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العنوان
Modulatory effect of ivabradine on autonomic neurotransmission :
المؤلف
ELNagar, Amany ELSayed Hussein.
هيئة الاعداد
باحث / أماني السيد حسين النجار
مشرف / فؤاد مصطفى شرابي
مشرف / سحر محمود الجويلي
مشرف / إيفان إبراهيم سعد
الموضوع
Pharmacology. Toxicology. Heart Failure.
تاريخ النشر
2018.
عدد الصفحات
133 p. :
اللغة
الإنجليزية
الدرجة
ماجستير
التخصص
العلوم الصيدلية
تاريخ الإجازة
1/1/2018
مكان الإجازة
جامعة الاسكندريه - كلية الصيدلة - علم الأدوية و السموم
الفهرس
Only 14 pages are availabe for public view

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Abstract

Ivabradine isa selective Ifinhibitor that lowers the heart rate. Clinically, ivabradine is used for treatment of stable angina.
It has been recently approved by the FDA for treatment of symptomatic chronic HFin patients who are in sinus rhythm and heart rate 70 bpm or greater and who are receiving GDMT, including a β-blocker at maximum tolerated dose.
Approval of ivabradine for treatment of HFwas gained after a number of clinical trials of which the SHIFT trial was the most important one that included large number of patients.
It was concluded that ivabradine effectively improved the quality of life, reduced the number of hospitalizations and reduced the mortality rate in patients surviving HF. However, limited data are availableabout the mechanisms justifying this improved outcomes.
Therefore, the aim of this study was to further investigate the hemodynamic and cardiac effects of ivabradine in HFand in normal rats as well. Furthermore, the possible modulatory effect of ivabradine on the autonomic control of the heart in HFand normal rats was studied.
To achieve this aim, HRV and BRS were measured.
Additionally, this study was performed to assess the effect of ivabradine treatment on the biochemical and histopathological changes in HF.
Finally, all these studied effects of ivabradine were compared with the effects of the first-line treatment of HF, β-blockers and ACEIs.
The experimental model of HFstudiedin the present work was the doxorubicin-induced cardiotoxicity and HF. All experiments were performed in conscious freely moving male rats. The main findings and conclusions of the present work are summarized below.
(1) Ivabradine effectively and safely reduced the heart rate without negative effects on cardiac contractility (max dP/dt) or lusitropy (Tau) after both acute and chronic administration.
<To the contrary, β-blockade significantly reduced the LVcontractility as evident from the decrease of max dP/dt. Therefore,ivabradine is devoid of the negative inotropic effect, an advantage over β-blockers.
(2) Ivabradine has littleor noeffect on the tonic autonomic control of the heart in normal rats.
This was concluded from the analysis oftime domain parameters (SDNN and rMSSD) and frequency domain parameters (LF, HF, LF/HF and TP) of HRV.Chronic treatment with ivabradine had no effect on HRV parameters whereasacute intravenous ivabradine injectionelevated only the time domain parameters of HRV.
(3) In order to study the effect of ivabradine on the reflex autonomic control of the heart, BRSwas measured.
Baroreflex curves relating the change in BPelicited by phenylephrine (increase) or sodium nitroprusside (decrease) to the reflex change in heart rate were established.
The slopes of the baroreflex regression lines were computed to serve as a measure of BRS.
<Ivabradine reduced the reflex tachycardia following SNPinjection which was associated with decreased baroreflex sensitivity measured by sodium nitroprusside (BRSSNP).
This indicates that ivabradine reduces the sympathetic baroreflexes.
Reduction of BRSSNPwas more evidenced by acute rather than chronic ivabradine administration. The reduction of BRSSNPmay be due to heart rate-dependent mechanism.
On the other hand, ivabradine reduced the reflex bradycardia without significantly affecting the baroreflex sensitivity measured by phenylephrine (BRSPE).
(4) In doxorubicin-induced heart failure, ivabradine reduced the mortality rate, lowered the observed tachycardia and efficiently improved the impaired LVfunction. Improving the LVfunction was shown by the significant increase in max dP/dt and tau. In contrast to ivabradine,
Summary and conclusions 111β-blockade only improved the diastolic function (tau) and not the systolic function (max dP/dt).
Improvement of LV function by ivabradine is suggested to be in part due to heart rate reduction.
(5) The autonomic imbalance in doxorubicin-treated rats was normalized by ivabradine treatment.
The reduced HF power and the elevated LF power and LF/HF ratio indicated a sympathetic predominance in doxorubicin-treated rats.
Ivabradine restored the autonomic balance through reducing the sympathetic overdrive in doxorubicin-treated rats. Additionally, ivabradine treatment increased the diminished overall HRV.
Improving HRV by ivabradine is suggestedto be as a result of improving the ventricular function which reduced the compensatory sympathetic overstimulation in doxorubicin-treated rats.
Beta-blocker (propranolol) and β-blocker-ACEI (bisoprolol-captopril) combination equally improved HRV in doxorubicin treated rats.
(6) In doxorubicin-treated rats, the sympathetic baroreflexes and BRSSNP weresignificantly increased.
This observationalong with tachycardia and increased LF/HF ratio confirmthe sympathetic predominance in doxorubicin treated rats.
Ivabradine significantly reduced the elevated tachycardic response to sodium nitroprusside which resulted in reducing the elevated BRSSNP.
(7) Ivabradine reduced the elevated serum levels of the biomarkers of injury in doxorubicin-treated rats such as cTn T and LDH.
This effect along with heart rate reductionaccounts for the improved LVfunction in doxorubicin-treated rats.
Furthermore, ivabradine, like aminoguanidine, reduced the elevated NOlevels observed in doxorubicin-treated rats.
This provides an additional mechanism for improving outcomes in doxorubicin-induced heart failure by ivabradine.
In contrast, propranolol treatment neither reducedthe elevated cardiac biomarkers nor the NOserum levels. Bisoprolol-captopril combination reduced the cTn Tand LDH serum levels while it failed to reduce the elevated NOlevels.
(8) The histopathological examination of the cardiac tissue of doxorubicin-treated rats revealed obvious myocardial damage in the form of interstitial edema, disorganization of myofibrillar arrays that showed occasional waviness, and focal cardiomyocyte necrosis with accumulation of mononuclear cells.
<In addition, cytoplasmic vacuolization of cardiomyocytes was occasionally observed.
Ivabradine treatment resulted in a well preserved cardiac structure, not substantially different from the normal myocardial tissue of control rats, apart from mild focal edema. On the other hand, slight interstitial edema, myofiber swelling and mild focal infiltration by mononuclear cells were still observed after propranolol treatment.
<Bisoprolol-captopril combination ameliorated the histopathological changes caused by doxorubicin except for some degree of interstitial edema, myofiber separation and cell swelling.
(9) Clinically, ivabradinemay providea possible potential therapeutic option for the treatment of doxorubicin-induced heart failure through improving the LV function, the autonomic control of the heart and attenuating the cardiac structural abnormaliti