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1.  Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits 
Cardiovascular Research  2008;81(4):678-685.
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.
doi:10.1093/cvr/cvn350
PMCID: PMC2642603  PMID: 19091790
Superoxide dismutase; Adenoviral vector; Carotid body; Sympathetic nerve activity; Chemoreceptor; Glomus cell; Chronic heart failure
2.  Activation of endothelin A-receptors contributes to the impaired responsiveness of renal mechanosensory nerves in congestive heart failure 
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.
doi:10.1139/y10-035
PMCID: PMC2907174  PMID: 20628427
renal nerves; kidney; prostaglandins; substance P; renal pelvic pressure; sodium retention; sodium excretion
3.  Role of Neurotransmitter Gases in the Control of the Carotid Body in Heart Failure 
The peripheral arterial chemoreflex, arising primarily from the carotid body in most species, plays an important role in the control of breathing and in autonomic control of cardiovascular function. The peripheral chemoreflex is enhanced in heart failure patients and animal models of heart failure and contributes to the sympathetic hyperactivity and breathing instability that exacerbates the progression of the disease. Studies in animal models have shown that carotid body chemoreceptor activity is enhanced under both normoxic and hypoxic conditions in heart failure due to disruption of local mediators that control carotid body function. This brief review highlights evidence that the alterations in the gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide in the carotid body contribute to the exaggerated carotid body function observed in heart failure.
doi:10.1016/j.resp.2012.07.010
PMCID: PMC3483421  PMID: 22842006
4.  NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits 
Cardiovascular research  2007;75(3):546-554.
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.
doi:10.1016/j.cardiores.2007.04.006
PMCID: PMC2062532  PMID: 17499230
Angiotensin; Reactive oxygen species; autonomic nervous system; chemoreceptor; heart failure
5.  Inhibition of Cardiac Sympathetic Afferent Reflex and Sympathetic Activity by Baroreceptor and Vagal Afferent Inputs in Chronic Heart Failure 
PLoS ONE  2011;6(10):e25784.
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.
doi:10.1371/journal.pone.0025784
PMCID: PMC3185007  PMID: 21991351
6.  Abnormal Baroreflex Function is Dissociated from Central Angiotensin II Receptor Expression in Chronic Heart Failure 
Shock (Augusta, Ga.)  2012;37(3):319-324.
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.
doi:10.1097/SHK.0b013e31824581e8
PMCID: PMC3281308  PMID: 22258229
Baroreflex; heart failure; sympathetic activity; angiotensin II receptor
7.  Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin 
Journal of Biomedical Research  2012;26(6):425-431.
Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure (CHF) induced by coronary artery ligation and contributes to the over-excitation of sympathetic activity. We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were enhanced in adriamycin-induced CHF and whether angiotensin II (Ang II) in the paraventricular nucleus (PVN) was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex. Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks (15 mg/kg). Six weeks after the first injection, the rats underwent anesthesia with urethane and α-chloralose. After vagotomy and baroreceptor denervation, cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure (MAP) response to epicardial application of capsaicin (1.0 nmol). The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity. The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depressor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats. Bilateral PVN microinjection of angiotensin II (Ang II) caused larger responses of the cardiac sympathetic afferent reflex, baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats. These results indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure.
doi:10.7555/JBR.26.20120035
PMCID: PMC3597045  PMID: 23554781
heart failure; adriamycin; sympathetic activity; angiotensin II; paraventricular nucleus
8.  The Mechanism of Adaptation of Left Atrial Stretch Receptors in Dogs with Chronic Congestive Heart Failure 
Journal of Clinical Investigation  1977;60(2):323-331.
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
PMCID: PMC372372  PMID: 874094
9.  Intermedin in the Paraventricular Nucleus Attenuates Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats 
PLoS ONE  2014;9(4):e94234.
Background and Aim
Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heart failure (CHF) rats. The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats.
Methodology/Principal Findings
Rats were subjected to left descending coronary artery ligation to induce CHF or sham-operation (Sham). Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Acute experiments were carried out 8 weeks after coronary ligation or sham surgery under anesthesia. IMD and angiotensin II (Ang II) levels in the PVN were up-regulated in CHF rats. Bilateral PVN microinjection of IMD caused greater decreases in CSAR and the baseline RSNA and MAP in CHF rats than those in Sham rats. The decrease of CSAR caused by IMD was prevented by pretreatment with AM receptor antagonist AM22-52, but not CGRP receptor antagonist CGRP8-37. Ang II in the PVN significantly enhanced CSAR and superoxide anions level, which was inhibited by PVN pretreatment with IMD or tempol (a superoxide anions scavenger) in Sham and CHF rats.
