Improvement Of Isoproterenol-induced Left Heart Failure In Rats By Sacubitril/valsartan

Takotsubo syndrome(TTS),also known as stress cardiomyopathy,heartbreak syndrome,it is an acute cardiac syndrome with chest pain and dyspnea as the main symptoms,characterized by local reversible left ventricular wall motion abnormalities.TTS has a high prevalence in middle-aged and older women.Most patients have a psychological or physical stress trigger before the onset of the disease,which usually recovers spontaneously within a few weeks.TTS is very similar to acute coronary syndrome(ACS)and has almost the same clinical presentation,however,TTS is not associated with coronary occlusion,and the area of abnormal ventricular wall motion often extends beyond the innervation of a single coronary artery.Therefore,differential diagnosis is crucial in clinical practice,and although the pathogenesis of TTS is not fully understood,several pathophysiological mechanisms have been proposed,such as toxic effects of catecholamines on cardiomyocytes,epicardial coronary artery spasm and microvascular dysfunction,estrogen deficiency and endothelial dysfunction,acute phase myocardial inflammatory response,neurogenic-mediated myocardial shock,etc.As the disease has received increasing attention in recent years,the diagnosis rate has increased year by year,However,there is still no global consensus on the pathogenesis and diagnostic criteria of TTS,and further research and studies on the disease are needed.Sacubitril/valsartan(Sac/val)is a class of angiotensin receptor enkephalinase inhibitors consisting of angiotensin receptor blockers(ARB)valsartan and enkephalinase inhibitors in a 1:1 ratio.Studies have shown that Sac/val has been shown to significantly reduce mortality in patients with heart failure with reduced ejection fraction.Sac/val was found to improve ventricular remodeling after myocardial infarction by inhibiting the release of pro-inflammatory cytokines and preventing the degradation of antioxidant enzymes,among other mechanisms.In addition,Sac/val was shown to inhibit TGF-β1-induced cardiac fibroblast viability and collagen synthesis,thereby inhibiting myocardial fibrosis and improving ventricular remodeling in an in vitro hypoxic cardiac fibroblast assay.At present,the mechanism of the protective effect of Sac/val on TTS is not clear.In this paper,we used retrospective analysis of case data of six TTS patients in our hospital and construction of TTS rat model to investigate the protective effect and mechanism of action of Sac/val on TTS.Part Ⅰ.Analysis of clinical data of patients with stress cardiomyopathyPurpose:Takotsubo syndrome,also known as apical spherical syndrome and octopus pot cardiomyopathy,is an acute reversible heart failure that is usually considered to be a benign,self-limiting disease.In practical terms,however,the length of stay and long-term prognosis of patients with TTS are largely comparable to those of age-and sex-matched patients with acute coronary syndromes.Early identification and standardized treatment are essential to increase patient survival and improve patient prognosis,but there is no definitive treatment available.Methods:By screening patients with diagnosed or proposed TTS admitted to our hospital between January 1,2019 and February 28,2023,a total of 6 cases,the clinical case data of these 6 patients,including serology,imaging,and late follow-up of treatment regimens,were collected for summary analysis.Results:TTS occurs in middle-aged and older women,and the most common symptoms are dyspnea,chest pain or syncope,with elevated troponin in most cases.Echocardiography in the acute phase mostly shows left ventricular,apical ventricular wall motion abnormalities and significantly reduced ejection fraction.Coronary angiography suggests that most patients do not show significant obstruction.The morbidity characteristics of patients with a diagnosis or proposed diagnosis of TTS collected in this study were similar to those of previous studies,the patient’s cardiac funtion improved after the administration of Sac/val and conventional anti-heart failure drugs,improving the patient’s prognosis.Conclusion:Patients presenting with acute chest pain,especially middle-aged and elderly women,with physiological or psychological stress factors,combined with electrocardiograph(ECG)ST-segment elevation and elevated cardiac troponin levels,and angiography showing no significant coronary artery stenosis,were considered for the diagnosis of TTS.Improvement in cardiac function after treatment with Sac/val and conventional anti-heart failure drugs improves the patient’s prognosis.Part Ⅱ Basic study on the improvement of isoproterenol-induced left heart failure in rats by sacubitril/valsartanPurpose:In this experiment,we established a stress cardiomyopathy model in SD rats to investigate whether Sac/val given by gavage at different concentrations could regulate and protect cardiac function in TTS rat model,and to screen out the concentration of Sac/val with the best protective effect on TTS rats.Methods:Female Sprague Dawley(SD)rats were pretreated with different concentrations of Sac/val(50,75,100mg/kg)for 7 days.The TTS rat model was constructed by a single intraperitoneal injection of isoprenaline(ISO)100 mg/kg on day 8.Echocardiography and electrocardiography were used to analyze cardiac function,HE staining and Masson staining,immunohistochemistry were used to assess pathological changes in cardiac tissue,and western blot was used to detect the expression levels of pro-inflammatory and pro-fibrotic factor proteins.Results:1.A rat model of TTS was successfully constructed by single intraperitoneal injection of isoprenaline into the rat’s abdomen2.Sac/val pretreatment improved cardiac function and cardiac morphological indices in TTS rats.3.Sac/val pretreatment reduces inflammatory cell infiltration in myocardial tissue,attenuates myocardial injury,and reduces collagen fiber deposition.4.TLR4 and NF-κB protein expression were elevated in myocardial tissue of TTS rats,and Sac/val pretreatment downregulated TLR4 expression in myocardial tissue,thereby inhibiting NF-κB activation,The inhibition of inflammation by Sac/val may be achieved through the activation of TLR4/NF-κB signaling pathway.5.coll A1,TGF-β1,α-SMA protein expression was elevated in myocardial tissue of TTS rats,and Sac/val pretreatment down-regulated collAl,TGF-β1,α-SMA protein expression,thereby inhibiting myocardial fibrosis in rats.Conclusion:Administration of a single intraperitoneal injection of ISO 100 mg/kg to rats can well mimic TTS in the clinic,and administration of Sac/val pretreatment can inhibit cardiac inflammation and fibrosis to improve cardiac dysfunction in rats.