Abstract
Both deterioration of the mechanical vascular properties of barosensitive vessels and autonomic derangement lead to modification of baroreflex sensitivity (BRS) in coronary artery disease (CAD) individuals. Type 2 diabetes (T2D) reduces BRS as well even in absence of cardiac autonomic neuropathy. The aim of the study is to clarify whether, assigned the degree of mechanical vascular impairment and without cardiac autonomic neuropathy, the additional autonomic dysfunction imposed in CAD patients by T2D (CAD-T2D) decreases BRS further. We considered CAD (n = 18) and CAD-T2D (n = 19) males featuring similar increases of average carotid intima media thickness (ACIMT) and we compared them to age- and gender-matched healthy (H, n = 19) subjects. BRS was computed from spontaneous beat-to-beat variability of heart period (HP) and systolic arterial pressure (SAP) at supine resting (REST) and during active standing (STAND). BRS was estimated via methods including time domain, spectral, cross-spectral, and model-based techniques. We found that (i) at REST BRS was lower in CAD and CAD-T2D groups than in H subjects but no difference was detected between CAD and CAD-T2D individuals; (ii) STAND induced an additional decrease of BRS visible in all the groups but again BRS estimates of CAD and CAD-T2D patients were alike; (iii) even though with different statistical power, BRS markers reached similar conclusions with the notable exception of the BRS computed via model-based approach that did not detect the BRS decrease during STAND. In presence of a mechanical vascular impairment, indexes estimating BRS from spontaneous HP and SAP fluctuations might be useless to detect the additional derangement of the autonomic control in CAD-T2D without cardiac autonomic neuropathy compared to CAD, thus limiting the applications of cardiovascular variability analysis to typify CAD-T2D individuals.

Graphical representation of the baroreflex sensitivity (BRS) estimated from spontaneous fluctuations of heart period and systolic arterial pressure via transfer function (TF) in low frequency (LF) band (from 0.04 to 0.15 Hz). BRS was reported as a function of the group (i.e., healthy (H), coronary artery disease (CAD) and CAD with type 2 diabetes (CAD-T2D) groups) at REST (black bars) and during STAND (white bars). Values are shown as mean plus standard deviation. The symbol “*” indicates a significant difference between conditions within the same group (i.e., H, CAD, or CAD-T2D) and the symbol “§” indicates a significant difference between groups within the same experimental condition (i.e., REST or STAND). BRS cannot distinguish CAD and CAD-T2D groups both at REST and during STAND, while it is useful to distinguish experimental conditions and separate pathological groups from H subjects.

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Smyth HS, Sleight P, Pickering GW (1969) Reflex regulation of the arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24:109–121
Pickering TG, Gribbin B, Sleight P (1972) Comparison of the reflex heart rate response to rising and falling arterial pressure in man. Cardiovasc Res 6:277–283
Kawada T, Shimizu S, Hayama Y, Yamamoto H, Saku K, Shishido T, Sugimachi M (2018) Derangement of open-loop static and dynamic characteristics of the carotid sinus baroreflex in streptozotocin-induced type 1 diabetic rats. Am J Phys 315:R553–R567
Robertson D, Diedrich A, Chapleau MW (2012) Editorial on arterial baroreflex issue. Auton Neurosci-Basic Clin 172:1–3
Penzel T, Kantelhardt JW, Bartsch RP, Riedl M, Kraemer JF, Wessel N, Garcia C, Glos M, Fietze I, Schöbel C (2016) Modulations of heart rate, ECG, and cardio-respiratory coupling observed in polysomnography. Front Physiol 7:460
Furlan R, Jacob G, Snell M, Robertson D, Porta A, Harris P, Mosqueda-Garcia R (1998) Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation 98:2154–2159
Lucini D, Furlan R, Villa P, Mosqueda Garcia R, Diedrich A, Robertson D, Malliani A, Porta A, Pagani M (2004) Altered profile of baroreflex and autonomic responses to lower body negative pressure in chronic orthostatic intolerance. J Hypertens 22:1535–1542
