Cardiovascular Safety Considerations in the Treatment of Neurogenic Orthostatic Hypotension
2020; Elsevier BV; Volume: 125; Issue: 10 Linguagem: Inglês
10.1016/j.amjcard.2020.01.037
ISSN1879-1913
AutoresBrian Olshansky, James A.S. Muldowney,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoNeurogenic orthostatic hypotension (nOH), a drop in blood pressure upon standing resulting from autonomic malfunction, may cause debilitating symptoms that can affect independence in daily activities and quality-of-life. nOH may also be associated with cardiovascular comorbidities (e.g., supine hypertension, heart failure, diabetes, and arrhythmias), making treatment decisions complicated and requiring management that should be based on a patient's cardiovascular profile. Additionally, drugs used to treat the cardiovascular disorders (e.g., vasodilators, β-blockers) can exacerbate nOH and concomitant symptoms. When orthostatic symptoms are severe and not effectively managed with nonpharmacologic strategies (e.g., water ingestion, abdominal compression), droxidopa or midodrine may be effective. Droxidopa may be less likely than midodrine to exacerbate supine hypertension, based on conclusions of a limited meta-analysis. In conclusion, treating nOH in patients with cardiovascular conditions requires a balance between symptom relief and minimizing adverse outcomes. Neurogenic orthostatic hypotension (nOH), a drop in blood pressure upon standing resulting from autonomic malfunction, may cause debilitating symptoms that can affect independence in daily activities and quality-of-life. nOH may also be associated with cardiovascular comorbidities (e.g., supine hypertension, heart failure, diabetes, and arrhythmias), making treatment decisions complicated and requiring management that should be based on a patient's cardiovascular profile. Additionally, drugs used to treat the cardiovascular disorders (e.g., vasodilators, β-blockers) can exacerbate nOH and concomitant symptoms. When orthostatic symptoms are severe and not effectively managed with nonpharmacologic strategies (e.g., water ingestion, abdominal compression), droxidopa or midodrine may be effective. Droxidopa may be less likely than midodrine to exacerbate supine hypertension, based on conclusions of a limited meta-analysis. In conclusion, treating nOH in patients with cardiovascular conditions requires a balance between symptom relief and minimizing adverse outcomes. Neurogenic orthostatic hypotension (nOH), a drop in blood pressure when moving to an upright position without a sufficient compensatory increase in heart rate, is common in patients with autonomic failure due to neurodegenerative disorders.1Freeman R Clinical practice. Neurogenic orthostatic hypotension.N Engl J Med. 2008; 358: 615-624Crossref PubMed Scopus (281) Google Scholar In nOH, the inability to maintain effective venous return when standing reduces left ventricular filling, cardiac output, blood pressure, and cerebral perfusion, causing dizziness, lightheadedness, syncope, and falls, which can affect patient independence, quality-of-life, and activities of daily living.1Freeman R Clinical practice. Neurogenic orthostatic hypotension.N Engl J Med. 2008; 358: 615-624Crossref PubMed Scopus (281) Google Scholar, 2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar, 3Claassen DO Adler CH Hewitt LA Gibbons C Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers.BMC Neurol. 2018; 18: 125Crossref PubMed Scopus (29) Google Scholar, 4Merola A Romagnolo A Rosso M Suri R Berndt Z Maule S Lopiano L Espay AJ Autonomic dysfunction in Parkinson's disease: a prospective cohort study.Mov Disord. 