Raffaello Furlan

1. sympatho-sympatho neural reflexes with positive feed-back characteristics. They were hypothesized to constitute the anatomo/functional pathway of previously unknown neural mechanisms interacting with the negative feed-back mechanisms during physiological conditions. Also, it was hypothesized that neural positive feed-back mechanisms might play a role in pathophysiology by reinforcing the excitatory effects of the so called central command thus resulting in an excessive sympathetic activity to the vessels which in turn might underlie essential hypertension.
2. excitatory sympathetic reflexes elicited by intracoronary administration of low dosage of bradykinin. Bradykinin resulted in an increase of heart rate, blood pressure, left ventricle dP/dt in the absence of pain. This finding showed the potentiality of pressor reflexes arising from the intact heart and how they can manifest in the conscious state independently of pain (Circ Res 1985;56:175-183).

Detailed description of clinical research

• Beat by beat invasive blood pressure 24-hour monitoring in ambulant individuals (Circ Res  1986;59:178-193).

From 1982 to 1988 he contributed to develop a new technique for continuous 24-hour recording of direct high fidelity arterial pressure and electrocardiogram (Cardiovasc Res 1986;20:384-388) and right ventricle pressure (J Amb Monitoring 1993;6:47-54) in ambulant patients. The technique was based on the use of a Millar pressure tip microtransducer (diameter 0.8 mm, 3F) which was inserted into the radial artery of the non-dominant arm by a Seldinger’s approach and pushed up to the heart level. For right ventricular pressure recordings the transducer was inserted percutaneously through the right jugular vein and pushed down to the right ventricle. The transducer was connected to a modified 24-hour holter recorder which enabled us to record both arterial blood pressure (or right ventricular pressure) and ECG up to 24 hours.

• Assessment of the autonomic profile of humans in physiological and pathophysiological conditions by power spectrum analysis of heart rate and non-invasive beat by beat blood pressure variability (Circ Res  1986;59:178-193; Hypertension 1988;12:600-610)

– Physiological aspects

At rest two major spectral components characterize heart rate variability: the low frequency component: (LF_RR , ~0.1 Hz , in normalized units, n.u.) which quantifies the sympathetic modulation of the seno-atrial node and the high frequency component (HF_RR, ~0.25 Hz) an index of the cardiac vagal modulation. The low frequency component of systolic arterial pressure variability (LF_SAP) is a marker of the sympathetic vasomotor regulation.

Changes in these markers over 24 hours (Circulation 1990;81:537-547), during the up-right position (Circulation 2000;101:886-892), mental stress (J Auton Nerv Syst 1991;35:33-42), shift work (Circulation 2000;102:1912-1916), or following physical training (Cardiovasc Res 1993;27:482-488), have furnished valuable non-invasive information on the autonomic modifications attending different functional conditions in healthy subjects.

– Pathophysiological aspects

Since the beginning of the nineties and more recently, Dr Furlan used power spectrum analysis techniques to assess the changes of the autonomic profile preceding neurally-mediated syncope (Circulation 1998;98:1756-1761; Circulation 2000;102:2898-2906), in patients with dysautonomias and Pure Autonomic Failure (Pure Autonomic Failure), Chronic Orthostatic Intolerance (POTS) (Circulation  1998;98:2154-2159; Circulation 1999;99:1706-1712.), Fibromyalgia (J Rheumatol 2005;32:1787-1793), active ulcerative colitis (Am J Physiol Regul Integr Comp Physiol 2006;290:224-232), diabetes mellitus (J Clin Endocrinol Metab 2010) and Parkinson’s disease (Hypertension 2007;49:120-126.). As to patients with ulcerative colitis, it is important to point out that they showed a remarkable increase in the spectral indices of cardiac and vascular sympathetic activity together with huge sympathetic neural firing (muscle sympathetic nerve activity, MSNA) in baseline conditions. In addition, a subgroup of those patients who underwent transdermal sympatholitic treatment by clonidine showed a clinical and endoscopic amelioration of the disease, thus highlighting not only the crucial role played by the original sympathetic over-activity in sustaining active ulcerative colitis but also the potential usefulness of a pharmacology induced reduction of the sympathetic activity to clinically control the disease. (Am J Physiol Regul Integr Comp Physiol 2006;290:224-232).

