Artur Fedorowski

Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies

BACKGROUND Whether orthostatic hypotension (OH) is a risk factor for cardiovascular morbidity and death is uncertain. Currently available evidence derives from non-homogeneous and partly ambiguous studies. OBJECTIVE We aimed at assessing the relationship between OH and death or major adverse cardiac and cerebrovascular events (MACCEs) by integrating results of previous studies. METHODS We performed a meta-analysis of prospective observational studies reporting on the association between prevalent OH, mortality, and incident MACCE, published from 1966 through 2013. Mantel-Haenszel pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for all-cause death were assessed as the primary endpoint at the longest follow-up; incident coronary heart disease (CHD), heart failure (HF), and stroke were assessed as secondary endpoints. We also performed post hoc subgroup analyses stratified by age and a meta-regression analysis. RESULTS We identified a total of 13 studies, including an overall population of 121 913 patients, with a median follow-up of 6 years. Compared with the absence of OH, the occurrence of OH was associated with a significantly increased risk of all-cause death (RR 1.50; 95% CI 1.24-1.81), incident CHD (RR 1.41; 95% CI 1.22-1.63), HF (RR 2.25; 95% CI 1.52-3.33), and stroke (RR 1.64; 95% CI 1.13-2.37). When analysed according to age, pooled estimates of RR (95% CI) for all-cause death were 1.78 (1.25-2.52) for patients <65 years old, and 1.26 (0.99-1.62) in the older subgroup. CONCLUSION Orthostatic hypotension is associated with a significantly increased risk of all-cause death, incident CHD, HF, and stroke.

Syndromes of orthostatic intolerance: a hidden danger

Orthostatic hypotension (OH) is a relatively common heterogenous and multifactorial disorder, traditionally classified as neurogenic (less common but often more severe) or nonneurogenic (more common, with no direct signs of autonomic nervous system disease). The different clinical variants of orthostatic intolerance include initial, classical and delayed OH as well as postural tachycardia syndrome. Orthostatic instability may induce syncopal attacks either alone or in combination with other mechanisms, and is often dismissed as a precipitating factor. Moreover, prevalent OH is an independent risk factor for all‐cause mortality and cardiovascular morbidity, and the majority of patients with OH are asymptomatic or have few nonspecific symptoms. Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods, but it is not always successful and may lead to complications. Future studies of OH should focus on mechanisms that lead to neurogenic and nonneurogenic OH, novel diagnostic methods and more effective therapeutic modalities.

A dedicated investigation unit improves management of syncopal attacks (Syncope Study of Unselected Population in Malmö—SYSTEMA I)

Aims To investigate whether a systematic approach to unexplained syncopal attacks based on the European Society of Cardiology guidelines would improve the diagnostic and therapeutic outcomes. Methods and results Patients presenting with transient loss of consciousness to the Emergency Department of Skåne University Hospital in Malmö were registered by triage staff. Those with established cardiac, neurological, or other definite aetiology and those with advanced dementia were excluded. The remaining patients were offered evaluation based on an expanded head-up tilt test protocol, which included carotid sinus massage, and nitroglycerine challenge if needed. Out of 201 patients registered over a period of 6 months, 129 (64.2%) were found to be eligible; of these, 101 (38.6% men, mean age 66.3 ± 18.4 years) decided to participate in the study. Head-up tilt test allowed diagnoses in 91 cases (90.1%). Vasovagal syncope (VVS) was detected in 45, carotid sinus hypersensitivity (CSH) in 27, and orthostatic hypotension (OH) in 51 patients. Twelve patients with VVS and 15 with CSH also had OH, whereas 25 were diagnosed with OH only. In a multivariate logistic regression, OH was independently associated with age [OR (per year): 1.05, 95% CI 1.02–1.08, P = 0.001], history of hypertension (2.73, 1.05–7.09, P = 0.039), lowered estimated glomerular filtration rate (per 10 mL/min/1.73 m2: 1.17, 1.01–1.33, P = 0.032), use of loop diuretics (10.44, 1.22–89.08, P = 0.032), and calcium-channel blockers (5.29, 1.03–27.14, P = 0.046), while CSH with age [(per year) 1.12, 1.05–1.19, P < 0.001), use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (4.46, 1.22–16.24, P = 0.023), and nitrates (27.88, 1.99–389.81, P = 0.013). Conclusion A systematic approach to patients presenting with unexplained syncopal attacks considerably increased diagnostic efficacy and accuracy. Potential syncope diagnoses have a tendency to overlap and show diversity in demographic, anamnestic, and pharmacological determinants.

Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort

The aim of the study was to investigate the resting levels of novel cardiovascular biomarkers in common types of noncardiac syncope.

Impact of comorbidity on 6-month hospital readmission and mortality after hip fracture surgery.

OBJECTIVES Impact of comorbidity on risk of readmission and death after hip fracture surgery has not been sufficiently explored. We planned to investigate the role of common diseases in predicting adverse events during recovery after hip surgery. PATIENTS AND METHODS We prospectively evaluated 272 consecutive patients (age, 82.6±8.9 years; 196 females, 72.1%) who underwent acute surgery for hip fracture at a regional university hospital. Baseline comorbidity and hospital stay were analysed. Number, timing and reasons for readmissions as well as mortality within 6 months after hospital discharge were recorded. An age- and sex-adjusted logistic regression model was applied to assess relations between comorbidity and relative risk of rehospitalisation or death. RESULTS Hypertension (44%), cognitive disorders (26%), and ischaemic heart disease (19%) were the most common comorbidities. The mean length-of-postoperative-stay was 12.7±7.9 days. Eighty-six patients (32%) were readmitted to hospital within 6 months from initial discharge and 36 patients (13%) died during that period. Increased risk of readmission was associated with hypertension (odds ratio (OR): 2.0, 95%CI, 1.2-1.9, p=0.009), and pacemaker treatment (OR: 6.6, 95%CI, 1.7-26.3, p=0.007), while there was a tendency towards readmission among men with prostate disease (OR: 5.0, 95%CI, 0.9-27.2, p=0.06). In contrast, mortality was predicted by ischaemic heart disease (OR: 2.2, 95%CI, 1.0-4.9, p=0.05), and malignancy (OR: 2.5, 95%CI, 1.1-5.7, p=0.04). CONCLUSIONS Common comorbidities are associated with higher risk of rehospitalisation and mortality following hip fracture surgery in the elderly. This information may be useful in postoperative risk assessment and prevention of negative outcomes.

