGF-β1, IL-6, TNF-α and CXCL10 in cell culture supernatant. (n = 3 independent experiments; n = 3 technical replicates for ELISA and qRT-PCR measurement in each experimental sample. One-way ANOVA). * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

TGF-β1 neutralization curtails the impact of Tregs on MM cells

We hypothesized that Treg-derived TGF-β1 may account for the suppression of cGAS-STING signaling in MM cells. To test this hypothesis, we applied a TGF-β1 neutralizing antibody in the co-culture system, with the IgG isotype serving as the control. TGF-β1 neutralizing antibody effectively decreased the levels of labile TGF-β1 in the supernatant, while IL-10 level remained unchanged (Fig.  5 A). Interestingly, TGF-β1 neutralization promoted the expression of cGAS-STING signaling-dependent cytokines (IL-6, TNF-α, and CXCL10) in MM cells co-cultured with Tregs. Western blot analysis further confirmed that TGF-β1 neutralization increased the expression of cGAS and STING in MM cells and reactivated the phosphorylation of TBK1 and IRF3 (Fig.  5 B). Besides, neutralizing TGF-β1 restored the expression of class I MHC complex members and reduced the expression of PDL1 in MM cells co-cultured with Tregs (Fig.  5 C,D). These findings point that Treg-derived TGF-β1 induces the suppression of cGAS-STING signaling in MM cells.

TGF-β1 neutralization mitigates the effect of Tregs on MM cells. TGF-β1 neutralizing antibody was applied at 1 μg/mL in the co-culture system of MM cells and Tregs, with the IgG isotype as the control (MM cells were co-cultured with isolated Tregs at a ratio of 1:0.5 for 24 h). ( A ). ELISA analysis of IL-10, TGF-β1, IL-6, TNF-α and CXCL10 in cell culture supernatant. ( B ). Western blot analysis of the protein levels of cGAS, STING, TBK1, p-TBK1, IRF3 and p-IRF3. ( C ). qRT-PCR analsyis of HLA-A, HLA-B, HLA-C, MICA, MICB, and PDL1. ( D ). Western blot analysis of HLA-A, MICA, MICB, and PDL1. (n = 3 independent experiments; n = 3 technical replicates for ELISA and qRT-PCR measurement in each experimental sample. One-way ANOVA). * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

The pro-tumorigenic effect of Tregs is suppressed by STING agonist and TGF-β1 neutralization

To further elucidate the impact of Treg-mediated cGAS-STING suppression on MM cell tumorigenesis, the nude mice were injected with MM.1S cells, MM.1S cells with Tregs, MM.1S cells with Tregs and STING agonist-4, MM.1S cells with Tregs and IgG isotype or MM.1S cells with Tregs and TGF-β1 neutralizing antibody. The administration of Tregs promoted the tumor formation of MM cells in the nude mice (Fig.  6 A,B). Notably, both STING agonist-4 and TGF-β1 neutralizing antibody suppressed the pro-tumorigenic effect of Tregs. In the tumor samples, the administration of STING agonist-4 and TGF-β1 neutralizing antibody also counteracted the effect of Tregs on class I MHC molecule and PDL1 expression of MM cells (Fig.  6 C). ELISA analysis also showed STING agonist-4 and TGF-β1 neutralization promoted the expression of cGAS-STING signaling dependent cytokines (IL-6, TNF-α and CXCL10) in MM tumors (Fig.  6 D). In addition, TGF-β1 neutralization increased cGAS and STING expression and enhanced TBK1 and IRF3 phosphorylation in the group injected with Tregs. STING agonist-4 exhibited a similar effect on the activation of TBK1 and IRF3 phosphorylation (Fig.  6 E). These data suggest that TGF-β1-dependent suppression of cGAS-STING signaling in MM cells contributes to the pro-tumorigenic effect of Tregs. Of note, the activation of cGAS-STING pathway may exert a direct anti-tumorigenic effect on tumor, a potential effect that needs to be clarified by the future study.

STING agonist and TGF-β1 neutralization counteract the pro-tumorigenic effect of Tregs. The nude mice were injected with MM.1S cells, MM.1S cells plus Tregs, MM.1S cells plus Tregs and STING agonist-4, MM.1S cells plus Tregs and IgG isotype or MM.1S cells plus Tregs and TGF-β1 neutralizing antibody (n = 5 in each group). The tumor samples were harvested from nude mice on day 35. ( A ). Xenograft tumor images in each experimental group. ( B ). The summary of tumor weight in each group. ( C ). qRT-PCR analsyis of HLA-A, HLA-B, HLA-C, MICA, MICB, and PDL1 in the tumor tissues. ( D ). ELISA analysis of IL-10, TGF-β1, IL-6, TNF-α and CXCL10 in the tumor tissues. ( E ). Western blot analysis of the protein levels of cGAS, STING, TBK1, p-TBK1, IRF3 and p-IRF3 in the tumor tissues. (n = 5 animals in each group; n = 3 technical replicates for ELISA and qRT-PCR measurement in each experimental sample. One-way ANOVA).* P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

In this study, we demonstrated that Treg expansion was associated with elevated production of IL-10 and TGF-β1 in MM patients. The co-culture of Tregs with MM cells resulted in increased TGF-β production, downregulation of class I MHC members, and promoted the expression of PDL1. TGF-β1 derived from Tregs dampened the cGAS-STING signaling pathway in MM cells, contributing to the decreased MHC expression and elevated PDL1 levels in MM cells. Neutralizing TGF-β1 or activating cGAS-STING pathway not only antagonized the effect of Tregs on the tumor antigen presentation and immunosuppressive signal in MM cells, but also mitigated the pro-tumorigenic effect of Tregs in the mouse model.

Tregs are a specialized population of T cells that functions to dampen immune responses and maintain immune homeostasis and self-tolerance 22 . Tregs can suppress T cell proliferation, activation, and inflammatory cytokine production 23 . Thus, Tregs have great therapeutic potential in treating autoimmune and chronic inflammatory diseases 24 . However, in tumor tissues Treg recruitment and expansion created an immunosuppressive hurdle for antitumor immunity 25 . Target intratumoral Tregs becomes an attractive strategy to re-activate antitumor immunity in the tumor microenvironment 26 . In MM patients, myeloma drives the expansion of Tregs in the bone marrow through secreting cytokines 20 . Further, it has been widely reported that Treg expansion is a immunological feature in the peripheral blood of MM patients 20 , 27 , 28 . Increased Treg frequency in the blood has also been recognized as an adverse clinical feature that predicts progression in MM patients 29 . Consistent with the observation, we also showed that there is an increased percentage of CD4 + FoxP3 + Tregs in the CD4 + T cell population in the blood samples of MM patients. Treg expansion is also associated with the increased levels of anti-inflammatory cytokines (IL-10 and TGF-β1). Neutralizing TGF-β1 not only counteracted the effect of Tregs on MHC complex expression in MM cells, but also suppressed the pro-tumorigenic effect of Tregs in the mouse model. Since peripheral Tregs can be recruited into the tumor microenvironment and the elevated production of immunosuppressive cytokines may also affect the immunity in the tumor tissues 20 , 25 , 26 , we envision that Treg-derived cytokines might act systemically both in the blood and bone marrow of MM patients. Future work is required to clarify whether Treg-derived IL-10 exerts a similar effect on MM cells through the same or a different mechanism.

The loss or dampening of antigenicity in MM cells are widely reported 30 , 31 . This can happen through the downregulation of tumor-specific antigen, antigen shedding, genetic alteration, and the lowered expression of antigen presentation machinery 14 , 32 . Apart from the suppression of T cell activation and cytokine production, Tregs are also reported to modulate antigen presentation and the co-stimulatory signals on the antigen presenting cells (APCs). For examples, lymphocyte activation gene 3 (LAG3) expressed by Tregs can downregulate the expression of MHC II molecules in the dendritic cells (DCs) 33 . Treg also suppresses B7-2 co-stimulatory molecule and induces the expression of negative regulatory molecules B7-H3 and B7-H4 on DCs 34 . In our study, we showed that Tregs could dampen the expression of MHC I molecules on MM cells in a TGF-β1 dependent manner. The downregulation of MHC I molecule is a well-established cancer immune evasion mechanism 16 . The high level expression of MHC I molecule MICA on bone marrow myeloma cells renders them highly susceptible to the lysis by natural killer cells 35 . Inducible downregulation of MHC class I can lead to natural killer cell tolerance 36 . Thus, Treg induced MHC I molecule downregulation may serve as an immune evasion mechanism in MM cells.

