Conns syndrome Roger r Fo Foo Cardiac long noncoding RNA - PowerPoint PPT Presentation

Hypertension – Using the rare to deal with the common: Conn’s syndrome Roger r Fo Foo

Cardiac long noncoding RNA www.cardiolinc.org Lab of Cardiac Epigenomics, and molecular epigenetics www.Foo-lab.com

Transdifferentiated cardiomyocytes Fibroblasts  cardiomyocytes

Rare disease genomics Solving genetics for undiagnosed diseases @Genetics, KKH / NUH Inherited heart conditions HCM, DCM, Brugada, LQT, Marfan &c @NUH & CGH Please refer

Resistant Hypertension Clinic @NUH & CGH Please refer

Content 1.Low-renin hypertension  NASSH (normo-aldo Spiro-sensitive HTN)  Conn’s 2.Clinical vignettes 3.PHARst study 4.Cambridge  UK AB/CD rule for hypertension management 5. 11 C-metomidate PET-CT for adrenal adenomas 6.Singapore PA-CURE study 7.Renin for hypertension stratification

N.A.S.S.H. Normo-aldosterone Spironolactone-sensitive Hypertension October 2000 Grand Staff Round University of Cambridge School of Medicine

A Clinical Vignettes 180/105 176/100 190 144/80 170 150 130 110 90 c 70 Atenolol Bisoprolol Spironolactone 208/116 Lisinopril Irbesartan 200/100 220 Doxazosin Doxazosin 190 128/80 144/90 160 B 130 230/110 240 100 192/91 165/93 200 70 Losartan Losartan Spironolactone 160 Bisoprolol Bisoprolol 126/88 Spironolactone 120 Atenolol Atenolol 80 Enalapril Enalapril Atenolol Spironolactone BFZ BFZ Co-amilozide Indoramin Indoramin Lacidipine Amlodipine Clonidine Hydralazine Hydralazine

Spi piro ronolacton olactone-sens sensitive tive hype pertens rtension ion normal scan normal scan adenoma adenoma  K + nor K + Ratio  *Ratio  Ratio Normal N. N.A.S.S.H S.S.H. Conn’s  aldo N aldo N aldo  renin  renin  renin *ratio=aldo/renin

Normo No mo-aldo aldosteron sterone e Spirono ironolac lactone tone-sens sensitive tive hypertension pertension [N.A.S.S A.S.S.H.] .H.] AR CT/ Present age Pre-BP aldo renin Present Meds ratio MRI BP Spironolactone 25bd 55 KB 186/92 210 0.5 normal Doxazosin 8bd 146/80 420  Irbesartan 300od 48 Spironolactone 25bd SW 164/96 170 0.7 243 normal 128/88  Irbesartan 300od 63 JG 180/104 160 0.6 266 pending Spironolactone 50bd 164/78  58 Spironolactone 25bd IZ 210/104 260 0.6 433 pending 180/84  Irbesartan 300od 64 AS 150/95 230 0.3 767 normal Spironolactone 25bd 124/80  62 Spironolactone 75od CA 200/100 220 0.2 1100 pending 144/80  Enalapril 10od 54 Spironolactone 25bd GK 205/90 240 0.2 pending 130/80 1200  Doxazosin 2od 66 Spironolactone 25bd MB 180/102 280 0.2 1400 normal 148/98  Amlodipine 10od 53 JG 198/120 360 0.2 1800 pending Spironolactone 25bd 147/90 

Low ow-re renin in hype pertens rtension ion Low ow re renin N.A.S.S.H S.S.H. Conn’s HTN HTN Thiazide zide Spiro ronola nolactone ctone responsive ponsive responsive ponsive

The Red House Surgery, Cambridge

Mr r WI Hx Hx - 64 M - referred from The Red House Surgery - HT >30yrs, “difficult to treat” HT P/Hx Hx - out-of-hospital cardiac arrest - further episodes of VT → automated cardiac defib smoking 0 , alcohol 0 Rx Rx Atenolol 100mg od, Lisinopril 20mg bd O/E O/E 170/100 mmHg Heart/lungs clear fundi normal urine dipstix normal

Mr r WI K + 3.2 Other electrolytes normal  aldosterone 850 850 (100-450 pmol/l)  renin (PRA) 0.2 (0.5-3.1 pmol/ml/hour) 50   AR ratio 4250 (<750 units) CT adrena nal l glands ds

Mr r WI normal left adrenal gland, 1cm nodule on anterior aspect of the right gland

Mr r WI Ad Adre renal venous us samp mpli ling aldosterone / cortisol (280-650 nmol/l) 420 / 279 >330 300 0 / >1480 480 481 / 1455 348 / 310 • Normalised ratio unilat: 3x contralat contralat: suppressed (suprarenal IVC) • Confirm catheter position cortisol: 2x suprarenal IVC right hepatic tributaries

Mr r WI mmHg 180/105 176/100 190 144/80 170 150 130 110 90 70 Atenolol Bisoprolol Spironolactone Lisinopril Irbesartan Amlodipine

