Demography of Syncope
Alpha Agonists in Syncope
Aging and Alpha-Adrenoreceptors
Genetics of Baroreflex Function
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Focus on nitric oxide
Nitric oxide (NO) is arguably the most important local endogenous vasodilator. Its evanescent nature suggests that its effects are confined to the site of production. It has been argued that hemoglobin can act as a carrier, transporting NO to distal sites where it can be delivered and act as a distant vasodilator. Rassaf et al. report that NO can interact with plasma proteins to form S-nitrosothiols (RSNOs) which can also act as NO carriers. They infused pharmacological doses of aqueous NO solutions into a hand vein and showed increases in antecubital vein RNSO levels, and forearm vasodilation in the contralateral arm. Intravenous NO also lowered blood pressure without much change in heart rate. These results support the notion that NO can be transported to induce distal vasodilation. To what degree this occurs under physiological conditions is not clear.
It is known that the exercising muscle elicits systemic sympathetic activation but is locally protected from the resultant vasoconstriction by a process coined “functional sympatholysis”. To test the potential role of NO on this phenomenon, Chavoshan et al. induced sympathetic activation using lower body negative pressure (LBNP) while monitoring forearm muscle microcirculation with near-infrared spectroscopy. LBNP decreased muscle oxygenation by 20% in resting forearm, but only by 2% in exercising forearm. This functional sympatholysis was not observed after suppression of NO synthesis by L-NAME, suggesting a role of NO in this process (for more on functional sympatholysis, see Autonomic News, Clin Auton Res (2002) volume 12, number 4).
Despite its beneficial effects, NO may have a dark side. NO reacts with superoxide anion to form peroxynitrate which is damaging to the endothelium and the perinerium. This biochemical reaction can be estimated by measuring the nitrotyrosine component of protein. Hoedltke et al. followed 37 patients with type I diabetes for three years and measured peripheral nerve function and nitrosative stress annually. Levels of nitrite/nitrate (NO metabolites), nitrotyrosine (nitrosative oxidation) and isoprostanes (oxidative stress) were higher in diabetic patients, particularly those poorly controlled. These measurements correlated with impaired peripheral nerve function. Although a causal relationship was not established in this study, these results raise the possibility that nitrosative stress contributes to the pathophysiology of diabetes.
Rassaf T, Kleinbongard P, Preik M et al. (2002) Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO: Experimental and Clinical Study on the Fate of NO in Human Blood. Circ Res 91:470-477.
Chavoshan B, Sander M, Sybert TE et al. (2002) Nitric oxide-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle. J Physiol 540:377-386.
Hoeldtke RD, Bryner KD, McNeill DR et al. (2002) Nitrosative stress, uric Acid, and peripheral nerve function in early type 1 diabetes. Diabetes 51:2817-2825.
and prognosis of syncope in the general population. Confirming our suspicions.
Several studies have described the prognosis of the different causes of syncope, but virtually all have been based in referral centers and very little information is available in the general population. Soteriades et al. report that 822 out of 7814 participants in the Framingham study had syncope during an average follow-up of 17 years, an incidence of 6.2 per 1000 person-years. Assuming this figure can be applied to the US population (~288M), this would mean that 1.79M people will have syncope every year. The incidence of syncope increased significantly after age 70. The cause of syncope was assigned by review of medical records as vasovagal (21%), cardiac (10%), orthostatic (10%) and unknown (37%). Mortality was increased 2-fold in patients with cardiac syncope. Patients with vasovagal syncope had identical survival as subjects without syncope. Subjects with unknown causes of syncope were at intermediate risk. Subjects with neurological causes of syncope (stroke, transient ischemic attacks or seizure) had worse prognosis compare to vasovagal syncope, but this was mostly due to a higher incidence of stroke. This study confirms the widely held view that cardiogenic syncope carries a bad prognosis, whereas neurogenic (vasovagal) syncope is a benign condition. It also provides important incidence information in a general population.
