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Background: Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans. Methods: We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity. Results: nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (−3.3% [−6.5, −0.01], P =0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced −4.3% [−8.5, −0.1], P =0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms. Conclusions: Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.

Background: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. Methods: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. Results: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (−26±12 mm Hg; P =0.004), cold pressor test (−20±15 mm Hg; P P =0.01) were significantly reduced compared with no intervention (−34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (−391±206 dyne×s/cm 5 ; P =0.006) and cold pressor test (−386±179 dyne×s/cm 5 ; P =0.011) were significantly reduced compared with no intervention (−488±173 dyne×s/cm 5 ). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P Conclusion: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03970551.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

ObjectivePostural tachycardia syndrome (POTS), the most common form of dysautonomia, may be associated with autoimmunity in some cases. Autoantibodies against the ganglionic acetylcholine receptor (gAChR) have been reported in a minority of patients with POTS, but the prevalence and clinical relevance is unclear.MethodsClinical information and serum samples were systematically collected from participants with POTS and healthy control volunteers (n = 294). The level of positive gAChR antibodies was classified as very low (0.02–0.05 nmol/L), low (0.05–0.2 nmol/L), and high (>0.2 nmol/L).ResultsFifteen of 217 patients with POTS (7%) had gAChR antibodies (8 very low and 7 low). Six of the 77 healthy controls (8%) were positive (3 very low and 3 low). There were no clinical differences between seropositive and seronegative patients with POTS.ConclusionsPrevalence of gAChR antibody did not differ between POTS and healthy controls, and none had high antibody levels. Patients with POTS were not clinically different based on seropositivity. Low levels of gAChR antibodies are not clinically important in POTS.

Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

Orthostatic hypotension is a phenomenon commonly encountered in a cardiologist's clinical practice that has significant diagnostic and prognostic value for a cardiologist. Given the mounting evidence associating cardiovascular morbidity and mortality with orthostatic hypotension, cardiologists will play an increasing role in treating and managing patients with orthostatic hypotension.The American College of Cardiology, American Heart Association, and Heart Rhythm Society recently published consensus guidelines on the diagnosis, treatment, and management of syncope and their instigators, including orthostatic hypotension. Additionally, consensus guidelines have also been recently updated, reinforcing the universal definition orthostatic hypotension and its closely associated pathologies. Finally, the United States Food and Drug Administration (FDA) recently approved droxidopa, a synthetic oral norepinephrine prodrug, in 2014 for the treatment of neurogenic orthostatic hypotension (nOH), and it represents a well tolerated, effective, and easy to use intervention for nOH. This represents only the second drug approved by the FDA for orthostatic hypotension, the first being midodrine in 1986. A handful of smaller head-to-head studies have pitted not only pharmacologic agents to one another but also nonpharmacologic interventions to pharmacologic agents. Additionally, recent studies have also reported on more convenient screening tools for orthostatic hypotension.Though there have been many advances in the management of orthostatic hypotension, nOH remains a chronic, debilitating, and often progressively fatal condition. Cardiologists can play a very important role in optimizing hemodynamics in this patient population to improve quality of life and minimize cardiovascular risk.