2018; 33: 391-397Crossref PubMed Scopus (88) Google Scholar Successful management of nOH is challenging, especially if co-morbid cardiovascular conditions are present; available therapies may not be completely effective and may increase supine hypertension, a common morbidity in patients with nOH.2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar,5Espay AJ LeWitt PA Hauser RA Merola A Masellis M Lang AE Neurogenic orthostatic hypotension and supine hypertension in Parkinson's disease and related synucleinopathies: prioritisation of treatment targets.Lancet Neurol. 2016; 15: 954-966Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar This review addresses critical issues in the management of symptoms related to nOH in patients with cardiovascular co-morbidities. Patients with primary autonomic dysfunction (characterized by α-synuclein pathology such as Parkinson disease, multiple system atrophy, and pure autonomic failure) or secondary autonomic neuropathies (due to diabetes, amyloidosis, or chemotherapy) are at risk for nOH. In addition to symptoms of cerebral hypoperfusion (dizziness, lightheadedness, and confusion), nOH also causes other symptoms (e.g., shoulder heaviness ["coat-hanger syndrome"], orthostatic angina, and dyspnea).1Freeman R Clinical practice. Neurogenic orthostatic hypotension.N Engl J Med. 2008; 358: 615-624Crossref PubMed Scopus (281) Google Scholar,2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar Patients with autonomic failure conditions presenting with debilitating or serious symptoms (e.g., syncope) or certain characteristics (e.g., elderly, polypharmacy use) should be evaluated for nOH by asking about orthostatic symptoms and measuring orthostatic vital signs (Figure 1).2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar,6Freeman R Wieling W Axelrod FB Benditt DG Benarroch E Biaggioni I Cheshire WP Chelimsky T Cortelli P Gibbons CH Goldstein DS Hainsworth R Hilz MJ Jacob G Kaufmann H Jordan J Lipsitz LA Levine BD Low PA Mathias C Raj SR Robertson D Sandroni P Schatz I Schondorff R Stewart JM van Dijk JG Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.Clin Auton Res. 2011; 21: 69-72Crossref PubMed Scopus (1007) Google Scholar An otherwise unexplained, inadequate compensatory heart rate increase (i.e., ≤10 to 15 beats/min) upon standing helps distinguish nOH from OH.2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar,7Brignole M Moya A de Lange FJ Deharo JC Elliott PM Fanciulli A Fedorowski A Furlan R Kenny RA Martin A Probst V Reed MJ Rice CP Sutton R Ungar A van Dijk JG ESC Scientific Document Group2018 ESC guidelines for the diagnosis and management of syncope.Eur Heart J. 2018; 39: 1883-1948Crossref PubMed Scopus (854) Google Scholar If orthostatic vital signs indicate OH/nOH, a careful patient history, medication review, electrocardiogram, and directed testing should be conducted.2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar Common causes of non-neurogenic OH include medications (e.g., diuretics, vasodilators, anticholinergics, antihypertensive medications), hypovolemia, or deconditioning (e.g., due to a chronic illness).2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar If the cause is still unclear, specialized autonomic testing should be considered.2Gibbons CH Schmidt P Biaggioni I Frazier-Mills C Freeman R Isaacson S Karabin B Kuritzky L Lew M Low P Mehdirad A Raj SR Vernino S Kaufmann H The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.J Neurol. 2017; 264: 1567-1582Crossref PubMed Scopus (222) Google Scholar Studies of morbidity and mortality outcomes in patients with nOH or OH are listed in Table 1.3Claassen DO Adler CH Hewitt LA Gibbons C Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers.BMC Neurol. 2018; 18: 125Crossref PubMed Scopus (29) Google Scholar,4Merola A Romagnolo A Rosso M Suri R Berndt Z Maule S Lopiano L Espay AJ Autonomic dysfunction in Parkinson's disease: a prospective cohort study.Mov Disord. 