We further showed that Treg-derived TGF-β1 accounts for the downregulation of MHC I molecules in MM cells, since TGF-β1 neutralizing antibody could abrogate the effect of Tregs in the co-culture system. Accumulating evidence suggests that TGF-β signaling plays a pivotal role in regulating MHC molecules in different scenarios. The downregulation of class I MHC molecules by TGF-β1 was demonstrated in fibroblasts isolated from TGF-β1 null mice in an early study 37 . TGF-β1 can also suppress IFN-gamma dependent induction of class II MHC genes by attenuating mRNA transcription 38 . In human and horse mesenchymal stem cells, TGF-β signaling activation dampens antigen processing/presentation genes and MHC I molecule expression in a Smad3-dependent mechanism 39 . Therefore, our findings are in consistence with notion that TGF-β signaling negatively impacts on MHC molecule expression.

cGAS-STING signaling serves as a cytosolic double-stranded DNA (dsDNA) sensor and mounts antiviral innate immunity through activating downstream TBK1/IRF3 40 . Recently, cGAS-STING pathway has become a hot spot in cancer immunotherapy, since STING agonists can synergize with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors and adoptive T cell transfer, to boost the anticancer immunity in advanced cancer treatment 41 , 42 . However, the interplay of cGAS-STING pathway with other signaling processes and its role in regulating antigen presentation are elusive. Our data demonstrated that Treg-derived TGF-β1 can transcriptionally suppress the mRNA levels of cGAS and STING in MM cells. Neutralizing TGF-β1 and the administration of STING agonist were able to counteract the effect of Tregs on MHC I molecule downregulation in MM cells, as well as suppressing the pro-tumorigenic effect of Tregs on MM cells in mouse model. In agreement with our finding, the activation of cGAS-STING pathway promotes cytotoxic T cell-mediated cancer cell killing by increasing MHC I molecule expression on the surface of cancer cells 43 , 44 . Together, our findings imply that TGF-β1-cGAS/STING axis is an important regulator of MHC I expression in MM cells. The activation of cGAS/STING pathway is essential for the antigenicity in MM cells. Nonetheless, over-activation of cGAS/STING pathway may cause the hyper-activity in other immune cells and lead to side effect such as cytokine storm 45 . The strategy of selectively activating cGAS/STING pathway in MM cells may solve this concern. Moreover, future work is required to further dissect the mechanisms by which TGF-β1 regulates cGAS/STING expression and how cGAS/STING signaling modulates the expression of MHC I molecules in MM cells.

To conclude, we demonstrated that Tregs could induce the downregulation of class I MHC molecules and promoted the expression of PDL1 in MM cells in a TGF-β1 dependent manner. The suppression of cGAS-STING signaling pathway in MM cells underlies the effect of Treg-derived TGF-β1. Our findings suggest that neutralizing TGF-β1 or activating the cGAS-STING pathway could restore the expression of the antigen presentation system and immunosuppressive signal in MM cells affected by Tregs, potentially providing therapeutic strategies for MM treatment.

Clinical samples

The peripheral blood samples were collected from 20 healthy controls and 20 MM patients at the Department of Hematology of Yunnan Cancer Hospital. All the included subjects were primarily diagnosed with MM, without any clinical treatment. Patients diagnosed with other types of malignancies or had a clinical record of chronic diseases were also excluded from the study. The blood samples were snap-frozen in liquid nitrogen and stored in − 80 °C for further analyses. The collection and use of clinical blood specimens in this study were conducted following the Declaration of Helsinki. The research gained the approval by the Institutional Review Board of Yunnan Cancer Hospital (Kunming, China). All the recruited subjected signed the informed consent.

Treg isolation and analysis

For Treg isolation from the peripheral blood samples, CD4 + CD25 + Regulatory T Cell Isolation Kit, human (Miltenyi Biotec, CA, USA) was used based on the supplier’s instructions. The isolated Tregs were expanded using Human Treg Expansion Kit (Miltenyi Biotec, CA, USA). For cell surface antibody staining, cells were washed in PBS supplemented with 2% FBS and incubated with fluorophore conjugated antibodies (PB-αCD4, 1:400; Fc-Block (αCD16/32), 1:500) at 4 °C for 10 min. For intracellular staining of FoxP3, cells were then fixed and permeabilized using Foxp3 intracellular staining kit (eBioscience, CA, USA) before being stained with corresponding FoxP3 antibodies (APC-αFoxp3 1:100) for an hour. After three washes in permeabilizing buffer the stained cells were re-suspended in PBS and analyzed on an LSRII flow cytometer (BD Biosciences, CA, USA) ( Supplementary figures ).

Cell culture

Human MM cell lines (MM.1S and SK-MM-1) were purchased from Cobioer Biosciences (Nanjing, China). The cells were maintained in McCoy’s medium (Thermo Fisher Scientific, CA, USA) containing 10% FBS (Thermo Fisher Scientific, CA, USA) and 1% penicillin/streptomycin (Hyclone, CA, USA) under the condition of 37 °C and 5% CO 2 . For the co-culture experiment of Tregs and MM cells, MM cells were plated with Tregs at a ratio of 1:0.5 in a 24-well plate for 24 h. For STING stimulation, STING agonist-4 (MedChemExpress, Shanghai, China) was applied at 1 μM. To neutralize TGF-β1, NeutraKine® TGF beta 1 Monoclonal antibody (ProteinTech, IL, USA) was applied at 1 μg/ml, with 1 μg/ml IgG isotype as the control. For molecular characterization of MM cells, Tregs were removed by CD25 magnetic beads (Dynabeads™ CD25, Thermo Fisher Scientific, CA, USA).

Enzyme-linked immunosorbent assay (ELISA)

The relative levels of IL-6, IL-4, IL-10, TGF-β1, TNF-α, and CXCL10 in the blood sample or cell culture supernatant were determined using corresponding ELISA kits (Sigma, St. Louis, MO, USA). Briefly, the micro-assay plates were coated with corresponding antibodies at 4 °C overnight. 100 μl of samples or standards were added into the capture-antibody-coated plate for 2-h incubation at ambient temperature. After a washing step to remove unbound material, 100 μl of the biotin-labeled detection antibody was added for 1-h incubation, which was followed by the incubation with 50 μl of streptavidin-HRP. Next, 100 μl of chemiluminescent detection reagents were added for signal development and the optical densities of each sample and the standards were measured at 450 nm using a microplate reader (Infinite 200 PRO; Tecan).

qRT-PCR analysis

The total RNA samples from the plasma and cell specimens were extracted using TRIzol reagent (Qiagen, Shanghai, China), and reverse transcription was performed using the PrimeScript™ RT Reagent Kit (Takara Biotechnology, Otsu, Japan). The resulted cDNA was diluted and analyzed in a 7500 Real Time PCR System (Applied Biosystems, CA, USA) using SYBR premix EX TAQ II kit (Takara Biotechnology, Otsu, Japan). All PCR primers were purchased from Sangon Biotechnology (Shanghai, China). The 2 −ΔΔ CT method was used to quantify the relative gene expression, with β-actin as the reference gene.

Western blot

Total protein samples were extracted using the RIPA lysis buffer (Beyotime, Beijing, China) mixed with protease inhibitor and PMSF (ThermoFisher Scientific, CA, USA). The supernatant was then collected after 15 min incubation by centrifugation. After denaturation, the protein samples were subjected to separation in 12% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred onto a PVDF membrane (0.22 µm or 0.45 µm, Merck-Millipore, Darmstadt, Germany). 5% skimmed milk (w/v) in the TBST buffer was used to block the membrane for 1 h. The membrane was then incubated with primary antibodies (Abcam, Cambridge, UK): anti-HLA-A (ab52922, 1:1000), anti-beta actin antibody (ab8227, 1:1000), anti-MICA (ab62540, 1:1000), anti-MICB (ab167488, 1:1000), anti-PDL1 (ab205921, 1:1000), anti-cGAS (ab224144, 1:1000), anti-STING (ab181125, 1:1000), anti-TBK1 (ab40676), anti-pTBK1 (ab206124, 1:1000), anti-IRF3 (ab68481, 1:1000), and anti-pIRF3 (ab76439, 1:1000) at 4°C overnight. Afterward, the PVDF membrane was washed with 1× TBST buffer and further labeled with horseradish peroxidase (HRP)-conjugated secondary antibody at room temperature for 1 h (Abcam, ab205718, 1:2000). After 3 washes, the protein bands were developed using the ECL chemiluminescent solution (Beyotime, Beijing, China). The intensities of target protein bands were normalized to that of beta-actin (loading control).

