We thank Fred Roberts for exemplary technical support and also appreciate the help from the histology core in Beth Israel Hospital. We thank Brigham Women&#8217;s Hospital Cardiovascular Physiology Core for providing with the instrumentation and the funds for this work. This work was supported in part by a Department of Medicine Sundry Fund.

ملاحظة: تم تنفيذ كافة الإجراءات في الفئران وفقا للجمعية الأميركية للطب البيطري (اخر احصاء) المبادئ التوجيهية وافق المؤسسي رعاية الحيوان واستخدام اللجان (IACUC) البروتوكولات. 1. تصميم الدراسة <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> استخدام الذكور 8-10 أسبوع من العمر C57BL / 6 الفئران (BW ~ 25 ز) في الدراسة. </li><li style=";text-align:right;direction:rtl"> بطريقة عشوائية الفئران (ن = 11) إلى مجموعتين، المجموعة المختارة للدراسة النطاقات الأبهري (ن = 8)، والمجموعة الضابطة (ن = 3) للخضوع لعملية صورية عبر بضع الصدر. </li><li style=";text-align:right;direction:rtl"> إعداد الحيوان للتصوير عن طريق إزالة الشعر من الصدر باستخدام كريم مزيل الشعر الذي هو الصف الطبية. </li><li style=";text-align:right;direction:rtl"> إجراء الموجات فوق الصوتية الأولى (القسم 2) 24 ساعة قبل النطاقات الأبهر لتحديد المعايير الأساسية في يوم -1، بين مجموعة من 1٪ و 2.5٪ الأيزوفلورين (مختلطة مع 100٪ O 2 عن طريق الرؤوس) التخدير المتعمد. </li><li style=";text-align:right;direction:rtl"> اختيار وكيل مخدر وافق طبيا (أي الأيزوفلورين) ورصد درجة التخدير (2-3٪ إلى ايندوم، و 1.0٪ للحفاظ على). ملاحظة: التخدير السليم أمر بالغ الأهمية في الحفاظ على ضربات القلب في معدلات الفسيولوجية الطبيعية (حوالي 500 نبضة / دقيقة). </li><li style=";text-align:right;direction:rtl"> تأكيد عمق التخدير عن طريق فقدان الحركة من الحيوان ردا على رد الفعل دواسة الانسحاب. استخدام مرهم التعليم والتدريب المهني paralube على العيون لمنع جفاف بينما تحت التخدير. </li><li style=";text-align:right;direction:rtl"> إجراء عمليات جراحية في يوم 0 20،21. </li><li style=";text-align:right;direction:rtl"> لربط الأبهر، ligate الشريان الأورطي باستخدام خياطة 7-0 الحرير حول مدبب 26 G إبرة توضع على القوس. ملاحظة: تفاصيل بشأن بروتوكول تجريبي، بما في ذلك عمليات ربط الشريان الأبهر الجراحية، وقد وصفت سابقا 20،21. </li><li style=";text-align:right;direction:rtl"> أداء ما بعد الجراحة التصوير بالموجات فوق الصوتية (القسم 2) في يوم (ق) 2 و 6 و 13. </li><li style=";text-align:right;direction:rtl"> الموت ببطء الفئران في يوم 14 وحصاد قلوب لتقييم النسيجي. الموت ببطء الحيوانات باستخدام جرعة زائدة من بنتوباربيتال تليها إزالة الجهاز الحيوي مثل القلب. إلقاء القبض على قلوب في diastoلو وإصلاح مع الفورمالين. استخدام الداخلي للحصاد القلب الذي تم وصفه سابقا 22. </li><li style=";text-align:right;direction:rtl"> إصلاح جميع الأنسجة القلب مع مخزنة 10٪ من محلول الفورمالين. لتلوين ثلاثي الألوان، تضمين الأنسجة في البارافين قبل باجتزاء. استخدام تفاصيل بالترسيب تلطيخ التي تم يتضح جيدا من قبل 14،23. </li><li style=";text-align:right;direction:rtl"> تحليل البيانات باستخدام حاليا برنامج (القسم 3). </li></ol> 2. بروتوكول التصوير <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> الصور محور طويلة وقصيرة من الشريان التاجي الحاجز (SCA) (وضع B-) <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> باستخدام MS550D التحقيق مع مركز تردد 40 ميغاهيرتز متصلا منفذ نشط، تعيين التطبيق مسبقا ل&quot;تصوير القلب&quot;. </li><li style=";text-align:right;direction:rtl"> مع مستلق الحيوان على منصة ساخنة، وتحت التخدير التحكم فيها عن طريق مخروط الأنف، ضع التحقيق باستخدام نظام السكك الحديدية للحصول على رأي القص محور طويل (PSLAX) (الشكل 1A). تأكد دائما أن الحيوان يتم الاحتفاظ الحارة على المنهاج prewarmedويحتفظ م ودرجة حرارة الجسم عند مستويات الفسيولوجية. </li><li style=";text-align:right;direction:rtl"> تدوير