Sachin Y. Paranjape

Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome

Background—Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume. Methods and Results—Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with 131I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm, P<0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL, P<0.001), red blood cell volume (356±128 versus 218±140 mL, P=0.010), and total blood volume (689±270 versus 228±353 mL, P<0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL−1 · h−1, P=0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L; P=0.017). Conclusions—Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.

Autonomic Contribution to Blood Pressure and Metabolism in Obesity

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32±3 years) and 10 obese (35±3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (−17±3 versus −11±1 mm Hg; P=0.019) because of a greater decrease in total peripheral resistance (−310±41 versus 33±78 dynes/sec/cm−5; P=0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (−26±21 versus −86±15 kcal per day adjusted by fat-free mass; P=0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased −28±4 mm Hg (95% CI: −38 to −18.0; n=8) in obese hypertensive subjects compared with lean (−9±1 mm Hg; 95% CI: −11 to −6; n=22) or obese normotensive subjects (−14±2 mm Hg; 95% CI: −18 to −10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109±3 versus 98±2 mm Hg in lean and 103±2 mm Hg in obese normotensive subjects; P=0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.

Water Ingestion as Prophylaxis Against Syncope

Background—Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults. Methods and Results—Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-table testing at 60° for 45 minutes or until presyncope or syncope occurred. In their initial test, participants were randomized to either 16 oz (473 mL) of water drinking 5 minutes before tilt-table testing or tilt-table testing alone, with the alternative in a second test on a different day. During the first 30 minutes of tilt, 8 of 22 subjects without water experienced presyncope but only 1 of 22 who had ingested water (P =0.016). Water drinking attenuated the heart rate increase associated with tilt (P <0.001) while accentuating the increase in total peripheral resistance (P =0.012). The average time study participants tolerated head-up tilt was 26% longer after water (41.1±8.1 versus 32.6±14.3 minutes, mean±SD), with a pairwise mean difference of 8.5±14.0 minutes (95% CI, 2.3 to 14.7 minutes; P =0.011). Conclusions—Water enhances tolerance of upright posture. The effect of water is mediated by increased peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against vasovagal reactions in healthy subjects, such as those associated with blood donation.

Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome Less Is More

Background— Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate on standing. β-Blockade is an appealing treatment approach, but conflicting preliminary reports are conflicting. We tested the hypothesis that propranolol will attenuate the tachycardia and improve symptom burden in patients with POTS. In protocol 1, a low dose (20 mg) was compared with placebo, and the dose response was assessed in protocol 2. Methods and Results— In protocol 1, patients with POTS (n=54) underwent acute drug trials of propranolol 20 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, heart rate, and symptoms were assessed while the patients were seated and after standing for up to 10 minutes before and hourly after the study drug. Supine (P<0.001) and standing (P<0.001) heart rates were significantly lower after propranolol compared with placebo. The symptom burden improvement from baseline to 2 hours was greater with propranolol than placebo (median, −4.5 versus 0 arbitrary units; P=0.044). In protocol 2, 18 patients with POTS underwent similar trials of high-dose (80 mg) versus low-dose (20 mg) propranolol. Although the high dose elicited a greater decrease than the low dose in standing heart rate (P<0.001) and orthostatic tachycardia (P<0.001), the improvement in symptoms at 2 hours was greater with low-dose propranolol (−6 versus −2 arbitrary units; P=0.041). Conclusions— Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms.

Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans

Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by ≈15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. NG-Monomethyl-l-arginine (250 &mgr;g/kg per minute IV) increased mean BP by 6±3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21±8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11±4.5 versus 30±2.3 mm Hg in normotensive individuals; P<0.005). Thus, we report a novel approach to preferentially evaluate the role of eNO on BP control in normal and disease states. Our results suggest that eNO is one of the most potent metabolic determinants of BP in humans, tonically restraining it by ≈30 mm Hg.

Raised Cerebrovascular Resistance in Idiopathic Orthostatic Intolerance: Evidence for Sympathetic Vasoconstriction

