Related Articles

Aims

Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase-derived superoxide mediates angiotensin II (Ang II)-enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II- and CHF-enhanced superoxide anion effect. Here we investigated the role of cytoplasmic SOD [CuZn superoxide dismutase (CuZnSOD)] in the CB on chemoreceptor activity and function in CHF rabbits.

Methods and results

CuZnSOD protein expression was decreased in CBs from CHF rabbits vs. sham (P < 0.05). Adenoviral CuZnSOD (Ad CuZnSOD) gene transfer to the CBs increased CuZnSOD protein expression and significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits (P < 0.05). Single-fibre discharge from CB chemoafferents during normoxia (baseline, at ∼100 mmHg PO2) and in response to hypoxia were enhanced in CHF vs. sham rabbits (P < 0.05). Ad CuZnSOD decreased the baseline discharge (7.6 ± 1.3 vs. 12.6 ± 1.7 imp/s at ∼100 mmHg PO2) and the response to hypoxia (22.4 ± 1.6 vs. 32.3 ± 1.2 imp/s at ∼40 mmHg PO2, P < 0.05) in CHF rabbits. Ad CuZnSOD also normalized the blunted outward K+ current (IK) in CB glomus cells from CHF rabbits (369 ± 14 vs. 565 ± 31 pA/pF at +70 mV, P < 0.05). In addition, Ad CuZnSOD reduced the elevation of superoxide level in CBs from CHF rabbits.

Conclusion

Downregulation of CuZnSOD in the CB contributes to the enhanced activity of CB chemoreceptors and chemoreflex function in CHF rabbits.

Increasing renal pelvic pressure results in PGE2-mediated release of substance P leading to increases in afferent renal nerve activity (ARNA) and natriuresis: renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether an ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF vs. Sham-CHF rats. In CHF, increasing renal pelvic pressure 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12±3% and 21±3% (P<0.05 vs vehicle). In isolated renal pelvises from CHF, PGE2 increased substance P release from 5±0 to 7±1 pg/min without and from 4±1 to 9±1 pg/min with BQ123 in the bath(P<0.01 vs vehicle). BQ123 had no effect on the ARNA responses or substance P release in Sham-CHF. Conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.

Background

Cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation and angiotensin II (Ang II) in paraventricular nucleus (PVN) augments the CSAR in vagotomized (VT) and baroreceptor denervated (BD) rats with chronic heart failure (CHF). This study was designed to determine whether it is true in intact (INT) rats with CHF and to determine the effects of cardiac and baroreceptor afferents on the CSAR and sympathetic activity in CHF.

Methodology/Principal Findings

Sham-operated (Sham) or coronary ligation-induced CHF rats were respectively subjected to BD+VT, VT, cardiac sympathetic denervation (CSD) or INT. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded, and the CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Either CSAR or the responses of RSNA, MAP and CSAR to Ang II in PVN were enhanced in CHF rats treated with BD+VT, VT or INT. Treatment with VT or BD+VT potentiated the CSAR and the CSAR responses to Ang II in both Sham and CHF rats. Treatment with CSD reversed the capsaicin-induced RSNA and MAP changes and the CSAR responses to Ang II in both Sham and CHF rats, and reduced the RSNA and MAP responses to Ang II only in CHF rats.

Conclusions

The CSAR and the CSAR responses to Ang II in PVN are enhanced in intact CHF rats. Baroreceptor and vagal afferent activities inhibit CSAR and the CSAR responses to Ang II in intact Sham and CHF rats.

Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (bpm/mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals; control, one week CHF, two week CHF and three week CHF. CHF was induced by ventricular pacing at 360 bpm and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening and an increase in LVESD & LVEDD was observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA(% of maximum) after 1 week of pacing, a small but insignificant rise in RSNA was seen at 2 weeks and a significant rise in RSNA was observed at 3 weeks. AT1 receptor protein (Western Blot) and mRNA (RT-PCR) expression in the rostral ventrolateral medulla (RVLM) exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympatho-excitation and over-expression of AT1 receptors with the progression of CHF causing further impairment of cardiovascular control.

Objective:

A previous study from this laboratory showed that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin II type 1 (AT1) receptor in the carotid body (CB) are involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang II in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang II in CHF rabbits.