التحقيق (مع الشق مشيرا نحو caudally) في اتجاه عقارب الساعة بحيث زاوية التحقيق هي 15 درجة على خط اليسار المجاور للقص (طويلة محور رأي) (الشكل 1B). </li><li style=";text-align:right;direction:rtl"> ضبط زاوية التحقيق عن طريق إمالة قليلا على طول محور ذ لجنة التحقيق للحصول على رأي طولية طول الكامل للSCA في وسط الشاشة (الشكل 1B). </li><li style=";text-align:right;direction:rtl"> مرة واحدة وينظر المعالم الصحيحة (صمام الأبهر والشريان الرئوي)، وتخزين سينمائية الصورة باستخدام الإطار سعر أعلى ممكن. </li><li style=";text-align:right;direction:rtl"> باستخدام &quot;س ص&quot; محاور المتلاعبين الصغيرة (الشكل 1D)، وضبط الموقف التحقيق للحصول على أوضح صورة SCA. </li><li style=";text-align:right;direction:rtl"> تدوير التحقيق 90 درجة (مع الشق مشيرا نحو caudally) في اتجاه عقارب الساعة بحيث نهاية حقق لجنة التحقيق هي على يسار خط الوسط (محور القصير) (الشكل 1C). </li></ol></li><li style=";text-align:right;direction:rtl"> الصور محور طويلة وقصيرة من SCA (لون دوبلر وزارة الدفاعه) <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> مرة واحدة يتم التقاط صورة الوضع B أو تخزينها سينمائية، انقر فوق مفتاح لون دوبلر على لوحة المفاتيح لتشغيل لون دوبلر نافذة الصوتية (الشكل 2). ملاحظة: هذا يساعد على عزل الشريان التاجي (السهم الأبيض يشير SCA) إما في المدى (الشكل 2A) أو في محور القصير (الشكل 2C). وكما ينظر إلى اللون الأحمر في الوقت الحقيقي، ويدل على اتجاه تدفق (بعيدا عن الصمام الأبهري). </li><li style=";text-align:right;direction:rtl"> تأكد من أن عمق التركيز (المشار إليها بواسطة رأس السهم الأصفر على يمين الشاشة صورة)، وتقع في وسط الشريان التاجي. </li><li style=";text-align:right;direction:rtl"> ضمان أن يتم تسجيل البيانات، وذلك باستخدام مفتاح سينمائية متجر، على أعلى معدل الإطار الممكن (&gt; 100 لقطة / ثانية). </li></ol></li><li style=";text-align:right;direction:rtl"> PW دوبلر التصوير من SCA (نابض الموجة أو وضع PW) <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> بينما في وضع لون دوبلر، انقر على مفتاح PW لإحضار الخط الأصفر-مؤشر على الشريان التاجي (الشكل 2، كما هو موضح باللون الأحمر). </li><li style=";text-align:right;direction:rtl"> ضع الأصفرخط PW في منتصف الشريان التاجي في الرأي، في زاوية يوازي اتجاهها من التدفق. لاحظ أن قياسات السرعة تعتمد اعتمادا كبيرا على زاوية الحصول على الصور. </li><li style=";text-align:right;direction:rtl"> ضبط زاوية التدفق (PW مفتاح زاوية) وحجم العينة (مفتاح SV) مثل أن مفتاح زاوية PW هو 60 درجة أو أقل وحجم العينة يلتقط تدفق الحق في وسط SCA. </li><li style=";text-align:right;direction:rtl"> استخدام متجر سينمائية لالتقاط أشكال الموجة التي تشير إلى سرعة تدفق التاجي في ذروة الانقباض (S) وانبساط (D) (أرقام 3A و 3B)، وذلك باستخدام 1٪ و 2.5٪ الأيزوفلورين. </li></ol></li></ol> 3. حساب البيانات وتحليل <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> حدد الوقت والسرعة لا يتجزأ (VTI) أداة للحصول على الانقباضي الذروة والسرعات الانبساطي من الصور المعروضة في أرقام 3A و 3B. </li><li style=";text-align:right;direction:rtl"> حساب مؤشر احتياطي تدفق التاجي (CFR) كنسبة من تبيغي (2.5٪ الأيزوفلورين) ذروة الانبساطي وسرعة منخفضة لخط الأساس (1٪ الأيزوفلورين) الذروة الانبساطي سرعة التدفق. </li><li style=";text-align:right;direction:rtl"> حساب نسبة S / D باعتبارها ذروة الانقباضي سرعة تدفق التاجي / الذروة الانبساطي التاجية سرعة التدفق. تحديد نسبة في الأساس (1٪ الأيزوفلورين) وعلى احتقان (2.5٪ الأيزوفلورين). </li><li style=";text-align:right;direction:rtl"> لالقياسية المعلمات وظيفة القلب مثل FS، FAC، LVM، الرجوع إلى أدلة من الشركة المصنعة لإجراء تحليل البيانات باستخدام البرمجيات الاحتكارية أو الرجوع إلى تشنغ إن الرب في ورقة 2. </li></ol>

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The authors report no disclosures.