Conclusion
IMD in the PVN inhibits CSAR via AM receptor, and attenuates the effects of Ang II on CSAR and superoxide anions level in CHF rats. PVN superoxide anions involve in the effect of IMD on attenuating Ang II-induced CSAR response.
doi:10.1371/journal.pone.0094234
PMCID: PMC3978024  PMID: 24709972
10.  Congestive Heart Failure Effects on Atrial Fibroblast Phenotype: Differences between Freshly-Isolated and Cultured Cells 
PLoS ONE  2012;7(12):e52032.
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.
doi:10.1371/journal.pone.0052032
PMCID: PMC3522639  PMID: 23251678
11.  Angiotensin and Carotid Body Chemoreception in Heart Failure 
Current opinion in pharmacology  2011;11(2):144-149.
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.
doi:10.1016/j.coph.2010.12.004
PMCID: PMC3075378  PMID: 21242106
Carotid Body; Angiotensin; Heart Failure
12.  Brain-Selective Overexpression of Angiotensin Converting Enzyme 2 Attenuates Sympathetic Nerve Activity and Enhances Baroreflex Function in Chronic Heart Failure 
Hypertension  2011;58(6):1057-1065.
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.
doi:10.1161/HYPERTENSIONAHA.111.176636
PMCID: PMC3224814  PMID: 22025374
heart failure; angiotensin converting enzyme 2; angiotensin II; angiotensin I (1-7); autonomic function; baroreflex
13.  What We Know and Do Not Know about Sex and Cardiac Disease 
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.
doi:10.1155/2010/562051
PMCID: PMC2860154  PMID: 20445744
14.  CENTRAL ANG-(1–7) ENHANCES BAROREFLEX GAIN IN CONSCIOUS RABBITS WITH HEART FAILURE 
Hypertension  2011;58(4):627-634.
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.
doi:10.1161/HYPERTENSIONAHA.111.177600
PMCID: PMC3187859  PMID: 21844487
angiotensin-(1–7); heart failure; sympathetic nervous system; baroreflex; vagus nerve; blood pressure; heart rate
15.  Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans. 
Journal of Clinical Investigation  1987;79(2):508-516.
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.
PMCID: PMC424115  PMID: 3805279
16.  CENTRAL RHO KINASE INHIBITION RESTORES BAROREFLEX SENSITIVITY AND AT1R PROTEIN IMBALANCE IN CONSCIOUS RABBITS WITH CHRONIC HEART FAILURE 
Hypertension  2013;61(3):723-729.
The small GTPase RhoA and its associated kinase ROCKII are involved in vascular smooth muscle cell contraction and endothelial nitric oxide synthase (eNOS) mRNA destabilization. Overactivation of the RhoA/ROCKII pathway is implicated in a number of pathologies including chronic heart failure (CHF) and may contribute to the enhanced sympathetic outflow seen in CHF due to decreased nitric oxide (NO) availability. Thus, we hypothesized that central ROCKII blockade would improve the sympatho-vagal imbalance in a pacing rabbit model of CHF in an NO-dependent manner. CHF was induced by rapid ventricular pacing and characterized by an ejection fraction of ≤45%. Animals were implanted with an ICV cannula and osmotic minipump (rate: 1 µL/h) containing sterile saline, 1.5 µg/kg/day fasudil (Fas, a ROCKII inhibitor) for 4 days or Fas + 100 µg/kg/day L-NAME, a NOS inhibitor. Arterial baroreflex control was assessed by IV infusion of sodium nitroprusside and phenylephrine. Fas infusion significantly lowered resting HR by decreasing sympathetic and increasing vagal tone. Furthermore, Fas improved baroreflex gain in CHF in an NO-dependent manner. In CHF Fas animals, the decrease in HR in response to IV metoprolol was similar to sham and was reversed by L-NAME. Fas decreased AT1R and phospho-RhoA protein expression and increased eNOS expression in the brainstem of CHF animals. These data strongly suggest that central ROCKII activation contributes to cardiac sympatho-excitation in the setting of CHF and that central Fas restores vagal and sympathetic tone in an NO-dependent manner. ROCKII may be a new central therapeutic target in the setting of CHF.
doi:10.1161/HYPERTENSIONAHA.111.00396
PMCID: PMC3573242  PMID: 23283363
heart failure; rho-associated kinase; nitric oxide synthase; autonomic nervous system; Angiotensin AT1 receptor
17.  Clinical treatment reverses attentional deficits in congestive heart failure 
BMC Geriatrics  2001;1:2.