Methods and results:

By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 μM (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (Δ-12.5 ± 0.8 and Δ-12.8 ± 0.9 imp/s at 40.7 ± 2.3 mm Hg of PO2, and Δ-5.6 ± 0.5 and Δ-5.3 ± 0.4 imp/s at 60.2 ± 3.1 mm Hg of PO2, p<0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (Δ-13.6 ± 1.1 and Δ-13.7 ± 0.9 imp/s at 40.9 ± 3.1 mm Hg of PO2, and Δ-6.7 ± 1.2 and Δ-6.6 ± 0.8 imp/s at 59.8 ± 3.5 mm Hg of PO2, p<0.05). In addition, mRNA and protein expressions of NADPH oxidase components (gp91phox, p40phox and p47phox) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhanced superoxide anion production.

Conclusions:

These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang II in CHF rabbits occurs via a NADPH oxidase-superoxide signaling pathway.

Chronic congestive heart failure (CHF) was induced in dogs by the construction of an aorto-caval fistula below the level of the renal arteries. Aorto-caval fistula dogs showed signs of CHF which included ascites, hind limb edema, and pulmonary congestion. Ventricular catheterization indicated a significantly higher left ventricular end diastolic pressure and lower maximum velocity of left ventricular pressure development/left ventricular end diastolic pressure in CHF dogs when compared to sham-operated controls. Heart weight/body weight ratios were significantly higher in CHF dogs. Electrophysiological recordings from medullated left atrial type B receptors from the cervical vagus indicated a depressed sensitivity of these receptors in CHF dogs when compared to sham-operated control dogs. For any given change in left atrial pressure, the discharge of left atrial receptors was significantly reduced in CHF dogs compared with sham-operated controls. The mechanism for this depressed sensitivity was investigated. Sonomicrometry of the left atrial appendage indicated a decreased compliance of the left atrial appendage in the dogs with chronic CHF. In addition, microscope examination of the complex unencapsulated receptor endings taken from the left atrial endocardium indicated a marked alteration in receptor morphology. A loss of the end arborization was the most typical finding. It is concluded that chronic CHF brought about by an aorto-caval fistula results in a depressed left atrial stretch receptor response and that both decreased left atrial compliance and structural alterations in the receptor endings may account for this depressed sensitivity.

Images

The carotid body (CB) plays an important role in the control of breathing and in autonomic control of cardiovascular function. CB chemoreceptor activity is enhanced in chronic heat failure (CHF) and contributes to the sympathetic hyperactivity that exacerbates the progression of the disease. Studies in the past few years have revealed that a local angiotensin (Ang) system exists in the CB and plays an important role in altering CB function in CHF as well as other conditions, such as chronic hypoxia. This brief review highlights recent revelations that Ang I metabolites exert effects within the CB, and focuses on the influence of Ang II and Ang-(1–7) on CB function in CHF.

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2) and wild type littermates (WT) were used. CHF was induced by permanent coronary artery ligation (CAL). Four weeks after CAL, both WT and SYN-hACE2 mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in MAP was found only in SYN-hACE2 mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline RSNA (WT CHF: 71.6±7.6% Max vs. SYN-hACE2 CHF: 49.3±6.1% Max); and enhanced baroreflex sensitivity (Maximum Slope: WT Sham: 1.61±0.16 vs. SYN-hACE2 CHF: 1.51±0.17%/mmHg). Chronic subcutaneous blockade of mas receptor increased RSNA in SYN-hACE2 mice with CHF (A779: 67.3±5.8% vs. vehicle: 46.4±3.6% of Max). An up-regulation in angiotensin II type 1 receptor (AT1R) expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SYN-hACE2 mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling as well as a decrease in AT1R signaling in the medulla.