2018; 33: 391-397Crossref PubMed Scopus (88) Google Scholar,8Ricci F Fedorowski A Radico F Romanello M Tatasciore A Di Nicola M Zimarino M De Caterina R Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies.Eur Heart J. 2015; 36: 1609-1617Crossref PubMed Scopus (187) Google Scholar, 9Xin W Lin Z Mi S Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies.Heart. 2014; 100: 406-413Crossref PubMed Scopus (81) Google Scholar, 10Maule S Milazzo V Maule MM Di Stefano C Milan A Veglio F Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar, 11Goldstein DS Holmes C Sharabi Y Wu T Survival in synucleinopathies: a prospective cohort study.Neurology. 2015; 85: 1554-1561Crossref PubMed Scopus (72) Google Scholar, 12Merola A Sawyer RP Artusi CA Suri R Berndt Z Lopez-Castellanos JR Vaughan J Vizcarra JA Romagnolo A Espay AJ Orthostatic hypotension in Parkinson disease: impact on health care utilization.Parkinsonism Relat Disord. 2017; 47: 45-49Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 13Francois C Biaggioni I Shibao C Ogbonnaya A Shih HC Farrelly E Ziemann A Duhig A Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease.J Med Econ. 2017; 20: 525-532Crossref PubMed Scopus (17) Google Scholar, 14Goldstein DS Cardiac ectopy in chronic autonomic failure.Clin Auton Res. 2010; 20: 85-92Crossref PubMed Scopus (17) Google Scholar, 15Ali A Holm H Molvin J Bachus E Tasevska-Dinevska G Fedorowski A Jujic A Magnusson M Autonomic dysfunction is associated with cardiac remodelling in heart failure patients.ESC Heart Fail. 2018; 5: 46-52Crossref PubMed Scopus (20) Google Scholar, 16Magnusson M Holm H Bachus E Nilsson P Leosdottir M Melander O Jujic A Fedorowski A Orthostatic hypotension and cardiac changes after long-term follow-up.Am J Hypertens. 2016; 29: 847-852Crossref PubMed Scopus (22) Google Scholar, 17Ko D Preis SR Lubitz SA McManus DD Vasan RS Hamburg NM Benjamin EJ Mitchell GF Relation of orthostatic hypotension with new-onset atrial fibrillation (from the Framingham Heart Study).Am J Cardiol. 2018; 121: 596-601Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 18Fedorowski A Hedblad B Engstrom G Gustav Smith J Melander O Orthostatic hypotension and long-term incidence of atrial fibrillation: the Malmo Preventive Project.J Intern Med. 2010; 268: 383-389Crossref PubMed Scopus (52) Google Scholar, 19Milazzo V Maule S Di Stefano C Tosello F Totaro S Veglio F Milan A Cardiac organ damage and arterial stiffness in autonomic failure: comparison with essential hypertension.Hypertension. 2015; 66: 1168-1175Crossref PubMed Scopus (24) Google Scholar, 20Pavy-Le Traon A Piedvache A Perez-Lloret S Calandra-Buonaura G Cochen-De Cock V Colosimo C Cortelli P Debs R Duerr S Fanciulli A Foubert-Samier A Gerdelat A Gurevich T Krismer F Poewe W Tison F Tranchant C Wenning G Rascol O Meissner WG New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study.J Neurol Neurosurg Psychiatry. 2016; 87: 554-561Crossref PubMed Scopus (38) Google Scholar, 21Palma JA Redel-Traub G Porciuncula A Samaniego-Toro D Lui YW Norcliffe-Kaufmann L Kaufmann H The impact of supine hypertension on target organ damage and mortality in patients with neurogenic orthostatic hypotension [Abstract].Clin Auton Res. 2018; 28: 473Google Scholar, 22Fanciulli A Gobel G Ndayisaba JP Granata R Duerr S Strano S Colosimo C Poewe W Pontieri FE Wenning GK Supine hypertension in Parkinson's disease and multiple system atrophy.Clin Auton Res. 2016; 26: 97-105Crossref PubMed Scopus (74) Google Scholar Potential risk from falls is well recognized; patients with Parkinson disease and nOH/OH have greater healthcare resource use (e.g., falls that require medical treatment, more days of hospitalization, higher medical costs) than patients with Parkinson disease but without nOH/OH.12Merola A Sawyer RP Artusi CA Suri R Berndt Z Lopez-Castellanos JR Vaughan J Vizcarra JA Romagnolo A Espay AJ Orthostatic hypotension in Parkinson disease: impact on health care utilization.Parkinsonism Relat Disord. 