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Research Highlights from the Literature

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2004; Volume 14(1) from Clinical Autonomic Research    
Italo Biaggioni, M.D. with contributions by Emily Garland, PhD.                                       
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Modulation of synaptic acetylcholine.  A novel therapeutic approach in autonomic disorders
Most therapies for autonomic disorders are designed to replace or modulate sympathetic function.  Cholinergic neurotransmission is often overlooked as a therapeutic target despite its importance in ganglionic and parasympathetic neurotransmission.  Singer et al. explored the use of acetylcholinesterase inhibition in the treatment of patients with neuropathic orthostatic hypotension (seven with multiple system atrophy, three with Parkinson's disease, and five with idiopathic or secondary autonomic neuropathy), based on the theory that enhanced sympathetic ganglionic transmission would increase systemic resistance in proportion to orthostatic needs.  Pyridostigmine 60 mg produced only a modest increase in supine blood pressure but significantly increased blood pressure and peripheral resistance during head up tilt, and improved orthostatic symptoms.  This approach may represent a novel option in the treatment of neuropathic orthostatic hypotension, particularly in patients with “autonomic reserve” that can be recruited by enhancement of ganglionic cholinergic neurotransmission. 
    This approach may also be beneficial in congestive heart failure (HF).  Reduced vagal tone with decreased heart rate variability is a hallmark of this condition, and is associated with increased mortality.  Dunlap et al. investigated the mechanism of vagal dysfunction in a dog model of HF induced by rapid pacing.  Muscarinic blockade increased heart rate significantly more in controls compared to HF, indicating low levels of resting vagal tone.  Bradycardia elicited by electrical stimulation of the vagus nerve was also attenuated in the HF group. Conversely, muscarinic receptor activation by bethanechol, and indirectly by neostigmine, elicited exaggerated heart rate responses in HF.  Muscarinic receptor density was greater and acetylcholinesterase lower in sinoatrial nodes of HF animals.  It is possible, therefore, that cholinesterase inhibition improves cardiac parasympathetic function in HF by increasing acetylcholine levels in the setting of upregulated postsynaptic receptors. 
    Behling et al. tested this possibility in patients with heart failure and found that pyridostigmine lowered heart rate, increased heart rate variability (as determined by root-mean-square of successive differences) and decreased ventricular arrhythmias in HF patients.  These results justify trials to determine if this improvement in cardiac parasympathetic function translates into improved survival in HF, particularly if these results can be confirmed using spectral analysis of heart rate variability.

     Singer,W, Opfer-Gehrking,TL, McPhee,BR et al (2003)  Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension.  J Neurol Neurosurg Psychiatry 74:1294-1298.
    Dunlap,ME, Bibevski,S, Rosenberry,TL et al (2003)  Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity.  Am J Physiol Heart Circ Physiol 285:H1632-H1640.
    Behling,A, Moraes,RS, Rohde,LE et al (2003)  Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure.  Am Heart J 146:494-500.

Nitrergic mechanisms of neural and vascular dysfunction in diabetes
Nitric oxide (NO) acts as a neurotransmitter in central and peripheral neurons expressing nNOS.  Impairment of these nitrergic fibers may contribute to erectile dysfunction, gastroparesis and other neural complications of diabetes.  Decreased expression of neuronal nNOS has been reported in diabetes, but it has not been clear whether this is a primary phenomenon or simply the consequence of nerve degeneration.  Studies by Cellek et al. suggest that both are true, and that nitrergic neuropathy occurs in two phases.  In the first phase neuronal nNOS is decreased in axons but not in cell bodies, suggesting a defect in axonal transport.  This phase is reversible by insulin treatment and is not associated with degenerative changes.  As diabetes progresses, the accumulation of nNOS in neuronal bodies results in increased NO production which interacts synergistically with advanced glycation endproducts (AGEs) inducing an oxidative process that leads to apoptosis.  This second degenerative phase of nitrergic neuropathy is not reversible by insulin treatment. 
    Nitric oxide can also be formed by inducible nitric oxide synthase (iNOS) normally expressed in inflammatory cells, but also in blood vessels in response to inflammation or diabetes. Gunnett et al studied vascular function in wild type (WT) and iNOS-deficient (KO) mice made diabetic with streptozotocin.  As expected, endothelium-mediated vasodilation induced by acetylcholine was impaired by diabetes in WT mice, but this was not observed in iNOS-KO mice.  These results suggest that iNOS contributes to impaired endothelium-induced relaxation characteristic of the vascular dysfunction of diabetes.

    Cellek,S, Foxwell,NA, and Moncada,S (2003)  Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats.  Diabetes 52:2353-2362.
    Cellek,S, Qu,W, Schmidt,AM et al (2003)  Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes.  Diabetologia Published on line
    Gunnett,CA, Heistad,DD, and Faraci,FM (2003)  Gene-targeted mice reveal a critical role for inducible nitric oxide synthase in vascular dysfunction during diabetes.  Stroke 34:2970-2974.

