Translational Animal Models in Drug Discovery and Development

Experimental Models of Heart Failure: Translational Investigation of Cardiac Drug Safety

Author(s): Xinkang Wang

Pp: 24-41 (18)

DOI: 10.2174/978160805469511201010024

* (Excluding Mailing and Handling)

Abstract

Heart failure (HF) is a major cause of morbidity and mortality. While the current therapies for inhibition of the rennin-angiotensin-aldosterone and sympathetic adrenergic systems have provided clear benefits to HF patients, the disease still progresses in most patients and development of novel therapeutics is still needed. Moreover, concerns about cardiac safety in drug development have taken center stage following recent reports of adverse cardiovascular effects with the use of PPARγ- modulators for the treatment of type-2 diabetes. Issues related to drug efficacy and safety call for appropriate preclinical models of HF that mirror the complex pathophysiological conditions in patients. In particular, cardiovascular drug safety is conventionally assessed pre-clinically in young healthy animals, whereas patients subjected to treatment with drugs such as PPARγ-modulators often have multiple risk factors for cardiovascular disease. While a number of animal models have been developed to explore the pathophysiology of HF and to develop novel therapies, only a few reports address use of these models to assess cardiac drug safety. This chapter focuses on the use of experimental models of HF to assess drug-induced cardiovascular liability by means of biochemical, pharmacogenomic, physiological and imaging biomarkers. Rosiglitazone, a PPARγ activator that has cardiovascular liability in humans, is used as an example for translational investigation in HF models.


