Point:Counterpoint: Cardiac denervation does/does not play a major role in exercise limitation after heart transplantation
2007; American Physiological Society; Volume: 104; Issue: 2 Linguagem: Inglês
10.1152/japplphysiol.00694.2007
ISSN8750-7587
Autores Tópico(s)Cardiac Ischemia and Reperfusion
ResumoPOINT-COUNTERPOINTPoint:Counterpoint: Cardiac denervation does/does not play a major role in exercise limitation after heart transplantationArne K. AndreassenArne K. AndreassenPublished Online:01 Feb 2008https://doi.org/10.1152/japplphysiol.00694.2007This is the final version - click for previous versionMoreSectionsPDF (68 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat POINT: CARDIAC DENERVATION DOES PLAY A MAJOR ROLE IN EXERCISE LIMITATION AFTER HEART TRANSPLANTATIONWith more than 100,000 procedures performed worldwide, more than 50% of patients undergoing orthotopic heart transplantation (HTx) survive longer than 10 years and enjoy significant and lasting improvements in their quality of life. However, exercise capacity by objective exercise testing has been shown to be markedly reduced. Despite normal ventricular ejection fraction at rest and a peak oxygen consumption that is higher than compared with preoperative values, exercise performance is typically only 40–60% of age-, sex-, and weight-matched controls. This phenomenon is best explained by the consequences of cardiac denervation at the time of explantation of a donor heart with subsequent HTx.In nontransplanted subjects, the capacity for performing aerobic exercise depends on the ability of the heart to augment its output to exercising muscles and the ability of these muscles to use oxygen from the delivered blood. The increase in cardiac output (typically 4- to 6-fold) is caused by tachycardia operating in concert with increased myocardial contractility (20–50% augmentation of stroke volume) brought about by the greater sympathetic activity, together with the Frank-Starling mechanism (1). The autonomic nervous system plays a key role in the regulation of heart rate. The initial rise in heart rate is due to withdrawal of vagal tone, resulting in an increase of 30–50 beats/min. Thereafter, increments are attributed to an increase in activity to cardiac sympathetic nerves (20).HTx recipients modulate their cardiac output in response to exercise in a different manner than in the normal heart, with no direct parasympathetic or sympathetic innervation. Due to lack of efferent vagal control, resting heart rate is elevated and with limited ability to increase heart rate early in exercise. Thus initial increases in cardiac output are completely dependent on augmented stroke volume (18). Increases in heart rate during later phases of exercise rely on an increase in circulating catecholamines because of sympathetic denervation (18). Importantly, the expected maximal inotropic left ventricular stimulation may also suffer from denervation due to at least two mechanisms. First, intact sympathetic nerve terminals with local norepinephrine release are required for maximum ventricular inotropic stimulation (20). Second, according to the frequency-force relationship, the time interval between beats is a determinant of the force of myocardial contraction. While the background for this last phenomenon is uncertain, it has been linked with calcium availability to contractile elements (4).Several reports have demonstrated an association between subnormal exercise capacity and chronotropic incompetence in the form of reductions in the rate of rise in heart rate, increase in heart rate, and peak exercise heart rate (2, 5, 8–10, 14, 15, 19, 21, 22, 26). The largest studies have also shown that heart rate is a powerful and independent predictor of exercise capacity (8, 9, 14). Assessing maximal symptom-limited graded upright bicycle testing with simultaneous invasive hemodynamic monitoring, Kao et al. (10) described the consequences of a 30% lower heart rate response and 79% lower heart rate reserve in 30 HTx recipients compared with healthy controls. The lower stroke and cardiac index throughout exercise, coupled with inability to compensate with the Starling mechanism, resulted in 43% lower peak weight-adjusted oxygen consumption than in controls. The authors conclude that the chronotropic incompetence “is no doubt a result of the effects of denervation” and a major limiting factor to exercise capacity. The lack of direct innervation of the sinoatrial node as the cause for the attenuated response to peak heart rate to exercise in HTx is strongly supported by the observations that the rise in circulating catecholamines is normal or increased at peak exercise, and the responsiveness of the sinoatrial node to beta-adrenergic stimulation is also normal or increased (7, 23).Serial assessment of exercise capacity in HTx recipients demonstrates some improvement in heart rate and peak V̇o2 during the first postoperative year (9). Nevertheless, they remain less fit at 1 year also compared with patients undergoing coronary artery bypass graft surgery (23). Interestingly, when extending comparisons to renal transplant recipients without denervated hearts, a near-normal exercise capacity is reached within a few months after surgery (6). The latter observation shows that contrary to speculations, the use of standard immunosuppressive medication does not necessarily relate to below-normal exercise capacity. Furthermore, while regular exercise and rehabilitation can improve peak V̇o2 and workload in various patient groups, improvements in heart rate reserve and peak heart rate in HTx recipients are either modest or negligible. In