• Direct recording of post-ganglionic sympathetic nerve activity (Muscle sympathetic nerve activity, MSNA)

During a 18-month sabbatical at the Autonomic Dysfunction Center, Clinical Research Center, Vanderbilt University (Nashville, TN, USA) in 1995, as a visiting scholar he was taught to use microneurography techniques to directly record the sympathetic neural firing in humans (J Clin Invest 1997;99:2736-2744). Thereafter, as a visiting professor with Vanderbilt colleagues, he used such a technique to assess the role of carotid baroreceptor modulation and the problem of laterality in the sympathetic neural traffic (Am J Physiol Heart Circ Physiol 2009;296:H1758-H1765; J Physiol 2012;590:647-648). By adding to that methodology the plasma catecholamines assessment and their systemic and local spill-over, he studied the cardiovascular autonomic changes before neurally-mediated syncope (J Clin Invest 1997;99:2736-2744; J Clin Invest 1998;102:1824-1830; Circulation 2000;102:2898-2906),) and in POTS (Circulation  1998;98:2154-2159). Since 1997, MSNA recordings have been performed in Italy in patients with fibromyalgia (J Rheumatol 2005;32:1787-1793), baroreceptor failure (Orthostatic Intolerance: Different Abnormalities in the Neural Sympathetic Response to a Gravitational Stimulus. Autonomic Neuroscience: Basic and Clinic 2001;90:83-88.), ulcerative colitis (Am J Physiol Regul Integr Comp Physiol 2006;290:224-232). Studies are in progress to assess the autonomic profile of patients with Sjogren disease.

• Arterial and cardiopulmonary baroreceptor control of heart rate and MSNA (Hypertension 1988, Circulation 2004, Circulation 2003).

In collaboration with Vanderbilt University colleagues, by using pharmachological probes such as Atenolol (Circulation 2004;110:2786-2791), Sodium Nitroprusside and Phenylephrine (J Clin Invest 1997;99:2736-2744.) infusions, progressive orthostatic stimulus (15° step-wise Head-up Tilt test) (Circulation 2000;101:886-892.), increasing levels of lower body negative pressure (LBNP) up to -40 mmHg (Circulation 2001;104:2932-2937), or neck chamber sinusoidal stimulation (Circulation 2003;108:717-723), arterial and cardiopulmonary baroreceptor mechanisms were studied in healthy subjects and in patients with neurally mediated syncope and POTS.

• Miscellanea

Dr Furlan used power spectrum analysis techniques to evaluate autonomic rhythms potentially reflected in growth lines of teeth in humans and extinct archosaurs. (Autonomic Neuroscience: Basic and Clinic 2005;117:115-119.). Same spectrum analysis techniques were used to assess the influence of climate on emergency department visits for syncope and the role of air temperature variability (PLoS ONE 2011;6:e22719). In collaboration with the bioengineers of the Politecnico (Milan, L. Divieti laboratory for the study of movement disorders), the effects of a mechanical stimulation of the feet on gait and cardiovascular autonomic control were assessed in patients with Parkinson’s disease. (J Appl Physiol  2014;116:495-503).

• Clinical studies

From January to July 2004, the Sacco Hospital Syncope Unit leaded a prospectic multicenter clinical study aimed at evaluating the short and long term prognosis of patients presenting to the Emergency Department (ED) for syncope (STePS study, Short Term Prognosis of Syncope). This study (J Am Coll Cardiol 2008;51:276-283) addressed a major weakness of the letterature that is the comparison between the 10-day and one-year prognoses of syncope and the related risk factors. Short and long-term risk factors turned out to be different. We hypothesized that the prompt identification of short-term risk factor might help emergency doctors in their decision making process and in turn reduce inappropriate hospital admissions. From the STePS data base, a second study was organized. That investigation focused on the problems of the risk stratification in the ED (Am J Emerg. Med. 2010). A third related study addressed the criteria used by ED physician when admitting patients with syncope to hospital (Int J Cardiol 2012;161:182-183.) and a fourth one addressed the role of environmental temperature changes in the rate of ED admission for syncope(PLoS ONE 2011;6:e22719).

In 2005, the Sacco Hospital Syncope Unit took part to a multicenter clinical study (EGSYS2) aimed at evaluating the suitability of the European Society of Cardiology syncope guide-lines in helping doctors in their ED decision making (Eur Heart J 2006;27:76-82).

In September 2013, Dr. Furlan organized the First International Workshop on Syncope Risk Stratification in the Emergency Department (Gargnano, BS). From that International Consensus, priorities about clinical research on syncope (Ann Emerg Med 2014;64:649-655) and an international consensus on syncope clinical management in the ED setting (Eur Heart J. 2016;37:1493-8) were obtained. More recently, the Artificial Neural Network approach was used as a toll to stratify syncope risk in the Emergency Departments (Health Policy 2016;120:111-119).

Current research interests

[number of dissertations available (N=) for medical students and medical doctors specializing in Internal and Emergency Medicine]

• Dynamics of pulmonary gas exchange and systemic oxygen delivery during exercise in patients affected by Postural Tachycardia Syndrome (POTS) and Hypertension (N=1).
• Altered sympathetic response to gravitational stimulus after bed rest: mechanistic insights into orthostatic intolerance from MSNA (N=2).