2017; 47: 45-49Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar,13Francois C Biaggioni I Shibao C Ogbonnaya A Shih HC Farrelly E Ziemann A Duhig A Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease.J Med Econ. 2017; 20: 525-532Crossref PubMed Scopus (17) Google Scholar Falls also have functional and psychosocial consequences, such as a fear of walking or of falling again, resulting in secondary immobility, decreased activity, and subsequent negative outcomes (e.g., development/progression of co-morbidities, social isolation).23Voermans NC Snijders AH Schoon Y Bloem BR Why old people fall (and how to stop them).Pract Neurol. 2007; 7: 158-171Crossref PubMed Scopus (69) Google ScholarTable 1Studies of morbidity and mortality associated with nOH or OH3Claassen DO Adler CH Hewitt LA Gibbons C Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers.BMC Neurol. 2018; 18: 125Crossref PubMed Scopus (29) Google Scholar,4Merola A Romagnolo A Rosso M Suri R Berndt Z Maule S Lopiano L Espay AJ Autonomic dysfunction in Parkinson's disease: a prospective cohort study.Mov Disord. 2018; 33: 391-397Crossref PubMed Scopus (88) Google Scholar,8Ricci F Fedorowski A Radico F Romanello M Tatasciore A Di Nicola M Zimarino M De Caterina R Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies.Eur Heart J. 2015; 36: 1609-1617Crossref PubMed Scopus (187) Google Scholar, 9Xin W Lin Z Mi S Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies.Heart. 2014; 100: 406-413Crossref PubMed Scopus (81) Google Scholar, 10Maule S Milazzo V Maule MM Di Stefano C Milan A Veglio F Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar, 11Goldstein DS Holmes C Sharabi Y Wu T Survival in synucleinopathies: a prospective cohort study.Neurology. 2015; 85: 1554-1561Crossref PubMed Scopus (72) Google Scholar, 12Merola A Sawyer RP Artusi CA Suri R Berndt Z Lopez-Castellanos JR Vaughan J Vizcarra JA Romagnolo A Espay AJ Orthostatic hypotension in Parkinson disease: impact on health care utilization.Parkinsonism Relat Disord. 2017; 47: 45-49Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 13Francois C Biaggioni I Shibao C Ogbonnaya A Shih HC Farrelly E Ziemann A Duhig A Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease.J Med Econ. 2017; 20: 525-532Crossref PubMed Scopus (17) Google Scholar, 14Goldstein DS Cardiac ectopy in chronic autonomic failure.Clin Auton Res. 2010; 20: 85-92Crossref PubMed Scopus (17) Google Scholar, 15Ali A Holm H Molvin J Bachus E Tasevska-Dinevska G Fedorowski A Jujic A Magnusson M Autonomic dysfunction is associated with cardiac remodelling in heart failure patients.ESC Heart Fail. 2018; 5: 46-52Crossref PubMed Scopus (20) Google Scholar, 16Magnusson M Holm H Bachus E Nilsson P Leosdottir M Melander O Jujic A Fedorowski A Orthostatic hypotension and cardiac changes after long-term follow-up.Am J Hypertens. 2016; 29: 847-852Crossref PubMed Scopus (22) Google Scholar, 17Ko D Preis SR Lubitz SA McManus DD Vasan RS Hamburg NM Benjamin EJ Mitchell GF Relation of orthostatic hypotension with new-onset atrial fibrillation (from the Framingham Heart Study).Am J Cardiol. 2018; 121: 596-601Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 18Fedorowski A Hedblad B Engstrom G Gustav Smith J Melander O Orthostatic hypotension and long-term incidence of atrial fibrillation: the Malmo Preventive Project.J Intern Med. 2010; 268: 383-389Crossref PubMed Scopus (52) Google Scholar, 19Milazzo V Maule S Di Stefano C Tosello F Totaro S Veglio F Milan A Cardiac organ damage and arterial stiffness in autonomic failure: comparison with essential hypertension.Hypertension. 