Beneficial effect of ACE inhibitor in congestive heart failure

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopriltreated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5–75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.     

Circadian rhythm of blood pressure in congestive heart failure and effects of ACE inhibitors.

In 33 patients with heart failure (NYHA II-III), the 24-h blood pressure rhythm was examined before and after the titration period of two ACE inhibitors. Blood pressure was measured by the oscillometric method using the blood pressure monitor 90202 from SpaceLabs, Inc. The measurements were taken from 06:00 to 22:00 h every 20 min and from 22:00 to 06:00 h every hour. Patients were randomized to therapy with either captopril (group 1, n = 17) or enalapril (group 2, n = 16). The average daily dosage of captopril was 41 +/- 3 mg given in three divided doses (08:00, 12:00, and 17:00 h). The mean dose of enalapril was 8 +/- 1 mg once daily (08:00 h). Serum electrolytes, serum creatinine, and plasma renin activity were measured before and during therapy with both ACE inhibitors. Twenty-four-hour blood pressure measurements were taken before and on the fifth day of treatment with ACE inhibitors. Both groups were not different with respect to the degree of heart failure, the concomitant medication, and the 24-h profiles of blood pressure and heart rate before initiation of ACE inhibition. The 24-h blood pressure values on day 5 were consistently below the pretreatment values (p less than 0.005) in both groups. Both groups did not differ significantly during ACE inhibition in their 24-h blood pressure and heart rate profiles. In both groups, the mesor of the systolic and diastolic blood pressure decreased significantly by the same degree (by 4.7/5.1 mmg Hg in group 1 and 6.4/4.1 mm Hg in group 2). The systolic/diastolic blood pressure amplitude decreased slightly in both groups. Before treatment, serum sodium, potassium, and creatinine were within the normal range. The increase in potassium (0.5 +/- 0.1 mmol/L) reached statistical significance (p less than 0.01) only in the captopril group, whereas it was not significant in the enalapril group (0.1 +/- 0.1 mmol/L). Serum creatinine was not significantly altered by both ACE inhibitors. No relationship could be found between the changes in serum potassium or creatinine and the mean of the 24-h blood pressure values during ACE inhibition. Captopril and enalapril showed comparable blood pressure profiles and similar effects on renal function at the end of the titration on day 5. It can therefore be concluded that the effects on blood pressure rhythm and renal function are similar with a single daily dose of enalapril compared to captopril given three times daily.     

Changes in lipid spectrum in rats with chronic heart failure of different severity on the background of angiotensin-converting enzyme inhibitors and beta-adrenoblockers

The character of lipid spectrum changes in rats with experimental heart failure of non-ischemic genesis depended on its severity. In mild heart failure there was found an increase in the low-density lipoprotein levels, whereas in the severe one-a decrease of total cholesterol levels at the expense of low-density lipoproteins. The ACE inhibitors produced no significant changes in the lipid spectrum. The effect of β-adrenoblockers was determined by their selectivity for β₁-adrenoreceptors. The most selective drugs were distinguished by the metabolically neutral activity. On the contrary, nonselective β-adrenoblockers increased the degree of plasma atherogeneity.     

Glycogen concentrations and endurance capacity of rats with chronic heart failure

