How to unblur the vasovagal evidence?

Paroxysmal Cerebral Disorder

Classical and delayed orthostatic hypotension in patients with unexplained syncope and severe orthostatic intolerance

Background: Orthostatic hypotension (OH) is a major sign of cardiovascular autonomic failure leading to orthostatic intolerance and syncope. Orthostatic hypotension is traditionally divided into classical OH (cOH) and delayed OH (dOH), but the differences between the two variants are not well-studied. We performed a systematic clinical and neuroendocrine characterization of OH patients in a tertiary syncope unit. Methods: Among 2,167 consecutive patients (1,316 women, 60.7%; age, 52.6 ± 21.0 years) evaluated for unexplained syncope and severe orthostatic intolerance with standardized cardiovascular autonomic tests including head-up tilt (HUT), we identified those with a definitive diagnosis of cOH and dOH. We analyzed patients' history, clinical characteristics, hemodynamic variables, and plasma levels of epinephrine, norepinephrine, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1, mid-regional-fragment of pro-atrial-natriuretic-peptide and pro-adrenomedullin in the supine position and at 3-min HUT. Results: We identified 248 cOH and 336 dOH patients (27% of the entire cohort); 111 cOH and 152 dOH had blood samples collected in the supine position and at 3-min HUT. Compared with dOH, cOH patients were older (68 vs. 60 years, p < 0.001), more often male (56.9 vs. 39.6%, p < 0.001), had higher systolic blood pressure (141 vs. 137 mmHg, p = 0.05), had lower estimated glomerular filtration rate (73 vs. 80 ml/min/1.73 m2, p = 0.003), more often pathologic Valsalva maneuver (86 vs. 49 patients, p < 0.001), pacemaker-treated arrhythmia (5 vs. 2%, p = 0.04), Parkinson's disease (5 vs. 1%, p = 0.008) and reported less palpitations before syncope (16 vs. 29%, p = 0.001). Supine and standing levels of CT-proAVP were higher in cOH (p = 0.022 and p < 0.001, respectively), whereas standing norepinephrine was higher in dOH (p = 0.001). After 3-min HUT, increases in epinephrine (p < 0.001) and CT-proAVP (p = 0.001) were greater in cOH, whereas norepinephrine increased more in dOH (p = 0.045). Conclusions: One-quarter of patients with unexplained syncope and severe orthostatic intolerance present orthostatic hypotension. Classical OH patients are older, more often have supine hypertension, pathologic Valsalva maneuver, Parkinson's disease, pacemaker-treated arrhythmia, and lower glomerular filtration rate. Classical OH is associated with increased vasopressin and epinephrine during HUT, but blunted increase in norepinephrine

Tilt table testing, methodology and practical insights for the clinic.

Tilt table testing (TTT) has been used for decades to study short-term blood pressure (BP) and heart rate regulation during orthostatic challenges. TTT provokes vasovagal reflex in many syncope patients as a background of widespread use. Despite the availability of evidence-based practice syncope guidelines, proper application and interpretation of TTT in the day-to-day care of syncope patients remain challenging. In this review, we offer practical information on what is needed to perform TTT, how results should be interpreted including the Vasovagal Syncope International Study classification, why syncope induction on TTT is necessary in patients with unexplained syncope and on indications for TTT in syncope patient care. The minimum requirements to perform TTT are a tilt table with an appropriate tilt-down time, a continuous beat-to-beat BP monitor with at least three electrocardiogram leads and trained staff. We emphasize that TTT remains a valuable asset that adds to history building but cannot replace it, and highlight the importance of recognition when TTT is abnormal even without syncope. Acknowledgement by the patient/eyewitness of the reproducibility of the induced attack is mandatory in concluding a diagnosis. TTT may be indicated when the initial syncope evaluation does not yield a certain, highly likely, or possible diagnosis, but raises clinical suspicion of (1) reflex syncope, (2) orthostatic hypotension (OH), (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT in the patient with a certain, highly likely or possible diagnosis of reflex syncope, may be to educate patients on prodromes. In patients with reflex syncope with OH TTT can be therapeutic to recognize hypotensive symptoms causing near-syncope to perform physical countermanoeuvres for syncope prevention (biofeedback). Detection of hypotensive susceptibility requiring therapy is of special value

Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium

Aims Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. Methods and resultsA total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8) met the diagnostic criteria for OH (systolic/diastolic BP drop <20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95 confidence interval: 0.90, 0.850.96; P=0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.750.95; P=0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.870.98; P=0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.021.24; P=0.02, rs198358: 1.10, 1.011.20; P=0.04, and rs5068: 1.22, 1.041.43; P=0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P=0.04). ConclusionThe overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components

Outcomes of primary vs. delayed strategy of implanting a cardiac monitor for unexplained syncope.

OBJECTIVE: Implantable cardiac monitors (ILR) have an important role in diagnosing unexplained syncope. However, outcomes of primary vs. delayed ILR implantation after initial syncope evaluation have not been explored. METHODS: A total of 1705 patients with unexplained syncope were prospectively enrolled in the SYSTEMA (Syncope Study of Unselected Population in Malmö) cohort. Patients who underwent cardiovascular autonomic testing (CAT) and ILR were grouped into those referred to CAT after ILR implantation (primary ILR) and those in whom ILR was indicated after CAT (post-CAT ILR). RESULTS: One-hundred-and-fifteen patients (6.7%) received ILRs. ILR recipients were older (58 vs. 52 years; p = 0.002), had more syncope recurrences (6 vs. 4; p &lt; 0.001), more traumatic falls (72% vs. 53%; p &lt; 0.001), and less prodrome (40% vs. 55%; p = 0.005) than patients without ILRs. During follow-up ≥16 months after ILR, 67 (58%) had normal sinus rhythm, 10 (8.7%) had sinus arrest, 10 (8.7%) AV-block, 13 (11.3%) atrial fibrillation, 9 (7.8%) supraventricular tachycardia, 4 (3.5%) sinus tachycardia and 2 (1.7%) ventricular tachycardia with clinical symptom reproduction. There were 52 patients (45%) in the primary-ILR group and 63 (55%) in the post-CAT ILR group. Proportions of negative ILR monitoring (17/52 vs. 25/63; p = 0.56) and pacemaker implantations (7/52 vs. 15/63; p = 0.23) did not differ between groups. Baseline ECG conduction disorders predicted pacemaker implantation (n = 11/17; odds ratio:10.6; 95%CI: 3.15-35.3; p &lt; 0.001). CAT was more often positive (73% vs. 40%; p &lt; 0.001) in primary-ILR group. CONCLUSIONS: Primary ILR implantation was associated with more positive CAT compared with delayed ILR implantation, but negative monitoring and pacemaker implantations were not different between groups. ECG conduction disorders predicted subsequent pacemaker implantation

Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension

OBJECTIVE: To investigate the relationship of hospital admissions due to unexplained syncope and orthostatic hypotension (OH) with subsequent cardiovascular events and mortality. METHODS: We analysed a population-based prospective cohort of 30 528 middle-aged individuals (age 58±8 years; males, 40%). Adjusted Cox regression models were applied to assess the impact of unexplained syncope/OH hospitalisations on cardiovascular events and mortality, excluding subjects with prevalent cardiovascular disease. RESULTS: After a median follow-up of 15±4 years, 524 (1.7%) and 504 (1.7%) participants were hospitalised for syncope or OH, respectively, yielding 1.2 hospital admissions per 1000 person-years for each diagnosis. Syncope hospitalisations increased with age (HR, per 1 year: 1.07, 95% CI 1.05 to 1.09), higher systolic blood pressure (HR, per 10 mm Hg: 1.06, 95% CI 1.01 to 1.12), antihypertensive treatment (HR: 1.26, 95% CI 1.00 to 1.59), use of diuretics (HR: 1.77, 95% CI 1.31 to 2.38) and prevalent cardiovascular disease (HR: 1.59, 95% CI 1.14 to 2.23), whereas OH hospitalisations increased with age (HR: 1.11, 95% CI 1.08 to 1.12) and prevalent diabetes (HR: 1.82, 95% CI 1.23 to 2.70). After exclusion of 1399 patients with prevalent cardiovascular disease, a total of 473/464 patients were hospitalised for unexplained syncope/OH before any cardiovascular event. Hospitalisation for unexplained syncope predicted coronary events (HR: 1.85, 95% CI 1.49 to 2.30), heart failure (HR: 2.24, 95% CI 1.65 to 3.04), atrial fibrillation (HR: 1.84, 95% CI 1.50 to 2.26), aortic valve stenosis (HR: 2.06, 95% CI 1.28 to 3.32), all-cause mortality (HR: 1.22, 95% CI 1.09 to 1.37) and cardiovascular death (HR: 1.72, 95% CI 1.23 to 2.42). OH-hospitalisation predicted stroke (HR: 1.66, 95% CI 1.24 to 2.23), heart failure (HR: 1.78, 95% CI 1.21 to 2.62), atrial fibrillation (HR: 1.89, 95% CI 1.48 to 2.41) and all-cause mortality (HR: 1.14, 95% CI 1.01 to 1.30). CONCLUSIONS: Patients discharged with the diagnosis of unexplained syncope or OH show higher incidence of cardiovascular disease and mortality with only partial overlap between these two conditions

