REGULATION OF CARDIAC RHYTHM & CONDUCTION WITH AGING

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Sinus and atrioventricular (AV) node dysfunction are predominantly diseases of the elderly. Although these disorders occur spontaneously, a frequent presentation of the geriatric patient is bradycardia or heart block after receiving a cardioactive drug such as digoxin, a calcium channel blocker, beta-adrenergic blocker, or antiarrhythmic drug. In studying the increased sensitivity of the sinus node to verapamil in senescent humans and right atria from senescent Fischer 344 rats, striking and consistent age-related differences in heart rate were seen between senescent and mature humans and in tissues from senescent vs. mature rats in the absence of any drugs. Preliminary analyses of heart rate variation show decreases in both sympathetic and parasympathetic input on regulation of heart rate in intact senescent humans. However, in three denervated models of aging--beagles following pharmacologic autonomic blockade, isolated right atria and Langendorff perfused hearts from Fischer 344 rats--decreases in heart rate and increases in AV conduction time were also consistently seen with aging. These data lead to the hypothesis that the intrinsic function of the sinus and AV nodes, autonomic influences on their function, and responsiveness to these structures to drugs are significantly altered with aging. Our long- term goals are to determine the mechanisms underlying age-related differences in autonomic regulation of heart rate, AV conduction, and metabolic and receptor-regulated activities of cardiac nodal tissues to understand how aging alters the sensitivity of these critical structures to many of the pharmacologic interventions frequently used in the treatment of the elderly. We propose studies in man to investigate age-related changes in autonomic influences by analyzing heart rate variation and AV conduction before and after autonomic blockade and stimulation. Using the Fischer 344 rat heart, we propose to evaluate age-related differences in adrenergic, cholinergic, purinergic, and calcium receptor-mediated regulation of AV nodal conduction using a combination of electrophysiologic, scintigraphic, and biochemical techniques. The Langendorff perfusion model will be used to assess age- related dromotropic responses to adrenergic, cholinergic, purinergic, calcium, and caffeine stimulation. With radioiodinated metaiodobenzylguanidine (MIBG), a guanidine analogue used to quantitatively assess sympathetic innervation, scintigraphy will be used to assess age- related changes in norepinephrine uptake and release in AV nodal tissues in the absence and presence of drugs and stimuli which modulate sympathetic activity. Potential age-related changes in cholinergic, adrenergic, purinergic, and calcium receptor density in the AV nodal region will be assessed with quantitative autoradiography. Using quantitative histochemistry, adrenergic signal transduction in sections from the AV nodal region will be assessed by measurement of cAMP accumulation. These experiments are a biochemical correlate of post-beta-receptor alterations with aging. Age differences in glycolytic metabolic enzymes, glycogen, and glycogen electrophysiologic, scintigraphic, and biochemical techniques should provide important new insights into the mechanisms underlying the striking changes in heart rate, AV conduction, and sensitivity to cardioactive drugs in the elderly.