The endurance capacities of rats with myocardial infarctions (MI) and of rats having undergone sham operations (SHAM) were tested during a submaximal exercise regimen that consisted of swimming to exhaustion. During this test, a decrement in the endurance capacity of the MI rat was demonstrated as the SHAM rat swam 25% longer than the MI rat (65 +/- 4 vs. 52 +/- 4 min). Glycogen concentrations were measured in the liver and the white gastrocnemius, plantaris, and soleus muscles of SHAM and MI rats that were randomly divided into four subgroups, which consisted of resting control, swim to exhaustion, swim to exhaustion + 24 h recovery, and swim to exhaustion + 24 h recovery + a second swim to exhaustion. The results demonstrated that the glycogen concentrations found in the liver, white gastrocnemius, plantaris, and soleus muscles of the SHAM and MI rats belonging to the resting control groups were similar. After swimming to exhaustion the glycogen concentrations in these tissues were significantly reduced compared with those found in the resting control groups of rats, and after 24 h of recovery the glycogen concentrations in these tissues were again similar to those found in the resting control groups of rats. Since the magnitude of the glycogen depletion in the liver and the white gastrocnemius, plantaris, and soleus muscles was similar in the SHAM and MI rats and because the SHAM rats consistently swam for longer periods of time in each of the experimental groups, it would be logical to assume that the rates of glycogen utilization for the various tissues may have been greater in the MI rat during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of estrogen on venous function in rats with chronic heart failure

The effect of 17beta-estradiol on venous function was investigated in ovariectomized rats with heart failure. Rats (50-60 days old) were ovariectomized and implanted with 60-day-release pellets that contain 17beta-estradiol (1.5 mg) or vehicle. The left coronary artery was ligated 7 days later. Another group of ovariectomized rats was given vehicle pellets and then a sham operation was performed. The rats were studied while under pentobarbital anesthesia at 7 wk after ligation. Ligated rats, relative to sham groups, had lower mean arterial pressure (MAP, -34 mmHg) and cardiac output (CO, -38%); higher arterial resistance (R(A), +12%) and venous resistance (R(V), +116%); mean circulatory filling pressure (MCFP, +40%) and left ventricular end-diastolic pressure (LVEDP, +11 mmHg); and similar cardiovascular responses to norepinephrine (NE). Treatment of ligated rats with 17beta-estradiol increased CO (+16%); reduced R(A) (-16%), R(V) (-35%), MCFP (-23%), and LVEDP (-3 mmHg); and augmented MAP, R(V,) and MCFP responses to NE. Therefore, 17beta-estradiol reduced MCFP, and this reduced preload (LVEDP). 17beta-Estradiol decreased R(V), which, along with decreased R(A) (afterload), led to an increase in CO. 17beta-Estradiol likely augmented vasoconstriction to NE through an improvement on the cardiovascular status.     

敦煌疗风虚瘦弱方对大鼠慢性心衰的治疗作用及其机制

目的：观察敦煌疗风虚瘦弱方（LXD）对慢性心衰大鼠的治疗作用及机制。方法：48只Wistar雄性大鼠随机分为6组（n=8）：正常组、模型组、卡托普利组和LXD高、中、低剂量组。除正常组外,其余各组大鼠尾静脉注射阿霉素（2.5 mg/kg）,每周1次,连续6周复制慢性心衰模型,末次注射阿霉素60 min后,卡托普利组灌胃卡托普利,LXD高、中、低剂量组分别以灌胃LXD水煎液80、40、20 g/kg （生药/体重）,正常组和模型组灌胃等容量生理盐水,每天1次,连续6周,同时每周腹腔注射15 mg/kg异丙肾上腺素1次。记录各组大鼠的呼吸、皮毛颜色、活动、体重、力竭游泳时间、心率（HR）、平均动脉压（MAP）、左室收缩压（LVSP）、左室舒张末压（LVEDP）、左室内压最大上升速率（+dp/dtmax）,左室内压最大下降速率（-dp/dtmax）,检测血清白介素-6（IL-6）及肿瘤坏死因子-α（TNF-α）水平,评价抗氧化活性和心室质量指数,光镜下观察心肌组织形态变化。结果：与正常组比较,模型大鼠体重增长减慢,力竭游泳时间明显缩短,心脏功能减弱,出现细胞因子激活、自由基损伤、心肌酶释放增多,HE染色显示心肌组织形态出现损伤,心肌纤维断裂等。与模型组比较,各剂量LXD对模型大鼠有不同程度的治疗作用,给药第42天,LXD各剂量组体重明显增长;LXD高、中剂量组力竭游泳时间明显延长（P<0.05）,MAP、血清IL-6、TNF-α、MDA、LVMI和RVMI显著降低（P<0.05,P<0.01）,LVSP、+dp/dtmax及-dp/dtmax均显著升高（P<0.05,P<0.01）,LXD高剂量组LVEDP显著降低（P<0.01）,LXD中、低剂量组CK和AST显著降低（P<0.05,P<0.01）;LXD各剂量组血清SOD升高。结论：敦煌疗风虚瘦弱方对阿霉素诱导的慢性心衰模型大鼠具有一定的治疗作用,作用机制与改善血流动力学,降低心肌组织损伤有关。     

Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure

Previous studies have indicated that there is increased activation of the paraventricular nucleus (PVN) in rats with chronic heart failure (CHF); however, it is not clear if the preautonomic neurons within the PVN are specifically overactive. Also, it is not known if these neurons have altered responses to baroreceptor or osmotic challenges. Experiments were conducted in rats with CHF (6-8 wk after coronary artery ligation). Spontaneously active neurons were recorded in the PVN, of which 36% were antidromically activated from the rostral ventrolateral medulla (RVLM). The baseline discharge rate in RVLM-projecting PVN (PVN-RVLM) neurons from CHF rats was significantly greater than in sham-operated (sham) rats (6.0 ± 0.6 vs. 2.6 ± 0.3 spikes/s, P < 0.05). Picoinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid significantly decreased the basal discharge of PVN-RVLM neurons by 80% in CHF rats compared with 37% in sham rats. Fifty-two percent of spontaneously active PVN-RVLM neurons responded to changes in the mean arterial pressure (MAP). The changes in discharge rate in PVN-RVLM neurons after a reduction in MAP (+52 ± 7% vs. +184 ± 61%) or an increase in MAP (-42 ± 8% vs. -71 ± 6%) were significantly attenuated in rats with CHF compared with sham rats. Most PVN-RVLM neurons (63%), including all barosensitive PVN-RVLM neurons, were excited by an internal carotid artery injection of hypertonic NaCl (2.1 osmol/l), whereas a smaller number (7%) were inhibited. The increase in discharge rate in PVN-RVLM neurons to hypertonic stimulation was significantly enhanced in rats with CHF compared with sham rats (134 ± 15% vs. 92 ± 13%). Taken together, these data suggest that PVN-RVLM neurons are more active under basal conditions and this overactivation is mediated by an enhanced glutamatergic tone in rats with CHF. Furthermore, this enhanced activation of PVN-RVLM neurons may contribute to the altered responses to baroreceptor and osmotic challenges observed during CHF.     

Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure

Angiotensin-converting enzyme (ACE) inhibitors represent the front-line pharmacological treatment of heart failure, which is characterized by left ventricular (LV) dilatation and inappropriate hypertrophy. The mechanism of action of ACE inhibitors is still unclear, but evidence suggests that they may act by influencing matrix metalloproteinase (MMP) activity. This study sought to determine whether ACE inhibitors can directly regulate MMP activity and whether this results in positive structural and functional adaptations to the heart. To this end, MMP-2 activity in LV tissue extracted from rats with an aortocaval (AV) fistula was assessed by in vitro incubation as well as in vivo treatment with captopril, lisinopril, or quinapril. Furthermore, LV size and function were determined in untreated AV fistula rats, AV fistula rats treated with lisinopril (3, 5, and 8 wk), and age-matched sham-operated controls. In vitro incubation with captopril, lisinopril, or quinapril significantly reduced MMP-2 activity, as did in vivo treatment. This occurred without a reduction in the available pool of MMP-2 protein. Long-term in vivo administration of lisinopril also prevented LV dilatation, attenuated myocardial hypertrophy, and prevented changes in myocardial compliance and contractility. The results herein demonstrate that ACE inhibitors prevent MMP-2 activity and, in so doing, represent a mechanism responsible for preventing the negative structural and functional changes that occur in the rat AV fistula model of heart failure.     

