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Jackpot City Play Money Casino Review
Jackpot City is already known as one of the top online gaming sites on the web – and, now it is available as a social casino app. At Jackpot City's social casino, you can play your favorite Microgaming titles for free. The best part is that you can access all of these amazing games from virtually anywhere, as the app features impressive mobile optimization that is compatible with iOS, Android, Windows and Blackberry devices.
Claim 100% up to
50 Free Spins
- Mobile-optimized web app for all devices
- Huge selection of top-rated slots
- High quality games powered by Microgaming
- Hundreds of Microgaming slots
- Plenty of table games available
- Compatible with all mobile devices
- Top-quality software for great gaming
- Impressive site design and user experience
- Few promotions available
- USA players not accepted
Online Gaming Excellence - Microgaming's Finest Slots
At Jackpot City, you'll find hundreds of amazing games from one of the top developers in the market – Microgaming. The company has been around for nearly two decades, and in that time, has created some of the most popular games that slots fans around the world go wild for. Some of the top-performing games that you'll find at the Jackpot City social casino include Tomb Raider, Thunderstruck and Immortal Romance.
Microgaming is known for its vast array of online slots, each featuring unique themes and innovative bonuses. The design also aims to release new games on a monthly basis, so there's never any shortage of exciting slots at Jackpot City.
Casino games from Microgaming are also known for their high quality of graphics and gameplay. They are always bright and vibrant games that definitely outshine the competition, and they run just as smoothly on mobile devices as they do on desktop computers. So, you're always in for a great experience when you play at Jackpot City's social casino.
Plenty of Table Games, Too
Most social casinos tend to focus mainly on slots, and that's great – but only for slots fans. What about those players who enjoy a spin on the roulette wheel or love calling out "blackjack"? Well, Jackpot City caters to you, too.
There is a great range of Microgaming-powered table games on offer at this social casino. You'll be able to play roulette, craps, blackjack, baccarat and video poker. There are even poker and bingo games available that you can play for free.
Jackpot City's social casino aims to provide players with an authentic online gaming experience. You'll be able to find just about any game that you could possibly be after – and, you're sure to be impressed by the quality of the software. After all, Microgaming is known for designing some of the best games around.
Earn Loyalty Rewards
As a Jackpot City social casino player, every time you play you'll be rewarded with some pretty juicy perks. You'll be able to gain loyalty points for every wager that you make, which you can cash in for credits.
Loyalty points are always a great bonus at social casinos. You get rewarded simply for playing slots and casino games. Nothing else is required of you – just have a good time! Your loyalty points are automatically credited to your account as you play, and you can cash them in whenever you want.
Mobile Compatibility
The Jackpot City social casino app can be played on just about any mobile app that you can imagine. Whether your tablet or smartphone runs on iOS, Android, Blackberry or Windows software, you'll be able to use the same app and have the same great gaming experience.
The best thing about playing casino games on the Jackpot City social app is that you don't have to download any software. You can save space on your device, as Jackpot City is a web app, which means that it loads directly within your web browser. You also don't have to worry about updating the software and whether or not you'll be able to use the app if you get a new device.
If you would prefer to download the mobile app, you can find it in the Apple App Market and the Google Play Store. Both versions are highly reviewed by players, with an average score of over 4/5 stars.
No matter how you choose to play, Jackpot City social casino games still feature the same impressive graphics with fast-paced gameplay. The mobile software does not lag at all, so you can have the same great experience as if you were playing at a desktop casino.
Contact Information
Players at Jackpot City will benefit from impressive customer service as they play their favorite casino games. Should you ever need advice or assistance, you can talk to a customer service agent 24 hours a day and 7 days a week. Both email and live chat options are available and, if you would rather speak to a person in real time, you can also give them a call on the telephone.
As you would expect from any big-name casino, Jackpot City offers up exceptional customer service. You can always expect a quick response to your query – with friendly and polite service from support agents who are happy to help.
If you would prefer to troubleshoot your issues yourself, there is a FAQ available. There are plenty of questions and advice in the FAQ, which should help you get back to playing as soon as possible.
- Live Chat: Available


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The trug has been traditionally crafted for over two hunderd years. The aspen boards are steamed and bent into shape while the rim and handle are made of willow. The wood is not oiled or varnished or treated in any way so that over time they gain a beautiful patina which adds to their charm. While the trug is extremely light it is also extremely strong which makes it very practical.
A trug is tradionally a garden tool but it has a myriad of uses - it can hold flowers, fruit, magazines, provide a place for the cat to nap or fill it with bread, wine, cheese and grapes for a picnic.
28cm high
30cm wide
50cm long
Made in New Zealand

subset: commoncrawl


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After much prayer by all involved, and with grieving hearts, the Board of Directors and the Session have decided to end the Trinity Preschool program effective May 21st. You can read the full letter from the board here.
Trinity Asheville Preschool is a community-based preschool that partners with families to provide a learning environment that encourages children to feel safe, secure, and free to develop his or her own mental, physical, and spiritual capabilities.
Meet our staff
We have a fantastic staff with years of combined experience and expertise.
Contact us
For all inquiries, including registration, please contact our director through the link below.


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Post Holiday Mingle
We hope you'll stop by on Friday January 4th from 5 – 6:30 to meet recent Green Works alums, our staff and board, volunteers and friends of Green Works.
The festivities take place at our classroom at 607 East 31st Street, KCMO. Parking is available on the street or on the west side of the building in the city-owned parking lot.
Please help us plan with an RSVP by Monday, Dec. 31.
Finger food and festive drinks provided.


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Parks will feature free concerts for the public
From staff reports
A number of local concert series will be kick off in June at public parks throughout the Mid-Ohio Valley, including Marietta, Belpre, Williamstown and Parkersburg.
In Marietta, Music in the Park is a free concert series sponsored by the Marietta Welfare League. The concerts start at 6 p.m. each Thursday in June through August at Muskingum Park along Front Street in downtown Marietta.
This year's schedule includes:
* June 6: Veritas Singers
* June 13: Marietta Children's Choir
* June 20: The Tunesmiths
* June 27: High Schools that Rock and the Marietta Ukulele Choir
* July 4: Special Independence Day Party featuring Levi Westfall and Newfeather. There will be food trucks, games, and more starting at 6 p.m.
* July 11: St. Marys Community Band
* July 18: Fifth Street Quartet
* July 25: Karl Kesselring
* Aug. 1: Madeline Brookover
* Aug. 8: Neon Moon Band
* Aug. 15: Sienna Stockey
* Aug. 22: Marietta High School Vocal Point
* Aug. 29: Marietta High School Wall of Sound
In Belpre, the Music by the River Concerts began this week and run through Aug. 27 at 7:30 p.m. each Tuesday at the bandstand in Civitan Park. The concerts are free. Bring your own lawn chair. Inclement weather decisions are made by 5:30 p.m. the day of the concert.
The schedule of performers includes:
* June 11: Band of Brothers (classic rock)
* June 18: The Carriers (gospel)
* June 25: Plan B (variety)
* July 2: St. Marys Community Band (patriotic)
* July 9: Steve and Bev Pottmeyer (classic country)
* July 16: Michael Tobar Jazz Trio
* July 23: Henrie Lane (acoustic)
* July 30: RB3 (easy listening)
* Aug, 6: Sherri Braid as Patsy Cline
* Aug. 13: Jim Forshey (Elvis Tribute Artist)
* Aug. 20; Britain
* Aug. 27: Tall Grass (bluegrass) and Belpre High School Marching Band
In Williamstown, the schedule for the 25th annual Music in the Park series at Tomlinson Parl has been announced.
Shows are scheduled for 7 p.m. Tuesdays starting June 11. The concerts are free:
* June 11: The Tune Smiths
* June 18: Randy and Highway 7 Band
* June 25: Tom Roddy
* July 2: Ed Vanhorn – 4 On the Floor
* July 9: The Kappel Family
* July 16: Jimmy Howson from the Ohio Valley Opry
* July 23: Windy Ridge
* July 30: St. Marys Community Concert Band
* Aug. 6: Eugene Haught – All of God's Children
* Aug. 13: Jerry and Lisa Queen
* Aug. 20: Laurel Creek
* Aug. 27: The Clark Family from the Ohio Valley Opry
* Sept. 3: Dennis Sipoe – Alpha and Omega
* Sept. 10: Band of Brothers
In Parkersburg, the Artsbridge Summer Music in the Park and the Southwood Park Music Series are both free.
The Southwood Park series began this week and will have a concert from 7 to 8 p.m. one Tuesday a month at the Al Smith Stage in Southwood Park.
The shows will be: July 2, JP Chandler (folk/Americana); Aug. 6, Levi Westfall (country/blues); and Sept. 3, Henrie Lane (classic rock).
The Artsbridge Summer Music in the Park will be from 7 to 8 p.m. each Thursday from June 6-Aug. 29 at the City Park Bandshell. The schedule of entertainers includes:
* June 6: Mike Morningstar and Dustin McCray (folk rock)
* June 13: Sherry Wilson Braid as Patsy Cline
* June 20: The Johnny Staats Project (country)
* June 27: The Sheppard Brothers (bluegrass)
* July 4: Insured Sound (classic rock)
* July 11: Britain (60s music)
* July 18: Sunset Roosters (rock)
* July 25: Anthony Mossburg (folk)
* Aug. 1: Hank Poole and Jim Forshey (Elvis Tribute Artists)
* Aug. 8: Band of Brothers (80s through current)
* Aug. 15: Track 9 (classic rock)
* Aug. 22: Laurel Creek (bluegrass)
* Aug. 29: PHS and PSHS Marching Bands.


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Beginner's Guide To Success On Etsy
Etsy Printful Success Guide
Most creative entrepreneurs interested in making their own merchandise aren't in it for the glory of taping bubble-wrap and boxes together after a flurry of orders comes through. To keep the inspiration going and develop an audience's sustained interest, you need to focus on your design process and digital presence, instead.
As merchandise fulfillment services like Printful become easier to pair and use with new or existing Etsy stores, the opportunity to maximize your profits by cutting out upfront overhead and tedious tasks is here. Whether you're new to either of these platforms or a veteran of the design and drop-ship game, this guide will help you navigate your way through keeping these two services merged successfully and using their combined features to increase sales.