Soteriades ES, Evans JC, Larson MG et al. (2002) Incidence and prognosis of syncope. N Engl J Med 347:878-885.
in the treatment of syncope and hypotension
Despite the high incidence of neurogenic syncope and the medical costs associated with it, treatment remains a challenge. Kaufmann reports a double-blind, randomized, crossover study showing that the selective α1-adrenergic agonist midodrine (5 mg) prevented head-up tilt induced syncope in 10/12 patients with a history of recurrent syncope, compared to 4/12 while on placebo. These results indicate that midodrine significantly improves orthostatic tolerance during head-up tilt in patients with recurrent neurally-mediated syncope. It is still not clear if normalization of tilt responses predicts response to therapy. However, a similar study by Takata et al. using lower body negative pressure to simulate orthostatic stress found that the serotonin reuptake inhibitor Paxil, another drug commonly used to treat neurocardiogenic syncope, did not improve orthostatic tolerance. Hoeben et al. found that midodrine also prevents hypotension in end-stage renal disease patients during dialysis. Of interest, this was associated with preservation of central blood volume and cardiac output, rather than by elevating peripheral vascular resistance. Such a hemodynamic profile, if documented during upright tilt, would be ideal in the management of orthostatic hypotension.
Kaufmann H, Saadia D, and Voustianiouk A (2002) Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study. Ann Neurol 52:342-345.
Takata TS, Wasmund SL, Smith ML et al. (2002) Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. Circulation 106:1500-1504.
Hoeben H, Abu-Alfa AK, Mahnensmith R et al. (2002) Hemodynamics in patients with intradialytic hypotension treated with cool dialysate or midodrine. American Journal of Kidney Diseases 39:102-107.
vasoconstriction with aging
Sympathetic nerve activity (measured in the muscle, MSNA) and plasma norepinephrine increase with age. However, there is evidence that sympathetically-mediated vasoconstriction is decreased in the elderly. To determine if this paradoxical response is due to a reduction in postjunctional α-adrenergic responsiveness to norepinephrine, Dinenno et al. examined the forearm vasoconstrictor response to α-agonists (phenylephrine for α1 and clonidine for α2) and endogenously released norepinephrine (induced by tyramine) in 10 young (mean age 26 years) and 10 older (65 years) healthy men. Studies were done in the presence of β-blockade with propranolol and all drugs were infused into the brachial artery. Tyramine produced less forearm vasoconstriction in the older group, despite inducing a greater increase in venous norepinephrine. The vasoconstrictive response to phenylephrine was also impaired, but that of clonidine was not. These results indicate that aging is associated with a reduction in vasoconstrictive α-adrenergic responsiveness. A similar conclusion was reached by Seals and Jones in a preliminary study presented to the Society (Clin Auton Res (2002) 12:306). These investigators found a decrease in the pressor effect of intravenous phenylephrine in the elderly during ganglionic blockade with trimethaphan (to eliminate baroreflex mechanisms). It is possible that this defect may lead to impair orthostatic tolerance in the elderly.
Dinenno FA, Dietz NM, and Joyner MJ (2002) Aging and forearm postjunctional alpha-adrenergic vasoconstriction in healthy men. Circulation 106:1349-1354.
Genetics of baroreflex
There is substantial evidence that resting blood pressure and baroreflex regulation of blood pressure are strongly influenced by genetic variance. Recently, a mice with disrupted expression of the calcium-sensitive potassium channel (BK) was found to have increased blood pressure. Gollasch et al. used the twin model to determine if this gene (KCNMB1) would play a role in blood pressure regulation in humans. The sequenced the KCNMB1 gene in 30 individuals and found two known and four new single-nucleotide polymorphisms (SNPs). Four of them track with heart rate variability. In particular exon 4b SNP AA individuals had higher high frequency heart rate variability, compared to CA or CC persons. Homozygous AA persons had greater baroreflex slopes than CA or CC persons. These results support the notion that heart rate variability and baroreflex gain are under genetic modulation. It is possible that such variation may also play a role in the development of hypertension.
Gollasch M, Tank J, Luft FC et al. (2002) The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation. Journal of Hypertension 20:927-933.