In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of Angiotensin II (Ang II), Ang-(1–7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1–7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1–7) on baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF. We hypothesized that central Ang-(1–7) would improve baroreflex function in CHF. Ang-(1–7) (2 nmol/1 μl/hour) or artificial cerebrospinal fluid (1 μl/hour) was infused by an osmotic mini-pump for 4 days in sham and pacing-induced CHF rabbits (n=3–6/group). Ang-(1–7) treatment had no effects in sham rabbits but reduced HR and increased baroreflex gain (7.4±1.5 bpm/mm Hg vs. 2.5±0.4 bpm/mm Hg, P<0.05) in CHF rabbits. The Ang-(1–7) antagonist A779 (8 nmol/1 μl/hr) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1–7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline RSNA was significantly lower and baroreflex control of RSNA was enhanced in CHF rabbits receiving Ang-(1–7). These data suggest that augmentation of central Ang-(1–7) inhibits sympathetic outflow and increases vagal outflow in CHF thus contributing to enhanced baroreflex gain in this disease state.

Congestive heart failure (CHF) is associated with neurohumoral activation. Only very few studies have examined the progression of autonomic dysfunction in CHF in humans and scanty data are available in animal models of CHF. This study was performed to assess the changes in cardiac autonomic modulation during the progression of CHF in a rat model, using an innovative analysis of heart rate variability. Progression of cardiovascular autonomic dysfunction was assessed in a rat model of CHF induced by coronary artery ligation. Spectral and symbolic analyses were performed on heart period (approximated with pulse interval, PI) and systolic arterial pressure (SAP) signals, acquired ~2 and ~4 weeks after the surgical procedure. As CHF developed, symbolic analysis revealed a decrease of rhythmical physiological sympathetic modulation, as indicated by the reduction of the percentage of stable patterns. In addition, symbolic analysis revealed that runs of short-long-short and/or long-short-long PI values and high-low-high and/or low-high-low SAP values were more and more frequent as CHF progressed. On the contrary, spectral analysis of PI and SAP series was not able to detect any impairment of autonomic regulation. Indeed, low frequency and high frequency powers derived from both PI and SAP series were not significantly changed. These data indicate that the autonomic cardiovascular modulation is altered during the progression of CHF and that symbolic analysis seems to be more suitable than spectral analysis to describe alterations of heart period dynamics and of cardiovascular regulation in this animal model of CHF.

Chronic heart failure (CHF) is characterized by increased sympathetic tone. The glutamatergic input in the rostral ventrolateral medulla (RVLM), which is a key region involved in sympathetic outflow, seems not to be involved in the generation of sympathetic tone in the normal state. The aim of this study was to determine the role of the RVLM glutamate receptors in generation of sympathetic tone in CHF. CHF was produced by left coronary artery ligation. Bilateral microinjection of the glutamate receptor antagonist kynurenic acid (KYN), the N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5, or the non-NMDA receptor antagonist CNQX into the RVLM dose-dependently reduced resting blood pressure and renal sympathetic nerve activity in CHF but not in sham rats. Picoinjection of KYN (100 pmol in 5 nl) significantly decreased the basal discharge by 47% in 25 RVLM presympathetic neurons in CHF rats, In contrast, KYN had no effect on the discharge in all 22 RVLM presympathetic neurons tested in sham rats. These data suggest that upregulated glutamate receptors, including NMDA and non-NMDA, in the RVLM are involved in tonic control of elevated sympathetic tone in CHF.

Introduction

Fibroblasts are important in the atrial fibrillation (AF) substrate resulting from congestive heart failure (CHF). We previously noted changes in in vivo indices of fibroblast function in a CHF dog model, but could not detect changes in isolated cells. This study assessed CHF-induced changes in the phenotype of fibroblasts freshly isolated from control versus CHF dogs, and examined effects of cell culture on these differences.

Methods/Results

Left-atrial fibroblasts were isolated from control and CHF dogs (ventricular tachypacing 240 bpm×2 weeks). Freshly-isolated fibroblasts were compared to fibroblasts in primary culture. Extracellular-matrix (ECM) gene-expression was assessed by qPCR, protein by Western blot, fibroblast morphology with immunocytochemistry, and K+-current with patch-clamp. Freshly-isolated CHF fibroblasts had increased expression-levels of collagen-1 (10-fold), collagen-3 (5-fold), and fibronectin-1 (3-fold) vs. control, along with increased cell diameter (13.4±0.4 µm vs control 8.4±0.3 µm) and cell spreading (shape factor 0.81±0.02 vs. control 0.87±0.02), consistent with an activated phenotype. Freshly-isolated control fibroblasts displayed robust tetraethylammonium (TEA)-sensitive K+-currents that were strongly downregulated in CHF. The TEA-sensitive K+-current differences between control and CHF fibroblasts were attenuated after 2-day culture and eliminated after 7 days. Similarly, cell-culture eliminated the ECM protein-expression and shape differences between control and CHF fibroblasts.