the mentioned comparison with bypass-treated patients, heart rate reserve was unchanged among HTx recipients while it increased significantly in the former group (16). In the only controlled trial of postoperative rehabilitation after HTx, Kobashigawa et al. (13) demonstrated a 2.5 ml·kg−1·min−1 higher increase in peak V̇o2 after 6 mo in the exercise group than in the nonexercising group without any difference in improvement of peak heart rate at the end of the study. Thus, whereas exercise training within the first year after HTx modestly increases the capacity for physical work compared with a more sedentary daily life, this must either be due to a physiological training effect such as improved muscle-skeletal weakness or merely an ability to exercise with greater effort.Although conflicting results have been obtained, some studies describe the abnormal chronotropic response to exercise initially after HTx to return toward normal after 1–2 yr, suggesting sympathetic reinnervation (9, 21). Conclusively observed in animals (12), reinnervation in humans has also been inferred from invasive measurements of transcardiac epinephrine spillover (26), noninvasive imaging with radiolabeled catecholamine analogs (24), and by heart rate variability analyses (11), supported by observations such as typical anginal pain in those with graft vasculopathy (25) and regrowth of nerves across the aortic anastomosis determined by microscopy (17). Taken together, experimental and clinical evidence suggests that some degree of sympathetic reinnervation takes place over time at the sinus and the ventricular level, but not in all patients.Is there a correlation between documented graft reinnervation and physiological improvements in response to exercise, underlining the major role of an intact autonomous nervous system during strenuous activity? Indeed, two studies report improved functional parameters of exercise testing. Evaluated up to 13.4 yr postoperatively, positron emission tomographic (PET) evidence of reinnervation was found in 80% of patients more than 3 yr after HTx, with better peak V̇o2 values than those without signs of reinnervation (27). Bengel et al. (3) added radionuclide angiography to PET examinations and demonstrated sympathetic reinnervation mainly in the anteroseptal wall in 16 of 29 patients with a mean follow-up of 3.2 yr after HTx. Reinnervated patients had a significantly longer exercise time and higher peak heart rate compared with those with denervation. Furthermore, the contractile response to exercise was significantly enhanced in the former group. Although workload and maximal heart rate reached levels that did not differ significantly from controls in this study, reinnervation is incomplete and with a broad individual spread, perhaps explaining why not all follow-up studies are able to pick up improvements in heart rate and peak V̇o2 over time (8).In summary, the persistent impairment in exercise capacity after HTx relates strongly to a combination of chronotropic and inotropic incompetence, both consequences of cardiac denervation. 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Circulation 88: 165–171, 1993.Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByPre-innervated tissue-engineered muscle promotes a pro-regenerative microenvironment following volumetric muscle loss25 June 2020 | Communications Biology, Vol. 3, No. 1Impaired Exercise Tolerance Early After Heart Transplantation Is Associated With Development of Cardiac Allograft Vasculopathy3 January 2020 | Transplantation, Vol. 104, No. 10Cardiac reinnervation affects cardiorespiratory adaptations to exercise training in individuals with heart transplantation11 October 2019 | European Journal of Preventive Cardiology, Vol. 27, No. 11Increasing heart transplant donor pool by liberalization of size matchingThe Journal of Heart and Lung Transplantation, Vol. 38, No. 11Sinus tachycardia is associated with impaired exercise tolerance following heart transplantation9 April 2017 | Clinical Transplantation, Vol. 31, No. 5Allometry of left ventricular myocardial innervation10 December 2013 | Journal of Anatomy, Vol. 224, No. 4Cardiac Size and Sex-Matching in Heart TransplantationJACC: Heart Failure, Vol. 2, No. 1The relationship between physical activity and heart rate variability in orthotopic heart transplant recipients17 September 2012 | Journal of Clinical Nursing, Vol. 21, No. 21-22Exercise Limitation Following Transplantation1 July 2012Cardiac allograft hypertrophy is associated with impaired exercise tolerance after heart transplantationThe Journal of Heart and Lung Transplantation, Vol. 30, No. 10Rebuttal from Dr. Andreassen1 February 2008 | Journal of Applied Physiology, Vol. 104, No. 2Rebuttal from Drs. Richard, Zoll, Mettauer, Piquard, and Geny1 February 2008 | Journal of Applied Physiology, Vol. 104, No. 2Last Word on Point:Counterpoint: Cardiac denervation does/does not play a major role in exercise limitation after heart transplantationBernard Geny, Ruddy Richard, Joffrey Zoll, Anne Charloux, and Francois Piquard1 February 2008 | Journal of Applied Physiology, Vol. 104, No. 2Cardiac denervation does/does not play a major role in exercise limitation after heart transplantationClaudio Marconi, Mauro Marzorati, and Paolo Cerretelli1 February 2008 | Journal of Applied Physiology, Vol. 104, No. 2 More from this issue > Volume 104Issue 2February 2008Pages 559-560 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00694.2007PubMed17615275History Published online 1 February 2008 Published in print 1 February 2008 Metrics
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