Creating And Linking Accounts
Both services offer free account creation so users can explore the wide range of capabilities available to them before they formalize their storefronts and start selling to customers. While Etsy does require you to note Printful as a production partner when creating listings, you don't have to list this information in your product descriptions or in your store profile.
Though they are integration affiliates, Printful and Etsy are separate business entities and as such, terms of use and fee structures can differ or be changed by one or both companies at any time they choose. When in doubt, always check the latest updates on each site regularly so that you stay aware of any new changes.
For Newcomers
Signing up with either Etsy or Printful is a free and straightforward process and both sites offer a lot of information about account creation right upfront. You do have to be signed up to each site separately as there is no way to automate new account creation from one site to the other. For organizational purposes, try to use consistent emails, names and personal information for both accounts. This can help save steps later on if you ever need to verify your account information or find related documents. For initial sign up, Printful asks for:
● Full Name
● Password
And Etsy asks for:
● First Name
● Password
● Optional use of existing Facebook or Google account.
In order to link your accounts successfully, follow the steps necessary for opening your shop before trying to connect Printful with your Etsy account, otherwise you will receive an error message. If you're just trying to get the accounts up and running and aren't ready to stock an entire store right away, you can create the required first listing using generic information and delete it after the store is finalized.
For Existing Accounts
Using Multiple Stores
Etsy Printful Success Launch: Concepts And Development
Fostering Creativity
Licensing And Copyright
The ins and outs of intellectual property rights are so complex and complicated that Printful and Etsy both work under general guidelines that might privately limit what sort of content can be sold on their sites even if it's not technically breaking a specific law.
Generally speaking, if you didn't make it yourself or personally secure the rights to the intellectual property, you can't use it for Printful products or for an Etsy shop. Because they take potential violations very seriously, accounts can be temporarily limited or closed down if suspected of using protected designs, characters or quotes.
Generally speaking, if you didn't make it yourself or personally secure the rights to the intellectual property, you can't use it for Printful products or for an Etsy shop. Because they take potential violations very seriously, accounts can be temporarily limited or closed down if suspected of using protected designs, characters or quotes.
Stock Sites And Public Domain
When you need to use work from third-party sources, stock photo and font sites are a great way to bridge the gap between making everything from scratch or using existing content to transform into your own unique design. Depending on how frequently you're interested in using these resources will determine if an ongoing membership or a single purchase will be best suited for your needs. As well, Printful and Etsy both allow the use of work in the public domain, but if you're not familiar with how that works, it helps to check with their customer service representatives about any applicable interpretation of the laws and international policies.
How To Success On Etsy : Pairing With The Right Products
No matter how great your design is, it might not look right on every kind of product or in various different sizes. Printful's site offers a robust mockup generator so you can get a preview of how your design works on a t-shirt or other merchandise products. Where appropriate, making sure the item's base color doesn't conflict with the design being print is another important consideration. This can be a little difficult to judge properly without seeing it in person, but if you're really concerned about making the right match then you can stick with neutral base colors for customer selection.
Design Dimensions
Because Printful is able to take one file and fit it to several different types of merchandise, they will require the uploaded print file to meet certain standard specifications. These include:
● Maximum printing area: 12X16 inches, which will be automatically scaled per
● DPI: Also known as digital pixels per inch. For optimal quality, files must have a
minimum of 150 dpi.
● Allowed formats: The upload manager accepts file types ending in .png, .psd.
● DPI: Also known as digital pixels per inch. For optimal quality, files must have a
minimum of 150 dpi.
● Allowed formats: The upload manager accepts file types ending in .png, .psd.
Printful's upload manager will not accept file types ending in .ai, .pdf, or .eps. Sublimation shirts, or t-shirts with an all-over print, have different rules for the print files they use. Because of how sensitive to error the printing process for these shirts can be when the file is not properly formatted and applied, Printful offers in-depth instruction and shirt style templates so that you can make the most accurate design for the chosen product. Other merchandise categories may have all-over print options that may include additional details and templates. Things to keep in mind for this printing style include:
● Allowed formats: For these shirts, Printful accepts .jpg, .png or .psd with at least
150 dpi.
● Font files: In order to avoid including font files for the upload, use your design
software to convert fonts used in the print file into outlines to prevent errors.
● Printing imperfections: Because this style of printing starts with a premade piece of merchandise, like a shirt or a pillowcase, and prints the design directly on to the fabric as if it were a sheet of paper, some imperfections near the creases seams and natural folds can result in smudges or streaks. This occurs with all fabrics and designs manufactured in this way, though excessive mistakes across large print sections are not common and should be an issue submitted to Printful for resolution.
150 dpi.
● Font files: In order to avoid including font files for the upload, use your design
software to convert fonts used in the print file into outlines to prevent errors.
● Printing imperfections: Because this style of printing starts with a premade piece of merchandise, like a shirt or a pillowcase, and prints the design directly on to the fabric as if it were a sheet of paper, some imperfections near the creases seams and natural folds can result in smudges or streaks. This occurs with all fabrics and designs manufactured in this way, though excessive mistakes across large print sections are not common and should be an issue submitted to Printful for resolution.
Product Categories And Their Variants
When working with Printful's catalog of merchandise, it's important to understand the difference between a product's category and their variant information. For example, "poster" is the name of a category while the different measurements available, such as 10X10 or 12X12, are the variants. When you're managing your listings and the data each one needs on the backend, pay close attention to the Variant IDs you're assigning for each item. If there are mistakes with the listing's Variant IDs, customers will receive your design printed on the wrong item.
Product categories currently offered by Printful for Etsy integration:
● Clothing: shirts, all-over shirts, dresses, skirts, leggings, socks, and
embroidered hats.
● Accessories: ceramic mugs, totes, bags, towels and phone cases
embroidered hats.
● Accessories: ceramic mugs, totes, bags, towels and phone cases
● Decor: posters, canvas, photo prints and frames.
Popular Product Types
What makes the best seller list in your store can change from season to season and from one design style to the next, but it's safe to say that t-shirts, coffee mugs and pillows are timeless choices suitable for a wide variety of recipients all year long. This doesn't mean you can't test your design's popularity on other types of products, of course, or come up with designs that work best specifically for the chosen product style.
A phone case with a design that looks like a phone booth isn't necessarily going to translate to other products and sell well, but it may be a popular choice on its own. This can often be a creative way to feature a design or to increase related sales by selling designs that match but are exclusively printed on different product types.
Getting A Listing Ready
Learning the secret to creating listings with attractive pictures, informative descriptions and keywords that drive high-volume traffic to your store seems simple on the surface but can take some testing, some trial and maybe a little bit of error before you get the knack of it. Remember that before a listing can be fully public in your Etsy store, you may have to pay a listing fee. Promo codes and referral rewards programs can help cut these fees down, so look around for savings before you start spending.
Printful: Step By Step Guide
In Printful's dashboard, select which Etsy account to use from the Stores tab. Under Product Sync, choose Add to bring up product category and variant selection windows.
Once you've settled on the relevant details for your base product (size, color, etc), you'll be able to upload the print file and make adjustments from there. Printful gives you different preview choices as you work so you can have an idea of what the final result will look before publishing the listing.
From there, you'll be shown mock-up choices, the customer-facing preview of what your design will look like on the final product. For shirts, this can vary from a photo showing a flat-front shirt or a wrinkle-front style. This really comes down to a matter of taste depending on what kind "glamour shot" you or your customers may prefer.
After that, Printful will show you Product Title and Description dialog boxes that may already have information about the base product itself filled in. You can leave this or delete it and replace it with your own information, but many users prefer to keep it and simply add information related to the design details, instead.
Pricing options put the power of profit in your hands, but be careful to not price your items to far out of the average ranges for those items and stores like yours. Printful shows you the breakdown of their price and the final retail price depending on the profit amount you select. For shirts and other items that offer size selections, Printful's price may include increases for larger sizes.
Finishing Up For Etsy
After you've set the final retail price for your listing, Printful's ready to send the information off to Etsy as a draft. When the upload is finished processing, you can select the link provided there to edit the listing on Etsy or find the draft via your Etsy shop manager. This is where you'll select how many preview photos the listing will provide and make final edits to the thumbnail customers see in your store.
The title and description you set on Printful will copy over, of course, but taking a moment to make sure you caught typos or included all the details you wanted is a step that can save you problems later. Prices, colors, variations and shipping information will also transfer over but review it for accuracy just in case.
You can use some of the keywords included in the title and description for ideas on which tags to include, but try to think of special occasions or seasonal trends that might be related search terms for
the time of product and design you're selling.
the time of product and design you're selling.
Production Partner Requirements
Etsy also requires listings to note any partnership with a third party when it comes to manufacturing and fulfilling orders through your store. There is a place to input this information as you create the listing, so you can fill it out with the basic information required. Printful has two locations in the United States: Los Angeles, California and Charlotte, North Carolina. It doesn't seem to matter which location is chosen for these requirements.
The description of the service is also up to you to word in your own way, but simply stating that they are a print-on-demand fulfillment service should be all you need to complete that section. Etsy also asks a few questions and provides preset multiple choice answers that cover the different reasons why you might be using a production partner. As it relates to Printful, the most suitable answers confirm you being the designer and business owner while they handle manufacturing and shipping.


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Explorer's Anchorage is an Ocellus Starport located in the Stuemeae FG-Y d7561 system, near Sagittarius A*. It was constructed by the Distant Worlds II expedition and began operation on February 21, 3305. It is the most distant station from Sol, as well as the closest station to both Sagittarius A* and Beagle Point.
Planning and Preparation
On January 14, 3304, about four months after the Distant Worlds II expedition had been announced and entered the early stages of planning, the first tentative ideas for a science installation to be built at the galactic core were proposed.[1] The creation of this installation was eventually incorporated into the main goals of the expedition.[2]
Sagittarius A* at the heart of the Milky Way is the only supermassive black hole the human race has access to. Situated approximately 23,000 light years away, these days it is well within commute range of the scientific community. Close up scientific study of the supermassive black hole is an opportunity that humanity would embrace.