Conclusions

Freshly-isolated CHF and control atrial fibroblasts display distinct ECM-gene and morphological differences consistent with in vivo pathology. Culture for as little as 48 hours activates fibroblasts and obscures the effects of CHF. These results demonstrate potentially-important atrial-fibroblast phenotype changes in CHF and emphasize the need for caution in relating properties of cultured fibroblasts to in vivo systems.

Abnormalities of myocardial sympathetic nerve function were reported in congestive heart failure (CHF). To assess myocardial sympathetic nerve function, we obtained metaiodobenzylguanidine (MIBG) images 15 min and 180 min after the injection of iodine-123 MIBG at a dose of 111 MBq and calculated the ratio of heart to mediastinum count (H/M) and the washout rates (WRs) in 59 consecutive patients with CHF and age-matched subjects without CHF (n=23). The plasma levels of B-type natriuretic peptide were measured. H/M ratio was significantly lower in the CHF group (1.8±0.9) than in the control group (2.6±0.4; P<0.01). WR was higher in the CHF group (38±4%) than in the control group (28±3%; P<0.01). H/M was inversely correlated with the plasma B-type natriuretic peptide (r=−0.46, P<0.05). Eighteen patients suffered cardiac events (two deaths, 16 hospitalizations) during a mean follow-up period of three years. Kaplan-Meier analysis showed that a low H/M was associated with a poor prognosis in patients with CHF. These findings indicate that the H/M ratio on MIBG imaging is a useful predictor of mortality and morbidity in patients with CHF.

Introduction

Risk stratification in congestive heart failure (CHF) patients is based on a variety of clinical and laboratory variables. We analysed renal function, BNP, water composition, echocardiographic and functional determinations in predicting mid-term outcome in CHF patients discharged after decompensation.

Material and methods

All subjects with NYHA class II-IV were enrolled at hospital discharge. NYHA class, BNP, water body composition, non-invasive cardiac output and echocardiogram were analysed. Death, cardiac transplantation and hospital readmission for CHF were scheduled.

Results

Two-hundred and thirty-seven (64.5% males, age 71.1±10.1) patients were discharged after obtaining normal hydration; left ventricular ejection fraction (LVEF) was 43.2±16.2%, cardiac output was 3.8±1.1 l/min and BNP at discharge resulted 401.3±501.7 pg/ml. During the 14-month follow-up 15 patients (6.3%) died, 1 (0.4%) underwent cardiac transplantation and 18 (7.6%) were readmitted for CHF (event group); in 203 (85.6%) no events were observed (no-event group). Higher NYHA class (2.1±0.7 vs. 1.9±0.4, p=0.01), BNP at discharge (750.2±527.3 pg/ml vs. 340.7±474.3 pg/ml, p=0.002) and impaired LVEF (33.7±15.7% vs. 44.5±15.8%, p=0.0001) and creatinine (1.7±0.6 vs. 1.2±0.8 mg/dl, p=0.004) were noticed in the event group. At multivariate Cox analysis LVEF (p=0.0009), plasma creatinine (p=0.006) and BNP at discharge (p=0.001) were associated with adverse mid-term outcome. Kaplan-Meier survival curves demonstrated that adding cut-off points for creatinine 1.5 mg/dl and discharged BNP of 250 pg/ml discriminated significantly prognosis (p=0.0001; log rank 21.09).

Conclusions

In predicting mid-term clinical prognosis in CHF patients discharged after acute decompensation, BNP at discharge ≥ 250 pg/ml added with plasma creatinine > 1.5 mg/dl are strong adverse predictors.

The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF.

We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.

