* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Complexity of Impaired Parasympathetic Heart Rate Regulation in
Survey
Document related concepts
Remote ischemic conditioning wikipedia , lookup
Saturated fat and cardiovascular disease wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Heart failure wikipedia , lookup
Cardiovascular disease wikipedia , lookup
Coronary artery disease wikipedia , lookup
Electrocardiography wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Cardiac surgery wikipedia , lookup
Baker Heart and Diabetes Institute wikipedia , lookup
Myocardial infarction wikipedia , lookup
Transcript
Diabetes Volume 63, June 2014 1847 Jens Jordan and Jens Tank Complexity of Impaired Parasympathetic Heart Rate Regulation in Diabetes Diabetes 2014;63:1847–1849 | DOI: 10.2337/db14-0304 parasympathetic heart rate control is a cardiovascular risk marker (6,7). Whether or not this measurement adds much prognostic information in addition to more readily available risk markers such as microalbuminuria is an unresolved issue. Yet, there may be a window of opportunity when cardiovascular autonomic neuropathy is recognized at an early stage. Treatments slowing the progression of autonomic dysfunction may be particularly beneficial in this setting. For example, in the Diabetes Control and Complications Trial (DCCT), intensive glycemic control substantially reduced the risk for diabetic cardiovascular autonomic neuropathy in type 1 diabetic patients (8). Several other treatments have been suggested but none has been validated in properly controlled clinical trials. Mechanistic insight from suitable animal models could unravel more promising treatment targets. Such studies are difficult because insight at the cellular or molecular level must be translated into whole animals and vice versa. In this issue, Zhang et al. (9) conducted such a study in diabetic Akita mice. In these animals, a point mutation in the insulin 2 gene leads to production of a misfolded protein, pancreatic b-cell destruction, and a metabolic phenotype resembling type 1 diabetes. In an earlier study, the authors had observed diminished bradycardia to muscarinic cholinergic stimulation with carbamylcholine in diabetic Akita mice (10). In this model, impaired parasympathetic heart rate control may result in part from reduced cardiac responsiveness to the parasympathetic neurotransmitter acetylcholine. In the current study, the authors studied heart rate regulation in diabetic Akita mice and in wild-type animals equipped with radiotelemetry electrocardiogram transmitters in more detail. Akita mice showed abnormalities in heart rate variability and exhibited a smaller heart rate increase with atropine. The observation is consistent with impaired parasympathetic heart rate control. Insulin treatment ameliorated cardiac parasympathetic dysfunction. In cardiac atria, diabetic Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany © 2014 by the American Diabetes Association. See http://creativecommons.org /licenses/by-nc-nd/3.0/ for details. Corresponding author: Jens Jordan, [email protected]. See accompanying article, p. 2097. COMMENTARY The autonomic nervous system is crucial for blood pressure and heart rate regulation. Sympathetic efferent fibers elicit vasoconstriction, raise heart rate and cardiac contractility, and promote sodium reabsorption through direct renal tubular actions and renin-angiotensin system activation. Parasympathetic efferent fibers rapidly reduce heart rate. Both autonomic branches are tightly controlled by baroreflex, stabilizing blood pressure in a feedback fashion (1). Severe autonomic failure due to sympathetic and parasympathetic dysfunction typically occurs in patients with long-standing and poorly controlled diabetes. The condition is associated with profound orthostatic hypotension, postprandial hypotension, a fixed heart rate, and exercise intolerance. Positron emission tomography or single photon emission tomography imaging with tracers taken up by adrenergic sympathetic nerve endings suggest that autonomic efferent nerves are irreversibly damaged in these patients (2,3). There are no causative treatments for late-stage disease and symptomatic treatment is difficult. Clinicians caring for autonomic failure patients are faced with the therapeutic dilemma that blood pressure is often markedly elevated in the supine position (4). Yet, antihypertensive treatment exacerbates orthostatic hypotension. Conversely, treatment of orthostatic hypotension with pressor agents might hasten cardiovascular and renal disease progression. The condition carries a poor prognosis. More subtle changes in cardiovascular autonomic regulation are common early in the course of type 1 or type 2 diabetes. Typically, impaired parasympathetic heart rate control precedes sympathetic dysfunction. Simple bedside tests, such as respiratory sinus arrhythmia assessment during deep breathing, are often diagnostic (5). Heart rate variability and noninvasive baroreflex sensitivity measurements are also useful diagnostic tools, particularly in epidemiologic or clinical studies. Early-stage diabetic cardiovascular autonomic dysfunction with impaired 1848 Commentary Akita mice exhibited decreased expression of G-protein coupled inward rectifying K+ channel (GIRK)-4 subunit, which is part of the potassium channel through which muscarinic acetylcholine receptors regulate heart rate. A possible limitation of these ex vivo experiments is that heart rate is generated in specialized pacemaker cells in the sinus node, which likely differ from cardiac atrial cells. Through a series of experiments using elegant pharmacologic, genetic, and electrophysiologic approaches, the authors demonstrated that the impairment in heart rate regulation in diabetic Akita mice could result from glycogen synthase kinase-3b hyperactivity secondary to insulin deficiency. Given the prognostic implications and the symptomatic burden associated with diabetic cardiovascular autonomic dysfunction, it is surprising that studies in suitable animal models are few (11). The difficulty in assessing cardiovascular autonomic regulation in small animals and the lack of methodological standardization may be responsible for lack of progress in this area. For