The construction of an orbiting science installation close to the event horizon of Sag-A* would be an endeavor we feel humanity would have undertaken once it became feasible to travel to the galactic core in relatively short time frames, and coupled with the manpower that the DW2 Expedition can muster, we feel it is now logistically viable to begin construction of a science outpost at this unique location.
— Erimus Kamzel, DW2 Project Leader[1]
After Distant Worlds II launched from Pallaeni on January 13, 3305, it set course for its first official waypoint in the Omega Sector VE-Q b5-15 system, which also featured the Omega Mining Operation Asteroid Base. A Community Goal held at Omega Mining Operation began on January 17, and requested deliveries of certain minerals and metals to be used in the construction of a Starport that would be stationed near Sagittarius A* and dedicated to studying the supermassive black hole.[3] On January 24, the Community Goal concluded successfully, having collected 3,000,000 tonnes of material that had been mined by 5,198 independent pilots, and Stuemeae FG-Y d7561 was announced as the future site of the Starport.[4]
On February 21, 3305, the new Starport's completed docking hub arrived at its final destination in the orbit of Stuemeae FG-Y d7561 CD 4, an Earth-like World, and its name was unveiled: Explorer's Anchorage. This marked the completion of the first of five stages of the Starport's construction, which would be conducted over the course of five weeks in February and March of 3305.[5]
When it was first deployed, Explorer's Anchorage was equipped with only the most basic services. Distant Worlds II organizers planned to hold a Community Goal to mine additional resources from local systems in order to expand the station's available services so that it could become a convenient hub for explorers. However, additional services were brought online ahead of schedule, and the organizers decided to redirect the CG's resources into the construction of a Megaship and an Installation in Stuemeae FG-Y d7561 to better facilitate the study of Sagittarius A*. The CG opened ran from March 7 to March 14, with 2,812 pilots contributing a total of 2,367,428 tonnes of material.[6][7][8]
|Services Added
|February 21, 3305
|Mobile docking hub launched from Omega Sector VE-Q b5-15, arrives at destination site in Stuemeae FG-Y d7561
|Commodities, Mission Board, Outfitting, Passenger Lounge, Refuel, Blackmarket
|February 28, 3305
|Thruster assembly removed, beginning of superstructure construction (partial solar panels, habitat ring support struts)
|Contacts, Repair, Restock, Universal Cartographics
|March 7, 3305
|Construction of superstructure continues (beginning of habitat ring)
|March 14, 3305
|Construction of superstructure continues (more solar panels, majority of habitat ring)
|Crew Lounge
|March 21, 3305
|Construction of superstructure concludes, reactor module added, station is complete
The completion of Explorer's Anchorage was hailed in a GalNet report on March 21, 3305:
The first starport constructed in the Galactic Centre region has officially opened its doors.
Explorer's Anchorage, an Orbis starport, has been built in the Stuemeae FG-Y d7561 system as part of the Distant Worlds II expedition.
Councillor Magnolia Gill, the starport administrator, announced its operational status:
"For the last four weeks we have watched our new home take shape, using materials delivered by many hard-working pilots. Now it spins in the galaxy's heart, a monument to humanity's ingenuity."
"As well as serving as a safe haven for future explorers, Explorer's Anchorage is a scientific research installation. We hope to learn more about the supermassive black hole at Sagittarius A* and other astronomical phenomena in the Galactic Centre."The Distant Worlds II exploration fleet is continuing its journey across the galaxy towards Beagle Point.
- ↑ 1.0 1.1 Frontier Forums: Some ideas on getting the most out of the upcoming content
- ↑ GalNet: Countdown to Second Distant Worlds Expedition
- ↑ GalNet: Distant Worlds Initiative
- ↑ GalNet: Success for Distant Worlds Initiative
- ↑ Frontier Forums: Anyone got an Alt to scan the new station in Stuemeae FG-Y d7561 ?, post #57
- ↑ GalNet: Distant Worlds Mining Campaign
- ↑ GalNet: Distant Worlds Campaign Concludes
- ↑ Frontier Forums: Distant Worlds 2 - A Journey of Discovery, post #1854
- ↑ GalNet: Distant Worlds Starport Operational


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July 19
Freddie Ephrem, the longtime AMA official from Florida, passed away after suffering a fatal heart attack on July 19, 1989. Ephrem was a former maintenance director of the Jacksonville Motorcycle Police Force and a lifelong motorcycle enthusiast who was a regular fixture at the starting lines and finishing lines of tracks all over the southeast. He was also his own halftime entertainment in the early days of Bill West's Florida Winter-AMA Series, stunt-riding and crashing through burning walls and jumping through flames on his Harley-Davidson. After he passed, the AMA bought the back cover of Cycle News for a memorial shot of Freddie Ephrem.
Jimmy Ellis won the Superbowl of Motocross aboard a Can-Am, giving him a perfect four-for-four in what's now considered the AMA Supercross Championship. Ellis topped Yamaha rider Jimmy Weinert and Czech CZ rider Zdenek Velky. The race was filmed by sponsor Olympia Beer and included spectacular footage of Honda rider Marty Smith's crash off the start in the first race, when he forgot to make the bannered-off first turn and instead motored right into a set of whoops. Check it out at the 1:30 mark of this short film, narrated by Dave Despain, then with the AMA, and pit reporter Joe Parkhurst, the founder of Cycle World magazine.
Suzuki's Mark Barnett, the reigning AMA 125 Pro Motocross and AMA Supercross Champion, dominated the last Valvoline 125cc U.S. Grand Prix at Mid-Ohio on his works Suzuki. It happened one week after Barnett clinched that SX title at the Los Angeles Superbowl of Motocross. Defending 125cc Motocross World Champion Harry Everts ended up an unlikely second overall via 5-5 moto scores on a muddy day where only only the Bomber was on point in both motos. Honda's Johnny O'Mara, the previous year's USGP winner, finished third with 10-2 scores.
Meanwhile, over at Carlsbad Raceway, the CMC held their Four-Stroke World Championship, and Team Honda's Donnie Hansen showed up on a Mugen Honda thumper and took the overall win. Finishing second was Horsepower Factory Honda rider Marty Moates and Honda-mounted David Gerig.
American Honda superstar Rick Johnson topped HRC Honda Europe's Eric Geboers at the 250cc U.S. Grand Prix at Hollister, California. The race was held at Hollister rather than its traditional home across the country at Unadilla because the New York track was hosting the '87 FIM Motocross of Nations, and back then, the host track could not have a Grand Prix in the same year. RJ went 1-1 for the win while Geboers would finish 5-2 for second overall. Geboers would go on to win the FIM 250cc Motocross World Championship, then set his sights on adding a 500cc crown the following year in his bid to became the first rider to win all three titles at the time: 125cc, 250cc, 500cc. Finishing third overall on the day was Johnny O'Mara on a Suzuki.
And happy birthday to Damon Bradshaw, the Beast from the East! One of our favorite moments of nineties' motocross was Bradshaw's victory lap after he won the High Point National while riding for Manchester Honda. Damon survived a swamped race track after a deluge turned High Point into a mud bog, but he was so thrilled with the win—which would turn out to be the last of his career—that he decided to go another lap and celebrate with the fans. He even stopped at one point and took off his jersey and gave it one of them, then continued to soak it all in...
And here's one of his better supercross wins, after a great duel with Jeff Matiasevich:
Andre Malherbe won the 500cc Grand Prix of Holland at Lichtenvoorde with 2-2 moto scores. The moto winners—Honda's Graham Noyce and Suzuki's Jean-Jacques Bruno—had problems in the other moto, opening the door to Malherbe for the win.
At what turned out to be the last 250cc U.S. Grand Prix at Unadilla, Team Honda's Jeff Stanton swept all three motos for his third straight USGP win. Behind him there was real drama, as series points leader Donny Schmit of the Chesterfield Yamaha team was knocked out in practice after a big crash left him with what they thought may be a fractured neck. He was taken by ambulance to a local hospital. X-rays proved negative, so he quickly checked out and then raced back to the track. Schmit missed the first moto, but managed to finish eleventh in the second moto, and then second in the finale, salvaging 22 points on a day that seemed lost. Two weeks later, he won the Swedish GP and clinched the 1992 FIM 250cc World Championship.
Check out a photo of Schmit before his ride to the hospital:
At the Spring Creek National in Millville, Minnesota, local product Ryan Dungey was beaten by Eli Tomac, then on a GEICO Honda 450. Eli went 1-1 on the day to the 3-2 for Red Bull KTM's Dungey and the 2-4 of his teammate Ken Roczen. The win was Tomac's first on a 450.
But Minnesota fans got a popular win when Jeremy Martin got a hometown victory on his Star Racing Yamaha YZ250F. Martin went 1-2 to better the 2-4 of Red Bull KTM's Marvin Musquin and the 9-1 of Cooper Webb.


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The demon lord rears his ugly head for Halloween, bringing new heroes to the game!
Halloween rapidly approaches, and while the students of "Marvel Avengers Academy" prepare their costumes and plan their parties, the demon Mephisto assembles his minions for a celebration of his own.
Mephisto will soon cross over from his hellscape to the Academy's plane of existence, hungry for new souls and servants. With the villain flanked by Dracula, Satana, and an army of Fire Demons, the Avengers have their work cut out for them if they hope to put an end to his invasion.
We sat down with Allen Warner, Lead Narrative Designer at TinyCo, to get the low-down on Mephisto and his motivations, along with what Halloween celebrations we'll see at the Academy.
Marvel.com: What brings Mephisto to our plane?
Allen Warner: We learned at the end of the Daredevil event that Kingpin had struck a deal with Mephisto to help him enter our dimension, and was working with the Hand to use their occult magic to open a dimensional rift. Of course, with those three factions, there was and will continue to be plenty of double and triple-crossing, as each one tries to use the others to get what they want. The Avengers Academy students and the heroes of Hell's Kitchen managed to stop Kingpin and the Hand before they could open the portal, but the Hand still weakened the area enough for Mephisto to finish the job as the Halloween season further blurred the boundary between the physical and supernatural worlds.