Patients with chronic heart failure (CHF) have a significantly lower peak aerobic capacity compared to healthy subjects, and, may therefore experience more inconvenience during the performance of domestic activities of daily life (ADLs). To date, the extent to which task-related oxygen uptake, heart rate, ventilation and symptoms during the performance of ADLs in CHF patients is different than in healthy subjects remains uncertain. General demographics, pulmonary function, body composition and peak aerobic capacity were assessed in 23 CHF outpatients and 20 healthy peers. In addition, the metabolic requirement of five simple self-paced domestic ADLs was assessed using a mobile oxycon. Task-related oxygen uptake (ml/min) was similar or lower in CHF patients compared to healthy subjects. In contrast, patients with CHF performing ADLs consumed oxygen at a higher proportion of their peak aerobic capacity than healthy subjects (p < 0.05). For example, getting dressed resulted in a mean task-related oxygen uptake of 49% of peak aerobic capacity, while sweeping the floor resulted in a mean task-related oxygen uptake of 52% of peak aerobic capacity, accompanied by significantly higher Borg symptom scores for dyspnea and fatigue (p < 0.05). Patients with CHF experience use a higher proportion of their peak aerobic capacity, peak ventilation and peak heart rate during the performance of simple self-paced domestic ADL than their healthy peers. These findings represent a necessary step in improving our understanding of improving what troubles patients the most—not being able to do the things that they could when they were healthy.

Cardiovascular disease (CVD) remains the single leading cause of death in both men and women. A large proportion of the population with CVD will die with a diagnosis of congestive heart failure (CHF). It is becoming increasingly recognized that sex differences exist in the etiology, development, and outcome of CHF. For example, compared to male counterparts, women that present with CHF are typically older and have systolic cardiac function that is not impaired. Despite a growing body of literature addressing the underlying mechanisms of sex dimorphisms in cardiac disease, there remain significant inconsistencies reported in these studies. Given that the development of CHF results from the complex integration of genetic and nongenetic cues, it is not surprising that the elucidation and subsequent identification of molecular mechanisms remains unclear. In this review, key aspects of sex differences in CVD and CHF will be highlighted with an emphasis on some of the unanswered questions regarding these differences. The contention is presented that it becomes critical to reference cellular mechanisms within the context of each sex to better understand these sex dimorphisms.

Our previous study demonstrated that oral treatment with simvastatin (SIM) suppressed renal sympathetic nerve activity (RSNA) in the rabbits with chronic heart failure (CHF). The purpose of this experiment was to determine the effects of direct application of SIM to the central nervous system on RSNA and its relevant mechanisms. Experiments were carried out on 21 male New Zealand White rabbits with pacing induced CHF. The CHF rabbits received infusion of vehicle, SIM, or SIM + L-NAME into the lateral cerebral ventricle via osmotic minipump for 7 days. We found that, (1) In CHF rabbits, icv infusion of SIM significantly suppressed basal RSNA (1st day 69.5 ± 8.9 % of Max; 7th day 26.0 ± 6.0 % of Max. P < 0.05, n = 7) and enhanced arterial baroreflex function starting from the 2nd day and lasting through the following 5 days; (2) Statin treatment significantly upregulated nNOS protein expression in the rostral ventrolateral medulla (RVLM) (Control, n = 6, 0.12 ± 0.04; SIM treated, n = 7, 0.31 ± 0.05. P < 0.05); (3) In CATH.a neurons, incubation with SIM significantly upregulated the nNOS mRNA expression, which was blocked by co-incubation with Mevalonate, farnesyl-pyrophosphate, or geranylgeranyl-pyrophosphate; (4) Incubation with Y-27632 significantly upregulated nNOS mRNA expression in these neurons. These results suggest that central treatment with SIM decreased sympathetic outflow in CHF rabbits via up regulation of nNOS expression in RVLM, which may be due to the inhibition of HMG-CoA reductase and a decrease in Rho Kinase by SIM.

Background

Intracerebroventricular infusion of NaHS, a hydrogen sulfide (H2S) donor, increased mean arterial pressure (MAP). This study was designed to determine the roles of H2S in the paraventricular nucleus (PVN) in modulating sympathetic activity and cardiac sympathetic afferent reflex (CSAR) in chronic heart failure (CHF).

