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1.
Pediatric patients' head-up-tilt-test with pharmacological challenge, it is safe?
García, A, Bustillos-García, GA, Rivera-Roodríguez, L
Archivos de cardiologia de Mexico. 2020;(2):163-172
Abstract
Syncope in pediatrics represents an important cause of visits to the emergency units. For this reason, excluding a cardiac or malignant origin is essential at the time of the initial approach to determine what is the next step in management, or if they need to be referred to a pediatric cardiologist and/or electrophysiologist. Vasovagal syncope is the most frequent cause of syncope in pediatrics, in which a detailed clinical history is enough to make the diagnosis. If no diagnosis is concluded by the history, or if it is necessary to define the hemodynamic response of the patients, the head-up-tilt-test is indicated; this will trigger syncope due to an orthostatic stress caused by the angulated table (passive phase). If a negative response remains, it can be followed by a pharmacologic challenge to trigger the hemodynamic response, which is still controversial in pediatrics. The pharmacologic challenge increases the sensitivity with a slight reduction in test specificity. Although there is not a specific drug for the challenge in pediatric patients yet, the most commonly drugs used are nitrates and isoproterenol, the latter related to a great number of adverse effects. Sublingual administration of nitrates in the challenge has been proven to be ideal, effective, and safe in this specific age group. The aim of this article is to make a literature search to demonstrate the effectiveness and safety of the pharmacologic challenge during the head-up-tilt-test in pediatrics, emphasizing a study conducted at the National Institute of Cardiology with isosorbide dinitrate.
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2.
Pediatrics patients head-up tilt test with pharmacological challenge, it is safe?
García, A, Bustillos-García, GA, Rivera-Rodríguez, L
Archivos de cardiologia de Mexico. 2020;(2):178-188
Abstract
Syncope in pediatrics represents an important cause of visits to the emergency units. For this reason, excluding a cardiac or malignant origin is essential at the time of the initial approach in order to determine what is the next step in management, or if they need to be referred to a pediatric cardiologist and/or electrophysiologist. Vasovagal syncope is the most frequent cause of syncope in pediatrics, in which a detailed clinical history is enough to make the diagnosis. If no diagnosis is concluded by the history, or if it is necessary to define the hemodynamic response of the patients, the head-up tilt test is indicated; this will trigger syncope due to an orthostatic stress caused by the angulated table (passive phase). If a negative response remains, it can be followed by a pharmacologic challenge in order to trigger the hemodynamic response, which is still controversial in pediatrics. The pharmacologic challenge increases the sensitivity with a slight reduction in test specificity. Although there is not a specific drug for the challenge in pediatric patients yet, the most commonly drugs used are nitrates and isoproterenol, the latter related to a great number of adverse effects. Sublingual administration of nitrates in the challenge has been proven to be ideal, effective and safe in this specific age group. The aim of this article is to make a literature search in order to demonstrate the effectiveness and safety of the pharmacologic challenge during the head-up tilt test in pediatrics, emphasizing a study conducted at the National Institute of Cardiology with isosorbide dinitrate.
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3.
Hypotensive Drugs and Syncope Due to Orthostatic Hypotension in Older Adults with Dementia (Syncope and Dementia Study).
Testa, G, Ceccofiglio, A, Mussi, C, Bellelli, G, Nicosia, F, Bo, M, Riccio, D, Curcio, F, Martone, AM, Noro, G, et al
Journal of the American Geriatrics Society. 2018;(8):1532-1537
Abstract
OBJECTIVES To determine whether hypotensive drugs may play a pivotal role in inducing orthostatic hypotension (OH)-related syncope. DESIGN Prospective, observational, multicenter study. SETTING Acute care wards, syncope units, and centers for the diagnosis of dementia. PARTICIPANTS Individuals aged 65 and older with a diagnosis of dementia and 1 or more episodes of transient loss of consciousness of a suspected syncopal nature or unexplained falls during the previous 3 months MEASUREMENTS Blood pressure was measured in the supine position and in the orthostatic position after 1 and 3 minutes. OH was defined as a decrease in systolic blood pressure of 20 mmHg or more and in diastolic blood pressure of 10 mmHg or more within 3 minutes of standing. Univariate and multivariate analyses were used to evaluate associations between hypotensive drugs and their combinations with OH-related syncope. RESULTS The mean age of the study population (n=522; women, n=324) was 83.5±6.1, and the most frequent comorbidity was arterial hypertension (74.5%); 324 (67.8%) participants had had a syncopal fall and 168 (32.2%) a nonsyncopal fall. The mean number of hypotensive drugs administered (2.9±3.1) did not differ between the two groups. Syncopal falls was OH-related in 170 participants (48.0%). OH-related syncopal falls were more frequent in participants receiving nitrates (15.3% vs 9.8%, p=.06), alpha-blockers (16.5% vs 9.8%, p=.04), or combinations of angiotensin-converting enzyme inhibitors (ACE-Is) and diuretics (20.6% vs 13.0%, p=.04), alpha-blockers and diuretics (8.2% vs 3.3%, p=0.036), and ACE-Is and nitrates (8.2% vs 3.3%, p=.10). Multivariate analysis confirmed a greater risk of OH-related syncopal fall for nitrates (relative risk (RR)=1.77), combinations of ACE-Is and diuretics (RR=1.66), and combinations of ACE-Is and nitrates (RR=2.32). CONCLUSION In older adults with dementia, OH-related syncopal falls are significantly related to treatment with nitrates, combinations of ACE-Is and diuretics, and combinations of ACE-Is and nitrates.
