Sally G. Hood

MECHANISMS OF SYMPATHETIC ACTIVATION IN HEART FAILURE

1 Heart Failure (HF) is a serious, debilitating condition with poor survival rates and an increasing level of prevalence. A characteristic of HF is a compensatory neurohumoral activation that increases with the severity of the condition. 2 The increase in sympathetic activity may be beneficial initially, providing inotropic support to the heart and peripheral vasoconstriction, but in the longer term it promotes disease progression and worsens prognosis. This is particularly true for the increase in cardiac sympathetic nerve activity, as shown by the strong inverse correlation between cardiac noradrenaline spillover and prognosis and by the beneficial effect of β‐adrenoceptor antagonists. 3 Possible causes for the raised level of sympathetic activity in HF include altered neural reflexes, such as those from baroreceptors and chemoreceptors, raised levels of hormones, such as angiotensin II, acting on circumventricular organs, and changes in central mechanisms that may amplify the responses to these inputs. 4 The control of sympathetic activity to different organs is regionally heterogeneous, as demonstrated by a lack of concordance in burst patterns, different responses to reflexes, opposite responses of cardiac and renal sympathetic nerves to central angiotensin and organ‐specific increases in sympathetic activity in HF. These observations indicate that, in HF, it is essential to study the factors causing sympathetic activation in individual outflows, in particular those that powerfully, and perhaps preferentially, increase cardiac sympathetic nerve activity.

Basis for the preferential activation of cardiac sympathetic nerve activity in heart failure

In heart failure (HF), sympathetic nerve activity is increased. Measurements in HF patients of cardiac norepinephrine spillover, reflecting cardiac sympathetic nerve activity (CSNA), indicate that it is increased earlier and to a greater extent than sympathetic activity to other organs. This has important consequences because it worsens prognosis, provoking arrhythmias and sudden death. To elucidate the mechanisms responsible for the activation of CSNA in HF, we made simultaneous direct neural recordings of CSNA and renal SNA (RSNA) in two groups of conscious sheep: normal animals and animals in HF induced by chronic, rapid ventricular pacing. In normal animals, the level of activity, measured as burst incidence (bursts of pulse related activity/100 heart beats), was significantly lower for CSNA (30 ± 5%) than for RSNA (94 ± 2%). Furthermore, the resting level of CSNA, relative to its maximum achieved while baroreceptors were unloaded by reducing arterial pressure, was set at a much lower percentage than RSNA. In HF, burst incidence of CSNA increased from 30 to 91%, whereas burst incidence of RSNA remained unaltered at 95%. The sensitivity of the control of both CSNA and RSNA by the arterial baroreflex remained unchanged in HF. These data show that, in the normal state, the resting level of CSNA is set at a lower level than RSNA, but in HF, the resting levels of SNA to both organs are close to their maxima. This finding provides an explanation for the preferential increase in cardiac norepinephrine spillover observed in HF.

Renal histopathology during experimental septic acute kidney injury and recovery

Objectives:Our understanding of septic acute kidney injury is limited. We therefore assessed renal histopathological changes induced by septic acute kidney injury and their evolution during recovery. Design:Prospective experimental study. Setting:Physiology Research Institute. Subjects:Twenty-two Merino sheep. Intervention:We induced septic acute kidney injury by continuous IV infusion of Escherichia coli. We studied histology, immunohistochemistry, markers of apoptosis, and expression of nitric oxide synthase isoforms and hypoxia-inducible factor-1&agr;. Analysis was performed on kidneys from normal sheep, sheep with septic acute kidney injury, and sheep after recovery from septic acute kidney injury. Measurements and Main Results:In normal, septic, and recovery sheep, respectively, serum creatinine was (median) 82 (interquartile range, 70–85), 289 (171–477), and 70 (51–91) &mgr;mol/L and renal blood flow was 270 ± 42, 653 ± 210, and 250 ± 49 mL/min. There were no histological differences between baseline, acute kidney injury, and recovery sheep. There was no evidence of macrophage or myofibroblast infiltration, no evidence of caspase-3 cleavage to suggest activation of apoptotic pathways, and no increase in neutrophil gelatinase-associated lipocalin to suggest tubular injury. Similarly, quantification of apoptosis revealed no differences between the normal and septic groups (normal: median, 3; interquartile range, 0–5 cells per visual field and septic acute kidney injury: median, 3.5; interquartile range, 0–8 cells per visual field; p = 0.618), but in the recovery group, there was increased apoptosis (median, 14; interquartile range, 4–34 cells per visual field; p = 0.002). Expression of all nitric oxide synthase subtypes increased significantly in the renal cortex during septic acute kidney injury but tended to decrease in the medulla. Medullary hypoxia-inducible factor gene expression decreased from 1.00 (95% CI, 0.74–1.36) to 0.26 (95% CI, 0.09–0.76) in recovery (p = 0.0106). Both inducible nitric oxide synthase and neuronal nitric oxide synthase expressions correlated with renal blood flow. Conclusion:The lack of any tubular injury or increased apoptosis, the increased expression of all cortical nitric oxide synthase isoforms, and the link between inducible nitric oxide synthase and neuronal nitric oxide synthase with renal blood flow suggest in this experimental model that severe sepsis acute kidney injury can develop in the absence of histological or immunohistological changes and may be functional in nature.

