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Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model.

ABSTRACT: Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which results in quick symptom relief but still poor prognostic outcome. This study utilizes a zebrafish AHF model induced by aristolochic acid (AA) to look for natural products that could attenuate the progression of AHF. The project started off by testing nearly seventy herbal crude extracts. Two of the positive extracts were from Chinese water chestnuts and are further studied in this report. After several rounds of chromatographical chemical fractionation and biological tests, a near pure fraction, named A2-4-2-4, with several hydrophilic compounds was found to attenuate the AA-induced AHF. A2-4-2-4 appeared to inhibit inflammation and cardiac hypertrophy by reducing MAPK signaling activity. Chemical analyses revealed that the major compound in A2-4-2-4 is actually lactate. Pure sodium lactate showed attenuation of the AA-induced AHF and inflammation and cardiac hypertrophy suppression as well, suggesting that the AHF attenuation ability in A2-4-2-4 is attributable to lactate. Our studies identify lactate as a cardiac protectant and a new therapeutic agent for AHF.

SUBMITTER: Haege ER

PROVIDER: S-EPMC7999541 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF.We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann's solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality.The infusion of half-molar sodium lactate increased (mean?±?SD) CO from 4.05?±?1.37 L/min to 5.49?±?1.9 L/min (P?<?0.01) and TAPSE from 14.7?±?5.5 mm to 18.3?±?7 mm (P?=?0.02). Plasma sodium and pH increased (136?±?4 to 146?±?6 and 7.40?±?0.06 to 7.53?±?0.03, respectively; both P?<?0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality.Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function.Clinicaltrials.gov NCT01981655. Registered 13 August 2013.

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Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model.

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