في هذه الدراسة على أساس الموجات فوق الصوتية، تم إجراء تقييم غير الغازية من تدفق التاجي بتكاثر في الوقت الحقيقي، على مدى أيام، في فئران التجارب الحية. وعلاوة على ذلك، تظاهر بروتوكول القدرة على كشف الخلل الشريان التاجي التي كانت موجودة في مرحلة مبكرة وكان مرتبطا مع نق?...

السريرية تضيق الأبهر (AS) هو معروف جيدا لتعزيز زيادة مطردة في البطين الأيسر (LV) حمولة تلوية. للتعويض عن هذا ارتفاع مزمن تحميل الدورة الدموية، LV تضخم (LVH) تستتبعه باعتباره 1،2 ردا على التكيف. وكثيرا ما يرتبط تطور تضخم البطين الأيسر مع تشوهات في دوران الأوعية الدقيقة التاجي. ويعتقد أن خلل الأوعية الدموية الدقيقة يساهم في نقص التروية المزمن في هؤلاء المرضى 5. بالإضافة إلى تدفق التاجي 3،4، احتياطي تدفق التاجي (CFR) يمثل التغيير الوظيفي للشرايين التاجية 1،3 ويعرف بأنه نسبة القصوى سرعة تدفق في احتقان في الأساس سرعة تدفق أو يستريح تدفق سرعة 4،6،7. وانخفضت CFR خلال LV إعادة عرض 1-3،5-9، ويستخدم كمؤشر لمدى شدة وظيفية من اختلال وظيفي التاجي 1،10،17. ومن المعروف أن يكون ضعف في أشكال عديدة من تمدد عضلة القلب 10 وأيضا الصورة التاجيةtenosis 6. CFR هو أيضا علامة النذير لنتائج سريرية الفقيرة 12. ويرافق إعادة عرض LV في تحديد الخلل في القلب مثل نقص التروية أو LVH أيضا تليف واسع النطاق، والتغيرات في دوران الأوعية الدقيقة التاجي وسماكة الشرايين التاجية 1،2. ونتيجة لهذه التغييرات في علم وظائف الأعضاء التاجي، هناك إعادة عرض المرجح الشرايين التاجية. وهذا يساعد على التخفيف من آثار انخفاض انتشار الأوكسجين وLV اختلال وظيفي الانبساطي التي يمكن أن تؤدي في التعرض للعضلة القلب نقص تروية 1،2،13. الفئران المعدلة وراثيا هي الآن أداة الفحص سائدة على نطاق واسع لمحاكاة الظروف الأمراض البشرية مثل تصلب الشرايين التاجية 5،7،10،12،17. ولا سيما نموذج الزائد الضغط في الفئران وقد درس على نطاق واسع 14،17. وقد تبين أن نموذج انقباض عبر الأبهر (TAC) لتترافق مع تليف واسع النطاق، وcoronarذ تضيق الناتجة عن ذلك، في جزء منه، من سماكة وسطي من الشرايين التاجية ومع المرافق التغيرات في أنماط تدفق التاجية 1،11،17،19 مماثلة إلى ما ينظر إليه في تحديد LVH في البشر. في حين أنه من المعروف أن الضغط الزائد لفترات طويلة يؤدي إلى قصور في القلب اللا تعويضية في حوالي 4-8 أسابيع، وآثار على ديناميات تدفق التاجية واحتياطي التدفق في هذه النماذج، في وقت مبكر من عملية تطور المرض، وفي مراحل مختلفة بعد النطاقات، هي حتى الآن ليتم محددة بوضوح. هي سلالات عديدة من الفئران المتاحة حاليا للاستخدام البحوث، بما في ذلك جيدا اتسم LDLR - / - أو APOE - / - الفئران 10-12، ودفعت هذه تطوير تقنيات حساسة لتقييم وظيفة القلب والأوعية الدموية والتشكل في الفئران التي تعيش 11-15. وتشمل هذه التقنيات التصوير بالرنين المغناطيسي، PET، وعلى النقيض CT، وارتفاع الموجات فوق الصوتية تردد، والإلكترون شعاع التصوير المقطعي 2،9،17،19، كل منها توفير بدائل واعدة لالغازيةأساليب مثل قسطرة القلب وتصوير الأوعية التاجية 12. ومع ذلك، في الفئران مع حجم صغير جدا من الشرايين التاجية وارتفاع معدل ضربات القلب (HR)، والتصوير من الدوران التاجي لا يزال يشكل تحديا تقنيا للعديد من التقنيات المتاحة حاليا 4،12. ومن المثير للاهتمام، كان هناك ارتفاع هائل في التقدم التقني في مجال تخطيط صدى القلب عبر الصدر دوبلر (TTDE)، بما في ذلك تطوير عالية التردد رؤساء مجموعة المسح الضوئي مع ترددات مركز 15-50 ميجا هرتز مما يسمح القرارات المحورية حوالي 30-100 ميكرون، في أعماق 8-40 ملم، ومعدلات الإطار أكبر من 400 إطارات القبض على / ثانية. في المقابل، ظهرت تقنيات القائم على TTDE كأداة قوية لتصوير الأوعية الكبيرة 2 أو حتى أصغر مثل الشرايين التاجية 5،12. آخر مسبقا الحرج الذي سمح للمحققين لإجراء دراسات التصوير التشخيصي من الأوعية الدموية في صغيرnimals هو استخدام تسيطر عليها بعناية من التخدير التي تحافظ على القلب ومعدل التنفس من الحيوانات أثناء التصوير 11. تسيطر صيانة التخدير أهمية خاصة للدراسات المتعلقة توسع الأوعية في الفئران، ويحتاج تأثير التخدير أيضا إلى مزيد من استكشافها في هذا السياق 10،11. في البشر، من ناحية أخرى، أصبحت القياسات CFR TTDE المستمدة من أداة أكثر شيوعا لتقييم الشرايين التاجية النخابية stenosed وغير عرقلت، في الغالب في الأمامي الأيسر النازل (LAD) الشريان التاجي 5،16. ومع ذلك، فإن دور النذير من CFR والتغيرات تدفق التاجية في المرضى الذين يعانون أعراض أو الفئران مع الحفاظ على وظيفة LV الانقباضي في بقية أقل بكثير استكشاف 16. ولذلك، كان الهدف من هذه الدراسة لإنشاء أول بروتوكول واضح خطوة بخطوة، لتقييم التغيرات في تدفق التاجية باستخدام TTDE في نموذج الضغط الزائد الماوس؛ الثانية، وتناولت هذه الدراسة علامة النذيرificance من CFR والتغيرات تدفق التاجية في استجابة للضغط الإجهاد الزائد في هذه الفئران. لقد افترضنا أن تقييم TTDE أساس من CFR وتدفق التاجي قد تكون مفيدة في الكشف المبكر عن ضعف التاجي التي قد تسبق ضعف LV.