Septic shock induces distinct changes in sympathetic nerve activity to the heart and kidney in conscious sheep

Sepsis and septic shock are the chief cause of death in intensive care units, with mortality rates between 30 and 70%. In a large animal model of septic shock, we have demonstrated hypotension, increased cardiac output, and tachycardia, together with renal vasodilatation and renal failure. The changes in cardiac sympathetic nerve activity (CSNA) that may contribute to the tachycardia have not been investigated, and the changes in renal SNA (RSNA) that may mediate the changes in renal blood flow and function are unclear. We therefore recorded CSNA and RSNA during septic shock in conscious sheep. Septic shock was induced by administration of Escherichia coli, which caused a delayed hypotension and an immediate, biphasic increase in heart rate (HR) associated with similar changes in CSNA. After E. coli, RSNA decreased for over 3 h, followed by a sustained increase (180%), whereas renal blood flow progressively increased and remained elevated. There was an initial diuresis, followed by oliguria and decreased creatinine clearance. There were differential changes in the range of the arterial baroreflex curves; it was depressed for HR, increased for CSNA, and unchanged for RSNA. Our findings, recording CSNA for the first time in septic shock, suggest that the increase in SNA to the heart is not driven solely by unloading of baroreceptors and that the increase has an important role to increase HR and cardiac output. There was little correlation between the changes in RSNA and renal blood flow, suggesting that the renal vasodilatation was mediated mainly by other mechanisms.

Specific control of sympathetic nerve activity to the mammalian heart and kidney

There is a large body of evidence indicating that sympathetic nerves to individual organs are specifically controlled, but only few studies have compared the control of cardiac sympathetic nerve activity (CSNA) with activity in other sympathetic nerves. In this review, changes in sympathetic activity to the heart and kidneys are described during increases in brain [Na+] and in heart failure (HF). In conscious sheep, increases in brain [Na+] increased CSNA and arterial pressure and, conversely, decreased renal sympathetic nerve activity (RSNA), promoting urinary sodium loss. These organ‐specific effects are mediated via a neural pathway that includes an angiotensinergic synapse, the lamina terminalis and the paraventricular nucleus of the hypothalamus. There is also evidence of differential control of SNA in HF. In normal sheep, the resting burst incidence of CSNA was much lower than that of RSNA, whereas in HF they increased to similar, almost maximal levels in both nerves. Arterial baroreflex control of both these nerves was unchanged in HF, but the response of CSNA to changes in blood volume was almost absent. These data indicate that in HF the lower arterial pressure leads to reduced baroreflex inhibition of SNA, which, together with the lack of an inhibitory response to the increased volume and cardiac pressures, would contribute to the sympathoexcitation observed. These studies demonstrate differences in the control of CSNA and RSNA, enabling selective actions on the heart and kidney to restore fluid and electrolyte homeostasis in the case of elevated brain [Na+] and to increase cardiac output in HF.

Discharge properties of cardiac and renal sympathetic nerves and their impaired responses to changes in blood volume in heart failure

Sympathetic nerve activity (SNA) consists of discharges that vary in amplitude and frequency, reflecting the level of recruitment of nerve fibers and the rhythmic generation and entrainment of activity by the central nervous system. It is unknown whether selective changes in these amplitude and frequency components account for organ-specific changes in SNA in response to alterations in blood volume or for the impaired SNA responses to volume changes in heart failure (HF). To address these questions, we measured cardiac SNA (CSNA) and renal SNA (RSNA) simultaneously in conscious, normal sheep and sheep in HF induced by rapid ventricular pacing. Volume expansion decreased CSNA (-62 +/- 10%, P < 0.05) and RSNA (-59 +/- 10%, P < 0.05) equally (n = 6). CSNA decreased as a result of a reduction in burst frequency, whereas RSNA fell because of falls in burst frequency and amplitude. Hemorrhage increased CSNA (+74 +/- 9%, P < 0.05) more than RSNA (+21 +/- 5%, P < 0.09), in both cases because of increased burst frequency, whereas burst amplitude decreased. In HF, burst frequency of CSNA (from 26 +/- 3 to 75 +/- 3 bursts/min) increased more than that of RSNA (from 63 +/- 4 to 79 +/- 4 bursts/min). In HF, volume expansion caused no change in CSNA and an attenuated decrease in RSNA, due entirely to decreased burst amplitude. Hemorrhage did not significantly increase SNA in either nerve in HF. These findings support the concept that the number of sympathetic fibers recruited and their firing frequency are controlled independently. Furthermore, afferent stimuli, such as changes in blood volume, cause organ-specific responses in each of these components, which are also selectively altered in HF.