Mephisto collects souls and thrives on fear and subservience, so he sees this new dimension and campus filled with superhuman and supernatural heroes as an untouched realm for him to conquer that will expand his kingdom and take his already incredible powers to the next level. Part of the evil joy he gets out of collecting souls is forcing people to give them up voluntarily, so he uses his charms, his minions, and his talents for emotional manipulation to trick and torment the students rather than immediately launching a full-scale assault. He wants to humiliate his adversaries as much as he wants to collect their souls, and we'll learn over the course of the event that he's really after one person in particular. Only one soul has ever challenged him in his own dimension and escape unscathed, and he can't rest until he gets his revenge.
Marvel.com: While Mephisto is the big-bad here, what other threats does he bring with him?
Allen Warner: He's working with a couple of other shady, self-interested characters who are perfect for Halloween in Dracula and Satana. Dracula actually has sort of "good" intentions, trying to turn the Avengers Academy students into vampires as a means of rebuilding his vampire nation, which has fallen on hard times and is nearly extinct. The demoness Satana simply wants to feed on souls. She's always hungry for more, and Avengers Academy seems like the perfect place to sink her teeth into. We see very quickly that she doesn't like to take orders from anyone, and she doesn't share Mephisto's love for drawn out mind games, so there's a lot of friction there that will eventually result in her setting her eyes on a much bigger prize. Along with these two powerful helpers, Mephisto is also bringing a legion of Fire Demons from his home dimension that come in all shapes and sizes, and will try to drag anyone they battle back to Hell.
Marvel.com: What new heroes will be brought into the fold in order to help dispatch their new supernatural foes?
Allen Warner: A really exciting lineup: Misty Knight, Ghost Rider, Moon Knight, and Blade. Each one brings something completely different to the table, and comes with awesome abilities and a great backstory. If players can defeat Dracula and Satana, they'll also be able to recruit them to the Academy to help in the battle with Mephisto. There will also be one more surprise character who will be revealed further into the event. It's someone I don't think many players will be expecting, but a character who couldn't be better suited for Halloween.
Marvel.com: Ghost Rider comes to the game hot on the heels of his TV debut in "Marvel's Agents of S.H.I.E.L.D.," while Misty Knight just made her live-action debut in "Marvel's Luke Cage" today on Netflix. What actions and abilities do these heroes bring to the Academy and the fight against Mephisto?
Allen Warner: Yeah, the timing is amazing. To be honest, we planned this out so long ago that we had no idea either one of these characters would be debuting in different TV shows at the same time the event is launching, but we obviously couldn't be [happier]. It's always great when we can support Marvel characters in different media and vice versa, and both of these characters are so awesome that I'm glad to see them getting introduced to a new audience.
Ghost Rider is someone we connected to a potential Halloween event way back at the beginning of development. Like ["Marvel's Agents of S.H.I.E.L.D."], we're also using the Robbie Reyes Ghost Rider to include even more diversity in the game, and support the more modern approach to the character. It's great because he's one of those characters like Ms. Marvel or Miles Morales that already have this youthful approach and energy, and they can walk right off of the comic page into our game without some extensive reimagining that we do for other characters. We love that aspect of our game, but it's also cool and exciting when a traditionally young character enters the game and interacts with characters like Black Widow and Captain America who aren't usually in their age range. Ghost Rider will use all of his awesome abilities from wrapping bad guys in his flaming chains to hopping inside of his fiery car to take off and do donuts.
Misty Knight might seem like a strange fit for Halloween at first because she doesn't have the obvious supernatural connection the rest of these characters do, but she might play the most critical role in the whole event. I always like to connect all of our events together narratively, and there were a few mentions in the Daredevil event of Misty investigating exactly what Kingpin and the Hand were planning. We focus on her great detective skills, and I like the idea of a "normal" character being in an event filled with supernatural characters because she can be the voice and viewpoint of the player, and comment on all of the weirdness like we would. She'll have actions relating to her awesome skills and abilities from martial arts, detective work, and using her bionic arm to not only punch, but to use its cryogenic blast for an amazing animation.
Marvel.com: Blade and Moon Knight round out the additions; what new, unique actions will players see these two tackling?
Allen Warner: Blade is the ultimate vampire hunter and the Daywalker, having all of the vampire strengths without any of their weaknesses. We had some fun with those ideas in his actions and animations, along with playing to his traditionally stoic persona. He's a no-nonsense guy in a campus filled with nonsense, so it's fun to see how he bounces off of the other students. He was another character we mentioned from the very beginning as being part of a potential Halloween event, so it's great to see him finally entering the game, and embodying everything that makes him so cool in the comics and movies.
Moon Knight is such a unique character that you can approach in so many different ways. We wanted to address him being embodied by an Egyptian god. The split personalities. The fact that he's literally come back from the dead. Not to mention that he has a huge collection of awesome moon-themed gadgets and vehicles. He has some really fun animations, some awesome combat animations, and some great decorations related to his backstory and tools of the trade.
Marvel.com: The Academy students will be fending off Mephisto and his subordinates, but what other activities will players be able to participate in during this event?
Allen Warner: There are a lot of fun new things to do in this event. The main event building is Haunted Avengers Mansion. It's the iconic Avengers HQ decked out in creepy, authentic Halloween decorations for Wasp's big Halloween party. We're also adding a Halloween themed park, and a bunch of characters will use both places for brand-new actions and animations. You'll also be able to send characters through Mephisto's portals for some extra-dimensional trick-or-treating, bringing back materials to defeat him and his minions. Last but not least, we're introducing a feature that lets players pair up characters, using a bunch of fun dual actions and animations. Completing these actions gives you access to outfits and other prizes that you can't get anywhere else. The students have to strengthen their relationships with each other to combat Mephisto's manipulative powers, culminating in an iconic multi-character animation that I think people are going to love.
Marvel.com: This new threat arises during a Halloween party, so our heroes must be rocking costumes. What will players see their favorite characters dressing up as?
Allen Warner: This is one of the most exciting parts of the entire event. We're adding new Halloween costumes for every main story character in the game to this point, from Iron Man to Hulk. We usually only give new event outfits to the earliest characters since some people may have just started playing the game, but Halloween seemed like too good of an opportunity to not give everyone at least one outfit. If you just started, and it will still be awhile before you reach characters like Ant-Man or Maria Hill, you can still acquire the outfits, and the outfit and related quests will unlock as soon as you've recruited that character. For our longtime players, it will be the first time we've offered alternate outfits for characters like Ms. Marvel, Enchantress, and Taskmaster. Since most of the new characters in this event are pretty serious people, we decided to go with the opposite approach for the costumes. Even if you're a lifelong Marvel fan, I guarantee you've never seen a lot of these characters look anything close to what they'll look like in some of these Halloween costumes.
It was a ton of fun brainstorming and creating the different looks, and we owe a big thanks to our fans on Facebook, Twitter, and Reddit for suggesting and voting on outfits they wanted to see. The winner was Cap-Wolf, which looks great with some amazing animations, but we also used quite a few of the other suggestions we received: Loki dressed as Thor, Black Widow wearing a "This is my Halloween Costume" T-shirt in classic unimpressed Black Widow fashion, and more. My personal favorite is Falcon dressed like a Penguin. I don't want to spoil everything just yet, but I really feel like people are going to get so many smiles and laughs from the awesome designs and animations created by our always amazing art and animation teams, and the great ideas suggested by our creative and passionate fans.
Marvel.com: How will the event district play into Mephisto's siege?
Allen Warner: The event district is Mephisto's hellscape. It's a massive area of fire and brimstone where Mephisto watches everything from his throne. This is where the recruitable heroes will be trapped in Mephisto's magic, along with the portals used for extra-dimensional trick-or-treating. There's a large open area in front of Mephisto's throne because when it's time to finally battle the big boss, the students will have to bond together, and perform an iconic Halloween activity to infuriate the demon, and distract him with synchronized hilarity before taking him down for good.
Hopefully, they'll be able to defeat him and close the dimensional rift once and for all, but if not, they may have to seek out the assistance of a certain sorcerer who's no stranger to dimensional travel…
Play "Marvel Avengers Academy" today and stay tuned for further updates and events!


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Starting A Property Development Business
Last updated 31st July 2018 • JaeVee Marketing • JaeVee
The idea has been bubbling away for some time.
You've done some research and now you want to make a go of it.
How exactly do you go about starting a property development business?
Read on for our top tips.
Starting your own company
The first thing to do when starting a property development business whether it be full or part time is to decide if you are going to do this as:
- A sole trader
- A business partnership
- A limited company
Being a limited company does limit your financial responsibility and also has some tax advantages such as being able to claim back the cost of materials and pay yourself a wage.
Sitting down right at the beginning of starting a property development business to find out exactly what you need is a good idea.
Take the time to prepare by looking at the market, upcoming and developing areas as well as doing your homework on what is and isn't selling.
Things like the name of your company, registering yourself as a limited company, looking at the types of property available on the market as well as the market itself all need to be factored in.
You will need to know if you need an licences, insurances or planning permission and ensure all of the relevant legislation is completed.
Having a business plan which details if you are going to buy to let, or buy to sell is a great way to start your own property development business.
If you are unsure where to start it is advisable to speak to a professional to guide you along the way.
You do not need any experience or qualifications to start your own property development business but having some knowledge and business savvy will give you a slight advantage.
Additional finances
Starting your own property development business comes with some additional costs that you may not have known about that you will need to finance. These costs may include;
- Purchase of property
- Paying builders and materials
- Changing utilities and services
- Decorating the property
- Insurances
- Solicitor fees
- Legal fees
- Stamp Duty Land Tax
It can take a while to see the return on the property, whether this be via buy to let or if you plan to renovate and sell the property on for capital growth you must know your additional costs if you are starting a property development business.
Now, you have the tips on starting your own property development business, have a look at the JaeVee Blog for further info.
Getting started
- Sign up for your free developer account
- Sign up for your free investor account
- Our Online Learning Platform


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Although emotions are part of human life and something everyone has to live with, Empaths and HSPs are known to have heightened emotions. This basically means they get upset easier, feel fear and nervousness more readily, and when they get down it can take them longer to get back up… But did you know there was a reason for this?
There is a certain part of the brain called the amygdala which plays a part in emotional overload.
Dr. Elaine Aron, a research psychologist, found the amygdala to be highly activated in Sensitive people. The more Sensitive you are the more this gland seems to work.