Animal model

Balb/c nude mice (male, 4–5 weeks old) were purchased from the Shanghai Laboratory Animal Center (SLAC) Co., Ltd. (Shanghai, China) and housed at the SPF facility. All animal procedures were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Yunnan Cancer Hospital (Kunming, China). The following experimental groups were established: control (injected with 1 × 10 6 MM.1S cells); Tregs group (injected with 1 × 10 6 MM.1S cells and 5 × 10 5 Tregs); Tregs + STING agonist-4 group (injected with 1 × 10 6 MM.1S cells and 5 × 10 5 Tregs, and administrated with STING agonist-4 at 5 mg/kg every week). Tregs + IgG group (injected with 1 × 10 6 MM.1S cells and 5 × 10 5 Tregs, and administrated with IgG isotype at 1 mg/kg every week); Tregs + Anti-TGF-β1 group (injected with 1 × 10 6 MM.1S cells and 5 × 10 5 Tregs, and administrated with TGF-β1 neutralizing antibody at 1 mg/kg every week). All the mice were also injected with 1 × 10 6 of human CD45 + lymphocytes. Cells were injected subcutaneously at the right flank of the mice, and STING agonist-4, Anti-TGF-β1 antibody and IgG were administered intraperitoneally. The tumor volume was measured every week. The mice were euthanized by intraperitoneal injection of excessive pentobarbital sodium (200 mg/kg) on day 35 and the tumor samples were collected for further analysis.

Statistical analysis

Data were analyzed by GraphPad Prism software (GraphPad Software, NY. USA) and expressed as mean ± standard deviation (SD). The analysis between different groups was based on the Student's t-test or one-way ANOVA at a defined statistical threshold of P  < 0.05.

Ethic statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Yunnan Cancer Hospital (Kunming, China) (protocol code YJZ201904). Written informed consent was obtained from each participant prior to the collection of clinical specimens. The animal experiments were also approved by the Institutional Animal Care and Use Committee (IACUC) of Yunnan Cancer Hospital (Kunming, China) (protocol code kmmu2021692), and were conducted according to the relevant guidelines and regulations. The study was carried out in compliance with the ARRIVE guidelines.

Data availability

The data supporting this study's findings are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by Qiu Lu Gui Expert Workstation in Yunnan Province (Project No. 202105AF150051), National Natural Science Foundation of China (Received No. 8216010239), Kunming Joint Special Project (Received No. 202001AC070617), Kunming Joint Special Project (Received No. 202001AC070202), Yunnan Fundamental Research Projects (Grant NO.202101AT070199), The Joint Project of Kunming Medical University and Science and Technology Agency (Grant NO.202101AY070001-049).

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These authors contributed equally: Disi Zhang and Dong Zhan.

Authors and Affiliations

Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, No. 519 Kunzhou Road, Xishan District, Kunming, Yunnan Province, China

Disi Zhang, Rui Zhang, Yunyan Sun, Ci Duan, Jia Wei, Xianshi Li, Yanqi Lu & Xun Lai

Department of Human Anatomy and Histology and Embrology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan Province, China

Department of Thoracic Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, No. 519 Kunzhou Road, Xishan District, Kunming, Yunnan Province, China

Jiapeng Yang

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DS.Z.: Investigation, Conceptualization, Methodology, Data curation, Validation, Data analysis, Writing., Review & Editing. D.Z.: Investigation, Conceptualization, Methodology, Data curation, Data analysis, Writing, Review & Editing, Resources. R.Z.: Investigation, Conceptualization, Data curation, Data analysis, Resources. Y.S.: Conceptualization, Methodology, Review & Editing. C.D., J.Y.: Conceptualization, Methodology, Validation. J.W., X.L., Y.L.: Methodology, Supervision, Review & Editing. X.L.: Investigation, Conceptualization, Methodology, Supervision, Review & Editing, Funding acquisition. DS.Z. and D.Z. contributed equally. All authors have read and approved the final version of the manuscript.

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Correspondence to Xun Lai .

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Zhang, D., Zhan, D., Zhang, R. et al. Treg-derived TGF-β1 dampens cGAS-STING signaling to downregulate the expression of class I MHC complex in multiple myeloma. Sci Rep 14 , 11593 (2024). https://doi.org/10.1038/s41598-024-62298-3

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DOI : https://doi.org/10.1038/s41598-024-62298-3

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#SummerReady FEMA Extreme Heat Summit, Chicago

As part of FEMA’s #SummerReady campaign series of heat events this meeting focuses on actions state, local, tribal, territorial leaders can take to reduce the effects of extreme temperatures.

Date: 2024-05-21T13:30:00 2024-05-22T22:00:00 May 22, 2024 May 21, 2024 - May 22, 2024

Time: 1:30 pm - 10:00 pm

Location: Onsite and Virtual

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Event Details

This event builds upon lessons learned from FEMA’s 2023 Extreme Heat Summit in Chicago and is open to government leaders, resilience focused private sector, nonprofit and academic organizations. Presentations and paneled discussions will be led by subject matter experts, local emergency managers, and climate resilience practitioners. Speakers will focus on raising awareness of the increasing frequency and severity of extreme heat events, highlighting mitigation best practices across the country, and discussing ways of communicating extreme heat risks and implications to communities and stakeholders.

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This event will be held in Central Standard Time (CST). Please note the time different for your time zone.

May 21, 2024: 8:30 a.m. - 5:00 p.m. CST

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536 South Clark Street Chicago, IL 60605 (space limited, physical attendance by invite only)

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Overview of Climate Science

• Dr. Wenying Su , Senior Scientist, National Aeronautics and Space Administration (NASA)

Extreme Heat Impacts

• Dr. Kristie Ebi , Professor, University of Washington
• Carolyn Levering , Emergency Management Administrator, City of Las Vegas Emergency Management
• Andrew Phelps , Former Emergency Management Director, Oregon Department of Emergency Management
• Dr. Denise Smith , Director, National Fire Research and Data Center, United States Fire Administration (USFA)
• Sunny Wescott , Chief Meteorologist, Cybersecurity Infrastructure Security Agency (CISA)

Communications & Messaging

• Adrienne Bechelli , Deputy Director, San Francisco Department of Emergency Management
• Joseph Giguere , Research Technician, Climate Data Science, Climate Central
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• Cecylia Fortunska , GIS and Climate Data Subject Matter Expert and Consultant, Climate Resilience Integration Branch, Office of Resilience (ORS), FEMA
• Danielle Fox , Community Conservationist, City of Colombia, Missouri
• Raed Mansour , Chief Heat Officer and Director, Chicago Heat Watch Program of Environmental Innovation, Chicago Department of Public Health

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For questions about the Summit in Chicago, registration, or arrangements, contact [email protected] .

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Seasonal activities planned at Fort Harrison State Park

Fort Harrison State Park in Lawrence offers numerous events through the spring and summer season, including guided nature walks, concerts and presentations.

Upcoming events at Fort Harrison are:

• Sweeping Swallows : Naturalist Sarah Fox will lead a presentation about the swooping birds that can be seen around Delaware Lake, including the best places to watch swallows in the park. The presentation starts at 1 p.m. May 25 at the park’s information center, 6000 N. Post Rd. No registration is required for this free event.
• Sunday Morning Bird Walk: The last Sunday Morning Bird Walk of the season is set for 8 a.m. May 26, led by naturalist Emilie Sweet. Participants are encouraged to bring binoculars, water and appropriate footwear for a two-hour walk. Meet at the northeast corner of Delaware Lake parking lot. No registration is required for this free event.
• Indiana Mammals : Naturalist Sarah Fox will lead a presentation about the variety of mammals in Indiana, their characteristics and how to identify individual species. The presentation starts at 1 p.m. May 26 at the park’s information center, 6000 N. Post Rd. No registration is required for this free event.
• Summer Concert Series : Park visitors are invited to bring a lawn chair and relax on the park’s sledding hill while listening to a free concert by local musicians. The music begins at 7 p.m. Leashed dogs are welcome.
• Intro to Fishing: Registration has closed for this free class, which takes place at 9 a.m. June 16. For information about future classes, contact Christopher Conner at [email protected] .
• Beginner Catfishing : Registration has closed for this free class, which takes place at 12:30 p.m. June 16. For information about future classes, contact Christopher Conner at [email protected] .

New events are added to the park’s calendar throughout the season. For updated information, visit bit.ly/3woYIYC .