Keywords: Animal model, biomarker, cardiac safety, drug safety, heart failure, myocardial infarction, PPARγ, rosiglitazone, translational medicine, type-2 diabetes.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1740496207 and j.to_date >= 1740496207 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4523) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1740496207 and j.to_date >= 1740496207 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4523) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1740496207 and j.to_date >= 1740496207 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4523)
      670μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1119 and `b`.`banner_from_date` <= 1740496207 and `b`.`banner_to_date` >= 1740496207 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.28msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1119
      • 3: 1740496207
      • 4: 1740496207
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='0eb2192107d2b3629a3f129d8531edff'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    10Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        GvhNlNhFMJ4m8P5tc4Ncu3ausJzzGJq39yADQ45P
        uc_cart_id
        0eb2192107d2b3629a3f129d8531edff
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4523" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/4523
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Iit6aTVvY0pIcDliRmlLNEJMaDNNZlE9PSIsInZhbHVlIjoiTitOellybFF2OE9URlhwTG5FVWZzU2JmWFFJWkUvcVBlMHRuZWRSYkdGcz0iLCJtYWMiOiJmOWU1MmE5YTQ2NDRkZmMwOTUwNDUxZDA0NGU2YTYwMWY3MTU0ZmU2YjlkNWExYTBmZmM2MTEwNmU1OTBmZDQxIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Iit6aTVvY0pIcDliRmlLNEJMaDNNZlE9PSIsInZhbHVlIjoiTitOellybFF2OE9URlhwTG5FVWZzU2JmWFFJWkUvcVBlMHRuZWRSYkdGcz0iLCJtYWMiOiJmOWU1MmE5YTQ2NDRk" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:10:07 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImJMMVhCYVYwaTVBSTZDUFgwc2YxWXc9PSIsInZhbHVlIjoiOVFBck1vTU5ZNTluWEpnRFUwa3VPcmh5VFkvcDdkM1QyK1FKc0ZMWTRVT2Vob0pZK0tmRUgyVXhxNGgxK1NaWWpOdjBwVDlKRmJUYVV3TFVRZzU4UytSb284V2V1YjJIYlBKdklSSzFGQnhZUzZjYlc3dk5aS3BJeWN4RGE2Qi8iLCJtYWMiOiIyZThjNzdhMThlM2RlZDFhNjQ3Njk3YWI3MTUzZjgzY2MwMmViN2I1NWVkNDdmNmY2NDlkM2FjM2Q5YzUxMDg1IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:10:07 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImJMMVhCYVYwaTVBSTZDUFgwc2YxWXc9PSIsInZhbHVlIjoiOVFBck1vTU5ZNTluWEpnRFUwa3VPcmh5VFkvcDdkM1QyK1FKc0ZMWTRVT2Vob0pZK0tmRUgyVXhxNGgxK1NaWWpOdjBwV" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ilc2M0tnU25UNDlRTWpnWFo1ZVFnaEE9PSIsInZhbHVlIjoid2ZSa2NZVDM0eGQzTENrc3dTcEtDOVRlN1U5MFhhQjVHNHJ2a01QVEJaS21qSEwxeFlGYzJ3cHU2K3V3TEtNbW8vVEFwUDBYZHJtUjNlT3pXalJrQ0IyQTh2cUdVMVRuRmZCQjhJNmNIeUJJUjZvZXNFMnJhRnVwbm9WWTFwTk0iLCJtYWMiOiIxMjA5ZjI0Y2I4ODA1ODE3NDQxYTQ1YzE2ODAxZGE4YmQ2YjI0OTI2MTExYTc1NjI5YjE1ZmM0MWNjNTdkY2I3IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Ilc2M0tnU25UNDlRTWpnWFo1ZVFnaEE9PSIsInZhbHVlIjoid2ZSa2NZVDM0eGQzTENrc3dTcEtDOVRlN1U5MFhhQjVHNHJ2a01QVEJaS21qSEwxeFlGYzJ3cHU" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImJMMVhCYVYwaTVBSTZDUFgwc2YxWXc9PSIsInZhbHVlIjoiOVFBck1vTU5ZNTluWEpnRFUwa3VPcmh5VFkvcDdkM1QyK1FKc0ZMWTRVT2Vob0pZK0tmRUgyVXhxNGgxK1NaWWpOdjBwVDlKRmJUYVV3TFVRZzU4UytSb284V2V1YjJIYlBKdklSSzFGQnhZUzZjYlc3dk5aS3BJeWN4RGE2Qi8iLCJtYWMiOiIyZThjNzdhMThlM2RlZDFhNjQ3Njk3YWI3MTUzZjgzY2MwMmViN2I1NWVkNDdmNmY2NDlkM2FjM2Q5YzUxMDg1IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:10:07 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImJMMVhCYVYwaTVBSTZDUFgwc2YxWXc9PSIsInZhbHVlIjoiOVFBck1vTU5ZNTluWEpnRFUwa3VPcmh5VFkvcDdkM1QyK1FKc0ZMWTRVT2Vob0pZK0tmRUgyVXhxNGgxK1NaWWpOdjBwV" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ilc2M0tnU25UNDlRTWpnWFo1ZVFnaEE9PSIsInZhbHVlIjoid2ZSa2NZVDM0eGQzTENrc3dTcEtDOVRlN1U5MFhhQjVHNHJ2a01QVEJaS21qSEwxeFlGYzJ3cHU2K3V3TEtNbW8vVEFwUDBYZHJtUjNlT3pXalJrQ0IyQTh2cUdVMVRuRmZCQjhJNmNIeUJJUjZvZXNFMnJhRnVwbm9WWTFwTk0iLCJtYWMiOiIxMjA5ZjI0Y2I4ODA1ODE3NDQxYTQ1YzE2ODAxZGE4YmQ2YjI0OTI2MTExYTc1NjI5YjE1ZmM0MWNjNTdkY2I3IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Ilc2M0tnU25UNDlRTWpnWFo1ZVFnaEE9PSIsInZhbHVlIjoid2ZSa2NZVDM0eGQzTENrc3dTcEtDOVRlN1U5MFhhQjVHNHJ2a01QVEJaS21qSEwxeFlGYzJ3cHU" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "GvhNlNhFMJ4m8P5tc4Ncu3ausJzzGJq39yADQ45P" "uc_cart_id" => "0eb2192107d2b3629a3f129d8531edff" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4523" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:10:07GET/chapter/45231121912