To determine if beta-(β)-blockers improve outcomes after acute traumatic brain injury (TBI).There have been no new inpatient pharmacologic therapies to improve TBI outcomes in a half-century. Treatment of TBI patients with β-blockers offers a potentially beneficial approach.Using MEDLINE, EMBASE, and CENTRAL databases, eligible articles for our systematic review and meta-analysis (PROSPERO CRD42016048547) included adult (age ≥ 16 years) blunt trauma patients admitted with TBI. The exposure of interest was β-blocker administration initiated during the hospitalization. Outcomes were mortality, functional measures, quality of life, cardiopulmonary morbidity (e.g., hypotension, bradycardia, bronchospasm, and/or congestive heart failure). Data were analyzed using a random-effects model, and represented by pooled odds ratio (OR) with 95% confidence intervals (CI) and statistical heterogeneity (I).Data were extracted from 9 included studies encompassing 2005 unique TBI patients with β-blocker treatment and 6240 unique controls. Exposure to β-blockers after TBI was associated with a reduction of in-hospital mortality (pooled OR 0.39, 95% CI: 0.27-0.56; I = 65%, P0.00001). None of the included studies examined functional outcome or quality of life measures, and cardiopulmonary adverse events were rarely reported. No clear evidence of reporting bias was identified.In adults with acute TBI, observational studies reveal a significant mortality advantage with β-blockers; however, quality of evidence is very low. We conditionally recommend the use of in-hospital β-blockers. However, we recommend further high-quality trials to answer questions about the mechanisms of action, effectiveness on subgroups, dose-response, length of therapy, functional outcome, and quality of life after β-blocker use for TBI.

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin–angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT 1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson’s disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P =0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P =0.492; nocturnal weight loss: −1.19±0.15 kg placebo versus −1.18±0.15 kg eplerenone, P =0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients.

Background Both the adrenergic and renin‐angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome ( POTS ). Activating autoantibodies to the α1‐adrenergic and β1/2‐adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor ( AT 1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT 1R autoantibodies in POTS . Methods and Results Serum immunoglobulin G from 17 patients with POTS , 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT 1R and alter AT 1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT 1R antibody activity in immunoglobulin G purified from their serum. No significant AT 1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT 1R activation by POTS immunoglobulin G was specifically blocked by the AT 1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT 1R and α1‐adrenergic receptor. Conclusions Most patients with POTS harbor AT 1R antibody activity. This supports the concept that AT 1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS .

Objective: To understand the burden and impact of symptoms of neurogenic orthostatic hypotension (nOH) on patients Background: nOH and its symptoms such as dizziness/lightheadedness are common in patients with Parkinson disease (PD) and other forms of autonomic dysfunction. Methods: An author-designed, US-based survey was conducted by Harris Poll. Eligible participants were aged ≥18 years with PD, multiple system atrophy (MSA), or pure autonomic failure and ≥1 of the following: orthostatic hypotension, nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Results: Most patients (90%) had a diagnosis of PD, and most caregivers (88%) cared for a patient with PD (Table 1) . Patients (34%) and caregivers (49%) reported experiencing nOH symptoms before PD or MSA motor symptoms and >40% indicated that nOH symptoms were more troublesome than motor manifestations of PD or MSA. Less than a quarter (22%) of respondents suggested symptoms were most severe in the morning; more (30%) reported a consistent severity throughout the day. Patients (40%) and caregivers (63%) reported trouble managing symptoms during the day. In the past 12 months, a fall due to nOH symptoms was reported by 57% of patients and 80% of caregivers. Conclusions: These findings suggest that nOH symptoms may predate the onset of motor symptoms in neurodegenerative conditions linked to alpha-synuclein pathology. Many respondents report nOH symptoms are the same severity through the day. Patients with nOH may have trouble managing symptoms and note an increased risk for falls.

Objective: To understand the patient and caregiver experience with the management of neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Clinical symptoms may include falls, leading to activity limits and a diminished sense of well-being. Methods: A US-based survey designed by the authors was conducted by Harris Poll. Eligible participants had Parkinson disease (PD), multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Descriptive statistics are reported. Results: PD was the most frequent underlying diagnosis (Table 1) . Healthcare provider (HCP) communication with patients was rated as satisfactory by ≥75% of respondents, yet when nOH symptoms were first discussed with the HCP, only 35% of patients and 31% of caregivers reported the patient received guidance on management. The most frequently recommended interventions are listed in Table 1 ; 25% of patients reported that no interventions were recommended. Medication prescribed to treat nOH was reported by 34% of patients and 45% of caregivers. Among patients treated, 79% of patients and 71% of caregivers said that the patient’s symptoms were somewhat to very well managed. Conclusions: Survey findings suggest the need for increased awareness of nOH and engagement with patients and caregivers regarding symptom management. A variety of interventions were recommended; no single treatment approach was noted. Respondents felt nOH symptoms were at least somewhat well managed with treatment.

