Sacubitril/valsartan decreases mortality in the rat model of the isoprenaline-induced takotsubo-like syndrome.
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ABSTRACT: Aims
Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline-induced takotsubo-like phenotype in rats.Methods and results
A total number of 186 Sprague-Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high-resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS-like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0.Conclusions
Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline-induced apical akinesia in the TTS-like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans.
SUBMITTER: Ali A
PROVIDER: S-EPMC8497381 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsCardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies.Methods and resultsAn isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P > 0.0001). Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05).ConclusionDysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.
| S-EPMC9239582 | biostudies-literature
Project description:Left ventricular remodeling due to pressure overload is associated with poor prognosis. Sacubitril/valsartan is the first-in-class Angiotensin Receptor Neprilysin Inhibitor and has been demonstrated to have superior beneficial effects in the settings of heart failure. The aim of this study was to determine whether sacubitril/valsartan has cardioprotective effect in the early intervention of pressure overloaded hearts and whether it is superior to valsartan alone. We induced persistent left ventricular pressure overload in rats by ascending aortic constriction surgery and orally administrated sacubitril/valsartan, valsartan, or vehicle one week post operation for 10 weeks. We also determined the effects of sacubitril/valsartan over valsartan on adult ventricular myocytes and fibroblasts that were isolated from healthy rats and treated in culture. We found that early intervention with sacubitril/valsartan is superior to valsartan in reducing pressure overload-induced ventricular fibrosis and in reducing angiotensin II-induced adult ventricular fibroblast activation. While neither sacubitril/valsartan nor valsartan changes cardiac hypertrophy development, early intervention with sacubitril/valsartan protects ventricular myocytes from mitochondrial dysfunction and is superior to valsartan in reducing mitochondrial oxidative stress in response to persistent left ventricular pressure overload. In conclusion, our findings demonstrate that sacubitril/valsartan has a superior cardioprotective effect over valsartan in the early intervention of pressure overloaded hearts, which is independent of the reduction of left ventricular afterload. Our study provides evidence in support of potential benefits of the use of sacubitril/valsartan in patients with resistant hypertension or in patients with severe aortic stenosis.
| S-EPMC8368201 | biostudies-literature
Project description:Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40-41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
| S-EPMC9360576 | biostudies-literature
Project description:L-Arginine:glycine amidinotransferase (AGAT) catalyzes the formation of L-homoarginine (hArg) and L-ornithine (Orn) from L-arginine (Arg) and L-lysine (Lys): Arg + Lys ↔ hArg + Orn; equilibrium constant KhArg. AGAT also catalyzes the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly ↔ GAA + Orn; equilibrium constant KGAA. In humans, pharmacological hArg is metabolized to Lys. Low circulating and low excretory concentrations of hArg are associated with worse outcomes and mortality in the renal and cardiovascular systems. The metabolism and pharmacology of hArg have been little investigated. In the present study, we investigated the effects of pharmacological hArg (i.p., 0, 20, 220, 440 mg/kg at time point 0 min) on amino acids homeostasis in a rat model of isoprenaline-induced takotsubo cardiomyopathy (i.p., 50 mg/kg at time point 15 min). We measured by gas chromatography-mass spectrometry free and proteinic amino acids, as well as the polyamines putrescine and spermidine in the heart, lung, kidney, and liver of ten rats sacrificed at various time points (range, 0 to 126 min). hArg administration resulted in multiple changes in the tissue contents of several free and proteinic amino acids, as well as in the putrescine-spermidine molar ratio, an indicator of polyamines catabolism. Our results suggest that Lys and Arg are major metabolites of pharmacological hArg. Kidneys and heart seem to play a major metabolic role for hArg. Circulating Lys does not change over time, yet there is a considerable interchange of free Lys between organs, notably kidney and heart, during the presence of isoprenaline in the rats (time range, 15 to 90 min). Antidromic changes were observed for KhArg and KGAA, notably in the heart in this time window. Our study shows for the first time that free hArg and sarcosine (N-methylglycine) are positively associated with each other. The acute effects of high-dosed hArg administration and isoprenaline on various amino acids and on AGAT-catalyzed reaction in the heart, lung, kidney, and liver are detailed and discussed.
| S-EPMC9103764 | biostudies-literature
Project description:Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including miRNAs, mRNAs, lncRNAs, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human-induced pluripotent stem cell-derived cardiomyocytes under normoxic and hypoxic injury model in vitro, and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell-derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next-generation sequencing of these exosomes exhibited downregulation of the expression of rno-miR-181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR-181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR-181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the miRNA expression level in the exosome payload.