Norcliffe-Kaufmann L, Axelrod F, Kaufmann H (2010) Afferent baroreflex failure in familial dysautonomia. Neurology 75:1904–1911
Goldstein DS (2014) Dysautonomia in Parkinson’s disease: neurocardiological abnormalities. Compr Physiol 4:805–826
Monahan KD, Dinenno FA, Seals DR, Clevenger CM, Desouza CA, Tanaka H (2001a) Age associated changes in cardiovascular baroreflex sensitivity are related to central arterial compliance. Am J Phys 281:H284–H289
Monahan KD, Tanaka H, Dinenno FA, Seals DR (2001b) Central arterial compliance is associated with age-and habitual exercise- related differences in cardiovagal baroreflex sensitivity. Circulation 104:1627–1632
Gianaros PJ, Jennings RJ, Olafsson GB, Steptoe A, Sutton-Tyrrell K, Muldoon MF, Manuck SB (2002) Greater intima-media thickness in the carotid bulb is associated with reduced baroreflex sensitivity. Am J Hypertens 15:486–491
Mattace-Raso F, van den Meiracker AH, Bos WJ, van der Cammen TJM, Westerhof BE, Elias-Smale S, Reneman RS, Hoeks APG, Hofman A, Witteman JCM (2007) Arterial stiffness, cardiovagal baroreflex sensitivity and postural blood pressure changes in older adults: the Rotterdam study. J Hypertens 25:1421–1426
Lucini D, Palombo C, Malacarne M, Pagani M (2012) Relationship between carotid artery mechanics and the spontaneous baroreflex: a noninvasive investigation in normal humans. J Hypertens 30:1809–1816
Labrova R, Honzikova N, Maderova E, Vysocanova P, Novakova Z, Zavodna E, Fiser B, Semrad B (2015) Age-dependent relationship between the carotid intima-media thickness, baroreflex sensitivity, and the inter-beat interval in normotensive and hypertensive subjects. Physiol Res 54:593–600
Nollo G, Porta A, Faes L, Del Greco M, Disertori M, Ravelli F (2001) Causal linear parametric model for baroreflex gain assessment in patients with recent myocardial infarction. Am J Phys 280:H1830–H1839
Diaz T, Taylor JA (2006) Probing the arterial baroreflex: is there a ‘spontaneous’ baroreflex? Clin Auton Res 16:256–261
Katsube Y, Sato H, Naka M, Kim BH, Kinoshita N, Koretsune Y, Hori M (1996) Decreased baroreflex sensitivity in patients with stable coronary artery disease is correlated with the severity of coronary narrowing. Am J Cardiol 78:1007–1010
Radaelli A, Castiglioni P, Balestri G, Cesana F, De Carlini C, Soriano F, Azzellino A, di Rienzo M, Paolini G, Ferrari AU, Mancia G (2010) Increased pulse wave velocity and not reduced ejection fraction is associated with impaired baroreflex control of heart rate in congestive heart failure. J Hypertens 28:1908–1912
Kablak-Ziembicka A, Tracz W, Przewlocki T, Pieniazek P, Sokolowski A, Konieczynska M (2004) Association of increased carotid intima-media thickness with the extent of coronary artery disease. Heart 90:1286–1290
Nasr N, Pavy-Le Traon A, Larrue V (2005) Baroreflex sensitivity is impaired in bilateral carotid atherosclerosis. Stroke 36:1891–1895
Airaksinen KE, Ikaheimo MJ, Linnaluoto MK, Niemela M, Takkunen JT (1987) Impaired vagal heart rate control in coronary artery disease. Br Heart J 58:592–597
Hayano J, Sakakibara Y, Yamada M, Ohte N, Fujinami T, Yokoyama K, Watanabe Y, Takata K (1990) Decreased magnitude of heart rate spectral components in coronary artery disease its relation to angiographic severity. Circulation 81:1217–1224
Huikuri HV, Niemelä MJ, Ojala S, Rantala A, Ikäheimo MJ, Airaksinen KE (1994) Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease. Effects of arousal and upright posture. Circulation 90:121–126
Ghaffari S, Kazemi B, Aliakbarzadeh P (2011) Abnormal heart rate recovery after exercise predicts coronary artery disease severity. Cardiol J 18:47–54
Karjalainen JJ, Kiviniemi AM, Hautala AJ, Piira O-P, Lepojärvi ES, Peltola MA, Ukkola OH, Hedberg PSM, Huikuri HV, Tulppo MP (2014) Determinants and prognostic value of cardiovascular autonomic function in coronary artery disease patients with and without type 2 diabetes. Diabetes Care 37:286–294
