慢性心力衰竭患者内源性促红细胞生成素的改变及临床意义

目的：探讨内源性促红细胞生成素（EPO）在慢性心力衰竭（CHF）及CHF贫血发病中的作用及临床价值。方法;采用放射性免疫分析法测定117例CHF患者和40例非CHF患者血浆EPO水平,分析EPO水平与心功能分级、贫血以及CHF患者预后的关系。结果：心功能II-IV患者EPO水平显著上升,与对照组比较均有显著性差异（P〈0．05）;EPO水平随着心功能分级增高而逐渐上升,在各级间比较有显著性差异（P〈0．05）;CHF伴贫血患者EPO水平随着心功能分级增高和贫血程度的加重而逐渐上升,在各级间比较有显著性差异（P〈0．05）;死亡组EPO水平显著高于存活组,而Hb水平显著低于存活组,相比较有显著性差畀（P〈0．05）。结论：CHF患者和CHF伴贫血患者内源性EPO水平升高,EPO水平的上升与CHF患者病情严重程度有关,并且是CHF患者预后不良的预测指标。     

慢性心力衰竭患者内源性促红细胞生成素的改变及临床意义

目的:探讨内源性促红细胞生成素(EPO)在慢性心力衰竭(CHF)及CHF贫血发病中的作用及临床价值。方法:采用放射性免疫分析法测定117例CHF患者和40例非CHF患者血浆EPO水平,分析EPO水平与心功能分级、贫血以及CHF患者预后的关系。结果:心功能II～IV患者EPO水平显著上升,与对照组比较均有显著性差异(P<0.05);EPO水平随着心功能分级增高而逐渐上升,在各级间比较有显著性差异(P<0.05);CHF伴贫血患者EPO水平随着心功能分级增高和贫血程度的加重而逐渐上升,在各级间比较有显著性差异(P<0.05);死亡组EPO水平显著高于存活组,而Hb水平显著低于存活组,相比较有显著性差异(P<0.05)。结论:CHF患者和CHF伴贫血患者内源性EPO水平升高,EPO水平的上升与CHF患者病情严重程度有关,并且是CHF患者预后不良的预测指标。     

Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.     

Pulmonary,cardiac and renal distribution of ACE2, furin,TMPRSS2 and ADAM17 in rats with heart failure: Potential implication for COVID-19 disease

Congestive heart failure (CHF) is often associated with kidney and pulmonary dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid sodium retention, cardiac hypertrophy and oedema formation, including lung congestion. While the status of the classic components of RAAS such as renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II) and angiotensin II receptor AT-1 is well studied in CHF, the expression of angiotensin converting enzyme-2 (ACE2), a key enzyme of angiotensin 1-7 (Ang 1-7) generation in the pulmonary, cardiac and renal systems has not been studied thoroughly in this clinical setting. This issue is of a special interest as Ang 1-7 counterbalance the vasoconstrictory, pro-inflammatory and pro-proliferative actions of Ang II. Furthermore, CHF predisposes to COVID-19 disease severity, while ACE2 also serves as the binding domain of SARS-CoV-2 in human host-cells, and acts in concert with furin, an important enzyme in the synthesis of BNP in CHF, in permeating viral functionality along TMPRSST2. ADAM17 governs ACE2 shedding from cell membranes. Therefore, the present study was designed to investigate the expression of ACE2, furin, TMPRSS2 and ADAM17 in the lung, heart and kidneys of rats with CHF to understand the exaggerated susceptibility of clinical CHF to COVID-19 disease. Heart failure was induced in male Sprague Dawley rats by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls. One week after surgery, the animals were subdivided into compensated and decompensated CHF according to urinary sodium excretion. Both groups and their controls were sacrificed, and their hearts, lungs and kidneys were harvested for assessment of tissue remodelling and ACE2, furin, TMPRSS2 and ADAM17 immunoreactivity, expression and immunohistochemical staining. ACE2 immunoreactivity and mRNA levels increased in pulmonary, cardiac and renal tissues of compensated, but not in decompensated CHF. Furin immunoreactivity was increased in both compensated and decompensated CHF in the pulmonary, cardiac tissues and renal cortex but not in the medulla. Interestingly, both the expression and abundance of pulmonary, cardiac and renal TMPRSS2 decreased in CHF in correlation with the severity of the disease. Pulmonary, cardiac and renal ADAM17 mRNA levels were also downregulated in decompensated CHF. Circulating furin levels increased in proportion to CHF severity, whereas plasma ACE2 remained unchanged. In summary, ACE2 and furin are overexpressed in the pulmonary, cardiac and renal tissues of compensated and to a lesser extent of decompensated CHF as compared with their sham controls. The increased expression of the ACE2 in heart failure may serve as a compensatory mechanism, counterbalancing the over-activity of the deleterious isoform, ACE. Downregulated ADAM17 might enhance membranal ACE2 in COVID-19 disease, whereas the suppression of TMPRSS2 in CHF argues against its involvement in the exaggerated susceptibility of CHF patients to SARS-CoV2.     

GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 mug/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.     

Cardioprotective effects of recombinant human erythropoietin in rats with experimental autoimmune myocarditis

Erythropoietin (EPO) has been known to have cytoprotective effects on several types of tissues, presumably through modulation of apoptosis and inflammation. The effect of EPO on myocardial inflammation, however, has not yet been clarified. We investigated the cardioprotective effects of EPO in rats with experimental autoimmune myocarditis (EAM). Seven-week-old Lewis rats immunized with cardiac myosin were treated either with EPO or vehicle and were examined on day 22. EPO attenuated the functional and histological severity of EAM along with suppression of mRNAs of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the hearts as well as a reduction of apoptotic cardiomyocytes. The EPO receptor (EPO-R) was upregulated in the myocardium of EAM compared with that of healthy rats. These results may suggest that EPO ameliorated the progression of EAM by modulating myocardial inflammation and apoptosis.     

Impaired central hemodynamic response and exaggerated vasoconstriction during muscle metaboreflex activation in heart failure patients

The muscle metaboreflex is enhanced in chronic heart failure (CHF) patients, and this fact has been associated with the early fatigue shown by these patients in response to exercise. In animal studies of CHF, it was found that the limited capacity to enhance ventricular performance is responsible for a functional shift from a cardiac output to a systemic vascular resistance (SVR) increase in the mechanism by which the cardiovascular system raises blood pressure in response to the metaboreflex. However, the existence of this functional shift is still unknown in humans. The present study was undertaken to test the hypothesis that a similar hemodynamic response was also present in humans with CHF. The hemodynamic response to metaboreflex activation obtained through postexercise ischemia was assessed in nine patients with CHF and nine healthy controls (CTL) by means of impedance cardiography. The main results were that 1) the blood pressure rise due to the metaboreflex was similar in the two groups; 2) the CTL group achieved the blood pressure response via cardiac output increase, and the CHF group, via SVR increase; and 3) stroke volume was enhanced in the CTL group and decreased in the CHF group. This study demonstrates that in CHF patients, metaboreflex recruitment causes a functional shift from flow increase to peripheral vasoconstriction in the mechanism through which blood pressure is increased. The incapacity to enhance cardiac performance and stroke volume is probably the primary cause of this cardiovascular alteration.     

Chronic exercise training preserves prostaglandin-induced dilation of epicardial coronary artery during development of heart failure in awake dogs

Although it has been shown that long-term exercise training preserves endothelium-mediated nitric oxide vasodilator function in chronic heart failure (CHF), whether exercise training exerts similar beneficial effects on endothelial/prostaglandin-mediated vasodilator capacity in coronary circulation during the development of CHF has not been determined. Fifteen mongrel dogs were surgically instrumented for measurement of left ventricular pressure, aortic pressure, coronary blood flow and left circumflex coronary artery diameter. Dogs (n = 5) who underwent 4 weeks of cardiac pacing (210 b/min for 3 weeks and 240 b/min for the 4th week) developed CHF as characterized by significant reduction in left ventricular systolic pressure, mean arterial pressure and left ventricular dP/dt, increases in left ventricular end-diastolic pressure and heart rate, as well as clinical signs of CHF. Endothelial prostaglandin-mediated vasodilation of the epicardial coronary artery was impaired, as manifested by an attenuated arachidonic acid (AA)-induced dilation of the artery (epicardial artery diameter increased by: 0.78 +/- 0. 84% in CHF versus 4.6 +/- 0.89% in normal, P < 0.05); however, prostacyclin (PGI(2))-induced and nitroglycerin-induced vasodilation of the coronary circulation were not altered. In contrast, dogs (n = 6) with cardiac pacing plus daily exercise training (4.4 +/- 0.3 km/h, 2 h/day) only developed mild cardiac dysfunction, and the response of the epicardial coronary artery diameter to AA was preserved (epicardial artery diameter increased by 4.2 +/- 0.98% from baseline, P 0.05 compared to its respective control). Thus, long-term exercise training preserves endothelial/prostaglandin-mediated dilation of epicardial coronary artery during development of CHF.     

Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells

We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 microg/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 microg/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone (n = 10). After 8 wk of treatment, the animals underwent echocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density (P < 0.05) and by a higher number of EPC (P < 0.05). Both darbepoetin doses increased the hematocrit, whereas MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.     

New insights into the pathological role of TNF-alpha in early cardiac dysfunction and subsequent heart failure after infarction in rats

A marked increase in plasma TNF-alpha has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-alpha receptor type II (sTNF-RII, 40 microg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-alpha, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI (P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-alpha plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.     

Erythropoietin attenuates cardiac dysfunction by increasing myocardial angiogenesis and inhibiting interstitial fibrosis in diabetic rats

ABSTRACT: BACKGROUND: Recent studies revealed that erythropoietin (EPO) has tissue-protective effects in the heart by increasing vascular endothelial growth factor (VEGF) expression and attenuating myocardial fibrosis in ischemia models. In this study, we investigated the effect of EPO on ventricular remodeling and blood vessel growth in diabetic rats. METHODS: Male SD rats were randomly divided into 3 groups: control rats, streptozotocin (STZ)-induced diabetic rats, and diabetic rats treated with 1000 U/kg EPO by subcutaneous injection once per week. Twelve weeks later, echocardiography was conducted, and blood samples were collected for counting of peripheral blood endothelial progenitor cells (EPCs). Myocardial tissues were collected, quantitative real-time PCR (RT-PCR) was used to detect the mRNA expression of VEGF and EPO-receptor (EPOR), and Western blotting was used to detect the protein expression of VEGF and EPOR. VEGF, EPOR, transforming growth factor beta (TGF-beta), and CD31 levels in the myocardium were determined by immunohistochemistry. To detect cardiac hypertrophy, immunohistochemistry of collagen type , collagen type , and Picrosirius Red staining were performed, and cardiomyocyte cross-sectional area was measured. RESULTS: After 12 weeks STZ injection, blood glucose increased significantly and remained consistently elevated. EPO treatment significantly improved cardiac contractility and reduced diastolic dysfunction. Rats receiving the EPO injection showed a significant increase in circulating EPCs (27.85+/-3.43%, P < 0.01) compared with diabetic untreated animals. EPO injection significantly increased capillary density as well as EPOR and VEGF expression in left ventricular myocardial tissue from diabetic rats. Moreover, EPO inhibited interstitial collagen deposition and reduced TGF-beta expression. CONCLUSIONS: Treatment with EPO protects cardiac tissue in diabetic animals by increasing VEGF and EPOR expression levels, leading to improved revascularization and the inhibition of cardiac fibrosis. Key words: erythropoietin; vascular endothelial growth factor; diabetes mellitus; endothelial progenitor cell; myocardial interstitial fibrosis; transforming growth factor beta.     

Regulation of cardiac adrenomedullin in heart failure.

