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Milrinone effects on cardiac mitochondria, hemodynamics, and death in catecholamine-infused rats.

ABSTRACT: Catecholamine-storm is considered the major cause of enterovirus 71-associated cardiopulmonary death. To elucidate the effect of milrinone on cardiac mitochondria and death, a rat model of catecholamine-induced heart failure was investigated. Young male Spray-Dawley rats received a continuous intravenous infusion of norepinephrine then followed by co-treatment with and without milrinone or esmolol. Vital signs were monitored and echocardiography was performed at indicated time points. At the end of experiments, hearts were extracted to study mitochondrial function, biogenesis, and DNA copy numbers. Hypernorepinephrinemia induced persistent tachycardia, hypertension, and high mortality and significantly impaired the activities of the electron transport chain and suppressed mitochondrial DNA copy number, mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator 1-α. Norepinephrine-induced hypertension could be significantly suppressed by milrinone and esmolol. Milrinone improved but esmolol deteriorated the survival rate. The left ventricle was significantly enlarged shortly after norepinephrine infusion but later gradually reduced in size by milrinone. The impairment and suppression of mitochondrial function could be significantly reversed by milrinone but not by esmolol. Milrinone may protect the heart via maintaining mitochondrial function from hypernorepinephrinemia. This study warrants the importance of milrinone and the preservation of mitochondrial function in the treatment of catecholamine-induced death. Milrinone may protect the heart from hypernorepinephrinemia-induced death via maintaining myocardial mitochondrial activity, function, and copy number. Maintenance of cardiac mitochondrial function may be a potential therapeutic strategy in such catecholamine-induced heart failure.

SUBMITTER: Lin IC

PROVIDER: S-EPMC8814569 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Post-cardiac arrest myocardial dysfunction is a common phenomenon after return of spontaneous circulation (ROSC) and contributes to hemodynamic instability and low survival rates after cardiac arrest. Mild hypothermia for 24 h after ROSC has been shown to significantly improve neurologic recovery and survival rates. In the present study we investigate the influence of therapeutic hypothermia on hemodynamic parameters in resuscitated patients and on contractility in failing human myocardium. We analyzed hemodynamic data from 200 cardiac arrest survivors during the hypothermia period. The initial LVEF was 32.6 +/- 1.2% indicating a significantly impaired LV function. During hypothermia induction, the infusion rate of epinephrine could be significantly reduced from 9.1 +/- 1.3 microg/min [arrival intensive care unit (ICU) 35.4 degrees C] to 4.6 +/- 1.0 microg/min (34 degrees C) and 2.8 +/- 0.5 microg/min (33 degrees C). The dobutamine and norepinephrine application rates were not changed significantly. The mean arterial blood pressure remained stable. The mean heart rate significantly decreased from 91.8 +/- 1.7 bpm (arrival ICU) to 77.3 +/- 1.5 bpm (34 degrees C) and 70.3 +/- 1.4 bpm (33 degrees C). In vitro we investigated the effect of hypothermia on isolated ventricular muscle strips from explanted failing human hearts. With decreasing temperature, the contractility increased to a maximum of 168 +/- 23% at 27 degrees C (n = 16, P < 0.05). Positive inotropic response to hypothermia was accompanied by moderately increased rapid cooling contractures as a measure of sarcoplasmic reticulum (SR) Ca(2+) content, but can be elicited even when the SR Ca(2+) release is blocked in the presence of ryanodine. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca(2+) sensitivity as the main mechanism responsible for inotropy. In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors which might contribute to improved survival rates in these patients. Mechanistically, we demonstrate that hypothermia improves contractility in failing human myocardium most likely by increasing Ca(2+)-sensitivity.

Project description:BACKGROUND:Several choices of inotropic therapy are available and used in relation to cardiac surgery. Comparisons are necessary to select optimal therapy. In Denmark, dobutamine and milrinone are the two inotropic agents most commonly used to treat post-bypass low cardiac output syndrome. This study compares all-cause mortality with these drugs. METHODS:In a retrospective observational study we investigated 10,700 consecutive patients undergoing cardiac surgery from 1 April 2006 to 31 December 2013 at Aarhus and Aalborg University Hospitals in the Central and Northern Denmark Region. Prospectively entered data in the Western Danish Heart Registry on intraoperative use of inotropes were used to identify 952 patients treated with milrinone, 418 patients treated with dobutamine, and 82 patients receiving a combination of the two inotropes. All-cause mortality among patients receiving dobutamine was compared to all-cause mortality among milrinone receivers. Multiple logistic regression analyses including preoperative and intraoperative variables along with g-formula analyses were used to model 30-day and 1-year mortality risks. Reported were standardized mortality risk differences between the treatment groups. RESULTS:Among patients receiving intraoperative dobutamine, 18 (4.3%) died within 30 days and 49 (11.7%) within 1 year. Corresponding 30-day and 1-year mortality for milrinone receivers were 81 (8.5%) and 170 (17.9%). Risk of death within 30 days and 1 year was increased for intraoperative milrinone compared to dobutamine with a standardized risk difference of 4.06% (confidence interval (CI) 1.23; 6.89, p = 0.005) and 4.77% (CI 0.39; 9.15, p = 0.033), respectively. Sensitivity analyses including adjustment for milrinone preference, hemodynamic instability prior to cardiopulmonary bypass, and separate analyses on hospital level all confirmed a sign toward increased mortality among milrinone receivers. CONCLUSIONS:Intraoperative use of milrinone in cardiac surgery may be associated with an increase in all-cause mortality compared to use of dobutamine.

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Milrinone effects on cardiac mitochondria, hemodynamics, and death in catecholamine-infused rats.

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