Patients with idiopathic orthostatic intolerance (IOI) exhibit symptoms suggestive of cerebral hypoperfusion and an excessive decrease in cerebral blood flow associated with standing despite sustained systemic blood pressure. In 9 patients (8 women and 1 man aged 22 to 48 years) with IOI, we tested the hypothesis that volume loading (2000 cc normal saline) and alpha-adrenoreceptor agonism improve systemic hemodynamics and cerebral perfusion and that the decrease in cerebral blood flow with head-up tilt (HUT) could be attenuated by alpha-adrenoreceptor blockade with phentolamine. At 5 minutes of HUT, volume loading (-20+/-3.2 bpm) and phenylephrine (-18+/-3.4 bpm) significantly reduced upright heart rate compared with placebo; the effect was diminished at the end of HUT. Phentolamine substantially increased upright heart rate at 5 minutes (20+/-3.7 bpm) and at the end of HUT (14+/-5 bpm). With placebo, mean cerebral blood flow velocity decreased by 33+/-6% at the end of HUT. This decrease in cerebral blood flow with HUT was attenuated by all 3 interventions. We conclude that in patients with IOI, HUT causes a substantial decrease in cerebrovascular blood flow velocity. The decrease in blood flow velocity with HUT can be attenuated with interventions that improve systemic hemodynamics and therefore decrease reflex sympathetic activation. Moreover, alpha-adrenoreceptor blockade also blunts the decrease in cerebral blood flow with HUT but at the price of deteriorated systemic hemodynamics. These observations may suggest that in patients with IOI, excessive sympathetic activity contributes to the paradoxical decrease in cerebral blood flow with upright posture.

Modafinil Elicits Sympathomedullary Activation

The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mg×1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2±2.0 bpm; mean [±SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3±3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3±1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8±0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1±1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3±0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). &agr;1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Background and Purpose— The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. Methods— To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results— Adenosine at a dosage of 125 &mgr;g/min increased FBF from 4.6±0.9 to 29.4±5.3 (539% increase) with dipyridamole/aspirin and from 3.9±0.8 to 12±2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (P=0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r2=0.6); no correlation was observed with acetylcholine- or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. Conclusion— The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions.

Desmopressin acutely decreases tachycardia and improves symptoms in the postural tachycardia syndrome

BACKGROUND Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate on standing, and many patients with POTS have low blood volume. Increasing blood volume is a promising approach to this problem. OBJECTIVE To test the hypothesis that desmopressin (DDAVP) will attenuate the tachycardia and improve symptom burden in patients with POTS. METHODS In this protocol, patients with POTS (n = 30) underwent acute drug trials with DDAVP 0.2 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, heart rate, and symptoms were assessed while seated and after standing for up to 10 minutes prior to and hourly for 4 hours following study drug. RESULTS The standing heart rate was significantly lower following DDAVP than placebo (101.9 ± 14.5 beats/min vs 109.2 ± 17.4 beats/min; P <.001). Standing blood pressure was not affected (P = .28). The symptom burden improved with DDAVP (from a score of 18 ± 18 arbitrary units [AU] to 13 ± 15 AU at 2 hours) compared with placebo (from 18 ± 17 AU to 19 ± 16 AU; P = .010). CONCLUSIONS Oral DDAVP significantly attenuated tachycardia and improved symptoms in POTS. The safety profile of this approach would need to be examined before it can be recommended for routine treatment of these patients.

Diagnosing postural tachycardia syndrome: comparison of tilt testing compared with standing haemodynamics.

POTS (postural tachycardia syndrome) is characterized by an increased heart rate (ΔHR) of ≥30 bpm (beats/min) with symptoms related to upright posture. Active stand (STAND) and passive head-up tilt (TILT) produce different physiological responses. We hypothesized these different responses would affect the ability of individuals to achieve the POTS HR increase criterion. Patients with POTS (n=15) and healthy controls (n=15) underwent 30 min of tilt and stand testing. ΔHR values were analysed at 5 min intervals. ROC (receiver operating characteristic) analysis was performed to determine optimal cut point values of ΔHR for both tilt and stand. Tilt produced larger ΔHR than stand for all 5 min intervals from 5 min (38±3 bpm compared with 33±3 bpm; P=0.03) to 30 min (51±3 bpm compared with 38±3 bpm; P<0.001). Sn (sensitivity) of the 30 bpm criterion was similar for all tests (TILT10=93%, STAND10=87%, TILT30=100%, and STAND30=93%). Sp (specificity) of the 30 bpm criterion was less at both 10 and 30 min for tilt (TILT10=40%, TILT30=20%) than stand (STAND10=67%, STAND30=53%). The optimal ΔHR to discriminate POTS at 10 min were 38 bpm (TILT) and 29 bpm (STAND), and at 30 min were 47 bpm (TILT) and 34 bpm (STAND). Orthostatic tachycardia was greater for tilt (with lower Sp for POTS diagnosis) than stand at 10 and 30 min. The 30 bpm ΔHR criterion is not suitable for 30 min tilt. Diagnosis of POTS should consider orthostatic intolerance criteria and not be based solely on orthostatic tachycardia regardless of test used.