When Blood Pressure Increases with Standing: Consensus Definition for Diagnosing Orthostatic Hypertension

When changing from the supine to the standing position approximately 500–1000 ml blood is pooled below the diaphragm and hydrostatic pressure forces fluids from the intravascular to the interstitial compartment. These changes impose a major hemodynamic burden on the cardiovascular system. Baroreflex-mediated withdrawal of cardiac parasympathetic activity and sympathetic activation maintain standing blood pressure in healthy persons. Orthostatic hypotension occurs when these counterregulatory mechanisms fail. Conversely, some patients have a paradoxical increase in upright blood pressure to hypertensive levels, presumably due to sympathetic activation overshoot. This orthostatic hypertension is not a benign condition because it is associated with increased cardiovascular morbidity and mortality independently of traditional risk factors.Citation1,Citation2 Yet, there has not been a uniform definition of orthostatic hypertension and the entity is not covered in current hypertension guidelines. Because diagnostic criteria vary profoundly between studies, data on epidemiology, associated health risks, and management of orthostatic hypertension in the existing literature is difficult to interpret

Risk of incident fractures in individuals hospitalised due to unexplained syncope and orthostatic hypotension

Background Impaired orthostatic blood pressure response and syncope confer a high risk of falls and trauma. The relationship between a history of unexplained syncope and orthostatic hypotension (OH) with subsequent fractures, however, has not been thoroughly examined. In this study, we aimed to investigate the relationship between previous hospital admissions due to unexplained syncope and OH and incident fractures in a middle-aged population. Methods We analysed a large population-based prospective cohort of 30,399 middle-aged individuals (age, 57.5 ± 7.6; women, 60.2%). We included individuals hospitalised due to unexplained syncope or OH as the main diagnosis. Multivariable-adjusted Cox regression analysis was applied to assess the impact of unexplained syncope and OH hospitalisations on subsequent incident fractures. Results During a follow-up period of 17.8 + 6.5 years, 8201 (27%) subjects suffered incident fractures. The mean time from baseline and first admission for syncope (n = 493) or OH (n = 406) was 12.6 ± 4.2 years, and the mean age of the first hospitalisation was 74.6 ± 7.4 years. Individuals with incident fractures were older, more likely to be women, and had lower BMI, higher prevalence of prevalent fractures, and family history of fractures. Multivariable-adjusted Cox regression showed an increased risk of incident fractures following hospitalisations due to unexplained syncope (HR 1.20; 95% CI 1.02–1.40; p = 0.025) and OH (HR 1.42; 95% CI 1.21–1.66; p < 0.001) compared with unaffected individuals. Conclusions Individuals hospitalised due to unexplained syncope and orthostatic hypotension have an increased risk of subsequent fractures. Our findings suggest that such individuals should be clinically assessed for their syncope aetiology, with preventative measures aimed at fall and fracture risk assessment and management