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ultrasound based assessment of coronary artery flow and coronary flow reserve using the pressure overload model in mice

Transthoracic Doppler echocardiography (TTDE) is a clinically useful, noninvasive tool for studying coronary artery flow velocity and coronary flow reserve (CFR) in humans. Reduced CFR is accompanied by marked intramyocardial and pericoronary fibrosis and is used as an indication of the severity of dysfunction. This study explores, step-by-step, the real-time changes measured in the coronary flow velocity, CFR and systolic to diastolic peak velocity (S/D) ratio in the setting of an aortic banding model in mice. By using a Doppler transthoracic imaging technique that yields reproducible and reliable data, the method assesses changes in flow in the septal coronary artery (SCA), for a period of over two weeks in mice, that previously either underwent aortic banding or thoracotomy. 
During imaging, hyperemia in all mice was induced by isoflurane, an anesthetic that increased coronary flow velocity when compared with resting flow. All images were acquired by a single imager. Two ratios, (1) CFR, the ratio between hyperemic and baseline flow velocities, and (2) systolic (S) to diastolic (D) flow were determined, using a proprietary software and by two independent observers. Importantly, the observed changes in coronary flow preceded LV dysfunction as evidenced by normal LV mass and fractional shortening (FS). 
The method was benchmarked against the current gold standard of coronary assessment, histopathology. The latter technique showed clear pathologic changes in the coronary artery in the form of peri-coronary fibrosis that correlated to the flow changes as assessed by echocardiography. 
The study underscores the value of using a non-invasive technique to monitor coronary circulation in mouse hearts. The method minimizes redundant use of research animals and demonstrates that advanced ultrasound-based indices, such as CFR and S/D ratios, can serve as viable diagnostic tools in a variety of investigational protocols including drug studies and the study of genetically modified strains.

من 11 الفئران التي تمت دراستها (النطاقات، ن = 8 و صورية، ن = 3)، تم الحصول على صور مناسبة وقابلة للتكرار من قبل مراقب واحد في عدة نقاط في الوقت: في الأساس (D 1)، D2، D6 وD13 . أيضا، تم قياس سرعة تدفق في موقع التضييقية كما 2225 ± 110.9 ملم / ثانية، مقارنة مع 277.5 ± 10.51 ملم / ثانية في الفئران ?...