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.
doi:10.1186/1471-2318-1-2
PMCID: PMC57979  PMID: 11604103
18.  Impact of Peripheral Arterial Disease on Functional Limitation in Congestive Heart Failure: Results from the National Health and Nutrition Examination Survey (1999–2004) 
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.
doi:10.1155/2012/306852
PMCID: PMC3533604  PMID: 23346456
19.  Chronic Heart Failure Does Not Attenuate the Total Activity of Sympathetic Outflow to Skin During Whole Body Heating 
Circulation. Heart failure  2013;6(2):271-278.
Background
Previous studies show that the rise in skin blood flow and cutaneous vascular conductance (CVC) during heat stress is substantially attenuated in chronic heart failure (CHF) patients. The mechanism(s) responsible for this finding is not clear. In particular, little is known regarding the responses of skin sympathetic nerve activity (SSNA) that control the skin blood flow during heat stress in CHF patients. We examined the effects of a modest heat stress to test the hypothesis that SSNA responses could be attenuated in CHF.
Methods and Results
We assessed SSNA (microneurography) from the peroneal nerve and skin blood flow (forearm laser Doppler) in 9 patients with stable class II-III CHF and in matched healthy subjects during passive whole body heating with a water perfused suit. Whole body heating induced similar increases in internal temperature (~0.6 °C) in both groups. Whole body heat stress evoked similar SSNA activation in CHF patients (Δ891±110 units/min) and the control subjects (Δ787±84 units/min, P=0.66), while the elevation in forearm CVC in patients with CHF was significantly lower than that in healthy control subjects (Δ131±29 vs. Δ623±131%, P=0.001).
Conclusions
The present data show that SSNA activation during a modest whole body heat stress is not attenuated in CHF. Thus, the attenuated skin vasodilator response in CHF patients is not due to a reduction in total activity of sympathetic outflow to skin.
doi:10.1161/CIRCHEARTFAILURE.112.000135
PMCID: PMC3738175  PMID: 23395933
autonomic; regional blood flow; vasodilation; heart failure
20.  Symbolic analysis detects alterations of cardiac autonomic modulation in congestive heart failure rats 
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.
doi:10.1016/j.autneu.2009.03.009
PMCID: PMC2931340  PMID: 19403339
nonlinear dynamics; autonomic nervous system; congestive heart failure
21.  Seasonal congestive heart failure mortality and hospitalisation trends, Quebec 1990–1998 
Study objective: To describe seasonal congestive heart failure (CHF) mortality and hospitalisations in Quebec, Canada between 1990–1998 and compare trends in CHF mortality and morbidity with those in France.
Design: Population cohort study.
Setting: Province of Quebec, Canada.
Patients: Mortality data were obtained from the Quebec Death Certificate Registry and hospitalisation from the Quebec Med-Echo hospital discharge database. Cases with primary ICD-9 code 428 were considered cases of CHF.
Results: Monthly CHF mortality was higher in January, declined until September and then rose steadily (p<0.05). Hospital admissions for CHF declined from May until September (moving averages analysis p<0.0001). Seasonal mortality patterns observed in Quebec were similar to those observed in France.
Conclusion: CHF mortality in Quebec is highest during the winter and declines in the summer, similar to observations in France and Scotland. This suggests that absolute temperatures may not necessarily be that important but increased CHF mortality is observed once environmental temperatures fall below a certain "threshold" temperature. Alternatively better internal heating and warmer clothing required for survival in Quebec may ameliorate mortality patterns despite colder external environments.
doi:10.1136/jech.58.2.129
PMCID: PMC1732686  PMID: 14729893
22.  Tonic Glutamatergic Input in The Rostral Ventrolateral Medulla is Increased in Rats With Chronic Heart Failure 
Hypertension  2008;53(2):370-374.
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.
doi:10.1161/HYPERTENSIONAHA.108.122598
PMCID: PMC3574554  PMID: 19029485
sympathoexcitation; glutamate receptors; micro/picoinjection; extracellular recording; presympathetic neuron
23.  Influence of Blood Pressure and Blood Pressure Change on the Risk of Congestive Heart Failure in the Elderly 
Swiss Medical Weekly  2010;140(13-14):202-208.
Background
While elevated blood pressure (BP) has been consistently associated with incident congestive heart failure (CHF), much less is known about the effect of BP change. We therefore assessed the association of BP change over time with subsequent risk of CHF.