The amygdala is a set of small almond-shaped clusters of nuclei, located deep within the brain's temporal lobe, which plays a huge part in processing emotions. The more aggressive the emotion the more responsive the amygdala becomes, and is responsible for triggering the stress response hormones.
Dr. Aron found, through a series of trials and research, that when Sensitive people (Empaths and HSPs) were shown pictures of human suffering the amygdala became highly activated. Which in turn released hormones, such as cortisol and adrenaline into the bloodstream, which further enticed emotional responses.
The amygdala is not a thinking part of the brain. It is a reacting part which activates when exposed to stimuli such as stress, fear or other strong emotions. It causes an automatic response known as the fight-or-flight response.
The fight-or-flight response is the body's way of protecting us from dangerous situations. The process elevates hormones to give the energy and strength to run away from danger or stay and fight.
Two of the hormones released into the body, by amygdala activation, are adrenalin and cortisol. These hormones increase heart rate, respiration and glucose levels. All of which are essential for increased body activity. But, they can also ignite fearful emotions and anxiety.
When these hormones are constantly activated by the endocrine glands (courtesy of amygdala activation), and not used through body movement, etc. it can cause heightened emotional responses. This eventually puts other organs and hormones out of balance and leads to illnesses (such as heart disease, adrenal fatigue and diabetes), as well as problems within the energy body (leaky aura and blocked or excessively open chakras).
An Empath does not need to watch another endure pain to experience suffering. Simply being in the presence of someone suffering emotionally is enough to ignite a reaction, whether the other person shows their emotions or not. An Empath feels them and therefore reacts to them. This means the Empath often overproduces adrenalin and cortisol. Both of which stimulate fearful emotions and can lead to weight gain (another reason many Empaths have pot bellies).
In normal situations, when a stressful situation is removed stress levels return to normal, and the amygdala stops reacting. It is when the stress triggers do not decrease that problems arise. This is where issues can occur for the Empath.
Empaths don't get away from stressful emotions easily. Not only do they have to deal with their own day-to-day stresses but that of others too…
The Empath may stop feeling other people's emotions soon after leaving them. But this is not always the case. Some people's emotional energy can cling to the Empath for days after (see this post to learn more). Which means the amygdala is constantly activated and large amounts of unnecessary hormones are dumped into the body.
What to do about it?
1. Avoid triggers:
The first step we can take in preventing unnecessary amygdala activation is to avoid known triggers. The people you know who stimulate a negative emotional response (see post here) lasting more than a day should be avoided.
The amygdala is a defence mechanism activated by emotional responses. It can also be triggered by emotional memories.
People who bring nothing to your life but emotional pain eventually become an Empath trauma trigger and should probably be avoided.
2. Control your mind and thoughts:
Keep the mind quiet to stop unnecessary amygdala activation from thoughts, read post here
3. Avoid stimulants:
Sensitives react to coffee and other stimulants more than most. It is best to know your caffeine intake limits and stay within them (take note at which point you get a physical response – too much caffeine can cause shakiness, pounding heart, flushing, faster breathing and an aching chest – and stay under the that amount). Also drug-like food has a huge impact on an Empath brain (read more about this subject here) and should be avoided.
4. Exercise daily:
Exercise has many redeeming benefits for the Empath. In the case of amygdala activation, it helps clear excess stress hormones from the bloodstream (which would otherwise cause damage).
5. Control glucose levels through diet:
Regularly experiencing stressful emotions, your own or off others', results in extra glucose being dumped into the bloodstream (from amygdala hormone activation), the last thing an Empath needs is their diet to contribute to this problem. Avoiding sugar or sugar-forming foods can prevent this from happening.
If you are one who carries excess belly fat, your body is receiving too much glucose for its needs. If you want to learn more about how the right diet can transform an Empath's life you may want to read this post.
I hope this blog post helped you understand how your brain plays a vital part in your Empath wellbeing, and how the amygdala's activation impacts your emotional health.
If you want to learn more about the ways Empaths are affected by the energy of others click on the attached links above.
Hope all is keeping really well in your Empath corner of the world…
If you have found my work to be helpful please consider donating here
©Diane Kathrine at Empaths Empowered
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The (in)famous Prop 8, banning same-sex marriage in California, was approved by a democratic majority. This raises the interesting question whether democracy means something more than majority rule. Does democracy mean that a majority can decide whatever it wants? I don't think so. That would not be a democracy but a tyranny of the majority. Democracy is much more than simple majority rule. (By the way, dictatorships can also have majority approval, but that doesn't make them democracies).
The decisions of a majority have to take place within a framework of rules. These rules have two functions.
- First, they facilitate the decision making (e.g. rules on free speech, freedom of assembly and association etc.), and therefore they cannot, logically, be violated without undermining the whole system.
- Secondly, these rules limit the kind of decisions that can be taken by the majority. For instance, majorities cannot decide to violate the human rights of a minority. Why? Because these latter rules are basically the same as the former ones. The rules necessary for the successful operation of majority rule are the same, or at least profoundly connected to, the rules granting protection to the minorities. This is called the interdependence of human rights.
If a democratic majority decides to enact laws or policies that violate the human rights of minorities (or individuals, or even majorities), then courts have to step in and enforce the rules of the game. This is not judicial activism by anti-democratic and elitist judges infringing on the democratic rights of the people. It's judges enforcing democracy, but democracy as something more and better than tyranny of the majority.
We have a clear example of all this in the case of Prop 8 (unfortunately, the courts don't seem to be playing their constitutional role, yet):
It is our position in this case that Proposition 8, as upheld by the California Supreme Court, denies federal constitutional rights under the equal protection and due process clauses of the constitution. The constitution protects individuals' basic rights that cannot be taken away by a vote. If the people of California had voted to ban interracial marriage, it would have been the responsibility of the courts to say that they cannot do that under the constitution. We believe that denying individuals in this category the right to lasting, loving relationships through marriage is a denial to them, on an impermissible basis, of the rights that the rest of us enjoy…I also personally believe that it is wrong for us to continue to deny rights to individuals on the basis of their sexual orientation. Ted Olson (source)
There is some discussion on whether the courts should be playing a role in this. Some gay rights advocates insist that it is better to work on public opinion and hope for a general public approval of same-sex marriage in the decades to come. Of course this is a useful strategy, if perhaps somewhat naive (who knows what would have happened to the civil rights movement had the same strategy been applied then). However, the dismissal of any role for the courts, for example because of the fear of a popular backlash against equal rights enforced by unelected courts, amounts to a profound misunderstanding of democracy.


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Straight after breakfast this morning we cranked up the heating and whipped off the nappy. Potty training attempt 1 here we go.... Day 1 went really well. Charlie can hold his wee I'll give him that!! I took off his nappy at 9am and he did his first wee at 12:40! And it was on… Continue reading POTTY TRAINING DAY 1
Tag: mummy blogger
Down To Our Last 5p | How We Budget
DOWN TO OUR LAST 5p It's been in the news recently about rising inflation and the increasing cost of living. In order to control our finances we have been setting ourselves a weekly budget - setting a figure which covers food, petrol & outings to playgroup etc. We withdraw that figure in cash for the… Continue reading Down To Our Last 5p | How We Budget
Last week I did a few things I have never done in my life- 1. Travelled to London on the train by myself 2. Walked the streets of london alone 3. Stayed in a hotel by myself 4. Starred in a video that will be one of 4 to air in October for the Let's… Continue reading MUMMY GOES TO LONDON 🇬🇧
Charlie's almost TWO! | Feeling Broody
Where has the time gone, it seems like only yesterday we arrived home with our little bundle of joy, faced with the task of figuring out how he worked. In just 30 days my "baby" will be TWO! Unfortunately Daddy has to work on his actual birthday but we plan on making up for it… Continue reading Charlie's almost TWO! | Feeling Broody
Well Mummy | Summer Shredding
Today I have launched my website http://www.wellmummy.com On the site there is information about nutrition, how to plan and schedule your workouts, finding what works for you. I have also included some posts from my Facebook page in which I suggest ways in which to save money on weekly food shops by planning your… Continue reading Well Mummy | Summer Shredding
Sunday | Fresh Air | Banana Nut Muffins
Sunday. My favourite day of the week. Almost every Sunday the three of us go for a walk around a nearby lake. On cold days we stop at Costa for a takeaway coffee to warm up our hands and our insides. Today's walk was lovely, a perfect mixture of sunshine and coldness. We are approaching… Continue reading Sunday | Fresh Air | Banana Nut Muffins
Let me start by saying that I am not a naturally confident person. When I was at school I was so incredibly shy. I attribute this to my being overweight at the time. Every person has confidence in different ways and their confidence can be linked to certain things about themselves or their lives. This… Continue reading CUP OF JO #2 CONFIDENCE
Cup Of Jo #1 TIME
Firstly I would like to thank you for reading this post. Many of my blogs have tended to be quite lengthy and so I have decided to create a mini-series of short blogs where I will share my thoughts on a particular subject. Also I realise that you may not know my name, its Jo… Continue reading Cup Of Jo #1 TIME
My Fertility Story | As featured on Bud Fertility
I have recently written an article for http://www.littlebud.com - a website dedicated to breaking the silence around infertility and to help those who are on their own journey to parenthood. Below is my story as featured on their site: Our inability to conceive naturally to this day remains unexplained. We are lucky that our one… Continue reading My Fertility Story | As featured on Bud Fertility
Autumn months | Tips to stay motivated & energised.
So it's that time of year where the clocks have changed, the evenings are darker and the cold weather makes you want to hibernate underneath warm snuggly blankets whilst stuffing your face with comfort food. Autumn is my favourite season but I struggle with my levels of energy and motivation like a lot of people… Continue reading Autumn months | Tips to stay motivated & energised.


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Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney
Author + information
- Received October 24, 2016
- Revision received August 21, 2017
- Accepted August 21, 2017
- Published online October 16, 2017.