Vatican releases new norms on alleged supernatural phenomena

V ATICAN— A new document from the Dicastery for the Doctrine of the Faith published on Friday, May 17, has updated the  norms for discerning alleged supernatural phenomena . The norms come into force on Sunday, May 19, the feast of Pentecost.

The document is preceded by a detailed presentation by Cardinal Víctor Manuel Fernández, Prefect of the Dicastery, followed by an introduction and six possible conclusions. The procedure allows for faster decisions while respecting popular devotion.

As a rule, the Church’s authority will no longer be engaged to officially define the supernatural nature of a phenomenon, a process that can require large amounts time to thoroughly study an event.

Another new norm involves the explicit involvement of the Dicastery for the Doctrine of the Faith, which must approve the local bishop’s final decision and which has the authority to intervene motu proprio at any time.

Many cases in recent decades have involved the former Holy Office, even when individual bishops have expressed themselves. However, the interventions have usually remained behind the scenes and were never made public.

The Dicastery’s new explicit involvement also relates to the difficulty in circumscribing phenomena, which in some cases reach national and even global dimensions, “meaning that a decision made in one Diocese has consequences also elsewhere.”

Reasons for the new norms

The document originates from the long experience of the last century, which saw cases where the local bishop (or bishops of a region) rapidly declared a phenomenon’s supernatural nature, only for the Holy Office to express a different decision later. Other cases involved a bishop saying one thing and his successor deciding the opposite (regarding the same phenomenon).

Each event also required lengthy discernment periods to evaluate all elements in order to reach a decision on the supernatural nature or non-supernatural nature of the phenomena. These time periods sometimes contrasted with the urgency to give pastoral responses for the good of the faithful.

The Dicastery began revising the norms in 2019, leading to the current text approved by Pope Francis on May 4.

Spiritual fruits and risks

In his presentation, Cardinal Fernández explains that, “many times, these events have led to a great richness of spiritual fruits, growth in faith, devotion, fraternity, and service. In some cases, they have given rise to shrines throughout the world that are at the heart of many people’s popular piety today.”

However, there is also the possibility that “in some events of alleged supernatural origin,” serious issues that harm the faithful may arise. These include cases where from the alleged phenomena, “profit, power, fame, social recognition, or other personal interest” (II, Art. 15, 4°) are derived, even to the point of “exerting control over people or carrying out abuses (II, Art. 16).”

There may be “doctrinal errors, an oversimplification of the Gospel message, or the spread of a sectarian mentality.” There is the possibility of believers “being misled by an event that is attributed to a divine initiative but is merely the product of someone’s imagination, desire for novelty, tendency to fabricate falsehoods (mythomania), or inclination toward lying.”

General guidelines

According to the new norms, the Church will exercise her duties of discernment, based on the following:

“(a) whether signs of a divine action can be ascertained in phenomena that are alleged to be of supernatural origin; (b) whether there is anything that conflicts with faith and morals in the writings or messages of those involved in the alleged phenomena in question; (c) whether it is permissible to appreciate their spiritual fruits, whether they need to be purified from problematic elements, or whether the faithful should be warned about potential risks; (d) whether it is advisable for the competent ecclesiastical authority to realize their pastoral value” (I, 10).

However, “it is not foreseen in these Norms that ecclesiastical authority would give a positive recognition of the divine origin of alleged supernatural phenomena” (I, 11).

Therefore, as a rule, “neither the Diocesan Bishop, nor the Episcopal Conferences, nor the Dicastery will declare that these phenomena are of supernatural origin, even if a Nihil obstat is granted. It remains true, however, that the Holy Father can authorize a special procedure in this regard” (I, 23).

Possible conclusions regarding an alleged phenomenon

The discernment of an alleged supernatural phenomenon may reach the following six conclusions.

– Nihil Obstat: Without expressing any certainty about the supernatural authenticity of the phenomenon itself, many signs of the action of the Holy Spirit are acknowledged. The bishop is encouraged to appreciate the pastoral value and promote the dissemination of the phenomenon, including pilgrimages;

– Prae oculis habeatur: Although important positive signs are recognized, some aspects of confusion or potential risks are also perceived that require the diocesan bishop to engage in a careful discernment and dialogue with the recipients of a given spiritual experience. If there were writings or messages, doctrinal clarification might be necessary;

– Curatur: Various or significant critical elements are noted, but the phenomenon is already spread widely, and verifiable spiritual fruits are connected to it. Therefore, a ban that could upset the faithful is not recommended, but the local bishop is advised not to encourage the phenomenon;

– Sub mandato: The critical issues are not connected to the phenomenon itself but to its improper use by people or groups, such as undue financial gain or immoral acts. The Holy See entrusts the pastoral leadership of the specific place to the diocesan bishop or a delegate;

– Prohibetur et obstruatur: Despite various positive elements, the critical issues and risks associated with this phenomenon appear to be very serious. The Dicastery asks the local bishop to offer a catechesis that can help the faithful understand the reasons for the decision and reorient their legitimate spiritual concerns;

– Declaratio de non supernaturalitate: The Dicastery for the Doctrine of the Faith authorizes the local bishop to declare that the phenomenon is found to be not supernatural based on concrete facts and evidence, such as the confession of an alleged visionary or credible testimonies of fabrication of the phenomenon.

Procedures to follow

The new norms then indicate the procedures to be implemented. It is up to the diocesan bishop to examine cases and submit their judgment to the Dicastery for approval. The bishop is asked to refrain from making public declarations about the authenticity or supernatural nature and to ensure there is no confusion or sensationalism.

If the elements of the case “seem sufficient,” the diocesan bishop will then set up an investigative commission, which should include at least one theologian, one canonist, and an expert chosen based on the nature of the phenomenon.

Positive and negative criteria

The document lays out several positive criteria to evaluate the alleged supernatural phenomenon.

These include: “the credibility and good reputation of the persons who claim to be recipients of supernatural events or to be directly involved in them, as well as the reputation of the witnesses who have been heard…; the doctrinal orthodoxy of the phenomenon and any messages related to it; the unpredictable nature of the phenomenon, by which it is evident that it is not the result of the initiative of the people involved; and, fruits of the Christian life” (II, 14).

The negative criteria involve: “the possibility of a manifest error about the event; potential doctrinal errors…; a sectarian spirit that breeds division in the Church; an overt pursuit of profit, power, fame, social recognition, or other personal interest closely linked to the event; gravely immoral actions…; psychological alterations or psychopathic tendencies in the person that may have exerted an influence on the alleged supernatural event; and, any psychosis, collective hysteria, and other elements traceable to a pathological context” (II, 15).

Finally, “the use of purported supernatural experiences or recognized mystical elements as a means of or a pretext for exerting control over people or carrying out abuses” (II, 16) is considered of particular moral gravity.

Regardless of the final approved determination, the diocesan bishop “must continue to watch over the phenomenon and the people involved, exercising his ordinary power” (II, 24).

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The characterization of functional conduction block in patients with multiple types of atrial tachycardia- A discussion on the mechanism of multiple atrial tachycardia

• Original Research
• Open access
• Published: 21 May 2024

Cite this article

You have full access to this open access article

• Bin Zhu 1 ,
• GuoHua Zhang 2 ,
• SongCai Xie 1 ,
• Ying Luan 1 ,
• Wei Cao 1 ,
• Jian Xu 1 ,
• Shuo Zhang 1 ,
• JinWei Tian 1 , 3 ,
• Fan Wang   ORCID: orcid.org/0000-0002-6439-7540 1 , 3 &
• ShuFeng Li 1  

High-resolution mapping offers superior accuracy in delineating conduction features; however, certain characteristics are still linked to elevated recurrence rates of atrial tachycardia (AT), suggesting the influence of additional mechanisms. This study systematically assessed the substrate of functional conduction block (FCB) regions in relation to the mechanisms of multiple ATs.

In this study, the Carto system facilitated the mapping of ATs in 13 patients undergoing ablation, each presenting with more than two AT variants. FCB regions were marked and further analyzed.

A total of 33 sustained ATs were mapped across the patient cohort. FCB regions showed convertibility in 7 of 13 patients (54%). Three kinds of presentations can be summarized by the FCB region: Firstly, the FCB region could act as the main obstacle sustaining the localized reentrant pathway, for which rounding obviously has a direct correlation with the mechanism of the AT (27%). Secondly, the FCB regions could act as obstacle lines to reorganize the propagation of the reentry in localized AT and macroreentrant AT (55%). Lastly, the FCB region could act as a bystander and may not be related to the mechanism of the ATs (18%). The potentials in FCB regions mostly performed low voltages or fragmented potentials (FPs) in the ATs which they did not perform the conduction block (90%).

