Postsynaptic α1-Adrenergic vasoconstriction is impaired in young patients with vasovagal syncope and is corrected by nitric oxide synthase inhibition

BACKGROUND: Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS, gravitational pooling excessively reduces central blood volume and cardiac output. In VVS, as in hemorrhage, impaired adrenergic vasoconstriction and venoconstriction result in hypotension. We hypothesized that impaired adrenergic responsiveness because of excess nitric oxide can be reversed by reducing nitric oxide. METHODS AND RESULTS: We recorded cardiopulmonary dynamics in supine syncope patients and healthy volunteers (aged 15-27 years) challenged with a dose-response using the α1-agonist phenylephrine (PE), with and without the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA). Systolic and diastolic pressures among control and VVS were the same, although they increased after L-NMMA and saline+PE (volume and pressor control for L-NMMA). Heart rate was significantly reduced by L-NMMA (P<0.05) for control and VVS compared with baseline, but there was no significant difference in heart rate between L-NMMA and saline+PE. Cardiac output and splanchnic blood flow were reduced by L-NMMA for control and VVS (P<0.05) compared with baseline, while total peripheral resistance increased (P<0.05). PE dose-response for splanchnic flow and resistance were blunted for VVS compared with control after saline+PE, but enhanced after L-NMMA (P<0.001). Postsynaptic α1-adrenergic vasoconstrictive impairment was greatest in the splanchnic vasculature, and splanchnic blood flow was unaffected by PE. Forearm and calf α1-adrenergic vasoconstriction were unimpaired in VVS and unaffected by L-NMMA. CONCLUSIONS: Impaired postsynaptic α1-adrenergic vasoconstriction in young adults with VVS can be corrected by nitric oxide synthase inhibition, demonstrated with our use of L-NMMA

[Cost]effectiveness of withdrawal of fall-risk increasing drugs versus conservative treatment in older fallers: design of a multicenter randomized controlled trial (IMPROveFALL-study)

Background: Fall incidents represent an increasing public health problem in aging societies worldwide. A major risk factor for falls is the use of fall-risk increasing drugs. The primary aim of the study is to compare the effect of a structured medication assessment including the withdrawal of fall-risk increasing drugs on the number of new falls versus 'care as usual' in older adults presenting at the Emergency Department after a fall. Methods/Design. A prospective, multi-center, randomized controlled trial will be conducted in hospitals in the Netherlands. Persons aged 65 years who visit the Emergency Department due to a fall are invited to participate in this trial. All patients receive a full geriatric assessment at the research outpatient clinic. Patients are randomized between a structured medication assessment including withdrawal of fall-risk increasing drugs and 'care as usual'. A 3-monthly falls calendar is used for assessing the number of falls, fallers and associated injuries over a one-year follow-up period. Measurements will be at three, six, nine, and twelve months and include functional outcome, healthcare consumption, socio-demographic characteristics, and clinical information. After twelve months a second visit to the research outpatient clinic will be performed, and adherence to the new medication regimen in the intervention group will be measured. The primary outcome will be the incidence of new falls. Secondary outcome measurements are possible health effects of medication withdrawal, health-related quality of life (Short Form-12 and EuroQol-5D), costs, and cost-effectiveness of the intervention. Data will be analyzed using an intention-to-treat analysis. Discussion. The successful completion of this trial will provide evidence on the effectiveness of withdrawal of fall-risk increasing drugs in older patients as a method for falls reduction. Trial Registration. The trial is registered in the Netherlands Trial Register (NTR1593)

When sinus tachycardia becomes too much: negative effects of excessive upright tachycardia on cardiac output in vasovagal syncope, postural tachycardia syndrome, and inappropriate sinus tachycardia.

Background - Upright posture reduces venous return, stroke volume and cardiac output (CO) while causing reflex sinus rate (HR) increase. Yet, in inappropriate sinus tachycardia (IST), postural tachycardia syndrome (POTS), and vasovagal syncope (VVS) symptomatic excessive HR occurs. We hypothesized CO reaches maximum as function of HR in all. Methods - We recruited 12 healthy controls, 9 IST, 30 VVS and 30 POTS patients (13-23years) selected randomly by disorder not by HR, each fulfilled appropriate diagnostic criteria. Subjects were instrumented for electrocardiography, beat-to-beat blood pressure, respiratory rate, CO-Modelflow algorithm, and central blood volume (CBV) from impedance cardiography; 10min data was collected supine; subjects were tilted head-up for =/0.5, describing extent/validity of CO/HR coupling. We graphed results supine, 1min-post-tilt-up, mid-tilt, and pre-tilt-down using polar coordinates (HR - radius, ΔΦ - angle) plotting cos(ΔΦ) vs HR to determine if transition HR exists at which in-phase shifts to anti-phase above which CO decreases when HR further increases. Results - At baseline HR, diastolic and mean arterial pressure in IST and POTS were higher vs controls. Upright HR increased most in POTS then IST and VVS, with diverse changes in CO, SVR, and CBV. Each patient grouping was separately and collectively analyzed for HR change showing transition from in-phase to anti-phase (ΔΦ) as HR increased: HRtransition =115±6(IST),123±8(POTS),124±7(VVS), p=ns. Controls never reached transitional HR. Conclusions - Excessive HR independently and equivalently reduces upright CO, in IST, POTS and VVS

Mechanisms of vasovagal syncope in the young: reduced systemic vascular resistance versus reduced cardiac output

Background Syncope is a sudden transient loss of consciousness and postural tone caused by cerebral hypoperfusion. The most common form is vasovagal syncope (VVS). Presyncopal progressive early hypotension in older VVS patients is caused by reduced cardiac output (CO); younger patients have reduced systemic vascular resistance (SVR). Using a priori criteria for reduced CO (↓CO) and SVR (↓SVR), we studied 48 recurrent young fainters comparing subgroups of VVS with VVS‐↓CO, VVS‐↓SVR, and both VVS‐↓CO&↓SVR. Methods and Results Subjects were studied supine and during 70‐degrere upright tilt with a Finometer to continuously measure blood pressure, CO, and SVR and impedance plethysmography to estimate thoracic, splanchnic, pelvic, and calf blood volumes, blood flows, and vascular resistances and electrocardiogram to measure heart rate and rhythm. Central blood volume was decreased in all VVS compared to control. VVS‐↓CO was associated with decreased splanchnic blood flow and increased splanchnic blood pooling compared to control. Seventy‐five percent of VVS patients had reduced SVR, including 23% who also had reduced CO. Many VVS‐↓SVR increased CO during tilt, with no difference in splanchnic pooling, caused by significant increases in splanchnic blood flow and reduced splanchnic resistance. VVS‐↓CO&↓SVR patients had splanchnic pooling comparable to VVS‐↓CO patients, but SVR comparable to VVS‐↓SVR. Splanchnic vasodilation was reduced, compared to VVS‐↓SVR, and venomotor properties were similar to control. Combined splanchnic pooling and reduced SVR produced the earliest faints among the VVS groups. Conclusions Both ↓CO and ↓SVR occur in young VVS patients. ↓SVR is predominant in VVS and is caused by impaired splanchnic vasoconstriction