Abdominal Aortic Constriction Research Articles

Remodeling of adult rat heart subjected to pressure overload from the neonatal period is dependent on the sex

Abstract Background Congenital heart diseases (CHD) represents the most common birth defect. Despite progress in their treatment improving acute survival, there is a paucity of data concerning the long-term consequences of CHD in adults. Purpose Here, we investigate the remodeling in adult rat hearts subjected to pressure overload from the early postnatal period. Methods We used the neonatal abdominal aortic constriction (AAC) model to analyze morphological, functional (by echocardiography), and electrophysiological long-term outcomes. Given the known differences in cardiac pathologies between males (M) and females (F), we focused on the role of sex in cardiac remodeling. Results Our data showed that both sexes exhibited a similar left ventricular weight/body weight ratio at the age of 12 weeks, indicating comparable left ventricle (LV) enlargement as a response to AAC (increase by 103 ± 9 % in M AAC and 99 ± 10 % in F AAC vs. sham-operated animals). However, the right ventricular weight/body weight and lung/ body weight ratios, indicative of LV failing, differed significantly between sexes with better values in F AAC. The favorable cardiac remodeling in F AAC was corroborated by significantly smaller LV systolic and diastolic diameters, along with a lower amount of myocardial fibrosis. Using optical mapping, we revealed preserved longitudinal and transversal conduction velocities (CVL; CVT) in females (CVL 104 ± 8 vs. 109 ± 8 cm/s and CVT 66 ± 7 vs. 59 ± 6 cm/s in F AAC and F Sham, respectively). However, compared to M Sham, the conduction velocities in M AAC showed a significant decrease (CVL 80 ± 3 vs. 92 ± 3 cm/s and CVT 35 ± 2 vs. 54 ± 3 cm/s). Similarly, the amount of connexion 43 (Cx43) and its phosphorylated state (Cx43Ser368) was preserved in F AAC while exhibiting a decrease in M AAC compared to the sham-operated controls. Thus, electrophysiological findings implicate that while the adult M AAC underwent pro-arrhythmogenic remodeling due to the elevated workload, the adult F AAC preserved physiological conduction properties. Conclusion Our data showed different consequences of the increased pressure load exposed from early after birth to the adult M and F heart. These findings highlighted the involvement of both sexes in cardiac studies.

Odoratin balances ROS/NO through EZH2/PPARγ signalling to improve myocardial fibrosis.

Myocardial fibrosis is a critical concern in clinical medicine. This study explores the potential of odoratin as a treatment for myocardial fibrosis and investigates its underlying mechanisms. In vitro experiments involved stimulating primary mouse cardiomyocytes with TGF-β1, followed by odoratin treatment, to assess levels of reactive oxygen species (ROS) and nitric oxide (NO). In vivo, a mouse model of myocardial fibrosis was established using abdominal aortic constriction (AAC) and treated with odoratin. ROS and NO levels in myocardial tissue were then evaluated. Immunofluorescence and Western blotting analysis showed that odoratin reduced excess ROS, enhanced NO production and decreased fibrosis-related protein expression in vitro. In vivo, odoratin significantly improved cardiac function, reduced ROS, increased NO levels and mitigated fibrosis in AAC-induced mice. Both in vitro and in vivo, odoratin inhibited the expression of NADPH oxidase 4 and EZH2, while promoting the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) and PPARγ. The anti-fibrotic effects of odoratin were reversed by PPARγ antagonism, and EZH2 overexpression diminished PPARγ activation by odoratin. These findings suggest that odoratin may combat myocardial fibrosis by balancing ROS and NO through PPARγ activation, with EZH2 inhibition likely playing a key regulatory role.

Effects of Different Exercise Intensities on the Rat Model of Heart Failure.