Adrenomedullin (ADM), a potent natriuretic and vasorelaxing peptide with inotropic properties, is elevated in plasma in human and experimental congestive heart failure (CHF). Recent studies suggest that angiotensin II stimulates ADM production and secretion from cardiac myocytes and fibroblasts. In the present study, we investigated cardiac ADM in experimental CHF, and tested the hypothesis that angiotensin converting enzyme (ACE) inhibition modulates cardiac ADM in CHF. Cardiac tissue ADM immunoreactivity and gene expression were assessed by radioimmunoassay, immunohistochemistry, in situ hybridization and Northern blot analysis in normal and CHF dogs in the presence and absence of ACE inhibition. Experimental CHF was produced by progressive rapid ventricular pacing and characterized by increased ventricular ADM concentrations as well as increased ventricular ADM gene expression. ACE inhibition abolished the increases in ventricular ADM concentrations and ventricular ADM gene expression in CHF. Ventricular ADM gene expression was localized to ventricular myocytes and correlated with left ventricular mass index, suggesting that ventricular ADM is a marker for ventricular hypertrophy. In contrast, atrial ADM concentrations and gene expression did not change in CHF with or without ACE inhibition. Increased plasma ADM concentrations in CHF were also abolished with ACE inhibition. The present study demonstrates that circulating and ventricular ADM are activated in pacing-induced experimental CHF and that ACE inhibition reverses ventricular ADM activation in CHF. This study also indicates that cardiac ADM gene expression is differently regulated between atrium and ventricle in CHF.     

Mechanisms of sympathoexcitation: single-unit analysis of muscle vasoconstrictor neurons in awake OSAS subjects.

In congestive heart failure (CHF), muscle sympathetic activity (MSNA) is greatly elevated, but our laboratory has shown that single muscle vasoconstrictor neurons primarily fire only once per cardiac interval, as in normal subjects (Elam M and Macefield VG. J Appl Physiol 91: 717-724, 2001; Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708-1713, 1999). In this study, we used patients with obstructive sleep apnea syndrome (OSAS) to test the hypothesis that this firing pattern is maintained in other states of sympathoexcitation. Unitary recordings were made from muscle vasoconstrictor neurons in eight awake OSAS patients. The average firing frequency of 12 units was 0.96 Hz and the firing probability 51%, similar to previous observations in CHF patients (0.98 Hz, 55%) but higher than in healthy subjects (0.40 Hz, 31%). However, the percentages of cardiac intervals in which neurons generated one, two, three, or four spikes were 59, 27, 10, and 3% in OSAS, compared with 71, 18, 7, and 2% in CHF and 73, 18, 5, and 3% in healthy subjects. Thus the firing pattern is different in OSAS and CHF, leading to rejection of the hypothesis: although in both conditions individual neurons show an increase in firing probability, in OSAS patients they also fire more often within a cardiac interval. It is likely that differences may also be apparent in other states of sympathoexcitation.     

BNP Predicts Chemotherapy-Related Cardiotoxicity and Death: Comparison with Gated Equilibrium Radionuclide Ventriculography

Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients.

Methods

We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry.

Results

During follow-up (mean 1,360 days), 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml (HR 5.5; CI 1.8–17.2; p = 0.003) and LVEF <50% (HR 7.9; CI 3.0–21.4; p<0.001) both significantly predicted CHF. Using the same cut-off points only BNP (HR 1.9; CI 1.3-2.9; p = 0.002) and not LVEF (HR 1.1; CI 0.7–1.8; p = 0.58) was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death.

Conclusion

In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death.     

Short-term treatment using insulin-like growth factor-1 (IGF-1) improves life expectancy of the delta-sarcoglycan deficient hamster

BACKGROUND: The hamster strain CHF147 presents a progressive dilated cardiomyopathy (DCM) due to a large deletion of the delta-sarcoglycan gene that leads to heart failure. This cardiomyopathy induces premature death. We have previously shown that a short-term treatment using IGF-1 preserves cardiac structure and improves function of the CHF147 hamster. METHODS: In the current study, we measured long-term effects of short-term treatment with recombinant human IGF-1 (rhIGF-1) in CHF147 hamsters. CHF147 hamsters (7-8 months old) were implanted under the skin with an osmotic pump filled either with saline or with recombinant human IGF-1 at a total dose of 25 microg. The osmotic pump allowed a continuous delivery of the protein for a mean duration of 19 days. RESULTS: We observed a significant increase in overall survival, as well as preservation of cardiac function, in the rhIGF-1-treated group. At the time of death, hearts of treated animals did not present any macroscopical or histological differences compared to those of sham hamsters. These results show that rhIGF-1 treatment slows down the evolution of the DCM in the CHF147 hamster. Moreover, the low dose treatment did not increase IGF-1 serum levels. CONCLUSIONS: This study is the first one reporting beneficial effects of IGF-1 treatment on survival of an animal model presenting DCM. Our results raise hopes for a new therapeutic approach of this pathology.     