Mrs rs DB DB Hx Hx 68 F HT >20yrs, resistant to therapy No cardiovascular symptoms P/Hx Hx nil of note F/ F/Hx x brother HT smoking 0 , alcohol 0 Rx Rx Atenolol 100mg, Enalapril 20mg, bendrofluazide 2.5mg, indoramin 12.5mg, lacidipine 60mg, hydralazine 50mg bd, clonidine 75ug bd O/E O/E 230/110 mmHg Heart/lungs clear fundi normal urine dipstix trace protein

Mrs rs DB DB K + 3.5 Other electrolytes normal aldosterone 290 290 (100-450 pmol/l) N renin (PRA) < 0.2  (0.5-3.1 pmol/ml/hour) 50  AR ratio 1450 (<750 units) CT adrena nal l glands ds – normal

Mrs rs DB DB mmHg 230/110 240 192/91 165/93 200 160 126/88 120 80 Atenolol Atenolol Enalapril Atenolol Spironolactone Enalapril BFZ Co-amilozide BFZ Indoramin Indoramin Lacidipine Amlodipine Clonidine Hydralazine Hydralazine

Mr r PR Hx Hx 57 M 6-year history of uncontrolled hypertension No cardiovascular symptoms P/Hx x nil of note F/Hx x smoking 0 , alcohol 0 Rx Rx Bisoprolol 5mg, Losartan 100mg O/E O/E 220/116 mmHg Heart/lungs clear fundi normal urine dipstix normal

Mr r PR Electrolytes normal Aldosterone190 (100-450 pmol/l) N ↓ renin (PRA) 0.4 (0.5-3.1 pmol/ml/hour) AR ratio 475 475 (<750 units) N

Mr r PR mmHg 208/116 200/100 220 190 128/80 144/90 160 130 100 70 Losartan Spironolactone Losartan Bisoprolol Bisoprolol Spironolactone CT adrenal glands – normal

Prevalence of Primary Hyperaldosteronism measured by Aldosterone to Renin ratio and Spironolactone Testing (PHArst) study Sue Hood, John Cannon, Roger Foo, Michael Scanlon, Morris Brown Clinical Pharmacology Unit, Addenbrooke ’ s Hospital

Backgro ckground und • Gordon RD et al . Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin.Exp.Pharmacol.Physiol 1993;20:296-298. • Lim et al. Potentially high prevalence of primary aldosteronism in a primary-care population (14.4%: 18/125) (versus: 16% in resistant HTN clinic) Lancet 1999;353:40. • Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone. Br J Clin Pharmacol . 1999;48:756-60.

Clin Med , 2005 St Study dy Plan 3-5 general practices (urban & rural); patients on hypertension register invited to screening session K + (and other electrolytes) measured in all patients Aldosterone/renin ratio measured  400  800 Trial of Spironolactone 50 mg/day CT of adrenals  sBP > 20 mmHg Diagnosis nosis of PHA

Distribution Di tribution of of al aldos oste terone/r rone/reni enin n ra rati tio 3 0 8 2 8 0 Prevalence of ratio: 2 5 2 72.7 (<400) 2 2 4 17.2 1 9 6 (400-800) 1 6 8 (>800) 12.3 1 4 0 1 1 2 8 4 s n tio a rv 5 6 e s b f o o o N 2 8 0 0 4 0 0 8 0 0 1 2 0 0 1 6 0 0 2 0 0 0 2 4 0 0 2 8 0 0 3 2 0 0 2 0 0 6 0 0 1 0 0 0 1 4 0 0 1 8 0 0 2 2 0 0 2 6 0 0 3 0 0 0 A l d o s t e r o n e / R e n i n R a t i o

Be Beta-bl blocke ockers rs but t not other her Rx affect ct aldo/re o/renin in ra ratio

Sc Scattergr tergram am of aldost ster eron one e and re renin levels ls

Plasma ma re renin pre redicts icts re respon ponse se to spiron ronola olactone ctone (e (excludin uding g patien ients ts on BB BB)

Conclusion usions Low-ren renin HTN N !!!

Renin and hypertension Prima mary ry causes ses > 50 yrs old < 50 yrs old Conn’s N. N.A.S .S.S.H. .S.H. Lo Low-re renin nin HTN Hig igh-renin renin HTN Thiazide/ Betablocker/ Spironolactone CCB ACEI or ARB responsive Cambridge UK: AB/CD rule

• Clear inverse relation between BP fall with Spironolactone and plasma renin • BP response was superior to Bisoprolol or Doxazosin across most plasma renin distribution Bisoprolol Lancet 2015

• Clear inverse relation between BP fall with Spironolactone and plasma renin • BP response was superior to Bisoprolol or Doxazosin across most plasma renin distribution Bisoprolol Conn’s Renal artery stenosis Lancet 2015

Cambridge ABCD rule < 50 yrs > 50 yrs A C B D

Cambridge ABCD rule < 50 yrs > 50 yrs Amlodipine Lisinopril A C Nifedipine LA Candesartan Co-amilozide B D Bisoprolol Bendrofluazide  1- blockers - Doxazosin Centrally acting - Moxonidine Potent vasodilators - Minoxidil

Cambridge Hypertension Clinic Protocol Clinical examination • primary causes: RAS, Cushing’s, renal disease • target organ damage: fundoscopy, urinstix Routine investigations • U+E+Cr • renin (aldosterone) • cholesterol • echocardiogram • random glucose • ECG • 24h ur VMA Primary causes: suspect in young HT primary hyperaldosteronism and others