Author Information
- David J. Polhemus, PhDa,b,
- Rishi K. Trivedi, PhDa,b,
- Juan Gao, MDa,b,
- Zhen Li, BSa,b,
- Amy L. Scarborough, BSa,
- Traci T. Goodchild, PhDa,b,
- Kurt J. Varner, PhDa,b,
- Huijing Xia, PhDb,
- Frank W. Smart, MDa,c,
- Daniel R. Kapusta, PhDa,b and
- David J. Lefer, PhDa,b,∗ (dlefe1{at}lsuhsc.edu)
- aCardiovascular Center of Excellence, Louisiana State University (LSU) Health Sciences Center, New Orleans, Louisiana
- bDepartment of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana
- cDepartment of Medicine, Division of Cardiology, LSU Health Sciences Center, New Orleans, Louisiana
- ↵∗Address for correspondence:
Dr. David J. Lefer, Cardiovascular Center of Excellence, LSU Health Sciences Center, 533 Bolivar Street, Suite 408, New Orleans, Louisiana 70112.
Central Illustration
Background Sustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF).
Objectives This study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism.
Methods Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN.
Results Following RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta1 antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF.
Conclusions This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.
Heart failure (HF) continues to grow as an inefficiently managed health care burden that affects nearly 6 million people in the United States alone, which is projected to double by 2030 (1). In HF, activation of the sympathetic nervous system contributes to the progression of myocardial dysfunction (2,3) and current HF pharmacotherapies that target the autonomic nervous system (i.e., beta-blockers and renin-angiotensin system [RAS] inhibitors) reduce morbidity and mortality (4–7). However, the many adverse effects and patient nonadherence rates limit optimal use of these drugs (8).
Alternative interventional therapeutic approaches are under development to replace or supplement contemporary pharmacologic strategies for the treatment of HF (9). Renal denervation (RDN) is a minimally invasive endovascular procedure whereby radiofrequency (RF) energy is used to ablate the sympathetic nerves that traverse the renal artery (10). Originally developed for the treatment of resistant hypertension, mixed clinical trial results have sparked debate over whether this strategy effectively lowers blood pressure in hypertensive patients (10–13). Despite this debate, it is likely that RF-RDN has beneficial effects on cardiovascular function beyond lowering blood pressure. In particular, RF-RDN may have cardioprotective effects by interrupting pathological afferent and central reflex mechanisms that contribute to the progression of HF.
Numerous clinical trials in HF patients report that beta-blockers augment cardioprotective and vasculoprotective circulating natriuretic peptide (NP) levels by some unidentified mechanism(s) (14–19). Beta1-adrenergic receptors are located in the kidneys and are innervated by renal sympathetic nerves. Therefore, we propose that in HF, elevated renal nerve activity opposes the beneficial renal, vascular, and cardiac protective effects of NP by a pathway involving enhanced metabolism of NP.
Therefore, the aim of these investigations was to test the efficacy of RF-RDN as a treatment of HF and to determine the effects of this procedure on the synthesis and metabolism of NP. For these studies, changes in cardiac and vascular function and NP levels produced by bilateral RF-RDN were examined in spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) rats with HF.
Male SHR and male WKY 19 to 20 weeks of age (Charles River Laboratories, Wilmington, Massachusetts) were used in the study (Online Appendix). Myocardial ischemia reperfusion was performed as previously described (19). Following 45 min of ischemia, rats were reperfused for 12 weeks and assessed for cardiac remodeling and failure. The experimental protocol is described in Figure 1.
SHR and WKY were randomized into either a RF-RDN or sham-RDN group 4 weeks after ischemia reperfusion using 2-h plasma cardiac troponin I concentrations to ensure equal initial cardiac injury and myocardial cell death between groups. RF-RDN was performed as previously described (19,20).
Additional SHR (n = 4 to 5 per group) and WKY (n = 7 per group) at 19 weeks of age were implanted with a radio telemetry transmitter (Data Sciences International, St. Paul, Minnesota) for measurement of blood pressure and heart rate as previously described (19).
Long-axis, 2-dimensional echocardiography was performed at baseline, 1-, 2-, 4-, 6-, 8-, 10-, and 12-week time points on a Vevo 2100 (VisualSonics, Toronto, Ontario, Canada) (Online Appendix).
Plasma norepinephrine measurement
At the 12-week endpoint, plasma was collected and catecholamine levels were measured using enzyme-linked immunosorbent assay technique according to the manufacturer's recommendations (Abnova Corp., Taipei, Taiwan).
Plasma renin measurement, angiotensin II measurement
See the Online Appendix.
Tyrosine hydroxylase staining of renal arteries
At 8 weeks following sham-RDN or RF-RDN (12 weeks after reperfusion), renal arteries distal to the RF lesion were excised, fixed, sectioned, stained, and scored as previously described (19).
Myocardial nitrite levels
Nitrite concentrations were quantified as previously described (21) using an automated ion chromatography system (ENO30 Analyzer, Eicom, San Diego, California).
Ribonucleic acid isolation and reverse transcriptase real-time polymerase chain reaction, natriuretic peptide quantification
See the Online Appendix.
Neprilysin activity assay
Neprilysin enzyme activity was determined as previously described (22) (Online Appendix).
Myocardial fibrosis
Hearts were collected at the 12-week endpoint, tissues were paraffin embedded and stained with either Masson trichrome or picrosirius red (Online Appendix).
Ex vivo aortic vascular reactivity experiments
See the Online Appendix.
Bisoprolol preparation and administration
WKY rats received 1 mg/kg/day bisoprolol in the drinking water. This dose was selected based on previous rat studies to ensure cardiac improvements and heart rate reduction (23). Prior to administration, drinking studies were performed to calculate appropriate drug concentrations in the drinking water. Bisoprolol fumarate was provided by DC Chemicals (Shanghai, China, DCAPI1411).
Sacubitril preparation and administration
WKY rats received 37 mg/kg/day sacubitril in the drinking water. Prior to administration, drinking studies were performed to calculate appropriate drug concentrations in the drinking water, and 37 mg/kg/day was chosen based on previous rat studies (24,25). Sacubitril (AHU-337 hemicalcium salt, DC Chemicals DC8735) was dissolved in 0.5% ethanol. Animals that did not receive sacubitril were administered 0.5% ethanol in the drinking water.
Vascular compliance
See the Online Appendix.
Statistical analysis
All data in this study are expressed as the mean ± SEM. Differences in data between the groups were compared using Prism 6 (GraphPad Software, San Diego, California) with Student unpaired, 2-tailed t test when only 2 groups were compared at a single time point. A repeated measure 2-way analysis of variance with matched values and Bonferroni post-test were used for blood pressure, heart rate, and echocardiography analysis. Mann-Whitney U tests were used for ranked histological analysis. All p values of <0.05 were considered statistically significant. A limitation of the multiple comparison analyses used in this study is an increased risk of false-positive results.
Renal artery nerve viability and norepinephrine levels in SHR in HF following RF-RDN
We used renal artery sympathetic nerve tyrosine hydroxylase (TH) staining as an index of renal sympathetic nerve activity and viability in animals receiving sham-RDN or RF-RDN. Renal artery nerve TH staining at 8 weeks following RF-RDN or sham-RDN in SHR is reported in Figure 2. Representative photomicrographs (Figures 2A to 2D) demonstrate significantly reduced renal nerve viability following RF-RDN as compared to sham-RDN procedures. These data are summarized in Figure 2E. Kidney and plasma norepinephrine (NE) levels were measured as a biomarker for sympathetic outflow in SHR at 8 weeks following RF-RDN or sham-RDN. There was a significant reduction in kidney and circulating NE following RF-RDN compared with the sham-RDN in SHR (Figures 2F and 2G).
Delayed RF-RDN therapy preserves LV function following ischemic-reperfusion injury in SHR
Left ventricular (LV) function, as quantified by LV ejection fraction (LVEF), was markedly improved as early as 4 weeks following therapy and was significantly improved compared with LV function of sham-treated animals through the 12-week endpoint (Figure 3A). LV end-systolic diameter was significantly reduced at 10 weeks, compared with that of sham-RDN animals (Figure 3B). There were no differences in LV end-diastolic diameter between groups at all time points (Figure 3C). These findings support a significant contributory role for the renal nerves in the progression of HF and demonstrate that RF-RDN has a major protective effect on cardiac contractile function in this pathology.
RF-RDN modulates circulating NP in SHR in HF
In addition to improved LV function, 12-week plasma atrial natriuretic peptide (ANP) (Figure 3D), B-type natriuretic peptide (BNP) (Figure 3E), and C-type natriuretic peptide (CNP) (Figure 3F) levels were significantly (p < 0.05) elevated in the RF-RDN-treated group compared with the levels in the sham-RDN. However, these changes were not due to increased gene transcription of ANP, BNP, and CNP in the myocardium (Figures 4A to 4C). Additionally, N-terminal pro-BNP levels in the LV and plasma indicate that RF-RDN did not enhance the release of NP from the myocardium (Figures 4D and 4E). These data clearly demonstrate that RF-RDN preserves circulating NP in the setting of severe HF.
RF-RDN inhibits renal neprilysin activity in SHR in HF
Because increases in the transcription on NP genes in the myocardium were not the cause of augmented NP levels in the circulation, we next investigated the clearance and degradation of NP. NP are primarily cleared in the kidney via the NP clearance receptor and are principally degraded into inactive fragments by the metallo-endopeptidase, neprilysin. Neprilysin is present in a wide variety of tissues, but it is particularly abundant in the kidney. Analyses of messenger RNA (mRNA) and protein levels indicate that RF-RDN does not alter circulating, myocardial, or kidney neprilysin levels (Online Figures 1B to 1D). However, RF-RDN significantly inhibited renal neprilysin activity (Figure 4F) at 12 weeks following the onset of HF (p < 0.05 vs. sham-RDN). Additionally, neprilysin degrades other potentially cardioprotective and vasculoprotective peptides such as substance P and bradykinin. The mRNA levels of the NP clearance receptor in the kidney following RF-RDN indicate that reduced clearance did not contribute to elevated NP in circulation (Online Figure 1A). RF-RDN did not significantly alter circulating substance P levels (Figure 4G), but it did significantly (p < 0.05) increase bradykinin levels in the circulation (Figure 4H). It is well established that bradykinin augments NO levels by activating endothelial NO synthase. Increased LV nitrite levels following RF-RDN (Figure 4I) indicate improved NO signaling and suggest another possible mechanism of cardioprotection.