2015; 66: 1168-1175Crossref PubMed Scopus (24) Google Scholar, 20Pavy-Le Traon A Piedvache A Perez-Lloret S Calandra-Buonaura G Cochen-De Cock V Colosimo C Cortelli P Debs R Duerr S Fanciulli A Foubert-Samier A Gerdelat A Gurevich T Krismer F Poewe W Tison F Tranchant C Wenning G Rascol O Meissner WG New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study.J Neurol Neurosurg Psychiatry. 2016; 87: 554-561Crossref PubMed Scopus (38) Google Scholar, 21Palma JA Redel-Traub G Porciuncula A Samaniego-Toro D Lui YW Norcliffe-Kaufmann L Kaufmann H The impact of supine hypertension on target organ damage and mortality in patients with neurogenic orthostatic hypotension [Abstract].Clin Auton Res. 2018; 28: 473Google Scholar, 22Fanciulli A Gobel G Ndayisaba JP Granata R Duerr S Strano S Colosimo C Poewe W Pontieri FE Wenning GK Supine hypertension in Parkinson's disease and multiple system atrophy.Clin Auton Res. 2016; 26: 97-105Crossref PubMed Scopus (74) Google ScholarStudyStudy typePopulationMean age, yKey findingsBurden Francois, 201713Francois C Biaggioni I Shibao C Ogbonnaya A Shih HC Farrelly E Ziemann A Duhig A Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease.J Med Econ. 2017; 20: 525-532Crossref PubMed Scopus (17) Google ScholarRetrospective analysis of a US medical claims databasePD + nOH (n = 281) vs PD alone (n = 17,421)74–77• nOH associated w/↑ falls, ↑ ED visits, ↑ inpatient stays, and ↑ costs (p ≤0.02 for all vs PD alone) Merola, 201712Merola A Sawyer RP Artusi CA Suri R Berndt Z Lopez-Castellanos JR Vaughan J Vizcarra JA Romagnolo A Espay AJ Orthostatic hypotension in Parkinson disease: impact on health care utilization.Parkinsonism Relat Disord. 2017; 47: 45-49Abstract Full Text Full Text PDF PubMed Scopus (29) Google ScholarRetrospective record review at 1 PD center (Cincinnati, OH, USA)PD + OH (n = 93) vs PD alone (n = 224)70–74• OH associated w/↑ ED visits, ↑ hospitalization days, and ↑ healthcare costs (p <0.05 for all vs PD alone) Claassen, 20183Claassen DO Adler CH Hewitt LA Gibbons C Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers.BMC Neurol. 2018; 18: 125Crossref PubMed Scopus (29) Google ScholarPatient and caregiver survey of nOH burdennOH due to PD, MSA, or PAF (363 patients; 128 caregivers)63–71*Mean ages of patient respondents or patient being cared for by caregiver respondents.• nOH symptoms associated w/falls, ↓ function, and ↓ patient QoL Merola, 20184Merola A Romagnolo A Rosso M Suri R Berndt Z Maule S Lopiano L Espay AJ Autonomic dysfunction in Parkinson's disease: a prospective cohort study.Mov Disord. 2018; 33: 391-397Crossref PubMed Scopus (88) Google ScholarProspective cohort from 2 specialty centers (Cincinnati, OH, USA, and Torino, Italy)PD (n = 122)66• Symptomatic and asymptomatic OH associated w/↓ ADL, ↓ HRQoL, ↑ falls, and ↑ healthcare use (p ≤0.009 for all vs no OH)SH Pavy-Le Traon, 201620Pavy-Le Traon A Piedvache A Perez-Lloret S Calandra-Buonaura G Cochen-De Cock V Colosimo C Cortelli P Debs R Duerr S Fanciulli A Foubert-Samier A Gerdelat A Gurevich T Krismer F Poewe W Tison F Tranchant C Wenning G Rascol O Meissner WG New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study.J Neurol Neurosurg Psychiatry. 2016; 87: 554-561Crossref PubMed Scopus (38) Google ScholarMulticenter cohort study of European MSA Study groupMSA (N = 349)64• Statistically significant association of orthostatic symptom severity w/ SH Fanciulli, 201622Fanciulli A Gobel G Ndayisaba JP Granata R Duerr S Strano S Colosimo C Poewe W Pontieri FE Wenning GK Supine hypertension in Parkinson's disease and multiple system atrophy.Clin Auton Res. 2016; 26: 97-105Crossref PubMed Scopus (74) Google ScholarRetrospective record review at 2 centers (Innsbruck, Austria, and Rome, Italy)PD or MSA (n = 275)65–71• Rates