Anuradha Aggarwal

Alfred Hospital, Melbourne, Victoria, Australia

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Publications (11)121.04 Total impact

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    ABSTRACT: There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.
    Hypertension 03/2004; 43(2):169-75. DOI:10.1161/01.HYP.0000103160.35395.9E · 6.48 Impact Factor
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    Nina Eikelis · Markus Schlaich · Anuradha Aggarwal · David Kaye · Murray Esler ·
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    ABSTRACT: Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin (r=0.628, P<0.01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found; a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1+/-1.2 vs 12.8+/-3.1 ng/mL in healthy subjects); and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7+/-1.1 ng/mL vs 4.0+/-0.9 ng/mL in men >60 years and <35 years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0+/-30.5 mL/min, compared with 56.9+/-18.9 mL/min (P<0.05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.
    Hypertension 06/2003; 41(5):1072-9. DOI:10.1161/01.HYP.0000066289.17754.49 · 6.48 Impact Factor
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    Anuradha Aggarwal · Murray D Esler · Margaret J Morris · Gavin Lambert · David M Kaye ·
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    ABSTRACT: This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 microg/kg of clonidine resulted in a fall in cardiac (326+/-73 to 160+/-40 pmol/min, P<0.001), renal (2.5+/-0.6 to 1.5+/-0.3 nmol/min, P=0.01), and global norepinephrine spillover (4.0+/-0.6 to 3.1+/-0.5 nmol/min, P<0.01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity (P<0.05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.
    Hypertension 03/2003; 41(3):553-7. DOI:10.1161/01.HYP.0000055779.93635.A2 · 6.48 Impact Factor
  • Anuradha Aggarwal · David M Kaye ·

    Coronary Artery Disease 01/2003; 13(8):415-9. DOI:10.1097/00019501-200212000-00005 · 1.50 Impact Factor

  • Heart, Lung and Circulation 01/2003; 12(2). DOI:10.1046/j.1443-9506.2003.03532.x · 1.44 Impact Factor
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    ABSTRACT: Although it is established that heightened sympathetic drive exists in congestive heart failure (CHF), the reflex processes by which this may occur and the sites in the central nervous system that may be responsible for mediating this process are not yet fully elucidated. Eight patients with moderate to severe CHF and 8 healthy control subjects underwent simultaneous arterial and bilateral internal jugular venous blood sampling and cerebral venous blood pool scanning for anatomical determination of the origin of internal jugular venous blood flow. We estimated sympathetic nervous activity by measuring total body norepinephrine (NE) spillover using radiotracer methodology and determined brain NE turnover by measuring the internal jugular overflow of NE and its lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol. Suprabulbar subcortical turnover of NE was significantly greater in CHF patients than in the healthy group (2.77 +/- 0.75 versus 0.66 +/- 0.40 nmol/min, P<0.05). There was a significant positive correlation between suprabulbar subcortical turnover of NE and total body NE spillover (r=0.62, P=0.01). This study, for the first time, demonstrates elevated suprabulbar subcortical noradrenergic activity in human CHF and identifies a positive correlation between this and the level of whole-body NE spillover. The findings suggest that the activation of noradrenergic neurons projecting rostrally from the brain stem mediates sympathetic nervous stimulation in CHF.
    Circulation 04/2002; 105(9):1031-3. · 14.43 Impact Factor
  • Duncan J Campbell · Anuradha Aggarwal · Murray Esler · David Kaye ·
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    ABSTRACT: Blood concentrations of angiotensin II are often raised in patients with heart failure, despite treatment with angiotensin-converting-enzyme (ACE) inhibitors. We compared concentrations of angiotensin II in two groups of matched patients, receiving ACE inhibitor therapy with or without concomitant administration of beta-blockers. Concentrations of angiotensin II were lower in individuals taking beta-blockers than in those who were not (geometric mean 1.1 [95% CI 0.4-2.7] vs 15.5 [4.6-52.6] fmol/mL, 95% CI for difference 3-59). Our findings indicate that a reduction in angiotensin II concentrations might contribute to the therapeutic benefits of beta-blockade in heart failure, especially in patients who simultaneously receive ACE inhibitor treatment.
    The Lancet 12/2001; 358(9293):1609-10. DOI:10.1016/S0140-6736(01)06660-0 · 45.22 Impact Factor
  • A Aggarwal · P Bergin · P Jessup · D Kaye ·

    The Journal of Heart and Lung Transplantation 12/2001; 20(11):1241-4. DOI:10.1016/S1053-2498(01)00313-8 · 6.65 Impact Factor
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    D M Kaye · D Mansfield · A Aggarwal · M T Naughton · M D Esler ·
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    ABSTRACT: Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood. Methods and In the present study, we examined the effect of short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3 to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although total systemic norepinephrine spillover was unchanged. The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
    Circulation 06/2001; 103(19):2336-8. DOI:10.1161/01.CIR.103.19.2336 · 14.43 Impact Factor
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    Anuradha Aggarwal · Murray D Esler · Flora Socratous · David M Kaye ·
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    ABSTRACT: OBJECTIVESThe aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF).BACKGROUNDActivation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release.METHODSFifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 μg and 0.48 μg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics.RESULTSIntra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004).CONCLUSIONSPeripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.
    Journal of the American College of Cardiology 04/2001; 37(5-37):1246-1251. DOI:10.1016/S0735-1097(01)01121-4 · 16.50 Impact Factor
  • A. Aggarwal · F. Socratous · M. Esler · D. Kaye ·

    Heart, Lung and Circulation 12/2000; 9(3). DOI:10.1046/j.1443-9506.2000.06061.x · 1.44 Impact Factor