Postural Tachycardia Syndrome (POTS) – What? Why? How? Satish R Raj MD MSCI FACC FHRS FRCPC Associate Professor of Cardiac Sciences University of Calgary Adjunct Associate Professor of Medicine Autonomic Dysfunction Center Vanderbilt University School of Medicine Birmingham, UK - October 2014 Case Presentation - AP ONSET Age 26 years; SWF; works in music industry Dx “Pneumonia” -> inhalers Developed “spells of tachycardia” Cardiologist #1 proposed EP Study/Ablation Cardiologist #2 -> Tilt Test Associated Symptoms Lightheaded/presyncope (standing) Intermittent stabbing chest pains (standing) Mental clouding (“brain fog”) Severe fatigue Case Presentation – AP (2) Orthostatic Challenge Position HR (bpm) BP (mmHg) Supine – 15 min 73 103/72 Upright – 1 min 106 109/80 Upright – 3 min 105 106/83 Upright – 5 min 122 118/75 Upright – 10 min 121 118/78 WHAT is POTS? Postural Tachycardia Syndrome - Common Criteria Orthostatic tachycardia > 30 bpm BP > 20/10 mmHg Symptoms of sympathetic activation >40 bpm required if <18 years No consistent orthostatic hypotension Phillip Low MD Mayo Clinic Worse upright; better recumbent Chronic symptoms > 6 months POTS - Mimics & Associations Mimics Acute infections Multiple sclerosis Sjogren’s syndrome Associations Joint Hypermobility Syndrome Ehlers Danlos Syndrome – Hypermobility Fibromyalgia Chronic Fatigue Syndrome POTS - Common Symptoms Cardiac Non-Cardiac Rapid Heartbeat Chest Discomfort Short of Breath Lightheaded Exercise Intolerance Mental Clouding Headache Nausea Tremulousness Fatigue Sleep Complaints Tilt Testing POTS Control 200 Heart Rate (bpm) 0 200 Blood Pressure (mmHg) 50 Tilt Angle (deg) 60 0 SR Raj, Indian Pacing Electrophysiol J. 2006;6:84-99 Symptoms Score (au) POTS: Feel awful when upright 35 POTS Control 30 25 20 15 10 5 0 0 10 20 30 Tilt (60) Time SR Raj & RS Sheldon, Tilt Table Testing in S Saksena & AJ Camm Electrophysiological Disorders of the Heart 2nd Ed. (2011) POTS – Who is affected? Prevalence ½ million in USA Female (~80-85%) Typically aged 13-50 years Significant functional disability Quality of Life in POTS Kanika Bagai Health Related Quality of Life (SF-36) – Chronic Illnesses Back Pain ESRD Dialysis 100 Score 75 50 25 0 Physical Mental SF36 Sub-Scores Health Related Quality of Life (SF-36) – Chronic Illnesses POTS Back Pain ESRD Dialysis 100 Score 75 50 25 0 Physical Mental SF36 Sub-Scores Modified from K Bagai et al., J Clin Sleep Med 2011 Sleep Problems Correlate with Poor HRQL Physical Mental 60 70 Healthy SF36 Physical 60 50 POTS 30 40 POTS 30 20 20 2 R-Square = 0.62 R =0.62 10 Healthy 40 50 SF36 Mental R2=0.60 R-Square = 0.60 10 0 25 50 75 MOS Sleep Problems Index 100 0 25 50 75 100 MOS Sleep Problems Index Modified from K Bagai et al., J Clin Sleep Med 2011 WHY do they have POTS? … ‘final common pathway’ of hundreds of genetic and acquired autonomic and cardiovascular entities - David Robertson David Robertson Pathophysiology of POTS – The Challenge Blind men and the Elephant It was six men of Hindustan To learning much inclined, Who went to see the Elephant (Though all of them were blind), That each by observation Might satisfy his mind They conclude that the elephant is like a wall, snake, spear, tree, fan or rope, depending upon where they touch. Ancient Hindu Parable retold by John Godfrey Saxe (1816–1887) Pathophysiology of POTS Satish POTS - Pathophysiologies Mast Cell Activation Partial Autonomic Neuropathy Leg Blood Flow Abnormalities Hypovolemia Hyperadrenergic Increased Release Decreased Clearance Antibodies are Evil… POTS and Mast Cells Spot (4 hour) urine collection If syncopal/flushing attack, 1-2 hour urine collection Mast cell activation disorder Often aspirin sensitivity Therapy: H1 + H2 blockade ASA Alpha-methyldopa Italo Biaggioni C Shibao et al., Hypertension 2005 Neuropathic POTS Normal nPOTS Giris Jacob Reduced NE Spillover in legs Abnormal sweat test (QSART) in legs G Jacob et al., N Engl J Med. 2000;343:1008-14 Leg Blood Flow May Identify Different Subpopulations of POTS Julian Stewart Stewart J M et al. AJP Heart Circ Physiol 2003;285:H2749-H2756 