of coexistent OH + SH: 49% in MSA; 10% in PD• Association of OH w/SH in patients w/MSA (OR, 15; p = 0.002) Palma, 201821Palma JA Redel-Traub G Porciuncula A Samaniego-Toro D Lui YW Norcliffe-Kaufmann L Kaufmann H The impact of supine hypertension on target organ damage and mortality in patients with neurogenic orthostatic hypotension [Abstract].Clin Auton Res. 2018; 28: 473Google ScholarProspective studynOH due to PD, MSA, or PAF (n = 57)NR• 67% had SH; SH associated w/↑ kidney damage (↑ BUN levels, ↓ GFR), ↑ LVH, ↑ WMHI, ↑ CV AEs, and ↑ death riskCV Risks Ko, 201817Ko D Preis SR Lubitz SA McManus DD Vasan RS Hamburg NM Benjamin EJ Mitchell GF Relation of orthostatic hypotension with new-onset atrial fibrillation (from the Framingham Heart Study).Am J Cardiol. 2018; 121: 596-601Abstract Full Text Full Text PDF PubMed Scopus (20) Google ScholarLongitudinal study of a US community cohort (Framingham Heart Study)1736 individuals; 256 w/OH at BL72• 224 participants developed AF during follow-up (mean, 8.3 y)• OH associated w/↑ AF (adjusted HR,†10-y follow-up; adjusted for age, sex, BP, heart rate, height, weight, tobacco use, antihypertensive use, diabetes, history of myocardial infarction or HF. 1.6; p <0.01) Fedorowski, 201018Fedorowski A Hedblad B Engstrom G Gustav Smith J Melander O Orthostatic hypotension and long-term incidence of atrial fibrillation: the Malmo Preventive Project.J Intern Med. 2010; 268: 383-389Crossref PubMed Scopus (52) Google ScholarLongitudinal study of a Swedish community cohort (Malmö Preventive Project)32,628 individuals; 1987 w/OH at BL47–49 at BL• 10% of OH group developed AF during follow-up (mean, 23 y)• OH associated w/↑ AF (adjusted HR,‡Adjusted for age, sex, BP, BMI, smoking, total cholesterol, diabetes. 1.2; p = 0.035) Magnusson, 201616Magnusson M Holm H Bachus E Nilsson P Leosdottir M Melander O Jujic A Fedorowski A Orthostatic hypotension and cardiac changes after long-term follow-up.Am J Hypertens. 2016; 29: 847-852Crossref PubMed Scopus (22) Google ScholarLongitudinal study of a Swedish community cohort (Malmö Preventive Project)974 individuals; 40 w/OH at BL43–47 at BL• OH predictive of cardiac remodeling at follow-up (mean, 23 y), including LVH, ↓ RVIDd, and ↓ ésept (adjusted HRs,§Adjusted for age, sex, systolic BP, BMI, antihypertensive treatment. 1.5‒2.0, p ≤0.05) Ali, 201815Ali A Holm H Molvin J Bachus E Tasevska-Dinevska G Fedorowski A Jujic A Magnusson M Autonomic dysfunction is associated with cardiac remodelling in heart failure patients.ESC Heart Fail. 2018; 5: 46-52Crossref PubMed Scopus (20) Google ScholarCross-sectional study of patients hospitalized w/HF (Malmö, Sweden)149 patients w/HF, 34 w/HF + OH74• OH associated w/cardiac remodeling, including ↑ LA volume, ↑ IVSDd, and ↑ LVM (p ≤0.07) Goldstein, 201014Goldstein DS Cardiac ectopy in chronic autonomic failure.Clin Auton Res. 2010; 20: 85-92Crossref PubMed Scopus (17) Google ScholarRetrospective record review at NIH Clinical Center (Bethesda, MD, USA)PD, PD + nOH, MSA, or PAF (n = 138) vs controls (n = 41)59–71• Statistically significant ↑ atrial ectopy in PD + nOH, MSA, and PAF vs controls or PD alone Milazzo, 201519Milazzo V Maule S Di Stefano C Tosello F Totaro S Veglio F Milan A Cardiac organ damage and arterial stiffness in autonomic failure: comparison with essential hypertension.Hypertension. 2015; 66: 1168-1175Crossref PubMed Scopus (24) Google ScholarCross-sectional study of patients referred to an Italian autonomic unit (Torino, Italy)Autonomic failure due to PD, MSA, or PAF (n = 27)66• ↑ LVM and ↑ atrial stiffness (measured by PWV) in autonomic failure patients vs healthy controls; damage similar to patients w/EHMortality Maule, 201210Maule S Milazzo V Maule MM Di Stefano C Milan A Veglio F Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google ScholarRetrospective record review of patients referred to an autonomic unit (Turin, Italy)nOH and underlying autonomic neuropathy (n = 104)71• Patients w/nOH 3 × greater risk of death vs general population¶General population of same geographic region of similar age during same period.