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4.
Vasospastic Angina Presenting With Syncope and Chest Pain: A Case Report and Brief Literature Review.
Malik, SA, Porter, TT, Pavlides, G, Chatzizisis, Y
South Dakota medicine : the journal of the South Dakota State Medical Association. 2017;(11):498-502
Abstract
A 65-year-old male presented to the hospital with chest pain associated with recurrent syncope. He had a history of coronary artery disease and a long-standing history of smoking. While he was hospitalized, he had an episode of chest pain during which he was found to have transient ST segment elevation in the inferior leads. He was also noted to have a brief cardiac tachyarrhythmia. Coronary arteriography revealed vasospasm of the left anterior descending artery and right coronary artery, which were relieved to a significant extent after administration of intracoronary nitroglycerin. Subsequent angiograms and fractional flow reserve studies, demonstrated underlying non-obstructive coronary artery disease at the sites of spasm. No percutaneous coronary intervention was pursued. The patient was started on a calcium channel blocker on dismissal from the hospital. Upon follow up several months later, he remained free of symptoms that brought him to the hospital.
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5.
The effects of body weight status on orthostatic intolerance and predisposition to noncardiac syncope.
Christou, GA, Kiortsis, DN
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2017;(3):370-379
Abstract
Orthostatic intolerance (OI) is frequently the mechanism underlying the occurrence of noncardiac syncope (NCS) and is associated with substantial risk for injury. Body weight status appears to be a modifier of orthostatic responses and possibly influences the propensity to NCS. The majority of cross-sectional studies have found that the lower the body mass index (BMI) the greater the predisposition to OI is, accompanied with both down-regulation of sympathetic nervous system activity and up-regulation of parasympathetic nervous system activity. These changes appear to occur across the whole spectrum of BMI values from underweight to obesity, while they may be associated more strongly with central body fat than total body fat. Weight loss following bariatric surgery has been consistently found to increase OI, attributed first to the effects of weight loss per se, second to the specific type of surgical procedure and third to the potential postoperative autonomic neuropathy due to vitamin deficiency. The increased OI following bariatric surgery renders this intervention not easily tolerable for the affected individuals, mandating increased fluid and salt intake, pharmacological measures or surgical adjustments to attenuate OI. All future studies investigating orthostatic responses and NCS should implement a matching of the population arms for BMI and ideally for body fat.
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6.
Pathophysiology of neurally-mediated syncope.
Malamud-Kessler, C, Bruno, E, Chiquete, E, Sentíes-Madrid, H, Campos-Sánchez, M
Neurologia (Barcelona, Spain). 2016;(9):620-627
Abstract
INTRODUCTION Neurally-mediated syncope (NMS) is defined as a transient loss of consciousness due to an abrupt and intermittent drop in blood pressure (BP). OBJECTIVES This study describes the putative pathophysiological mechanisms giving rise to NMS, the role of baroreflex (BR), and the interaction of its main haemodynamic variables: heart rate (HR) and BP. DEVELOPMENT Episodic dysregulation affects control over the haemodynamic variables (HR and BP) mediated by baroreflex mechanisms. During active standing, individuals experience a profound transient drop in systolic BP due to the effect of gravity on the column of blood and probably also because of reflex vasodilation. Abnormalities in the BR in NMS could be due to a more profound drop in BP upon standing, or to delayed or incomplete vasoconstriction resulting from inhibited or delayed sympathetic activity. CONCLUSIONS Sympathetic hyperactivity is present in patients with NMS at rest and before syncope. During active standing or passive tilting, excessive tachycardia may be followed by bradycardia and profound hypotension. Recovery of systolic BP is delayed or incomplete.
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7.
Safety, Tolerability, and Pharmacokinetic Profile of the Novel Translocator Protein 18 kDa Antagonist ONO-2952 in Healthy Volunteers.