In multiple ATs, FCB regions may not be uncommon. The participation of FCB regions in the mechanism of ATs showed three different kinds of performance. The dynamic nature of this substrate may provide insight into the reasons for the high recurrence of related ATs.

Avoid common mistakes on your manuscript.

1 Introduction

AT related to atrial scarring and postoperative Atrial fibrillation (AF) often results in the coexistence of multiple types of AT, typically requiring more complex ablation procedures. It was previously believed that the main mechanisms for the occurrence of multiple types of AT in a patient were related to scar-associated electrically silent areas and slow conduction [ 1 ]. However, in recent years, high-resolution mapping technology has greatly improved the resolution of excitation mapping and can accurately display the excitation conduction pathway for targeted ablation. But the recurrence rate of this type of AT is still high (40–50%) [ 1 , 2 ]. This predicts that the occurrence and coexistence of multiple ATs may also be related to other mechanisms. In explaining the mechanisms of ventricular arrhythmias (VAs) and AFs, functional conduction block has been proven to play an important role [ 3 ]. However, there is little description of functional conduction block in AT [ 4 , 5 ]. In our hospital’s AT ablation cases, we prospectively conducted detailed substrate mapping and excitation mapping on cases where multiple types of AT coexist in the same patient, aiming to explore the possible mechanisms underlying the maintenance of ATs and the high recurrence rate of arrhythmias in such patients.

2.1 Patient characteristics

This study prospectively and continuously conducted high-density excitation mapping and substrate mapping on 105 patients with atrial fibrillation/flutter who underwent catheter radiofrequency ablation in our hospital from April 2018 to December 2021. Among these 105 patients, 13 patients (7 males and 6 females) who experienced 2 or more types of AT during the ablation process were included in this study. Cases with unstable cycle length (CL), non-sustained AT, and failed ablation were excluded. Even with the application of antiarrhythmic drugs, the AT of these patients cannot be effectively controlled. Among them, 11 patients had sustained AT, and 2 patients had paroxysmal AT, with an average duration of AT of 12 months (minimum 1 month, maximum 36 months). All patients underwent routine anticoagulation therapy before ablation and esophageal echocardiography to exclude left atrial (LA) thrombus. Oral anticoagulants were discontinued on the day of surgery, replaced with heparin during surgery, to maintain the activated partial thromboplastin time at 2–3 times the normal value. All patients provided written informed consent, and the study protocol was approved by the local Research and Human Ethics Committees.

2.2 Electrophysiological Study and Mapping

Antiarrhythmic drugs (except amiodarone) were discontinued at least 5 half-lives before the operation; amiodarone was discontinued one month before the operation. A deflectable decapolar catheter (Dynamic XT, Boston Scientific) was positioned within the coronary sinus. Atrial mapping was performed with a Navistar Thermocool 3.5-mm D-F curve ablation catheter with Smart Touch technology (Biosense Webster) or multipolar mapping catheters (Pentaray, Biosense Webster Inc.). Bipolar electrograms filtered at 10–400 Hz were recorded. A bipolar signal from the coronary sinus (CS) electrode was used as the timing reference.

During the reconstruction of the atrial anatomy, excitation mapping and voltage mapping were performed simultaneously, and the electrically silent area (ESA) and double potential (DP) area were specifically marked. The definition of scar in mapping is as follows: scar, < 0.05 mV; scar border zone, between 0.05 ~ 0.5 mV; and normal tissue, 0.5 mV. Double potential is defined as: two high-frequency potentials with a minimum interval of a 30 ms isopotential line. The high-frequency fragmented potential is defined as: relatively long conduction time, multi-directional reentrant bipolar potential, but the voltage is within the basic range. The slow conduction potential is defined as: relatively long duration (mostly more than 1/3 of the circumference), lower voltage, and a fragmented low-frequency waveform. However, the earliest activation potential phase locally (compared with the earliest phase of the potential in the surrounding excited area) remains the earliest phase in the fragmented potentials, indicating that local conduction is still primarily sourced from slow conduction, Fig.  1 A. The conduction block is defined as: (1) Locally manifested as double potentials. The phase of the first potential of the double potentials did not occur later than the activation time on one side, and the phase of the tail potential of the double potentials did not occur earlier than the activation time on the other side, see Fig.  1 B. (2) Locally manifested as fragmented potentials. Fragmented potentials generally have a longer duration, and the latest phase of fragmented potentials is significantly longer than the latest excitation phase around it (indicating complex internal conduction, the internal conduction time is too long, its output time is later than its surrounding myocardium bypass conduction time), see Fig.  1 C. FCB is defined as: when subjected to excitations from different directions or different frequencies show different conduction properties. Specifically, manifested as for example, during one AT, it shows as defined conduction block, while during another AT or sinus rhythm, it does not show as defined conduction block ( Figs. 2 – 4 ). In the CARTO system, lines showing as defined conduction blocks are represented by white lines. During radiofrequency ablation, if the P wave morphology or tachycardia cycle length (CL) changes, remapping is performed. Routine entrainment mapping is performed to verify the tachycardia mechanism or determine the ablation target, but it is not used when strongly suspected that entrainment will cause tachycardia change or termination.

The relationship between potentials and anatomical locations in slow conduction and conduction block. A. The relationship of potentials at different positions in slow conduction. B.The relationship of potentials at different positions in the Type 1 conduction block. C. The relationship of potentials at different positions in the Type 2 conduction block

An example of the FCB region acting as the main obstacle to maintaining multiple ATs. The mapping results of two kinds of ATs in Patient 11. A, Activation map of the first AT showing a PTF. B, Activation mapping of the right atrial septum of the first AT shows that although the operative incision made conduction nonhomogeneous, forming a winding conduction from the anterior septum to the posterior septum (white arrow line), several breakouts still caused no obvious conduction block or delay. C, After ablation of the CTI, a second AT was induced through burst pacing. Activation mapping shows a localized reentry run around the obstruct line (white line), which is not shown in the first AT. The DPs are shown near the white line, while in the same location in the first AT (B), they showed low-amplitude biphasic or polyphasic potentials of short duration (potential box). Some break-out positions convert to conduction blocks that form a longer obstacle line and may more easily induce reentrant cycle rounding. This suggests that these positions may be the FCB region, which is only present in the second AT and provides an important obstacle line rounded for reentry. D, Voltage map of the second AT before ablation. The potential FCB region was related to the border zone of the scar tissue (white dotted box). AT = atrial tachycardia; CL = cycle length; CTI = cavotricuspid isthmus; DP = double potential; FCB = functional conduction block; FP = fragmented potential; PTF = peritricuspid flutter; SR = sinus rhythm; SVC = superior vena vein; TVA = tricuspid valve annulus

An example of FCB region acting as an obstacle line demarcating the reorganized propagation of the MAT in multiple ATs and acting as a bystander unrelated to the mechanism of AT. A-D, The mapping results of two kinds of ATs in Patient 2. A, Activation mapping showing a localized reentry run around the obstruct line formed by scars. The DPs are shown near the scar line in the first AT. B, Voltage map of the first AT before ablation. C-D, After ablation of the isthmus in the scars (marked as a red point), the AT converted to an RMAT depending on the LPV (the left atrium of these patients was scar dispersed, and there was an abundance of spontaneous scarring in the mitral isthmus and the ridge of the left pulmonary vein, which may lead to RMAT without CPVA. The location that first showed DP showed normal potential in the second AT, and the white block line disappeared due to nearby atrial re-conduction, which suggests that the upper part of the obstruct line which showed DPs in the first AT may be the FCB region, and that it may provide an important obstacle line rounded for reentry. There is a new white block line near the LAA and the location where the FP shown in AT1 converted to a DP in AT2, which suggests that this position may also be the FCB region that was only present in the second AT. Furthermore, this new obstruct line resulted in the longer conduction pathway that may make the reentrant cycle easier to maintain. After ablation, the mitral isthmus AT converted to SR. Note that there were two regions of the FCB in this patient that functioned in different mechanisms of ATs. The potential FCB region was related to the border zone of the scar tissue (white dotted box). E–G, The mapping results of two kinds of ATs in Patient 10. E, Activation mapping showing a PMF. There was an obstructed line near the LAA that showed DPs in the first AT. F, Voltage map of the first AT before ablation. G, After ablation of the mitral valve to the right superior pulmonary vein (this ablation line was chosen due to the scar at the anterior wall of the LA and the lack of electrical activity in the right superior pulmonary vein), AT converted to PTF. The location which showed DP in the first AT showed FP in the second AT, and the white block line disappeared due to nearby synchronous atrial activation, suggesting that the obstruct line, which showed DPs in the first AT, may be the FCB region and that it may not be related to the second AT. After ablation of the CTI, AT converted to SR. AT = atrial tachycardia; CL = cycle length; DP = double potential; FCB = functional conduction block; FP = fragmented potential; LAA = left atrial appendage; LPV = left pulmonary vein; MA = mitral annulus; PMF = perimitral flutter; PTF = peritricuspid flutter; RMAT = roof-dependent macroreentrant tachycardia; SR = sinus rhythm; SVC = superior vena vein; TVA = tricuspid valve annulus