Watch this Scientific Journal Video about Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice at JoVE.com

Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice

Coronary flow reserve (CFR) is useful for assessment of myocardial oxygen demand and evaluation of cardiovascular risk. This study establishes a step-by-step transthoracic Doppler echocardiographic (TTDE) method for longitudinal monitoring of the changes in CFR, as measured from coronary artery in mice, under the experimental pressure overload of aortic banding.

تقييم الموجات فوق الصوتية وبناء من الشريان التاجي تدفق وتدفق التاجي الاحتياطي باستخدام نموذج الزائد الضغط في الفئران

Transthoracic Doppler echocardiography (TTDE) is a clinically useful, noninvasive tool for studying coronary artery flow velocity and coronary flow ...

ultrasound-based-assessment-coronary-artery-flow-coronary-flow

Research

JoVE Journal

Medicine

14.8K Views.  Brigham and Women's Hospital, Harvard Medical School. Coronary flow reserve (CFR) is useful for assessment of myocardial oxygen demand and evaluation of cardiovascular risk. This study establishes a step-by-step transthoracic Doppler echocardiographic (TTDE) method for longitudinal monitoring of the changes in CFR, as measured from coronary artery in mice, under the experimental pressure overload of aortic banding.

Video: Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice

Use of a Hanging Weight System for Coronary Artery Occlusion in Mice

Murine studies of acute injury are an area of intense investigation, as knockout mice for different genes are becoming increasingly available 1-38. Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of knockout mouse studies is particularly important 7, 14, 30, 39. Despite the fact that previous studies have already successfully performed cardiac ischemia and reperfusion in mice, this model is technically very challenging. Particularly, visual identification of the coronary artery, placement of the suture around the vessel and coronary occlusion by tying off the vessel with a supported knot is technically difficult. In addition, re-opening the knot for intermittent reperfusion of the coronary artery during IP without causing surgical trauma adds additional challenge. Moreover, if the knot is not tied down strong enough, inadvertent reperfusion due to imperfect occlusion of the coronary may affect the results. In fact, this can easily occur due to the movement of the beating heart.
Based on potential problems associated with using a knotted coronary occlusion system, we adopted a previously published model of chronic cardiomyopathy based on a hanging weight system for intermittent coronary artery occlusion during IP 39. In fact, coronary artery occlusion can thus be achieved without having to occlude the coronary by a knot. Moreover, reperfusion of the vessel can be easily achieved by supporting the hanging weights which are in a remote localization from cardiac tissues.
We tested this system systematically, including variation of ischemia and reperfusion times, preconditioning regiments, body temperature and genetic backgrounds39. In addition to infarct staining, we tested cardiac troponin I (cTnI)
as a marker of myocardial infarction in this model. In fact, plasma levels of cTnI correlated with infarct sizes (R2=0.8). Finally, we could show in several studies that this technique yields highly reproducible infarct sizes during murine IP and myocardial infarction6, 8, 30, 40, 41. Therefore, this technique may be helpful for researchers who pursue molecular mechanisms involved in cardioprotection by IP using a genetic approach in mice with targeted gene deletion. Further studies on cardiac IP using transgenic mice may consider this technique.

A murine model for myocardial ischemia and ischemic preconditioning is an important tool study cardioprotective mechanisms in vivo. Here, we report an easy applicable in situ model for cardiac IP using a hanging-weight system for coronary artery occlusion.

استخدام نظام وزن المعلقة لانسداد الشريان التاجي في الفئران

Murine studies of acute injury are an area of intense investigation, as knockout mice for different genes are becoming increasingly available 1-38. ...

Coronary Artery Ligation and Intramyocardial Injection in a Murine Model of Infarction