Heart failure (HF) is a clinical syndrome caused by the progression of various cardiac diseases to severe stages, and exercise training plays a positive role in the development of HF. This study aimed to investigate the impact of different intensities of exercise training on HF rats.In this study, we established two HF rat models by intraperitoneal injection of isoproterenol at 2.5 mg/kg/day and abdominal aortic coarctation. After exercise training for 4 weeks, the heart weight/body weight ratio and echocardiography results were measured. Moreover, the regulatory effect of different exercise intensities on myocardial function in HF model rats was verified using tissue staining, western blotting, and reagent kits.Exercise training had a bidirectional adjust effect on HF. A running training program of 20 minutes/time had the most significant effect on improving myocardial function in HF rats, whereas exercise intensity of 40 minutes/time or 50 minutes/time did not significantly improve myocardial function in HF rats. Moreover, exercise intensities of 20 minutes/time and 30 minutes/time could reduce the expression levels of the HF markers NT-proBNP and BNP in rats, but the effect was more significant at a duration of 20 minutes/time. We also found that compared with other exercise intensities, 20 minutes/time exercise intensity could significantly improve myocardial fibrosis, promote cardiomyocyte autophagy, and reduce apoptosis in combating HF.Furthermore, an exercise intensity of 20 minutes/time can significantly ameliorate the progression of HF. However, the degree of significance of increasing exercise intensity in improving HF progression is weakened or has no significant effect.

Disruption of the interaction between caveolae and Piezo1 promotes pressure overload-induced cardiac remodeling

Piezo1 channels are activated by mechanical stress and play a significant role in cardiac hypertrophy and fibrosis. However, the molecular mechanisms underlying Piezo1 activation on the cell membrane following pressure overload remain unclear. Caveolae are known to mitigate mechanical forces and regulate Piezo1 function. Therefore, this study aimed to investigate the interaction between caveolae and Piezo1 in the development of pressure overload-induced cardiac remodeling. We observed reduced colocalization between Piezo1 and Caveolin-3 in hypertrophic cardiomyocytes following abdominal aortic constriction and Angiotensin-II treatment, accompanied by increased Piezo1 function and expression. Furthermore, enhanced Piezo1 function was also noted upon caveolae disruption using methyl-beta-cyclodextrin (mβCD). Thus, our findings suggested that pressure overload led to Piezo1 translocation from caveolae, thereby augmenting its function and expression, which may contribute to cardiac remodeling.

Curcumin alone not combined with piperine exerts cardioprotective effects in pressure-overload rats by increasing glucagon-like peptide-1 receptor signaling and additional properties

Background and aimCurcumin has shown significant cardiovascular protective effects. However, the low bioavailability limits its practical application. As a natural bioenhancer, piperine is expected to increase the bioavailability of curcumin, and then, enhance its beneficial effects. Meanwhile, glucagon-like peptide-1 receptor (GLP-1R) signaling has been confirmed to be involved in the regulation of cardiovascular events. Herein, this study aimed to investigate whether piperine could enhance the beneficial effects of curcumin in pressure-overload rats and whether GLP-1/GLP-1R signaling is involved in their action mechanism. Methods and resultsMale Sprague-Dawley (SD) adult rats were subjected to abdominal aortic constriction (AAC) surgery to 16 weeks, which elevated blood pressure and induced cardiac hypertrophy. Curcumin (100 mg/kg/day) or/and piperine (20 mg/kg/day) were orally given for 4 weeks from the 17th week after AAC surgery. Curcumin alone treatment significantly lowered blood pressure, ameliorated cardiovascular remodeling, improved left ventricular performance and endothelium-dependent vascular relaxation. Accompanied by these results, GLP-1R expression in the myocardium was up-regulated. Piperine alone also exhibited a certain positive inotropic cardiac activity, but the effect was less significant. The combination of curcumin and piperine didn't show enhanced cardiovascular protective effects relative to curcumin, along with decreased fasting serum GLP-1 level and GLP-1R expression in the myocardium. ConclusionCurcumin exerts cardiovascular protective effects in pressure-overload rats by upregulating GLP-1R, and inhibiting of GLP-1/GLP-1R signaling pathway may be related to the limited beneficial effects of combination of curcumin and piperine. This study provides a new thinking that oral administration of some spices may affect cardiovascular function by modulating the GLP-1/GLP-1R system in a mode of gut-heart axis regulation.

Shen'ge Formula Protects Cardiac Function in Rats with Pressure Overload-Induced Heart Failure.