Role of nitric oxide in mediating cardiovascular alterations accompanying heart failure in rats

The present study was designed to evaluate the role of endothelial NO in the hemodynamics and vascular changes that occur in heart failure following myocardial infarction in rats. Left ventricular systolic pressure (LVSP), mean blood pressure (MBP), aortic morphology (media thickness) and reactivity were evaluated in rats with coronary artery ligation (heart failure, HF) or sham operation (SO) untreated or treated for four weeks with either a low dose of NG-nitro-L-arginine methyl ester (L-NAME, 6 mg.kg(-1).day(-1)) or L-arginine (1.5 g.kg(-1).day(-1)). In rats with HF LVSP (HF = 111 +/- 8 mmHg; SO = 143 +/- 6 mmHg, p < 0.05), MBP (HF = 98 +/- 8 mmHg; SO = 127 +/- 6 mmHg, p < 0.05) and aortic media thickness (HF = 68 +/- 6 microm; SO = 75 +/- 2 microm, p < 0.05) were significantly reduced. The contractile response to phenylephrine and the endothelium-independent relaxation to sodium nitroprusside were similar in HF and SO aortas, but the sensitivity (pD2) to acetylcholine (HF = 7.5 +/- 0.06; SO = 7.1 +/- 0.08, p < 0.05) was significantly increased in HF aortas, indicating an enhanced basal NO release. Treatment with L-NAME (LN) reversed the effects of HF on LVSP (HF-LN = 143 +/- 9 mmHg, p < 0.05 vs. HF), MBP (HF-LN = 128 +/- 8 mmHg, p < 0.05 vs. HF), sensitivity to acetylcholine (HF-LN = 6.9 +/- 0.10, p < 0.05 vs. HF) and aortic media thickness (HF-LN = 79 +/- 2 microm, p < 0.05 vs. HF), without changing these parameters in SO rats. L-NAME also selectively increased the maximal response to phenylephrine in HF aortas (HF-LN = 2.4 +/- 0.20 g; HF = 1.6 +/- 0.17 g, p < 0.05). L-arginine (LA) did not change the effects of HF on LSVP, MBP or aortic media thickness, but it reduced the sensitivity to phenylephrine in aortas from SO rats (SO-LA = 6.5 +/- 0.12; SO = 7.0 +/- 0.09, p < 0.05). Taken together, these results suggest an important role for endothelial NO in mediating the reduced vascular growth, myocardial dysfunction and hypotension in rats with HF.     

Increased renal ENaC subunits and sodium retention in rats with chronic heart failure

The goal of this study was to examine acute morphological changes, edema, muscle damage, inflammation, and hypoxia in urethral and vaginal tissues with increasing duration of vaginal distension (VD) in a rat model. Twenty-nine virgin Sprague-Dawley rats underwent VD under anesthesia with the use of a modified Foley catheter inserted into the vagina and filled with saline for 0, 1, 4, or 6 h. Control animals were anesthetized for 4 h without catheter placement. Urogenital organs were harvested after intracardiac perfusion of fixative. Tissues were embedded, sectioned, and stained with Masson's trichrome or hematoxylin and eosin stains. Regions of hypoxia were measured by hypoxyprobe-1 immunohistochemistry. Within 1 h of VD, the urethra became vertically elongated and displaced anteriorly. Edema was most prominent in the external urethral sphincter (EUS) and urethral/vaginal septum within 4 h of VD, while muscle disruption and fragmentation of the EUS occurred after 6 h. Inflammatory damage was characterized by the presence of polymorphonuclear leukocytes in vessels and tissues after 4 h of VD, with the greatest degree of infiltration occurring in the EUS. Hypoxia localized mostly to the vaginal lamina propria, urethral smooth muscle, and EUS within 4 h of VD. Increasing duration of VD caused progressively greater tissue edema, muscle damage, and morphological changes in the urethra and vagina. The EUS underwent the greatest insult, demonstrating its vulnerability to childbirth injury.     