Mouse models are a valuable tool for studying acute injury and chronic remodeling of the myocardium in vivo. With the advent of genetic modifications to the whole organism or the myocardium and an array of biological and/or synthetic materials, there is great potential for any combination of these to assuage the extent of acute ischemic injury and impede the onset of heart failure pursuant to myocardial remodeling. 
Here we present the methods and materials used to reliably perform this microsurgery and the modifications involved for temporary (with reperfusion) or permanent coronary artery occlusion studies as well as intramyocardial injections. The effects on the heart that can be seen during the procedure and at the termination of the experiment in addition to histological evaluation will verify efficacy. 
Briefly, surgical preparation involves anesthetizing the mice, removing the fur on the chest, and then disinfecting the surgical area. Intratracheal intubation is achieved by transesophageal illumination using a fiber optic light. The tubing is then connected to a ventilator. An incision made on the chest exposes the pectoral muscles which will be cut to view the ribs. For ischemia/reperfusion studies, a 1 cm piece of PE tubing placed over the heart is used to tie the ligature to so that occlusion/reperfusion can be customized. For intramyocardial injections, a Hamilton syringe with sterile 30gauge beveled needle is used. When the myocardial manipulations are complete, the rib cage, the pectoral muscles, and the skin are closed sequentially. Line block analgesia is effected by 0.25% marcaine in sterile saline which is applied to muscle layer prior to closure of the skin. The mice are given a subcutaneous injection of saline and placed in a warming chamber until they are sternally recumbent. They are then returned to the vivarium and housed under standard conditions until the time of tissue collection. At the time of sacrifice, the mice are anesthetized, the heart is arrested in diastole with KCl or BDM, rinsed with saline, and immersed in fixative. Subsequently, routine procedures for processing, embedding, sectioning, and histological staining are performed. 
Nonsurgical intubation of a mouse and the microsurgical manipulations described make this a technically challenging model to learn and achieve reproducibility. These procedures, combined with the difficulty in performing consistent manipulations of the ligature for timed occlusion(s) and reperfusion or intramyocardial injections, can also affect the survival rate so optimization and consistency are critical.

Numerous genetic manipulations and/or intramyocardial injections of genes, proteins, cells, and/or biomaterials are superimposed upon the dimension of time in studies of acute ischemia/ reperfusion injury and chronic remodeling in mice. This video illustrates the microsurgical procedures for ischemia/reperfusion, permanent coronary artery ligation, and intramyocardial injection studies.

الشريان التاجي ربط Intramyocardial وحقن الفئران في نموذج من احتشاء

Mouse models are a valuable tool for studying acute injury and chronic remodeling of the myocardium in vivo.  With the advent of genetic modifications to ...

Modified Technique for Coronary Artery Ligation in Mice

Myocardial infarction (MI) is one of the most important causes of mortality in humans1-3. In order to improve morbidity and mortality in patients with MI we need better knowledge about pathophysiology of myocardial ischemia. This knowledge may be valuable to define new therapeutic targets for innovative cardiovascular therapies4. Experimental MI model in mice is an increasingly popular small-animal model in preclinical research in which MI is induced by means of permanent or temporary ligation of left coronary artery (LCA)5. In this video, we describe the step-by-step method of how to induce experimental MI in mice.
The animal is first anesthetized with 2% isoflurane. The unconscious mouse is then intubated and connected to a ventilator for artificial ventilation. The left chest is shaved and 1.5 cm incision along mid-axillary line is made in the skin. The left pectoralis major muscle is bluntly dissociated until the ribs are exposed. The muscle layers are pulled aside and fixed with an eyelid-retractor. After these preparations, left thoracotomy is performed between the third and fourth ribs in order to visualize the anterior surface of the heart and left lung. The proximal segment of LCA artery is then ligated with a 7-0 ethilon suture which typically induces an infarct size ~40% of left ventricle. At the end, the chest is closed and the animals receive postoperative analgesia (Temgesic, 0.3 mg/50 ml, ip). The animals are kept in a warm cage until spontaneous recovery.

The surgical procedure used to induce experimental myocardial infarction in mice begins with left thoracotomy between the third and the fourth ribs in order to visualize the anterior surface of the heart and left lung. The left coronary artery is ligated, the chest is closed and the mouse is allowed to recover spontaneously.

تقنية لربط تعديل الشريان التاجي في الفئران

Myocardial infarction (MI) is one of the most important causes of mortality in humans1-3. In order to improve morbidity and mortality in patients with MI ...

Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery in Clinical Research

The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The endothelium acts as a barrier, preventing leukocyte adhesion and aggregation, as well as controlling permeability to plasma components. Functionally, the endothelium affects vessel tone.
Endothelial dysfunction is an imbalance between the chemical species which regulate vessel tone, thombroresistance, cellular proliferation and mitosis. It is the first step in atherosclerosis and is associated with coronary artery disease, peripheral artery disease, heart failure, hypertension, and hyperlipidemia.
The first demonstration of endothelial dysfunction involved direct infusion of acetylcholine and quantitative coronary angiography. Acetylcholine binds to muscarinic receptors on the endothelial cell surface, leading to an increase of intracellular calcium and increased nitric oxide (NO) production. In subjects with an intact endothelium, vasodilation was observed while subjects with endothelial damage experienced paradoxical vasoconstriction.
There exists a non-invasive, in vivo method for measuring endothelial function in peripheral arteries using high-resolution B-mode ultrasound. The endothelial function of peripheral arteries is closely related to coronary artery function. This technique measures the percent diameter change in the brachial artery during a period of reactive hyperemia following limb ischemia.
This technique, known as endothelium-dependent, flow-mediated vasodilation (FMD) has value in clinical research settings. However, a number of physiological and technical issues can affect the accuracy of the results and appropriate guidelines for the technique have been published. Despite the guidelines, FMD remains heavily operator dependent and presents a steep learning curve. This article presents a standardized method for measuring FMD in the brachial artery on the upper arm and offers suggestions to reduce intra-operator variability.