Blood Volume & Renin-AngiotensinAldosterone System in POTS Plasma Volume is Low in POTS PV Deviation (%) 15 10 Control POTS P<0.001 5 0 -5 -10 -15 -20 -25 Adapted from SR Raj et al., Circulation 2005;111:1574-1582 Plasma Renin Activity & Aldosterone are inappropriately low in POTS…when one would expect them elevated POTS P=0.996 P=0.941 3.0 1000 Aldosterone (pM) Renin ((ng/ml)/hr) 3.5 Control 2.5 2.0 1.5 1.0 0.5 0.0 POTS P=0.017 Control P=0.019 750 500 250 0 Supine Standing Supine Standing Adapted from SR Raj et al., Circulation 2005;111:1574-1582 RAAS Schema in POTS PRA AGT ACE ANG I ANG II Aldo ACE2 ANG (1-7) Blood Volume Adapted from HI Mustafa et al., Heart Rhythm. 2011;8:422-8. Conclusions – RAAS in POTS Things are screwy Unusual RAAS profile in POTS More work is needed to understand physiology Low blood volume Low plasma renin activity Low aldosterone Decreased ACE2 activity? Elevated ANG II due to less degradation? Why are aldosterone levels low? Can the kidney not hold onto sodium in POTS? May explain the need for high sodium diets and low blood volume in POTS. Hyperadrenergic POTS – Increased SNS Nerve Firing Normal hPOTS Hyperadrenergic POTS – Decreased NE Clearance A Norepinephrine Synapse NET Slide courtesy of Alex Nackenoff (Vanderbilt) A Norepinephrine Synapse NET SNS Tone Slide courtesy of Alex Nackenoff (Vanderbilt) SS A369P N375S N292T A4 5 7 P K463R G4 7 8 S T9 9 I Y548H P V6 9 I P P V356L P V4 4 9 I P V2 4 5 I F528C P Shannon JR, NEJM 2000; 342:541-9. Reaction at Vanderbilt Excitement The cause of POTS has been found!!! POTS Patients with NET mutations: 2000-2010 No other patients had this mutation. We had just about given up hope in NET defects as a cause of POTS… Variable Expression of NET Protein in POTS Courtesy of Murray Esler, Baker IDI (Melbourne, Australia) Decreased NET Protein Expression in some POTS Patients Lambert E et al. Circ Arrhythm Electrophysiol 2008;1:103-109 Role of Antibodies in POTS 1. 2. 3. AChR Antibody Adrenergic Antibodies Lipid/Cardiac RAFT Antibodies Ganglionic Acetylcholine Receptor Ab Discovered at Mayo Clinic Steve Vernino & Vanda Lennon Loss of function Ab at Autonomic Ganglia Prevalence in POTS Mayo: ~7-14% of POTS patients Now reportedly lower per Dr. P Low (Mayo) Vanderbilt: 0% of POTS patients Presentation is usually Autonomic Failure Orthostatic hypotension Constipation, pupil findings Schroeder C et al. NEJM 2005;353:1585-1590 POTS Patient serum stimulates adrenergic receptors H Li et al., JAHA 2014; 3(1):e000755. 1-AR mediated cAMP release 2-AR mediated cAMP release Beta-receptor activation from POTS sera H Li et al., JAHA 2014; 3(1):e000755. The Model How could the Ab contribute to the POTS phenotype? H Li et al., JAHA 2014; 3(1):e000755. POTS – HOW to Manage? Investigation & Treatment POTS: Investigations History & Physical Examination Orthostatic Vital Signs CBC, BMP Autonomic Reflex Testing Echocardiogram Blood Volume Assessment Exercise Capacity Assessment POTS: Treatment Approaches Exercise Increase Blood Volume Hemodynamic Agents Oral Water Increase Salt (diet vs. tablets) Fludrocortisone Octreotide IV Saline Acute DDAVP-H2O Midodrine Propranolol Pyridostigmine Ivabradine (emerging) Behavioral Therapies Exercise in POTS Historically “good thing to do” Many patients could not/would not Anecdotally, those patients that did exercise did better over time excessive fatigue (~days) and intolerance Cause/effect vs. selection bias Now Recent data on effects of exercise training in POTS from Dallas, Vienna, & Mayo… Exercise Study in POTS - Design Cardiac MRI Maximal Exercise Test Blood Volume Measurement 3 months of exercise training 45-min 60 Upright Tilt Screening 45-min 60 Upright Tilt Blood Volume Measurement Maximal Exercise Test Cardiac MRI Exercise in POTS - Benefits Short-term exercise training in POTS Increases fitness levels Increases blood volume Cardiac Remodeling Normalizes Sympathetic Activity Decreases Orthostatic Tachycardia Qi Fu et al., JACC 2010;55:2858-68 Exercise in POTS – How To? Focus on Aerobic Activity Must be Regular Every other day (4/week) 30min/session -> 