| S-EPMC7670523 | biostudies-literature
Project description:Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded. To investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis. This retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024. New use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs. The associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample. Participants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily). In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.
| S-EPMC11337068 | biostudies-literature
Project description:AimsTakotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine-induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine-mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third-degree atrioventricular block, prevents isoprenaline-induced TS-like akinesia in an experimental animal model.Methods and resultsWe used 142 female Sprague-Dawley rats in two separate protocols. The TS-like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high-resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS-like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter-quartile range (IQR) 0.0-18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0-0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS-like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89-95) and IVAB2 groups (93%, IQR 87-96) than in the CONTROL group (78%, IQR 63-87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9-24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0-0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87-92) than in the CTRL group (51%, IQR 87-92, P < 0.05).ConclusionsIsoprenaline-induced TS-like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS.
| S-EPMC7524126 | biostudies-literature
Project description:Recent studies have suggested a pathogenetic link between impaired mitochondria and Takotsubo syndrome (TTS), which is closely connected with catecholamine overstimulation, poor outcomes, and changes in lipid metabolism. We investigated the changes in lipid metabolism at the level of fatty acid β-oxidation and changes in the intracellular lipidomic spectrum. The immortalized cell line of HL-1 cardiomyocytes was used in this study as an established in vitro model of TTS. The cells were exposed to the non-selective β-agonist isoprenaline (ISO) for acute (2 h) and prolonged (24 h) periods. We investigated the impact on mitochondrial adenosine 5'-triphosphate (ATP) production and β-oxidation using real-time cell metabolic analysis, total lipid content, and changes in the lipidomic spectrum using high-performance liquid chromatography (HPLC) and mass spectrometry. Furthermore, modifications of selected lipid transporters were determined using real-time - polymerase chain reaction (RT-PCR) and/or Western blot techniques. By choosing this wide range of targets, we provide a detailed overview of molecular changes in lipid metabolism during catecholamine overstimulation. The present study demonstrates that acute exposure to ISO decreased ATP production by up to 42.2%, and prolonged exposure to ISO decreased β-oxidation by 86.4%. Prolonged exposure to ISO also increased lipid accumulation by 4%. Lipid spectrum analysis of prolonged exposure to ISO showed a reduced concentration of cardioprotective and an increased concentration of lipotoxic lipid molecules during long-term exposure. Decreased lipid utilization can lead to higher intracellular lipid accumulation and the formation of lipotoxic molecules. Changes in the lipid spectrum can induce pathophysiological signaling pathways leading to cardiomyocyte remodeling or apoptosis. Thus, changes in lipid metabolism induced by excessive doses of catecholamines may cause TTS and contribute to a progression of heart failure, which is at increased risk after a TTS episode.
| S-EPMC9441769 | biostudies-literature
Project description:Background Heart failure (HF) is invariably accompanied by development of cardiac fibrosis, a form of scarring that increases muscular tissue rigidity and decreases cardiac contractility. Cardiac fibrosis arises from a pathological attempt to repair tissue damaged during maladaptive remodeling. Treatment options to block or reverse fibrosis have proven elusive. Neprilysin is an endopeptidase that degrades vasoactive peptides, including atrial natriuretic peptide. Thus, neprilysin inhibition reduces hypertension, ultimately limiting maladaptive cardiac remodeling. LCZ696, which consists of an angiotensin receptor blocker (valsartan [VAL]) and a neprilysin inhibitor (sacubitril [SAC]), was shown to be well tolerated and significantly reduced the risk of death and hospitalization in HF patients with reduced ejection fraction. We hypothesized that SAC/VAL directly inhibits fibroblast activation and development of pathological fibrosis. Methods and Results We used a mouse model of left ventricle pressure overload coupled to in vitro studies in primary mouse and human cardiac fibroblasts (CFs) to study the impact of SAC/VAL on CF activation and cardiac fibrosis. SAC/VAL significantly ameliorated pressure overload-induced cardiac fibrosis by blocking CF activation and proliferation, leading to functional improvement. Mechanistically, the beneficial impact of SAC/VAL at least partially stemmed from restoration of PKG (protein kinase G) signaling in HF patient-derived CF, which inhibited Rho activation associated with myofibroblast transition. Conclusions This study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload-induced hypertrophy and suggests that SAC/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.
| S-EPMC6530564 | biostudies-literature
Project description:Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.
| S-EPMC7841406 | biostudies-literature