Endothelial dysfunction is associated with numerous disease states and is predictive of adverse cardiovascular events in humans. Flow-mediated vasodilation (FMD) is a non-invasive ultrasound method of evaluating endothelial function. Methodological choices and operator experience may affect results. A systematic approach to FMD in human studies is discussed here.

تقييم الموجات فوق الصوتية من غشائي التي تعتمد على تدفق بوساطة توسع الأوعية في الشريان العضدي في البحوث السريرية

The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The ...

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure.
Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload. Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure. A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion. In contrast, the infarct area at 24 hr after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling.
Besides the model of permanent ligation of the left anterior descending coronary artery, the technique of invasive hemodynamic measurements in mice is presented in detail.

Heart failure is the leading cause of hospitalization and a major cause of mortality. A model of permanent ligation of the left anterior descending coronary artery in mice is applied to investigate ventricular remodelling and cardiac dysfunction post-myocardial infarction. The technique of invasive hemodynamic measurements in mice is presented.

ربط دائم في الشريان التاجي الأيسر الأمامي تنازلي في الفئران: نموذج ما بعد إعادة تشكيل عضلة القلب احتشاء وقصور القلب

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It ...

Direct Re-implantation of Left Coronary Artery into the Aorta in Adults with Anomalous Origin of Left Coronary Artery from the Pulmonary Artery (ALCAPA)

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly which is one of leading causes of myocardial ischemia and infarction in children. If left untreated, it results in a 90% mortality rate in the first year of life. In patients who survive to the adulthood, the coronary steal phenomenon and retrograde left-sided coronary flow provide a substrate for chronic subendocardial ischemia, which may lead to left ventricular dysfunction, ischemic mitral regurgitation, malignant ventricular arrhythmias, and sudden cardiac death. The average age of life-threatening presentation is 33 years and of sudden cardiac death 31 years. Therefore, surgical correction is highly recommended as soon as the diagnosis is made, regardless of age. In adult-type ALCAPA originating from the right-facing sinus of the pulmonary artery, direct re-implantation of the ALCAPA into the aorta is the more physiologically sound repair technique to re-establish the dual-coronary perfusion system and is recommended. This protocol describes the technique of direct re-implantation of adult-type ALCAPA into the aorta.

Direct Re-implantation of Left Coronary Artery into the Aorta in Adults with Anomalous Origin of Left Coronary Artery from the Pulmonary Artery ALCAPA

Surgical correction of ALCAPA is highly recommended, regardless of age or the degree of intercoronary collateralization. This protocol presents a technique for the direct re-implantation of adult-type ALCAPA into the aorta to re-establish the dual-coronary perfusion. Whenever feasible, direct re-implantation is preferred to other surgical correction techniques.

مباشر إعادة زرع الشريان التاجي الأيسر إلى الشريان الأبهر في البالغين الذين يعانون الشاذة منشأ الشريان التاجي الأيسر من الشريان الرئوي (ALCAPA)

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly which is one of leading causes of myocardial ...

Evaluation of Coronary Flow Reserve After Myocardial Ischemia Reperfusion in Rats

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via recanalization of the coronary artery is the most effective strategy for reducing the size of ischemic myocardium. The coronary microvasculature cannot be visualized and imaged&#160;in vivo, but there are several invasive and noninvasive techniques that can be used to assess parameters which depend directly on coronary microvascular function. The endothelial function after ischemia reperfusion can be assessed also at the level of the coronary circulation via the coronary flow reserve (CFR).&#160;In this study, peak velocity of left anterior descending (LAD) coronary arteries was measured in rats in vivo via Transthoracic Doppler Echocardiography during resting and stress challenge (induced by Dobutamine). A normal heart can increase its coronary blood flow up to four times above the resting values during stress induction. Following ischemia reperfusion, we found a significantly diminished CFR, which can be used as a marker of coronary microvascular dysfunction. CFR has opened a window on the importance of microvascular dysfunction and has been shown to predict cardiovascular risk independent of whether the severe obstructive disease is present.

Coronary flow reserve (CFR), is defined as the ratio of maximal coronary blood flow to the resting coronary blood flow. We present a protocol for evaluating CFR in rats via ultrasound, which offers the opportunity to predict cardiovascular risk factors in the absence of obstructive coronary disease.

تقييم احتياطي التدفق التاجي بعد إعادة ضخ الإقفارية عضلة القلب في الفئران

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via ...