The mapping results of three kinds of ATs in Patient 3. A, Activation mapping shows that the mechanism of the first AT was PMF. B, AT 1 converted to a localized reentry with two breakouts running around the obstruct line (white line) after ablation of the mitral isthmus. A DP was observed near the white line. This suggests that this position may be the FCB region, which was only present in the second AT, and it provides an important obstacle line rounded for reentry. C, AT 2 converted to a localized reentry running around the LAA after ablation of the upper breakout, and the white block line disappeared, again causing synchronous activation near the atrium. The DP converted to the FP. Note that the disappearance of the FCB region caused the reconduction of this region, which is part of the reentrant pathway and may be one of the requirements maintaining the third AT. After ablation of the FPs near the LAA, AT converted to SR. There was a constant scar line near the LSPV (white line; the obstructing line was part of the prior incomplete roof line). D, The intracardiac electrogram showed that the first AT converted to the second AT. E, The intracardiac electrogram showed that the second AT converted to the third AT. AT = atrial tachycardia; CL = cycle length; DPs = double potentials; FCB = functional conduction block; FP = fragmented potential; LAA = left atrial appendage; PMF = perimitral flutter; PTF = peritricuspid flutter; LSPV = left superior pulmonary vein

For each area of interest, data on intracavitary bipolar electrograms (EGMs) morphology, amplitude (in millivolts), and duration (in milliseconds) were collected and analyzed. At least 5 EGMs were collected for each area of interest, and each collection area had a density of at least 15 points to verify and ensure the accuracy of the recorded data.

2.3 Definition of the Reentry Circuit and Classification of the AT

AT is classified according to the mode of excitation into focal AT, anatomical macroreentrant AT (AMAT), and non-AMAT (localized reentry) [ 1 ]. AMAT includes cavotricuspid isthmus-dependent atrial flutter (CTI), perimitral flutter dependent on the mitral isthmus (PMF), and roof-dependent macroreentrant tachycardia (RMAT). Localized reentry is defined as: the entire tachycardia excitation cycle length can be recorded in a local area, with the size of the localized reentry circuit varying, mostly centered around scars that appear as conduction blocks [ 1 ]. Focal AT is defined as: the earliest excitation of the atrium originates from a point and spreads to the surroundings at the same time (the excitation time measured in general is less than the tachycardia cycle length) [ 6 ]. Multi-loop AT is defined as: multiple reentry loops share an isthmus, including double-loop AT and triple-loop AT, each loop excitation time meets the tachycardia circumference [ 6 ]. When a time jump phenomenon appears between the distal end of the coronary sinus and the left atrial appendage in the tachycardia excitation mapping, and this position (PPI-TCL) < 20 ms, while the left atrial anterior wall, mitral 6 o’clock-11 o’clock position (PPI-TCL) > 20 ms, is suspected to be epicardial AT involving the coronary sinus or Marshall vein [ 7 , 8 , 9 ].

2.4 Catheter Ablation

Ablation strategies were adopted according to the mechanisms of ATs. Generally, the ablation of localized reentrant AT targets the isthmus that exhibits fragmented potentials (FPs) related to myocardial excitation during diastole, most of which are viable slow conduction sites left by scars or anatomical blocks. The ablation of macroreentry atrial tachycardia (MAT) selects the narrowest conductive tissue between scars or anatomical obstacles based on anatomical length, catheter stability, tissue thickness, and proximity to vulnerable structures. For focal AT, ablation is performed at the early excitation site based on mapping results. Ablation uses a saline-infused catheter with a tip length of 3.5 mm (Thermocool®ST catheter, Biosense Webster) in power mode, with an output power of 25–45 W.

Two main situations may occur during the ablation process for multiple ATs. (1) The patient is in a persistent AT attack at the start of surgery: high-density mapping is performed (to avoid termination or conversion of tachycardia, entrainment mapping is only performed when the final reentry diagnosis is confirmed). To avoid iatrogenic AT due to incomplete ablation, changes in P wave morphology, tachycardia cycle length, or reference coronary sinus excitation sequence that occur during ablation will be evaluated after completing the planned ablation. If the AT cannot be terminated or converts to a new AT after completing the planned ablation, re-mapping will be performed and mapping and ablation will be performed using the same strategy as above. If the AT terminates after planned ablation, stimulation-induced AT will be performed. The endpoint of surgery is defined as no sustainable AT can be induced by either programmed stimulation or Burst stimulation. (2) The patient was in sinus rhythm at the start of surgery: pacing-induced AT is performed. If the induced AT is clinical AT or stable sustainable AT, high-density mapping is performed and the abovementioned ablation procedure is executed.

2.5 Postoperative management and follow-up

Patients underwent continuous electrocardiographic monitoring during their postoperative hospital stay until discharge, then continued treatment with the anticoagulant and rhythm control drugs they were already taking preoperatively. Three months after discharge, if there was no recurrence of arrhythmia or symptoms related to arrhythmia, the use of rhythm control drugs will be discontinued. In addition, if conditions permit, anticoagulant therapy with warfarin or dabigatran etexilate will also be discontinued. All patients received follow-up examinations in the outpatient clinic at 3, 6, and 12 months after ablation. At each follow-up, patients underwent 24-h Holter monitoring and echocardiography. In cases where symptoms suggestive of an arrhythmia attack occur, additional 12-lead electrocardiogram (ECG) examinations or multiple Holter monitorings are performed to confirm the recurrence of AT.

2.6 Statistical analysis

All continuous variables are expressed as mean ± standard deviation or median. Statistical differences were evaluated using an ANOVA. P < 0.05 was considered statistically significant. Statistical testing was performed with SAS version 9.2.

3.1 Patient characteristics

The clinical characteristics of the 13 patients included in the study are shown in Table  1 . Multiple reentrant circuits occurred in patients with a history of postoperative disease (8 patients) and those without a history of previous surgery or catheter intervention (5 patients). One patient had dilated cardiomyopathy with left bundle branch block (LBBB) and received CRT-D treatment. One patient underwent surgery due to atrial myxoma. One patient underwent cavotricuspid isthmus (CTI) ablation surgery due to typical AT. Six patients underwent AF ablation, and another five patients had no obvious structural heart disease on echocardiography and had no history of previous surgery or catheter intervention. Six patients underwent AF ablation without any ablation based on fragment electrogram.

3.2 Mapping Results

The mapping results of AT are shown in Table  2 . Among these 13 patients, a total of 33 types of persistent AT could be mapped. During ablation, 7 patients presented with 2 different types of AT, 5 patients presented with 3 different types, and 1 patient presented with 4 different types. Among these patients, 17 had new ATs that transformed after ablation, and 3 had new-onset ATs induced after ablation. In the first mapping, 5 cases had localized ATs related to scars, 5 cases were MAT related to the mitral annulus, 2 patients presented with MAT dependent on the tricuspid annulus, and 1 case presented with RMAT dependent on the left atrium. In the second type of AT, 5 cases were localized ATs related to scars, 6 cases were MAT, and 2 cases were Focal AT. There were 6 cases with a third type of AT, among which 2 cases were localized ATs related to scars, 2 cases were RMAT, and 2 cases were focal ATs. One patient had four types of AT, which manifested as localized AT related to scars.

3.3 Occurrence and Manifestation of FCB in Multiple ATs

In this series of cases of multiple ATs, some areas showed complete conduction block only during specific AT attacks, and showed continuous conduction or slow conduction but not complete block in sinus rhythm or other ATs, suggesting a manifestation of FCB. Among the 13 patients, 7 (54%) showed FCB during AT conversion. Most of these FCB areas seemed to be near scar areas (spontaneous or iatrogenic). According to the excitation mapping results, the mechanism of FCB areas involved in maintaining AT can be summarized into three situations. Firstly, the FCB area serves as the main obstacle for maintaining the circular reentry pathway (as shown in Fig.  2 ), and this phenomenon occurred in 3 out of 7 patients.