In China, Shen'ge formula (SGF), a Traditional Chinese Medicine blend crafted from ginseng and gecko, holds a revered place in the treatment of cardiovascular diseases. However, despite its prevalent use, the precise cardioprotective mechanisms of SGF remain largely uncharted. This study aims to fill this gap by delving deeper into SGF's therapeutic potential and underlying action mechanism, thus giving its traditional use a solid scientific grounding. In this study, rats were subjected to abdominal aortic constriction (AAC) to generate pressure overload. Following AAC, we administered SGF and bisoprolol intragastrically at specified doses for two distinct durations: 8 and 24 weeks. The cardiac function post-treatment was thoroughly analyzed using echocardiography and histological examinations, offering insights into SGF's influence on vital cardiovascular metrics, and signaling pathways central to cardiac health. SGF exhibited promising results, significantly enhanced cardiac functions over both 8 and 24-week periods, evidenced by improved ejection fraction and fractional shortening while moderating left ventricular parameters. Noteworthy was SGF's role in the significant mitigation of myocardial hypertrophy and in fostering the expression of vital proteins essential for heart health by the 24-week mark. This intervention markedly altered the dynamics of the Akt/HIF-1α/p53 pathway, inhibiting detrimental processes while promoting protective mechanisms. Our research casts SGF in a promising light as a cardioprotective agent in heart failure conditions induced by pressure overload in rats. Central to this protective shield is the modulation of the Akt/HIF-1α/p53 pathway, pointing to a therapeutic trajectory that leverages HIF-1α promotion and p53 nuclear transport inhibition.

Preventive and Therapeutic Effects of Crocetin in Rats with Heart Failure.

Gardenia is both a food and medicine plant. It is widely used for cardiovascular protection, and its main bioactive ingredient is crocetin. This study aims to observe the therapeutic effects of crocetin on chronic heart failure in rats induced by various etiologies. It further compares the efficacy differences between preventative and treatment administration, varying dosages, and treatment durations, to provide improved guidance for medication in heart failure rats and determine which categories of chronic heart failure rats might benefit most from crocetin. Chronic heart failure models induced by abdominal aorta constriction, renal hypertension, and coronary artery ligation were constructed. By examining cardiac function, blood biochemistry, and histopathology, the study assessed the preventive and therapeutic effects of crocetin on load-induced and myocardial ischemia-induced heart failure. The results showed that in all three models, both treatment and preventative administration of crocetin significantly improved chronic heart failure in rats, especially in preventative administration. The results indicate crocetin may be beneficial for improving symptoms and functional capacity in rats with heart failure. Furthermore, long-term administration was more effective than short-term administration across all three rat models, with therapeutic onset observed over 6 weeks.

Toll-like Receptor 4 Differentially Modulates Cardiac Function in Response to Chronic Exposure to High-Fat Diet and Pressure Overload.

The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors. TLR4-deficient (TLR4-/-) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions. TLR4-/- mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV). TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload.

Surgical treatment of thoracoabdominal and abdominal aortic coarctations in adults

Surgical treatment of thoracoabdominal and abdominal aortic coarctations in adults

New insights into the effect of VMP1 on the treatment of pressure overload-induced pathological cardiac hypertrophy: Involving SERCA-regulated autophagic flux

Pathological cardiac hypertrophy is an adaptive reaction in response to pressure or volume overload. Autophagy is critical for damage caused by pathological cardiac hypertrophy. Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that is effective in activating autophagy. However, the role of VMP1 in pathological cardiac hypertrophy and its underlying mechanisms remain elusive. This study was designed to explore the potential mechanisms of VMP1 on pressure overload-induced pathological cardiac hypertrophy. In this work, abdominal aorta constriction (AAC) surgery was used to induce pathological cardiac hypertrophy in male C57BL/6 mice. H9C2 cardiomyocytes were treated with phenylephrine stimulation (PE) to induce the hypertrophic response. The in vivo results revealed that mice with AAC surgery caused pathological cardiac hypertrophy as evidenced by improved cardiac function according to multiple echocardiographic parameters. Moreover, elevated VMP1 expression was also observed in mice after AAC surgery. VMP1 knockdown aggravated changes in cardiac structure, cardiac dysfunction, and fibrosis. Meanwhile, VMP1 knockdown suppressed autophagy and endoplasmic reticulum calcium ATPase (SERCA) activity in heart tissues. H9C2 cardiomyocytes with VMP1 overexpression were used to investigate the specific mechanism of VMP1 in pathological cardiac hypertrophy, and VMP1 overexpression increased autophagic flux by upregulating SERCA activity. In conclusion, these findings revealed that VMP1 protected against pressure overload-induced pathological cardiac hypertrophy by inducing SERCA-regulated autophagic flux. Our results provide valuable insights regarding the pathophysiology of pathological cardiac hypertrophy and clues to a novel target for the treatment of pathological cardiac hypertrophy.