Impaired capillary hemodynamics in skeletal muscle of rats in chronic heart failure.

Skeletal muscle blood flow is reduced and O(2) extraction is increased at rest in chronic heart failure (CHF). Knowledge of red blood cell (RBC) flow distribution within the capillary network is necessary for modeling O(2) delivery and exchange in this disease. Intravital microscopy techniques were used to study the in vivo spinotrapezius muscle microcirculation in rats with CHF 7 wk after myocardial infarction and in sham-operated controls (sham). A decrease in mean muscle fiber width from 51.3 +/- 1.9 microm in sham to 42.6 +/- 1.4 microm in CHF rats (P < 0.01) resulted in an increased lineal density of capillaries in CHF rats (P < 0.05). CHF reduced (P < 0.05) the percentage of capillaries supporting continuous RBC flow from 87 +/- 5 to 66 +/- 5%, such that the lineal density of capillaries supporting continuous RBC flow remained unchanged. The percentage of capillaries supporting intermittent RBC flow was increased in CHF rats (8 and 27% in sham and CHF, respectively, P < 0.01); however, these capillaries contributed only 2.3 and 3.3% of the total RBC flux in sham and CHF rats, respectively. In continuously RBC-perfused capillaries, RBC velocity (252 +/- 20 and 144 +/- 9 microm/s in sham and CHF, respectively, P < 0.001) and flux (21.4 +/- 2.4 and 9.4 +/- 1.1 cells/s in sham and CHF, respectively, P < 0.01) were markedly reduced in CHF compared with sham rats. Capillary "tube" hematocrit remained unchanged (0.22 +/- 0.02 and 0.19 +/- 0.02 in sham and CHF, respectively, P > 0.05). We conclude that CHF causes spinotrapezius fiber atrophy and reduces the number of capillaries supporting continuous RBC flow per fiber. Within these capillaries supporting continuous RBC flow, RBC velocity and flux are reduced 45-55%. This decreases the potential for O(2) delivery but enhances fractional O(2) extraction by elevating RBC capillary residence time. The unchanged capillary tube hematocrit suggests that any alterations in muscle O(2) diffusing properties in CHF are mediated distal to the RBC.     

A model of chronic heart failure in spontaneous hypertensive rats (SHR)

Common models of chronic heart failure (CHF) do not always result in parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The aim of this study was to establish and validate a new model of CHF in the rat. CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive (SHR/NHsd) rats by creating a permanent (8-week) occlusion of the left coronary artery 2 mm distal to the origin from the aorta by a modified technique. This resulted in a large infarction of the free left ventricular wall. The focus of attention was the validation of the geometric properties of the left ventricle and its contractility. The validation of the geometric properties of the left ventricle was done by a non-invasive magnetic resonance imaging (MRI) technique and by planimetry (stereology). Cardiodynamics (e.g. contractility) were evaluated in the isolated 'working heart' model. We were able to establish a new and predictive model of heart failure in the spontaneously hypertensive rat 8 weeks after coronary artery ligation. At this time point, the WKY rat did not show any symptoms of CHF. The model represents characteristic parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of congestive heart failure were prominent, such as dyspnoea, subcutaneous oedema, pale-bluish limbs and impaired motion. Non-invasive sequential measurements by NMR techniques showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. The infarcted animals showed a reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd rat than in the WKY/NHsd rat. Furthermore the infarcted animals showed enhanced levels of hydroxyproline/proline ratios, again much more so in the SHR/NHsd rat than in the WKY/NHsd rat.     

Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands

Aims

Data from patient registries give insight into the management of patients with heart failure (HF), but actual data from unselected real-world HF patients are scarce. Therefore, we performed a cross sectional study of current HF care in the period 2013–2016 among more than 10,000 unselected HF patients at HF outpatient clinics in the Netherlands.