Second, the FCB area plays the role of an obstacle line in the reentry pathway, significantly prolonging the total reentry path (as shown in Fig.  3 A-D). This phenomenon occurred in 6 out of 7 patients. This transformation of the reentry pathway caused by the appearance or disappearance of the FCB area may participate in anatomical macroreentrance, as shown in Fig. 3 .

Thirdly, the FCB area acts as a bystander and does not affect the main reentry circuit path, which may be unrelated to the mechanism of AT(as shown in Fig.  3 E-G). This phenomenon occurred in 2 out of 7 patients.

The FCB area may have different functions in different types of AT in the same patient (as shown in Fig.  4 ).

The incidence of FCB phenomena and the role of FCB areas shown by mapping in different cases are summarized in Fig. 6 .

An analysis of the potential FCB areas during AT and sinus rhythm that did not manifest as blockages is shown in Table  3 . 10% of potential FCB areas EGM showed near-normal voltage, amplitude 0.692 ± 0.382 mV, duration 31.833 ± 11.035 ms; a total of 53.3% of EGM showed low voltage, amplitude 0.241 ± 0.107 mV, duration 41.813 ± 10.431 ms. 20% of EGM showed complex fragmented electrical conduction, presenting multiple rapid peaks, amplitude 0.523 ± 0.317 mV, duration 66.750 ± 15.316 ms. 10% of EGM showed slow electrical conduction, presenting low-amplitude long-range fragmented potentials, amplitude 0.103 ± 0.058 mV, duration 75.9 ± 15.007 ms.

3.4 Catheter Radiofrequency Ablation

The ablation strategy depends on the results of the excitation mapping. The local reentrant AT ablation mainly seeks the residual isthmus, which is mostly located between two anatomical obstacles, such as natural valve rings, pulmonary veins, or between the ESAs area, often showing fragmented potentials. In ablation related to large reentry, the shortest or easiest ablation line is typically designed for catheter operation, forming a barrier between anatomical structures or scars. In five cases of mitral valve-related AT ablation, there were ablation lines connecting the mitral valve to the left superior pulmonary vein (n = 4) and the mitral valve to the right superior pulmonary vein (n = 1). In the ablation of roof-related reentry, the ablation lines connect the upper pulmonary veins on both sides of the left atrial roof (n = 4), and the upper pulmonary vein to the mitral valve annulus (n = 1). Focal AT was ablated at the earliest excitation site (n = 4). During mapping, the FCB area is often not the target ablation area, but the target area for ablation may be residual conduction tissue near the FCB area ( Fig. 3 ). None of patients underwent substrate modification ablation during sinus rhythm or AT onset.

3.5 Follow-up

There were no procedure-related complications. All 13 patients were in sinus rhythm after ablation. After programmed stimulation and burst stimulation induction, 11 of these patients were noninducible; atypical nonsustained flutter was inducible in 1 patient, and nonsustained AF was inducible in 1 patient. A pacemaker was implanted in 1 patient due to sinus bradycardia 3 days after ablation. With a mean follow-up of 12 months, 9 patients were successfully treated without the use of antiarrhythmic drugs. ATs reoccurred in 4 patients (31%).

4 Discussion

4.1 main findings.

In a series of cases with multiple ATs, we observed that 7 patients (54%) exhibited the phenomenon of existing FCB regions. This may suggest that in cases of multiple ATs, especially in scar-related AT, FCB may be a not uncommon electrophysiological phenomenon. Among the 18 cases of AT that occurred in these 7 patients, the mechanisms of 11 ATs (61%) were related to the conversion of the FCB region ( Fig. 6 ). According to the results of excitation mapping, the FCB region can play three different roles in the mechanism of AT. First, the FCB region serves as the main central block area for maintaining local reentry, which is obviously directly related to the maintenance of AT (27%). Second, the appearance of the FCB region may serve as a barrier line, reorganizing the conduction pathway of local AT or large reentry AT. This may result in the potential taking more time to conduct to the native location prolong the reentry time ( Figs. 3C and D ), making reentry easier to maintain or more likely to occur (55%). Third, the FCB region acts as a bystander and may not be significantly related to the maintenance of AT (18%). The FCB is a manifestation of anisotropic conduction in local tissues, and this anisotropic conduction is often related to different directions of excitation sources and different input frequencies. In multiple ATs, each type of AT may have different cycle length and conduction path, which makes this anisotropic manifestation more likely to occur, greatly increasing the probability of the appearance of FCB regions. In our research results, potential FCB regions may be involved in mediating 84% of the maintenance of multiple ATs, and this special mechanism may be one of the mechanisms by which a single patient has multiple ATs. Currently, most ablation strategies are still mainly based on “what we can see”, relying more on the results of excitation mapping at the time of AT. The special performance of the FCB region only appears under specific conduction modes or frequencies. This unpredictability may be ignored in actual operation procedures and may be one of the reasons for the high recurrence rates related AT.

4.2 Occurrence of the FCB and Substrate Characteristics

It is not difficult to observe that in multifocal AT, the scar substrate often participates in the conduction process. Scar tissue can increase the anisotropy of tissue conduction, and the local tissue conduction anisotropy manifests as: when receiving excitation from a certain direction or different input frequencies, it may include 1. Local conduction time is relatively prolonged; 2. An increase in the voltage dispersion; 3. The amplitude of the voltage decreases per unit time. During mapping, the characteristics of bipolar potentials will be displayed as changing from simple less-amplitude inflection potentials to complex multi-amplitude fragmented potentials ( Fig. 5 ). These local characteristics may cause prolongation of local conduction time or further block. In the analysis of potentials in potential FCB areas (Table  3 ), 90% of the locations showed low voltage or complex potentials. A total of 53.3% of the areas show low voltage, which may be caused by local scars. When low voltage manifests as simple potentials (few positive and negative deflections) and is accompanied by a short potential duration, it suggests that severe scarring can lead to a reduction in the number of excitable cardiomyocytes, resulting in low voltage. When anisotropy occurs at this location, it is more likely to cause source-sink mismatch, thereby more easily to form local block. 20% of the areas show high-frequency complex potentials, which are mainly produced due to complex conduction formed by the intersection between different layers of myocardium. Its potential duration is slightly longer, mainly due to more (thicker) local myocardium. Such locations are also more likely to have anisotropic conduction, but the conditions for forming local block may be stricter. 10% of the areas show low-frequency, long-range complex potentials, which suggests that anisotropic delay conduction has occurred in the current state. When changing conduction conditions (such as the excitation direction), it may convert to near-normal conduction (Fig.  5 C) or form a local block.

The manifestation of anisotropic conduction between different tissues with different conduction directions. A, In the conduction process of normal tissue, the excitation from the left simultaneously excites the subsequent row of cells. The entire excitation process occurs within 3 units of time, forming a narrow potential normal conduction potential. B, In the tissue where the scar causes local block (black line), the excitation from the left, due to the local block, needs 6 units of time to complete the excitation of the entire piece of cells. The voltage is discretely distributed over time, forming fragmented potentials. C, In the same tissue where the scar causes local block (black line), the excitation from the right can complete the excitation of the entire piece of cells within 4 units of time. The potential is similar to normal potential. This shows that different excitation source directions can produce conduction heterogeneity. Note: This scheme demonstrated intracellular conduction dispersion, with scar isolation being just one of the reasons for this dispersion. The scheme also includes frequency dependence, which can cause local cell conduction interruption. Frequency-dependent conduction interruption can be a disease of the cell itself (cannot accept a higher frequency response), or it can be scar-induced (a local scar causes intracellular discrete conduction, which delays the outgoing time significantly, forming a local 8 reentry)

FCB regions are often found near scar areas or near the intersection of different anatomical structures (such as near the base of the atrial appendage). The main role of FCB in local reentry is to provide continuous (Fig.  1 ) or extended (Fig.  2 ) block lines, allowing the tissue to recover conduction within the propagation time provided by the obstacle, thereby satisfying the minimum cycle length of reentry (Fig.  6 A). In macroreentrant AT, the block area provided by the FCB will change the conduction path, generally prolonging the conduction time, which may make it easier to maintain the macroreentrant circuit (Fig.  6 B).