example, Diabetes Volume 63, June 2014 there is controversy in how parasympathetic and sympathetic activity affect heart rate variability in mice across different frequency ranges. Human low-frequency range heart rate variability is generated by sympathetic and parasympathetic activity. In mice, low-frequency heart rate variability is virtually abolished with atropine, consistent with mainly parasympathetic modulation (12). Spontaneous heart rate variability and power spectra in a healthy human being and in a mouse are illustrated in Fig. 1. The mechanism disturbing parasympathetic heart rate control in diabetic Akita mice likely differs from latestage human diabetic autonomic dysfunction. Indeed, not all diabetic mouse models reproduce human cardiovascular autonomic dysfunction. Nonobese diabetic mice exhibit improvements in heart rate variability and baroreflex sensitivity probably through selective sympathetic degeneration (13). Nevertheless, the study by Zhang et al. (9) raises several important issues. The study reminds us that the diagnosis “cardiac autonomic neuropathy” Figure 1—The figure illustrates the profound differences in heart rate regulation between human subjects and mice. Shown are RR-interval (RR-I) changes over 5 min in resting healthy human subject (top left panel). The mean RR-I is 852 ms corresponding to a heart rate of 71 bpm. Pulse intervals (PI) derived from telemetry blood pressure recordings in a healthy mouse (top right panel) over 1 min under resting conditions are shown. The mean PI during the recording is 123 ms corresponding to a heart rate of 487 bpm. We applied power spectral analysis using fast Fourier transformation after interpolation and resampling (4 Hz in human, 12 Hz in mouse) to analyze heart rate variability in the frequency domain. The resulting power spectra are shown in the lower panels (left, human subject; right, mouse). Please note the profound differences in the x- and y-axes scaling indicating an ;1,000 times higher maximum spectral power at much lower frequencies in humans. The definition of low- and high-frequency ranges is somewhat arbitrary and may not reflect the same physiologic mechanism in human subjects and mice. HF, high-frequency range, 0.15–0.4 Hz in humans, 1–6 Hz in mice; LF, low-frequency range, 0.04–0.15 Hz in humans, 0.25–1 Hz in mice; PSD, power spectral density. diabetes.diabetesjournals.org implicating irreversible neuronal damage can be misleading. Much like in diabetic Akita mice, functional and potentially reversible reductions in parasympathetic heart rate control can occur in human beings. More detailed physiologic (14) or pharmacologic (15) tests may be required to differentiate functional and structural parasympathetic dysfunction in diabetic patients. Furthermore, the cause of the change in parasympathetic heart rate control is difficult to localize. Responses to autonomic testing, heart rate variability, and baroreflex sensitivity can be affected by afferent baroreflex input, central nervous autonomic integration, efferent parasympathetic transmission, and end-organ responsiveness. In rabbits with alloxan-induced diabetes, impaired baroreflex heart rate regulation was attributed to impaired activation of central nervous parasympathetic pathways (16). Overall, observations in animal models and in patients strongly support the idea that different mechanisms can elicit cardiovascular autonomic dysfunction. Better dissection of these mechanisms using state-of-the-art integrative physiology may be required to develop better treatments and to target the right treatment to the right patient. Duality of Interest. No potential conflicts of interest relevant to this article were reported. References 1. Jordan J, Tank J, Shannon JR, et al. Baroreflex buffering and susceptibility to vasoactive drugs. Circulation 2002;105:1459–1464 2. Kreiner G, Wolzt M, Fasching P, et al. Myocardial m-[123I]iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM. Comparison with cardiovascular reflex tests and relationship to left ventricular function. Diabetes 1995;44:543–549 3. Allman KC, Stevens MJ, Wieland DM, et al. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol 1993;22:1425–1432 Jordan and Tank 1849 4. Shannon JR, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension 1997;30:1062–1067 5. Tank J, Neuke A, Mölle A, Jordan J, Weck M. Spontaneous baroreflex sensitivity and heart rate variability are not superior to classic autonomic testing in older patients with type 2 diabetes. Am J Med Sci 2001;322:24–30 6. Liao D, Carnethon M, Evans GW, Cascio WE, Heiss G. Lower heart rate variability is associated with the development of coronary heart disease in individuals with diabetes: the atherosclerosis risk in communities (ARIC) study. Diabetes 2002;51:3524–3531 7. Gerritsen J, Dekker JM, TenVoorde BJ, et al. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care 2001;24:1793–1798 8. Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998;41: 416–423 9. Zhang Y, Welzig CM, Picard KL, et al. Glycogen synthase kinase-3b inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice. Diabetes 2014;63:2097–2113 10. Park HJ, Zhang Y, Du C, et al. Role of SREBP-1 in the development of parasympathetic dysfunction in the hearts of type 1 diabetic Akita mice. Circ Res 2009;105:287–294 11. Stables CL, Glasser RL, Feldman EL. Diabetic cardiac autonomic neuropathy: insights from animal models. Auton Neurosci 2013;177:74–80 12. Tank J, Jordan J, Diedrich A, et al. Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension 2004;43:1042–1047 13. Gross V, Tank J, Partke HJ, et al. Cardiovascular autonomic regulation in Non-Obese Diabetic (NOD) mice. Auton Neurosci 2008;138:108–113 14. Rosengård-Bärlund M, Bernardi L, Fagerudd J, et al.; FinnDiane Study Group. Early autonomic dysfunction in type 1 diabetes: a reversible disorder? Diabetologia 2009;52:1164–1172 15. Tank J, Heusser K, Diedrich A, Luft FC, Jordan J. A novel pharmacological approach to determining parasympathetic heart rate reserve in human subjects. Clin Pharmacol Ther 2010;88:630–633 16. McDowell TS, Hajduczok G, Abboud FM, Chapleau MW. Baroreflex dysfunction in diabetes mellitus. II. Site of baroreflex impairment in diabetic rabbits. Am J Physiol 1994;266:H244–H249