Background: Postural tachycardia syndrome (POTS) is characterized by an increase in sympathetic activity, with an exaggerated rise in heart rate upon standing and symptoms of cerebral hypoperfusion. Endothelial/Nitric Oxide (NO) dysfunction might be involved in POTS pathophysiology. As part of the non-pharmacologic treatment of POTS, a high sodium diet is often recommended to increase plasma volume. We assessed endothelial/NO function in conduit vessels (using flow-mediated dilation, FMD) and resistance vessels (using finger pulse arterial tonometry, PAT) in POTS patients during high and low salt diets. Methods: In 14 female POTS patients (34±9 years, BMI 23±3 kg/m 2 ) and 13 matched healthy control subjects (29±4 years, BMI 24±3 kg/m 2 ), we evaluated the time course responses to FMD and PAT. Subjects were randomly assigned to either high salt diet (300mEq/day) or low salt diet (10mEq/day) for 6 days and crossed over to the other arm after 1 month. The areas under the curve for brachial artery diameter by FMD and finger artery dilation by PAT were compared between interventions and groups. Results: No differences in NO function in a conduit artery were seen. In contrast, in resistance vessels, high salt diet increased vasodilation in both POTS and healthy subjects (figure). In addition, POTS patients have greater vasodilation than healthy subjects during both low and high salt diets (p=0.036 and 0.033 for high and salt diets respectively). Conclusions: POTS patients may have an exaggerated NO response to reactive hyperemia in resistance vessels, but not in conductance vessels. This excessive vasodilation could contribute to POTS symptoms on standing.

Objective: To understand the challenges to diagnosis in patients with neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Despite symptoms of nOH, many patients struggle to find an accurate diagnosis. Methods: An online, US-based survey designed by the authors was conducted by Harris Poll. Eligible participants were ≥18 years of age with Parkinson disease, multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible participants. Results: The survey included 363 patients and 128 caregivers. Groups were separate, where caregivers were not the caregivers to patient responders. Respondents indicated that patients experienced nOH symptoms long term (Table 1) . Most patients (69%) and caregivers (59%) reported discussing nOH symptoms with a healthcare provider (HCP) within the first year of symptom onset, but only 36% of patients and 16% of caregivers reported a formal diagnosis of OH or nOH. Of those with a formal diagnosis, the majority of patients (50%) were frustrated by the path to diagnosis and more than 40% of patients and caregivers reported that the patient saw ≥3 HCPs before diagnosis. After diagnosis, most patients (70%) and caregivers (60%) reported improved symptom management. Conclusions: This survey reveals that patients and caregivers may find the path to nOH diagnosis challenging and suggests increased awareness among HCPs is needed. Once a diagnosis is made nOH symptoms are better managed.

Background: Primary prevention implantable cardioverter defibrillators (ICD) are under-utilized despite multiple clinical trials that demonstrated reduced mortality and cost-effectiveness in patients at risk for sudden cardiac death. Our objectives were to determine physician knowledge about primary prevention ICD guidelines and to identify potential barriers impacting referral rates. Methods: The Cardiovascular Arrhythmia and Stroke Working Group from Alberta, Canada developed a web- based survey as part of a quality assurance initiative to aid in the design of a complex device care pathway. The survey consisted of five case scenarios regarding primary prevention ICD guidelines and a list of potential barriers for ICD referral. Through expert consensus, case scenarios were developed based on current device guidelines. The survey was administered to physicians encountering patients eligible for ICD therapy, including General Internists and Cardiologists with Alberta Medical Association membership and Cardiology residents. Results: The survey was completed by 109 of 799 (response rate =14%). Of those, 55% were General Internists, 32% were Cardiologists and 13% were Cardiology residents. The majority of physicians were male (62%) and practicing at a University Hospital (66%). Overall, 34% of participants answered all case scenarios correctly. A correct answer on all five case scenarios was demonstrated by 62.5% of Cardiologists, 61.5% of Cardiology residents and 16% of General Internists (p Conclusion: Knowledge of indications for a primary prevention ICD is poor and a recognized barrier among physicians who may refer patients for device therapy. Adequate knowledge translation of ICD guidelines is crucial in order to improve ICD utilization.