Mapping results and the roles of FCB regions acting in different cases, and the schematic of the FCB acting in ATs. * The appearance or disappearance of both may reorganize the conduction pathway of the reentrant cycle. In 10 ATs without FCB, 3 ATs, including 2 MATs and 1 localization AT, may be sustained due to the reconduction of the FCB regions. A, Conduction pattern near the scar of the right atrial septum during sinus rhythm. The time to reach the tissue of the two sides of the scar was the same (the underlying FCB regions are marked with black dotted lines). B, The conduction pattern near the scar of the right atrial septum during AT 1 was not related to scarring. During AT 1, the conduction direction changed according to the different times required to reach the tissue of the two sides of the scar; at this time, the underlying FCB region could still conduct with no obvious time interval difference. C, During induced pacing or after ablation, the conduction first blocked the isthmus and underlying FCB regions (the upper brown line) and made the conduction pathway downward; at this time, underlying FCB regions showed conduction blocks. D, Due to the sustained conduction block of the FCB regions and the long pathway that allowed the isthmus to recover conduction after CL, localized reentry could be sustained. E, Typical RMAT with a round LPV; the conduction pathway is relatively short. F, Once the underlying FCB region showed conduction block, the reentrant pathway length may have made the reentry easier to induce or sustain. AT = atrial tachycardia; CL = cycle length; MAT = macroreentry atrial tachycardia; FCB = functional conduction block; LPV = left pulmonary vein; RMAT = roof-dependent macroreentrant tachycardia

The scar may be caused by myocardial injury or by iatrogenic surgery. Some new scars produced by intraoperative ablations can lead to the occurrence of multiple AT. For example, the 8th patient, who had 3 ATs, the first of which was tricuspid valve-dependent AT, underwent tricuspid isthmus ablation. It then transformed into mitral flutter, which is obviously unrelated to tricuspid ablation. After the subsequent isolation of the mitral isthmus, it transforms into a focal AT of the lower left pulmonary vein, which may be related to the scar caused by the mitral isthmus line.

We can predictively describe the different manifestations of FCB phenomena in multiple ATs, mainly because the alternation of various ATs provides opportunities to show different conduction characteristics of potential FCB regions under different circumstances. In fact, in addition to mediating the conversion between different ATs, FCB is also the reason for the occurrence of AT that alternate with changes in cycle length [ 10 , 11 , 12 ].

4.3 Ablation of Multiple ATs

Multiple ATs are often associated with more than two reentry circuits, which often involves more complex ablation procedures 1 . Our ablation strategy in the study still relies on the results of excitation mapping. Despite high-density mapping, only one patient (double-loop local reentry, FCB region not shown) could predict the reentry circuit of the second AT before the first ablation. The instability of the functional area makes the second or third AT unpredictable. The main role of the FCB region is to maintain the path of reentry. After mapping, these areas are usually not the target sites for ablation. Meanwhile, if substrate ablation is performed in these areas, the current AT may not be terminated. The ablation site still depends on the narrowest conduction tissue between the reentry isolation line or scar or anatomical obstacles. In the context of stable atrial tachycardia, the FCB can manifest, which essentially represents the anisotropic conduction of this area ( Fig. 5 ). In potential morphology, it exhibits fragmented potentials under conduction in a certain direction. We hypothesize that this may be based on the same principle as the varying potentials exhibited at the same location during atrial fibrillation at different times. Atrial fibrillation, compared to multifocal atrial tachycardia, involves a greater number of excitation directions (and frequencies), which can maximally reveal the anisotropy of the local tissue. In some cases of persistent atrial fibrillation, it is common to observe that at some locations, the potential morphology does not significantly change during the fibrillation process. However, other locations intermittently exhibit fragmented potentials of prolonged duration, suggesting significant anisotropy of the substrate at these sites. These locations may indicate targets for substrate modification ablation. Such ablation choices are reasonable, because the prolonged discrete conduction within the tissue at these sites could potentially form the basis for local micro-reentry. In multiple types of atrial tachycardia, the FCB merely mediates local block (which may manifest as prolonged fragmented potentials or double potentials), and the actual ablation targets are inevitably the isthmus areas adjacent to the block. However, this does not imply that the FCB areas are not worthy of ablation. They still possess characteristics that could potentially lead to local micro-reentry. Future studies will require higher resolution mapping to solve these critical questions, such as identifying which types of complex fragmented potential are essential for maintaining arrhythmia and which types do not influence the occurrence of tachycardia, regardless of changes in conditions (e.g., in cases of atrial fibrillation or atrial tachycardia with extensive scarring, where complex fragmented potential is abundant).

In cases with multiple atrial tachycardia of this study, FCB is a special manifestation of the substrate, and its instability may lead to an unpredictable AT, which may be a reason for the relatively high recurrence rate of multiple ATs. In addition, the occurrence of FCBs is related to the direction of excitation and frequency. Entrainment mapping may cause AT to convert, making the mechanism of clinical AT complex and not recommended for use. Judging the FCB region by substrate mapping under sinus rhythm or artificially different cycle length pacing may have lower effectiveness because individual FCB regions only work for their matching AT. Therefore, providing more conduction conditions with different pacing strategies to induce possible ATs and performing targeted ablation may be more effective in reducing the recurrence rate than performing substrate ablation under sinus rhythm. Future computer simulations may be used to identify the conditions and intervention strategies required for FCB.

5 Limitation

This study has several limitations: (1) It only contain the patient group who underwent radiofrequency catheter ablation, and the number of patients was limited. (2) Only cases that were successfully ablated from the original pool were included. While this strategy provided more confidence in the proposed mechanism for patients who were successfully ablated, it also indicates that in several patients, this strategy might not be fruitful if not mechanistically accurate. Cases that fail to achieve successful ablation after repeated mapping may involve other overlooked factors contributing to tachycardia, such as epicardial structures or limitations of the current mapping resolution. In this study, direct epicardial mapping was not performed on patients suspected of having extracardiac connections. (3) This study analyzed the conduction substrate of multiple ATs. Although we noticed that the incidence of FCB regions in multiple ATs is relatively high (54% in our study), we did not systematically evaluate the FCB phenomenon before ablation. In addition, there is a lack of effective measures for identifying FCB without specific AT attacks. (4) Although the FCB is related to atrial scars, it is not the target ablation site under excitation mapping. However, as a strategy, ablation targeting the FCB region to avoid recurrence of other ATs still requires careful consideration. (5) In this study, most mapping results were performed with Penta-Ray catheter, and the definition of most scar area were < 0.05 mV. Although in some cases this definition was relaxed to a voltage of 0.02 mV due to controversial positions with low-amplitude signals, this may filter out some important information, leading to a different activation map. Using smaller electrodes may improve the resolution.

6 Conclusion

In multiple ATs, the FCB phenomenon may be a common electrophysiological feature, especially for scar-related ATs. According to the results of excitation mapping, FCB regions can describe three manifestations in the maintenance mechanism of multiple ATs. First, the FCB region acts as a central block, maintaining the reentry circuit. Second, the FCB region acts as a barrier line, which may reorganize the propagation of reentry. Third, the FCB region acts as a bystander and may be unrelated to the mechanism of AT. FCB is a manifestation of local block conduction anisotropy, and this dynamic property of the substrate may be one of the most important reasons for the high recurrence rate of related ATs.

Data availability

The datasets used and/or analysed during the current study are available from the publisher on reasonable request.

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Acknowledgements

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Natural Science Foundation of Heilongjiang Province of China (ZD2023H005).

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Department of Cardiology, 2, Affiliated Hospital of Harbin Medical University, Harbin, China

Bin Zhu, SongCai Xie, Ying Luan, Wei Cao, Jian Xu, Shuo Zhang, JinWei Tian, Fan Wang & ShuFeng Li

Department of Cardiology, The Second Hospital of Harbin, Harbin, China

GuoHua Zhang

Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, China

JinWei Tian & Fan Wang

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Contributions

Bing Zhu: Conceptualization, Methodology. Guohua Zhang: Software, Methodology. Songcai Xie: Writing- Original draft preparation, Writing- Reviewing and Editing, Methodology. Ying Luan: Writing- Reviewing and Editing. Wei Cao: Writing- Reviewing and Editing. Jian Xu: Writing- Reviewing and Editing. Shuo Zhang: Writing- Reviewing and Editing. JinWei Tian:Funding acquisition, Supervision; Fan Wang: Supervision, Writing- Original draft preparation, Writing- Reviewing and Editing. Shufeng Li: Supervision, Funding acquisition, Project administration, Writing- Reviewing and Editing.

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Zhu, B., Zhang, G., Xie, S. et al. The characterization of functional conduction block in patients with multiple types of atrial tachycardia- A discussion on the mechanism of multiple atrial tachycardia. J Interv Card Electrophysiol (2024). https://doi.org/10.1007/s10840-024-01817-8

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Received : 05 December 2023

Accepted : 24 April 2024

Published : 21 May 2024

DOI : https://doi.org/10.1007/s10840-024-01817-8

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