Methodology/Principal Findings

CHF was induced by left descending coronary artery ligation in rats. Renal sympathetic nerve activity (RSNA) and MAP were recorded under anesthesia. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. PVN microinjection of low doses of a H2S donor, GYY4137 (0.01 and 0.1 nmol), had no significant effects on RSNA, MAP and CSAR. High doses of GYY4137 (1, 2 and 4 nmol) increased baseline RSNA, MAP and heart rate (HR), and enhanced CSAR. The effects were greater in CHF rats than sham-operated rats. A cystathionine-β-synthase (CBS) inhibitor, hydroxylamine (HA) in PVN had no significant effect on the RSNA, MAP and CSAR. CBS activity and H2S level in the PVN were decreased in CHF rats. No significant difference in CBS level in PVN was found between sham-operated rats and CHF rats. Stimulation of cardiac sympathetic afferents with capsaicin decreased CBS activity and H2S level in the PVN in both sham-operated rats and CHF rats.

Conclusions

Exogenous H2S in PVN increases RSNA, MAP and HR, and enhances CSAR. The effects are greater in CHF rats than those in sham-operated rats. Endogenous H2S in PVN is not responsible for the sympathetic activation and enhanced CSAR in CHF rats.

Background

Chronic heart failure (CHF) is a chronic debilitating condition with economic consequences, mostly because of frequent hospitalisations. Physical activity and adequate self-management capacity are important risk reduction strategies in the management of CHF. The Home-Heart-Walk is a self-monitoring intervention. This model of intervention has adapted the 6-minute walk test as a home-based activity that is self-administered and can be used for monitoring physical functional capacity in people with CHF. The aim of the Home-Heart-Walk program is to promote adherence to physical activity recommendations and improving self-management in people with CHF.

Methods/Design

A randomised controlled trial is being conducted in English speaking people with CHF in four hospitals in Sydney, Australia. Individuals diagnosed with CHF, in New York Heart Association Functional Class II or III, with a previous admission to hospital for CHF are eligible to participate. Based on a previous CHF study and a loss to follow-up of 10%, 166 participants are required to be able to detect a 12-point difference in the study primary endpoint (SF-36 physical function domain).

All enrolled participant receive an information session with a cardiovascular nurse. This information session covers key self-management components of CHF: daily weight; diet (salt reduction); medication adherence; and physical activity. Participants are randomised to either intervention or control group through the study randomisation centre after baseline questionnaires and assessment are completed. For people in the intervention group, the research nurse also explains the weekly Home-Heart-Walk protocol. All participants receive monthly phone calls from a research coordinator for six months, and outcome measures are conducted at one, three and six months. The primary outcome of the trial is the physical functioning domain of quality of life, measured by the physical functioning subscale of the Medical Outcome Study Short Form -36. Secondary outcomes include physical functional capacity measured by the standard six minute walk test, self-management capacity, health related quality of life measured by Medical Outcome Study Short Form -36 and Minnesota Living With Heart Failure Questionnaire, self-efficacy and self-care behaviour.

Discussion

A self-monitoring intervention that can improve individual's exercise self-efficacy, self-management capacity could have potential significance in improving the management of people with chronic heart failure in community settings.

Trial Registration

Australian New Zealand Clinical Trial Registry 12609000437268

The current studies were designed to investigate the functional significance of elevated endogenous atrial natriuretic factor (ANF) in acute congestive heart failure (CHF). Integrated cardiorenal and endocrine function were measured in three models of acute low-output congestive heart failure with comparably reduced cardiac output (CO) and mean arterial pressure (MAP). Acute CHF was produced by rapid right ventricular pacing (group I, n = 5) which decreases CO and increases atrial pressures and plasma ANF. In group II, n = 5, thoracic inferior vena caval constriction (TIVCC) was produced to decrease venous return and CO but without increases in atrial pressure or plasma ANF. In group III, n = 5, TIVCC was performed and exogenous ANF infused to achieve plasma concentrations observed in acute CHF. In acute CHF with increases in endogenous ANF, sodium excretion (UNaV), renal blood flow (RBF), plasma renin activity (PRA), and plasma aldosterone (PA) were maintained despite decreases in CO and MAP. In contrast, TIVCC with similar reductions in CO and MAP but without increases in ANF resulted in decreases in UNaV and RBF and increases in PRA and PA. Exogenous administration of ANF in TIVCC to mimic levels in acute CHF prevented sodium retention, renal vasoconstriction, and activation of renin and aldosterone. These studies demonstrate that endogenous ANF serves as an important physiologic volume regulator in acute CHF to maintain sodium excretion and possibly participate in the suppression of activation of the renin-angiotensin-aldosterone system despite the stimulus of arterial hypotension.