Nebivolol, unlike other selective β 1 -receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)–lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of β-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69±2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am . Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night ( P P =0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of −20±6 and −24±9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall >20 mm Hg at 4:00 am ) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (−44±13 mm Hg) but not in nonresponders (1±11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of β 1 -blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.

Postural tachycardia syndrome (POTS) is characterized clinically not only by an exaggerated increase in heart rate (HR), but an associated cognitive impairment that disables many patients. Modafinil might be effective in improving the cognitive symptoms, but modafinil may stimulate the sympathetic nervous system and worsen tachycardia in POTS. We tested the hypothesis that modafinil would worsen tachycardia and orthostatic symptoms in POTS.Patients with POTS (n = 54) underwent a randomized crossover trial with modafinil 100 mg versus placebo. Heart rate and systolic blood pressure (SBP) were measured seated and standing before modafinil or placebo administration and then hourly for 4 hours.Over 4 hours, standing HR was not significantly different between the modafinil and placebo groups (analysis of variance [ANOVA] Pdrug = 0.328), but seated SBP was significantly higher in the modafinil group (mean [SD], 109 [12] mm Hg vs 104 [10] mm Hg; P = 0.004). Modafinil also significantly increased both the seated SBP (ANOVA Pdrug = 0.004) and the standing SBP (ANOVA Pdrug = 0.041) over time. There was no significant difference between modafinil and placebo over the 4-hour period with regard to POTS symptom burden scores (14 [12] vs 14 [12]; P = 0.962).Modafinil did not significantly worsen standing HR or acute orthostatic symptoms in patients with POTS compared with the placebo group and improved upright blood pressure. Therefore, modafinil could be tested as a potential treatment for the cognitive impairment in POTS.

Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake ( M BW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N -monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m 2 body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P =0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects ( M BW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P =0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation.

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin–angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P =0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P =0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT 1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration ( P P =0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT 1 receptor blockers for treatment of these patients.

Primary autonomic failure (AF) is characterized by disabling orthostatic hypotension that is acutely worsened by environmental heat. Given that about half of AF patients have paradoxical supine hypertension, we hypothesized that controlled local passive heat would lower supine blood pressure (BP) in these patients. Fourteen AF patients with supine hypertension (age 71±2 years, 9 men, systolic BP 172±6 mmHg) were randomized to receive passive heat (40-42°C, commercial heating pad over abdomen and pelvis) and sham control for up to 2 hours in a 2-day crossover study. Hemodynamic parameters and core body and skin temperatures were measured in the supine position. The heating pad increased abdominal skin temperature to 40.8±0.4°C and 40.1±0.3°C after 1 and 2 hours of passive heat (vs 35.2±0.2°C and 35.1±0.4°C in sham controls). Core body temperature increased after 1 hour (by 0.2±0.1°C [to 36.9±0.8°C] vs 0.0°C [36.7±0.1°C] in sham controls; P=0.04) and 2 hours (by 0.4±0.1°C [to 37.2±0.1°C] vs 0.1±0.03°C [to 36.8±0.1°C] in sham controls; P=0.04). Systolic BP decreased during heat stress compared to sham control (P