CASE REPORT OF A RARE CAUSE OF SECONDARY HYPERTENSION ILLUSTRATING THE IMPORTANCE OF CARDIO-OBSTETRICS PRECONCEPTION COUNSELING

Objective: Our objective is to illustrate the value of preconception management of rare case of secondary hypertension namely Middle Aortic Coarctation (MAC), which is characterized by a constriction of the upper abdominal aorta. During pregnancy, MAC can lead to feto-maternal unfavorable hemodynamic balance (Fig.1). On the one hand, elevation of the arterial blood pressure (BP) of the upper part of the body increases the maternal cardiovascular risk i.e. stroke or aortic dissection. On the other hand, hypo-perfusion of the lower part of the body reduces uterine perfusion, increases fetal risk of preeclampsia, placental insufficiency or fetal growth restriction. Design and method: Here, we report the case of a 30-year-old woman with severe hypertension and plans to become pregnant. She previously underwent percutaneous transluminal angioplasty (PTA) and aortic stenting and presented with elevated BP in both arms (right 177/117 mmHg, left 180/121 mmHg) and decreased ABI bilaterally (Tab. 1). A computed tomography angiography of the aorta was performed showing an aortic stent in a supraceliac position with 79% in-stent stenosis. She underwent a new PTA with in-stent re-stenting (Fig. 2). Results: Post PCA, the four extremities BP measurements showed a reduction of her BP values and a normalization of the ABI bilaterally (Table 1). 24h-ABPM confirmed the BP reduction (mean 24h- systolic BP of 135 mmHg, diastolic BP of 101 mmHg), but still remaining-elevated. Therefore, we started an antihypertensive treatment with a successful BP control (125/82 mmHg). Conclusions: The management of MAC in already pregnant women can be particularly challenging. Indeed, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are contraindicated. Furthermore, PTA during pregnancy expose the fetus to radiation and reports for CoA angioplasty and stenting during pregnancy are very limited. Herby, we decided on an interventional rather than conservative approach. This case illustrates the importance of preconception screening and treatment of chronic hypertension in women with plans to become pregnant. It highlights the fact that secondary causes of hypertension do not have to be overlooked in this population.

Time of the day negatively impacts immune cell myocardial recruitment and cardiac remodeling induced by abdominal aortic constriction in mice

Consequences of myocardial infarction are more severe when it occurred in the middle of the day (active phase) rather than in the resting phase; and patients operated in the afternoon displayed fewer cardiovascular events after cardiac surgery than patients operated in the morning, suggesting that circadian rhythm may affect cardiovascular events or cardiac remodeling. Interestingly, the immune system plays a critical role in the myocardial remodeling process, and the heart is submitted to circadian variations of immune cells amount. Our objective is to determine the impact of abdominal aortic constriction surgery (AAC) time of day on the severity of cardiac remodeling and the myocardial immune profile induced by the pressure overload in mice. We compared hearts of AAC (ligation 27G) mice operated in their resting phase, at Zeitgeber time 5 (ZT5 n = 6) and early active phase (ZT13 n = 8) with SHAM mice (ZT5 n = 7; ZT13 n = 7). Animal survival, heart weights, and cardiac immunophenotyping analyzed by flow cytometry were studied one week after AAC. Heart weights of AAC mice were increased 7 days after surgery (+20% at ZT5 and +40% at ZT13; P < 0.05 and P < 0.01 compared to SHAM groups respectively). Immune cell analysis showed a 1.7-fold increase in myocardial leukocyte infiltration in ZT13 vs. ZT5 AAC group (P < 0.05) with increased numbers of total, resident, and monocyte-derived macrophages. Myocardial infiltration of dendritic cells and granulocytes was also greater in AAC ZT13 mice compared with AAC ZT5 mice and SHAM groups. Finally, we showed higher mortality in AAC mice operated at ZT13 (vs. ZT5). Time of day when sustained cardiac pressure overload occurs affected cardiac remodeling one week after the onset of AAC; with more pronounced innate immune cells infiltration and hypertrophy of the myocardium at ZT13 (vs. ZT5). Further explorations are needed to determine the link between the increased number of immune cells and the more severe phenotype observed in the ZT13 group.