Images

Congestive heart failure (CHF) has emerged as a major worldwide epidemic and its main causes seem to be the aging of the population and the survival of patients with post-myocardial infarction. Cardiomyocyte dropout (necrosis and apoptosis) plays a critical role in the progress of CHF; thus treatment of CHF by exogenous cell implantation will be a promising medical approach. In the acute phase of cardiac damage cardiac stem cells (CSCs) within the heart divide symmetrically and/or asymmetrically in response to the change of heart homeostasis, and at the same time homing of bone marrow stem cells (BMCs) to injured area is thought to occur, which not only reconstitutes CSC population to normal levels but also repairs the heart by differentiation into cardiac tissue. So far, basic studies by using potential sources such as BMCs and CSCs to treat animal CHF have shown improved ventricular remodelling and heart function. Recently, however, a few of randomized, double-blind, placebo-controlled clinical trials demonstrated mixed results in heart failure with BMC therapy during acute myocardial infarction.

Background

Congestive heart failure (CHF) is associated with cognitive deficits, particularly of memory and attention. The present study aims to clarify whether clinical treatment can reverse the attentional deficits of patients with CHF.

Methods

A convenience sample of 50 patients with CHF functional class IV and 30 elderly controls were recruited from a teaching hospital in Brazil. Participants received a clinical and cognitive examination that included the Mini-Mental State Examination (MMSE), Cambridge Cognitive Examination of the Elderly (CAMCOG), Digit Span, Digit-Symbol Substitution, and Letter Cancellation test. The cognitive performance of CHF patients was reassessed 6 weeks after the introduction of clinical treatment.

Results

Twenty-seven CHF subjects had MMSE<24, compared to only 10 of the controls (p = 0.07). CHF patients also had lower CAMCOG scores (mean = 71.8) than controls (mean = 82.0; p < 0.01). Digit Span, Digit Symbol and Letter Cancellation scores were lower for patients with CHF than controls (p < 0.01). Similarly patients with CHF took longer to complete the Trail Making A (p = 0.07) and B (p < 0.01). CAMCOG scores and left ventricular ejection fraction were moderately correlated (rho = 0.4, p < 0.01). Nineteen patients were lost for follow-up (11 deceased). Clinical treatment was associated with significant improvement of cognitive scores, particularly on the Digit Symbol (p < 0.01) and Letter Cancellation Tests (p < 0.01). Digit Span, Digit Symbol, Letter Cancellation and Trail Making scores of treated CHF patients and controls were similar (p > 0.10).

Conclusions

CHF is associated with deficits in attention and psychomotor speed. These deficits improve with clinical treatment.

Background. Peripheral arterial disease (PAD) often coexists with congestive heart failure (CHF) and can be masked by symptoms of CHF such as functional limitation (FL), a common manifestation for both. Therefore, we sought to estimate the prevalence of PAD and its independent association with FL in CHF. Methods. We conducted a cross-sectional study on National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 to quantify weighted prevalence of CHF and PAD. Study cohort consisted of 7513, with ankle brachial index (ABI) measurements at baseline. Independent association of PAD (ABI ≤ 0.9) with FL in CHF was determined with multivariate logistic regression (MVLR). Results. Overall weighted PAD prevalence was 5.2%. CHF was present in 305 participants, and the weighted prevalence of PAD in this subgroup was 19.2%. When compared, participants with CHF and PAD were more likely to be older (P < 0.001), hypertensive (P = 0.005) and hypercholesterolemic (P = 0.013) than participants with CHF alone. MVLR showed that PAD (adjusted OR = 5.15; 95% CI: 2.2, 12.05: P < 0.05) and arthritis (adjusted OR = 2.36; 95% CI: 1.10, 5.06: P < 0.05) were independently associated with FL in CHF. Conclusion. Independent association of PAD with FL suggests the need for reinforced screening for PAD in individuals with CHF.