Methods

In 34 participating centres, all 10,910 patients with chronic HF treated at cardiology centres were included in the CHECK-HF registry. Of these, most (96%) were managed at a specific HF outpatient clinic. Heart failure was typically diagnosed according to the ESC guidelines 2012, based on signs, symptoms and structural and/or functional cardiac abnormalities. Information on diagnostics, treatment and co-morbidities were recorded, with specific focus on drug therapy and devices. In our cohort, the mean age was 73 years (SD 12) and 60% were male. Frequent co-morbidities reported in the patient records were diabetes mellitus 30%, hypertension 43%, COPD 19%, and renal insufficiency 58%. In 47% of the patients, ischaemia was the origin of HF. In our registry, the prevalence of HF with preserved ejection fraction was 21%.

Conclusion

The CHECK-HF registry will provide insight into the current, real world management of patient with chronic HF, including HF with reduced ejection fraction, preserved ejection fraction and mid-range ejection fraction, that will help define ways to improve quality of care. Drug and device therapy and guideline adherence as well as interactions with age, gender and co-morbidities will receive specific attention.

     

Changes in the pro-inflammatory cytokine production and peritoneal macrophage function in rats with chronic heart failure

Chronic heart failure (CHF) is a state of immune activation, and pro-inflammatory cytokines play an important role in its development and progression. Macrophages (Mphis), when activated, are the main source of pro-inflammatory cytokines. We measured interleukin-6 (IL-6), interleukin (IL-1beta) and tumor necrosis factor - alpha (TNF-alpha) production after lipopolysaccharide (LPS)-stimulation, as well as peritoneal Mphis migration, phagocytic capacity, chemotaxis index, and hydrogen peroxide production, in an attempt to clarify the role of this cell in an animal model of CHF. Ligature of the left coronary artery or sham operation was performed in adult Wistar rats. After 12 weeks, resident and total cell number, phagocytic capacity, chemotaxis index, and hydrogen peroxide production in Mphis were significantly higher in CHF than in control rats. The production of IL-6 and TNF- alpha was similarly significantly enhanced in CHF as compared with controls. Mphis obtained from CHF rats were more responsive to LPS, suggesting the existence, in vivo, of possible factor(s) modulating the production of pro-inflammatory cytokines. The results demonstrated that there is modification of peritoneal Mphis function along CHF development, possibly contributing to the pathophysiological process in the establishment of CHF.     

The features of mitochondria of cardiomyocytes from rats with chronic heart failure

Electron-microscopy study of rat myocardium 2 weeks after a heart attack revealed significant alterations in the ultrastructure of cardiomyocytes than for the control. The location of myofibrils was less regular than for normal cells. The population of interfibrillar mitochondria decreased. Mitochondrial cristae were located less densely and formed cellated structures. Swollen mitochondria were observed in the periinfarction and intact areas, indicating the development of ischemia in the myocardium as a whole. Six months after the occlusion of coronary vessels alterations in the location of myofibrils and mitochondria were mainly observed in the peri-infarction area. Mitochondria also formed cellated structures. A 30% decrease in the density of the arrangement of the inner membranes of mitochondria on an area unit was found in the periinfarction zone. The ratio between the relative volumes of mitochondria and myofibrils in the cardiomyocytes of the peri-infarction area was increased by 20%. The area of mitochondria in the intact zone of the left ventricle was 30% greater than for the control. A study of isolated living cardiomyocytes revealed that the mitochondrial- membrane potential in the rats subjected to myocardial infarction half a year ago previously was significantly lower than for the mitochondrial-membrane potential in the control rats. Thus, cardiomyocytes that were similar to healthy cardiomyocytes in their morphology exhibited lower total mitochondrial-membrane potential, indicating their decreased energy state.     

Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice.

