Jorge E. Celedonio

Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance

Postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance for which the hallmark physiological trait is an excessive increase in heart rate with assumption of upright posture. The orthostatic tachycardia occurs in the absence of orthostatic hypotension and is associated with a >6-month history of symptoms that are relieved by recumbence. The heart rate abnormality and orthostatic symptoms should not be caused by medications that impair autonomic regulation or by debilitating disorders that can cause tachycardia. POTS is a “final common pathway” for a number of overlapping pathophysiologies, including an autonomic neuropathy in the lower body, hypovolemia, elevated sympathetic tone, mast cell activation, deconditioning, and autoantibodies. Not only may patients be affected by more than one of these pathophysiologies but also the phenotype of POTS has similarities to a number of other disorders, e.g., chronic fatigue syndrome, Ehlers-Danlos syndrome, vasovagal syncope, and inappropriate sinus tachycardia. POTS can be treated with a combination of non-pharmacological approaches, a structured exercise training program, and often some pharmacological support.

A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

CONTEXT The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. OBJECTIVE To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. DESIGN IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). SETTING Two-center study. PARTICIPANTS Obese AA women. INTERVENTION A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. MAIN OUTCOME IS, FMD. RESULTS G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04). CONCLUSIONS The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

Time‐Course Analysis of Flow Mediated Dilation for the Evaluation of Endothelial Function After a High‐Fat Meal in African Americans

Background Flow‐mediated dilation (FMD) is used to assess endothelial function through changes in vascular diameter after hyperemia. High‐fat meal (HFM) has been shown to induce endothelial dysfunction; recent studies, however, reported conflicting results in obese African American women (AAW). Differences in the method used to analyze FMD may explain these discrepancies. Methods and Results In protocol 1, we assessed the time course of FMD and compared the repeatability of FMD using the individual maximum peak dilation (FMD peak) and the dilation at 60 seconds (FMD 60). Sixteen AAW (age, 42±10.4 years; body mass index [BMI], 39±5.8 kg/m2) were studied on 2 occasions, 4 weeks apart, under fasting conditions (study 1 and study 2). In protocol 2, we used the most repeatable measurement from protocol 1 to assess changes in endothelial function after an HFM in 17 AAW (agen 42±11.1 years; BMIn 38±5.6 kg/m2). We found that FMD peak was the most repeatable measurement (N=16; study 1, 5.31±3.12% and study 2, 5.80±2.91%; r=0.94). After an HFM, the baseline brachial artery diameter significantly increased at 2 hours (0.10 mm; 95% confidence interval [CI], 0.01–0.18; P=0.03) and at 4 hours (0.17 mm; 95% CI, 0.09–0.25; P<0.001). At 2 hours, the FMD peak decreased compared with pre‐HFM (−1.76; 95% CI, −3.55–0.02; P≤0.05). Conclusions The individuals maximum peak dilation after hyperemia is the most consistent measure to assess the effect of an HFM on endothelial function. Endothelial dysfunction occurred at 2 hours after an HFM in AAW. Clinical Trial Registration URL: https://clinicaltrials.gov/ Unique identifiers: NCT01334554 and NCT02126735.

Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency

Context Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.

Hypertension in Obese Black Women is Not Caused by Increased Sympathetic Vascular Tone

Background Black women have one of the highest prevalence rates of hypertension and obesity in the United States. We previously reported that sympathetic activation induced by obesity is a significant contributor to hypertension in white patients. It is unknown whether sympathetic activity similarly contributes to hypertension in obese black women. Methods and Results We studied 42 obese women (16 white, body mass index 36±4 kg/m2, 44% with hypertension; 26 black, body mass index 35±4 kg/m2, 46% with hypertension). Antihypertensive medications were discontinued for 2 weeks before the day of the study. All patients underwent complete autonomic blockade with trimethaphan at a dosage of 4 mg/min. Resting sympathetic activity determined from muscle sympathetic nerve recordings was similar between obese black women with hypertension and those with normotension. In whites, sympathetic activity was elevated in obese patients with hypertension compared with normotension; the decrease in mean arterial blood pressure produced by trimethaphan was greater in obese white patients with hypertension compared with those with normotension (−26.8±9.7 mm Hg versus −14.8±7.9 mm Hg, P=0.02). In contrast, there was no difference in the depressor responses induced by trimethaphan between obese black women with hypertension and those with normotension (−15.5±10.5 mm Hg versus −12.3±10.2 mm Hg, P=0.45). Mean arterial blood pressure remained elevated in obese blacks with hypertension compared with those with normotension during trimethaphan infusion (83.7±15.0 mm Hg versus 71.7±9.8 mm Hg, P=0.02). Heart rate increased similarly with trimethaphan between white (P=0.11) and black (P=0.76) women with hypertension and normotension. Conclusions These findings suggest that sympathetic activity does not contribute to hypertension in obese black women and provide further evidence for racial differences in hypertension mechanisms.

Effects of High Sodium Intake on Plasma Volume and Physical Fitness in Patients with Postural Tachycardia Syndrome and Healthy Females

Background: Patients with postural tachycardia syndrome (POTS) oftenhave lowblood volumeand are advised to increase sodium intake to restore intravascular volume. However, the benefit of a high-sodium diet has not been systematically examined in POTS. Methods: We studied 12 female POTS patients (mean± SD; 34 ±9 years, BMI 23 ± 3 kg/m) and 8 female healthy control subjects (HC; 29 ± 4 years, BMI 24 ± 3 kg/m) randomly assigned to 6 days of low (LS; 10 mEq/day) or high sodium (HS; 300 mEq/day) diet and then crossed-over. Procedures performed on Day 6 included: posture study, plasma volume (PV) measurement by I-albumin, maximal oxygen consumption (VO2max) using a supine bicycle ergometer, and cardiac output (CO) and stroke volume (SV) assessments by the inert gases rebreathing technique in the flat and tilted head-up positions. Results: PV was significantly higher after HS than LS in POTS patients (PV: 2706 ± 110 ml vs. 2390 ± 89 ml, P b 0.001). Orthostatic tachycardia was reduced in POTS with HS (49 ± 16 bpm vs. 63 ±11 bpm, P = 0.001), but still increased compared with HC (49 ± 16 bpm vs. 23 ± 11 bpm, P = 0.001). Upright SV was significantly higher after HS than LS in POTS (35 ± 11ml vs. 25 ± 7ml, P = 0.023) but remained lower than HC (35 ± 11 ml vs. 52 ± 16ml, P = 0.033). Upright CO and VO2max did not differ significantly between POTS for either LS or HS. Conclusions: HS diet caused a reduction in orthostatic tachycardia, and increased PV and SV in POTS patients. Patients with POTS experienced improvement in their condition in association with higher sodium intake, but did not ‘normalize’ compared with HC.