Iron chelation alleviates multiple pathophysiological pathways in a rat model of cardiac pressure overload.

Iron dysmetabolism affects a great proportion of heart failure patients, while chronic hypertension is one of the most common risk factors for heart failure and death in industrialized countries. Serum data from reduced ejection fraction heart failure patients show a relative or absolute iron deficiency, whereas cellular myocardial analyses field equivocal data. An observed increase in organellar iron deposits was incriminated to cause reactive oxygen species formation, lipid peroxidation, and cell death. Therefore, we studied the effects of iron chelation on a rat model of cardiac hypertrophy. Suprarenal abdominal aortic constriction was achieved surgically, with a period of nine weeks to accommodate the development of chronic pressure overload. Next, deferiprone (100mg/kg/day), a lipid-permeable iron chelator, was administered for two weeks. Pressure overload resulted in increased inflammation, fibrotic remodeling, lipid peroxidation, left ventricular hypertrophy and mitochondrial iron derangements. Deferiprone reduced cardiac inflammation, lipid peroxidation, mitochondrial iron levels, and hypertrophy, without affecting circulating iron levels or ejection fraction. In conclusion, metallic molecules may pose ambivalent effects within the cardiovascular system, with beneficial effects of iron redistribution, chiefly in the mitochondria.

Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload-induced cardiac hypertrophy model.

Tropisetron exerts a protective effect against cardiac complications, particularly cardiac hypertrophy. Oxidative stress and apoptosis are the main contributors to the pathogenesis of cardiac hypertrophy. Sirtuins, a family of histone deacetylases, are connected to cellular oxidative stress signaling and antioxidant defense. Sirtuins are also linked to apoptosis which is an important mechanism in the progression of cardiac hypertrophy to heart failure. Literature also suggests that tropisetron impedes apoptosis, partly mediated through an antioxidant mechanism. Therefore, we examined if tropisetron fights cardiac hypertrophy by adjusting sirtuin family proteins (Sirts) and components of mitochondrial death pathway, Bcl-associated X (BAX), Bcl-2-associated death promoter (BAD). Male Sprague-Dawley rats got divided into four groups, including control (Ctl), tropisetron (Trop), cardiac hypertrophy (Hyp), and hypertrophic rats under tropisetron treatment (Hyp + Trop). Pathological cardiac hypertrophy was induced by surgical abdominal aortic constriction (AAC). The increased expression of brain natriuretic peptide (BNP) in the Hyp group confirms the cardiac hypertrophy establishment. The mRNA levels of SIRT1, SIRT3, SIRT7, and BAD also upregulated in the hypertrophic group (p < 0.001). Postoperational administration of tropisetron for 3 weeks lowered the increased expression of BNP (p < 0.05) and BAD (p < 0.001), though the reduction of BAX expression was statistically insignificant (p > 0.05). Tropisetron treatment also restored the normal level of SIRT1/3/7 genes expression in the Hyp + Trop group (p < 0.05). Present findings suggest that tropisetron can suppress cardiomyocyte hypertrophy progression to heart failure by counteracting BNP, SIRT1, SIRT3, Sirt7, and BAD overexpression-mediated apoptosis in a rat model of cardiac hypertrophy.