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 results A 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, 0.85–0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75–0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87–0.98; 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, 1.02–1.24; P = 0.02, rs198358: 1.10, 1.01–1.20; P = 0.04, and rs5068: 1.22, 1.04–1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04). Conclusion The 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.

Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients

Background Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained. Methods Six-hundred-and-seventy-one patients (299 males; 55±22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively. Results Higher resting CT-proET-1 predicted BP fall at 3min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18–2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28–2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3min (1.33, 1.03–1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38–2.51; p = 0.00005) and epinephrine (1.47, 1.12–1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3min (0.37, 0.24–0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29–0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15–2.21; p = 0.005), and norepinephrine (1.87, 1.38–2.53; p = 0.005). Conclusions Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.

Antiadrenergic autoimmunity in postural tachycardia syndrome

Abstract Aims Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR). Methods and results Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of α1AR and β1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of α1AR and β1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays. Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. Eight of 17 POTS IgG decreased the α1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by α1AR blockade. The upright heart rate correlated with IgG-mediated β1AR and α1AR activity but not with β2AR activity. Conclusion These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the α1AR and β1AR responsiveness are important in the pathophysiology of postural tachycardia.

Orthostatic blood pressure response, carotid intima-media thickness, and plasma fibrinogen in older nondiabetic adults.

Objective: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension (OHTN) independently predict cardiovascular events, the underlying mechanisms are still debatable. Methods: A total of 700 nondiabetic adults (43% men, age 64 years) were examined by orthostatic blood pressure (BP) test, carotid artery ultrasonography, and biochemical tests including plasma fibrinogen and lipid profile. Multivariate-adjusted logistic regression was applied to assess association of intima–media thickness (IMT) and P-fibrinogen with orthostatic hypotension and OHTN. In addition, distribution of IMT and P-fibrinogen across quintiles of orthostatic systolic BP (SBP) response was analyzed. Results: Orthostatic hypotension and OHTN were found in 40 (5.7%) and 45 (6.4%) study participants, respectively. Both IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.27, 1.01–1.60; P = 0.04] and P-fibrinogen (OR 1.44, 1.07–1.93; P = 0.02) were associated with orthostatic hypotension in a crude model. After adjustment relationship between orthostatic hypotension and IMT was slightly attenuated (OR 1.26, 0.96–1.65; P = 0.09) but was substantially unchanged in regard to P-fibrinogen (OR 1.45, 1.06–1.99; P = 0.02). In contrast, OHTN showed no association with either IMT or P-fibrinogen (adjusted OR 1.09, 0.78–1.52; P = 0.61, and 0.97, 0.70–1.34; P = 0.84, respectively). Distribution of IMT across quintiles of orthostatic SBP response was U-shaped, whereas that of fibrinogen was more linear but none of borderline quintiles (with pronounced hypertensive or hypotensive response) significantly differed from the middle quintiles in a fully adjusted model. Conclusion: In older nondiabetic adults only orthostatic hypotension seems to independently correlate with increased carotid atherosclerosis and systemic inflammation.

Systolic and diastolic component of orthostatic hypotension and cardiovascular events in hypertensive patients: the Captopril Prevention Project.

Objective: Impact of SBP vs. DBP decrement during orthostasis on cardiovascular events in hypertension is not clear. Methods: We assessed prospective association of orthostatic hypotension with mortality and major cardiovascular events [myocardial infarction (MI) and stroke] among 8788 treated hypertensive patients (52.2% men; mean age 52 years, mean BP 161/99 mmHg) without history of MI or stroke at baseline. Orthostatic hypotension was defined according to combined international consensus criteria, and as either systolic (decrease ≥20 mmHg) or diastolic orthostatic hypotension (decrease ≥10 mmHg). Final Cox regression model was adjusted for age, sex, supine SBP and DBP, diabetes, smoking, and total cholesterol. Results: A total of 1060 (12.1%) study participants fulfilled combined orthostatic hypotension criteria, of these 886 (10.1%) met systolic and 290 (3.3%) diastolic criterion. In the crude analysis, combined orthostatic hypotension criteria were predictive of the composite endpoint, major cardiovascular event, total mortality, and stroke but not MI. After full adjustment, combined orthostatic hypotension criteria and systolic orthostatic hypotension were independently associated with stroke only (hazard ratio: 1.48, 1.07–2.05, P = 0.019, and 1.53, 1.08–2.15, P = 0.015, respectively), whereas the composite endpoint tended in the same direction (hazard ratio: 1.21, 0.98–1.51, P = 0.075, and 1.24, 0.99–1.55, P = 0.066, respectively). In contrast, diastolic orthostatic hypotension was associated with increased risk of MI (hazard ratio: 2.04, 1.20–3.46, P = 0.008). Conclusion: Orthostatic hypotension has a dual role in cardiovascular events among hypertensive patients: SBP fall indicates higher risk of stroke, whereas DBP fall confers higher risk of MI.