Methods
4655 participants ≥65 years old from the prospective Established Populations for Epidemiologic Studies of the Elderly program who were alive and free of CHF after 6 years of follow-up were included. Categories of sustained high BP, sustained low BP, BP progression and BP regression were defined according to BP differences between study entry and 6 years of follow-up. The primary endpoint was incident CHF subsequent to the 6-year examination.
Results
During 4.3 years of follow-up after the 6-year examination, 642 events occurred. The hazard ratio (HR) (95% confidence interval (CI)) for systolic BP ≥160 compared to <120 mmHg at 6 years was 1.39 (1.04–1.86). Conversely, the lowest diastolic BP category at 6 years was associated with an increased risk of incident CHF (HR (95% CI) <70 mmHg versus 70–79 mmHg 1.42 (1.18–1.71)). Systolic and diastolic BP were better predictors than pulse pressure. The HRs (95% CI) for incident CHF associated with sustained high systolic BP ≥160 mmHg and systolic BP progression were 1.35 (0.97–1.89) and 1.45 (1.14–1.85), respectively. Conversely, significant associations were found in those with sustained low diastolic BP or diastolic BP regression (HR (95% CI) 1.42 (1.11–1.83) and 1.45 (1.19–1.76), respectively).
Conclusion
While persistently elevated systolic BP and systolic BP progression were strong predictors of CHF in the elderly, inverse associations were found with regard to diastolic BP. Systolic and diastolic BP were better predictors of CHF than pulse pressure.
PMCID: PMC3387917  PMID: 20072936
Hypertension; Blood pressure; Pulse pressure; Heart failure; Mortality
24.  Degree of Disability and Patterns of Caregiving among Older Americans with Congestive Heart Failure 
OBJECTIVES
Although congestive heart failure (CHF) is a common condition, the extent of disability and caregiving needs for those with CHF are unclear. We sought to determine: (1) prevalence of physical disability and geriatric conditions, (2) whether CHF is independently associated with disability, (3) rates of nursing home admission, and (4) formal and informal in-home care received in the older CHF population.
METHODS
We used cross-sectional data from the 2000 wave of the Health and Retirement Study. We compared outcomes among three categories of older adults: (1) no coronary heart disease (CHD), (2) CHD, without CHF, and (3) CHF. Compared to those without CHF, respondents reporting CHF were more likely to be disabled (P < 0.001) and to have geriatric conditions (P < 0.001). Respondents reporting CHF were more likely to have been admitted to a nursing home (P < 0.05). CHF respondents were more functionally impaired than respondents without CHF.
RESULTS
The adjusted average weekly informal care hours for respondents reporting CHF was higher than for those reporting CHD but without CHF and those reporting no CHD (6.7 vs 4.1 vs 5.1, respectively; P < 0.05). Average weekly formal caregiving hours also differed among the three groups (1.3 CHF vs 0.9 CHD without CHF vs 0.7 no CHD; P > 0.05).
CONCLUSIONS
CHF imposes a significant burden on patients, families, and the long-term care system. Older adults with CHF have higher rates of disability, geriatric conditions, and nursing home admission.
doi:10.1007/s11606-007-0456-1
PMCID: PMC2173919  PMID: 18030537
CHF; disability; formal and informal caregiving
25.  Physical training in patients with chronic heart failure 
Netherlands Heart Journal  2004;12(6):279-286.
Chronic heart failure (CHF) can be defined as a complex of symptoms and signs caused by cardiac dysfunction. Dyspnoea on exertion, fatigue, reduced exercise tolerance and fluid retention are hallmarks of the syndrome.
Reduced peripheral blood flow, endothelial dysfunction, alterations in skeletal muscle structure and function, an increased activity of the muscle ergoreflex, as well as autonomic and neurohormonal activation reduce exercise performance, ultimately leading to physical deconditioning in CHF patients.
The beneficial effects of physical training for CHF patients are increasingly acknowledged. Based on European and American guidelines on physical training in CHF, results from controlled randomised trials (summarised in this paper) and expert opinions, the Dutch Committee on Cardiac Rehabilitation has formulated statements on physical training in CHF.
In addition, recommendations implementing physical training programmes in CHF patients are given. The selection criteria, contraindications and methods, and duration of a physical training programme in heart failure are discussed. Concomitant with the training programme, a multidisciplinary intervention programme is needed to stimulate patients to adopt and maintain an active and healthy lifestyle.
PMCID: PMC2497123
guidelines; heart failure; management; rehabilitation; physical training

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