Integrated network pharmacology and molecular docking analyses of the mechanisms underlying the antihypertensive effects of lotusine

Hypertension is a modifiable cardiovascular risk factor and cause of death worldwide. Lotusine, an alkaloid extracted from a plant used in traditional Chinese Medicine, has shown anti-hypertensive effects. However, its therapeutic efficacy requires further investigation. We adopted integrated network pharmacology and molecular docking approaches with the aim of investigating lotusine's antihypertensive effects and mechanisms of action in rat models. After identifying the optimal intravenous dosage, we observed the effects of lotusine administration on two-kidney, one-clip (2K1C) rats and spontaneously hypertensive rats (SHRs). Based on network pharmacology and molecular docking analyses, we measured renal sympathetic nerve activity (RSNA) to evaluate lotusine's effect. Finally, an abdominal aortic coarctation (AAC) model was established to evaluate lotusine's long-term effects. The network pharmacology analysis identified 21 intersection targets; of these, 17 were also implicated by the neuroactive live receiver interaction. Further integrated analysis showed high lotusine affinity for the cholinergic receptor nicotinic alpha 2 subunit, adrenoceptor beta 2, and adrenoceptor alpha 1B. Blood pressure of the 2K1C rats and SHRs decreased after treatment with 2.0 and 4.0 mg/kg of lotusine (P < 0.001 versus saline control). We also observed RSNA decreases consistent with the network pharmacology and molecular docking analysis results. Results from the AAC rat model indicated that myocardial hypertrophy was decreased with lotusine administration, demonstrated by echocardiography and hematoxylin and eosin and Masson staining. This study provides insights into the antihypertensive effects and underlying mechanisms of lotusine; lotusine may exert long-term protective effects against myocardial hypertrophy caused by elevated blood pressure.

Protective effect of crocin on chronic heart failure and its mechanism of action

Purpose: To explore the mechanism of action of crocin in rat chronic heart failure (CHF).&#x0D; Methods: One hundred male Sprague Dawley (SD) rats were used to establish CHF rat model by the abdominal aorta constriction method. They were equally randomized into either the model control group (injected with distilled water), crocin low, medium, and high dose groups (daily administered 0.05, 0.1, and 0.75 g/kg of crocin, respectively), or positive control group (daily administration of benazepril hydrochloride), and normal control (without treatment). Parameters evaluated include heart function, inflammatory index changes, and oxidative stress damage.&#x0D; Results: The crocin low, medium, and high dose groups and the positive control group had significantly better cardiac function indices versus the model control group (p &lt; 0.05). High-dose crocin resulted in significantly lower levels of inflammatory factors than a low or medium dose (p &lt; 0.05). Rats that received a medium or high dose of crocin showed significantly increased activity of myocardial antioxidant enzymes, and reduced malondialdehyde (MDA) and reactive oxygen species (ROS) content when compared to those given low doses of crocin (p &lt; 0.05). Protein expressions of Bax-activated caspase-3, and NF-kB decreased significantly with increase in crocin dosage. A high dose of crocin produced a significantly lower apoptotic rate of cardiomyocytes, sodium–calcium exchanger (NCX) level and higher content of sarcoplasmic reticulum calcium pump 2a (SERCA2a) compared with low- and medium-doses.&#x0D; Conclusion: Crocin protects myocardial tissue and enhances ventricular diastolic function of CHF rats through down-regulation of NCX expression and up-regulation of SERCA2a expression. Further studies using clinical CHF models to categorize and analyze crocin-related cellular pathways will be required.

PS-B02-5: NICORANDIL SUPPRESSES ISCHEMIA-INDUCED CARDIAC NOREPINEPHRINE ENHANCEMENT AND VENTRICULAR ARRHYTHMIAS IN PRESSURE OVERLOAD-INDUCED HYPERTROPHIC HEARTS.

Objective: Ventricular arrhythmias are a common cause of sudden death in acute myocardial infarction (MI) and hypertension is a major risk factor of MI. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute MI. KATP expresses in nerve terminals as well as cardiomyocytes and KATP in nerve terminals regulates norepinephrine release. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, the roles of nicorandil on ischemic norepinephrine release in hypertrophic cardiac tissue has remained unexplored. We examined whether nicorandil suppressed interstitial norepinephrine level and ventricular arrhythmia during acute ischemia in chronic pressure overload-induced hypertrophic hearts. Design and Methods: Rats were divided into two groups: abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography and hemodynamic measurements, and cardiac tissues were stained with hematoxylin and eosin and Sirius Red for histological examinations. In other rats, 4 weeks after constriction myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results: Four weeks after constriction, remarkable left ventricular wall thickening and diastolic dysfunction were observed in AAC group. In histological examination, remarkable myocyte hypertrophy and interstitial fibrosis were observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (−20 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group, and ischemia increased norepinephrine concentration in both groups. Nicorandil administration in ischemic period significantly suppressed the number of ventricular arrhythmias and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations in hypertrophic hearts. Nicorandil also attenuated epinephrine enhancement in acute ischemic period in hypertrophic hearts. Conclusion: Ischemia-induced ventricular arrhythmias were more frequent and severe in hypertrophic hearts and associated with high interstitial norepinephrine concentration. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in pressure overload-induced hypertrophic hearts.