Garcia de Moura-Tonello SC, Porta A, Marchi A, de Almeida Fagundes A, de Oliveira Francisco C, Rehder-Santos P, Milan-Mattos JC, Polaquini Simões R, de Oliveira Gois M, Catai AM (2016) Cardiovascular variability analysis and baroreflex estimation in patients with type 2 diabetes in absence of any manifest neuropathy. PLoS One 11:e0148903
Kiviniemi AM, Hautala AJ, Karjalainen JJ, Piira OP, Lepojärvi S, Tiinanen S, Seppanen T, Ukkola O, Huikuri HV, Tulppo MP (2013) Impact of type 2 diabetes on cardiac autonomic responses to sympathetic stimuli in patients with coronary artery disease. Auton Neurosci-Basic Clin 179:142–147
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115:459–467
Robbe HWJ, Mulder LJM, Ruddel H, Langewitz WA, Veldman JBP, Mulder G (1987) Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10:538–543
Pagani M, Somers VK, Furlan R, Dell’Orto S, Conway J, Baselli G, Cerutti S, Sleight P, Malliani A (1988) Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 12:600–610
De Boer RW, Karemaker JM, Strackee J (1985) Relationships between short-term blood pressure fluctuations and heart rate variability in resting subjects I: a spectral analysis approach. Med Biol Eng Comput 23:352–358
Saul JP, Berger RD, Chen MH, Cohen RJ (1989) Transfer function analysis of autonomic regulation II. Respiratory sinus arrhythmia. Am J Phys 256:H153–H161
Porta A, Baselli G, Rimoldi O, Malliani A, Pagani M (2000) Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration. Am J Phys 279:2558–2567
Baselli G, Cerutti S, Badilini F, Biancardi L, Porta A, Pagani M, Lombardi F, Rimoldi O, Furlan R, Malliani A (1994) Model for the assessment of heart period and arterial pressure variability interactions and of respiration influences. Med Biol Eng Comput 32:143–152
Porta A, Bassani T, Bari V, Pinna GD, Maestri R, Guzzetti S (2012) Accounting for respiration is necessary to reliably infer granger causality from cardiovascular variability series. IEEE Trans Biomed Eng 59:832–841
Porta A, Bari V, Bassani T, Marchi A, Pistuddi V, Ranucci M (2013) Model-based causal closed-loop approach to the estimate of baroreflex sensitivity during profol anesthesia in patients undergoing coronary artery bypass graft. J Appl Physiol 115:1032–1042
Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KUO, Eckberg DL (1999) Human responses to upright tilt: a window on central autonomic integration. J Physiol 517:617–628
Furlan R, Porta A, Costa A, Tank J, Baker L, Schiavi R, Robertson D, Malliani A, Mosqueda-Garcia R (2000) Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. Circulation 101:886–892
Marchi A, Colombo R, Guzzetti S, Bari V, Bassani T, Raimondi F, Porta A (2013) Characterization of the cardiovascular control during modified head-up tilt test in healthy adult humans. Auton Neurosci-Basic Clin 179:166–169
Marchi A, Bari V, De Maria B, Esler M, Lambert E, Baumert M, Porta A (2016) Simultaneous characterization of sympathetic and cardiac arms of the baroreflex through sequence techniques during incremental head-up tilt. Front Physiol 7:438
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26:5–20
Boulton AJM, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D (2005) Diabetic neuropathies. A statement by the American Diabetes Association. Diabetes Care 28:956–962
Rowaiye OO, Jankowska EA, Ponikowska B (2013) Baroceptor sensitivity and diabetes mellitus. Cardiol J 20:453–463
Matos-Souza JR, Pithon KR, Gemignani T, Cliquet A, Nadruz W (2009) Carotid intima-media thickness is increased in patients with spinal cord injury independent of traditional cardiovascular risk factors. Atherosclerosis 202:29–31
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability: standards of measurements, physiological interpretation, and clinical use. Circulation 93:1043–1065
Bertinieri G, di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G (1985) A new approach to analysis of the arterial baroreflex. J Hypertens 3:S79–S81
Moura-Tonello SC, Takahashi AC, Francisco CO, Lopes SL, Del Vale AM, Borghi-Silva A, Leal AM, Montano N, Porta A, Catai AM (2014) Influence of type 2 diabetes on symbolic analysis and complexity of heart rate variability in men. Diabetol Metab Syndr 6:13