RF-RDN attenuates cardiac fibrosis and profibrotic signaling following ischemic injury in SHR
RF-RDN significantly reduced LV fibrosis score and percentage area of fibrosis in the LV (29 ± 2.7% vs. 16 ± 3.0%; p < 0.05 vs. sham-RDN) at 12 weeks following myocardial ischemia reperfusion injury (Figures 5B and 5C). Gene quantification revealed that RF-RDN mitigated profibrotic signaling, collagen type 1 alpha-1 and type 3 alpha-1, transforming growth factor-beta1, interleukin-6, and connective tissue growth factor in the infarct border zone (Figure 5D). We observed no differences in matrix metalloproteinase 2, metallopeptidase inhibitor 1, or TIMP2 gene expression in the RF-RDN–treated group (Figure 5D). Additionally, RF-RDN significantly (p < 0.05 vs. sham-RDN group) inhibited infarct expansion compared with sham (Figures 5E and 5F).
Blood pressure following myocardial infarction in hypertensive SHR and normotensive WKY treated with RDN
RF-RDN, compared with sham-RDN, produced a small, but not statistically different decrease in systolic, diastolic, and mean arterial blood pressure (Online Figure 2). Furthermore, the RF-RDN–treated animals remained hypertensive with a systolic pressure above 150 and diastolic pressure above 110 mm Hg. RF-RDN did not significantly alter heart rate (Online Figure 2). In normotensive WKY, RF-RDN had no significant effect on systolic pressure, diastolic pressure, or heart rate when compared with sham-RDN–treated WKY (Online Figure 3).
RAS activity following RF-RDN in HF
The sympathetic nervous system can activate the RAS to further exacerbate the pathogenesis and progression of heart failure. Specifically, angiotensin II causes peripheral vasoconstriction and promotes cardiac remodeling to exacerbate heart failure. We therefore explored the role of RF-RDN on RAS in heart failure. In hypertensive rats, RF-RDN resulted in significant reductions in plasma renin and plasma angiotensin II at 12 weeks following reperfusion (Online Figures 4A and 4B). However, RF-RDN did not significantly alter the RAS system in normotensive rats (Online Figures 4C and 4D). These results suggest that the cardioprotective effects of RF-RDN extend beyond inactivation of the RAS system.
Renal artery nerve viability and norepinephrine levels in WKY following RF-RDN in HF
Renal artery nerve TH staining at 8 weeks following RF-RDN or sham-RDN in WKY rats revealed a significant (p < 0.05) reduction in renal nerve viability in RF-RDN as compared with that in sham-RDN SHR (Figure 6E). Plasma and kidney NE levels were measured 8 weeks following RF-RDN or sham-RDN and there were significant reductions in kidney and circulating NE following RF-RDN versus sham-RDN in WKY (Figures 6F and 6G).
Delayed RF-RDN therapy preserves LV function in normotensive WKY
The cardioprotective effects of RF-RDN therapy in HF in the SHR could be attributed in part to a modest reduction in systolic and diastolic pressure, which reduces the afterload of the heart. To control for the effects of RF-RDN on blood pressure, we performed identical experiments in normotensive WKY. In these experiments, LV function (Figure 7) was improved in normotensive animals as early as 2 weeks following therapy and remained significantly improved when compared with LV function in the sham-treated animals through the 12-week endpoint (Figure 7A). RF-RDN also preserved LV dimensions in WKY subjected to HF. Following RF-RDN therapy, LV end-diastolic diameter was reduced at the 6-week time point compared with that of sham-RDN animals, but remained unchanged between groups throughout the remainder of the study (Figure 7C). LV end-systolic diameter was maintained below the sham-RDN dimension from week 6 through the 12-week endpoint following RF-RDN (Figure 7B). These results indicate that RF-RDN may have therapeutic potential for HF in both hypertensive and normotensive patients.
RF-RDN inhibits renal neprilysin activity and increases circulating NP in WKY in HF
We investigated whether renal sympathetic denervation modulates endogenous regulation of NP in normotensive animals subjected to HF. In a similar fashion to SHR, 12-week plasma BNP (Figure 7D) and CNP (Online Figure 5C) levels were significantly elevated in the RF-RDN–treated WKY versus sham-RDN–treated animals. RF-RDN–induced BNP elevation peaked at the 6-week time point and remained higher than that of sham-RDN–treated animals throughout the study (Online Figure 5G). Plasma levels of ANP (Online Figure 5A) were not increased in WKY subjected to HF and RF-RDN. This disparity from the other NP is likely due to the significant reduction in ANP production in LV of the RF-RDN group as quantified by LV mRNA levels (Online Figure 5B). The changes in BNP and CNP were not a result of increased myocardial gene transcription (Figure 7E, Online Figure 5D). Plasma N-terminal pro-BNP levels were unchanged between the sham- and RF-RDN groups, indicating that RF-RDN did not significantly enhance the release of NP from the cardiac myocyte (Online Figure 5E). As in the setting of hypertension, RF-RDN significantly inhibited renal neprilysin activity during HF (Figure 7F). Likewise, RF-RDN significantly increased circulating bradykinin levels following RF-RDN in WKY in the setting of HF (Online Figure 5F).
Beta1 antagonist, bisoprolol, improves cardiac function, inhibits neprilysin, and increases circulating BNP levels in HF
When administered 4 weeks following myocardial infarction, bisoprolol significantly improved systolic function in WKY rats starting 4 weeks after the onset of treatment compared with systolic function in sham-RDN–treated WKY (Figure 8A). This improvement was preserved through the 12-week endpoint. There were no significant differences in LVEF between bisoprolol and RF-RDN–treated rats. Similar to RF-RDN, bisoprolol treatment resulted in a >2-fold increase in BNP levels (p < 0.05 vs. sham-RDN) and a significant (p <0.001 vs. sham-RDN) reduction in renal neprilysin activity measured at the study endpoint (Figures 8B and 8C).
Neprilysin inhibitor, sacubitril, does not improve cardiac function as does RF-RDN in WKY following ischemia reperfusion injury
When administered to WKY 4 weeks following myocardial infraction, sacubitril was superior to sham-RDN only at the 8-week time point. Comparatively, RF-RDN–treated animals had significantly improved LVEF at all time points following therapy compared with sham-RDN and RF-RDN was superior to sacubitril at the 6- and 10-week time points (Figure 8D). Interestingly, sacubitril did not enhance the effects of RF-RDN, suggesting that some of the protective actions of sacubitril are related to neprilysin inhibition. Sacubitril treatment resulted in a >3-fold increase in BNP levels and significantly reduced renal neprilysin activity measured at the study endpoint (Figures 8E and 8F).
RF-RDN improves vasorelaxation in SHR and WKY in HF
We next investigated the effects of RF-RDN on peripheral vessel vasoreactivity in the setting of HF. At the 12-week endpoint, thoracic aortas were removed and tested in an isolated organ bath system. Sodium nitroprusside (SNP) and acetylcholine (ACh) were administered in increasing concentrations following phenylephrine-induced contraction to test smooth muscle– and endothelial-dependent relaxation, respectively. Aortas from the RF-RDN–treated SHR exhibited significantly greater relaxation to SNP and Ach than did the sham-RDN group (Figures 9A and 9B). Similarly, aortas isolated from RF-RDN–treated WKY exhibited greater relaxation with both SNP and ACh than sham-RDN control aortas did (Figures 9C and 9D). Vascular compliance was also significantly (p < 0.01 vs. sham-RDN) improved in SHR treated with RF-RDN (Online Figure 6A), but not in WKY (Online Figure 6B).
Bisoprolol improves vascular relaxation to a lesser extent than RF-RDN
At the 12-week endpoint, thoracic aortas were excised from WKY and tested for vascular reactivity. There were no significant differences in SNP-mediated relaxation between bisoprolol- and RF-RDN–treated rats (Figure 9C). Aortic vascular segments isolated from RF-RDN–treated rats exhibited superior relaxation to ACh (Figure 9D). Bisoprolol and RF-RDN–treated animals were superior to sham-RDN control animals in terms of SNP- and ACh-induced relaxation (Figures 9C and 9D).
Sacubitril augments circulating angiotensin II and impairs vascular relaxation
Angiotensin II is a substrate for neprilysin degradation. Animals treated with the neprilysin inhibitor, sacubitril, had a >2-fold increase in plasma angiotensin II than did sham-RDN WKY (Online Figure 4D). This was accompanied by impaired vascular relaxation to both SNP and ACh compared with relaxation in sham-RDN control animals (Figures 9E and 9F). These data provide insight as to why neprilysin inhibitors, when used alone, are ineffective at reducing blood pressure and do not preserve cardiac function.
Modulation of the autonomic nervous system as a treatment for HF has been limited to pharmacologic therapies. In the current study, we examined the effects of RF-RDN on post-infarction remodeling in both the setting of hypertension (SHR) and normal blood pressure (WKY) (Central Illustration).
We observed significant preservation of LV systolic function in both hypertensive and normotensive rats following RF-RDN therapy at 4 weeks post-myocardial infarction. This improvement in LV function was accompanied by increases in plasma NP in rats treated with RF-RDN therapy. RF-RDN–induced augmentation of BNP peaked at the 6-week time point (2 weeks after RF-RDN) and was maintained above the sham-RDN control throughout the study. We did not observe any changes in LV and plasma N-terminal pro-BNP following RF-RDN, suggesting that the synthesis of BNP and other NP was not increased by RF-RDN. We did, however, observe significant inhibition of the activity of the NP degrading enzyme, neprilysin, in rats subjected to HF that received RF-RDN. Because total neprilysin protein levels were unchanged, the inhibition of activity was likely due to a post-translation modification of the protein.