45-60min/session NO UPRIGHT EXERCISES Some resistance training focused on thighs Rowing machines Recumbent Cycles Swimming Takes 4-5 weeks to start seeing benefits Qi Fu et al., JACC 2010;55:2858-68 POTS: Treatment Approaches Exercise Increase Blood Volume Hemodynamic Agents Oral Water Increase Salt (diet vs. tablets) Fludrocortisone Octreotide IV Saline Acute DDAVP-H2O Midodrine Propranolol Pyridostigmine Ivabradine (emerging) Behavioral Therapies IV Saline (1L) Acutely Decreases Orthostatic Tachycardia…a LOT!! G Jacob et al. Circulation 1997;96:575-580 DDAVP+H2O reduces standing HR Heart Rate (bpm) 125 Placebo DDAVP+H2O 120 115 PTime =0.001 110 PDrug=0.001 105 PINT =0.001 100 95 90 85 Pre 1H 2H 3H 4H Time Post Dose ST Coffin et al., Heart Rhythm. 2012;9:1484-90 POTS: Treatment Approaches Exercise Increase Blood Volume Hemodynamic Agents Oral Water Increase Salt (diet vs. tablets) Fludrocortisone Octreotide IV Saline Acute DDAVP-H2O Midodrine Propranolol Pyridostigmine Ivabradine (emerging) Behavioral Therapies Midodrine Decreases Orthostatic Tachycardia…a little bit. Jacob, G. et al. Circulation 1997;96:575-580 Beta-Blockers in POTS PRO Intuitively appealing High HR -> Lower it CON Stewart et al. studied IV esmolol and found that it DID NOT improve orthostatic tolerance Many patients report “intolerance to betablockers” Propranolol 20mg lowers Orthostatic Tachycardia Orthostatic Increase in HR Heart Rate (bpm) Placebo Propranolol 130 PDrug <0.001 PInt <0.001 120 110 100 90 80 70 Pre 1H 2H 3H Time Post Dose 4H Change in Heart Rate (bpm) Standing HR Propranolol 40 Placebo PDrug <0.001 30 20 10 0 Pre 1H 2H 3H 4H Time Post Dose SR Raj et al. Circulation 2009;120:725-734 Propranolol Improves Symptoms… Symptoms Symptoms (a.u.) 26 Propranolol Placebo 24 22 20 PInt =0.04 18 16 14 12 Pre 2H 4H Time Post Dose SR Raj et al. Circulation 2009;120:725-734 …but Less is More Symptoms Score (a.u.) Propranolol 20mg Propranolol 80mg 0 -5 -10 P =0.041 Wilcoxon -15 SR Raj et al. Circulation 2009;120:725-734 Acetylcholinesterase Inhibition Pyridostigmine Peripheral AChEI Increases availability of synaptic ACh Ganglionic Nicotinic Receptor Postganglionic Muscarinic Receptor SNS & PNS PNS Might decrease tachycardia in POTS Acetylcholinesterase Inhibition 135 130 125 120 115 110 105 100 95 90 Pyridostigmine P=0.001 Placebo P=0.160 P<0.001 P<0.001 Pre 2H 4H Symptoms Change in Symptom Score (au) Heart Rate (bpm) Standing Heart Rate 5 Pyridostigmine Placebo 0 -5 P=0.025 -10 -15 Time Post Dose SR Raj et al., Circulation 2005;111:2734-2740 Norepinephrine Transporter Inhibition Standing A Atomoxetine 100 Placebo Heart Rate (bpm) Heart Rate (bpm) 130 Seated B 120 110 100 PInt <0.001 90 Atomoxetine 95 Placebo 90 85 80 75 PInt =0.029 70 Pre 1H 2H 3H Time Post Dose 4H Pre 1H 2H 3H 4H Time Post Dose SR Raj et al., AAS Presentation (2010) Norepinephrine Transporter Inhibition Orthostatic Change Heart Rate (bpm) 40 Atomoxetine Symptoms: 0 to 2h Placebo 35 30 25 20 PInt =0.001 15 Pre 1H 2H 3H Time Post Dose 4H Symptoms Score (a.u.) C 6 4 2 0 -2 -4 Atomoxetine Placebo P =0.028 -6 -8 SR Raj et al., AAS Presentation (2010) POTS: Treatment Approaches Exercise Increase Blood Volume Hemodynamic Agents Oral Water Increase Salt (diet vs. tablets) Fludrocortisone Octreotide IV Saline Acute DDAVP-H2O Midodrine Propranolol Pyridostigmine Ivabradine (emerging) Behavioral Therapies What Type of POTS Do I Have? Challenges: 1. Overlapping Subsets 2. Lost in Translation What Type of POTS Do I Have? Hyperadrenergic POTS Hypovolemic POTS Neuropathic POTS What Type of POTS Do I Have? Hyperadrenergic POTS Hypovolemic POTS Neuropathic POTS Lost in Translation Not my M-I-L Prognosis of POTS “Prediction is very difficult, especially about the future.” Niels Bohr (1885-1962); Nobel Prize (Physics) 1922 POTS – Take Home Messages POTS chronic disorder associated with significant disability Syndrome…not one disease Multiple pathophysiologies Treatment Exercise Volume expansion Heart rate control Manage the “living with a chronic illness” Questions?
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