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart: Importance of Cyclic GMP

Abstract—The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3′5′-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 &mgr;mol/L) against Ang II (1 &mgr;mol/L)–induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 &mgr;mol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)–induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 &mgr;mol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 &mgr;mol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.

The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep

•  Heart failure is associated with large increases in sympathetic nerve activity to organs like the heart and kidney and this increase is detrimental to patients. •  We explored the role played by the paraventricular nucleus of the hypothalamus (PVN), a central brain region, in mediating the increase in sympathetic drive during heart failure. •  We show that neurons in the PVN selectively mediate changes in sympathetic drive to the kidney, but not to the heart when blood volume is increased. •  In addition, neurons in the PVN do not contribute to the resting levels of sympathetic drive to the heart during normal conditions or in heart failure. •  Our data demonstrates striking differences in the central mechanisms that control sympathetic drive to the heart and kidney during heart failure.

Central Angiotensin Type 1 Receptor Blockade Decreases Cardiac But Not Renal Sympathetic Nerve Activity in Heart Failure

In heart failure (HF), cardiac sympathetic nerve activity (SNA; CSNA) is increased, which has detrimental effects on the heart and promotes arrhythmias and sudden death. There is evidence that the central renin-angiotensin system plays an important role in stimulating renal SNA in HF. Because SNA to individual organs is differentially controlled, we have investigated whether central angiotensin receptor blockade decreases CSNA in HF. We simultaneously recorded CSNA and renal SNA in conscious normal sheep and in sheep with HF induced by rapid ventricular pacing (ejection fraction: <40%). The effect of blockade of central angiotensin type 1 receptors by intracerebroventricular infusion of losartan (1 mg/h for 5 hours) on resting levels and baroreflex control of CSNA and renal SNA were determined. In addition, the levels of angiotensin receptors in central autonomic nuclei were determined using autoradiography. Sheep in HF had a large increase in CSNA (43±2 to 88±3 bursts per 100 heart beats; P<0.05) and heart rate, with no effect on renal SNA. In HF, central infusion of losartan for 5 hours significantly reduced the baseline levels of CSNA (to 69±5 bursts per 100 heart beats) and heart rate. Losartan had no effect in normal animals. In HF, angiotensin receptor levels were increased in the paraventricular nucleus and supraoptic nucleus but reduced in the area postrema and nucleus tractus solitarius. In summary, infusion of losartan reduced the elevated levels of CNSA in an ovine model of HF, indicating that central angiotensin receptors play a critical role in stimulating the increased sympathetic activity to the heart.

Pulmonary Artery Catheter (PAC) Accuracy and Efficacy Compared with Flow Probe and Transcutaneous Doppler (USCOM): An Ovine Cardiac Output Validation

Background. The pulmonary artery catheter (PAC) is an accepted clinical method of measuring cardiac output (CO) despite no prior validation. The ultrasonic cardiac output monitor (USCOM) is a noninvasive alternative to PAC using Doppler ultrasound (CW). We compared PAC and USCOM CO measurements against a gold standard, the aortic flow probe (FP), in sheep at varying outputs. Methods. Ten conscious sheep, with implanted FPs, had measurements of CO by FP, USCOM, and PAC, at rest and during intervention with inotropes and vasopressors. Results. CO measurements by FP, PAC, and USCOM were 4.0 ± 1.2 L/min, 4.8 ± 1.5 L/min, and 4.0 ± 1.4 L/min, respectively, (n = 280, range 1.9 L/min to 11.7 L/min). Percentage bias and precision between FP and PAC, and FP and USCOM was −17 and 47%, and 1 and 36%, respectively. PAC under-measured Dobutamine-induced CO changes by 20% (relative 66%) compared with FP, while USCOM measures varied from FP by 3% (relative 10%). PAC reliably detected −30% but not +40% CO changes, as measured by receiver operating characteristic area under the curve (AUC), while USCOM reliably detected ±5% changes in CO (AUC > 0.70). Conclusions. PAC demonstrated poor accuracy and sensitivity as a measure of CO. USCOM provided equivalent measurements to FP across a sixfold range of outputs, reliably detecting ±5% changes.