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in HR and symptoms consistent with cerebral hypoperfusion while upright. Increased sympathetic activity may contribute to this condition and may also impair nitric oxide (NO)-function. We evaluated NO function using flow-mediated dilation (FMD) and Peripheral Artery Tonometry (PAT) in POTS patients and age-matched controls. We studied 16 POTS patients (30±2 years, BMI 22.3±1 kg/m 2 ) and 7 healthy control subjects (HC; 31±2 years, BMI 22.1±1 kg/m 2 ). Medications affecting BP, blood volume, the immune system, and autonomic function, were withheld for ≥5 half-lives. All subjects followed the same low-monoamine, caffeine-free diet for ≥3 days before testing. Endothelial function was measured as the percentage change in FMD (%FMD) and using the reactive hyperemic index (RHI) for PAT. We also measured autonomic function, plasma levels of catecholamines, renin activity (PRA) and aldosterone. We found that POTS patients had a significantly blunted FMD (6.11±0.8 vs. 9.67±1.6 %, P=0.049, figure), compared to healthy controls. This blunted FMD response was similar as what our group has reported in obese hypertensive females (N=13, 5.7±0.9%, figure). Also, as expected they had higher upright HR (121±6 vs. 90±6 bpm, for POTS and HC, P=0.020). There were no differences in PAT (2.08±0.12, vs. 1.8±0.13 RHI, for POTS and HC, P=0.168). There were no differences in norepinephrine (765±150 vs. 545±39 pg/mL, P=0.955), renin activity (5.3±1.3 vs. 5.2±1.6 ng/mL/hr, P=0.735) or aldosterone (19.6±3.8 vs. 15.9±5.5 ng/dL, P=0.129).

Background— Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls. Methods and Results— Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean±SEM, 30±2 versus 26±1 years; P =0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10±1 versus 14±1 mm Hg, P =0.01) and diastolic BP (9±1 versus 13±1 mm Hg, P =0.01) but not systolic BP (13±2 versus 15±2 mm Hg, P =0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (−166±20 versus −181±17 mL/min per 1.73 kg/m 2 , P =0.58). Postinfusion, the decrease in plasma renin activity (−0.9±0.2 versus −0.6±0.2 ng/mL per hour, P =0.43) and the increase in aldosterone (17±1 versus 15±2 pg/mL, P =0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (−49±12 versus −60±16 mEq/g creatinine, P =0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1±1.2 versus 16.8±1.5 ms/mm Hg, P =0.003), and it was further reduced with Ang II infusion. Conclusions— Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00962949.

Severe autonomic failure occurs in approximately 1 in 1,000 people. Such patients are remarkable for the striking and sometimes paradoxic responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less understood findings also occur. These findings include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea, and other neurologic disturbances. In this article the authors will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative setting. Strategies used by clinicians in diagnosis and treatment of these patients, and the effect of these interventions on the preoperative, intraoperative, and postoperative care that these patients undergo is a crucial element in the optimized management of care in these patients.

To compare odor identification function in patients with peripheral or central autonomic neurodegeneration and in patients with intact autonomic neurons but undetectable norepinephrine.Olfactory function was evaluated with the University of Pennsylvania Smell Identification Test (UPSIT) in 12 patients with pure autonomic failure, 10 patients with multiple system atrophy, and 4 patients with dopamine β-hydroxylase deficiency. Blood pressure and catecholamine data were also compared.Odor identification was significantly impaired in patients with pure autonomic failure relative to patients with multiple system atrophy or dopamine β-hydroxylase deficiency. Out of 40 odors, the patients correctly identified mean (95% confidence interval) 19.2 (14.1 to 24.2), 34.4 (32.2 to 36.6), and 31.7 (29.4 to 34.1) (p0.001). The difference between patients with pure autonomic failure and those with multiple system atrophy or dopamine β-hydroxylase deficiency persisted after adjustment for age (p = 0.001). Patients with pure autonomic failure also had a greater orthostatic fall in blood pressure and lower plasma norepinephrine levels than patients with multiple system atrophy.Olfactory function was relatively intact in patients with dopamine β-hydroxylase deficiency, who have intact noradrenergic neurons but lack norepinephrine. Odor identification was impaired in pure autonomic failure but not in multiple system atrophy, suggesting that 1) peripheral noradrenergic innervation is important for olfactory identification but norepinephrine is not essential and 2) UPSIT may be useful in the differential diagnosis between these disorders.

Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel ( Trpv4 ) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4 −/− mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.

Supine hypertension is difficult to manage in patients with pure autonomic failure (PAF), because treatment can worsen orthostatic hypotension. Supine hypertension in PAF has been associated with left ventricular hypertrophy, but end organ damage in the kidney has not been assessed. We reviewed hemodynamic and laboratory data of 64 male patients with PAF who were 69±11 (mean±SD) years old. Systolic blood pressure fell by 67±40 mm Hg within 10 minutes of standing, with an inappropriately low 13±11-bpm increase in heart rate. Plasma norepinephrine levels were below normal (0.62±0.32 nmol/L supine and 1.28±1.25 nmol/L standing). A control data set of 75 men (67±12 years) was obtained from a deidentified version of the Vanderbilt University Medical Center electronic medical chart database. Compared with controls, PAF patients had lower hemoglobin (8.3±0.9 versus 9.3±0.8 mmol/L; P P 12 versus 5.0±0.5×10 12 cells/L; P P =0.021) and estimated glomerular filtration rate was lower (57±22 versus 70±20 mL/min per 1.73 m 2 ; P =0.022) compared with patients who did not have supine hypertension. These findings may indicate that renal function is diminished in PAF in association with supine hypertension.

Most drugs are not used to treat heart disease. However, such “noncardiovascular” medications can often have cardiovascular effects. In this review, we discuss some cardiovascular manifestations of drugs used for noncardiovascular indications. We discuss these in the text according to the manifestations with which patients present; selected drugs are listed in Table 1 by their indication/drug class. The same medication may appear in different sections, reflecting the varied cardiovascular consequences of a particular drug. We also discuss cardiovascular effects of noncardiovascular drugs that arise indirectly from drug interactions that cause an increase or decrease in the concentration of a cardiovascular drug. View this table: Table 1. Selected Noncardiovascular Drugs With Cardiovascular Effects by Indication/Drug Class ### Atrial Fibrillation Most reports of atrial fibrillation (AF) induced by noncardiovascular drugs are case reports, and because AF is so common, it is difficult to determine whether the association is causal or incidental. The ability to reproduce AF with drug rechallenges supports causality, as does a mechanistic rationale. Table 1 lists drugs with a well-established association with AF. After numerous case reports of the onset of AF after pulse methylprednisolone, van der Hooft et al1 conducted a nested case-control study in the Rotterdam study that comprised almost 8000 adults. They found that high-dose corticosteroid use (≥7.5 mg prednisone equivalents) was associated with a significantly increased risk of new-onset AF (odds ratio [OR]=6.1; 95% confidence interval [CI], 3.9 to 9.4) but that low-dose corticosteroid use was not associated with AF (OR=1.4; 95% CI, 0.7 to 2.8). This increase in AF risk was seen with all indications for high-dose corticosteroids. It has been postulated that high-dose corticosteroids might mediate cellular potassium efflux and that this may in turn predispose to arrhythmia.2 There is concern that bisphosphonates may increase the risk of serious AF (AF resulting in hospitalization or disability or …

Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N G -monomethyl- l -arginine, suggesting increased NO function rather than deficiency; a lower dose of N G -monomethyl- l -arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171±37 mg versus 512±81 mg, respectively; P =0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182±11 to 138±4 mm Hg in 8 AF patients with supine hypertension ( P =0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N G -monomethyl- l -arginine (56±6° versus 41±4° with placebo; n=7; P =0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.