Autonomic dysfunction precedes the development of type 2 diabetes and hypertension?
Autonomic neuropathy is a frequent complication in diabetes mellitus, and reduced high frequency power of heart rate variability is often an early finding.  Carnethon et al tested the hypothesis that autonomic abnormalities precede overt diabetes, by measuring baseline heart rate variability (HRV) in a cohort of 8,185 subjects.  After a mean follow up of 8.3 years, 1,063 subjects developed clinical diabetes.  Subjects with low-frequency power HRV in the lowest quartile (<7.7 ms2) had a 1.2 higher relative risk of developing diabetes (95% CI 1.0-1.4) after adjustment of age, race, gender, body mass index, physical activity, and others.  This increased risk was still present in participants who had normal fasting glucose at baseline.  No differences, however, were found in high frequency spectra. These findings suggest that autonomic dysfunction is seen early in the development of diabetes in otherwise healthy adults.
    Schroeder et al. studied the association of HRV and hypertension in a large cohort of 11,061 individuals.  Individuals with hypertension at baseline had decreased heart rate variability. Among 7,099 individuals without hypertension at baseline, low heart rate variability predicted a greater risk of hypertension over 9 years of follow-up. The hazard ratio for the lowest compared with the highest quartile of the standard deviation of normal-to-normal R-R intervals was 1.24 (95% CI, 1.10-1.40), for the root mean square of successive differences in normal-to-normal R-R intervals was 1.36 (95% CI, 1.21-1.54), and for R-R interval was 1.44 (95% CI, 1.27-1.63).  There was no significant change in heart rate variability within subjects over time.  These findings thus support the thesis that the autonomic nervous system is involved early in the development of hypertension, yet suggest that differences in the autonomic profile of hypertensives and normotensives do not increase with time.  The estimate of heart rate variability in the time domain used in this study, however, can be confounded by non-autonomic influences, including physical activity.

    Carnethon,MR, Golden,SH, Folsom,AR et al (2003)  Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes. The Atherosclerosis Risk In Communities Study, 1987-1998.  Circulation 107:2190-2195.
    Schroeder,EB, Liao,D, Chambless,LE et al (2003)  Hypertension, Blood Pressure, and Heart Rate Variability. The Atherosclerosis Risk in Communities (ARIC) Study.  Hypertension 42:1106-1111.

Blood pressure and dementia.  A bell-shaped curve?         
    Hypertension is a risk factor for the development of dementia in middle-aged populations, but the opposite has been proposed in elderly subjects.  Verghese et al. reviewed this relationship in a cohort of 406 participants, ages 75 to 85 years.  Dementia developed in 122 subjects after a median follow-up of 6.7 years (range 1 to 21), with 65 diagnosed as Alzheimer’s disease (AD), 28 as vascular dementia, 29 as other dementias.  Subjects who developed dementia had lower systolic (149 ± 23.4 vs. 155 ± 24.8 mmHg; P = 0.047) and diastolic (82.8 ± 12.3 vs. 86.8 ± 12.4 mm Hg; P = 0.003) (mean ± SD) pressure at enrollment than those who remained dementia-free. When examined as a continuous variable and adjusted for age, sex and education, the risk of developing dementia for each 10-mm Hg decrement in BP was significant for AD (hazard ratio (HR) = 1.23) but not for vascular dementia (HR = 1.15).  Low diastolic BP (£ 70 mm Hg) increased the risk of developing dementia (HR = 1.64, n = 24), especially AD (HR = 1.91, n = 15). 
    In a similar study, Qiu et al studied a community-based, dementia-free cohort (n = 1,270) aged 75 to 101 years.  During the 6-year follow up period, 339 subjects were diagnosed with dementia (256 persons with AD). Subjects with very high systolic pressure (>180 vs 141-180 mm Hg) had an adjusted relative risk of 1.5 (95% CI 1.0-2.3; P =.07) for AD, and 1.6 (95% CI, 1.1-2.2) for dementia. In contrast, extremely low diastolic pressure (</=65 vs 66-90 mm Hg) produced an adjusted relative risk of 1.7 (95% CI, 1.1-2.4) for AD and 1.5 (95% CI, 1.0-2.1; P =.03) for dementia. Limitations inherent to epidemiological observations should be considered when interpreting these results, but lower diastolic blood pressure was associated with increased risk of dementia in these large cohorts of elderly subjects.

    Verghese,J, Lipton,RB, Hall,CB et al (2003)  Low blood pressure and the risk of dementia in very old individuals.  Neurology 61:1667-1672.
    Qiu,C, von Strauss,E, Fastbom,J et al (2003)  Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study.  Arch Neurol 60:223-228.

Venous compliance is genetically determined
Approximately 75% of the circulating blood volume is contained in veins.  Therefore, relatively small changes in venous function may have a substantial effect on the cardiovascular system, particularly in the upright posture, when 500-1000 ml pool below the diaphragm.  Brinsuk et al. studied the heritability of venous function in 22 dizygotic and 24 monozygotic twins.  Venous compliance was assessed by measuring the increase limb volume (impedance) induced by occluding venous return at increasing pressures.  Venous compliance was highly correlated between monozygotic twins but not between dizygotic twins.  Heritability estimate for venous compliance was significant even after adjustment for age, gender and body mass index.  These results suggest that venous function is influenced by genetic factors, and demonstrate the power of this approach in screening for genetic traits. 

Brinsuk,M, Tank,J, Luft,FC et al (2004)  Heritability of venous function in humans.  Arter Thromb Vasc Biol 24:207-211.