Suto, F, Wood, AT, Kobayashi, M, Komaba, J, Duffy, K, Bruce, M
Clinical therapeutics. 2015;(9):2071-84
Abstract
PURPOSE To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO-2952 in healthy subjects. METHODS Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined. FINDINGS Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean accumulation ratios (95% CI) of AUC24 were 2.50 (2.09-2.98 [30 mg]), 2.23 (1.85-2.68 [60 mg]), and 2.73 (2.10-3.55 [100 mg]); and Cmax were 1.65 (1.43-1.90 [30 mg]), 1.56 (1.31-1.85 [60 mg]), and 1.85 (1.38-2.49 [100 mg]). IMPLICATIONS ONO-2952 was safe and well tolerated in these early clinical studies investigating safety, tolerability, and pharmacokinetic properties of single and multiple doses. ONO-2952 systemic exposure increased in a less than dose-proportional manner under fasted conditions and in a slightly greater than dose-proportional manner under fed conditions. These results support the progression of ONO-2952 to further studies in humans. SAD study: ClinicalTials.gov identifier: NCT01364441. MAD study: ClinicalTrials.gov identifier: NCT01489345.
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8.
Neurally mediated syncope as a cause of syncope in patients with Brugada electrocardiogram.
Yokokawa, M, Okamura, H, Noda, T, Satomi, K, Suyama, K, Kurita, T, Aihara, N, Kamakura, S, Shimizu, W
Journal of cardiovascular electrophysiology. 2010;(2):186-92
Abstract
INTRODUCTION Patients with type 1 Brugada electrocardiogram (ECG) and an episode of syncope are diagnosed as symptomatic Brugada syndrome; however, all episodes of syncope may not be due to ventricular tachyarrhythmia. METHODS AND RESULTS Forty-six patients with type 1 Brugada ECG (all males, 51 +/- 13 years, 29 spontaneous, 17 Ic-drug induced), 20 healthy control subjects (all males, 35 +/- 11 years), and 15 patients with suspected neurally mediated syncope (NMS; 9 males, 54 +/- 22 years) underwent the head-up tilt (HUT) test. During the HUT test, 12-lead ECGs were recorded in all patients, and the heart rate variability was investigated in some patients. Sixteen (35%) of 46 patients with Brugada ECG, 2 (10%) of 20 control subjects, and 10 (67%) of 15 patients with suspected NMS showed positive responses to the HUT test. Although no significant differences were observed in HUT-positive rate among Brugada patients with documented VT (7/14; 50%), syncope (5/19; 26%) and asymptomatic patients (4/13; 31%), the HUT-positive rate was significantly higher in patients with documented VT (50%) and those with VT or no symptoms (11/27, 41%) compared to that in control subjects (10%) (P < 0.05). Augmentation of ST-segment amplitude (> or =0.05 mV) in leads V1-V3 was observed in 11 (69%) of 16 HUT-positive patients with Brugada ECG during vasovagal responses, and was associated with augmentation of parasympathetic tone following sympathetic withdrawal. CONCLUSION Thirty-five percent of patients with Brugada ECG showed vasovagal responses during the HUT test, suggesting that some Brugada patients have impaired balance of autonomic nervous system, which may relate to their syncopal episodes.
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9.
The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.
Medeiros-Domingo, A, Bhuiyan, ZA, Tester, DJ, Hofman, N, Bikker, H, van Tintelen, JP, Mannens, MM, Wilde, AA, Ackerman, MJ
Journal of the American College of Cardiology. 2009;(22):2065-74
Abstract
OBJECTIVES This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). BACKGROUND Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. METHODS Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). RESULTS Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. CONCLUSIONS Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
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10.
[Brugada syndrome].
Leenhardt, A, Hamdaoui, B, Di Fusco, S, Extramiana, F, Meddane, M, Denjoy, I, Milliez, P, Dejode, P, Cauchemez, B
Archives des maladies du coeur et des vaisseaux. 2003;:30-7
Abstract
The Brugada syndrome is characterised clinically by the occurrence of syncope or sudden death due to ventricular arrhythmias in patients with structurally normal hearts and electrocardiographic signs of right bundle branch block and ST elevation in the right precordial leads (V1 to V3). The transmission of the condition is autosomal dominant with variable penetration. Mutations have been identified in a gene coding for the alpha sub-unity of the sodium channel (SCN5A) on chromosome 3 in only 30% of cases. This mutation is responsible for a reduction of the density of the sodium current and explains the aggravation of the electrocardiographic anomalies by antiarrhythmic drugs which block the sodium channels. The prognosis is poor in symptomatic patients and depends on the prevention of sudden death by the implantation of an automatic defibrillator. The therapeutic decision is much more difficult in asymptomatic patients without a family history. The authors propose a decisional algorithm. The management may have to be modified in the months or years to come depending on advances in the understanding of this syndrome.