• Adjusted HR⁎⁎Adjusted for age, hypertension, use of fludrocortisone, midodrine, or angiotensin-converting enzyme inhibitors. for death (any cause): MSA, 1.0; PD, 0.6; PAF, 0.3 Goldstein, 201511Goldstein DS Holmes C Sharabi Y Wu T Survival in synucleinopathies: a prospective cohort study.Neurology. 2015; 85: 1554-1561Crossref PubMed Scopus (72) Google ScholarProspective cohort of patients referred to NIH Clinical Center (Bethesda, MD, USA)PD, PD + OH, MSA, or PAF (n = 206)57–69 at BL• Survival (10-y probabilitySurvival probabilities from symptom onset or first evaluation, adjusted for age and sex.): MSA (0.03–0.39) < PD + OH (0.23–0.74) < PAF (0.64–0.87) < PD no OH (0.67–0.93) Xin, 20149Xin W Lin Z Mi S Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies.Heart. 2014; 100: 406-413Crossref PubMed Scopus (81) Google ScholarMeta-analysis of 9 cohort studiesOH (N = 56,125)46–86• 6/9 individual studies showed statistically significant ↑ risk of death w/OH; pooled all-cause mortality RR, 1.4 (p <0.0001) Ricci, 20158Ricci F Fedorowski A Radico F Romanello M Tatasciore A Di Nicola M Zimarino M De Caterina R Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies.Eur Heart J. 2015; 36: 1609-1617Crossref PubMed Scopus (187) Google ScholarMeta-analysis of 13 prospective observational studies (10 of mortality)OH (N = 121,913); mortality and OH analyses (n = 65,174)46–93• 6/10 individual studies showed statistically significant ↑ risk of death w/OH; pooled all-cause mortality RR, 1.5 (95% CI, 1.2–1.8)ADL = activities of daily living; AE = adverse event; AF = atrial fibrillation; BL = baseline; BMI = body mass index; BP = blood pressure; BUN = blood urea nitrogen; CI = confidence interval; CV = cardiovascular; ED = emergency department; EH = essential hypertension; ésept = early diastolic tissue velocity at mitral annulus in septal wall; GFR = glomerular filtration rate; HF = heart failure; HR = hazard ratio; HRQoL = health-related quality-of-life; IVSDd = interventricular septal diameter at diastole; LA = left atrial; LVH = left ventricular hypertrophy; LVM = left ventricular mass; MSA = multiple system atrophy; NIH = National Institutes of Health; nOH = neurogenic orthostatic hypotension; NR = not reported; OH = orthostatic hypotension; OR = odds ratio; PAF = pure autonomic failure; PD = Parkinson disease; PWV = carotid-femoral pulse wave velocity; QoL = quality-of-life; RR = risk ratio; RVIDd = right ventricular inner diameter in diastole; SH = supine hypertension; WMHI = white matter hyperintensities. Mean ages of patient respondents or patient being cared for by caregiver respondents.† 10-y follow-up; adjusted for age, sex, BP, heart rate, height, weight, tobacco use, antihypertensive use, diabetes, history of myocardial infarction or HF.‡ Adjusted for age, sex, BP, BMI, smoking, total cholesterol, diabetes.§ Adjusted for age, sex, systolic BP, BMI, antihypertensive treatment.¶ General population of same geographic region of similar age during same period. Adjusted for age, hypertension, use of fludrocortisone, midodrine, or angiotensin-converting enzyme inhibitors.†† Survival probabilities from symptom onset or first evaluation, adjusted for age and sex. Open table in a new tab ADL = activities of daily living; AE = adverse event; AF = atrial fibrillation; BL = baseline; BMI = body mass index; BP = blood pressure; BUN = blood urea nitrogen; CI = confidence interval; CV = cardiovascular; ED
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