Cardiac remodeling induced by early postnatal abdominal aorta constriction in rats: Sex differences in heart function and geometry

Cardiac remodeling induced by early postnatal abdominal aorta constriction in rats: Sex differences in heart function and geometry

Abstract 14533: Molecular Imaging of Fibroblast Activity in Pressure Overload Heart Failure

Introduction: Cardiac fibrosis, mediated by the activation of cardiac fibroblasts, is critical in pressure overload-induced heart failure. Fibroblast activation protein (FAP), specifically expressed by activated fibroblasts, can be visualized by radiolabeled FAP inhibitors (FAPI) PET/CT. Hypothesis: To evaluate whether 68Ga-FAPI-04 could characterize the early stages of cardiac fibrosis in pressure overload heart failure. Methods: Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with 68 Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. Cardiac function was measured by echocardiography. The expression of FAP in the myocardium was detected by immunohistochemistry. Results: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p &lt; 0.01). The AAC group showed higher 68 Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, respectively (all p &lt; 0.001), and FAPI increased significantly from 2 to 8 weeks. Immunohistochemistry confirmed the higher density of the FAP + area in the AAC group. The intensity of the 68 Ga-FAPI-04 PET signal correlated with the density of the FAP + area on histology (p &lt; 0.001). The expression of the 68 Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = -0.87; FS: R = -0.72; LVIDd: R = 0.77; LVIDs: R= 0.79; all p &lt; 0.001). The AAC group also showed an increased 68 Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals directly correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010). A combination of the FAPI intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks. Conclusion: The activated fibroblasts in the heart and liver after pressure overload can be monitored by 68 Ga-FAPI-04 PET/CT. This imaging technique reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

A Heart Failure Model Established by Pressure Overload Caused by Abdominal Aortic Contraction in Rat.

Heart failure is a complex clinical syndrome in which ventricular filling or ejection capacity is impaired due to structural or functional diseases of the heart. In order to establish a stable heart failure model, we investigated cardiac parameters in rats with abdominal aortic contraction and normal rats, including the left ventricular posterior wall diameter (LVPWd), the interventricular septum thickness of end-diastolic (IVSd), the left ventricular end-diastolic diameter (LVEDd), the left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). Rats were randomly divided into experimental group (n = 20) and control group (n = 20). The experimental group underwent modified abdominal aortic constriction, while the control group only isolated the abdominal aorta without constriction. The results showed that the survival rate of rats in the experimental group was 85% after one week of operation, while the survival rate of rats in the control group was 100%. Five weeks after operation, the left ventricular posterior wall diameter (LVPWd) and the interventricular septum thickness of end-diastolic (IVSd) in the experimental group were all increased compared with those in the control group, and the differences were statistically significant (p < 0.05); the left ventricular end-diastolic diameter (LVEDd) in the experimental group showed an increasing trend compared with the control group, but p > 0.05; compared with the control group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the experimental group showed downward trend, but p > 0.05. 10 weeks after operation, the LVPWd, IVSd, and LVEDd of the experimental group were increased compared with the control group, p < 0.05, and the LVEF and LVFS of the experimental group were decreased compared with the control group, p < 0.05. Compared with the control group, the BNP of the experimental group increased significantly, p < 0.05. The heart weight index and left ventricular weight index of rats in the experimental group were significantly higher than those in the control group, p < 0.05. HE staining showed that the myocardial cells in the experimental group increased in volume, disordered cell arrangement, widened gaps, increased nuclear hyperchromia, and uneven staining. This paper provides a theoretical basis for the study of heart failure.