In the 1980s, the heart was first recognized as an endocrine organ that secretes a family of hormones called NP (26). These peptides were originally shown to act on the vasculature and kidney to produce natriuresis, diuresis, and peripheral vasodilation to compensate for increased cardiac wall stress and volume (27). Ventricular dilation and myocyte stretch triggers the synthesis and release of NP, and therefore, circulating BNP levels are an established biomarker of HF severity (28–30). In addition to their ability to clear sodium and water and relax smooth muscle, NP act directly on the heart and elicit multiple protective signaling cascades. NP are a target for HF therapeutics and inhibitors of NP degradation (i.e., neprilysin inhibitors) are at the forefront of chronic HF therapy (31–33). ANP, BNP, and CNP bind to NP receptors A, B, and C (27). NP receptors A and B are G-protein coupled receptors that stimulate guanylyl cyclase to generate cyclic guanosine monophosphate and activate protein kinase G (27). Increasing cyclic guanosine monophosphate and activating protein kinase G inhibit hypertrophy and increase intracellular calcium to improve contractility (34–36). Additionally, BNP reduces transforming growth factor beta–induced effects on cardiac fibroblasts (37), and BNP inhibits the expression of genes related to fibrosis (collagen type 1, connective tissue growth factor, and metallopeptidase inhibitor 3), myofibroblast conversion, proliferation, and inflammation (COX2, interleukin 6, and tumor necrosis factor alpha) (37). In the current study we similarly observed reductions in gene transcription levels of transforming growth factor beta, collagen types 1 and 3, connective tissue growth factor, and interleukin 6 following RF-RDN therapy. Overall, we found that RF-RDN treatment reduced ventricular fibrosis, minimized infarct expansion, and improved LV function.
In the current study we also found that NP levels were elevated and renal neprilysin activity was inhibited in rats treated with the beta1-specific antagonist, bisoprolol. These findings indicate that blockade of the sympathetically innervated renal beta1-adrenergic receptor similarly regulates NP metabolism. Interestingly, endothelial-dependent vascular relaxation in RF-RDN–treated rats was superior to relaxation in bisoprolol-treated rats. One possibility for the superiority of RF-RDN on endothelial function, but not cardiac function when RF-RDN is compared with bisoprolol, is that the direct effect of RF-RDN is restricted to the kidney, whereas beta1 receptors are located on numerous cells types throughout the body. Moreover, these findings suggest that RF-RDN can influence vascular endothelial function via alternative pathways beyond blockade of beta-adrenergic pathways and augmentation of circulating NP levels.
When compared with the neprilysin inhibitor, sacubitril, RF-RDN outperformed sacubitril in both cardiac and vascular function. In fact, endothelial- and smooth muscle–dependent relaxation in sacubitril-treated rats were impaired compared with relaxation in sham-RDN–treated control rats. This can potentially be explained by a nearly 3-fold increase in angiotensin II levels, because it is known that significant elevation in circulating levels of this hormone can cause extensive damage to the integrity of the vessel. As was previously reported in clinical trials (38,39), when neprilysin inhibitors are used alone as an antihypertensive agent, a major limitation is that these drugs also obstruct the degradation of angiotensin II. Elevated blood levels of angiotensin II can produce arterial vasoconstriction and promote cardiac remodeling. Benefits of NP modulation are likely offset by these and other actions of angiotensin II. Although RF-RDN inhibits neprilysin activity and augments NP, angiotensin II levels were significantly reduced in SHR with HF, as compared to levels in sham-RDN–treated animals, and were unchanged in WKY with HF. This is likely due to the interruption of sympathetic nerve traffic to the kidneys, which blocks neural activation of the RAS. Therefore, we believe that RF-RDN–induced inhibition of neprilysin provides greater clinical benefits over a neprilysin inhibitor because of the simultaneous inhibition of RAS. Because angiotensin II is a substrate of neprilysin, clinical development of neprilysin inhibitors has involved the combined use of an angiotensin receptor blocker (24,40). This combination therapy has proven extremely efficacious in large clinical trials (31,32). RF-RDN has the potential to inhibit neprilysin in combination with dampening of the sympathetic nervous system and RAS. It is also important to note that the combination of RDN and sacubitril did not result in any additional benefit beyond RDN alone, suggesting that the protective actions of RDN are mediated in part via neprilysin inhibition. These data support our conclusion that the increased circulating levels of NP are a result of renal neprilysin inhibition.
There are several potential advantages to using RF-RDN as a treatment for HF instead of other sympatholytics. The most likely is that beta-blockers bind to the beta-adrenergic receptor and compete with endogenous ligands, epinephrine and NE, to antagonize their actions. In contrast, RF-RDN, by reducing sympathetic efferent nerve traffic, minimizes neurotransmitter release to the beta-adrenergic receptors and inhibits the sympathetic nervous system at a very proximal step in this pathological process. Another limitation of beta-blockers in HF is that they do not improve exercise capacity (41). Exercise capacity is related to peripheral vascular and endothelial function, and it is postulated that beta-blocker effects are limited to cardiac remodeling and function. We have shown that RF-RDN, compared with bisoprolol, improves vascular compliance and has significantly improved ACh-mediated vasorelaxation. In a previous study, we reported that RF-RDN improves endothelial NO synthase function and reduces oxidative stress in the setting of hypertension (19). Healthy redox balance and NO synthesis are critical for endothelial function, indicating another possible mechanism for superior vascular protection. Because RF-RDN improves vascular compliance and reactivity in HF, it is possible that RF-RDN therapy would have greater effects on exercise capacity than beta-blockers would in HF patients.
Study limitations
Despite the beneficial effects of RF-RDN observed in the present study, there remain several possible limitations for the use of RF-RDN as a treatment for HF. Peripheral nerves have the potential of regrowth (42). In the present study, reductions in renal nerve viability were maintained over the course of the study, but we have not examined whether or when these nerves can regrow or regain function. In the early RDN clinical trials for hypertension, blood pressure reductions were maintained up to 3-year follow-up (43). As the field remains in its infancy, we do not have long-term data to substantiate permanent denervation of the renal nerves.
We have shown that RF-RDN improves LV function in HF and that these cardioprotective actions are independent of changes in systolic and diastolic blood pressure. To date, there is no established relationship between the sympathetic nervous system and NP regulation in the kidney. Our results demonstrate that decreased sympathetic nerve activity to the kidney, via RF-RDN, or blockade of sympathetic nerve traffic to the kidney via beta1-adrenergic receptor blockade, inhibits renal neprilysin activity and leads to prolonged increases in vasculoprotective and cardioprotective NP in the setting of heart failure. We conclude that RF-RDN is worthy of further exploration as a promising minimally invasive strategy for the treatment of cardiac injury and HF.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with heart failure, activation of the sympathetic nervous system contributes to maladaptive cardiac remodeling, impaired ventricular function, peripheral vascular dysfunction, and adverse clinical outcomes. Renal sympathetic denervation inhibits the metabolism of protective natriuretic peptides.
TRANSLATIONAL OUTLOOK: Clinical trials of catheter-based renal sympathetic denervation in patients with heart failure are warranted.
The authors thank John Valentino, Daniel Yoo, and Drs. Hiroshi Koiwaya and Michael Hughes for their assistance during these studies.
This work was supported by grants from the National Heart, Lung, and Blood Institute, National Institutes of Health: 1R01 HL092141 (Dr. Lefer), 1R01 HL093579 (Dr. Lefer), 1U24 HL 094373 (Dr. Lefer), 1P20 HL113452 (Dr. Lefer), and P30GM106392 (Dr. Kapusta). This work was also supported by Biosense Webster IIS-175 (Drs. Kapusta and Smart) and the American Heart Association 14POST20450173 (Dr. Gao). Funding was also received from the LSU Medical School Foundation and the LSU Medical School Alumni Association. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
- Abbreviations and Acronyms
- Ach
- acetylcholine
- atrial natriuretic peptide
- B-type natriuretic peptide
- C-type natriuretic peptide
- heart failure
- left ventricular
- left ventricular ejection fraction
- mRNA
- messenger RNA
- norepinephrine
- natriuretic peptide
- renin-angiotensin system
- renal denervation
- radiofrequency
- spontaneously hypertensive rat
- sodium nitroprusside
- tyrosine hydroxylase
- Wistar-Kyoto
- Received October 24, 2016.
- Revision received August 21, 2017.
- Accepted August 21, 2017.
- 2017 American College of Cardiology Foundation
- ↵
- Mozaffarian D.,
- Benjamin E.J.,
- Go A.S.,
- et al.
- ↵
- ↵
- ↵
- ↵
- ↵
- Flather M.D.,
- Yusuf S.,
- Kober L.,
- et al.,
- for the ACE-Inhibitor Myocardial Infarction Collaborative Group
- ↵
- McMurray J.J.,
- Ostergren J.,
- Swedberg K.,
- et al.,
- for the CHARM Investigators and Committees
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵(2000) Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy: the randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation 101:378–384.
- ↵
- Luchner A.,
- Burnett J.C. Jr..,
- Jougasaki M.,
- Hense H.W.,
- Riegger G.A.,
- Schunkert H.
- ↵
- Davis M.E.,
- Richards A.M.,
- Nicholls M.G.,
- Yandle T.G.,
- Frampton C.M.,
- Troughton R.W.
- ↵
- ↵
- Nakaoka H.,
- Kitahara Y.,
- Amano M.,
- et al.
- ↵
- ↵
- Polhemus D.J.,
- Gao J.,
- Scarborough A.,
- et al.
- ↵
- ↵
- King A.L.,
- Polhemus D.J.,
- Bhushan S.,
- et al.
- ↵
- Carpenter T.C.,
- Stenmark K.R.
- ↵
- Watanabe K.,
- Ohta Y.,
- Inoue M.,
- et al.
- ↵
- ↵
- von Lueder T.G.,
- Wang B.H.,
- Kompa A.R.,
- et al.
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
- Packer M.,
- McMurray J.J.,
- Desai A.S.,
- et al.,
- for the PARADIGM-HF Investigators and Coordinators
- ↵
- Oliver P.M.,
- Fox J.E.,
- Kim R.,
- et al.
- ↵
- ↵
- Mohan P.,
- Brutsaert D.L.,
- Paulus W.J.,
- Sys S.U.
- ↵
- Kapoun A.M.,
- Liang F.,
- O'Young G.,
- et al.
- ↵
- Motwani J.G.,
- Lang C.C.,
- Cramb G.,
- Struthers A.D.
- ↵
- ↵
- ↵
- Australia-New Zealand Heart Failure Research Collaborative Group
- ↵
- ↵


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