Accumulation of oxidized extracellular matrix between endothelium and muscle is an important risk factor in the endothelium-myocytes uncoupling in congestive heart failure. Although ventricular remodeling is accompanied by increased matrix metalloproteinase (MMP)-9 activity, it is unclear whether MMP-9 plays a role in endothelial apoptosis in chronic volume overload congestive heart failure. We tested the hypothesis that, in chronic volume overload, myocardial dysfunction involves endocardial endothelial (EE) apoptosis in response to MMP-9 activation, extracellular matrix accumulation, and endothelium-myocytes uncoupling. Arteriovenous fistula (AVF) was created in control (FVB/NJ) and MMP-9 knockout (MMP-9KO; FVB.Cg-MMP9(tm1Tvu)/J) mice. Sham surgery was used as control. Mice were grouped as follows: wild type, n = 3 (sham control); MMP-9KO, n = 3 (sham); AVF, n = 3; and MMP-9KO + AVF (n = 3). Heart function was analyzed by M-mode and Doppler echocardiography, and with a pressure-tipped Millar catheter placed in the left ventricle of anesthetized mice 8 wk after AVF. Apoptosis was detected by measuring caspase-3, transferase-mediated dUTP nick-end labeling (TUNEL), and CD-31 by immunolabeling. Protease-activated receptors-1, connexin-43, and a disintegrin and MMP-12 (ADAM-12) expression were measured by Western blot analyses. MMP-2 and MMP-9 expression were measured by quantitative RT-PCR. Compared with control, AVF caused an increase in left ventricle end diastolic pressure and decrease in -dP/dt. In contrast, in the MMP-9KO + AVF group, these variables were changed toward control levels. Increased EE apoptosis (caspase-3 activation and TUNEL/CD-31 colabeling) in AVF mice was prevented in the MMP-9KO + AVF group. Protease-activated receptor-1, connexin-43, and ADAM-12 were induced in AVF. MMP-9 gene ablation ameliorated the induction. The results suggest that impaired cardiac function in volume overload is associated with EE apoptosis, cardiac remodeling, and endothelium-myocytes uncoupling in response to MMP-9 activation.     

Neurohumoral changes in chronic heart failure

Background: Humoral systems play an important role in the patophysiology and development of chronic heart failure (CHF). Methods: We conducted a search of neurohumoral activation in heart failure and its risk in the development of CHF. Results and conclusion: Neurohumoral factors may be divided into vasoconstrictive, vasodilative and cytokines. The main vasoconstrictive systems are the renin-angiotensin-aldosterone system (RAAS) and the sympathoadrenal system (SAS). Cytokines include tumour necrosis factor (TNF) alpha and interleukins. The systems of actions are interconnected and they mutually influence their secretion and activities. The possibilities of their detection and assessment for clinical purposes depend on their changes and kinetics in the organism and on the activity of individual metabolites. Apart from their vasoactive effects, the majority of humoral actions also interfere in the process of remodelling, function of the endothelium, blood elements, cardiomyocytes, cells of the smooth muscles, and in immunity as well as inflammatory processes. The rapid development of knowledge on the humoral actions in recent years has made possible their utilisation in diagnostics, treatment and prognosis.     

Role of endothelins in congestive heart failure

Despite major advances in conventional medical therapy, patients with heart failure continue to experience significant morbidity and mortality. Endothelin-1 (ET-1) is a potent vasocontrictor and mitogenic peptide that is activated in heart failure. There is increasing experimental and clinical evidence in support of an important role of ET-1 in the pathophysiology of heart failure. Manipulation of the activity of ET-1, especially using endothelin receptor blockers, has allowed for the further elucidation of the role of this neurohormonal system and development of novel therapeutic strategies in heart failure. Published clinical studies of these agents to date have involved relatively small numbers of patients with severe heart failure, followed for a relatively short period of time, and have mainly examined surrogate endpoints. Large-scale trials that address to hard clinical outcomes are ongoing and their results forthcoming. A key question that remains concerns whether selective ETA or dual ETA-ETB receptor blockade will be more effective.