Hypertension – Using the rare to deal with the common: Conn’s syndrome

Roger 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

5.11C-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

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

normal scan normal scan adenoma adenoma  K+ nor K+ Ratio Normal Ratio  *Ratio  N.A.S.S.H. Conn’s

N aldo N aldo aldo renin renin renin

*ratio=aldo/renin Normo-aldosterone Spironolactone-sensitive hypertension [N.A.S.S.H.]

AR CT/ Present age Pre-BP aldo renin Present Meds ratio MRI BP Spironolactone 25bd 55 KB 186/92 210 0.5 420 normal Doxazosin 8bd 146/80  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 1200 pending 130/80  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-renin hypertension

Low renin N.A.S.S.H. Conn’s HTN

Thiazide Spironolactone responsive responsive The Red House Surgery, Cambridge Mr WI

Hx - 64 M - referred from The Red House Surgery - HT >30yrs, “difficult to treat” HT

P/Hx - out-of-hospital cardiac arrest - further episodes of VT → automated cardiac defib

smoking 0, alcohol 0

Rx Atenolol 100mg od, Lisinopril 20mg bd

O/E 170/100 mmHg Heart/lungs clear fundi normal urine dipstix normal Mr WI

K+ 3.2 Other electrolytes normal

aldosterone 850  (100-450 pmol/l) renin (PRA) 0.2  (0.5-3.1 pmol/ml/hour) AR ratio 4250   (<750 units)

CT adrenal glands Mr WI

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

Adrenal venous sampling aldosterone / cortisol (280-650 nmol/l) 420 / 279

>3300 / >1480 481 / 1455

348 / 310 • Normalised ratio unilat: 3x contralat contralat: suppressed (suprarenal IVC) • Confirm catheter position cortisol: 2x suprarenal IVC right hepatic tributaries Mr WI

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

Hx 68 F HT >20yrs, resistant to therapy No cardiovascular symptoms

P/Hx nil of note F/Hx brother HT smoking 0, alcohol 0

Rx Atenolol 100mg, Enalapril 20mg, bendrofluazide 2.5mg, indoramin 12.5mg, lacidipine 60mg, hydralazine 50mg bd, clonidine 75ug bd

O/E 230/110 mmHg Heart/lungs clear fundi normal urine dipstix trace protein Mrs DB

K+ 3.5 Other electrolytes normal

aldosterone 290 N (100-450 pmol/l) renin (PRA) < 0.2  (0.5-3.1 pmol/ml/hour) AR ratio 1450  (<750 units)

CT adrenal glands – normal Mrs DB

mmHg 230/110 240 192/91 200 165/93

160 126/88 120

80 Atenolol Enalapril Atenolol Atenolol Spironolactone BFZ Enalapril Co-amilozide Indoramin BFZ Lacidipine Indoramin Clonidine Amlodipine Hydralazine Hydralazine Mr PR

Hx 57 M 6-year history of uncontrolled hypertension No cardiovascular symptoms

P/Hx nil of note F/Hx smoking 0, alcohol 0

Rx Bisoprolol 5mg, Losartan 100mg

O/E 220/116 mmHg Heart/lungs clear fundi normal urine dipstix normal Mr PR

Electrolytes normal

Aldosterone 190 N (100-450 pmol/l) renin (PRA) 0.4 ↓ (0.5-3.1 pmol/ml/hour) AR ratio 475 N (<750 units) Mr PR

mmHg 208/116 220 200/100

190 160 128/80 144/90

130

100 70 Losartan Losartan Spironolactone 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 Background

• 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 Study 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

sBP > 20 mmHg CT of adrenals

Diagnosis of PHA Distribution of aldosterone/renin ratio

308 280 Prevalence of ratio: 252 72.7 224 (<400) 196 17.2 (400-800) 168 140 12.3 (>800) 112 84 56

No of observations of No 28 0 0400 800 1200 1600 2000 2400 2800 3200 200 600 1000 1400 1800 2200 2600 3000 Aldosterone/Renin Ratio Beta-blockers but not other Rx affect aldo/renin ratio Scattergram of aldosterone and renin levels Plasma renin predicts response to spironolactone (excluding patients on BB) Conclusions

Low-renin HTN !!! Renin and hypertension

Primary causes > 50 yrs old < 50 yrs old

Conn’s N.A.S.S.H. Low-renin HTN High-renin HTN

Spironolactone Thiazide/ Betablocker/ responsive CCB ACEI or ARB 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 Lisinopril Amlodipine Candesartan A C Nifedipine LA

Bisoprolol Co-amilozide B D 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 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 Captopril Mag3 • ECG • 24h ur VMA Plasma catecholamines Renal angiography

Primary causes: suspect in young HT primary hyperaldosteronism and others Renin based proforma for treating resistant hypertension Incorporated into the BHS IV guidelines (2004)

ACEi + {Thiazide or CCB}

Measure Renin

Add CCB or Thiazide

Low Normal/High Thiazide  Spironolactone ACEi  SartanSartan && βblockerblocker + ACEi

Spironolactone + Sartan

Add long-acting  -blocker Unilateral APA Bilateral APA Negative

J Clin Endocrin Metab 2012 48 yo Afrocaribbean poorly controlled HTN on 5 drugs. Plasma renin 0.3pmol/ml/h off BB. Multiple CT adrenal over several years, reported variably as thickened left adrenal/small adenoma. 11C-PET CT showed clear, 6mm adenoma in left APA, visible on CT in retrospect. Surgical adrenalectomy. Normotensive. = Functional and anatomical diagnosis

J Clin Endocrin Metab 2012 52 yo man found to have primary aldosteronism. CT: 7mm right and 16mm left adrenal adenomas, no lateralization on AVS. 11C-PET CT: boyth adenomas relatively cold. Not suggestive of surgically-remeadiable unilateral cause. BP controlled by triple therapy: Losartan, amlodipine, BFZ + Eplerenone/amiloride. = Distinguish between APA and incidentalomas Curr Opin Endocrinol Diabetes Obes, 2015 Bilateral APAs: not suspected on original MRI, but apparent in retrospect Aldo-Producing Adenomas

Conn’s Obvious left adrenal adenoma on CT, but AVS technically unsuccessful original tumour >4cm ~2cm APA

Small is beautiful: sub-cm APA caused BP 240/140 mmHg despite 5 drugs Sub-cm micro APA Clin Endocrin 2015 PA-CURE Study

1. The use of 11C-metomidate PET-CT in Sg 2. Prevalence of low renin HTN

Audrey Wong, Consultant Physician, NUH

Troy Puar, Consultant Endocrinologist, CGH 1. However complex and continuous the spectrum, the rainbow reminds us that there are just 2 ends to a spectrum and some remarkable distinct patterns in Am J Hypertens 2014 between. 2. Much broader spread than single log unit of most hormones 3. Almost an entire log unit can be assigned high-renin and low-renin

Pressure = Force / area

High Pressure due to ↑ Force High Pressure due to ↓ Area Renin and hypertension

Primary causes > 50 yrs old < 50 yrs old

Conn’s N.A.S.S.H. Low-renin HTN High-renin HTN

Spironolactone Thiazide/ Betablocker/ responsive CCB ACEI or ARB Cambridge UK: AB/CD rule AB/CD rule and improvement in UK BP control

AB/CD rule

2004 2004

Hypertension, 2009 Thank you