Thayer JF, Yamamoto SS, Brosschot JF (2010) The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol 141:122–131
Zamir M, Coverdale NS, Barron CC, Sawicki CP, Shoemaker JK (2014) Baroreflex variability and “resetting”: a new perspective. J Biomech 47:237–244
Porta A, Takahashi ACM, Catai AM (2016) Cardiovascular coupling during graded postural challenge: comparison between linear tools and joint symbolic analysis. Braz J Phys Ther 20:461–470
Porta A, Bari V, De Maria B, Cairo B, Vaini E, Malacarne M, Pagani M, Lucini D (2018) Peripheral resistance baroreflex during incremental bicycle ergometer exercise: characterization and correlation with cardiac baroreflex. Front Physiol 9:688
Javorka M, Krohova J, Czippelova B, Turianikova Z, Lazarova Z, Javorka K, Faes L (2017) Basic cardiovascular variability signals: mutual directed interactions explored in the information domain. Physiol Meas 38:877–894
Porta A, Bassani T, Bari V, Tobaldini E, Takahashi ACM, Catai AM, Montano N (2012) Model-based assessment of baroreflex and cardiopulmonary couplings during graded head-up tilt. Comput Biol Med 42:298–305
Lucini D, Porta A, Milani O, Baselli G, Pagani M (2000) Assessment of arterial and cardiopulmonary baroreflex gains from simultaneous recordings of spontaneous cardiovascular and respiratory variability. J Hypertens 18:281–286
Ichinose M, Saito M, Ogawa T, Hayashi K, Kondo N, Nishiyasu T (2004) Modulation of control of muscle sympathetic nerve activity during orthostatic stress in humans. Am J Phys 287:H2147–H2153
Laude D, Elghozi JL, Girard A, Bellard F, Bouhaddi M, Castiglioni P, Cerutti C, Cividjian A, di Rienzo M, Fortrat JO, Janssen B, Karemaker JM, Leftheriotis G, Parati G, Persson PB, Porta A, Quintin L, Regnard J, Rudiger H, Stauss HM (2004) Comparison of various techniques used to estimate spontaneous baroreflex sensitivity (the EuroBaVar study). Am J Phys 286:R226–R231
La Rovere MT, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Febo O, Pinna GD (2011) Comparison of the prognostic values of invasive and noninvasive assessments of baroreflex sensitivity in heart failure. J Hypertens 29:1546–1552
Barthel P, Bauer A, Müller A, Huster KM, Kanters JK, Paruchuri V, Yang X, Ulm K, Malik M, Schmidt G (2012) Spontaneous baroreflex sensitivity: prospective validation trial of a novel technique in survivors of acute myocardial infarction. Heart Rhythm 9:1288–1294
Pinna GD, Porta A, Maestri R, De Maria B, Dalla Vecchia LA, La Rovere MT (2017) Different estimation methods of spontaneous baroreflex sensitivity have different predictive value in heart failure patients. J Hypertens 35:1666–1675
Ranucci M, Porta A, Bari V, Pistuddi V, La Rovere MT (2017) Baroreflex sensitivity and outcomes following coronary surgery. PLoS One 12:e0175008
Studinger P, Goldstein R, Taylor JA (2007) Mechanical and neural contributions to hysteresis in the cardiac vagal limb of the arterial baroreflex. J Physiol 583:1041–1048
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This study was supported by a Research Grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PNPD/Brazil, no. 23038.006927/2011-92; CAPES/CSF/PVE- no. 23038.007721/2013-41).
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All subjects gave their written informed consent. The study was conducted in accordance with the Declaration of Helsinki for medical research involving human subjects and was approved by the Ethics Committee of the Federal University of São Carlos, São Carlos, Brazil (number 311.260).
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de Oliveira Gois, M., Porta, A., Simões, R.P. et al. The additional impact of type 2 diabetes on baroreflex sensitivity of coronary artery disease patients might be undetectable in presence of deterioration of mechanical vascular properties. Med Biol Eng Comput 57, 1405–1415 (2019). https://doi.org/10.1007/s11517-019-01966-3
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DOI: https://doi.org/10.1007/s11517-019-01966-3
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