Cytokines in chronic heart failure: possible interaction in the neurohormonal and the cytokine system at the cAMP level?

In recent years, the pathophysiological concept of chronic heart failure (CHF) has changed from an isolated hemodynamic view to a more complex concept involving neuroendocrine and inflammatory pathways. New therapeutic strategies, such as beta-blocker therapy, are based on these new concepts and provide clinical evidence for a clinical benefit in patients with CHF. The survival benefit of beta-blocker therapy in CHF has been related to neurohumoral regulation. Thus, evidence evolved showing that following beta-blocker therapy cytokine levels in CHF patients are altered. We have shown that the levels of soluble TNF receptor type 2 correlated well with cAMP in leukocytes. Data from clinical studies in adult and infant CHF patients have demonstrated that beta-blocker therapy is accompanied by altered cytokine, cytokine antagonist, and/or soluble cytokine receptor levels. These alterations may result from a dysregulated interaction of beta-adrenergic pathways and the cytokine system, and are possibly related to cAMP-dependent regulation of the release or shedding of these mediators.     

ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure.

Chronic heart failure (CHF) is characterized by sympathoexcitation, and the cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex. Our previous studies have shown that the CSAR was enhanced in CHF. In addition, central angiotensin II (ANG II) is an important modulator of this reflex. This study was performed to determine whether the CSAR evoked by stimulation of cardiac sympathetic afferent nerves (CSAN) in rats with coronary ligation-induced CHF is enhanced by ANG II in the paraventricular nucleus (PVN). Under alpha-chloralose and urethane anesthesia, renal sympathetic nerve activity (RSNA) was recorded. The RSNA responses to electrical stimulation (5, 10, 20, and 30 Hz) of the CSAN were evaluated. Bilateral microinjection of the AT1-receptor antagonist losartan (50 nmol) into the PVN had no significant effects in the sham group, but it abolished the enhanced RSNA response to stimulation in the CHF group. Unilateral microinjection of three doses of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to stimulation. Although ANG II also potentiated the RSNA response to electrical stimulation in sham rats, the RSNA responses to stimulation after ANG II into the PVN in rats with CHF were much greater than in sham rats. The effects of ANG II were prevented by pretreatment with losartan into the PVN in CHF rats. These results suggest that the central gain of the CSAR is enhanced in rats with coronary ligation-induced CHF and that ANG II in the PVN augments the CSAR evoked by CSAN, which is mediated by the central angiotensin AT1 receptors in rats with CHF.     

Ghrelin对改善心衰大鼠左室功能紊乱的作用研究

目的:慢性心力衰竭(CHF)患者终末期阶段常发生左室(LV)重塑和心脏性恶病质,有研究称Ghrelin可能对CHFLV功能和能量代谢产生保护作用。本文旨在探讨Ghrelin对CHF大鼠LV功能紊乱和心源性恶病质的作用。方法:建立左冠状动脉结扎术和假手术组,手术后4周,给予大鼠Ghrelin或生理盐水3周。用超声心动图和心脏导管术监测结果。结果:与给予安慰剂组相比,用Ghrelin治疗的CHF和假手术组,血浆GH和胰岛素样生长因子1明显升高(t=1.49,t=0.71,P0.05)。与Sham-Placebo组相比,CHF-Placebo组大鼠体重明显减轻(t=2.18,P0.05)。然而与CHF-Placebo组相比,CHF-Ghrelin组大鼠,体重(t=3.89,P0.05),心输出量(t=3.28,P0.05),LV dP/dtmax(t=3.90,P0.05)明显增加。Ghrelin增加了CHF大鼠心脏舒张压,抑制LV扩大,增加LV缩短分数。结论:长期注射Ghrelin可改善CHF大鼠LV功能紊乱,减缓LV重构和心脏性恶病质的发展,有望为CHF的治疗提供新的途径和方法。