Murine Myocardial Infarction Model using Permanent Ligation of Left Anterior Descending Coronary Artery

Myocardial infarction (MI) and acute coronary diseases are among the most prominent causes of death in population with western lifestyle. The murine models of MI with permanent ligation of left-anterior descending (LAD) coronary artery closely mimics MI in humans. Murine models benefit from the extensive genetic engineering available nowadays. Here we propose a reproducible murine surgical model of myocardial infarction by permanent LAD coronary ligation. Our technique comprises anesthesia with ketamine/xylazine that can be rapidly reversed by administration of an antagonist, intubation without tracheotomy for mechanical-assisted ventilation, ventilation with application of extrinsic positive end-expiratory pressure (PEEP) to avoid alveolar collapse, a thoracotomy method limiting to the minimum surgical lesions made to skeletal muscles, and lung inflation without thoracentesis. This method is sparsely invasive, reproducible and reduces post-surgery mortality and complications.

Herein we describe a surgical procedure showing how to achieve permanent ligation of the left-anterior descending coronary artery in mice. This model is of high relevance to investigate the pathophysiology of myocardial infarction and the concomitant biological processes.

نموذج احتشاء عضلة القلب Murine باستخدام الربط الدائم للشريان التاجي الأمامي الأيسر

Myocardial infarction (MI) and acute coronary diseases are among the most prominent causes of death in population with western lifestyle. The murine ...

In Vitro Model of Coronary Angiogenesis

Here, we describe an in vitro culture assay to study coronary angiogenesis. Coronary vessels feed the heart muscle and are of clinical importance. Defects in these vessels represent severe health risks such as in atherosclerosis, which can lead to myocardial infarctions and heart failures in patients. Consequently, coronary artery disease is one of the leading causes of death worldwide. Despite its clinical importance, relatively little progress has been made on how to regenerate damaged coronary arteries. Nevertheless, recent progress has been made in understanding the cellular origin and differentiation pathways of coronary vessel development. The advent of tools and technologies that allow researchers to fluorescently label progenitor cells, follow their fate, and visualize progenies in vivo have been instrumental in understanding coronary vessel development. In vivo studies are valuable, but have limitations in terms of speed, accessibility, and flexibility in experimental design. Alternatively, accurate in vitro models of coronary angiogenesis can circumvent these limitations and allow researchers to interrogate important biological questions with speed and flexibility. The lack of appropriate in vitro model systems may have hindered the progress in understanding the cellular and molecular mechanisms of coronary vessel growth. Here, we describe an in vitro culture system to grow coronary vessels from the sinus venosus (SV) and endocardium (Endo), the two progenitor tissues from which many of the coronary vessels arise. We also confirmed that the cultures accurately recapitulate some of the known in vivo mechanisms. For instance, we show that the angiogenic sprouts in culture from SV downregulate COUP-TFII expression similar to what is observed in vivo. In addition, we show that VEGF-A, a well-known angiogenic factor in vivo, robustly stimulates angiogenesis from both the SV and Endo cultures. Collectively, we have devised an accurate in vitro culture model to study coronary angiogenesis.

In vitro models of coronary angiogenesis can be utilized for the discovery of the cellular and molecular mechanisms of coronary angiogenesis. In vitro explant cultures of sinus venosus and endocardium tissues show robust growth in response to VEGF-A and display a similar pattern of COUP-TFII expression as in vivo.

في المختبر نموذج الأوعية التاجية

Here, we describe an in vitro culture assay to study coronary angiogenesis. Coronary vessels feed the heart muscle and are of clinical importance. Defects ...

Echocardiographic Characterization of Left Ventricular Structure, Function, and Coronary Flow in Neonate Mice

Echocardiography is a non-invasive procedure that enables the evaluation of structural and functional parameters in animal models of cardiovascular disease and is used to assess the impact of potential treatments in preclinical studies. Echocardiographic studies are usually conducted in young adult mice (i.e., 4-6 weeks of age). The evaluation of early neonatal cardiovascular function is not usually performed because of the small size of the mouse pups and the associated technical difficulties. One of the most important challenges is that the short length of the pups&#39; limbs prevents them from reaching the electrodes in the echocardiography platform. Body temperature is the other challenge, as pups are very susceptible to changes in temperature. Therefore, it is important to establish a practical guide for performing echocardiographic studies in small mouse pups to help researchers detect early pathological changes and study the progression of cardiovascular disease over time. The current work describes a protocol for performing echocardiography in mouse pups at the early age of 7 days old. The echocardiographic characterization of cardiac morphology, function, and coronary flow in neonatal mice is also described.

The present protocol describes the echocardiographic assessment of left ventricular morphology, function, and coronary blood flow in 7-day old neonate mice.

توصيف تخطيط صدى القلب لبنية البطين الأيسر ووظيفته وتدفقه التاجي في الفئران حديثي الولادة

Echocardiography is a non-invasive procedure that enables the evaluation of structural and functional parameters in animal models of cardiovascular ...